· infliximab and etanercept in rheumatoid arthritis: systematic review of long-term clinical...

Infliximab and Etanercept in Rheumatoid Arthritis: Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-effectiveness

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APPENDIX 1: Literature Search Strategy Databases Limits Keyword/Descriptors National Library of Medicine PubMed

1. Receptors, Tumor Necrosis Factor [MeSH] 2. Etanercept [substance name] 3. 185243-69-0 [EC/RN Number] 4. (TNFR OR "TNF receptor*" OR "Cachectin receptor*" OR "tumor

necrosis factor receptor*" OR "tumour necrosis factor receptor*") AND (Fc OR "fusion protein*") [Title/Abstract]

5. "tumor necrosis factors/antagonists and inhibitors" [MeSH] 6. 170277-31-3 [EC/RN Number] 7. Infliximab OR Avakine OR IFX OR Revellex OR Remicade

[Title/Abstract] 8. Infliximab [Substance Name] 9. Adalimumab [Substance Name] 10. Adalimumab OR humira OR D2E7 [Title/Abstract] 11. "Anti-Tumor Necrosis Factor*" OR "Anti-Tumour Necrosis Factor*"

OR "Anti Tumor Necrosis Factor*" OR "Anti Tumour Necrosis Factor*" [Title/Abstract]

12. "anti-TNF*" OR antiTNF* OR "anti TNF*" [Title/Abstract] 13. "tumor necrosis factors inhibitor*" OR "tumour necrosis factors

inhibitor*" OR "tumor necrosis factors antibody" OR "tumour necrosis factors antibody" OR "tumor necrosis factors antibodies" OR "tumour necrosis factors antibodies" OR "tumor necrosis factors anti-bodies" OR "tumour necrosis factors anti-bodies" OR "tumor necrosis factors anti-body" OR "tumour necrosis factors anti-body" [Title/Abstract]

14. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13

15. Arthritis, Rheumatoid [MeSH] 16. Arthritis Rheumatoid OR rheumatoid arthritis OR RA [Title/Abstract] 17. Spondylitis Ankylosing OR Bechterew disease OR Bechterew's disease

OR Marie Struempell disease OR spondylarthritis ankylopoietica [Title/Abstract]

18. "still disease" OR "stills disease" [Title/Abstract] 19. "Felty Syndrome" OR "Felty's Syndrome" [Title/Abstract] 20. (Sjogren OR sjogrens OR Sjogren’s OR Sjoegren OR sjoegrens OR

Sjoegren’s OR Sicca) AND Syndrome) [Title/Abstract] 21. “caplan syndrome” OR”caplan’s syndrome” OR “caplans syndrome”

[Title/Abstract] 22. #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 23. #14 AND #22 See each study type description below for search date and records returned.

National Library of Medicine PubMed

Human (not applied to “Publisher” or”In process” records)

Clinical Trials: 24. Clinical Trials OR Drug Evaluation OR epidemiologic research design

OR Epidemiologic Studies [MeSH] 25. multicenter study OR randomized controlled trial OR controlled

clinical trial OR clinical trial [Publication Type] 26. random OR randomized OR randomized OR randomly OR sham OR

shams OR placebo OR placebos [Title/Abstract] 27. “single blind” OR “single blinded” OR “single dummy” OR “single

mask” OR “single masked” [Title/Abstract]


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28. RCT OR RCTS OR “double blind” OR “double blinded” OR “double dummy” OR “double mask” OR “double masked” [Title/Abstract]

29. “triple blind” OR “triple blinded” OR “triple dummy” OR “triple mask” OR “triple masked” [Title/Abstract]

30. “treble blind” OR “treble blinded” OR “treble dummy” OR “treble mask” OR “treble masked” [Title/Abstract]

31. “control study” OR “control studies” OR “controlled study” OR “controlled studies” OR “control trial” OR “control trials” OR “controlled trial” OR “controlled trials” [Title/Abstract]

32. “multicentre study” OR “multicentre studies” OR “multicentre trial” OR “multicentre trials” OR “multicenter study” OR “multicenter studies” OR “multicenter trial” OR “multicenter trials” [Title/Abstract]

33. “case-control study” OR “case-control studies” OR “case-control trial” “OR “case-control trials” [Title/Abstract]

34. case-controlled study OR case-controlled studies OR case-controlled trial OR case-controlled trials [Title/Abstract]

35. “case series” [Title/Abstract] 36. “retrospective study” OR “retrospective studies” OR “retrospective

trial” OR “retrospective trials” [Title/Abstract] 37. "cohort analysis" OR "cohort analyses" OR "cohort study" OR "cohort

studies" OR "cohort trial" OR "cohort trials" [Title/Abstract] 38. “prospective study” OR “prospective studies” OR “prospective trial”

OR “prospective trials” [Title/Abstract] 39. “observational study” OR “observational studies” OR “observational

trial” OR “observational trials” [Title/Abstract] 40. “follow-up study” OR “follow-up studies” OR “follow-up trial” OR

“follow-up trials” [Title/Abstract] 41. “followup study” OR “followup studies” OR “followup trial” OR

“followup trials” [Title/Abstract] 42. “open-label study” OR “open-label studies” OR “open-label trial” OR

“open-label trials” [Title/Abstract] 43. drug comparison OR drug comparisons OR comparative study OR

comparative studies OR comparative trials [Title/Abstract] 44. head-to-head OR crossover design OR crossover designs OR crossover

study OR crossover studies OR crossover trial OR crossover trials OR cross-over study OR cross-over studies OR cross-over trial OR cross-over trials [Title/Abstract]

45. #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44

46. #23 AND #45 Date SearchPerformed: 16 Mar 2005 Total Records Retrieved: 822 records



Meta-Analyses/Systematic Reviews: 47. meta-analysis [Publication Type] 48. meta-analysis [MeSH] 49. meta-analy* OR metaanaly* OR met-analy* OR metanaly*

[Title/Abstract] 50. meta-regression* OR metaregression* OR mega-regression*

[Title/Abstract] 51. “systematic literature review” OR “systematic literature reviews” OR

“systematic review” OR “systematic reviews” OR “systematic overview” OR “systematic overviews” [Title/Abstract]


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52. “methodologic* literature review” OR “methodologic* literature reviews” OR “methodologic* review” OR “methodologic* reviews” OR “methodologic* overview” OR “methodologic* overviews” [Title/Abstract]

53. “quantitative review” OR “quantitative reviews” OR “quantitative synthesis” OR “quantitative syntheses” OR “research integration*” OR “research overview” OR “research overviews” [Title/Abstract]

54. “integrative review” OR “integrative reviews” OR “integrative overview” OR “integrative overviews” OR “collaborative review” OR “collaborative reviews” OR “collaborative overview” OR collaborative overviews” OR “Pooled analysis” OR “pooled analyses” [Title/Abstract] 55. “data synthesis” OR “data syntheses” OR “data extraction*” OR “data abstraction*” [Title/Abstract]

56. #23 AND #55 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 42 records



Safety/Adverse Events: 57. adverse effects OR chemically induced OR drug toxicity [MeSH] 58. adverse effect OR adverse effects OR adverse reaction OR adverse

reactions OR adverse event OR adverse events OR adverse incident OR adverse incidents [Title/Abstract]

59. toxic OR toxicity [Title/Abstract] 60. (injurious OR undesirable) (effect OR effects OR reaction OR reactions

OR event OR events OR incident OR incidents) [Title/Abstract] 61. “drug safety” [Title/Abstract] 62. “drug-induced” OR “chemically-induced” [Title/Abstract] 63. #57 OR #58 OR #59 OR #60 OR #61 OR #62 64. #23 AND #63 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 276 records


Economics: 65. (economics OR “costs and cost analysis” OR “value of life” OR

economics, medical OR economics, hospital OR economics, nursing OR economics, pharmaceutical) [MeSH]

66. (“fees and charges” OR budgets OR models, economic OR markov chains OR monte carlo method OR decision trees OR quality of life) [MeSH]

67. (patient satisfaction OR quality-adjusted life-years) [MeSH] 68. (econom* OR cost OR costly OR costing OR costed OR price OR

prices OR pricing OR priced OR discount OR discounts OR discounted OR discounting) [Title/Abstract]

69. (expenditure OR expenditures OR budget* OR afford* OR pharmacoeconomic* OR pharmaco-economic*) [Title/Abstract]

70. (decision-tree OR decision-trees OR decision-analysis OR decision model OR decision models OR decision modeling) [ti,ab]

71. (QOL OR QOLY OR QOLYs OR HRQOL OR QALY OR QALYs OR “quality of life” OR “willingness to pay” OR “quality-adjusted-life” (year OR years)) [Title/Abstract]

72. #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 73. #23 AND #72

Date Search Performed: 16 Mar 2005 Total Records Retrieved: 145 records


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DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73

BIOSIS Previews® 5

Human 1. Receptors, Tumor Necrosis Factor/de from 155, 156 2. Tumor Necrosis Factor!(l)ai from 155,156 3. tumor necrosis factor receptor/de OR tumor necrosis factor alpha

antibody/de OR tumor necrosis factor antibody/de from 73 4. etanercept/maj OR infliximab/maj OR Adalimumab/maj from 73 5. TN=enbrel OR TN=revellex OR TN=remicade OR TN=humira 6. infliximab/de from 5 7. RN=185243-69-0 OR RN=170277-31-3 OR RN=331731-18-1 8. (Etanercept OR Enbrel OR (TNFR OR TNF()receptor? OR

Cachectin()receptor? OR (tumo?r()necrosis()factor()receptor?))(4n)(Fc OR fusion()protein?))/ti,ab

9. (Infliximab OR Avakine OR IFX OR Revellex OR Remicade)/ti,ab 10. (Adalimumab OR humira OR D2E7)/ti,ab 11. (Anti()Tumo?r()Necrosis)()Factor?/ti,ab 12. (anti()TNF OR antiTNF OR anti()TNF()alpha OR anti()TNFalpha OR

antiTNFalpha OR antiTNF()alpha)/ti,ab 13. (tumo?r()necrosis()factor? OR TNF OR TNF-alpha OR

TNFalpha)(2n)(antagonist? OR antibod? OR anti-bod? OR inhibitor?) 14. s1 OR s2 OR s3 OR s4 OR s5 OR s6 OR s7 OR s8 OR s9 OR s10 OR

s11 OR s12 OR s13 15. Arthritis, Rheumatoid!/de from 155, 156 16. Rheumatoid arthritis!/de OR Ankylosing spondylitis/de OR Sjoegren

syndrome/de from 73 17. (rheumatoid arthritis OR juvenile rheumatoid arthritis OR ankylosing

spondylitis OR sjogren syndrome OR sjogren’s syndrome OR still’s disease)/de from 5

18. (Arthritis(1n)Rheumatoid OR RA)/ti,ab 19. (Spondylitis(1n)Ankylosing OR Bechterew?()disease OR

Marie()Struempell()disease OR spondylarthritis()ankylopoietica)/ti,ab 20. (stills()disease OR still()s()disease)/ti,ab 21. (Felty()Syndrome OR Felty()s()Syndrome OR Feltys()syndrome)/ti,ab 22. (Sjogren OR sjogrens OR Sjogren()s OR Sjoegren OR sjoegrens OR

Sjoegren()s OR Sicca)()Syndrome)/ti,ab 23. (caplan OR caplan()s OR caplans)()(syndrome)/ti,ab 24. s15 OR s16 OR s17 OR s18 OR s19 OR s20 OR s21 OR s22 OR s23 25. s14 AND s24 See each study type description below for search date and records returned.


BIOSIS Previews® 5

Human Clinical Trials 26. (Clinical Trials! OR Drug Evaluation OR epidemiologic research

design! OR Epidemiologic Studies!)/de from 155, 156 27. dt=(multicenter study OR randomized controlled trial OR controlled

clinical trial OR clinical trial) from 155, 156 28. (major clinical study OR multicenter study OR controlled study! OR

randomized controlled trial)/de from 73 29. evidence based medicine!/de from 73 30. cohort analysis/de from 73 31. drug comparison!/de from 73 32. (multicenter study OR randomized controlled trial OR randomized

clinical trial)/de from 5 33. (randomized trial OR evidence-based medicine)/de from 5 34. cohort study/de from 5


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35. random?/ti,ab OR sham?/ti,ab OR placebo?/ti,ab OR singl?()(blind? OR dumm? OR mask?)/ti,ab OR doubl?()(blind? OR dumm? OR mask?)/ti,ab

36. tripl?()(blind? OR dumm? OR mask?)/ti,ab OR trebl?()(blind? OR dumm? OR mask?)/ti,ab

37. control?()(study OR studies OR trial?)/ti,ab OR RCT? ?/ti,ab 38. (multicent? OR multi()cent?)()(study OR studies OR trial?)/ti,ab 39. (case()control)()(study OR studies OR trial OR trials)/ti,ab 40. case()series/ti,ab 41. retrospective()(study OR studies OR trial OR trials)/ti,ab 42. cohort()(analysis OR analyses OR study OR studies OR trial OR

trials)/ti,ab 43. prospective()(study OR studies OR trial OR trials)/ti,ab 44. observational()(study OR studies OR trial OR trials)/ti,ab 45. (follow()up)()(study OR studies OR trial OR trials)/ti,ab 46. followup()(study OR studies OR trial OR trials)/ti,ab 47. (open()label)()(study OR studies OR trial OR trials)/ti,ab 48. (drug OR drugs)(2n)comparison?/ti,ab OR comparative()(study OR

studies OR trial?)/ti,ab 49. head()to()head/ti,ab OR (crossover OR cross()over)()(design? OR study OR studies OR trial?)/ti,ab 50. s26 OR s27 OR s28 OR s29 OR s30 OR s31 OR s32 OR s33 OR s34 OR s35 OR s36 OR s37 OR s38 OR s39 OR s40 OR s41 OR s42 OR s43 OR s44 OR s45 OR s46 OR s47 OR s48 OR s49 51. s25 AND s50 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 1711 Unique records MEDLINE – 625 ToxFile - 2 EMBASE - 1063 BIOSIS – 21


BIOSIS Previews® 5

Human Meta-Analyses/Systematic Reviews: 52. dt=meta-analysis OR meta-analysis/de from 155, 156 53. mETN analysis/de from 73 54. meta-analysis/de from 5 55. meta()analy?/ti,ab OR metaanaly?/ti,ab OR met()analy?/ti,ab OR metanaly?/ti,ab 56. meta()regression?/ti,ab OR metaregression?/ti,ab OR mega()regression?/ti,ab 57. systematic?()(literature()(review OR reviews) OR review OR reviews OR overview?)/ti,ab 58. methodologic?()(literature()(review OR reviews) OR review OR reviews OR overview?)/ti,ab 59. quantitative()(review? OR overview? OR synthes?)/ti,ab OR research()(integration? OR overview?)/ti,ab 60. integrative(2w)(review OR reviews OR overview?)/ti,ab OR collaborative()(review OR reviews OR overview?)/ti,ab OR pool?()analy?/ti,ab 61. data()synthes?/ti,ab OR data()extraction?/ti,ab OR data()abstraction?/ti,ab 62. s25 AND s61


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Date Search Performed: 16 Mar 2005 Total Records Retrieved: 27 unique records

(Excludes overlap with clinical trials) MEDLINE – 3 ToxFile - 4 EMBASE - 19

BIOSIS – 1 DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73

BIOSIS Previews® 5

Human Safety/Adverse Events: 63. (adverse effects! OR chemically induced OR drug toxicity!)/de from

155, 156 64. (etanercept(l)ae OR etanercept(l)ae OR infliximab(l)ae OR

infliximab(l)to OR Adalimumab(l)ae OR Adalimumab(l)to)/maj from 73

64. (side effect! OR adverse drug reaction! OR drug safety OR drug toxicity and intoxication!)/de from 73

65. (adverse effects OR adverse reactions OR adverse events)/de from 5 66. (adverse drug effects OR adverse drug reactions)/de from 5 67. (side effects OR drug toxicity OR drug side effects OR drug safety)/de

from 5 68. adverse(1w)(effect OR effects OR reaction OR reactions OR event OR

events OR incident OR incidents)/ti,ab 69. side(w)(effect OR effects)/ti,ab 70. (toxic OR toxicity)/ti,ab 71. (injurious OR undesirable)()(effect OR effects OR reaction OR

reactions OR event OR events OR incident OR incidents)/ti,ab 72. drug(2N)(safety OR toxicit? OR fatalit?)/ti,ab 73. drug()induced/ti,ab OR chemically()induced/ti,ab 74. s63 OR s64 OR s65 OR s66 OR s67 OR s68 OR s69 OR s70 OR s71

OR s72 OR s73 OR s74 75. s25 AND s74 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 921 unique records


BIOSIS – 33 DIALOG® MEDLINE® 155 ToxFile 156 EMBASE® 73

BIOSIS Previews® 5

Economics: 76. (economics! OR “costs and cost analysis”! OR value of life OR

economics, medical! OR economics, hospital! OR economics, nursing OR economics, pharmaceutical)/de from 155, 156

77. (“fees and charges”!/de OR budgets!/de OR models, economic!/de OR markov chains OR monte carlo method OR decision trees OR quality of life)/de from 155, 156

78. (Health economics! OR economic evaluation! OR pharmacoeconomics! OR economic aspect! OR quality adjusted life year OR quality of life!)/de from 73

79. (economic impact OR economic value OR pharmacoeconomics OR health care cost OR economic factors OR economics OR cost analysis OR economic analysis)/de from 5

80. (cost OR cost-effectiveness OR cost-effectiveness OR costs OR quality of life OR health care cost OR cost savings OR cost-benefit analysis)/de from 5


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81. (hospital costs OR medical costs OR quality-of-life)/de from 5 82. (econom? OR cost OR costly OR costing OR costed OR price OR

prices OR pricing OR priced OR discount OR discounts OR discounted OR discounting)/ti,ab

83. (expenditure OR expenditures OR budget? OR afford? OR pharmacoeconomic? OR pharmaco(1n)economic?)/ti,ab

84. (decision)(1n)(tree? OR analy? OR model?)/ti,ab 85. (value OR values OR valuation)(2n)(money OR monetary OR life OR

lives)/ti,ab 86. (QOL OR QOLY OR QOLYs OR HRQOL OR QALY OR QALYs

OR quality(1n)life OR willingness(1n)pay OR quality(1n)adjusted()life()year?)/ti,ab

87. s76 OR s77 OR s78 OR s79 OR s80 OR s81 OR s82 OR s83 OR s84 OR s85 OR s86 OR s87

88. s25 AND s87 Date Search Performed: 16 Mar 2005 Total Records Retrieved: 193 unique records


BIOSIS – 8 DIALOG® Alerts: MEDLINE® 154 EMBASE® Alert 172 BIOSIS Previews® 55

Human (for all searches except economic)

Updates performed biweekly from Mar 20, 2005 to Sep 4, 2005, inclusive

John Wiley & Sons, Inc. The Cochrane Library 2005, Issue 1

Same keywords and descriptors as PubMed, adjusting as per syntax 124 Records The Cochrane Database of Systematic Reviews = 2 complete reviews; The Database of Abstracts of Reviews of Effectiveness = 4 records; CENTRAL = 93 references; HTA database = 12 records; The NHS Economic Evaluation Database = 13 records

Regular updates performed to 2005, Issue 3, inclusive

OHE-IFPMA Database Ltd. HEED: health economic evaluations database Mar 2005 Issue

All drug names Date Search Performed: 30 Mar 2005 Total Records Retrieved: 20 records

Conference proceedings

2002-2005 American College of Rheumatology (ACR), European League against Rheumatism (EULAR), Health Technology Assessment International (ISTAHC/HTAi) and International Society for Pharmacoepidemiology and Outcomes Research (ISPOR)


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Websites of health technology assessment (HTA) and related agencies; clinical trial registries; other databases

e.g., AHFMR; NICE; National Research Register; University of York NHS Centre for Reviews and Dissemination – CRD databases; CMA Infobase


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APPENDIX 2: Outcome Measures for Clinical Review Long-term effectiveness

Measures of disease activity: swollen and tender joint counts, pain, disability score, patient’s global assessment, and physician’s global assessment and DAS (Disease Activity Score)

Disease Activity Score (DAS) DAS28 is a validated index of rheumatoid arthritis (RA) activity. It consists of four measures:

• 28 tender (TJC28) and swollen (SJC28) joint counts • erythrocyte sedimentation rate (ESR) • patient’s general health (GH) measured on 100 mm VAS.

It is calculated using the formula 0.56× (TJC28)+0.28× (SJC28)+0.70× ln(ESR)+0.014× (GH) The DAS28 provides a number, on a scale from zero to 10, indicating the current activity of the RA patient. A DAS28 >5.1 means high disease activity, whereas a DAS28 <3.2 indicates low disease activity. Remission is achieved with a DAS28 <2.6. Levels of improvement can be categorized as good improvement >1.2; moderate improvement >0.6 and <1.2; and non-responders <0.6. ACR improvement criteria (20, 50, 70)

Definition of American College of Rheumatology (ACR) clinical response criteria ACR20 response Must include:

• 20% improvement in tender joint count • 20% improvement in swollen joint count • 20% improvement in three of the following criteria:

o patient pain assessment o patient global assessment o physician global assessment o patient self-assessed disability o acute phase reactant value [ESR or C-reactive protein (CRP)]

ACR50 and ACR70 are calculated as ACR20 responses using 50% and 70% improvement respectively. ACR-N (ACR numeric response) ACR-N is defined as the smallest degree of improvement from baseline in the following three criteria:

• number of tender joints • number of swollen joints • median of the five remaining measures of disease activity

EULAR improvement criteria

The European League Against Rheumatism response criteria have been based on the DAS. The EULAR response criteria include not only change in disease activity but also current disease activity. To be classified as responders, patients have a significant change in DAS and low current disease activity. Three categories are defined: good, moderate, and non-responders.


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Physical functional status

Health Assessment Questionnaire (HAQ)

Patient Label Date We are interested in learning how your illness affects your ability to function in daily life. Please add comments at the end of this form. PLEASE TICK THE ONE RESPONSE THAT BEST DESCRIBES YOUR USUAL ABILITIES OVER THE PAST WEEK

Without ANY difficulty

With SOME difficulty

With MUCH difficulty

Unable to do

score=0 score=1 score=2 score=3

1. DRESSING AND GROOMING – Are you able to: dress yourself including tying shoelaces and doing

buttons? shampoo your hair

2. RISING - Are you able to: stand up from an armless straight chair? get in and out of bed?

3. EATING - Are you able to: cut your meat? lift a cup or glass to your mouth? open a new carton of milk (or soap powder)?

4. WALKING - Are you able to: walk outdoors on flat ground? climb up five steps?

5. HYGIENE – Are you able to: wash and dry your entire body? take a bath? get on and off the toilet?

6. REACH – Are you able to: reach and get a 5 lb object (e.g., a bag of potatoes)

from above your head? bend down to pick up clothing from the floor?

7. GRIP – Are you able to: open car doors? open jars that have been previously opened? turn taps on and off?

8. ACTIVITIES – Are you able to: run errands and shop? get in and out of a car? do chores such as vacuuming, housework, or light

gardening?

PLEASE TICK ANY AIDS OR DEVICES THAT YOU USUALLY USE FOR ANY OF THESE ACTIVITIES cane devices used for dressing (button hook, zipper pull, long-handled shoe horn) walking frame built-up or special utensils crutches special or built-up chair wheelchair other (specify) raised toilet seat jar opener (for jars previously opened) bath seat long-handled appliances for reach bath rail other (specify) PLEASE TICK ANY CATEGORIES FOR WHICH YOU USUALLY NEED HELP FROM ANOTHER PERSON dressing and grooming eating rising walking hygiene gripping and opening things reach errands and housework


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Scoring of HAQ

Add the maximum score for each of the eight sections and divide by eight to give a score between 0 and 3. If aid, device, or help is needed, the score for that activity=2 (unless 3 has been ticked). Normal function=0, most severely affected=3. Radiological damage

Sharp score

Radiographs of hands, wrists, and feet are scored. In all, 46 joints are scored for erosions. Erosions are scored on a six-point scale. A score of 0=no new erosion and no worsening of an existing erosion. Each point increase indicates occurrence of a new erosion or 20% worsening of an existing erosion. In all, 42 joints are scored for narrowing on a five-point scale. A score of 0=no narrowing, 1=minimal narrowing, 2=loss of 50% of the joint space, and 4=complete loss of the joint space. Scores for joint space narrowing and erosions are summed to give a total Sharp score. van der Heijde modification of Sharp method

The radiographs of hands, wrists, and feet are scored. In this case, 44 joints are scored for erosions, 32 in the hands and wrists, and 12 in the feet. Each hand or wrist joint is scored on a five-point scale according to the surface involved — 0=no erosion, 5=extensive loss of bone from more than half of the articulating bone. Each foot joint is scored a maximum of 10. The maximum erosion score for hands is 160 and for feet 120. Joint space narrowing is scored in 30 hand and wrist joints and 10 joints in the feet. A four-point scoring system is used. A score of 0=no narrowing, 1=focal or doubtful narrowing, 2=general narrowing of <50%, 3=general narrowing of >50% of the original joint space, and 4=bony ankylosis or complete luxation. The maximum score for joint space narrowing of hands is 120, and for feet, the maximum score is 48.


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APPENDIX 3: Selection Criteria Forms Step 2 – Selection form

Rater Citation Author Language (Initials) ID Year Source Master ID number English Other (specify): Abstract comments: Previous Rating Excluded Included Unsure

Excluded Select ALL that apply

laboratory (only)

scope extended beyond RA

no infliximab or etanercept

adalimumab ONLY

insufficient data

commentary, editorials, short updates,

news

opinion letters

language

unable to retrieve paper

other

other (specify)

_____________________________

excluded on abstract only (no full

paper available)

ongoing study

Included Unsure Select ALL that apply:

economic evaluation

clinical effectiveness

If clinical effectiveness, then select all categories that apply:

effectiveness, <12 months

effectiveness, at least 12 months

safety

dose escalation

sequential

switching anti TNF

included based on abstract only (specify abstract comments)

comments:

Study type (for included and unsure)

original data: full paper

original data: letter

original data: abstract

original data: other specify:

health technology assessment

clinical practice guidelines

review

economic evaluation

decision analysis

other specify:


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Step 3 – Original data for clinical effectiveness

ETANERCEPT

INFLIXIMAB

Final Inclusion Comments Original Inclusion Yes No

etanercept RCT/CCT (≥12 months) infliximab RCT/CCT (≥12 months) observational (ETN or IFX)/effectiveness (≥12 months) dose escalation (≥3 months) sequence of administration switching anti-TNF (≥3 months) safety

ETANERCEPT — RCT/CCT

INCLUSION CRITERIA (all criteria must be met)

Yes No Not specified Comments 1. duration ≥12 months 2. patients ≥16 years old 3. RA diagnosed by ACR criteria 4. disease activity with at least 2 of the following: tender joints swollen joints morning stiffness ≥30 minutes increased ESR or CPR

5. ETN SC 10 mg or 25 mg twice/week or 50 mg/week 6. control group: placebo or other (disease modifying anti-rheumatic drug, biologic, or steroid)

7. clinical outcomes: ACR outcomes (TJC, SJC, pain, patient global, physician

global, function, acute phase reactants), or DAS, or ACR improvement criteria, or EULAR improvement criteria, or radiologic damage, or quality of life

8. sufficient data reported


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INFLIXIMAB — RCT/CCT

INCLUSION CRITERIA (all criteria must be met)

Yes No Not specified Comments 1. duration ≥12 months 2. patients ≥16 years old 3. RA diagnosed by ACR criteria 4. disease activity with at least 2 of the following: tender joints swollen joints morning stiffness ≥30 minutes increased ESR or CPR

5. IFX ≥1 mg/kg induction, then every 8 weeks 6. control group: placebo or other (DMARD, biologic, or steroid)

7. clinical outcomes: ACR outcomes (TJC, SJC, pain, patient global,

physician global, function, acute phase reactants), or

DAS, or ACR improvement criteria, or EULAR improvement criteria, or radiologic damage, or quality of life


EFFECTIVENESS/OBSERVATIONAL – INCLUSION CRITERIA (all criteria must be met)

Yes No Not specified Comments 1. duration ≥12 months 2. RA as specified by authors 3. treatment with ETN or IFX 4. N≥30 5. clinical outcomes ≥1 of the following: SJC DAS ACR improvement criteria EULAR improvement criteria functional status quality of life radiologic damage terminations adverse events



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Step 3 – Selection form

Step 3 – Inclusion or Exclusion Form Clinical Effectiveness Rater Author ID Source (Initials) ETANERCEPT Master ID INFLIXIMAB

PREVIOUS RATINGS ID step 1 rating step 2 rating clinical effectiveness economic evaluation

DESIGNS RCT/CCT ETANERCEPT RCT/CCT INFLIXIMAB OBSERVATIONAL EFFECTIVENESS ETN (N≥30) OBSERVATIONAL EFFECTIVENESS IFX (N≥30) OBSERVATIONAL EFFECTIVENESS both (N≥30) CASE SERIES (N<30) CASE REPORTS (N=1) OTHER SPECIFY

Is this a parent study? (check if yes) A parent study is a large project leading to different subset of articles. Does this article have a parent study? (check if yes)

if yes, specify parent study (author and year)

parent study ID

adjudicator (check if yes)

comments

GENERAL EXCLUSION REASONS children pharmacokinetics different therapy laboratory drug development methods gene therapy other diseases genetics RA general comments: other (no drug, no disease)

FINAL INCLUSION full paper

abstract only, reviewed

ETANERCEPT RCT/CCT (at least 6 months) If so, was it at least 12 months?

INFLIXIMAB RCT/CCT (at least 6 months) If so, was it at least 12 months?

OBSERVATIONAL (ETN OR IFX)

EFFECTIVENESS (at least 12 months)

DOSE ESCALATION (at least 3 months) SEQUENCE OF ADMINISTRATION

SWITCHING ANTI-TNF

SAFETY ONLY (not otherwise included)

OF INTEREST

specify:

FINAL EXCLUSION RA patients poorly defined

(no ACR criteria)

duration <6 months

disease activity not specified

no clear control group

no clinical outcomes

insufficient data reported

duration <12 months

<30 patients



<3 months

RA poorly specified


RCT <6 months or observational <12 months

insufficient data

unclear identification of sequence of administration

duration <3 months

RA pts poorly defined


insufficient data


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Systematic review form

Rater Citation Author (Initials) ID Year Source

Review Review Feature Feature Characteristic Review Feature Feature Characteristic 1. question a focused question (check if yes) 4. appraisal rigorous critical appraisal (check if yes)

2a. sources not specified 5. synthesis quantitative summary (check if yes) explicit 6. inferences evidence-based (check if yes) comprehensive 2b. search not specified vague explicit 3. selection criterion-based uniformly applied (check if yes)

Topic effectiveness (check if yes) safety (check if yes) economic evaluation (check if yes) other (check if yes and specify) country of first author number of authors affiliation comments

Funding not specified funded (check if yes) specify If funded, select all types:

granting body industry not specified

Conflict of Interest (Relationship with industry) yes no not specified specify

If conflict of interest, select all types: employee consultant travel grant other honoraria not specified


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Economic evaluation selection form

Economic evaluations: inclusion or exclusion criteria Rater Citation Author (Initials) ID Year Source Master ID Select type: primary economic evaluation review Select review type: narrative systematic Criteria for primary economic evaluation (select all that apply) 1. RA as specified by author 2. treatment with etanercept or infliximab 3. at least 6 months horizon 4. estimate of at least direct medical costs (not cost of drug only) 5. adequate data on costs or effects 6. other if other, specify: Included (check if yes): Adjudicator needed (check if yes): Comments:


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APPENDIX 4: Data Extraction Forms

Form 1 – Data sets and study quality

baseline 12 months none

3 months 18 months single blind – patient

6 months 24 months single blind – observer

9 months 36 months double blind triple blind Reference Manager ID Title Language of publication Year published Journal title Volumes and pages Primary author Country of primary author Publication type Location of trial Review type Funding not specified Granting body Industry Other source of funding

Data set ID

Date

Data collected by

Duration of study (months)

REFERENCE MANAGER INFORMATION

GEOGRAPHY AND PUBLICATION

FUNDING

OUTCOMES REPORTED AT OTHER TIMEPOINTS BLINDING

Inclusion criteria diagnosed with RA appropriate doses? relevant outcomes? adequate data? adequate duration? included original study study related to

Excluded no OMERACT outcomes no placebo group withdrawal study insufficient data follow-up study

Jadad study quality RCT RCT bonus RCT double blinded study? double blind bonus withdrawals described? Jadad score ____________

STUDY QUALITY Concealment of allocation

adequate

unclear

inadequate

not used

Attrition (losses to follow-up) analysis of completers? <80% overall or not reported ≥80% intention to treat explicit, clear intention to treat statistics


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Form 2 – Outcomes

Measured? Circle one

Reported? Circle one

Measure Used Minimum Score Maximum Score Improvements Circle one

Tender joint count YES NO YES NO High Low

Tender joint index YES NO YES NO High Low

Swollen joint count YES NO YES NO High Low

Swollen joint index YES NO YES NO High Low

Pain YES NO YES NO High Low

Global patient YES NO YES NO High Low

Global physician YES NO YES NO High Low

Functional status YES NO YES NO High Low

X-rays YES NO YES NO High Low

Quality of life YES NO YES NO High Low

ESR YES NO YES NO High Low

Other: ACR YES NO YES NO High Low

Other: EULAR YES NO YES NO High Low

Other: DAS YES NO YES NO High Low

Data set ID Date

Comments


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Form 3 – Study Characteristics

INCLUDE FREQUENCY SCHEME VIA

TREATMENT/DOSAGE TREATMENT/DOSAGE TREATMENT/DOSAGE

Intervention class

Combination?

N randomized

% females

Mean age (SD)

Median/range of age

Mean of disease duration (SD)

Median of disease duration

Minimum/maximum disease duration

% positive rheumatoid factor (RF)

Concurrent DMARD? (yes/no)

Concurrent DMARD %

Concurrent steroids? (yes/no)

Concurrent steroids %

Previous steroids

Previous DMARD

Data set ID Date


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Form 4A – Continuous Outcome Data-Baseline

INTERVENTION INTERVENTION INTERVENTION

Tender joint count

N Mean Method SD Method N Mean Method SD Method N Mean Method SD Method

Tender joint index

Swollen joint count

Swollen joint index

Pain

Global patient

Global physician

Functional status

Walking distance

Quality of life

ESR

X-ray scores

CRP

DAS

Data Set ID Date

Method for calculating mean and SD

1) reported 6) imputed from IQ range 2) calculated 7) imputed from other data

3) calculated from graphs 8) imputed from other papers

4) imputed from median

5) imputed from range

Comments


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INTERVENTION INTERVENTION INTERVENTION INTERVENTION Number with feature Total N Number with feature Total N Number with feature Total N Number with feature Total N

INTERVENTION INTERVENTION INTERVENTION INTERVENTION Number with feature Total N Number with feature Total N Number with feature Total N Number with feature Total N

Radiologic erosions

Comments

Data set ID Date of data collection Date collected

by

BASELINE

Comments

TIME POINT

Radiologic erosions

ACR20

ACR50

Paulus

ACR70

Form 5 – Outcome Data (Other)


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INTERVENTION INTERVENTION INTERVENTION

Withdrawals Side-effects Comments Withdrawals Side-effects Comments Withdrawals Side-effects Comments

N

Total withdrawals N/A N/A N/A

Lack of efficacy N/A N/A N/A

Adverse effects N/A N/A N/A

Concurrent disease N/A N/A N/A

Other withdrawals N/A N/A N/A

Gastrointestinal (GI) problems

N/A N/A N/A

Upper GI problems

Lower GI problems

MC problems

Renal toxicity

Liver abnormality

Hematology

Infection

Headache/dizzy

Cardiovascular

Deaths N/A N/A N/A

Pulmonary

Drug termination

Serious morbidity

Hospitalization

Mortality

TIMEPOINT Data set ID Date Form 6 – Withdrawals and Side-Effects


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Economic Review – Data Extraction Rater Citation Author (Initials) ID Year Source Incremental and total analysis

Incremental (comparison of two alternatives)

Total Funding Comments

Government

Industry

Academic

Not specified

None Source of clinical data Comments

Single trial

Multiple trials/meta-analysis

Literature review

Retrospective analysis Trial data or modelling

Trial data

Modelling Adjustment for compliance

Check if yes Study outcomes

Tender joint counts

ACR20

ACR50

ACR70

QALYs

Mortality

HAQ Analytic Horizon Time frame Other (specify)


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Rater Citation Author (initials) ID Year Source Source of Preferences

Direct elicitation

standard gamble

Time-tradeoff (TTO)

Visual Analog Scale (VAS)

Indirect elicitation

Health Utilities Index (HUI)

EuroQol (EQ-5D)

Quality of Well-Being (QWB)

other

Other

professional opinion

literature review

proxy opinion Discounting Future Outcomes

Discount rate Cost Measurement (Resources Used)

Resources used in treatment described in natural (non-dollar) units

Relevant costs separate from transfer costs

Resource cost validated for Canadian practice Cost Evaluation

Category Value ($) Source

Direct medical costs

Direct non-medical costs

Indirect costs


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Rater Citation Author (initials) ID Year Source Probability of achieving clinical outcomes ACR20 ACR50 ACR70

infliximab

etanercept

adalimumab

NSAID

COX-2

other DMARD

placebo

other Incremental cost-effectiveness ratios

sensitivity analysis not performed

traditional/deterministic

on effect on cost

one-way one-way

two-way two-way

three-way three-way

threshold threshold

probabilistic

cost-effectiveness acceptability curves

software used DATA by TreeAge other Effects of sensitivity analysis on findings Notes


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APPENDIX 5: Quality Assessment Instruments RCTs – Jadad Scale

Category Score 1. Randomization

Was study described as randomized (including words such as randomly, random, Randomization)? A trial reporting that it is “randomized” receives one point, yes=1, no=0.

Trials describing an appropriate method of randomization (table of random numbers, computer generated) receive an additional point, appropriate=1, inappropriate=0.

If the report describes the trial as randomized and uses an inappropriate method of Randomization (e.g., date of birth, hospital numbers), a point is deducted,

inappropriate=−1. 2. Double-blinding

Was the study described as double-blind? A trial reporting that it is double-blind receives one point, yes=1, no=0.

Trials describing an appropriate method of double-blinding (identical placebo: colour, shape, taste) receive an additional point, yes=1, no=0. If the report describes a trial as double-blind and uses an inappropriate method (e.g., comparison of tablets versus injection with no dummy), a point is deducted, Inappropriate=−1.

3. Withdrawals and drop-outs Was there a description of withdrawals and drop-outs? A trial reporting the number of and reasons for withdrawals or drop-outs receives one point. If there is no description, no point is given, yes=1, no=0. Total score (for above three categories) (0 to 2=low, 3 to 5=high)

Adequacy level4. Adequacy of allocation concealment

Central randomization; numbered or coded bottles or containers; drugs prepared by a pharmacy; serially numbered, opaque, sealed envelopes=adequate Alternation; reference to case record number or date of birth=inadequate Allocation concealment is not reported or fits neither category=unclear


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Observational Studies — Newcastle-Ottawa Scale (NOS)

NOS — Case-Control Studies

A study can be awarded a maximum of one star (*) for each numbered item in the selection and exposure categories. A maximum of two stars can be given for comparability.

Selection

1. Is case definition adequate? (outcome) SCORE (0,1) a) yes, with independent validation* * b) yes, e.g., record linkage or based on self reports c) no description d) other

2. Representativeness of cases (outcome) SCORE (0,1) a) consecutive or obviously representative series of cases* * b) potential for selection biases or not stated c) other

3. Selection of controls SCORE (0,1) a) community controls* * b) hospital controls c) no description d) other

4. Definition of controls SCORE (0,1) a) no history of disease (endpoint)* * b) no description of source c) other

SUBTOTAL Comparability

1. Comparability of cases and controls on basis of design or analysis SCORE (0,1,2)

a) study controls for disease severity or activity* * b) study controls for disease duration* c) study controls for additional factor* (criteria could be modified to indicate specific control for second factor)

*

d) other

SUBTOTAL Exposure

1. Ascertainment of exposure SCORE (0,1) a) secure record (e.g., surgical records)* * b) structured interview where blind to case/control status* * c) interview not blinded to case/control status d) written self-report or medical record only


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e) no description f) other 2. Same method of ascertainment for cases and controls SCORE (0,1) a) yes* * b) no

c) other 3. Non-response rate SCORE (0,1) a) same rate for both groups* * b) non-respondents described c) rate different and no designation d) other

SUBTOTAL TOTAL SCORE

NOS - Cohort Studies with Controls (several groups)

(A study can be awarded a maximum of one star for each numbered item in the Selection and Outcome categories. A maximum of two stars can be given for Comparability.)

Selection 1. Representativeness of Exposed Cohort (Biologic Agent) SCORE (0,1) a) truly representative of average rheumatoid arthritis patients in community* * b) somewhat representative of average rheumatoid arthritis patients in community* * c) selected group of users (e.g., nurses, volunteers) d) no description of derivation of cohort e) other

2. Selection of Non-Exposed Cohort SCORE (0,1) a) drawn from same community as exposed cohort* * b) drawn from different source c) no description of derivation of non-exposed cohort d) other

3. Ascertainment of Exposure (Biologic Agent) SCORE (0,1) a) secure record (e.g., surgical records) or as administered by authors* * b) structured interview* * c) written self-report d) no description e) other

4. Demonstration that Outcome of Interest Not Present at Start of Study SCORE (0,1) a) yes* * b) no c) other

SUBTOTAL Comparability 1. Comparability of Cohorts on Basis of Design or Analysis SCORE (0,1,2) a) study controls for disease severity or activity* *


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b) study controls for disease duration* c) study controls for any additional factor* (criteria could be modified to indicate specific control for second factor) *

d) other

SUBTOTAL Outcome 1. Assessment of Outcome SCORE (0,1) a) independent blind assessment* * b) record linkage* * c) self-report d) no description e) other

2. Was Follow-Up Long Enough for Outcomes to Occur? SCORE (0,1) a) yes (one year)* * b) no c) other

3. Adequacy of Follow-Up of Cohorts SCORE (0,1) a) complete follow-up, all subjects accounted for* * b) subjects lost to follow-up unlikely to introduce bias, number lost <20% (description provided of those lost)* *

c) follow-up rate >80% and no description of those lost d) no statement e) other

SUBTOTAL TOTAL SCORE

NOS - Cohort Studies without Controls (single cohort)

(A study can be awarded a maximum of one star for each numbered item in the Selection and Outcome categories.)

Selection 1. Representativeness of exposed cohort SCORE (0,1) a) truly representative of average rheumatoid arthritis patients in community* * b) somewhat representative of average rheumatoid arthritis patients in community* * c) selected group of users (e.g., nurses, volunteers) d) no description of derivation of cohort e) other

2. Ascertainment of Exposure SCORE (0,1) a) secure record (e.g., surgical records)* * b) structured interview* * c) written self-report d) no description e) other


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3. Demonstration that Outcome of Interest Not Present at Start of Study SCORE (0,1) a) yes* * b) no c) other

Outcome 1. Assessment of Outcome SCORE (0,1) a) independent blind assessment* * b) record linkage* * c) self-report d) no description e) other

2. Was Follow-Up Long Enough for Outcomes to Occur? SCORE (0,1) a) yes (one year)* * b) no c) other

3. Adequacy of Follow-Up of Cohorts SCORE (0,1) a) complete follow-up, all subjects accounted for* * b) subjects lost to follow-up unlikely to introduce bias, number lost >20% follow-up, or description provided of those lost*

*

c) follow-up rate <80% and no description of those lost d) no statement e) other

TOTAL SCORE


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QUOROM Instrument for Systematic Reviews Rater (Initials) ID Citation Author Year Source

Heading Subheading Descriptor Reported? (yes or no) Page Number

Title Identify report as meta-analysis or systematic review of RCTs

Abstract Use structured format Objectives Describe clinical question explicitly Data sources Describe databases (i.e., list) and other information sources Review methods Describe selection criteria (i.e., population, intervention, outcome, study design): methods for validity assessment, data abstraction, study characteristics,

and quantitative data synthesis in enough detail to permit replication Results Describe characteristics of RCTs included and excluded; qualitative and quantitative findings (i.e., point estimates and confidence intervals), and subgroup analyses Conclusion Describe main results

Describe

Introduction explicit clinical problem, biological rationale for intervention, and rationale for review

Methods Searching information sources, in detail (e.g., databases, registers, personal files,

expert informants, agencies, hand-searching), and restrictions (years considered, publication status, language of publication) Selection inclusion and exclusion criteria (defining population, intervention, principal outcomes, and study design) Validity assessment criteria and process used (e.g., masked conditions, quality assessment, and findings) Data abstraction process or processes used (e.g., completed independently, in duplicate) Study characteristics type of study design, participants’ characteristics, details of intervention, outcome definitions, and how clinical heterogeneity was assessed Quantitative data principal measures of effect (e.g., relative risk), method of combining results synthesis (statistical testing and confidence intervals), handling of missing data; how statistical heterogeneity was assessed; rationale for a priori sensitivity and subgroup analyses; and assessment of publication bias

Results Trial flow Provide meta-analysis profile summarizing trial flow Study characteristics Present descriptive data for each trial (e.g., age, sample size, intervention, dose, duration, follow-up period) Quantitative data Report agreement on selection and validity assessment; present simple synthesis summary results (for each treatment group in each trial, for each primary outcome); present data needed to calculate effect sizes and confidence intervals in intention-to-treat analyses (e.g., 2× 2 table of counts, means and SDs, proportions)

Discussion Summarize key findings; discuss clinical inferences based on internal and external validity; interpret results in light of totality of available evidence; describe potential biases in review process (e.g., publication bias); and suggest future research agenda


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APPENDIX 6: Clinical Review — Excluded Studies RCTs <12 months duration

1. Brennan FM, Browne KA, Green PA, Jaspar JM, Maini RN, Feldmann M. Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumour necrosis factor-alpha (cA2) therapy. Br J Rheumatol 1997;36(6):643-50.

2. Durez P, Nzeusseu TA, Lauwerys BR, Manicourt DH, Verschueren P, Westhovens R, et al. A randomised comparative study of the short term clinical and biological effects of intravenous pulse methylprednisolone and infliximab in patients with active rheumatoid arthritis despite methotrexate treatment. Ann Rheum Dis 2004;63(9):1069-74.

3. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344(8930):1105-10.

4. Feldmann M, Elliott MJ, Brennan FM, Maini RN. Use of anti-tumor necrosis factor antibodies in rheumatoid arthritis. J Interferon Res 1994;14(5):299-300.

5. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50(5):1412-9.

6. Kalden-Nemeth D, Grebmeier J, Antoni C, Manger B, Wolf F, Kalden JR. NMR monitoring of rheumatoid arthritis patients receiving anti-TNF-alpha monoclonal antibody therapy. Rheumatol Int 1997;16(6):249-55.

7. Kavanaugh A, St Clair EW, McCune WJ, Braakman T, Lipsky P. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol 2000;27(4):841-50.

8. Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004;50(2):353-63.

9. Lan JL, Chou SJ, Chen DY, Chen YH, Hsieh TY, Young M. A comparative study of etanercept plus methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis: a 12-week, double-blind, randomized, placebo-controlled study. J Formos Med Assoc 2004;103(8):618-23.

10. Lorenz HM, Grunke M, Hieronymus T, Antoni C, Nusslein H, Schaible TF, et al. In vivo blockade of tumor necrosis factor-alpha in patients with rheumatoid arthritis: longterm effects after repeated infusion of chimeric monoclonal antibody cA2. J Rheumatol 2000;27(2):304-10.

11. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354(9194):1932-9.

12. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41(9):1552-63.


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13. Mathias SD, Colwell HH, Miller DP, Moreland LW, Buatti M, Wanke L. Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo. Clin Ther 2000;22(1):128-39.

14. Maurice MM, Van der Graaff WL, Leow A, Breedveld FC, Van Lier RAW, Verweij CL. Treatment with monoclonal anti-tumor necrosis factor alpha antibody results in an accumulation of TH1 CD4+ T cells in the peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum 1999;42(10):2166-73.

15. Moreland LW, Margolies G, Heck LW, Jr., Saway A, Blosch C, Hanna R, et al. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 1996;23(11):1849-55.

16. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337(3):141-7.

17. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130(6):478-86.

18. Paleolog EM, Hunt M, Elliott MJ, Feldmann M, Maini RN, Woody JN. Deactivation of vascular endothelium by monoclonal anti-tumor necrosis factor alpha antibody in rheumatoid arthritis. Arthritis Rheum 1996;39(7):1082-91.

19. Perkins DJ, St Clair EW, Misukonis MA, Weinberg JB. Reduction of NOS2 overexpression in rheumatoid arthritis patients treated with anti-tumor necrosis factor alpha monoclonal antibody (cA2). Arthritis Rheum 1998;41(12):2205-10.

20. Smeets TJ, Kraan MC, van Loon ME, Tak PP. Tumor necrosis factor alpha blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue. Arthritis Rheum 2003;48(8):2155-62.

21. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4):253-9.

RCTs subgroup analysis

1. Criswell LA, Lum RF, Turner KN, Woehl B, Zhu Y, Wang J, et al. The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 2004;50(9):2750-6.

2. Smolen JS, Han C, Bala M, Maini RN, Kalden JR, van der HD, et al. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum 2005;52(4):1020-30.


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RCTs laboratory study

1. Moreland LW, Bucy RP, Weinblatt ME, Mohler KM, Spencer-Green GT, Chatham WW. Immune function in patients with rheumatoid arthritis treated with etanercept. Clin Immunol 2002;103(1):13-21.

2. St Clair EW, Wagner CL, Fasanmade AA, Wang B, Schaible T, Kavanaugh A, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46(6):1451-9.

RCTs commentary, report on other included studies

1. Medical progress. On the trail of new arthritis treatments. Harv Health Lett 1997;23(1):7.

2. Antoni C, Kalden JR. Combination therapy of the chimeric monoclonal anti-tumor necrosis factor alpha antibody (infliximab) with methotrexate in patients with rheumatoid arthritis. Clin Exp Rheumatol 1999;17(6 Suppl 18):S73-7.

3. Bathon JM, Genovese MC. The Early Rheumatoid Arthritis (ERA) trial comparing the efficacy and safety of etanercept and methotrexate. Clin Exp Rheumatol 2003;21(5 Suppl 31):S195-7.

Observational studies or uncontrolled follow-up studies of <12 months duration or with <30 subjects

1. Alessandri C, Bombardieri M, Papa N, Cinquini M, Magrini L, Tincani A, et al. Decrease of anti-cyclic citrullinated peptide antibodies and rheumatoid factor following anti-TNFalpha therapy (infliximab) in rheumatoid arthritis is associated with clinical improvement. Ann Rheum Dis 2004;63(10):1218-21.

2. Baeten D, De Keyser F, Veys EM, Theate Y, Houssiau FA, Durez P. Tumour necrosis factor alpha

independent disease mechanisms in rheumatoid arthritis: a histopathological study on the effect of infliximab on rheumatoid nodules. Ann Rheum Dis 2004;63(5):489-93.

3. Balanescu A, Radu E, Nat R, Regalia T, Bojinca V, Ionescu R, et al. Early and late effect of infliximab on circulating dendritic cells phenotype in rheumatoid arthritis patients. Int J Clin Pharmacol Res 2005;25(1):9-18.

4. Bartram D, Sheeran T, Price T, Mulherin D. Anti-tumour necrosis factor therapy in the West Midlands [letter]. Rheumatology 2004;43(3):400-1.

5. Buch MH, Marzo-Ortega H, Bingham SJ, Emery P. Long-term treatment of rheumatoid arthritis with tumour necrosis factor alpha blockade: outcome of ceasing and restarting biologicals [letter]. Rheumatology (Oxford) 2004;43(2):243-4.

6. Buch MH, Seto Y, Bingham SJ, Bejarano V, Bryer D, White J, et al. C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to etanercept. Arthritis Rheum 2005;52(1):42-8.


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7. Capria A, De Nardo D, De Sanctis G, Simonelli AR, Kroegler B, Silvestri F, et al. Endothelial dysfunction in rheumatoid arthritis is improved by anti-tumor necrosis factoralpha treatment. Eur J Inflamm 2004;2(3):113-8.

8. Caramaschi P, Canestrini S, Biasi D, Carletto A, Scambi C, Scarperi A, et al. [Infliximab in aggressive and refractory rheumatoid arthritis: a pilot study]. Recenti Prog Med 2002;93(1):19-24.

9. Catrina AI, Lampa J, Ernestam S, af KE, Bratt J, Klareskog L, et al. Anti-tumour necrosis factor (TNF)-alpha therapy (etanercept) down-regulates serum matrix metalloproteinase (MMP)-3 and MMP-1 in rheumatoid arthritis. Rheumatology (Oxford) 2002;41(5):484-9.

10. Crnkic M, Mansson B, Larsson L, Geborek P, Heinegard D, Saxne T. Serum cartilage oligomeric matrix protein (COMP) decreases in rheumatoid arthritis patients treated with infliximab or etanercept. Arthritis Res Ther 2003;5(4):R181-5.

11. Cuchacovich M, Ferreira L, Aliste M, Soto L, Cuenca J, Cruzat A, et al. Tumour necrosis factor-alpha (TNF-alpha) levels and influence of -308 TNF-alpha promoter polymorphism on the responsiveness to infliximab in patients with rheumatoid arthritis. Scand J Rheumatol 2004;33(4):228-32.

12. Davis D, Charles PJ, Potter A, Feldmann M, Maini RN, Elliott MJ. Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade. Br J Rheumatol 1997;36(9):950-6.

13. De Rycke L, Verhelst X, Kruithof E, Van den BF, Hoffman IEA, Veys EM, et al. Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis. Ann Rheum Dis 2005;64(2):299-302.

14. Drynda S, Kuhne C, Kekow J. Soluble tumour necrosis factor receptor treatment does not affect raised transforming growth factor bETN levels in rheumatoid arthritis. Ann Rheum Dis 2002;61(3):254-6.

15. Elkayam O, Caspi D, Reitblatt T, Charboneau D, Rubins JB. The effect of tumor necrosis factor blockade on the response to pneumococcal vaccination in patients with rheumatoid arthritis and ankylosing spondylitis. Semin Arthritis Rheum 2004;33(4):283-8.

16. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993;36(12):1681-90.

17. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994;344(8930):1125-7.

18. Fabris M, Tolusso B, Di Poi E, Assaloni R, Sinigaglia L, Ferraccioli G. Tumor necrosis factor-alpha receptor II polymorphism in patients from southern Europe with mild-moderate and severe rheumatoid arthritis. J Rheumatol 2002;29(9):1847-50.

19. Familian A, Voskuyl AE, van Mierlo GJ, Heijst HA, Twisk JWR, Dijkmans BAC, et al. Infliximab treatment reduces complement activation in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64(7):1003-8.


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20. Fernandez-Nebro A, Tomero E, Ortiz-Santamaria V, Castro MC, Olive A, de Haro M, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med 2005;118(5):552-6.

21. Ferraccioli GF, Assaloni R, Di Poi E, Gremese E, De Marchi G, Fabris M. Rescue of combination therapy failures using infliximab, while maintaining the combination or monotherapy with methotrexate: results of an open trial. Rheumatology (Oxford) 2002;41(10):1109-12.

22. Fiocco U, Ferro F, Vezzu M, Cozzi L, Checchetto C, Sfriso P, et al. Rheumatoid and psoriatic knee synovitis: clinical, grey scale, and power Doppler ultrasound assessment of the response to etanercept. Ann Rheum Dis 2005;64(6):899-905.

23. Fitzcharles MA, Clayton D, Menard HA. The use of infliximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002;29(12):2525-30.

24. Flendrie M, Creemers MCW, Welsing PMJ, Van Riel PLCM. The influence of previous and concomitant leflunomide on the efficacy and safety of infliximab therapy in patients with rheumatoid arthritis; a longitudinal observational study. Rheumatology 2005;44(4):472-8.

25. Garces M, Lozada CJ. Pharmacologic management of rheumatoid arthritis. J Clin Outcomes Manage 2004;11(9):585-92.

26. Godinho F, Godfrin B, El Mahou S, Navaux F, Zabraniecki L, Cantagrel A. Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis. Clin Exp Rheumatol 2004;22(3):328-30.

27. Hansen KE, Cush J, Singhal A, Cooley DA, Cohen S, Patel SR, et al. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum 2004;51(2):228-32.

28. Heiberg MS, Nordvag B, Mikkelsen K, Rodevand E, Kaufmann C, Mowinckel P, et al. The comparative effectiveness of tumor necrosis factor-blocking agents in patients with rheumatoid arthritis and patients with ankylosing spondylitis: a six-month, longitudinal, observational, multicenter study. Arthritis Rheum 2005;52(8):2506-12.

29. Hermann J, Mueller T, Fahrleitner A, Dimai HP. Early onset and effective inhibition of bone resorption in patients with rheumatoid arthritis treated with the tumour necrosis factor alpha antibody infliximab. Clin Exp Rheumatol 2003;21(4):473-6.

30. Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002;106(17):2184-7.

31. Irace C, Mancuso G, Fiaschi E, Madia A, Sesti G, Gnasso A. Effect of anti TNFalpha therapy on arterial diameter and wall shear stress and HDL cholesterol. Atherosclerosis 2004;177(1):113-8.

32. Jacobsson Lennart TH, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005;32(7):1213-8.

33. Kiely PD, Johnson DM. Infliximab and leflunomide combination therapy in rheumatoid arthritis: an open-label study. Rheumatology (Oxford) 2002;41(6):631-7.


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34. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol 2004;31(2):238-42.

35. Korczowska I, Hrycaj P, Lacki JK. Does infliximab decrease bone turnover in rheumatoid arthritis patients. Joint Bone Spine 2003;70(5):398-400.

36. Kucharz EJ, Gozdzik J, Kopec M, Kotulska A, Lewicki M, Pieczyrak R, et al. A single infusion of infliximab increases the serum endostatin level in patients with rheumatoid arthritis. Clin Exp Rheumatol 2003;21(2):273-4.

37. Labarca C, Massardo L, Garcia PI, Jacobelli S. [Effectiveness of infliximab in patients with inflammatory arthritis refractory to conventional treatment]. Rev Med Chil 2003;131(10):1157-64.

38. Martinez A, Salido M, Bonilla G, Pascual-Salcedo D, Fernandez-Arquero M, De Miguel S, et al. Association of the major histocompatibility complex with response to infliximab therapy in rheumatoid arthritis patients. Arthritis Rheum 2004;50(4):1077-82.

39. Mugnier B, Balandraud N, Darque A, Roudier C, Roudier J, Reviron D. Polymorphism at position -308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003;48(7):1849-52.

40. Nikas SN, Temekonidis TI, Zikou AK, Argyropoulou MI, Efremidis S, Drosos AA. Treatment of resistant rheumatoid arthritis by intra-articular infliximab injections: a pilot study. Ann Rheum Dis 2004;63(1):102-3.

41. Nissinen R, Leirisalo-Repo M, Peltomaa R, Palosuo T, Vaarala O. Cytokine and chemokine receptor profile of peripheral blood mononuclear cells during treatment with infliximab in patients with active rheumatoid arthritis. Ann Rheum Dis 2004;63(6):681-7.

42. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K, Ishida H, et al. Long-term follow-up of the changes in circulating cytokines, soluble cytokine receptors, and white blood cell subset counts in patients with rheumatoid arthritis (RA) after monoclonal anti-TNF alpha antibody therapy. J Clin Immunol 1999;19(5):305-13.

43. Padyukov L, Lampa J, Heimburger M, Ernestam S, Cederholm T, Lundkvist I, et al. Genetic markers for the efficacy of tumour necrosis factor blocking therapy in rheumatoid arthritis. Ann Rheum Dis 2003;62(6):526-9.

44. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 2002;100(2):474-82.

45. Pawlik A, Ostanek L, Brzosko I, Brzosko M, Masiuk M, Machalinski B, et al. Therapy with infliximab decreases the CD4+CD28- T cell compartment in peripheral blood in patients with rheumatoid arthritis. Rheumatol Int 2004;24(6):351-4.

46. Ravindran J, Shenker N, Bhalla AK, Lachmann H, Hawkins P. Case report: response in proteinuria due to AA amyloidosis but not Felty's syndrome in a patient with rheumatoid arthritis treated with TNF-alpha blockade. Rheumatology 2004;43(5):669-72.


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47. Ribbens C, Andre B, Marcelis S, Kaye O, Mathy L, Bonnet V, et al. Rheumatoid hand joint synovitis: gray-scale and power Doppler US quantifications following anti-tumor necrosis factor-alpha treatment: pilot study. Radiology 2003;229(2):562-9.

48. Schotte H, Schluter B, Willeke P, Mickholz E, Schorat MA, Domschke W, et al. Long-term treatment with etanercept significantly reduces the number of proinflammatory cytokine-secreting peripheral blood mononuclear cells in patients with rheumatoid arthritis. Rheumatology (Oxford) 2004;43(8):960-4.

49. Schotte H, Schorat MA, Willeke P, Domschke W, Gaubitz M. Etanerceptbehandlung bei rheumatoider Arthritis - monozentrische Langzeitbeobachtung uber vier Jahre [Four-year observation of etanercept therapy for rheumatoid arthritis in a single German center]. Z Rheumatol 2005;64(4):265-73.

50. Shenker N, Haigh R, Clarke A. Worse patient VAS occurs at weeks 7 and 8 after infliximab infusions. Ann Rheum Dis 2005;64(3):502-3.

51. Shergy WJ, Isern RA, Cooley DA, Harshbarger JL, Huffstutter JE, Hughes GM, et al. Open label study to assess infliximab safety and timing of onset of clinical benefit among patients with rheumatoid arthritis. J Rheumatol 2002;29(4):667-77.

52. Singh R, Cuchacovich R, Huang W, Espinoza LR. Infliximab treatment in a patient with rheumatoid arthritis on hemodialysis. J Rheumatol 2002;29(3):636-7.

53. Smith GR, Tymms KE, Falk M. Etanercept treatment of renal amyloidosis complicating rheumatoid arthritis. Intern Med J 2004;34(9-10):570-2.

54. Smith JR, Levinson RD, Holland GN, Jabs DA, Robinson MR, Whitcup SM, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45(3):252-7.

55. Sokka T, Pincus T. Contemporary disease modifying antirheumatic drugs (DMARD) in patients with recent onset rheumatoid arthritis in a US private practice: methotrexate as the anchor drug in 90% and new DMARD in 30% of patients. J Rheumatol 2002;29(12):2521-4.

56. Straub RH, Pongratz G, Scholmerich J, Kees F, Schaible TF, Antoni C, et al. Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion. Arthritis Rheum 2003;48(6):1504-12.

57. Tak PP, Taylor PC, Breedveld FC, Smeets TJ, Daha MR, Kluin PM, et al. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor alpha monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996;39(7):1077-81.

58. Taylor PC, Peters AM, Glass DM, Maini RN. Effects of treatment of rheumatoid arthritis patients with an antibody against tumour necrosis factor alpha on reticuloendothelial and intrapulmonary granulocyte traffic. Clin Sci (Lond) 1999;97(1):85-9.

59. Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari PV, Drosos AA. Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis. Ann Rheum Dis 2002;61(9):822-5.


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60. Terslev L, Torp-Pedersen S, Qvistgaard E, Kristoffersen H, Rogind H, Danneskiold-Samsoe B, et al. Effects of treatment with etanercept (Enbrel, TNRF:Fc) on rheumatoid arthritis evaluated by Doppler ultrasonography. Ann Rheum Dis 2003;62(2):178-81.

61. Thonhofer R, Gaugg M, Kriessmayr M, Neumann HJ, Erlacher L. Spontaneous remission of marginal zone B cell lymphoma in a patient with seropositive rheumatoid arthritis after discontinuation of infliximab-methotrexate treatment. Ann Rheum Dis 2005;64(7):1098-9.

62. Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC. Systemic anti-tumor necrosis factor alpha therapy in rheumatoid arthritis down-regulates synovial tumor necrosis factor alpha synthesis. Arthritis Rheum 2000;43(11):2391-6.

63. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003;62(6):587-8.

64. van Oosterhout M, Levarht EWN, Sont JK, Huizinga TWJ, Toes REM, Van Laar JM. Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. Ann Rheum Dis 2005;64(4):537-43.

65. van Vollenhoven RF, Ernestam S, Harju A, Bratt J, Klareskog L. Etanercept versus etanercept plus methotrexate: a registry-based study suggesting that the combination is clinically more efficacious. Arthritis Res Ther 2003;5(6):R347-51.

66. Vassallo R, Matteson E, Thomas CF, Jr. Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition. Chest 2002;122(3):1093-6.

67. Vis M, Wolbink GJ, Lodder MC, Kostense PJ, Van De Stadt RJ, De Koning MHMT, et al. Early changes in bone metabolism in rheumatoid arthritis patients treated with infliximab [multiple letters]. Arthritis Rheum 2003;48(10):2996-7.

68. Vis M, Nurmohamed MT, Wolbink G, Voskuyl AE, De Koning MHMT, Van De Stadt RJ, et al. Short term effects of infliximab on the lipid profile in patients with rheumatoid arthritis. J Rheumatol 2005;32(2):252-5.

69. Wittwer H, Schattenkirchner M, Kellner H. Sichere und effiziente therapie mit infliximab in der rheumatologie: ein teilstationares modell [Safe and efficient therapy with Infliximab in rheumatology: a partly inpatient model]. Aktuelle Rheumatol 2003;28(1):49-52.

70. Wolbink GJ, Voskuyl AE, Lems WF, de Groot E, Nurmohamed MT, Tak PP, et al. Relationship between serum trough infliximab levels, pretreatment C reactive protein levels, and clinical response to infliximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005;64(5):704-7.

71. Zamarron C, Maceiras F, Mera A, Gomez-Reino JJ. Effect of the first infliximab infusion on sleep and alertness in patients with active rheumatoid arthritis. Ann Rheum Dis 2004;63(1):88-90.

Observational: drugs combined in report

1. Cannon GW, Holden WL, Juhaeri J, Dai W, Scarazzini L, Stang P. Adverse events with disease modifying antirheumatic drugs (DMARD): a cohort study of leflunomide compared with other DMARD. J Rheumatol 2004;31(10):1906-11.


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2. Wolfe F, Michaud K. Fatigue, rheumatoid arthritis, and anti-tumor necrosis factor therapy: an investigation in 24,831 patients. J Rheumatol 2004;31(11):2115-20.

Observational: pharmacokinetics

1. Zhou H, Mayer PR, Wajdula J, Fatenejad S. Unaltered etanercept pharmacokinetics with concurrent methotrexate in patients with rheumatoid arthritis. J Clin Pharmacol 2004;44(11):1235-43.

Observational: no clinical outcomes

1. Kaiser MJ, Bozonnat MC, Jorgensen C, Daures JP, Sany J. Effect of etanercept on tenosynovitis and nodules in rheumatoid arthritis. Arthritis Rheum 2002;46(2):559-60.

2. Wiland P, Wiela-Hojenska A, Glowska A, Chlebicki A, Hurkacz M, Orzechowska-Juzwenko K, et al. Renal function in rheumatiod arthritis patients treated with methotrexate and infliximab. Clin Exp Rheumatol 2004;22(4):469-72.

Observational: no TNF antagonists

1. Jobanputra P, Maggs F, Homer D, Bevan J. Monitoring and assessing the safety of disease-modifying antirheumatic drugs: a West Midlands experience. Drug Saf 2002;25(15):1099-105.

Observational: laboratory study

1. Garnero P, Gineyts E, Christgau S, Finck B, Delmas PD. Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. Arthritis Rheum 2002;46(1):21-30.

2. Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Gonzalez-Gay MA.

Active but transient improvement of endothelial function in rheumatoid arthritis patients undergoing long-term treatment with anti-tumor necrosis factor alpha antibody. Arthritis Rheum 2004;51(3):447-50.

3. Gonzalez-Juanatey C, Gonzalez-Gay MA. Long-term rheumatoid arthritis and endothelial dysfunction. Atherosclerosis 2004;176(1):197-8.

4. Ostanek L, Pawlik A, Brzosko I, Brzosko M, Sterna R, Drozdzik M, et al. The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab. Clin Rheumatol 2004;23(3):214-7.

5. Paleolog EM, Young S, Stark AC, McCloskey RV, Feldmann M, Maini RN. Modulation of angiogenic vascular endothelial growth factor by tumor necrosis factor alpha and interleukin-1 in rheumatoid arthritis. Arthritis Rheum 1998;41(7):1258-65.

Observational: different therapy

1. Pavletic SZ, Klassen LW, Pope R, O'Dell JR, Traynor AE, Haire CE, et al. Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis. J Rheumatol Suppl 2001;64:28-31.


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Observational: descriptive, no follow-up

1. Sokka T, Willoughby J, Yazici Y, Pincus T. Databases of patients with early rheumatoid arthritis in the USA. Clin Exp Rheumatol 2003;21(5 Suppl 31):S146-53.

2. Sokka T, Pincus T. Eligibility of patients in routine care for major clinical trials of anti-tumor

necrosis factor alpha agents in rheumatoid arthritis. Arthritis Rheum 2003;48(2):313-8.

Observational: addition of MTX to anti-TNF

1. Cohen JD, Zaltni S, Kaiser MJ, Bozonnat MC, Jorgensen C, Daures JP, et al. Secondary addition of methotrexate to partial responders to etanercept alone is effective in severe rheumatoid arthritis. Ann Rheum Dis 2004;63(2):209-10.

Observational: other diseases

1. Mealy NE, Bayes M. Infliximab. Drugs Future 2004;29(4):416-8.

Observational: commentary

1. Schmutz JL, Barbaud A, Trechot P. Effects secondaries des anti-TNFalpha [Side-effects of anti-TNFalpha agents]. Ann Dermatol Venereol 2004;131(2):226.

2. Winthrop KL, Siegel JN, Jereb J, Taylor Z, Iademarco MF. Tuberculosis associated with therapy against tumor necrosis factor alpha. Arthritis Rheum 2005;52(10):2968-74.

Observational: combined diseases

1. Cairns AP, Taggart AJ. Anti-tumour necrosis factors therapy for severe inflammatory arthritis: two years of experience in Northern Ireland. Ulster Med J 2002;71(2):101-5.

2. Geborek P, Saxne T, Emery P, Panayi G, Sturrock RD, Williams BD. Clinical protocol for monitoring of targeted therapies in rheumatoid arthritis [multiple letters]. Rheumatology 2000;39(10):1159-61.


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APPENDIX 7: Clinical Review – Study Characteristics

Table 1: Study characteristics — health technology assessments Country Publication

Date Search Dates

Outcomes Title Agency

Germany29 2002 1993-2001 clinical Wertigkeit von Tumor-Nekrose-Faktor Alpha-Antagonisten in der Behandlung der rheumatoiden Arthritis [Efficacy of TNF alpha antagonists in treatment of rheumatoid arthritis] Lehrstuhl für Allgemeine Betriebswirtschaftslehre und Gesundheitsmanagement, Ernst-Moritz-Arnd-Universität, Greifswald

Germany30 2004 1993-2001 clinical economic

Wertigkeit von Tumor-Nekrose-Faktor-alpha-Antagonisten in der Behandlung dre Rheumatoiden Arthritis [Efficacy of TNF alpha antagonists in treatment of rheumatoid arthritis] Deutsche Agentur für Health Technology Assessment des Deutschen Instituts für Medizinische Dokumentation und Information DAHTA@DIMDI

UK31 2001 1994-1999 clinical economic

The clinical effectiveness and cost-effectiveness of new drug treatments for rheumatoid arthritis: etanercept and infliximab West Midlands Development and Evaluation Service, The University of Birmingham. The National Institute for Clinical Excellence

UK32 2002 1996-1999 clinical economic

The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation Department of Rheumatology University Hospitals Birmingham, Selly Oak Hospital; Department of Public Health and Epidemiology, University of Birmingham; Health Economics Facility, Health Services Management Centre, University of Birmingham

UK33 2004 1991-2001 economic The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis Health Services Management Centre, University of Birmingham Department of Rheumatology, University Hospitals Birmingham, Selly Oak Hospital Department of Public Health and Epidemiology, University of Birmingham

Denmark18 2002 1999-2001 clinical economic

LEDDEGIGT – medicinsk teknologivurdering af diagnostic og behandling [Rheumatoid arthritis: medical technology of diagnosis and treatment] Sundhedsstyrelsen: Center for Evaluering og Medicinsk Teknologivurdering

Hungary19 2004 1994-2000 clinical economic

Az Infliximab (REMICADE) szerepe a rheumatoid arthritis terápiájában a szakirodalom szistemakus áttekintése és egészségügyi technológiaelemzési jelentés [Infliximab (Remicade) in management of rheumatoid arthritis, systematic review of literature, present practice, and RA patients’ data in Hungary] Egeszseg-gazdasagtani es Technologiaelemzesi Munkacsoport

Canada34 2006 1996-2003 clinical economic

Infliximab and etanercept in patients with rheumatoid arthritis: a systematic review and economic evaluation Canadian Coordinating Office for Health Technology Assessment


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Table 2: Study characteristics — systematic reviews Lead

Author Country Conflict of

Interest Agent(s) Review

Type Follow-up Number of Trials

Included,* Identified, Excluded

Number of Participants

Quantitative Reviews (Meta-Analysis) Blumenauer16 Canada none disclosed IFX efficacy

safety 6 to 12 months 2 RCTs included; 12

identified, 10 excluded 529

Blumenauer15 Canada none disclosed ETN efficacy safety

6 to 12 months 3 RCTs included; 10 identified, 7 excluded

955

Non-Quantitative Reviews de Vries35 UK none disclosed ETN, IFX efficacy,

safety, cost-effectiveness

6 to 12 months 8 RCTs included; 8 identified, 0 excluded

not provided

Rubio-Terres36

Spain Aventis Pharma

IFX, LEF, MTX

efficacy, safety, cost-effectiveness

12 months 4 RCTs included; 11 identified, 7 excluded

902

Culy37† New Zealand

Adis International Limited

ETN efficacy safety cost -effectiveness

12 months (early active RA patients; 2 non-comparative studies had up to 3 years FU); 3 to 6 months (patients with inadequate DMARD treatment response; patients continuing study treatment had up to 5 years FU)

2,674

Keating38†

New Zealand

Adis International Limited

ETN efficacy safety, cost-effectiveness

12 months (early active RA patients; 2 non-comparative studies had up to 3 years FU); 3 to 6 months (patients with inadequate DMARD treatment response; patients continuing study treatment had up to 5 years FU)

5 RCTs and 3 observational studies; number identified not provided, number excluded not provided

2,674

Hochberg39 US none disclosed ADM, ETN, IFX, MTX

efficacy 24 to 30 weeks 4 RCTs included; 4 trials identified, 0 excluded

1,053

Jones40 Australia none disclosed gold, steroids, cyclosporin, IFX, ANA, LEF, MTX, parenteral gold, SSZ

efficacy 24 to 104 weeks 25 RCTs included; 38 trials identified, 13 excluded

3,907

*Some reviews covered diseases other than RA but results shown here only pertain to RA; †similar information; FU=follow-up; RCT=randomized controlled trial.


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Table 3: Study characteristics — IFX RCTs Study Lipsky

ATTRACT41 Maini continuation of

ATTRACT42 St Clair

ASPIRE43 Taylor44 Quinn45

Country Multi-centre: UK; US; The Netherlands; Germany; Austria

As per ATTRACT multi-centre: UK; US; The Netherlands; Germany; Austria;

Canada

single centre: UK single centre: UK

Funding Centocor Centocor Centocor Centocor; Arthritis Research Campaign

Arthritis Research Campaign

Number of participants 428 as per ATTRACT 1,049 24 20 Participants’ characteristics mean age: 52.6+11.8 years

DD: 10.6+8.4 years RF (+): range 77% to 84%

as per ATTRACT mean age: 50.4+12.6 years DD range: 0.8 to 0.9 years RF(+) range: 71% to 73%

mean age range: 51 to 55 yearsDD range: 1.33 to 1.64 years

RF(+) range: NR

mean age range: 51 to 53 years DD range: 6 to 7.4 months RF(+) range: 60% to 70%

Previous treatment criterion failure to MTX 12.5 mg/wk as per ATTRACT no previous DMARDs failure to MTX 12.5 mg/wk no previous DMARDs Intervention N=number of patients per group

IFX 3 mg/kg/q8wk+MTX, N=86 IFX 3 mg/kg/q4wk+MTX, N=86

IFX 10 mg/kg/q8wk+MTX, N=87 IFX 10 mg/kg/q4wk+MTX, N=81

N=55 N=57 N=64 N=55

IFX 3 mg/kg/q8wk+MTX, N=373




Comparators N=number of patients per group

MTX 12.5 mg/wk to 35 mg/wk, N=88

N=28 MTX 7.5 mg/wk to 20 mg/wk, N=298

MTX 12.5 mg/wk to 17.5 mg/wk, N=12

MTX 7.5 mg/wk to 25 mg/wk, N=10

Follow-up: number of weeks 54 102 54 54 104 Primary outcomes efficacy ACR20, ACR50, ACR70, VAS,

HAQ, SF-36 HAQ, SF-36, vdH-S score ACR-N, HAQ, SF-36, DAS28 vdH-S score, ultrasound

assessment MRI-measured synovitis

Secondary outcomes efficacy SJC, TJC, CRP, vdH-S score ACR20, ACR50, ACR70, ANA, anti-dsDNA

ACR20, ACR50, ACR70, ACR 90, vdH-S score, ANA, anti-

dsDNA

ACR20, ACR50, DAS28, ESR ACR20, ACR50, ACR70, DAS28, HAQ, vdH-S, RAQoL

Outcomes assessment: number of weeks

0, 10, 30, 42, 54 62, 70, 78, 86, 94, 102 0, 24, 54 0, 4, 18, 54 0, 14, 30, 46, 54, 62, 78, 104

Allocation concealment adequate as per ATTRACT adequate adequate adequate

Jadad 5 3 4 3 4 Blinding yes yes (X-rays), no (clinical

outcomes) yes yes yes (clinical outcomes <54

weeks), no (clinical outcomes >54 weeks)

Intention to treat yes yes, unclear for some outcomes (X-rays)

no (completers) unclear yes

vdH-S=van der Heijde-Sharp score; MRI=magnetic resonance imaging; DD=disease duration; MTX=methotrexate; HAQ=Health Assessment Questionnaire; NR=not reported; DMARDs=disease-modifying antirheumatic drugs; ACR=American College of Rheumatology; DAS=Disease Activity Score; ANA=antinuclear auto antibodies; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; ATTRACT=Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group; ASPIRE=Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group; UK=United Kingdom; US=United States; RF=rheumatoid factor; IFX=infliximab; BID=twice a day (bis in die); SJC=swollen joint count; TJC=tender joint count; CRP=C-reactive protein; wk=weeks.


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Table 4: Study characteristics — ETN RCTs Study Bathon

ERA46 Kosinski

Subanalysis of ERA47

Genovese Continuation of

ERA48

Klareskog TEMPO49

Population origin multi-centre: US; Canada as in ERA as in ERA multi-centre: Sweden; The Netherlands; Spain; Czech Republic; Australia; UK;

Belgium; France; Greece; US Funding Immunex Wyeth-Ayerst,

Immunex Immunex Wyeth

Number of participants 632 424 as in ERA 682 Participants’ characteristics, N=number of patients per group]

mean age range: 49 to 51 years DD range: mean 11 to 12 months 74% <18 months; RF(+) range: 87% to 89%

as in ERA as in ERA mean age range: 52.5 to 53 years DD range: 6.3 to 6.8 years RF(+) range: 71% to 76%

Previous treatment criterion DMARDs discontinued at least 4 weeks before study began, patients

MTX-naive

as in ERA as in ERA failure of at least 1 DMARD; no MTX within 6 months of enrolment

Intervention, N=number of patients per group ETN 10 mg SC biw, N=208 ETN 25 mg SC biw, N=207

ETN 25 mg SC biw, N=207

N=166 N=177

ETN 25 mg SC biw alone, N=223 ETN 25 mg SC biw+MTX, N=231

Comparator MTX 7.5 mg/wk to 20 mg/wk, N=217 as in ERA N=169 MTX 7.5 mg to 20 mg/wk, N=228 Follow-up: number of weeks 52 52 104 52 Primary outcomes ACR20, ACR50, ACR70, ACR-N SF-36 ACR20, ACR50,

ACR70 ACR-N (AUC), ACR20, ACR50, ACR70,

DAS28, HAQ Secondary outcomes vdH-S score HAQ vdH-S score, HAQ vdH-S score Outcomes assessment 2 wk; 2, 4, 6, 8, 10, 12 months as in ERA 15, 18, 21, 24 months 0, 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 52 wk

Allocation concealment unclear unclear as in ERA adequate

Jadad 2 NR as in ERA 4 Blinding yes yes no (clinical

outcomes), yes (X-rays)

yes

Intention to treat yes yes unclear* yes (clinical outcomes), X-rays for most patients (some unavailable)

*Authors used last observation carried forward (LOCF) from year 1 to year 2; apparently not from baseline; vdH-S=van der Heijde-Sharp score; MRI=magnetic resonance imaging; DD=disease duration; MTX=methotrexate; HAQ=Health Assessment Questionnaire; NR=not reported; DMARDs=disease-modifying anti-rheumatic drugs; ACR=American College of Rheumatology; DAS=Disease Activity Score; ANA=antinuclear auto antibodies; anti-dsDNA=anti-double-stranded deoxyribonucleic acid; ERA=Etanercept and/versus Methotrexate in Patients with Early Rheumatoid Arthritis; TEMPO=Trial of Etanercept and Methotrexate with Radiographic Patients Outcomes; UK=United Kingdom; US=United States; RF=rheumatoid factor; ETN=etanercept; biw=biweekly; SC=subcutaneous; SJC=swollen joint count; TJC=tender joint count; CRP=C-reactive protein; wk=weeks; mg=milligrams.


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Table 5: Study characteristics — observational studies on effectiveness Study Study Type Country Conflict of

Interest Sample

Size Intervention Duration of

Follow-up Outcomes NOS

Score Abarca54 controlled

retrospective cohort US Wyeth Pharma 244 ETN (128), IFX (89),

ETN+IFX (27) >2 years discontinuation, dosage 6

Baumgartner64 controlled prospective cohort

US Immunex 671 recent onset RA, ETN (207); established RA, ETN (464)

3 years clinical (SJC, ACR, HAQ), discontinuation, timing

7

Breedveld72 controlled prospective cohort (open follow-up to trial)

UK, US, Germany, Austria, The Netherlands

Centocor 428 MTX, IFX 3 mg/kg q8wk, IFX 3 mg/kg q4wk, IFX 10 mg/kg q8wk, IFX 10 mg/kg q4wk,

102 wk clinical (radiologic) 7

Carreno56 uncontrolled prospective cohort

Spain ND 62 IFX+MTX (62) 18 months clinical (ACR, HAQ), discontinuation

5

Chevillotte-Maillard59

controlled prospective cohort

France ND 83 IFX (83) 1 year (median) discontinuation 5

Durez70 controlled prospective cohort

Belgium Schering - Plough

511 stable dose IFX (405) increased dose IFX (106)

62 wk clinical (ACR) 6

Feltelius66 uncontrolled prospective cohort

Sweden Wyeth Research 1,073 1st year ETN (820) 2nd to 4th yearr ETN (253)

4 years clinical (DAS), discontinuation, safety

5

Fleischmann71 controlled retrospective cohort

US Immunex 1,128 <65 ETN (931) >65 ETN (197)

1 year clinical (SJC, ACR), age 2

Flendrie53 controlled prospective cohort

Netherlands ND 230 ADM (94), ETN (16), IFX (120)

>30 months discontinuation, safety 7

Flendrie60 controlled prospective cohort

The Netherlands ND 162 IFX (105) LEF+IFX (57)

3 years discontinuation, clinical (DAS)

8

Geborek52 controlled prospective cohort

Sweden ND 404 ETN (166) IFX (135) LEF (103)

1 year clinical (ACR), discontinuation, safety

7

Genovese69 controlled prospective cohort (open follow-up to trial)

US Immunex 468 MTX followed byETN (143); low ETN followed by high ETN (163); high ETN followed by high ETN (162)

3 years clinical (SJC, ACR, DAS, HAQ, radiologic)

9

ACR=American College of Rheumatology improvement criteria; DAS=disease activity score; ETN=etanercept; HAQ=health assessment questionnaire; IFX=infliximab; LEF=leplunamide; ND=none disclosed; RA=rheumatoid arthritis; SJC=swollen joint count; UK=United Kingdom; US=United States.


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Table 5: Study characteristics — observational studies on effectiveness Study Study Type Country Conflict of

Interest Sample

Size Intervention Duration of Follow-up Outcomes NOS

Score Kremer67 uncontrolled prospective

cohort (open follow up to trial)

US Immunex 79 ETN+MTX (79)

3 years clinical (SJC, ACR, HAQ), safety, discontinuation

5

Moreland62 uncontrolled prospective cohort

US Immunex 628 ETN (628) 30 months clinical (SJC, ACR, HAQ), discontinuation

5

Ortiz-Garcia57 controlled retrospective cohort

Spain ND 45 IFX+LEF (45) 20 months discontinuation 4

Sfriso68 uncontrolled prospective cohort (open follow up to trial)

Italy ND 63 IFX (63) 1 year clinical (SJC, ACR) NA

Sidiropoulos61 uncontrolled prospective cohort

Greece Schering - Plough

68 IFX (68) 12 infusions discontinuation 4

Stern58 uncontrolled retrospective cohort uncontrolled prospective cohort

US Centocor 1,718 study 1 IFX (394) study 2 IFX (1,324)

3 years discontinuation 5 5

Voulgari65 uncontrolled prospective cohort

Greece ND 84 IFX (84) 3 years clinical (ACR), discontinuation

5

Yazici63 uncontrolled prospective cohort (biologics registry, single centre)

US ND 88 ETN (88) 1 year discontinuation, safety 8

Zink55 controlled retrospective cohort

Germany Essex Pharma, Wyeth Pharma, Amgen, Abbott

1,523 ETN (511), IFX (343), ANAK (70), DMARDs (599)

1 year discontinuation 7


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Table 6: Study characteristics — pharmacovigilance safety Study Study Type Country Data Source Method Cases Outcomes Patients

Askling83 report of TB hospitalization RR in RA patients in Sweden

Sweden Swedish Inpatient Register, Swedish Census Register

Database review; retrospective cohort

15 TB RA

Baldin88 report on data from national post-marketing adverse drug reaction databank

France l’Association des centres régionaux de pharmacovigilance and RATIO

Multi-centre retrospective survey of post-marketing adverse drug reaction database

56 TB NR

Brown74 review of monitoring system for TNF antagonist therapy and lymphoma development

US FDA MedWatch Spontaneous report; post-market adverse event surveillance system

26 Lymphoma development

RA, PA, CD

Carmona86 study examining data on effectiveness of recommendations to prevent reactivation of TB in patients treated with TNF antagonists

Spain BIOBADASER EMECAR

Database for active long-term follow up supported by the Spanish Society of Rheumatology Database on Biological Products; cohort study (“Morbidity and Clinical Expression of Rheumatoid Arthritis”)

34 patients TB RA

Costamagno75 study on TB associated with TNF blocking agents

US CDC; California county health department

Passive surveillance database and local jurisdiction solicitation

3 cases; 9 additional reports

TB RA, CD, JRA, dermatomyositis

Dunlop89 report on serious infections/TB and IFX/ETN

Canada Health Canada Passive surveillance 697 reports of suspected adverse reactions

TB RA, autoimmune disease

Geborek52 experience of structured follow-up program for monitoring

Sweden RAMONA Database for active long-term follow-up supported by University of Lund

8 participating centres

survival, AE per 100 treatments/year

RA

Geborek84 comparison of 2 cohorts to identify RR of lymphomas

Sweden SSATG registry Register Database for active long-term follow-up supported by southern Sweden

757 lymphomas RA

Gómez-Reino87

study of RA treatment on TNF inhibitors and increased TB risk

Spain BIOBADASER database for active long-term follow-up supported by Spanish Society of Rheumatology Database on Biological Products

71 participating centres; 1,578 treatments of IFX or ETN

TB RA

Keane76 report that analyzes reports of TB through MedWatch

US FDA (AERS and MedWatch)

passive and post-market surveillance database

70 cases TB CD, RA, JRA, AS, Behçet’s disease


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Table 6: Study characteristics — pharmacovigilance safety Study Study Type Country Data Source Method Cases Outcomes Patients

Kling85 study on reports involving sepsis as possible adverse drug reaction to TNF antagonists

Sweden Medical Product Agency

compulsory surveillance database

29 cases sepsis RA

Kwon77 review of monitoring system for heart failure after TNF antagonist treatment

US FDA MedWatch voluntary, post-market adverse event surveillance system

47 patients heart failure CD, JRA, RA, PA

Lee78 review of monitoring system for histoplasmosis associated with IFX and ETN

US FDA (AERS and MedWatch)

passive and post-market surveillance database

10 cases histoplasmosis RA, CD

Mohan79 review of monitoring system for leukocytoclastic vasculitis associated with TNF-blocking agents

US FDA AERS passive surveillance database 35 cases leukocytoclastic vasculitis

RA, JRA, AS, PA, CD

Mohan80 review of monitoring system for demyelination associated with anti-TNF therapy

US FDA AERS passive surveillance database 19 patients demyelination inflammatory arthritis

Mohan81 review of monitoring system for TB associated with ETN

US FDA AERS passive surveillance database 15 patients TB RA, JRA, PA, panniculitis, chronic heart failure

Slifman82 review of monitoring system for infections as complication of TNF neutralizing agents

US FDA AERS passive surveillance database 15 cases Listeria monocytogenes

RA, CD

ten Tusscher90

case study on bilateral anterior toxic optic neuropathy and IFX

The Netherlands

Netherlands Pharmacovigilance Centre

voluntary reporting 3 cases bilateral anterior toxic optic neuropathy

RA

AERS=Adverse Events Reporting System; AS=ankylosing spondylitis; BIOBADASER=Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología; CD=Crohn’s disease; IA=inflammatory arthritis; JRA=juvenile rheumatoid arthritis; PA=psoriatic arthritis; RA=rheumatoid arthritis; RAMONA= Rheumatoid Arthritis Monitoring National Protocol; SSATG=South Swedish Arthritis Treatment Group; TB=tuberculosis.


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Table 7: Study characteristics — other safety studies Author Country Study Type Conflict of

Interest Cases with

Adverse Event (n)

Population at Risk

Drug Duration of Observation

Outcomes

GENERAL Artacho*148 Spain cohort

(retrospective) 7 15/10 w/RA ETN 1 year (2001 to

2002) AE

Cabou149 France cohort (retrospective)

21 32 IFX 1 year (2000 to 2001)

AE

Molloy150 Ireland cohort 4 58 IFX, ETN, ADM

unspecified deaths

Neven151 The Netherlands

cohort 122 168 IFX 2 years (2000 to 2002)

AE

Saaverdra Marquez*152

Spain cohort (prospective)

13 40/23 w/RA IFX 1 year AE

Strusberg*153 Spain cohort - 18 events

45/37 w/RA, 207 infusions

IFX 15 to 18 months (2000 to 2003)

AE

TUBERCULOSIS Font*91 Spain cohort

(retrospective) 15/2 w/RA 3,634 not specified 9 years (1991 to

2000) incidence of TB

Wolfe92 US nested case-control

Centocor 4 6,460 IFX 1 year (1998 to 1999), 3 years (2000 to 2002)

incidence rate

OTHER SYSTEMIC INFECTIONS Bergstrom*93 US case series and

cohort (retrospective)

Centocor Wyeth

10 cases in 13 patients with RA, 6 cases in 11 patients with RA and IFX

- 985/845 w/RA

IFX - 5 years (1998 to 2003)

coccidioidomycosis

Kroesen154 Switzerland Cohort Essex Chemie

11 60 IFX, ETN October 1999 serious infections

Phillips*155 US Cohort 5/2 w/RA 180/119 w/RA

ETN 1 to 19 months (1998 to 2000)

serious infections

ORTHOPEDIC INFECTIONS Bibbo94 US cohort 16 31 ETN mean 10.6 months infection, complication,

healing. RA pts on TNF undergoing elective foot or ankle surgery


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ORTHOPEDIC INFECTIONS Talwalkar95 UK cohort

(retrospective) 3 11/10 w/RA

(16 operations)

ETN, IFX range 6 to 55 days complications in patients undergoing elective orthopedic surgery

CANCER Lebwohl106 US clinical trials

database Amgen 4 1,442 ETN 4 years SSC

Wolfe105 US nested case-control NDB

Amgen 14 5,025 ETN, IFX 3 years (1999 to 2002)

lymphoma

AUTOIMMUNITY Allanore96 France cohort without

control group 41 ANA (+), 46

anti-histone IgM(+), 19 anti-histone IgG(+), 19 anti-dsDNA IgM(+), 2 anti-dsDNA IgG(+)

59 IFX 30 wk ANA, anti-histone, anti-dsDNA

Bingham97 UK cohort Schering-Plough

33 40 IFX 12 wk ANAs

Charles73 US patients of 3 clinical trials

Centocor 45 ANA(+), 22 anti-dsDNA(+)

156 IFX 54 wk ANA, anti-dsDNA

De Rycke98 Belgium cohorts Vlaams Instituut

32 62 IFX 30 wk ANA

De Rycke99 Belgium cohort Vlaams Instituut

48 ANA (+), 29 anti-dsDNA(+)

59 IFX 2 years ANA, ENA, aCL, anti-dsDNA, anti-histone, AE

Elkayam100 France cohort 7 ANA(+), 4 anti-dsDNA IgG(+), 4 aCL IgM (+), 4 anti-histone H1(+)

26 IFX 14 wk ANA, anti-dsDNA, aCL, anti-histone, ENA, ANCA

Eriksson101 Sweden cohort at 54 weeks: 31 ANA(+), 20 anti-dsDNA IgG (+), 10 anti-nucleosome(+)

at 54 weeks: 45 44 40

IFX 54 wk anti-dsDNA, anti-nucleosome antibodies ANA, DAS28

Ferraro-Peyret*102 France cohort 21 ANA(+), 1 anti-dsDNA IgG-M(+) 2 aPL(+), 1 ANCA (+), 0 β2GPI (+)

39/24 w/RA IFX 2 years ANA, anti-dsDNA, aPL, ANCA, β2GPI, AE

Jonsdottir103 Sweden cohort (STURE registry)

Wyeth Schering-Plough

18 aCL IgG-M(+) 14 aCL IgG-M(+)

65 IFX 56 ETN

IFX ETN

6 months aCL, DAS28, AE


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Louis*104 Canada cohort None disclosed

32 42/33 w/RA IFX at least 5 infusions ANA, anti-dsDNA, anti-Sm, anti-RNP

INFUSION REACTIONS Wasserman156 Canada cohort without

control group 104/1,183

reactions/infusions 113 IFX 50.6+28.9 wk infusion reactions

Zeltser*157 US chart review (retrospective)

15/82 reactions/patients

103/82 w/RA

ETN (1999 to unclear) infusion reactions

OTHER ADVERSE EVENTS Petersen158 US cohort

(prospective and retrospective)

5 viral load decreased, 13 ESR decreased, 0 transaminasemia

8 24 9

IFX, ETN 1 to 34 months serum transaminases and viremia in HCV, ESR

Suissa108 Canada nested case-control

Aventis 42 1,402 IFX, ETN up to 2 years hepatic toxicity

Vanhoof109 The Netherlands

clinical trials database

4 88 IFX, ETN, ADM

1 year (2002) hepatic toxicity

Wolfe107 US cohort NDB Centocor 461 13,171 IFX, ETN 2 years heart failure rates PREGNANCY Katz*110 US cohort Centocor 64 pregnancies, 68

live births (4 sets of twins), 14 miscarriages, 18 therapeutic terminations

96/8 w/RA IFX 9 months miscarriages, live births

DRUG INTERACTIONS Zhou159 France crossover study Wyeth 8 treatment-

emergent AEs 12 healthy subjects

ETN 8 days no interaction with digoxin

Zhou160 France cohort Wyeth 11 treatment-emergent AEs, 5 non-serious infections

12 healthy subjects

ETN 29 days no interaction with warfarin

NDB=National Data Bank for Rheumatic Diseases (US); SSATG=South Swedish Arthritis Group; SSC=squamous cell carcinoma; wk=weeks; anti-dsDNA=antibodies to double-stranded DNA; ANA=antinuclear antibodies; ENA=anti-extractable nuclear antigen; aCL=anticardiolipin antibodies; aPL=antiphospholipid antibodies; ANCA=anti-neutrophil cytoplasmic autoantibodies; β2GPI=β2-glycoprotein 1 antibodies, anti-Sm=anti-Smith antibodies; anti-RNP=anti-ribonucleoprotein antibodies; HCV=hepatitis C virus; ESR=erythrocyte sedimentation rate; *includes other diseases.


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Table 8: Safety – case series and case reports Infections IFX ETN References Sepsis Fatal sepsis (Streptococcus pneumoniae)

0

1

Baghai161

Sepsis (Listeria monocytogenes) 3 0 Tweezer-Zaks,162 Glück163

Disseminated primary varicella infection 1 0 Vonkeman164 Meningitis Pneumococcal meningitis

0

1

Killingley165

Listeria meningitis 1 0 Bowie166

Tuberculosis and other mycobacteria Pulmonary tuberculosis

2

0

Parra,167 Roth,168 Taylor,169 Molenaar Esmeralda,170 Mayordomo171

Tuberculous tonsillitis 0 1 Derk172

Disseminated tuberculosis 1 0 Dimakou173

Pott’s disease 0 1 Yim174

Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex

1 0 Van Der Klooster175

Tuberculous peritonitis 1 0 Finlay176

Tenosynovitis (Mycobacterium marinum) 0 1 Chopra177 Other pulmonary infections Pneumocystis carinii pneumonia

1

0

Tai178

Legionella pneumophila infection 1 0 Christidis179

Invasive pulmonary aspergillosis 1 1 De Rosa,180 Lassoued181 Pulmonary cryptococcosis 3 0 Hage CA,182 True,183 Arend184

Histoplasmosis 2 1 Wood,185 Nakelchik186 Other infections Reactivation of brucellosis

1

0

Jimenez187

Fatal myositis (Microsporidian brachiola algerae) 1 0 Coyle188 Neck mass (Streptococcus constellatus) 0 1 Carter189 Cellulitis (Capnocytophaga cynodegmi) 0 1 Gerster190 Septic arthritis (Salmonella enteritidis) 1 0 Katsarolis191 Gastroenteritis (Strongyloides sterocoralis) 0 1 Boatright192 Severe Herpes zoster 1 0 Kinder193 Fasciitis Necrotising fasciitis (Haemolytic group A streptococcus)

1

0

Chan194

Ocular involvement Multiple bilateral eyelid (Molluscum contagiosum) lesions

1

0

Cursiefen195

Cytomegalovirus retinitis 1 0 Haerter196

Autoimmune Systemic lupus erythematosus Drug-induced SLE

6

7

Shakoor,197 Novak,198 Russo,199 Favalli,200 Debandt,201 Cairns,202 Benucci,203 Charles73

Discoid lupus Discoid lupus erythematosus-like eruption

2

0

Richez,204 Stratigos205

Discoid lupus and cryoglobulinemia 0 2 Misery206

Pulmonary Fatal exacerbation of RA associated fibrosing alveolitis

3

0

Ostor207

Pulmonary lymphohistiocytic reactions 0 3 Yousem208


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Vasculitis and nodulosis Drug-induced vasculitis

7

1

Jarrett209

Leukocytoclastic vasculitis 0 1 Galaria210

Necrotizing vasculitis and neuropathy 2 1 Richette211

Vasculitis and accelerated nodulosis 0 3 Cunnane212

Accelerated cutaneous nodulosis 1 0 Mackley213

Other skin involvement Cutaneous eruptions or rashes

11

4

Brion,214 Wright,215 Sfikakis,216 Soliotis,217 Dumont-Berset,218 Devos,219 Vergara,220 Kent221

Delayed multiple injection site reaction 0 1 Rajakulendran222 Recurrence of alopecia areata 0 1 Posten223 Neurologic involvement Aseptic meningitis

1

0

Marotte224

Mononeuritis 0 1 Richter225

Multifocal motor neuropathy with conduction block 1 0 Rodriguez-Escalera226

Retrobulbar optic neuritis 1 0 Foroozan227

Myositis Orbital myositis

0

1

Caramaschi228

Polymyositis 1 0 Musial229 Other Cancer Lymphoproliferative disorder

1

0

Hoshida230

Kaposi’s sarcoma 1 0 Cohen231

Sudden death 1 0 De’Clari232

Bone marrow toxicity 1 0 Marchesoni233

Progressive neutropenia 0 1 Ghavami234

Late onset of long-lasting fever 1 Tassiopoulos235

Atrial fibrillation 0 1 Wooten236

Ovulation induction, conception* 0 1 Alvarez-Requejo237

Safety in HCV 2 3 Parke111

*Cases reported as good prognosis.


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APPENDIX 8: Clinical Review Results — IFX RCTs

Table 1: IFX RCTs — ACR responses

Study and Intervention N ACR50 P value (versus control)

ACR70 P value (versus control)

ACR-N % improvement

(IQR) P value

(versus control)

1 year ATTRACT 54 wk41 Control -MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

88 86 86 87 81

7 (8%)

18 (21%) 29 (34%) 34 (39%) 31 (38%)

referent 0.027*

<0.001* <0.001* <0.001*

2 (2%)

9 (10%) 15 (17%) 22 (25%) 15 (19%)

referent 0.04*

0.001* <0.001* <0.001*

- - - - -

ASPIRE 54 wk43 Control -MTX IFX 3 mg/kg q8wk+MTX IFX 6 mg/kg q8wk+MTX

274 351 355

88 (32%) 161 (46%) 178 (50%)

referent <0.001* <0.001*

58 (21%)

112 (32%) 131 (37%)

referent 0.002*

<0.001*

26.4% (0.0, 64.3) 38.9% (0.0, 77.3) 46.7% (0.0, 82.1)

referent <0.001* <0.001*

Taylor 54 wk44 Control -MTX IFX 5 mg/kg q8wk+MTX

12 12

0 (0%) 3 (25%)

referent

0.22

- -

- -

Quinn 54 wk45 Control -MTX IFX 3 mg/kg q8wk+MTX

10 10

4 (40%) 8 (80%)

referent <0.05*

3 (30%) 7 (70%)

referent < 0.05

- -

2 years ATTRACT 102 wk42 Control -MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

28 55 57 64 55

2 (6%)

12 (21%) 17 (30%) 23 (36%) 11 (20%)

referent 0.003*

<0.001* <0.001* 0.006*

1 (1%)

6 (10%) 12 (21%) 13 (20%) 6 (10%)

referent 0.008*

<0.001* <0.001*

0.01*

- - - - -

Quinn 104 wk45 Control -MTX IFX 3 mg/kg q8w+MTX

10 10

5 (50%) 7 (70%)

referent

NS

5 (50%) 5 (50%)

referent

NS

*Statistically significant; NS=not statistically significant


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Table 2: IFX RCTs – ACR responses; relative benefit, and % benefit difference Relative Benefit (95% CI)† % Benefit Difference (95% CI)† Dose NT/NC Study

ACR50 ACR70 ACR50 NNT ACR70 NNT 1 year IFX 3 mg/kg q8wk+MTX versus MTX

86/88

351/274 -

10/10

ATTRACT 54 wk41 ASPIRE 54wk43 Taylor 54 wk44 Quinn 54 wk45

2.63 (1.16, 5.98)*

1.43 (1.16, 1.76)*-

2.00 (0.88, 4.54)

4.60 (1.02, 20.70)*

1.51 (1.15, 1.98)* -

2.33 (0.83, 6.54)

13% (3%, 23%)*

14% (6%, 21%)* -

40% (1%, 79%)*

7.7* 7.1*

2.5*

8% (1%, 15%)*

11% (4%, 18%)* -

40% (0%, 80%)

12.5* 14.3*

2.5

IFX 3 mg/kg q8wk+MTX versus MTX 447/372 POOLED 1.52 (1.25, 1.85)* 1.63 (1.26, 2.12)* 14% (8%, 20%)* 7.1* 11% (5%, 16%)* 9.1*

IFX 3 mg/kg q4wk+MTX versus MTX

86/88

ATTRACT 54 wk41 ASPIRE 54 wk43 Taylor 54 wk44 Quinn 54 wk45

4.24 (1.96, 9.16)* - - -

7.67 (1.81, 32.56)* - - -

26% (14%, 37%)* - - -

3.8* 15% (7%, 24%)* - - -

6.7*

IFX 5 to 6 mg/kg q8wk+MTX versus MTX

-

355/274 12/12

-


-

1.56 (1.28, 1.91)*7.00 (0.40, 122.44)

-

-

1.74 (1.34, 2.27)* - -

-

18% (10%, 26%)* 25% (-1%, 51%)

-

5.6* 4.5

-

16% (9%, 23%)* - -

6.2*

IFX 5 to 6 mg/kg q8wk+MTX versus MTX 367/286 POOLED 1.59 (1.30, 1.94)* - 18% (11%, 26%)* 3.2* -


87/88


4.91 (2.30, 10.48)* - - -

11.13 (2.70, 45.89)* - - -

31% (19%, 43%)* - - -

3.2* 23% (13%, 33%)* - - -

4.3*


81/88 ATTRACT 54 wk41 ASPIRE 54 wk43 Taylor 54 wk44 Quinn 54 wk45

4.81 (2.24, 10.32)* - - -

8.15 (1.92, 34.54)* - - -

30% (18%, 42%)* - - -

3.3* 16% (7%, 25%)* - - -

6.2*

*statistically significant; †relative benefit >1.0 and positive benefit differences indicate beneficial effect of IFX compared with controls; NNT=number needed to treat; NT=number in treatment group; NC=number in control group


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Table 2: IFX RCTs – ACR responses; relative benefit, and % benefit difference

Relative Benefit (95% CI)† % Benefit Difference (95% CI)† Dose NT/NC Study ACR50 ACR70 ACR50 NNT ACR70 NNT

2 years IFX 3 mg/kg q8wk+MTX versus MTX

55/28 10/10

ATTRACT 102 wk42 Quinn 104 wk45

3.05 (0.73, 12.71) 1.40 (0.67, 2.94)

3.05 (0.39, 24.15) 1.00 (0.42, 2.40)

15% (0%, 29%) 20% (-22%, 62%)

6.7 5.0

7% (-3%, 18%) 0% (-44%, 44%)

14.3 ‡


65/38 POOLED 1.97 (0.94, 4.13) 1.43 (0.61, 3.37) 16% (1%, 30%)* 6.2 6% (-7%, 18%) 16.7


57/28 -


4.18 (1.04, 16.82)*-

5.89 (0.81, 43.09) -

23% (7%, 38%)* -

4.3 17% (5%, 30%)*-

5.9*


64/28 -


5.03 (1.27, 19.90)*-

5.69 (0.78, 41.39) -

29% (14%, 44%)* -

3.4 17% (5%, 29%)*-

5.9*


55/28 -


2.80 (0.67, 11.77) -

3.05 (0.39, 24.15) -

13% (-1%, 27%) -

7.7 7% (-3%, 18%) -

14.3

*statistically significant; **relative benefit >1.0 and positive benefit differences indicate a beneficial effect of IFX compared with controls; NNT=number needed to treat; NT=number in treatment group; NC=number in control group; ‡=unable to estimate


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Figure 1: IFX RCTs – ACR50 response at 54 weeks; relative benefit (fixed effects)

)

RR=relative benefit

Review: Infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX) Outcome: ACR50 response rate

Study Infliximab/MTX Placebo/MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3mg/kg q8 weeks versus MTX(PBO) ATTRACT 18/86 7/88 6.30 2.63 [1.16, 5.98] ASPIRE 161/351 88/274 90.05 1.43 [1.16, 1.76] Quinn 2005 8/10 4/10 3.64 2.00 [0.88, 4.54] Subtotal (95% CI) 447 372 100.00 1.52 [1.25, 1.85]Total events: 187 (infliximab+MTX), 99 (placebo/MTX)Test for heterogeneity: chi²=2.50, df=2 (P=0.29), I²=20.1%Test for overall effect: Z=4.24 (P<0.0001) MTX and infliximab 3mg/kg q4 weeks versus MTX(PBO) ATTRACT 29/86 7/88 100.00 4.24 [1.96, 9.16] Subtotal (95% CI) 86 88 100.00 4.24 [1.96, 9.16]Total events: 29 (infliximab+MTX), 7 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.68 (P=0.0002) MTX and infliximab 10mg/kg q8 weeks versus MTX(PBO) ATTRACT 34/87 7/88 100.00 4.91 [2.30, 10.48] Subtotal (95% CI) 87 88 100.00 4.91 [2.30, 10.48]Total events: 34 (infliximab+MTX), 7 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.12 (P<0.0001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO ATTRACT 31/81 7/88 100.00 4.81 [2.24, 10.32] Subtotal (95% CI) 81 88 100.00 4.81 [2.24, 10.32]Total events: 31 (infliximab+MTX), 7 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.04 (P<0.0001) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 178/355 88/274 99.50 1.56 [1.28, 1.91] Taylor 2004 3/12 0/12 0.50 7.00 [0.40, 122.44] Subtotal (95% CI) 367 286 100.00 1.59 [1.30, 1.94]Total events: 181 (infliximab+MTX), 88 (placebo/MTX)Test for heterogeneity: chi²=1.06, df=1 (P=0.30), I²=5.7%Test for overall effect: Z=4.52 (P<0.00001)

0.001 0.01 0.1 1 10 100 1000

Favours control Favours treatment


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Figure 2: IFX RCTs – ACR50 response at 54 weeks; benefit difference (fixed effects)

RD=benefit difference

Review: infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX) Outcome: ACR50 response rate

Study Infliximab/MTX Placebo/MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3mg/kg q8 weeks versus MTX(PBO) ATTRACT 18/86 7/88 21.49 0.13 [0.03, 0.23] ASPIRE 161/351 88/274 76.04 0.14 [0.06, 0.21] Quinn 2005 8/10 4/10 2.47 0.40 [0.01, 0.79] Subtotal (95% CI) 447 372 100.00 0.14 [0.08, 0.20]Total events: 187 (infliximab/MTX), 99 (placebo/MTX)Test for heterogeneity: chi²=1.73, df=2 (P=0.42), I²=0%Test for overall effect: Z=4.46 (P<0.00001)

MTX and infliximab 3mg/kg q4 weeks versus MTX(PBO) ATTRACT 29/86 7/88 100.00 0.26 [0.14, 0.37] Subtotal (95% CI) 86 88 100.00 0.26 [0.14, 0.37]Total events: 29 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.40 (P<0.0001)



MTX and infliximab 5 to 6mg/kg q8 weeks versus MTX(PBO) ASPIRE 178/355 88/274 96.26 0.18 [0.10, 0.26] Taylor 2004 3/12 0/12 3.74 0.25 [-0.01, 0.51] Subtotal (95% CI) 367 286 100.00 0.18 [0.11, 0.26]Total events: 181 (infliximab/MTX), 88 (placebo/MTX)Test for heterogeneity: chi²=0.26, df=1 (P=0.61), I²=0%Test for overall effect: Z=4.85 (P<0.00001)

-1 -0.5 0 0.5 1



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RR=relative benefit



MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 9/86 2/88 2.82 4.60 [1.02, 20.70] ASPIRE 112/351 58/274 92.90 1.51 [1.15, 1.98] Quinn 2005 7/10 3/10 4.28 2.33 [0.83, 6.54] Subtotal (95% CI) 447 372 100.00 1.63 [1.26, 2.12]Total events: 128 (infliximab+MTX), 63 (placebo/MTX)Test for heterogeneity: chi²=2.61, df=2 (P=0.27), I²=23.4%Test for overall effect: Z=3.67 (P=0.0002)

MTX and infliximab 3 mg/kg q4weeks versus MTX(PBO) ATTRACT 15/86 2/88 100.00 7.67 [1.81, 32.56] Subtotal (95% CI) 86 88 100.00 7.67 [1.81, 32.56]Total events: 15 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.76 (P=0.006)

MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 22/87 2/88 100.00 11.13 [2.70, 45.89] Subtotal (95% CI) 87 88 100.00 11.13 [2.70, 45.89]Total events: 22 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.33 (P=0.0009)

MTX and infliximab 10mg/kg q4 weeks versus MTX ATTRACT 15/81 2/88 100.00 8.15 [1.92, 34.54] Subtotal (95% CI) 81 88 100.00 8.15 [1.92, 34.54]Total events: 15 (infliximab/MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.85 (P=0.004)

MTX and infliximab 6mg/kg q8 weeks versus MTX(PBO) ASPIRE 131/355 58/274 100.00 1.74 [1.34, 2.27] Subtotal (95% CI) 355 274 100.00 1.74 [1.34, 2.27]Total events: 131 (infliximab+MTX), 58 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.10 (P<0.0001)

0.001 0.01 0.1 1 10 100 1000



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MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 9/86 2/88 21.49 0.08 [0.01, 0.15] ASPIRE 112/351 58/274 76.04 0.11 [0.04, 0.18] Quinn 2005 7/10 3/10 2.47 0.40 [0.00, 0.80] Subtotal (95% CI) 447 372 100.00 0.11 [0.05, 0.16]Total events: 128 (infliximab+MTX), 63 (placebo/MTX)Test for heterogeneity: chi²=2.57, df=2 (P=0.28), I²=22.2%Test for overall effect: Z=3.87 (P=0.0001)

MTX and infliximab 3 mg/kg q4weeks versus MTX(PBO) ATTRACT 15/86 2/88 100.00 0.15 [0.07, 0.24] Subtotal (95% CI) 86 88 100.00 0.15 [0.07, 0.24]Total events: 15 infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.46 (P=0.0005)

MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 22/87 2/88 100.00 0.23 [0.13, 0.33] Subtotal (95% CI) 87 88 100.00 0.23 [0.13, 0.33]Total events: 22 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.67 (P<0.00001)

MTX and infliximab 10 mg/kg q4 weeks versus MTX ATTRACT 15/81 2/88 100.00 0.16 [0.07, 0.25] Subtotal (95% CI) 81 88 100.00 0.16 [0.07, 0.25]Total events: 15 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.53 (P=0.0004)

MTX and infliximab 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 131/355 58/274 100.00 0.16 [0.09, 0.23] Subtotal (95% CI) 355 274 100.00 0.16 [0.09, 0.23]Total events: 131 (infliximab+MTX), 58 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.42 (P<0.00001)

-1 -0.5 0 0.5 1



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RR=relative benefit

Review: infliximab for rheumatoid arthritisComparison: efficacy at 102 weeks (infliximab/MTX versus placebo/MTX)Outcome: ACR50 response rate


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 12/55 2/28 34.65 3.05 [0.73, 12.71]

Quinn 2005 7/10 5/10 65.35 1.40 [0.67, 2.94] Subtotal (95% CI) 65 38 100.00 1.97 [0.94, 4.13]Total events: 19 (infliximab+MTX), 7 (placebo/MTX)Test for heterogeneity: chi²=1.19, df=1 (P=0.28), I²=15.6%Test for overall effect: Z=1.81 (P=0.07) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 17/57 2/28 100.00 4.18 [1.04, 16.82] Subtotal (95% CI) 57 28 100.00 4.18 [1.04, 16.82]Total events: 17 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.01 (P=0.04) MTX and infliximab 10mg/kg q8 weeks versus MTX(PBO)

ATTRACT (continuation) 23/64 2/28 100.00 5.03 [1.27, 19.90] Subtotal (95% CI) 64 28 100.00 5.03 [1.27, 19.90]Total events: 23 (infliximab/MTX), 2 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.30 (P=0.02) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 11/55 2/28 100.00 2.80 [0.67, 11.77] Subtotal (95% CI) 55 28 100.00 2.80 [0.67, 11.77]Total events: 11 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=1.41 (P=0.16)

0.01 0.1 1 10 100



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MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 12/55 2/28 78.77 0.15 [0.00, 0.29] Quinn 2005 7/10 5/10 21.23 0.20 [-0.22, 0.62] Subtotal (95% CI) 65 38 100.00 0.16 [0.01, 0.30]Total events: 19 (infliximab+MTX), 7 (placebo/MTX)Test for heterogeneity: chi²=0.06, df=1 (P=0.80), I²=0%Test for overall effect: Z=2.14 (P=0.03)

MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 17/57 2/28 100.00 0.23 [0.07, 0.38] Subtotal (95% CI) 57 28 100.00 0.23 [0.07, 0.38]Total events: 17 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.92 (P=0.004)


MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 11/55 2/28 100.00 0.13 [-0.01, 0.27] Subtotal (95% CI) 55 28 100.00 0.13 [-0.01, 0.27]Total events: 11 (infliximab+MTX), 2 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.77 (P=0.08)

-1 -0.5 0 0.5 1



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RR=relative benefit



MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 6/55 1/28 20.95 3.05 [0.39, 24.15] Quinn 2005 5/10 5/10 79.05 1.00 [0.42, 2.40] Subtotal (95% CI) 65 38 100.00 1.43 [0.61, 3.37]Total events: 11 (infliximab+MTX), 6 (placebo/MTX)Test for heterogeneity: chi²=1.16, df=1 (P=0.28), I²=13.6%Test for overall effect: Z=0.82 (P=0.41) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 12/57 1/28 100.00 5.89 [0.81, 43.09] Subtotal (95% CI) 57 28 100.00 5.89 [0.81, 43.09]Total events: 12 (infliximab+MTX), 1 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=1.75 (P=0.08) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 13/64 1/28 100.00 5.69 [0.78, 41.39] Subtotal (95% CI) 64 28 100.00 5.69 [0.78, 41.39]Total events: 13 (infliximab+MTX), 1 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=1.72 (P=0.09) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 6/55 1/28 100.00 3.05 [0.39, 24.15] Subtotal (95% CI) 55 28 100.00 3.05 [0.39, 24.15]Total events: 6 (infliximab/MTX), 1 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=1.06 (P=0.29)

0.001 0.01 0.1 1 10 100 1000



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MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 6/55 1/28 78.77 0.07 [-0.03, 0.18] Quinn 2005 5/10 5/10 21.23 0.00 [-0.44, 0.44] Subtotal (95% CI) 65 38 100.00 0.06 [-0.07, 0.18]Total events: 11 (infliximab+MTX), 6 (placebo/MTX)Test for heterogeneity: chi²=0.15, df=1 (P=0.70), I²=0%Test for overall effect: Z=0.90 (P=0.37)



MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT (continuation) 6/55 1/28 100.00 0.07 [-0.03, 0.18] Subtotal (95% CI) 55 28 100.00 0.07 [-0.03, 0.18]Total events: 6 (infliximab+MTX), 1 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.34 (P=0.18)

-1 -0.5 0 0.5 1



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Table 3: IFX RCTs — DAS28 responses

Baseline 54 weeks 104 weeks Responders 54 weeks % Response Study and Intervention

N Mean Mean Mean change from baseline Mean Mean change

from baseline None Moderate Good ASPIRE 54 weeks43 Control: MTX IFX 3 mg/kg q8wk+MTX IFX 6 mg/kg q8wk+MTX

274 351 355

6.7 6.6 6.7

4.6 4.0 3.7

−2.1 −2.6* −3.0*

– – –

– – –

% remission 42 (15%)

76 (21.2%) 31 (31%)

Taylor 54 weeks44† Control: MTX IFX 5 mg/kg q8wk+MTX

12 12

5.2 5.4

4.9 3.1

−0.3 −2.3

6 (54.5%) 3 (25%)

3 (27.3%) 6 (50%)

2 (18.2%) 3 (25%)

Quinn 54 weeks45† Control: MTX IFX 3 mg/kg q8wk+MTX

10 10

7.0 6.3

4.6

2.8*

−2.4

−4.5*

3.4 2.5

−3.6 −3.8

POOLED 3 mg/kg q8wk+MTX WMD (random) – – −1.26 (−2.82, 0.31) SMD (random) – – −1.19 (−3.14, 0.76)

POOLED 5mg/kg to 6 mg/kg q8wk+MTX WMD (random) – – −1.37 (−2.43, −0.30)* SMD (random) – – −1.03 (−2.25, 0.18)

*statistically significant; †median


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Figure 9: IFX RCTs – DAS28 at 54 weeks; weighted mean difference (fixed effects)

WMD=weighted mean difference

Figure 10: IFX RCTs – DAS28 at 54 weeks; weighted mean difference (random effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: DAS28

Study Infliximab/MTX Placebo/MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO)ASPIRE 351 -2.60(1.80) 274 -2.10(1.80) 88.12 -0.50 [-0.78, -0.22] Quinn 2005 10 -4.50(0.75) 10 -2.40(1.00) 11.88 -2.10 [-2.87, -1.33]

Subtotal (95% CI) 361 284 100.00 -0.69 [-0.96, -0.42]Test for heterogeneity: chi²=14.44, df=1 (P=0.0001), I²=93.1%Test for overall effect: Z=5.07 (P<0.00001)

MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO)ASPIRE 355 -3.00(1.80) 274 -2.10(1.80) 90.59 -0.90 [-1.18, -0.62] Taylor 2004 12 -2.30(1.10) 12 -0.30(1.10) 9.41 -2.00 [-2.88, -1.12]


-4 -2 0 2 4

Favours treatment Favours control

Review: infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: DAS28

Study Infliximab/MTX Placebo/MTX WMD (random) Weight WMD (random)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI


Subtotal (95% CI) 361 284 100.00 -1.26 [-2.82, 0.31]Test for heterogeneity: chi²=14.44, df=1 (P=0.0001), I²=93.1%Test for overall effect: Z=1.57 (P=0.12)


Subtotal (95% CI) 367 286 100.00 -1.37 [-2.43, -0.30]Test for heterogeneity: chi²=5.44, df=1 (P=0.02), I²=81.6%Test for overall effect: Z=2.52 (P=0.01)

-4 -2 0 2 4



A-69

Figure 11: IFX RCTs – DAS28 at 54 weeks; standardized mean difference (fixed effects)

SMD=standardized mean difference

Figure 12: IFX RCTs – DAS28 at 54 weeks; standardized mean difference (random effects)



Study Infliximab/MTX Placebo/MTX SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI





-4 -2 0 2 4



Study Infliximab/MTX Placebo/MTX SMD (random) Weight SMD (random)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI





-4 -2 0 2 4



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Table 4: IFX RCTs — functional status (HAQ and SF-36) HAQ SF-36

Baseline % change Mean change from baseline Study and Intervention N Baseline % change Mean change

from baseline Mental Physical Mental Physical Mental Physical 1 year

ATTRACT 54 weeks41 Control -MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

88 86 86 87 81

1.7 1.8 1.7 1.7 1.7

10% 18%

29%* 33%* 32%*

0.17 0.32

0.49* 0.56* 0.54*

47 46 48 48 47

27 27 25 26 27

8%

10% 9%

10% 9%

18% 27% 49% 52% 40%

3.8 4.6 4.3 4.8 4.2

4.9 7.3

12.2* 13.5* 10.8*

ASPIRE 54 weeks43 Control -MTX IFX 3 mg/kg q8wk+MTX IFX 6 mg/kg q8wk+MTX

282 359 363

1.5 1.5 1.5

% pts who improved

65% 76% 76%

0.68

0.80* 0.88*

44.7 45.4 44.2

29.5 28.8 29.3

- - -

- - -

- - -

10.1 11.7 13.2

Quinn 54 weeks45† Control -MTX IFX 3 mg/kg q8wk+MTX

10 10

1.3 1.3

(median) 18% 82%

0.23 1.0*

POOLED 3 mg/kg q8wk+MTX

WMD (fixed) 455 - - 0.13 (0.05, 0.22)* 1.77 (0.19, 3.36)*

SMD (fixed) 455 - - 0.21 (0.08, 0.35)* 0.15 (0.02, 0.29)*

2 years

ATTRACT 102 weeks42 Control -MTX IFX 3 mg/kg q8w+MTX IFX 3 mg/kg q4w+MTX IFX 10 mg/kg q8w+MTX IFX 10 mg/kg q4w+MTX

88 86 86 87 81

1.7 1.8 1.7 1.7 1.7

5% 22% 23% 18% 23%

0.1 0.4 0.4 0.3 0.4

48.5 46.8 49.9 47.6 47.9

25.7 25.2 23.9 25.7 25.8

- - - - -

- - - - -

1.9 3.8 2.2 2.9 3.7

2.8 4.6 6.8 6.9 6.7

Quinn 104 weeks45† Control -MTX IFX 3 mg/kg q8w+MTX

10 10

1.3 1.3

(median) 22% 89%

0.28 1.1*

POOLED 3 mg/kg q8w+MTX

WMD (fixed) 96 - - 0.32 (0.15, 0.50)* SMD (fixed) 96 - - 0.53 (0.25, 0.82)*

*statistically significant; †for pooling, median assumed equal to mean.


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Figure 13: IFX RCTs – HAQ at 54 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX) Outcome: mean change in HAQ Study Infliximab/MTX Placebo/MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Infliximab 3 mg/kg q8 weeks ATTRACT 86 0.32(0.60) 88 0.17(0.60) 23.52 0.15 [-0.03, 0.33] ASPIRE 359 0.80(0.65) 282 0.68(0.63) 75.33 0.12 [0.02, 0.22] Quinn 2005 10 1.00(0.87) 10 0.23(0.97) 1.15 0.77 [-0.04, 1.58]

Subtotal (95% CI) 455 380 100.00 0.13 [0.05, 0.22]Test for heterogeneity: chi²=2.49, df=2 (P=0.29), I²=19.7%Test for overall effect: Z=3.05 (P=0.002) Infliximab 3 mg/kg q4 weeks

ATTRACT 86 0.49(0.60) 88 0.17(0.60) 100.00 0.32 [0.14, 0.50] Subtotal (95% CI) 86 88 100.00 0.32 [0.14, 0.50]Test for heterogeneity: not applicableTest for overall effect: Z=3.52 (P=0.0004) Infliximab 10 mg/kg q8 weeks

ATTRACT 87 0.56(0.60) 88 0.17(0.60) 100.00 0.39 [0.21, 0.57] Subtotal (95% CI) 87 88 100.00 0.39 [0.21, 0.57]Test for heterogeneity: not applicableTest for overall effect: Z=4.30 (P<0.0001) Infliximab 10 mg/kg q4 weeks

ATTRACT 81 0.54(0.60) 88 0.17(0.60) 100.00 0.37 [0.19, 0.55] Subtotal (95% CI) 81 88 100.00 0.37 [0.19, 0.55]Test for heterogeneity: not applicableTest for overall effect: Z=4.00 (P<0.0001) Infliximab 6 mg/kg q8 weeks

ASPIRE 363 0.88(0.65) 282 0.68(0.63) 100.00 0.20 [0.10, 0.30] Subtotal (95% CI) 363 282 100.00 0.20 [0.10, 0.30]Test for heterogeneity: not applicableTest for overall effect: Z=3.94 (P<0.0001)

-4 -2 0 2 4



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Figure 14: IFX RCTs – HAQ at 54 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX) Outcome: mean change in HAQ Study Infliximab/MTX Placebo/MTX SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Infliximab 3mg/kg q8 weeksATTRACT 86 0.32(0.60) 88 0.17(0.60) 21.05 0.25 [-0.05, 0.55] ASPIRE 359 0.80(0.65) 282 0.68(0.63) 76.73 0.19 [0.03, 0.34] Quinn 2005 10 1.00(0.87) 10 0.23(0.97) 2.22 0.80 [-0.12, 1.72]

Subtotal (95% CI) 455 380 100.00 0.21 [0.08, 0.35]Test for heterogeneity: chi²=1.73, df=2 (P=0.42), I²=0%Test for overall effect: Z=3.06 (P=0.002)

Infliximab 3 mg/kg q4 weeks ATTRACT 86 0.49(0.60) 88 0.17(0.60) 100.00 0.53 [0.23, 0.83]

Subtotal (95% CI) 86 88 100.00 0.53 [0.23, 0.83]Test for heterogeneity: not applicableTest for overall effect: Z=3.44 (P=0.0006)


Subtotal (95% CI) 87 88 100.00 0.65 [0.34, 0.95]Test for heterogeneity: not applicableTest for overall effect: Z=4.17 (P<0.0001)



Infliximab 6 mg/kg q8 weeks ASPIRE 363 0.88(0.65) 282 0.68(0.63) 100.00 0.31 [0.15, 0.47]


-4 -2 0 2 4



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Figure 15: IFX RCTs – HAQ at 102 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritisComparison: efficacy at 102 weeks (infliximab/MTX versus placebo/MTX) Outcome: mean change in HAQ


Infliximab 3 mg/kg q8 weeks ATTRACT (continuation) 86 0.40(0.60) 88 0.10(0.60) 95.35 0.30 [0.12, 0.48] Quinn 2005 10 1.10(0.87) 10 0.28(0.97) 4.65 0.82 [0.01, 1.63]

Subtotal (95% CI) 96 98 100.00 0.32 [0.15, 0.50]Test for heterogeneity: chi²=1.52, df=1 (P=0.22), I²=34.2%Test for overall effect: Z=3.65 (P=0.0003)

Infliximab 3 mg/kg q4 weeks ATTRACT (continuation) 86 0.40(0.60) 88 0.10(0.60) 100.00 0.30 [0.12, 0.48]






-4 -2 0 2 4



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Figure 16: IFX RCTs – HAQ at 102 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 102 weeks (infliximab/MTX versus placebo/MTX) Outcome: mean change in HAQ


Infliximab 3 mg/kg q8 weeks ATTRACT (continuation) 86 0.40(0.60) 88 0.10(0.60) 90.37 0.50 [0.20, 0.80] Quinn 2005 10 1.10(0.87) 10 0.28(0.97) 9.63 0.85 [-0.07, 1.78]








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Figure 17: IFX RCTs – SF-36 (physical component summary at 54 weeks; weighted mean difference (fixed effects)


Figure 18: IFX RCTs – SF-36 (physical component) at 102 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX)Outcome: SF-36 (mean change) physical component

Study Treatment Control WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Infliximab 3 mg/kg q8 weeks ATTRACT 86 7.30(11.00) 88 4.90(12.00) 21.54 2.40 [-1.02, 5.82] ASPIRE 359 11.70(11.60) 282 10.10(11.40) 78.46 1.60 [-0.19, 3.39]




-10 -5 0 5 10


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab/MTX versus placebo/MTX)Outcome: SF-36 (mean change) physical component

Study Treatment Control SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Infliximab 3mg/kg q8 weeksATTRACT 86 7.30(11.00) 88 4.90(12.00) 21.54 0.21 [-0.09, 0.51] ASPIRE 359 11.70(11.60) 282 10.10(11.40) 78.46 0.14 [-0.02, 0.29]




-1 -0.5 0 0.5 1



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Table 5: IFX RCTs — radiological outcomes Total Score Erosion Joint Space Narrowing

Study and Intervention N Baseline Mean change from baseline

Baseline Mean change from baseline


Other Radiological outcome

1 year

ATTRACT 54 weeks41 Control - MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

64 71 71 77 66

82 79 71 67 76

7

1.3* 1.6* 0.2* −0.7*

- - - - -

4

0.2* 0.3* 0.2* −0.7*

- - - - -

2.9 1.1* 0.7* 0* 0*

Major progression 20 (31%) 6 (8%) 9 (13%) 1 (1%) 0 (0%)

Improvement 9 (14%) 31 (44%) 34 (48%) 30 (39%) 36 (55%)

ASPIRE 54 weeks43 Control - MTX IFX 3 mg/kg q8wk+MTX IFX 6 mg/kg q8wk+MTX

282 359 363

11.3 11.6 11.2

3.7 0.4* 0.5*

8.25 8.75 8.27

3.0 0.3* 0.1*

3.0 2.9 2.9

0.6 0.1* 0.2

31 (11.0%)

14 (4%) 7 (2%)

- - -

Taylor 54 weeks44 Control - MTX IFX 5 mg/kg q8wk+MTX

12 12

7.1 9.0

12.2 3.3

- -

- -

- -

- -

Quinn 54 weeks45 Control - MTX IFX 3 mg/kg q8wk+MTX

10 10

- -

- -

- -

- -

- -

- -

(MRI erosive sites)

24 15

3 mg/kg q8wk+MTX versus MTX POOLED WMD −3.69 (−4.85, −2.53)* −2.93 (−3.85, −2.00)* −0.55 (−0.84, −0.26)* - - POOLED SMD −0.47 (−0.61, −0.33)* −0.46 (−0.61, −0.32)* −0.30 (−0.44, −0.15)* - -

POOLED RR - - - 0.32 (0.20, 0.53)*

-

5 mg/kg to 6 mg/kg q8wk + MTX versus MTX

POOLED WMD -3.44 (-4.67, -2.20)* - - - - POOLED SMD -0.44 (-0.60, -0.29)* - - - - POOLED RR - - - - -

*statistically significant


A-77

Total Score† Erosion† Joint Space Narrowing†

Study and Intervention N† Baseline Mean change from baseline



2 years ATTRACT 102 weeks42 Control - MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

50 to 51 58 to 59 66 to 70 69 to 71 66 to 68

82 79 71 67 76

12.59 1.02* 1.03* 1.14* −0.42*

- - - - -

6.65 0.25* 0.50* 0.43* -0.57*

- - - - -

5.91 0.77 0.10 0.63 0.17

Quinn 54 weeks45 Control - MTX IFX 3 mg/kg q8wk+MTX

10 10

- -

10 12

- -

(number of erosive sites)

24 15

- -

- -

*statistically significant; †different sample sizes used for each outcome.


A-78

Figure 19: IFX RCTs – total radiographic score at 54 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: total radiographic score (0 to 440); increase or decrease from baseline

Study Infliximab+MTX Placebo/MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO)ATTRACT 71 1.30(6.00) 64 7.00(10.30) 16.27 -5.70 [-8.58, -2.82] ASPIRE 359 0.40(5.80) 282 3.70(9.60) 83.73 -3.30 [-4.57, -2.03]


MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO)ATTRACT 71 1.60(8.50) 64 7.00(10.30) 100.00 -5.40 [-8.61, -2.19]

Subtotal (95% CI) 71 64 100.00 -5.40 [-8.61, -2.19]Test for heterogeneity: not applicableTest for overall effect: Z=3.30 (P=0.0010) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO)

ATTRACT 77 0.20(3.60) 64 7.00(10.30) 100.00 -6.80 [-9.45, -4.15] Subtotal (95% CI) 77 64 100.00 -6.80 [-9.45, -4.15]Test for heterogeneity: not applicableTest for overall effect: Z=5.03 (P<0.00001)

MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO)ATTRACT 66 -0.70(3.80) 64 7.00(10.30) 100.00 -7.70 [-10.38, -5.02]

Subtotal (95% CI) 66 64 100.00 -7.70 [-10.38, -5.02]Test for heterogeneity: not applicableTest for overall effect: Z=5.62 (P<0.00001)

MTX and inflixamb 5 to 6mg/kg q8 weeks versus MTX(PBO)ASPIRE 363 0.50(5.60) 282 3.70(9.60) 95.87 -3.20 [-4.46, -1.94] Taylor 2004 12 3.30(3.60) 12 12.20(10.10) 4.13 -8.90 [-14.97, -2.83]


-100 -50 0 50 100



A-79

Figure 20: IFX RCTs – total radiographic score at 54 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: total radiographic score (0 to 440); increase or decrease from baseline






ATTRACT 77 0.20(3.60) 64 7.00(10.30) 100.00 -0.91 [-1.26, -0.56] Subtotal (95% CI) 77 64 100.00 -0.91 [-1.26, -0.56]Test for heterogeneity: not applicableTest for overall effect: Z=5.12 (P<0.00001)

MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO)ATTRACT 66 -0.70(3.80) 64 7.00(10.30) 100.00 -0.99 [-1.36, -0.63]


MTX and inflixamb 5 to 6mg/kg q8 weeks versus MTX(PBO)ASPIRE 363 0.50(5.60) 282 3.70(9.60) 96.86 -0.42 [-0.58, -0.26] Taylor 2004 12 3.30(3.60) 12 12.20(10.10) 3.14 -1.13 [-2.01, -0.26]


-4 -2 0 2 4



A-80

Figure 21: IFX RCTs – score at 54 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: erosion score; increase or decrease from baseline



Subtotal (95% CI) 430 346 100.00 -2.93 [-3.85, -2.00]Test for heterogeneity: chi²=0.88, df=1 (P=0.35), I²=0%Test for overall effect: Z=6.17 (P<0.00001)



ATTRACT 77 0.20(2.90) 64 4.00(7.90) 100.00 -3.80 [-5.84, -1.76] Subtotal (95% CI) 77 64 100.00 -3.80 [-5.84, -1.76]Test for heterogeneity: not applicableTest for overall effect: Z=3.65 (P=0.0003) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO)

ATTRACT 66 -0.70(3.00) 64 4.00(7.90) 100.00 -4.70 [-6.77, -2.63] Subtotal (95% CI) 66 64 100.00 -4.70 [-6.77, -2.63]Test for heterogeneity: not applicableTest for overall effect: Z=4.46 (P<0.00001)

-10 -5 0 5 10



A-81

Figure 22: IFX RCTs – erosion score at 54 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: erosion Score; increase or decrease from baseline

Study Infliximab+MTX Placebo/MTX SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI




Subtotal (95% CI) 71 64 100.00 -0.57 [-0.92, -0.23]Test for heterogeneity: not applicableTest for overall effect: Z=3.26 (P=0.001)

MTX and iInfliximab 10 mg/kg q8 weeks versus MTX(PBO)ATTRACT 77 0.20(2.90) 64 4.00(7.90) 100.00 -0.66 [-1.00, -0.32]


MTX and infliximab 10 mg/kg q 4 weeks versus MTX(PBO)ATTRACT 66 -0.70(3.00) 64 4.00(7.90) 100.00 -0.79 [-1.14, -0.43]


-4 -2 0 2 4



A-82

Figure 23: IFX RCTs – joint space narrowing score at 54 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: joint space narrowing score; increase or decrease from baseline

Study Infliximab+MTX Placebo/MTX WMD (fixed) Weight WMD (fixed)or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI









-10 -5 0 5 10



A-83




Subtotal (95% CI) 430 346 100.00 -0.30 [-0.44, -0.15]Test for heterogeneity: chi²=0.56, df=1 (P=0.45), I²=0%Test for overall effect: Z=4.09 (P<0.0001)







-4 -2 0 2 4


Figure 24: IFX RCTs – joint space narrowing score at 54 weeks; standardized mean difference (fixed effects)



A-84

Figure 25: IFX RCTs – major radiographic progression at 54 weeks; relative benefit (fixed effects)

RR=relative benefit

Review: infliximab for rheumatoid arthritisComparison: efficacy at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: major radiographic progression

Study Infliximab+MTX Placebo/MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/71 20/64 37.73 0.27 [0.12, 0.63] ASPIRE 14/359 31/282 62.27 0.35 [0.19, 0.65] Subtotal (95% CI) 430 346 100.00 0.32 [0.20, 0.53]Total events: 20 (infliximab/MTX), 51 (placebo/MTX)Test for heterogeneity: chi²=0.26, df=1 (P=0.61), I²=0%Test for overall effect: Z=4.48 (P<0.00001) MTX and infliximab 3 mg/kg q4 weeks versus MTX ATTRACT 9/71 20/64 100.00 0.41 [0.20, 0.83] Subtotal (95% CI) 71 64 100.00 0.41 [0.20, 0.83]Total events: 9 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.49 (P=0.01) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 1/77 20/64 100.00 0.04 [0.01, 0.30] Subtotal (95% CI) 77 64 100.00 0.04 [0.01, 0.30]Total events: 1 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.15 (P=0.002) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 0/66 20/64 100.00 0.02 [0.00, 0.38] Subtotal (95% CI) 66 64 100.00 0.02 [0.00, 0.38]Total events: 0 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.64 (P=0.008) MTX and infliximab 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 7/363 31/282 100.00 0.18 [0.08, 0.39] Subtotal (95% CI) 363 282 100.00 0.18 [0.08, 0.39]Total events: 7 (infliximab/MTX), 31 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.24 (P<0.0001)

0.001 0.01 0.1 1 10 100 1000



A-85

Figure 26: IFX RCTs – major radiographic progression at 54 weeks; relative benefit (random effects)

RR=relative benefit


Study Infliximab+MTX Placebo/MTX RR (random) Weight RR (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/71 20/64 44.33 0.27 [0.12, 0.63] ASPIRE 14/359 31/282 55.67 0.35 [0.19, 0.65] Subtotal (95% CI) 430 346 100.00 0.32 [0.20, 0.53]Total events: 20 (infliximab/MTX), 51 (placebo/MTX)Test for heterogeneity: chi²=0.26, df=1 (P=0.61), I²=0%Test for overall effect: Z=4.46 (P<0.00001)

MTX and infliximab 3 mg/kg q4 weeks versus MTX ATTRACT 9/71 20/64 100.00 0.41 [0.20, 0.83] Subtotal (95% CI) 71 64 100.00 0.41 [0.20, 0.83]Total events: 9 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.49 (P=0.01)

MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 1/77 20/64 100.00 0.04 [0.01, 0.30] Subtotal (95% CI) 77 64 100.00 0.04 [0.01, 0.30]Total events: 1 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.15 (P=0.002)

MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 0/66 20/64 100.00 0.02 [0.00, 0.38] Subtotal (95% CI) 66 64 100.00 0.02 [0.00, 0.38]Total events: 0 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.64 (P=0.008)

MTX and infliximab 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 7/363 31/282 100.00 0.18 [0.08, 0.39] Subtotal (95% CI) 363 282 100.00 0.18 [0.08, 0.39]Total events: 7 (infliximab/MTX), 31 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.24 (P<0.0001)

0.001 0.01 0.1 1 10 100 1000



A-86

Figure 27: IFX RCTs – major radiographic progression at 54 weeks; benefit difference (fixed effects)



Study Infliximab+MTX Placebo/MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/71 20/64 17.57 -0.23 [-0.36, -0.10] ASPIRE 14/359 31/282 82.43 -0.07 [-0.11, -0.03] Subtotal (95% CI) 430 346 100.00 -0.10 [-0.14, -0.06]Total events: 20 (infliximab/MTX), 51 (placebo/MTX)Test for heterogeneity: chi²=5.46, df=1 (P=0.02), I²= 81.7%Test for overall effect: Z=4.68 (P<0.00001)

MTX and infliximab 3 mg/kg q4 weeks versus MTX ATTRACT 9/71 20/64 100.00 -0.19 [-0.32, -0.05] Subtotal (95% CI) 71 64 100.00 -0.19 [-0.32, -0.05]Total events: 9 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.65 (P=0.008)

MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 1/77 20/64 100.00 -0.30 [-0.42, -0.18] Subtotal (95% CI) 77 64 100.00 -0.30 [-0.42, -0.18]Total events: 1 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.05 (P<0.00001)

MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 0/66 20/64 100.00 -0.31 [-0.43, -0.20] Subtotal (95% CI) 66 64 100.00 -0.31 [-0.43, -0.20]Total events: 0 (infliximab/MTX), 20 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.33 (P<0.00001)

MTX and infliximab 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 7/363 31/282 100.00 -0.09 [-0.13, -0.05] Subtotal (95% CI) 363 282 100.00 -0.09 [-0.13, -0.05]Total events: 7 (infliximab/MTX), 31 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.54 (P<0.00001)

-0.5 -0.25 0 0.25 0.5



A-87

Figure 28: IFX RCTs – major radiographic progression at 54 weeks; benefit difference (random effects)



Study Infliximab+MTX Placebo/MTX RD (random) Weight RD (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/71 20/64 39.96 -0.23 [-0.36, -0.10] ASPIRE 14/359 31/282 60.04 -0.07 [-0.11, -0.03] Subtotal (95% CI) 430 346 100.00 -0.14 [-0.30, 0.02]Total events: 20 (infliximab+MTX), 51 (placebo/MTX)Test for heterogeneity: chi²=5.46, df=1 (P=0.02), I²=81.7%Test for overall effect: Z=1.70 (P=0.09) MTX and infliximab 3 mg/kg q4 weeks versus MTX ATTRACT 9/71 20/64 100.00 -0.19 [-0.32, -0.05] Subtotal (95% CI) 71 64 100.00 -0.19 [-0.32, -0.05]Total events: 9 (infliximab+MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.65 (P=0.008) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 1/77 20/64 100.00 -0.30 [-0.42, -0.18] Subtotal (95% CI) 77 64 100.00 -0.30 [-0.42, -0.18]Total events: 1 (infliximab+MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.05 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 0/66 20/64 100.00 -0.31 [-0.43, -0.20] Subtotal (95% CI) 66 64 100.00 -0.31 [-0.43, -0.20]Total events: 0 (infliximab+MTX), 20 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.33 (P<0.00001) MTX and infliximab 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 7/363 31/282 100.00 -0.09 [-0.13, -0.05] Subtotal (95% CI) 363 282 100.00 -0.09 [-0.13, -0.05]Total events: 7 (infliximab+MTX), 31 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.54 (P<0.00001)

-1 -0.5 0 0.5 1



A-88

Review: infliximab for rheumatoid arthritisComparison: efficacy at 102 weeks (infliximab+MTX versus placebo/MTX) Outcome: total radiographic score (0 to 440)

Study Infliximab+MTX MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO)ATTRACT (continuation) 58 1.02(7.13) 50 12.59(20.05) 100.00 -11.57 [-17.42, -5.72]






MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO)ATTRACT (continuation) 66 -0.42(6.10) 50 12.59(20.05) 100.00 -13.01 [-18.76, -7.26]


-100 -50 0 50 100


Figure 29: IFX RCTs – total radiographic score at 102 weeks; weighted mean difference (fixed effects)



A-89

Figure 30: IFX RCTs – total radiographic score at 102 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 102 weeks (infliximab+MTX versus placebo/MTX) Outcome: total radiographic score (0 to 440)

Study Infliximab+MTX MTX SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI









-4 -2 0 2 4



A-90

Figure 31: IFX RCTs – erosion score at 102 weeks; weighted mean difference (fixed effects)


Review: infliximab for rheumatoid arthritis Comparison: efficacy at 102 weeks (infliximab+MTX versus placebo/MTX) Outcome: erosion score; increase or decrease from baseline




ATTRACT (continuation) 70 0.50(9.05) 51 6.65(11.20) 100.00 -6.15 [-9.88, -2.42] Subtotal (95% CI) 70 51 100.00 -6.15 [-9.88, -2.42]Test for heterogeneity: not applicableTest for overall effect: Z=3.23 (P=0.001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO)

ATTRACT (continuation) 71 0.43(2.61) 51 6.65(11.20) 100.00 -6.22 [-9.35, -3.09] Subtotal (95% CI) 71 51 100.00 -6.22 [-9.35, -3.09]Test for heterogeneity: not applicableTest for overall effect: Z=3.89 (P<0.0001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO)

ATTRACT (continuation) 68 -0.57(3.85) 51 6.65(11.20) 100.00 -7.22 [-10.43, -4.01] Subtotal (95% CI) 68 51 100.00 -7.22 [-10.43, -4.01]Test for heterogeneity: not applicableTest for overall effect: Z=4.41 (P<0.0001)

-100 -50 0 50 100



A-91

Figure 32: IFX RCTs – erosion score at 102 weeks; standardized mean difference (fixed effects)


Review: infliximab for rheumatoid arthritisComparison: efficacy at 102 weeks (infliximab+MTX versus placebo/MTX) Outcome: erosion score; increase or decrease from baseline










-4 -2 0 2 4



A-92

Figure 33: IFX RCTs – joint space narrowing score at 102 weeks; weighted mean difference (fixed effects)








ATTRACT (continuation) 66 0.17(3.60) 50 5.91(10.59) 100.00 -5.74 [-8.80, -2.68] Subtotal (95% CI) 66 50 100.00 -5.74 [-8.80, -2.68]Test for heterogeneity: not applicableTest for overall effect: Z=3.68 (P=0.0002)

-10 -5 0 5 10



A-93

Figure 34: IFX RCTs – joint space narrowing score at 102 weeks; standardized mean difference (fixed effects)








ATTRACT (continuation) 66 0.17(3.60) 50 5.91(10.59) 100.00 -0.76 [-1.15, -0.38] Subtotal (95% CI) 66 50 100.00 -0.76 [-1.15, -0.38]Test for heterogeneity: not applicableTest for overall effect: Z=3.94 (P<0.0001)

-4 -2 0 2 4



A-94

Table 6: IFX RCTs — drug discontinuations Drug Discontinuations

Study and Intervention N All RR

(versus control)

Lack of efficacy

RR (versus control)

Toxicity RR

(versus control)

Other RR (versus control)

1 year ATTRACT Lipsky 54 weeks41 control - MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

88 86 86 87 81

44 (50%) 23 (27%) 20 (23%) 12 (15%) 16 (20%)

referent

0.53 (0.36, 0.80)*0.47 (0.30, 0.72)*0.28 (0.16, 0.49)*0.40 (0.24, 0.64)*

32 (36%) 17 (20%) 10 (12%) 6 (7%) 7 (9%)

referent

0.54 (0.33, 0.90)*0.32 (0.25, 0.58)*0.19 (0.08, 0.43)*0.24 (0.11, 0.51)*

7 (8%) 5 (6%) 9 (10%) 4 (5%) 8 (10%)

referent

0.73 (0.24, 2.21)1.32 (0.51, 3.37)0.58 (0.18, 1.90)1.24 (0.47, 3.27)

5 (8%) 1 (1%) 1 (1%) 2 (3%) 1 (1%)

referent

0.20 (0.02, 1.72) 1.20 (0.02, 1.72) 0.40 (0.08, 2.03) 0.22 (0.03, 1.82)

ASPIRE 54 weeks43 control - MTX IFX 3 mg/kg q8wk+MTX IFX 6 mg/kg q8wk+MTX

282 359 363

60 (21%) 66 (18%) 75 (21%)

referent

0.86 (0.63, 1.18) 0.97 (0.72, 1.31)

27 (10%) 7 (2%) 12 (3%)

referent

0.20 (0.09, 0.46)*1.35 (0.18, 0.67)*

9 (3%) 34 (9%)

35 (10%)

referent

2.97 (1.45, 6.08)*3.02 (1.48, 6.18)*

24 (9%) 25 (7%) 28 (8%)

referent

0.82 (0.48, 1.40) 1.91 (0.54, 1.53)

Taylor 54 weeks44 control - MTX IFX 5 mg/kg q8wk+MTX

12 12

0

1 (8%)

referent

3.00(0.13, 67.06)

0

1 (8%)

referent

3.00(0.13, 67.06)

0 0

referent

not estimable

0 0

referent

not estimable

Quinn 54 weeks45 control + MTX IFX 3 mg/kg q8wk+MTX

10 10

0

1 (10%)

referent

3.00(0.14, 65.90)

0 0

referent

not estimable

0

1(10%)

referent

3.00(0.14, 65.90)

0 0

referent

not estimable

POOLED 3 mg/kg q8wk+MTX 0.74(0.58, 0.95)* 0.38(0.25, 0.58)* 2.08(1.18, 3.68)* 0.72(0.43, 1.21)

POOLED 5 mg/kg to 6 mg/kg q8wk+MTX 0.99(0.73, 1.33) 0.39(0.21, 0.73)* 0.91(0.54,1.53)

RR=relative risk, RR<1.0=lowered discontinuation rate when IFX compared to controls; *statistically significant.


A-95

Drug Discontinuations Study and Intervention N All RR

(versus control) Lack of

efficacy† RR

(versus control)

Toxicity† RR (versus control) Other**

RR (versus control)

2 years ATTRACT 102 weeks42** control - MTX IFX 3 mg/kg q8wk+MTX IFX 3 mg/kg q4wk+MTX IFX 10 mg/kg q8wk+MTX IFX 10 mg/kg q4wk+MTX

88 86 86 87 81

58 (66%) 32 (37%) 30 (35%) 17 (20%) 22 (27%)

-

0.56 (0.41, 0.77)* 0.53 (0.38, 0.73)* 0.30 (0.19, 0.47)* 0.41 (0.28, 0.61)*

- - - - -

- - - - -

- - - - -

Quinn 54 weeks45 Control + MTX IFX 3 mg/kg q8w+MTX

10 10

0

1 (10%)

referent

3.00 (0.14, 65.90)

0 0

referent

not estimable

0

1 (10%)

referent

3.00 (0.14, 65.90)

0 0

referent

not estimable POOLED 3 mg/kg q8wk+MTX MTX 0.59 (0.43, 0.80)*

RR=relative risk; RR<1.0=lowered discontinuation rate when IFX compared to controls; *statistically significant; †discontinuations are sum of years 1 and 2, obtained from both ATTRACT publications.


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Figure 35: IFX RCTs – drug discontinuation (total) at 54 weeks; relative risk (fixed effects)

RR=relative risk

Review: infliximab for rheumatoid arthritis Comparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX)Outcome: total withdrawals


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 23/86 44/88 39.11 0.53 [0.36, 0.80] ASPIRE 66/359 60/282 60.44 0.86 [0.63, 1.18] Quinn 2005 1/10 0/10 0.45 3.00 [0.14, 65.90] Subtotal (95% CI) 455 380 100.00 0.74 [0.58, 0.95]Total events: 90 (infliximab/MTX), 104 (placebo/MTX)Test for heterogeneity: chi²=4.18, df=2 (P=0.12), I²=52.2%Test for overall effect: Z=2.35 (P=0.02) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 20/86 44/88 100.00 0.47 [0.30, 0.72] Subtotal (95% CI) 86 88 100.00 0.47 [0.30, 0.72]Total events: 20 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.43 (P=0.0006) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 12/87 44/88 100.00 0.28 [0.16, 0.49] Subtotal (95% CI) 87 88 100.00 0.28 [0.16, 0.49]Total events: 12 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.46 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 16/81 44/88 100.00 0.40 [0.24, 0.64] Subtotal (95% CI) 81 88 100.00 0.40 [0.24, 0.64]Total events: 16 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.74 (P=0.0002) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 75/363 60/282 99.27 0.97 [0.72, 1.31] Taylor 2004 1/12 0/12 0.73 3.00 [0.13, 67.06] Subtotal (95% CI) 375 294 100.00 0.99 [0.73, 1.33]Total events: 76 (infliximab/MTX), 60 (placebo/MTX)Test for heterogeneity: chi²=0.50, df=1 (P=0.48), I²=0%Test for overall effect: Z=0.09 (P=0.93)

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A-97

Figure 36: IFX RCTs – drug discontinuation (total) at 54 weeks; relative risk (random effects)

RR=relative risk

Review: infliximab for rheumatoid arthritisComparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: total withdrawals


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 23/86 44/88 46.06 0.53 [0.36, 0.80] ASPIRE 66/359 60/282 50.26 0.86 [0.63, 1.18] Quinn 2005 1/10 0/10 3.68 3.00 [0.14, 65.90] Subtotal (95% CI) 455 380 100.00 0.71 [0.46, 1.12]Total events: 90 (infliximab/MTX), 104 (placebo/MTX)Test for heterogeneity: chi²=4.18, df=2 (P=0.12), I²=52.2%Test for overall effect: Z=1.47 (P=0.14) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 20/86 44/88 100.00 0.47 [0.30, 0.72] Subtotal (95% CI) 86 88 100.00 0.47 [0.30, 0.72]Total events: 20 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.43 (P=0.0006) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 12/87 44/88 100.00 0.28 [0.16, 0.49] Subtotal (95% CI) 87 88 100.00 0.28 [0.16, 0.49]Total events: 12 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.46 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 16/81 44/88 100.00 0.40 [0.24, 0.64] Subtotal (95% CI) 81 88 100.00 0.40 [0.24, 0.64]Total events: 16 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.74 (P=0.0002) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 75/363 60/282 93.30 0.97 [0.72, 1.31] Taylor 2004 1/12 0/12 6.70 3.00 [0.13, 67.06] Subtotal (95% CI) 375 294 100.00 0.98 [0.73, 1.33]Total events: 76 (infliximab/MTX), 60 (placebo/MTX)Test for heterogeneity: chi²=0.50, df=1 (P=0.48), I²=0%Test for overall effect: Z=0.12 (P=0.90)

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A-98

Figure 37: IFX RCTs – drug discontinuation (total) at 54 weeks; risk difference (fixed effects)

RD=risk difference



MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 23/86 44/88 21.07 -0.23 [-0.37, -0.09] ASPIRE 66/359 60/282 76.51 -0.03 [-0.09, 0.03] Quinn 2005 1/10 0/10 2.42 0.10 [-0.14, 0.34] Subtotal (95% CI) 455 380 100.00 -0.07 [-0.13, -0.01]Total events: 90 (infliximab/MTX), 104 (placebo/MTX)Test for heterogeneity: chi²=8.75, df=2 (P=0.01), I²=77.1%Test for overall effect: Z=2.38 (P=0.02) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 20/86 44/88 100.00 -0.27 [-0.40, -0.13] Subtotal (95% CI) 86 88 100.00 -0.27 [-0.40, -0.13]Total events: 20 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.81 (P=0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 12/87 44/88 100.00 -0.36 [-0.49, -0.23] Subtotal (95% CI) 87 88 100.00 -0.36 [-0.49, -0.23]Total events: 12 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.58 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 16/81 44/88 100.00 -0.30 [-0.44, -0.17] Subtotal (95% CI) 81 88 100.00 -0.30 [-0.44, -0.17]Total events: 16 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.37 (P<0.0001) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 75/363 60/282 96.36 -0.01 [-0.07, 0.06] Taylor 2004 1/12 0/12 3.64 0.08 [-0.12, 0.29] Subtotal (95% CI) 375 294 100.00 0.00 [-0.06, 0.06]Total events: 76 (infliximab/MTX), 60 (placebo/MTX)Test for heterogeneity: chi²=0.71, df=1 (P=0.40), I²=0%Test for overall effect: Z=0.09 (P=0.93)

-1 -0.5 0 0.5 1



A-99

Figure 38: IFX RCTs – drug discontinuation (total) at 54 weeks; risk difference (random effects)

RD=risk difference

Review: infliximab for rheumatoid arthritis Comparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: total withdrawals

Study Infliximab/MTX Placebo/MTX RD (random) Weight RD (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 23/86 44/88 34.26 -0.23 [-0.37, -0.09] ASPIRE 66/359 60/282 40.66 -0.03 [-0.09, 0.03] Quinn 2005 1/10 0/10 25.09 0.10 [-0.14, 0.34] Subtotal (95% CI) 455 380 100.00 -0.07 [-0.23, 0.10]Total events: 90 (infliximab/MTX), 104 (placebo/MTX)Test for heterogeneity: chi²=8.75, df=2 (P=0.01), I²=77.1%Test for overall effect: Z=0.82 (P=0.41) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 20/86 44/88 100.00 -0.27 [-0.40, -0.13] Subtotal (95% CI) 86 88 100.00 -0.27 [-0.40, -0.13]Total events: 20 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.81 (P=0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 12/87 44/88 100.00 -0.36 [-0.49, -0.23] Subtotal (95% CI) 87 88 100.00 -0.36 [-0.49, -0.23]Total events: 12 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.58 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 16/81 44/88 100.00 -0.30 [-0.44, -0.17] Subtotal (95% CI) 81 88 100.00 -0.30 [-0.44, -0.17]Total events: 16 (infliximab/MTX), 44 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.37 (P<0.0001) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 75/363 60/282 58.99 -0.01 [-0.07, 0.06] Taylor 2004 1/12 0/12 41.01 0.08 [-0.12, 0.29] Subtotal (95% CI) 375 294 100.00 0.00 [-0.06, 0.06]Total events: 76 (infliximab/MTX), 60 (placebo/MTX)Test for heterogeneity: chi²=0.71, df=1 (P=0.40), I²=0%Test for overall effect: Z=0.06 (P=0.95)

-1 -0.5 0 0.5 1



A-100

Figure 39: IFX RCTs – drug discontinuation (lack of efficacy) at 54 weeks; relative risk (fixed effects)

RR=relative risk

Review: infliximab for rheumatoid arthritisComparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX)Outcome: withdrawals due to lack of efficacy


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/86 32/88 51.12 0.54 [0.33, 0.90] ASPIRE 7/359 27/282 48.88 0.20 [0.09, 0.46] Quinn 2005 0/10 0/10 Not estimable Subtotal (95% CI) 455 380 100.00 0.38 [0.25, 0.58]Total events: 24 (infliximab/MTX), 59 (placebo/MTX)Test for heterogeneity: chi²=4.18, df=1 (P=0.04), I²=76.1%Test for overall effect: Z=4.46 (P<0.00001) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 10/86 32/88 100.00 0.32 [0.17, 0.61] Subtotal (95% CI) 86 88 100.00 0.32 [0.17, 0.61]Total events: 10 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.47 (P=0.0005) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/87 32/88 100.00 0.19 [0.08, 0.43] Subtotal (95% CI) 87 88 100.00 0.19 [0.08, 0.43]Total events: 6 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.97 (P<0.0001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 7/81 32/88 100.00 0.24 [0.11, 0.51] Subtotal (95% CI) 81 88 100.00 0.24 [0.11, 0.51]Total events: 7 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.71 (P=0.0002) MTX and infliximab 6 mg/kg q8 weeks versus MTX (PBO) ASPIRE 12/363 27/282 98.38 0.35 [0.18, 0.67] Taylor 2004 1/12 0/12 1.62 3.00 [0.13, 67.06] Subtotal (95% CI) 375 294 100.00 0.39 [0.21, 0.73]Total events: 13 (infliximab/MTX), 27 (placebo/MTX)Test for heterogeneity: chi²=1.78, df=1 (P=0.18), I²=44.0%Test for overall effect: Z=2.94 (P=0.003)

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A-101

Figure 40: IFX RCTs – drug discontinuation (lack of efficacy) at 54 weeks; relative risk (random effects)

RR=relative risk

Review: infliximab for rheumatoid arthritisComparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: withdrawals due to lack of efficacy


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/86 32/88 62.84 0.54 [0.33, 0.90] ASPIRE 7/359 27/282 37.16 0.20 [0.09, 0.46] Quinn 2005 0/10 0/10 Not estimable Subtotal (95% CI) 455 380 100.00 0.35 [0.13, 0.93]Total events: 24 (infliximab/MTX), 59 (placebo/MTX)Test for heterogeneity: chi²=4.18, df=1 (P=0.04), I²=76.1%Test for overall effect: Z=2.10 (P=0.04) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 10/86 32/88 100.00 0.32 [0.17, 0.61] Subtotal (95% CI) 86 88 100.00 0.32 [0.17, 0.61]Total events: 10 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.47 (P=0.0005) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/87 32/88 100.00 0.19 [0.08, 0.43] Subtotal (95% CI) 87 88 100.00 0.19 [0.08, 0.43]Total events: 6 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.97 (P<0.0001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 7/81 32/88 100.00 0.24 [0.11, 0.51] Subtotal (95% CI) 81 88 100.00 0.24 [0.11, 0.51]Total events: 7 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.71 (P=0.0002) MTX and infliximab 6 mg/kg q8 weeks versus MTX (PBO) ASPIRE 12/363 27/282 92.82 0.35 [0.18, 0.67] Taylor 2004 1/12 0/12 7.18 3.00 [0.13, 67.06] Subtotal (95% CI) 375 294 100.00 0.59 [0.09, 3.62]Total events: 13 (infliximab/MTX), 27 (placebo/MTX)Test for heterogeneity: chi²=1.78, df=1 (P=0.18), I²=44.0%Test for overall effect: Z=0.58 (P=0.56)

0.01 0.1 1 10 100



A-102

Figure 41: IFX RCTs – drug discontinuation (lack of efficacy) at 54 weeks; risk difference (fixed effects)

RD=risk difference



MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/86 32/88 21.07 -0.17 [-0.30, -0.03] ASPIRE 7/359 27/282 76.51 -0.08 [-0.11, -0.04] Quinn 2005 0/10 0/10 2.42 0.00 [-0.17, 0.17] Subtotal (95% CI) 455 380 100.00 -0.09 [-0.13, -0.05]Total events: 24 (infliximab/MTX), 59 (placebo/MTX)Test for heterogeneity: chi²=3.09, df=2 (P=0.21), I²=35.3%Test for overall effect: Z=4.58 (P<0.00001) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 10/86 32/88 100.00 -0.25 [-0.37, -0.13] Subtotal (95% CI) 86 88 100.00 -0.25 [-0.37, -0.13]Total events: 10 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.00 (P<0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/87 32/88 100.00 -0.29 [-0.41, -0.18] Subtotal (95% CI) 87 88 100.00 -0.29 [-0.41, -0.18]Total events: 6 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.08 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 7/81 32/88 100.00 -0.28 [-0.39, -0.16] Subtotal (95% CI) 81 88 100.00 -0.28 [-0.39, -0.16]Total events: 7 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.62 (P<0.00001) MTX and infliximab 6 mg/kg q8 weeks versus MTX (PBO) ASPIRE 12/363 27/282 96.36 -0.06 [-0.10, -0.02] Taylor 2004 1/12 0/12 3.64 0.08 [-0.12, 0.29] Subtotal (95% CI) 375 294 100.00 -0.06 [-0.10, -0.02]Total events: 13 (infliximab/MTX), 27 (placebo/MTX)Test for heterogeneity: chi²=1.92, df=1 (P=0.17), I²=48.0%Test for overall effect: Z=2.93 (P=0.003)

-1 -0.5 0 0.5 1



A-103

Figure 42: IFX RCTs – drug discontinuation (lack of efficacy) at 54 weeks; risk difference (random effects)

RD=risk difference


Study Infliximab+MTX Placebo/MTX RD (random) Weight RD (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/86 32/88 30.59 -0.17 [-0.30, -0.03] ASPIRE 7/359 27/282 45.33 -0.08 [-0.11, -0.04] Quinn 2005 0/10 0/10 24.08 0.00 [-0.17, 0.17] Subtotal (95% CI) 455 380 100.00 -0.09 [-0.16, -0.01]Total events: 24 (infliximab/MTX), 59 (placebo/MTX)Test for heterogeneity: chi²=3.09, df=2 (P=0.21), I²=35.3%Test for overall effect: Z=2.33 (P=0.02) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 10/86 32/88 100.00 -0.25 [-0.37, -0.13] Subtotal (95% CI) 86 88 100.00 -0.25 [-0.37, -0.13]Total events: 10 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.00 (P<0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 6/87 32/88 100.00 -0.29 [-0.41, -0.18] Subtotal (95% CI) 87 88 100.00 -0.29 [-0.41, -0.18]Total events: 6 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.08 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 7/81 32/88 100.00 -0.28 [-0.39, -0.16] Subtotal (95% CI) 81 88 100.00 -0.28 [-0.39, -0.16]Total events: 7 (infliximab/MTX), 32 (placebo/MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.62 (P<0.00001) MTX and infliximab 6 mg/kg q8 weeks versus MTX (PBO) ASPIRE 12/363 27/282 68.77 -0.06 [-0.10, -0.02] Taylor 2004 1/12 0/12 31.23 0.08 [-0.12, 0.29] Subtotal (95% CI) 375 294 100.00 -0.02 [-0.15, 0.10]Total events: 13 (infliximab/MTX), 27 (placebo/MTX)Test for heterogeneity: chi²=1.92, df=1 (P=0.17), I²=48.0%Test for overall effect: Z=0.39 (P=0.70)

-1 -0.5 0 0.5 1



A-104

Figure 43: IFX RCTs – drug discontinuation (toxicity) at 54 weeks; relative risk (fixed effects)

RR=relative risk

Review: infliximab for rheumatoid arthritisComparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: withdrawals secondary to adverse events


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 5/86 7/88 39.54 0.73 [0.24, 2.21] ASPIRE 34/359 9/282 57.60 2.97 [1.45, 6.08] Quinn 2005 1/10 0/10 2.86 3.00 [0.14, 65.90] Subtotal (95% CI) 455 380 100.00 2.08 [1.18, 3.68]Total events: 40 (infliximab/MTX), 16 (placebo/MTX)Test for heterogeneity: chi²=4.42, df=2 (P=0.11), I²=54.7%Test for overall effect: Z=2.54 (P=0.01) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 9/86 7/88 100.00 1.32 [0.51, 3.37] Subtotal (95% CI) 86 88 100.00 1.32 [0.51, 3.37]Total events: 9 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.57 (P=0.57) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 4/87 7/88 100.00 0.58 [0.18, 1.90] Subtotal (95% CI) 87 88 100.00 0.58 [0.18, 1.90]Total events: 4 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.90 (P=0.37) MTX and infliximab 10 mg/kg q 4 weeks versus MTX(PBO) ATTRACT 8/81 7/88 100.00 1.24 [0.47, 3.27] Subtotal (95% CI) 81 88 100.00 1.24 [0.47, 3.27]Total events: 8 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.44 (P=0.66) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 35/363 9/282 100.00 3.02 [1.48, 6.18] Taylor 2004 0/12 0/12 Not estimable Subtotal (95% CI) 375 294 100.00 3.02 [1.48, 6.18]Total events: 35 (infliximab/MTX), 9 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.03 (P=0.002)

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A-105

Figure 44: IFX RCTs – drug discontinuation (toxicity) at 54 weeks; risk difference (fixed effects)

RD=risk difference

Review: infliximab for rheumatoid arthritisComparison: withdrawals at 54 weeks (infliximab+MTX versus placebo/MTX) Outcome: withdrawals secondary to adverse events


MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT 5/86 7/88 21.07 -0.02 [-0.10, 0.05] ASPIRE 34/359 9/282 76.51 0.06 [0.03, 0.10] Quinn 2005 1/10 0/10 2.42 0.10 [-0.14, 0.34] Subtotal (95% CI) 455 380 100.00 0.05 [0.01, 0.08]Total events: 40 (infliximab/MTX), 16 (placebo/MTX)Test for heterogeneity: chi²=4.10, df=2 (P=0.13), I²=51.2%Test for overall effect: Z=2.75 (P=0.006) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 9/86 7/88 100.00 0.03 [-0.06, 0.11] Subtotal (95% CI) 86 88 100.00 0.03 [-0.06, 0.11]Total events: 9 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.57 (P=0.57) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 4/87 7/88 100.00 -0.03 [-0.11, 0.04] Subtotal (95% CI) 87 88 100.00 -0.03 [-0.11, 0.04]Total events: 4 (infliximab/MTX), 7 (placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.92 (P=0.36) 04 MTX and infliximab 10 mg/kg q 4 weeks versus MTX(PBO) ATTRACT 8/81 7/88 100.00 0.02 [-0.07, 0.11] Subtotal (95% CI) 81 88 100.00 0.02 [-0.07, 0.11]Total events: 8 (Infliximab/MTX), 7 (Placebo/MTX)Test for heterogeneity: not applicableTest for overall effect: Z = 0.44 (P = 0.66) MTX and infliximab 5 to 6 mg/kg q8 weeks versus MTX(PBO) ASPIRE 35/363 9/282 96.36 0.06 [0.03, 0.10] Taylor 2004 0/12 0/12 3.64 0.00 [-0.15, 0.15] Subtotal (95% CI) 375 294 100.00 0.06 [0.03, 0.10]Total events: 35 (infliximab/MTX), 9 (placebo/MTX)Test for heterogeneity: chi²=0.69, df=1 (P=0.40), I²=0%Test for overall effect: Z=3.40 (P=0.0007)

-0.5 -0.25 0 0.25 0.5



A-106

Figure 45: IFX RCTs – drug discontinuation (total) at 102 weeks; relative risk (fixed effects)

RR=relative risk


Study Infliximab+MTX MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 32/86 58/88 99.14 0.56 [0.41, 0.77] Quinn 2005 1/10 0/10 0.86 3.00 [0.14, 65.90] Subtotal (95% CI) 96 98 100.00 0.59 [0.43, 0.80]Total events: 33 (infliximab/MTX), 58 (MTX)Test for heterogeneity: chi²=1.13, df=1 (P=0.29), I²=11.2%Test for overall effect: Z=3.38 (P=0.0007) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 30/86 58/88 100.00 0.53 [0.38, 0.73] Subtotal (95% CI) 86 88 100.00 0.53 [0.38, 0.73]Total events: 30 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=3.83 (P=0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/87 58/88 100.00 0.30 [0.19, 0.47] Subtotal (95% CI) 87 88 100.00 0.30 [0.19, 0.47]Total events: 17 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.27 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 22/81 58/88 100.00 0.41 [0.28, 0.61] Subtotal (95% CI) 81 88 100.00 0.41 [0.28, 0.61]Total events: 22 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.49 (P<0.00001)

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A-107

Figure 46: IFX RCTs – drug discontinuation (total) at 102 weeks; relative risk (random effects)

RR=relative risk

Review: infliximab for rheumatoid arthritis Comparison: withdrawals at 102 weeks (infliximab+MTX versus placebo/MTX)Outcome: total withdrawals

Study Infliximab+MTX MTX RR (random) Weight RR (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 32/86 58/88 97.37 0.56 [0.41, 0.77] Quinn 2005 1/10 0/10 2.63 3.00 [0.14, 65.90] Subtotal (95% CI) 96 98 100.00 0.63 [0.28, 1.42]Total events: 33 (infliximab/MTX), 58 (MTX)Test for heterogeneity: chi²=1.13, df=1 (P=0.29), I²=11.2%Test for overall effect: Z=1.11 (P=0.27) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 30/86 58/88 100.00 0.53 [0.38, 0.73] Subtotal (95% CI) 86 88 100.00 0.53 [0.38, 0.73]Total events: 30 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.83 (P=0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/87 58/88 100.00 0.30 [0.19, 0.47] Subtotal (95% CI) 87 88 100.00 0.30 [0.19, 0.47]Total events: 17 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.27 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 22/81 58/88 100.00 0.41 [0.28, 0.61] Subtotal (95% CI) 81 88 100.00 0.41 [0.28, 0.61]Total events: 22 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.49 (P<0.00001)

0.01 0.1 1 10 100



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Figure 47: IFX RCTs – drug discontinuation (total) at 102 weeks; risk difference (fixed effects)

RD=risk difference


Study Infliximab+MTX MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 32/86 58/88 89.69 -0.29 [-0.43, -0.14] Quinn 2005 1/10 0/10 10.31 0.10 [-0.14, 0.34] Subtotal (95% CI) 96 98 100.00 -0.25 [-0.38, -0.12]Total events: 33 (infliximab/MTX), 58 (MTX)Test for heterogeneity: chi²=8.53, df=1 (P=0.004), I²=88.3%Test for overall effect: Z=3.71 (P=0.0002) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 30/86 58/88 100.00 -0.31 [-0.45, -0.17] Subtotal (95% CI) 86 88 100.00 -0.31 [-0.45, -0.17]Total events: 30 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=4.30 (P<0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/87 58/88 100.00 -0.46 [-0.59, -0.33] Subtotal (95% CI) 87 88 100.00 -0.46 [-0.59, -0.33]Total events: 17 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=7.02 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 22/81 58/88 100.00 -0.39 [-0.53, -0.25] Subtotal (95% CI) 81 88 100.00 -0.39 [-0.53, -0.25]Total events: 22 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.48 (P<0.00001)

-1 -0.5 0 0.5 1



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Figure 48: IFX RCTs – drug discontinuation (total) at 102 weeks; risk difference (random effects)

RD=risk difference


Study Infliximab+MTX MTX RD (random) Weight RD (random)or subcategory n/N n/N 95% CI % 95% CI

MTX and infliximab 3 mg/kg q8 weeks versus MTX(PBO) ATTRACT (continuation) 32/86 58/88 57.69 -0.29 [-0.43, -0.14] Quinn 2005 1/10 0/10 42.31 0.10 [-0.14, 0.34] Subtotal (95% CI) 96 98 100.00 -0.10 [-0.51, 0.30]Total events: 33 (infliximab/MTX), 58 (MTX)Test for heterogeneity: chi²=8.53, df=1 (P=0.004), I²=88.3%Test for overall effect: Z=0.51 (P=0.61) MTX and infliximab 3 mg/kg q4 weeks versus MTX(PBO) ATTRACT 30/86 58/88 100.00 -0.31 [-0.45, -0.17] Subtotal (95% CI) 86 88 100.00 -0.31 [-0.45, -0.17]Total events: 30 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=4.30 (P<0.0001) MTX and infliximab 10 mg/kg q8 weeks versus MTX(PBO) ATTRACT 17/87 58/88 100.00 -0.46 [-0.59, -0.33] Subtotal (95% CI) 87 88 100.00 -0.46 [-0.59, -0.33]Total events: 17 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=7.02 (P<0.00001) MTX and infliximab 10 mg/kg q4 weeks versus MTX(PBO) ATTRACT 22/81 58/88 100.00 -0.39 [-0.53, -0.25] Subtotal (95% CI) 81 88 100.00 -0.39 [-0.53, -0.25]Total events: 22 (infliximab/MTX), 58 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=5.48 (P<0.00001)

-1 -0.5 0 0.5 1



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APPENDIX 9: Clinical Review Results – ETN RCTs

Table 1: ETN RCTs — ACR responses

Study and Intervention N ACR50 P value (versus control) ACR70 P value

(versus control) Mean†

ACR-N (%) P value

(versus control) 1 year ERA 52 weeks46 control - MTX (20 mg/wk by wk 8) ETN 10 mg biw ETN 25 mg biw

217 208 207

93 (43%) 67 (32%)

101 (49%)

referent

NS NS

48 (22%) 33 (16%) 52 (25%)

referent

NS NS

40% 34% 45%

NS

referent <0.05*

TEMPO 52 weeks49 control - MTX (20 mg/wk by wk 8) ETN 25 mg biw ETN 25 mg biw+MTX (20 mg/wk)

228 223 231

98 (43%)

107 (48%) 159 (69%)

referent

- <0.0001*

43 (19%) 54 (24%) 99 (43%)

referent

- <0.0001*

- - -

- - -

2 years ERA 104 weeks48 control - MTX (20 mg/wk by wk 8) ETN 10 mg biw ETN 25 mg biw

217 208 207

91 (42%) 73 (35%)

101 (49%)

referent

NS NS

52 (24%) 40 (19%) 60 (29%)

referent

NS NS

- - -

- - -

*statistically significant; †mean response of patients with RA to treatment, according to percent improvement from baseline; NS=not shown.


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*statistically significant; †relative benefit >1.0 and positive benefit differences indicate beneficial effect of ETN compared with controls; NNT=number needed to treat; ‡favours MTX; NT=number treatment; NC=number control

Table 2: ETN RCTs — ACR responses; relative benefit and % benefit difference Relative Benefit† Benefit Difference (%)† Dose NT/NC Study

ACR50 ACR70 ACR50 NNT ACR70 NNT 1 year ETN 10 mg biw versus MTX 208/217 ERA 52 wk46 0.75 (0.58, 0.97)* 0.72 (0.48, 1.07) -11% (−20%,−1%)* [9.1]*‡ −6% (−14%, 1%) [16.7]†

207/217 223/228

ERA 52 wk46 TEMPO 52 wk49

1.14 (0.93, 1.40) 1.12 (0.91, 1.37)

1.14 (0.81, 1.60) 1.28 (0.90, 1.83)

6% (−4%, 15%) 5% (−4%, 14%)

16.7 20.0

3% (−5%, 11%) 5% (−2%, 13%)

33.3 20.0 ETN 25 mg biw

versus MTX POOLED 1.13 (0.97, 1.30) 1.21 (0.94, 1.54) 5% (−1%, 12%) 20.0 4% (−1%, 10%) 25.0

ETN 25 mg biw+MTX versus MTX

231/228 TEMPO 52 wk49 1.60 (1.35, 1.90)* 2.27 (1.67, 3.09)* 26% (17%, 35%)* 4.2* 24% (16%, 32%)* 4.2*

ETN 25 mg biw+MTX versus ETN 25 mg biw

231/223 TEMPO 52 wk49 1.43 (1.22, 1.69)* 1.77 (1.34, 2.33)* 21% (12%, 30%)* 4.8* 19% (10%, 27%)* 5.3*

2 years ETN 10 mg biw versus MTX 208/217 ERA 104 wk48 0.84 (0.66, 1.07) 0.80 (0.56, 1.16) −7% (−16%, 2%) [14.3]† −5% (−13%, 3%) [20.0]†

ETN 25 mg biw versus MTX 207/217 ERA 104 wk48 1.16 (0.94, 1.44) 1.21 (0.88, 1.66) 7% (-3%, 16%) 14.3 5% (−3%, 13%) 20.0


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Figure 1: ETN RCTs – ACR50 response at 12 months; relative benefit (fixed effects) [ETN versus MTX]

RR=relative benefit

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: ACR50

Study Etanercept alone MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 10 mg SC twice weekly ERA 67/208 93/217 100.00 0.75 [0.59, 0.97] Subtotal (95% CI) 208 217 100.00 0.75 [0.59, 0.97]Total events: 67 (etanercept alone), 93 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.24 (P=0.03)

Etanercept 25 mg SC twice weekly ERA 101/207 93/217 48.37 1.14 [0.93, 1.40] TEMPO 107/223 98/228 51.63 1.12 [0.91, 1.37] Subtotal (95% CI) 430 445 100.00 1.13 [0.97, 1.30]Total events: 208 (etanercept alone), 191 (MTX)Test for heterogeneity: chi²=0.02, df=1 (P=0.89), I²= 0%Test for overall effect: Z=1.62 (P=0.11)

0.2 0.5 1 2 5 Favours control Favours treatment


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Figure 2: ETN RCTs – ACR50 response at 12 months; benefit difference (fixed effects) [ETN versus MTX]


Figure 3: ETN RCTs – ACR50 response at 12 months; relative benefit (no pooling) [ETN + MTX versus MTX]

RR=relative benefit


Study Etanercept alone MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 10 mg SC twice weekly ERA 67/208 93/217 100.00 -0.11 [-0.20, -0.01] Subtotal (95% CI) 208 217 100.00 -0.11 [-0.20, -0.01]Total events: 67 (etanercept alone), 93 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.28 (P=0.02)

Etanercept 25 mg SC twice weekly ERA 101/207 93/217 48.45 0.06 [-0.04, 0.15] TEMPO 107/223 98/228 51.55 0.05 [-0.04, 0.14] Subtotal (95% CI) 430 445 100.00 0.05 [-0.01, 0.12]Total events: 208 (etanercept alone), 191 (MTX)Test for heterogeneity: chi²=0.02, df=1 (P=0.89), I²= 0%Test for overall effect: Z=1.62 (P=0.10)

-0.5 -0.25 0 0.25 0.5 Favours control Favours treatment

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: ACR50

Study Etanercept/MTX MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

TEMPO 159/231 98/228 100.00 1.60 [1.35, 1.90]

Total (95% CI) 231 228 100.00 1.60 [1.35, 1.90]Total events: 159 (etanercept/MTX), 98 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.34 (P<0.00001)

0.5 0.7 1 1.5 2Favours control Favours treatment


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Figure 4: ETN RCTs – ACR50 response at 12 months; benefit difference (no pooling) [ETN + MTX versus MTX]


Figure 5: ETN RCTs – ACR50 response at 12 months; relative benefit (no pooling) [ETN + MTX versus ETN]

RR=relative benefit


Study Etanercept/MTX MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

TEMPO 159/231 98/228 100.00 0.26 [0.17, 0.35]



Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: ACR50

Study Etanercept/MTX Etanercept alone RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

TEMPO 159/231 107/223 100.00 1.43 [1.22, 1.69]

Total (95% CI) 231 223 100.00 1.43 [1.22, 1.69]Total events: 159 (etanercept/MTX), 107 (etanercept alone)Test for heterogeneity: not applicableTest for overall effect: Z=4.37 (P<0.0001)

0.5 0.7 1 1.5 2 Favours control Favours treatment


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Figure 6: ETN RCTs – ACR50 response at 12 months; benefit difference (no pooling) [ETN + MTX versus ETN]


Figure 7: ETN RCTs – ACR70 response at 12 months; relative benefit (fixed effects) [ETN versus MTX]

RR=relative benefit

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog)Outcome: ACR50

Study Etanercept/MTX Etanercept alone RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

TEMPO 159/231 107/223 100.00 0.21 [0.12, 0.30]




Study Etanercept MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 10 mg SC twice weekly ERA 33/208 48/217 100.00 0.72 [0.48, 1.07] Subtotal (95% CI) 208 217 100.00 0.72 [0.48, 1.07]Total events: 33 (etanercept), 48 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.63 (P=0.10)

Etanercept 25 mg SC twice weekly ERA 52/207 48/217 52.43 1.14 [0.81, 1.60] TEMPO 54/223 43/228 47.57 1.28 [0.90, 1.83] Subtotal (95% CI) 430 445 100.00 1.21 [0.94, 1.54]Total events: 106 (etanercept), 91 (MTX) Test for heterogeneity: chi²=0.24, df=1 (P=0.63), I²= 0%Test for overall effect: Z=1.49 (P=0.14)



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Figure 8: ETN RCTs – ACR70 response at 12 months; benefit difference (fixed effects) [ETN versus MTX]


Figure 9: ETN RCTs – ACR70 response at 12 months; relative benefit (no pooling) [ETN + MTX versus MTX]

RR=relative benefit

Review: etanercept for rheumatoid arthritisComparison: eficacy at 12 months: etanercept versus MTX (Bathon and Klareskog)Outcome: ACR70

Study Etanercept MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 10 mg SC twice weekly ERA 33/208 48/217 100.00 -0.06 [-0.14, 0.01] Subtotal (95% CI) 208 217 100.00 -0.06 [-0.14, 0.01]Total events: 33 (etanercept), 48 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.65 (P=0.10)

02 Etanercept 25 mg SC twice weekly ERA 52/207 48/217 48.45 0.03 [-0.05, 0.11] TEMPO 54/223 43/228 51.55 0.05 [-0.02, 0.13] Subtotal (95% CI) 430 445 100.00 0.04 [-0.01, 0.10]Total events: 106 (etanercept), 91 (MTX) Test for heterogeneity: chi²=0.17, df=1 (P=0.68), I²=0%Test for overall effect: Z=1.49 (P=0.14)




TEMPO 99/231 43/228 100.00 2.27 [1.67, 3.09]


0.1 0.2 0.5 1 2 5 10Favours control Favours treatment


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Figure 10: ETN RCTs – ACR70 response at 12 months; benefit difference (no pooling) [ETN + MTX versus MTX]


Figure 11: ETN RCTs – ACR70 response at 12 months; relative benefit (no pooling) [ETN + MTX versus ETN]

RR=relative benefit



TEMPO 99/231 43/228 100.00 0.24 [0.16, 0.32]


-0.5 -0.25 0 0.25 0.5Favours control Favours treatment


Study Etanercept/MTX Etanercept alone RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI

TEMPO 99/231 54/223 100.00 1.77 [1.34, 2.33]


0.1 0.2 0.5 1 2 5 10Favours control Favours treatment


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Figure 12: ETN RCTs – ACR70 response at 12 months; benefit difference (no pooling) [ETN + MTX versus ETN]


Figure 13: ETN RCTs – ACR50 response at 24 months; relative benefit (no pooling) [ETN versus MTX]

RR=relative benefit


Study Etanercept/MTX Etanercept alone RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

TEMPO 99/231 54/223 100.00 0.19 [0.10, 0.27]


-0.5 -0.25 0 0.25 0.5Favours control Favours treatment

Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: ACR50


Etanercept 10 mg SC twice weekly versus MTX ERA (continuation) 73/208 91/217 100.00 0.84 [0.66, 1.07] Subtotal (95% CI) 208 217 100.00 0.84 [0.66, 1.07]Total events: 73 (etanercept), 91 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.44 (P=0.15) Etanercept 25 mg SC twice weekly versus MTX ERA (continuation) 101/207 91/217 100.00 1.16 [0.94, 1.44] Subtotal (95% CI) 207 217 100.00 1.16 [0.94, 1.44]Total events: 101 (etanercept), 91 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.42 (P=0.16)



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Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: ACR 50


Etanercept 10 mg SC twice weekly versus MTX ERA (continuation) 73/208 91/217 100.00 -0.07 [-0.16, 0.02] Subtotal (95% CI) 208 217 100.00 -0.07 [-0.16, 0.02]Total events: 73 (etanercept), 91 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.45 (P=0.15) Etanercept 25 mg SC twice weekly versus MTX ERA (continuation) 101/207 91/217 100.00 0.07 [-0.03, 0.16] Subtotal (95% CI) 207 217 100.00 0.07 [-0.03, 0.16]Total events: 101 (etanercept), 91 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.42 (P=0.16)


Figure 14: ETN RCTs – ACR50 response at 24 months; benefit difference (no pooling) [ETN versus MTX]


Figure 15: ETN RCTs – ACR70 response at 24 months; relative benefit (no pooling) [ETN versus MTX]

RR=relative benefit



Etanercept 10 mg SC twice weekly versus MTX ERA (continuation) 40/208 52/217 100.00 0.80 [0.56, 1.16] Subtotal (95% CI) 208 217 100.00 0.80 [0.56, 1.16]Total events: 40 (etanercept), 52 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.18 (P=0.24) Etanercept 25 mg SC twice weekly versus MTX ERA (continuation) 60/207 52/217 100.00 1.21 [0.88, 1.66] Subtotal (95% CI) 207 217 100.00 1.21 [0.88, 1.66]Total events: 60 (etanercept), 52 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.17 (P=0.24)



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Figure 16: ETN RCTs – ACR70 response at 24 months; benefit difference (no pooling) [ETN versus MTX]


Table 3: ETN RCTs — DAS28 responses DAS28 Study and Intervention

N Baseline (mean)

54 weeks (mean)

Mean change from baseline

% response remission

TEMPO 52 weeks49 control - MTX (20 mg/wk) ETN 25 mg biw ETN 25 mg biw+MTX

228 223 231

5.5 5.7 5.5

3.0 (2.8 to 3.2) 3.0 (2.8 to 3.1) 2.3 (2.1 to 2.5)*

-2.5 -2.7

-3.2*

30 (13%) (9% to 18%) 36 (16%) (11% to 21%)

81 (35%) (29% to 41%)*




Etanercept 10 mg SC twice weekly versus MTX ERA (continuation) 40/208 52/217 100.00 -0.05 [-0.13, 0.03] Subtotal (95% CI) 208 217 100.00 -0.05 [-0.13, 0.03]Total events: 40 (etanercept), 52 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.19 (P=0.23) Etanercept 25 mg SC twice weekly versus MTX ERA (continuation) 60/207 52/217 100.00 0.05 [-0.03, 0.13] Subtotal (95% CI) 207 217 100.00 0.05 [-0.03, 0.13]Total events: 60 (etanercept), 52 (MTX) Test for heterogeneity: not applicableTest for overall effect: Z=1.17 (P=0.24)



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Table 4: ETN RCTs — functional status (HAQ and SF-36) HAQ SF-36

Baseline Percentage of Improvement

Mean change from baseline Study and Intervention N Baseline Percentage of

improvement Mean change from baseline

Mental Physical Mental Physical Mental Physical 1 year ERA subanalysis 52 weeks47† control - MTX (20 mg/wk) ETN 25 mg biw

217 207

NR NR

71% 65%

0.76 0.73

NR NR

NR NR

32% 30%

61% 65%

4.1 3.6

9.6 10.7


228 223 231

1.7 1.7 1.8

35% 41% 56%*

0.6 0.7 1.0*

- - -

- - -

- - -

- - -

- - -

- - -

POOLED WMD (fixed) −0.03 (−0.04, −0.02)* - - - - - - POOLED WMD (random) 0.02 (−0.11, 0.14) - - - - - - POOLED SMD (fixed) -0.21 (−0.35, −0.08)* - - - - - -

ETN 25 mg biw versus MTX (significant heterogeneity in fixed effects model)

POOLED WMD (random) −0.23 (−0.95, 0.48) - - - - - - 2 years ETN ERA 104 weeks48 control - MTX (20 mg/wk) ETN 10 mg biw ETN 25 mg biw

217 208 207

NR NR NR

37% NR

55%*

- - -

- - -

- - -

- - -

- - -

- - -

- - -

*statistically significant; †baseline results reported for all groups together; NR=not reported.


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Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: HAQ-mean change

Study Etanercept alone MTX WMD (fixed) Weight WMD (fixed)or su-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

Etanercept 25 mg SC twice weekly vs MTX ERA (subanalysis) 207 0.73(0.05) 217 0.76(0.05) 99.54 -0.03 [-0.04, -0.02] TEMPO 223 0.70(0.76) 228 0.60(0.76) 0.46 0.10 [-0.04, 0.24]


-0.5 -0.25 0 0.25 0.5



Study Etanercept alone MTX WMD (random) Weight WMD (random)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI


Subtotal (95% CI) 430 445 100.00 0.02 [-0.11, 0.14]Test for heterogeneity: chi²=3.28, df=1 (P=0.07), I²=69.5%Test for overall effect: Z=0.25 (P=0.80)


Figure 17: ETN RCTs – HAQ at 12 months; weighted mean difference (fixed effects) [ETN versus MTX]


Figure 18: ETN RCTs – HAQ at 12 months; weighted mean difference (random effects) [ETN versus MTX]



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Review: etanercept for rheumatoid arthritisComparison: eficacy at 12 months: etanercept versus MTX (Bathon and Klareskog)Outcome: HAQ-mean change

Study Etanercept alone MTX SMD (fixed) Weight SMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Etanercept 25 mg SC twice weekly vs MTXERA (subanalysis) 207 0.73(0.05) 217 0.76(0.05) 47.40 -0.60 [-0.79, -0.40] TEMPO 223 0.70(0.76) 228 0.60(0.76) 52.60 0.13 [-0.05, 0.32]

Subtotal (95% CI) 430 445 100.00 -0.21 [-0.35, -0.08]Test for heterogeneity: chi²=28.44, df=1 (P<0.00001), I²=96.5%Test for overall effect: Z=3.14 (P=0.002)

-1 -0.5 0 0.5 1 Favours control Favours treatment


Study Etanercept alone MTX SMD (random) Weight SMD (random)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI


Subtotal (95% CI) 430 445 100.00 -0.23 [-0.95, 0.48]Test for heterogeneity: chi²=28.44, df=1 (P<0.00001), I²=96.5%Test for overall effect: Z=0.64 (P=0.52)

-1 -0.5 0 0.5 1 Favours control Favours treatment

Figure 19: ETN RCTs – HAQ at 12 months; standardized mean difference (fixed effects) [ETN versus MTX]


Figure 20: ETN RCTs – HAQ at 12 months; standardized mean difference (random effects) [ETN versus MTX]



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Table 5: ETN RCTs — radiological outcomes Total Score Erosion Joint Space Narrowing

Study & Intervention N

Baseline Mean change

from baseline

Baseline Mean

change from

baseline Baseline Mean change

from baseline

Other Radiological Outcomes

1 year ERA 52 weeks46 MTX (20 mg/wk by wk 8) ETN 10 mg biw ETN 25 mg biw

217 208 207

12.9 11.2 12.4

1.6 1.5 1.0

7.5 6.1 6.4

1.0 0.8 0.5*

5.4 5.0 6.0

0.7 0.6 0.4

no progression 130 (60%)

- 149 (72%)

improvement - - -


212 212 218

26.8 21.8 21.8

2.80 0.52* −0.54*

11.5 8.0 9.5

1.68

0.21* −0.30*

13.3 11.5 10.3

1.12 0.32* −0.23*

no progression 130 (57%) 152 (68%)

185 (80%)*

improvement - - -

25 mg biw versus MTX POOLED WMD −1.78 (−3.32, −0.25)* −1.20 (−2.15, −0.25)* −0.67 (−1.38, 0.05)

POOLED SMD −0.14 (−0.27, 0.00) −0.15 (−0.29, −0.02)* −0.11 (−0.25, 0.02)

POOLED RR 1.20 (1.08, 1.32)*

POOLED RD 12% (5%, 18%)

2 years ERA 104 wk48 MTX (20 mg/wk by wk 8) ETN 10 mg biw ETN 25 mg biw

169 166 177

12.9 11.2 12.4

3.2 2.5

1.3*

7.5 6.1 6.4

1.9 1.4 0.7*

5.4 5.0 6.0

1.3 1.1 0.7

no progression 86 (51%) 88 (53%) 112 (63%)

improvement - - -


A-125

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: radiographic: total Sharp score (0 to 398); mean change


01 Etanercept 10 mg SC twice weekly ERA 208 1.50(14.80) 217 1.59(13.80) 100.00 -0.01 [-0.20, 0.18]

Subtotal (95% CI) 208 217 100.00 -0.01 [-0.20, 0.18]Test for heterogeneity: not applicableTest for overall effect: Z=0.06 ( =0.95) Etanercept 25 mg SC twice weekly

ERA 207 1.00(15.80) 217 1.59(13.80) 50.16 -0.04 [-0.23, 0.15] TEMPO 212 0.52(4.60) 212 2.80(12.78) 49.84 -0.24 [-0.43, -0.05]

Subtotal (95% CI) 419 429 100.00 -0.14 [-0.27, 0.00]Test for heterogeneity: chi² =2.05, df=1 (P=0.15), I²=51.3%Test for overall effect: Z=2.01 (P=0.04)

-1 -0.5 0 0.5 1 Favours treatment Favours control

Figure 21: ETN RCTs – total radiographic score at 12 months; weighted mean difference (fixed effects) [ETN versus MTX]


Figure 22: ETN RCTs – total radiographic score at 12 months; standardized mean difference (fixed effects) [ETN versus MTX]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: radiographic: total Sharp score (0 to 398); mean change

Study Etanercept alone MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI

Etanercept 10 mg SC twice weekly ERA 208 1.50(14.80) 217 1.59(13.80) 100.00 -0.09 [-2.81, 2.63]

Subtotal (95% CI) 208 217 100.00 -0.09 [-2.81, 2.63]Test for heterogeneity: not applicableTest for overall effect: Z=0.06 (P=0.95)

Etanercept 25 mg SC twice weekly ERA 207 1.00(15.80) 217 1.59(13.80) 29.46 -0.59 [-3.42, 2.24] TEMPO 212 0.52(4.60) 212 2.80(12.78) 70.54 -2.28 [-4.11, -0.45]

Subtotal (95% CI) 419 429 100.00 -1.78 [-3.32, -0.25]Test for heterogeneity: chi²=0.97, df=1 (P=0.33), I²=0%Test for overall effect: Z=2.27 (P=0.02)

-10 -5 0 5 10 Favours treatment Favours control


A-126

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: erosion Sharp score (0 to 230)





Subtotal (95% CI) 419 429 100.00 -1.20 [-2.15, -0.25]Test for heterogeneity: chi²=0.74, df=1 (P=0.39), I²=0%Test for overall effect: Z=2.48 (P=0.01)


Figure 23: ETN RCTs – erosion score at 12 months; weighted mean difference (fixed effects) [ETN versus MTX]


Figure 24: ETN RCTs – erosion score at 12 months; standardized mean difference (fixed effects) [ETN versus MTX]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: erosion Sharp score (0 to 230)








A-127

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: joint-space narrowing (0 to 168)

Study Etanercept alone MTX WMD (fixed) Weight WMD (fixed)or subcategory N Mean (SD) N Mean (SD) 95% CI % 95% CI



Etanercept 25 mg SC twice weekly ERA 207 0.40(8.20) 217 0.70(6.10) 26.95 -0.30 [-1.68, 1.08] TEMPO 212 0.32(2.30) 212 1.12(5.79) 73.05 -0.80 [-1.64, 0.04]

Subtotal (95% CI) 419 429 100.00 -0.67 [-1.38, 0.05]Test for heterogeneity: chi²=0.37, df=1 (P=0.54), I²=0%Test for overall effect: Z=1.82 (P=0.07)


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: joint-space narrowing (0 to 168)




Etanercept 25 mg SC twice weekly ERA 207 0.40(8.20) 217 0.70(6.10) 50.08 -0.04 [-0.23, 0.15] TEMPO 212 0.32(2.30) 212 1.12(5.79) 49.92 -0.18 [-0.37, 0.01]



Figure 25: ETN RCTs – joint space narrowing score at 12 months; weighted mean difference (fixed effects) [ETN versus MTX]


Figure 26: ETN RCTs – joint space narrowing score at 12 months; standardized mean difference (fixed effects) [ETN versus MTX]



A-128

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: no radiographic progression


Etanercept 25 mg SC twice weekly ERA 149/207 130/217 49.68 1.20 [1.05, 1.38] TEMPO 152/223 130/228 50.32 1.20 [1.04, 1.38] Subtotal (95% CI) 430 445 100.00 1.20 [1.08, 1.32]Total events: 301 (etanercept), 260 (MTX)Test for heterogeneity: chi²=0.00, df=1 (P=0.96), I²=0%Test for overall effect: Z=3.56 (P=0.0004)


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: no radiographic progression


Etanercept 25 mg SC twice weekly ERA 149/207 130/217 48.45 0.12 [0.03, 0.21] TEMPO 152/223 130/228 51.55 0.11 [0.02, 0.20] Subtotal (95% CI) 430 445 100.00 0.12 [0.05, 0.18]Total events: 301 (etanercept), 260 (MTX)Test for heterogeneity: chi²=0.02, df=1 (P=0.89), I²=0%Test for overall effect: Z=3.61 (P=0.0003)


Figure 27: ETN RCTs – no radiographic progression at 12 months; relative benefit (fixed effects) [ETN versus MTX]

RR=relative benefit

Figure 28: ETN RCTs – no radiographic progression at 12 months; benefit difference (fixed effects) [ETN versus MTX]



A-129

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: radiographic: total Sharp score (0 to 398)


TEMPO 218 -0.54(3.54) 212 2.80(12.78) 100.00 -3.34 [-5.12, -1.56]

Total (95% CI) 218 212 100.00 -3.34 [-5.12, -1.56]Test for heterogeneity: not applicableTest for overall effect: Z=3.67 (P=0.0002)


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: radiographic: total Sharp score (0 to 398)


TEMPO 218 -0.54(3.54) 212 2.80(12.78) 100.00 -0.36 [-0.55, -0.17]



Figure 29: ETN RCTs – total radiographic score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus MTX]


Figure 30: ETN RCTs – total radiographic score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus MTX]



A-130

Figure 31: ETN RCTs – erosion score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus MTX]


Figure 32: ETN RCTs – erosion score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus MTX]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: erosion Sharp score (0 to 230)


TEMPO 218 -0.30(2.56) 212 1.68(7.86) 100.00 -1.98 [-3.09, -0.87]



Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: erosion Sharp score (0 to 230)


TEMPO 218 -0.30(2.56) 212 1.68(7.86) 100.00 -0.34 [-0.53, -0.15]




A-131

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: joint-space narrowing (0 to 168)


TEMPO 218 -0.23(1.58) 212 1.12(5.79) 100.00 -1.35 [-2.16, -0.54]



Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: joint-space narrowing (0 to 168)


TEMPO 218 -0.23(1.58) 212 1.12(5.79) 100.00 -0.32 [-0.51, -0.13]


-1 -0.5 0 0.5 1


Figure 33: ETN RCTs – joint space narrowing score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus MTX]


Figure 34: ETN RCTs – joint space narrowing score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus MTX]



A-132

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: no radiographic progression

Study Etanercept plus MTX MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 25 mg SC twice weekly plus MTX vs MTX alone TEMPO 185/231 130/228 100.00 0.23 [0.15, 0.31] Subtotal (95% CI) 231 228 100.00 0.23 [0.15, 0.31]Total events: 185 (etanercept plus MTX), 130 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.49 (P<0.00001)


Figure 35: ETN RCTs – no radiographic progression at 12 months; relative benefit (no pooling) [ETN + MTX versus MTX]

RR=relative benefit

Figure 36: ETN RCTs – no radiographic progression at 12 months; benefit difference (no pooling) [ETN + MTX versus MTX]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus MTX alone (Klareskog) Outcome: no radiographic progression

Study Etanercept plus MTX MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

02 Etanercept 25 mg SC twice weekly plus MTX vs MTX alone TEMPO 185/231 130/228 100.00 1.40 [1.23, 1.60] Subtotal (95% CI) 231 228 100.00 1.40 [1.23, 1.60]Total events: 185 (etanercept plus MTX), 130 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=5.13 (P<0.00001)



A-133

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: radiographic: total Sharp score (0 to 398)


TEMPO 218 -0.54(3.54) 212 0.52(4.60) 100.00 -1.06 [-1.84, -0.28]



Figure 37: ETN RCTs – total radiographic score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus ETN]


Figure 38: ETN RCTs – total radiographic score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus ETN]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: radiographic: total Sharp score (0 to 398)

Study Treatment Control SMD (fixed) Weight SMD (fixed)or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI

TEMPO 218 -0.54(3.54) 212 0.52(4.60) 100.00 -0.26 [-0.45, -0.07]


-0.5 -0.25 0 0.25 0.5 Favours treatment Favours control


A-134

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: erosion Sharp score (0 to 230)


TEMPO 218 -0.30(2.56) 212 0.21(2.97) 100.00 -0.51 [-1.03, 0.01]

Total (95% CI) 218 212 100.00 -0.51 [-1.03, 0.01]Test for heterogeneity: not applicableTest for overall effect: Z=1.91 (P=0.06)


Figure 39: ETN RCTs – erosion score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus ETN]


Figure 40: ETN RCTs – erosion score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus ETN]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: erosion Sharp score (0 to 230)


TEMPO 218 -0.30(2.56) 212 0.21(2.97) 100.00 -0.18 [-0.37, 0.01]

Total (95% CI) 218 212 100.00 -0.18 [-0.37, 0.01]Test for heterogeneity: not applicableTest for overall effect: Z=1.90 (P=0.06)



A-135

Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: joint-space narrowing (0 to 168)


TEMPO 218 -0.23(1.58) 212 0.32(2.30) 100.00 -0.55 [-0.92, -0.18]



Figure 41: ETN RCTs – joint space narrowing score at 12 months; weighted mean difference (no pooling) [ETN + MTX versus ETN]


Figure 42: ETN RCTs – joint space narrowing score at 12 months; standardized mean difference (no pooling) [ETN + MTX versus ETN]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: joint-space narrowing (0 to 168)


TEMPO 218 -0.23(1.58) 212 0.32(2.30) 100.00 -0.28 [-0.47, -0.09]


-1 -0.5 0 0.5 1



A-136

Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: radiographic: total Sharp score (0 to 398)


Etanercept 10 mg SC twice weekly vs MTX ERA (continuation) 166 2.50(13.80) 169 3.20(13.00) 100.00 -0.70 [-3.57, 2.17]

Subtotal (95% CI) 166 169 100.00 -0.70 [-3.57, 2.17]Test for heterogeneity: not applicableTest for overall effect: Z=0.48 (P=0.63) Etanercept 25 mg SC twice weekly vs MTX

ERA (continuation) 177 1.30(14.80) 169 3.20(13.00) 100.00 -1.90 [-4.83, 1.03] Subtotal (95% CI) 177 169 100.00 -1.90 [-4.83, 1.03]Test for heterogeneity: not applicableTest for overall effect: Z=1.27 (P=0.20)


Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: radiographic: total Sharp score (0 to 398)




Etanercept 25 mg SC twice weekly versus MTXERA (continuation) 177 1.30(14.80) 169 3.20(13.00) 100.00 -0.14 [-0.35, 0.08]



Figure 43: ETN RCTs – total radiographic score at 24 months; weighted mean difference (no pooling) [ETN versus MTX]


Figure 44: ETN RCTs – total radiographic score at 24 months; standardized mean difference (no pooling) [ETN versus MTX]



A-137

Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: erosion Sharp score (0 to 230)







Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: erosion Sharp score (0 to 230)







Figure 45: ETN RCTs – erosion score at 24 months; weighted mean difference (no pooling) [ETN versus MTX]

WMD=weghted mean difference

Figure 46: ETN RCTs – erosion score at 24 months; standardized mean difference (no pooling) [ETN versus MTX]



A-138

Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: joint-space narrowing (0 to 168)







Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: joint-space narrowing (0 to 168)







Figure 47: ETN RCTs – joint space narrowing score at 24 months; weighted mean difference (no pooling) [ETN versus MTX]


Figure 48: ETN RCTs – joint-space narrowing score at 24 months; standardized mean difference (no pooling) [ETN versus MTX]



A-139

Figure 49: ETN RCTs – no radiographic progression at 24 months; relative benefit (no pooling) [ETN + MTX versus MTX]

RR=relative benefit

Figure 50: ETN RCTs – no radiographic progression at 24 months; benefit difference (no pooling) [ETN + MTX versus MTX]


Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: no radiographic progression


Etanercept 10 mg SC twice weekly ERA (continuation) 88/166 86/169 100.00 1.04 [0.85, 1.28] Subtotal (95% CI) 166 169 100.00 1.04 [0.85, 1.28]Total events: 88 (etanercept), 86 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.39 (P=0.70)

Etanercept 25 mg SC twice weekly ERA (continuation) 112/177 88/169 100.00 1.22 [1.01, 1.46] Subtotal (95% CI) 177 169 100.00 1.22 [1.01, 1.46]Total events: 112 (etanercept), 88 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.09 (P=0.04)


Review: etanercept for rheumatoid arthritisComparison: efficacy at 24 months: etanercept versus MTX (Genovese) Outcome: no radiographic progression


Etanercept 10 mg SC twice weekly ERA (continuation) 88/166 86/169 100.00 0.02 [-0.09, 0.13] Subtotal (95% CI) 166 169 100.00 0.02 [-0.09, 0.13]Total events: 88 (etanercept), 86 (MTX) Test for heterogeneity: not applicable Test for overall effect: Z=0.39 (P=0.70) Etanercept 25 mg SC twice weekly ERA (continuation) 112/177 88/169 100.00 0.11 [0.01, 0.22] Subtotal (95% CI) 177 169 100.00 0.11 [0.01, 0.22]Total events: 112 (etanercept), 88 (MTX)Test for heterogeneity: not applicable Test for overall effect: Z=2.12 (P=0.03)



A-140

Table 6: ETN RCTs – drug discontinuations Drug Discontinuations

Study and Intervention N

All RR (versus control) Lack of efficacy RR

(versus control) Toxicity RR

(versus control)

Others RR (versus control)

1 year

ERA 52 weeks46 control - MTX ETN 10 mg biw ETN 25 mg biw

217 208 207

45 (21%) 42 (20%) 31 (15%)

-

0.97 (0.67, 1.42) 0.72 (0.48, 1.09)

8 (4%)

15 (7%) 10 (5%)

-

1.96 (0.85, 4.52) 1.31 (0.53, 3.26)

24 (10%) 12 (6%) 11 (5%)

-

0.52 (0.27, 1.02) 0.48(0.24, 0.96)*

13 (7%) 15 (7%) 10 (5%)

-

1.20(0.59, 2.47) 0.81(0.36, 1.80)

TEMPO 52 weeks49 control - MTX ETN 25 mg biw ETN 25 mg biw+MTX (20 mg/wk)

228 223 231

69 (30%) 53 (24%) 38 (17%)

-

0.79 (0.58, 1.07) 0.54 (0.38, 0.77)*

21 (9%) 16 (7%) 6 (3%)

-

0.78 (0.42, 1.45) 0.28 (0.12, 0.69)*

32 (14%) 25 (11%) 24 (10%)

-

0.80 (0.49, 1.30) 0.74 (0.45, 1.22)

16 (7%) 12 (6%) 8 (4%)

-

0.77(0.37, 1.58) 0.49(0.22, 1.33)

ETN 25 mg biw POOLED 0.76 (0.59, 0.97)* 0.92 (0.55, 1.54) 0.66 (0.45, 0.99)* 0.78(0.46, 1.34)

2 years

ERA 104 weeks48 control - MTX ETN 10 mg biw ETN 25 mg biw

169 166 177

40 (18%) 35 (17%) 24 (12%)

-

0.89 (0.60, 1.33) 0.57 (0.36, 0.91)*

15 (7%) 18 (9%) 6 (3%)

-

1.22 (0.64, 2.34) 0.38 (0.15, 0.96)*

5 (2%) 2 (1%) 5 (3%)

-

0.41 (0.08, 2.07) 0.95 (0.28, 3.24)

20 (9%) 15 (7%) 12 (6%)

-

0.57(0.29, 1.14) 0.76(0.40, 1.44)

RR=relative risk, RR<1.0=lower discontinuation rate with ETN compared to controls;*statistically significant.


A-141

Figure 51: ETN RCTs – drug discontinuation (total) at 12 months; relative risk (fixed effects) [ETN versus MTX]

RR=relative risk

Figure 52: ETN RCTs – drug discontinuation (total) at 12 months; risk difference (fixed effects) [ETN versus MTX]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: total


10 mg ERA 42/208 45/217 100.00 -0.01 [-0.08, 0.07] Subtotal (95% CI) 208 217 100.00 -0.01 [-0.08, 0.07]Total events: 42 (etanercept alone), 45 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.14 (P=0.89)

25 mg ERA 31/207 45/217 48.45 -0.06 [-0.13, 0.02] TEMPO 53/223 69/228 51.55 -0.06 [-0.15, 0.02] Subtotal (95% CI) 430 445 100.00 -0.06 [-0.12, -0.01]Total events: 84 (etanercept alone), 114 (MTX)Test for heterogeneity: chi²=0.02, df=1 (P=0.89), I²=0%Test for overall effect: Z=2.19 (P=0.03)


Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: total


10 mg ERA 42/208 45/217 100.00 0.97 [0.67, 1.42] Subtotal (95% CI) 208 217 100.00 0.97 [0.67, 1.42]Total events: 42 (etanercept alone), 45 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.14 (P=0.89)

25 mg ERA 31/207 45/217 39.17 0.72 [0.48, 1.09] TEMPO 53/223 69/228 60.83 0.79 [0.58, 1.07] Subtotal (95% CI) 430 445 100.00 0.76 [0.59, 0.97]Total events: 84 (etanercept alone), 114 (MTX)Test for heterogeneity: chi²=0.10, df=1 (P=0.75), I²=0%Test for overall effect: Z=2.17 (P=0.03)

0.1 0.2 0.5 1 2 5 10 Favours treatment Favours control


A-142

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: lack of efficacy



25 mg ERA 10/207 8/217 27.33 1.31 [0.53, 3.26] TEMPO 16/223 21/228 72.67 0.78 [0.42, 1.45] Subtotal (95% CI) 430 445 100.00 0.92 [0.55, 1.54]Total events: 26 (etanercept alone), 29 (MTX)Test for heterogeneity: chi²=0.85, df=1 (P=0.36), I²=0%Test for overall effect: Z=0.30 (P=0.76)


Figure 53: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; relative risk (fixed effects) [ETN versus MTX]

RR=relative risk

Figure 54: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; risk difference (fixed effects) [ETN versus MTX]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: lack of efficacy


10 mg ERA 15/208 8/217 100.00 0.04 [-0.01, 0.08] Subtotal (95% CI) 208 217 100.00 0.04 [-0.01, 0.08]Total events: 15 (etanercept alone), 8 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.60 (P=0.11)

25 mg ERA 10/207 8/217 48.45 0.01 [-0.03, 0.05] TEMPO 16/223 21/228 51.55 -0.02 [-0.07, 0.03] Subtotal (95% CI) 430 445 100.00 0.00 [-0.04, 0.03]Total events: 26 (etanercept alone), 29 (MTX)Test for heterogeneity: chi²=1.05, df=1 (P=0.30), I²=5.1%Test for overall effect: Z=0.30 (P=0.76)



A-143

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: adverse event



25 mg ERA 11/207 24/217 42.55 0.48 [0.24, 0.96] TEMPO 25/223 32/228 57.45 0.80 [0.49, 1.30] Subtotal (95% CI) 430 445 100.00 0.66 [0.45, 0.99]Total events: 36 (etanercept alone), 56 (MTX)Test for heterogeneity: chi²=1.40, df=1 (P=0.24), I²=28.5%Test for overall effect: Z=2.03 (P=0.04)


Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept versus MTX (Bathon and Klareskog) Outcome: adverse event


10 mg ERA 12/208 24/217 100.00 -0.05 [-0.11, 0.00] Subtotal (95% CI) 208 217 100.00 -0.05 [-0.11, 0.00]Total events: 12 (etanercept alone), 24 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.98 (P=0.05)

25 mg ERA 11/207 24/217 48.45 -0.06 [-0.11, -0.01] TEMPO 25/223 32/228 51.55 -0.03 [-0.09, 0.03] Subtotal (95% CI) 430 445 100.00 -0.04 [-0.08, 0.00]Total events: 36 (etanercept alone), 56 (MTX)Test for heterogeneity: chi²=0.53, df=1 (P=0.47), I²=0%Test for overall effect: Z=2.06 (P=0.04)


Figure 55: ETN RCTs – drug discontinuation (toxicity) at 12 months; relative risk (fixed effects) [ETN versus MTX]

RR=relative risk

Figure 56: ETN RCTs – drug discontinuation (toxicity) at 12 months; risk difference (fixed effects) [ETN versus MTX]

RD=risk difference


A-144

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog)Outcome: total


Etanercept 25 mg SC twice weekly plus MTX versus MTX TEMPO 38/231 69/228 100.00 0.54 [0.38, 0.77] Subtotal (95% CI) 231 228 100.00 0.54 [0.38, 0.77]Total events: 38 (etanercept/MTX), 69 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.40 (P=0.0007)

0.2 0.5 1 2 5 Favours treatment Favours control

Figure 57: ETN RCTs – drug discontinuation (total) at 12 months; relative risk (no pooling) [ETN + MTX versus MTX]

RR=relative risk

Figure 58: ETN RCTs – drug discontinuation (total) at 12 months; risk difference (no pooling) [ETN + MTX versus MTX]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog)Outcome: total


Etanercept 25 mg SC twice weekly plus MTX versus MTX TEMPO 38/231 69/228 100.00 -0.14 [-0.21, -0.06] Subtotal (95% CI) 231 228 100.00 -0.14 [-0.21, -0.06]Total events: 38 (etanercept/MTX), 69 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.54 (P=0.0004)



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Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog)Outcome: lack of efficacy

Study Etanercept+MTX MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 25 mg SC twice weekly TEMPO 6/231 21/228 100.00 0.28 [0.12, 0.69] Subtotal (95% CI) 231 228 100.00 0.28 [0.12, 0.69]Total events: 6 (etanercept/MTX), 21 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.79 (P=0.005)


Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog)Outcome: lack of efficacy

Study Etanercept+MTX MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 25 mg SC twice weekly TEMPO 6/231 21/228 100.00 -0.07 [-0.11, -0.02] Subtotal (95% CI) 231 228 100.00 -0.07 [-0.11, -0.02]Total events: 6 (etanercept/MTX), 21 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=3.03 (P=0.002)


Figure 59: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; relative risk (no pooling) [ETN + MTX versus MTX]

RR=relative risk

Figure 60: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; risk difference (no pooling) [ETN + MTX versus MTX]

RD=risk difference


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Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog)Outcome: adverse event

Study Etanercept+MTX MTX RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 25 mg SC twice weekly TEMPO 24/231 32/228 100.00 0.74 [0.45, 1.22] Subtotal (95% CI) 231 228 100.00 0.74 [0.45, 1.22]Total events: 24 (etanercept/MTX), 32 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.19 (P=0.24)


Figure 61: ETN RCTs – drug discontinuation (toxicity) at 12 months; relative risk (no pooling) [ETN + MTX versus MTX]

RR=relative risk

Figure 62: ETN RCTs – drug discontinuation (toxicity) at 12 months; risk difference (no pooling) [ETN + MTX versus MTX]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus MTX (Klareskog) Outcome: adverse event

Study Etanercept+MTX MTX RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

Etanercept 25 mg SC twice weekly TEMPO 24/231 32/228 100.00 -0.04 [-0.10, 0.02] Subtotal (95% CI) 231 228 100.00 -0.04 [-0.10, 0.02]Total events: 24 (etanercept/MTX), 32 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=1.19 (P=0.23)



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Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog)Outcome: total

Study Etanercept+MTX Etanercept alone RD (fixed) Weight RD (fixed)or subcategory n/N n/N 95% CI % 95% CI

25 mg plus MTX versus 25 mg alone TEMPO 38/231 53/223 100.00 -0.07 [-0.15, 0.00] Subtotal (95% CI) 231 223 100.00 -0.07 [-0.15, 0.00]Total events: 38 (etanercept+MTX), 53 (etanercept alone)Test for heterogeneity: not applicableTest for overall effect: Z=1.95 (P=0.05)


Figure 63: ETN RCTs – drug discontinuation (total) at 12 months; relative risk (no pooling) [ETN + MTX versus ETN]

RR=relative risk

Figure 64: ETN RCTs – drug discontinuation (total) at 12 months; risk difference (no pooling) [ETN + MTX versus ETN]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: total

Study Etanercept+MTX Etanercept alone RR (fixed) Weight RR (fixed)or subcategory n/N n/N 95% CI % 95% CI

25 mg plus MTX versus 25 mg alone TEMPO 38/231 53/223 100.00 0.69 [0.48, 1.01] Subtotal (95% CI) 231 223 100.00 0.69 [0.48, 1.01]Total events: 38 (etanercept+MTX), 53 (etanercept alone)Test for heterogeneity: not applicableTest for overall effect: Z=1.93 (P=0.05)



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Figure 65: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; relative risk (no pooling) [ETN + MTX versus ETN]

RR=relative risk

Figure 66: ETN RCTs – drug discontinuation (lack of efficacy) at 12 months; risk difference (no pooling) [ETN + MTX versus ETN]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: lack of efficacy




Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog)Outcome: lack of efficacy


25 mg plus MTX versus 25 mg alone TEMPO 6/231 16/223 100.00 -0.05 [-0.09, -0.01] Subtotal (95% CI) 231 223 100.00 -0.05 [-0.09, -0.01]Total events: 6 (etanercept+MTX), 16 (etanercept alone)Test for heterogeneity: not applicableTest for overall effect: Z=2.27 (P=0.02)



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Figure 67: ETN RCTs – drug discontinuation (toxicity) at 12 months; relative risk (no pooling) [ETN + MTX versus ETN]

RR=relative risk

Figure 68: ETN RCTs – drug discontinuation (toxicity) at 12 months; risk difference (no pooling) [ETN + MTX versus ETN]

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: adverse event




Review: etanercept for rheumatoid arthritisComparison: withdrawals 12 months: etanercept plus MTX versus etanercept alone (Klareskog) Outcome: adverse event


25 mg plus MTX versus 25 mg alone TEMPO 24/231 25/223 100.00 -0.01 [-0.07, 0.05] Subtotal (95% CI) 231 223 100.00 -0.01 [-0.07, 0.05]Total events: 24 (etanercept+MTX), 25 (etanercept alone)Test for heterogeneity: not applicableTest for overall effect: Z=0.28 (P=0.78)



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Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: total


10 mg ERA (continuation) 35/166 40/169 100.00 -0.03 [-0.12, 0.06] Subtotal (95% CI) 166 169 100.00 -0.03 [-0.12, 0.06]Total events: 35 (etanercept alone), 40 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.57 (P=0.57)

25 mg ERA (continuation) 24/177 40/169 100.00 -0.10 [-0.18, -0.02] Subtotal (95% CI) 177 169 100.00 -0.10 [-0.18, -0.02]Total events: 24 (etanercept alone), 40 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=2.43 (P=0.02)


Figure 69: ETN RCTs – drug discontinuation (total) at 24 months; relative risk (no pooling)

RR=relative risk

Figure 70: ETN RCTs – drug discontinuation (total) at 24 months; risk difference (no pooling)

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: total


10 mg ERA (continuation) 35/166 40/169 100.00 0.89 [0.60, 1.33] Subtotal (95% CI) 166 169 100.00 0.89 [0.60, 1.33]Total events: 35 (etanercept alone), 40 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.57 (P=0.57)




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Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: lack of efficacy


10 mg ERA (continuation) 18/166 15/169 100.00 0.02 [-0.04, 0.08] Subtotal (95% CI) 166 169 100.00 0.02 [-0.04, 0.08]Total events: 18 (etanercept alone), 15 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.60 (P=0.55)



Figure 71: ETN RCTs – drug discontinuation (lack of efficacy) at 24 months; relative risk (no pooling)

RR=relative risk

Figure 72: ETN RCTs – drug discontinuation (lack of efficacy) at 24 months; risk difference (no pooling)

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: lack of efficacy






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Figure 73: ETN RCTs – drug discontinuation (toxicity) at 24 months; relative risk (no pooling)

RR=relative risk

Figure 74: ETN RCTs – drug discontinuation (toxicity) at 24 months; risk difference (no pooling)

RD=risk difference

Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: adverse event





Review: etanercept for rheumatoid arthritisComparison: withdrawals 24 months: etanercept versus MTX (Genovese) Outcome: adverse event



25 mg ERA (continuation) 5/177 5/169 100.00 0.00 [-0.04, 0.03] Subtotal (95% CI) 177 169 100.00 0.00 [-0.04, 0.03]Total events: 5 (etanercept alone), 5 (MTX)Test for heterogeneity: not applicableTest for overall effect: Z=0.07 (P=0.94)



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APPENDIX 10: Clinical Review Results — Effectiveness, Observational Studies

Includes discontinuations due to inefficacy, adverse events, lost to follow-up, patient refusal, physician decision, protocol violation, and other reasons, Y1 <18 months, Y2 18 to 24 months, Y3 25 to 36 months, Y4 >36 months; *Y1 ≤12 months, Y2 12 to 24 months, Y3 ≥ 24 months; †estimated from K-M graph; ‡mean treatment duration=72.6 weeks; NR=not reported.

Table 1: Observational studies — discontinuation rates, all causes IFX ETN N Y1 n (%) Y2 n (%) Y3 n (%) Y4 n (%) N Y1 n (%) Y2 n (%) Y3 n (%) Y4 n (%)

Geborek52† 135 34 (25%) 34 (25%) 166 25 (15%) 35 (21%) Flendrie53 83 35 (42%) 37 (44%)† 14 4 (29%) 5 (38%)†

Abarca54* 116 19 (16%) 53 (46%) 60 (52%) 155 13 (8%) 17 (11%) 27 (17%) IFX and

ETN

Zink55 343 119 (35%) 511 160 (31%)

Carreno56 62 NR 8 (13%) __ __ __ __ __ Ortiz Garcia57 45 NR 12 (27%) __ __ __ __ __ Sidiropoulos61 68 18 (27%) 20 (29%)‡ __ __ __ __ __ Stern58 Study 1 Study 2

394

(1324)

56 (14%)

NR

99 (25%)

NR

118 (30%)

NR

__ __ __ __ __

Chevillotte-Maillard59 age >70 age <70

11 72

4 (36%) 26 (36%)

__ __ __ __ __

Flendrie60 LEF+IFX† IFX†

57

105

17 (30%) 32 (30%)

30 (52%) 50 (48%)

33 (58 %) 74 (70%)

33 (58%) 74 (70%)

__ __ __ __ __

IFX Only

Voulgari65 __ __ __ __ __ 84 6 (7%) 19 (23%) 28 (33%) Moreland62¥ __ __ __ __ __ 628 NR NR 210 (33%) Yazici63 __ __ __ __ __ 88 21 (24%) Kremer67 __ __ __ __ __ 79 NR NR NR 14 (18%) Baumgartner64 recent RA established RA

__ __ __ __ __

207 464

NR NR

NR NR

59 (29%) 176 (38%)

ETN Only

Feltelius66 __ __ __ __ __ 1,073 NR 172 (16%)


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Table 2: Observational studies — discontinuation rates, lack of efficacy

IFX ETN

N Y1 n (%) Y2 n (%) Y3 n (%) Y4 n (%) N Y1 n (%) Y2 n (%) Y3 n (%) Y4 n (%)

Geborek52† 135 11 (8%) 11 (8%) 166 8 (5%) 13 (8%)

Flendrie53 83 13 (16%)* 14 1 (7%) Abarca54 – no inefficacy data given

__ __ __ __ __ __ __ __ __ __

IFX and ETN

Zink55 343 68 (20%) 511 92 (18%) Carreno56 62 NR 2 (3%) __ __ __ __ __

Ortiz Garcia57 45 NR 3 (7%) __ __ __ __ __ Sidiropoulos61 68 NR 5 (7%)** __ __ __ __ __ Stern58 Study 1 Study 2

394

(1,324)

12 (3%)

NR

__ __ __ __ __


11 72

0 (0%)

12 (17%)

__ __ __ __ __


57

105

5 (8%)

12 (11%)

12 (22%) 21 (20%)

12 (22%) 48 (46%)

12 (22%) 48 (46%)

__ __ __ __ __

IFX Only

Voulgari65 __ __ __ __ __ 84 2 (2%) 6 (7%) 9 (10 %) Moreland62‡ __ __ __ __ __ 628 NR NR 57 (9%) Yazici63 __ __ __ __ __ 88 11 (13%) Kremer67 __ __ __ __ __ 79 NR NR NR 3 (4%) Baumgartner64 recent RA established RA

__ __ __ __ __ 207 464

NR NR

NR NR

11 (5%) 42 (9%)

ETN Only

Feltelius66 __ __ __ __ __ 1073 NR 67 (6%)

*Includes patients who withdrew for inefficacy and safety reasons; †estimated from K-M graph; ‡median exposure time=25months; **mean treatment duration=72.6 weeks; NR=not reported.


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Table 3: Observational studies — clinical outcomes; swollen joints counts Swollen Joint Count N Baseline (n) 1yr (n) 2yr (n) 3yr (n)

Sfriso68 median median IFX IFX+MTX 63 10.0 (63) 2.0 (9)

Baumgartner64* mean mean mean mean recent RA 207 23.5 (207) 9.0 (207) 7.0 (207) 6.0 (207) established RA 464 25.1 (464) 9.8 (464) 7.5 (464) 7.5 (464) Genovese69* median median median median MTX to ETN 25 mg 143 6.2 (92) 4.0 (92) 4.5 (92) 4.2 (92) ETN 10 mg to ETN 25 mg 163 5.5 (103) 3.0 (103) 4.5 (103) 3.5 (103) ETN 25 mg 162 4.5 (98) 4.5 (98) 3.0 (98) 4.0 (98) Kremer67* median median median median ETN+MTX 79 18.0 (76) 4.0 (63) 5.1 (79) 6.0 (57) Fleischmann71* mean mean <65 years 931 24.8 (931) 9.7 (931) >65 years 197 26.5 (197) 10.0 (197) Moreland62 median median median median

ETN

ETN 628 25.5 (628) 7.5 (484) 5.0 (300) 4.5 (148)

* Calculated from graphs.


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Table 4: Observational studies — clinical outcomes; ACR responses N ACR20/50/70 Responses

1 year n/N (%)

2 years n/N (%)

3 years n/N (%)

Geborek52 IFX ACR20 135 22/34 (65%) ACR50 135 13/34 (38%) ACR70 135 6/34 (18%) Geborek52 ETN ACR20 166 71/107 (66%) ACR50 166 49/107 (46%)

IFX or ETN

ACR70 166 19/107 (18%) Voulgari65 ACR20 84 59/78 (76%) 35/45 (78%) 13/16 (81%) ACR50 84 38/78 (49%) 27/45 (60%) 10/16 (63%) Sfriso68 ACR20 63 9/9 (100%) ACR50 63 6/9 (67%) ACR70 63 4/9 (44%) Carreno56 ACR20 62 18/30 (60%) 10/18 (56%) ACR50 62 16/30 (53%) 10/18 (56%)

IFX

ACR70 62 4/30 (13%) 3/18 (17%) Baumgartner64Φ ACR20 recent RA 207 NR NR 157 (76%) estab RA 464 NR NR 357 (77%) ACR50 recent RA 207 NR NR 116 (56%) estab RA 464 NR NR 232 (50%) ACR70 recent RA 207 NR NR 68 (33%) estab RA 464 NR NR 130 (28%) Durez70*Φ ACR20 stable IFX 405 275 (68%) increased IFX 106 63 (59%) all patients 511 338 (66%) ACR50 all patients 511 221 (43%) ACR70 all patients 511 117 (22%) Genovese69* ACR20 MTX to ETN 25 mg 143 66/92 (72%) 66/92 (72%) 60/92 (65%) ETN 10 mg to ETN 25 mg 163 82/103 (80%) 78/103 (76%) 76/103 (74%) ETN 25 mg 162 74/98 (76%) 78/98 (80%) 67/98 (68%) ACR50 MTX to ETN 25 mg 143 52/92 (57%) 48/92 (52%) 48/92 (52%) ETN 10 mg to ETN 25 mg 163 57/103 (55%) 59/103 (57%) 59/103 (57%) ETN 25 mg 162 57/98 (58%) 57/98 (58%) 48/98 (49%) ACR70 MTX to ETN 25 mg 143 29/92 (32%) 33/92 (36%) 34/92 (37%) ETN 10 mg to ETN 25 mg 163 36/103 (35%) 36/103 (35%) 33/103 (32%) ETN 25 mg 162 35/98 (36%) 33/98 (34%) 32/98 (33%) Kremer67 ETN+MTX ACR20 79 61/76 (80%) 48/63 (76%) 44/57 (77%) ACR50 79 40/76 (53%) 30/63 (48%) 27/57 (47%)

ETN

ACR70 79 13/57 (23%)


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*Calculated from graphs; NR=not reported.

Table 5: Observational studies — clinical outcomes; DAS28 DAS28 N Baseline (n) 1 year (n) 2 years (n) 3 years (n)

Flendrie60* mean mean mean mean IFX 105 5.9 4.27 4.0 4.7 IFX LEF+IFX 57 5.7 4.19 3.6 5.0 Genovese69* median median median median

MTX to ETN 25 mg 143 3.3 (92) 3.0 (92) 3.0 (92) 2.8 (92)

ETN 10 mg to ETN 25 mg 163 3.5 (103) 3.1 (103) 2.7 (103) 3.0 (103)

ETN 25 mg 162 3.0 (98) 2.9 (98) 2.9 (98) 2.6 (98)

Feltelius66 ETN

1,073

Inactive n (%) 6/763 (0.8%) 133/556 (24%) 125/470 (27%)

Low activity n (%) 6/763 (0.8%) 69/556 (12%) 63/470 (13%)

Intermediate activity n (%) 151/763 (20%) 279/556 (50%) 219/470 (47%)

ETN

High activity n (%) 601/763 (79%) 75/556 (13%) 63/470 (13%)

*calculated from graphs

ETN Fleischmann71 ACR20 <65 years 931 642 (69%) ≥65 years 197 130 (66%) ACR50 <65 years 931 410 (44%) ≥65 years 197 79 (40%) ACR70 <65 years 931 186 (20%) ≥65 years 197 33 (17%) Moreland62 ACR20 628 NR NR 109/149 (73%)

ACR50 628 NR NR 75/149 (50%) ACR70 628 NR NR 39/149 (26%)


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*calculated from graphs; †18 months; ‡30 months.

Table 6: Observational studies — clinical outcomes; HAQ HAQ N Baseline

(n) 1 year (n) 2 years (n) 3 years (n)

IFX Carreno56* IFX+MTX

62

mean 2.3

mean 2.0

mean† 2.0

Baumgartner64* recent RA established RA

207 464

mean 1.45 (207) 1.64 (464)

mean 0.75 (207) 1.0 (464)

mean 0.7 (207) 1.0 (464)

mean 0.7 (207)

0.95 (464)

ETN Genovese69* MTX to ETN 25 mg ETN 10 mg to ETN 25 mg ETN 25mg

143 163 162

median 0.5 (92) 0.6 (103) 0.5 (98)

median 0.5 (92) 0.6 (103) 0.5 (98)

median 0.6 (92) 0.6 (103) 0.5 (98)

median 0.6 (92) 0.6 (103) 0.6 (98)

HAQ - % patients with HAQ=0 or HAQ <1 N 1 year, n/N (%) 2 years, n/N (%) 3 years, n/N (%)

Baumgartner64* HAQ<1 recent RA established RA HAQ=0 recent RA established RA

207 464

207 464

92/148 (62%) 150/288 (52%)

39/148 (26%) 40/288 (14%)

Kremer (2003)67 HAQ=0 ETN+MTX

79

10/57 (18%)

ETN

Moreland62 HAQ=0

628

61/484 (13%)

42/300 (14%)

‡ 27/149 (18%)


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*calculated from graphs; †n at year 5.

Table 7: Observational studies — clinical outcomes; radiological scores (van der Heijde-Sharp) N† Baseline 1 year 2 years 3 years 4 years 5 years

IFX (ATTRACT follow-up) Breedveld72 Total (Hands and Feet) MTX only MTX+IFX 3 mg/kg q8wk MTX+IFX 3 mg/kg q4wk MTX+IFX 10 mg/kg q8wk MTX+IFX 10 mg/kg q4wk Total IFX Erosion Score MTX only MTX+IFX 3 mg/kg q8wk MTX+IFX 3 mg/kg q4wk MTX+IFX 10 mg/kg q8wk MTX+IFX 10 mg/kg q4wk Total IFX Joint Space Narrowing MTX only MTX+IFX 3 mg/kg q8wk MTX+IFX 3 mg/kg q4wk MTX+IFX 10 mg/kg q8wk MTX+IFX 10 mg/kg q4wk Total IFX

12 10 16 17 6 49

12 10 16 17 6 49

12 10 16 17 6 49

- - mean change from baseline

25.03 −0.63 −2.51 1.67 −1.39 −0.54

12.21 −1.02 −1.07 0.46 −0.78 −0.49

12.82 0.39 −1.44 1.21 −0.61 −0.05

- - -

ETN (ERA follow-up) Genovese69* Total MTX to ETN 25 mg ETN 10 mg to ETN 25 mg ETN 25 mg Erosion Score MTX to ETN 25 mg ETN 10 mg to ETN 25 mg ETN 25 mg Joint Space Narrowing MTX to ETN 25 mg ETN 10 mg to ETN 25 mg ETN 25 mg

91 106 100

91

106 100

91

106 100

mean 13.0 10.0 14.6

7.3 5.9 7.4

5.7 4.1 7.2

- - -

mean

13.4 11.2 16.0

7.3 6.7 8.0

6.0 4.6 8.2

mean

13.8 11.2 16.4

7.7 6.7 8.2

6.1 4.6 8.4


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APPENDIX 11: Clinical Review Results — Safety

Table 1: IFX RCTs — selected adverse events Infliximab

n/N Infliximab+MTX n/N MTX Type of AE Studies

3 mg/kg q8wk 3 mg/kg q4wk

6 mg/kg q8wk

10 mg/kg q8wk

10 mg/kg q4wk

7.5 mg to 20 mg per wk

1 year ATTRACT 54 wk41 ASPIRE 54 wk43

10/88 (11%) 52/372 (14%)

14/86 (16%)

-

- 51/377 (14%)

17/87 (20%)

-

16/81 (20%)

-

18/86 (21%) 32/291 (11%)

Serious AE

POOLED 1.03 (0.72, 1.46)

- - - - referent

ATTRACT 54 wk41 ASPIRE 54 wk43

0/88 2/372 (0.5%)

0/86 -

- 2/377 (0.5%)

0/87 -

0/81 -

0/86 0/291

Serious infusion reactions

POOLED 3.91 (0.19, 81.22)

- - - - referent


50/74 (68%) 118/298 (40%)

40/64 (62%)

-

- 106/309 (34%)

44/71 (62%)

-

34/64 (53%)

-

18/69 (26%) 29/256 (11%)

ANA

POOLED 3.16 (2.38, 4.19)*

- - - - referent


9/88 (10%) 71/298 (24%)

9/85 (11%)

-

- 64/309 (21%)

9/87 (10%) -

6/81 (7%)

-

0/84 1/256 (0.4%)

DNA

POOLED 47.19 (9.36, 237.81)*

3/86*

Death† ASPIRE 54 wk43 1/372 - 1/377 - - 2/291 Malignancies† ATTRACT 54 wk41

ASPIRE 54 wk43 -

0/372 - -

- 4/377

- -

2/81 -

- 0/291

Anaphylactoid reaction

ASPIRE 54 wk43 0/372 - 3/377 (1%) - - 0/291

ASPIRE 54 wk43 Quinn 54 wk45

79/372 (21%) 1/10 (10%)

- -

56/377 (15%)

-

- -

- -

20/291 (7%) 0/10

Non-serious infusion reactions

POOLED 3.09 (1.95, 4.90)*

referent

Rash ATTRACT 54 wk41 - - - - 1/81 - Cutaneous vasculitis

Quinn 54 wk45 1/10 (10%) - - - - -

Abnormal liver function

Quinn 54 wk45 1/10 (10%) - - - - -


2/88 (2%) 21/372 (5.6%)

6/86 (7%)

-

- 19/377 (5.0%)

7/87 (8%) -

6/81 (7%)

-

7/86 (8%) 6/291 (2.1%)

Serious infections

POOLED 1.48 (0.74,2.93) - - - - referent 2 years Serious AE ATTRACT 102 wk42 29/88 (33%) 20/86

(23%) - 25/87

(29%) 26/81 (32%)

28/86 (33%)

Serious infections

ATTRACT 102 wk42 10/88 (11%) 11/86 (13%)

- 11/87 (13%)

8/81 (10%)

11/86 (13%)


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Table 1: IFX RCTs — selected adverse events Infliximab

n/N Infliximab+MTX n/N MTX Type of AE Studies

3 mg/kg q8wk 3 mg/kg q4wk

6 mg/kg q8wk

10 mg/kg q8wk

10 mg/kg q4wk

7.5 mg to 20 mg per wk

Serious infusion reactions

ATTRACT 102 wk42 0/88 1/86 (1%)

- 0/87 0/81 0/88

Death ATTRACT 102 wk42 3/88 (3%) 2/86 (2%) - 1/87 (1%) 1/81 (1%) 4/86 (5%)

Malignancies ATTRACT 102 wk42 1/88 (1%) 0/86 - 3/87 (3%) 5/81 (6%) 1/86 (1%)

* statistically significant; †ATTRACT reported five deaths in IFX+MTX groups and three deaths in MTX only group. Cancer developed in five IFX treated patients (two recurrences and three new cases). Serious AE according to World Health Organization classification; ANA=antinuclear antibodies; DNA=anti double-stranded deoxyribonucleic acid antibodies.


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Table 2: ETN RCTs — selected adverse events Etanercept n/N etanercept alone n/N Etanercept+MTX n/N MTX

Type of AE Studies ERA reported n patients TEMPO reported n events

10 mg SC biw 25 mg SC biw 25 mg SC biw+MTX 7.5 mg to 20 mg per week

1 year Serious AE TEMPO 52 wk49 - 25/223 (11%) 19/231 (8%) 27/228 (12%)

Reaction at injection site ERA 52 wk46 TEMPO 52 wk49*

63/208 (30%) -

77/207 (37%) 46/223 (21%)*

- 23/231 (10%)*

16/217 (7%) 4/228/ (2%)*

Upper respiratory tract infection ERA 52 wk46 57/208 (27%) 72/207 (35%) - 84/217 (39%)

Serious infections TEMPO 52 wk49 - 10/223 (4%) 10/231 (4%) 10/228 (4%) Death ERA 52 wk46

TEMPO 52 wk49 1/208 (1%)

- 1/207 (1%)

1/223 -

1/231 (1%) 0/207 1/228

Malignancies ERA 52 wk46 TEMPO 52 wk49

2/208 (1%) -

3/207 (2%) 4/223 (2%)

- 1/231 (1%)

2/217 (1%) 1/228 (1%)

2 years

Injection site reaction ERA 104 wk48 66/208 (32%) 81/207 (39%) - 19/207 (9%)

Non serious infections ERA 104 wk48 5/208 (2%) 7/207 (3%) - 9/217 (4%)

Serious infections ERA 104 wk48 1/208 (1%) 1/207 (1%) - 1/217 (1%)

Death ERA 104 wk48 0/208 0/207 - 0/217

Malignancies ERA 104 wk48 3/208 (1.4%) 4/207 (1.9%) - 3/217 (1.4%)

*statistically significant.


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Table 3: Observational studies — discontinuation rates due to adverse events IFX ETN N Y1 Y2 Y3 Y4 N Y1 Y2 Y3 Y4

Geborek84† 135 24 (18%)

24 (18%)

166 12 (7%)

25 (15%)

Flendrie53 83 25 (30%)*

14 1 (7%)

IFX and ETN

Zink55 343 64 (19%)

511 64 (13%)

Carreno56 62 NR 6 (10%)

Ortiz Garcia57 45 NR 9 (20%)

Sidiropoulos61 68 NR 7 (10%) Φ

Stern58 Study 1 Study 2

394

1324

10 (3%)

NR


11 72

3 (27%) 9 (13%)


57 105

9 (16%)

23 (22%)

14

(25%) 35

(33%)

20

(35%) 39

(37%)

20

(35%) 39

(37%)

IFX Only

Voulgari65 84 3 (4%)

11 (13%)

16 (19%)

Moreland62† 628 NR NR 44 (7%)

Yazici63 88 7 (8%)

Kremer67 79 NR NR NR 2 (3%)

Baumgartner64 recent RA established RA

207 464

NR NR

NR NR

17

(8%) 42

(9%)

ETN Only

Feltelius66 1073 NR 59 (6%)

* Includes patients who withdrew for inefficacy and safety reasons; †estimated from K-M graph; ‡median exposure time=25 months; NR=not reported.


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APPENDIX 12: Economic Review—Excluded Studies Other or no economic evaluation 1. Erkan D, Yazici Y, Harrison MJ, Paget SA. Physician treatment preferences in rheumatoid arthritis of

differing disease severity and activity: the impact of cost on first-line therapy. Arthritis Rheum 2002;47(3):285-90.

2. Fraenkel L, Bogardus ST, Concato J, Felson DT, Wittink DR. Patient preferences for treatment of rheumatoid arthritis. Ann Rheum Dis 2004;63(11):1372-8.

3. Jobanputra P, Wilson J, Douglas K, Burls A. A survey of British rheumatologists' DMARD preferences for rheumatoid arthritis. Rheumatology 2004;43(2):206-10.

4. Lu CY, Williams K, Day R, March L, Sansom L, Bertouch J. Access to high cost drugs in Australia. Br Med J 2004;329(7463):415-6.

5. Mera VA, Blanco RJ, Caamaño FM. [Approximation to the cost of pharmacological treatment of rheumatoid arthritis in Spain]. An Med Interna 2003;20(3):114-21.

6. Shah ND, Hoffman JM, Vermeulen LC, Hunkler RJ, Hontz KM. Projecting future drug expenditures: 2003. Am J Health Syst Pharm 2003;60(2):137-49.

7. Slothuus U, Larsen ML, Junker P. The contingent ranking method: a feasible and valid method when eliciting preferences for health care? Soc Sci Med 2002;54(10):1601-9.

8. Young D. Medicare holds lottery for access to expensive drugs. Am J Health Syst Pharm 2004;60(16):1632, 1636.

Incomplete data or analysis

1. Erkan D, Yazici Y, Paget SA. The impact of pharmacoeconomics on the treatment of rheumatoid arthritis: a 3-year longitudinal study. Drug Benefit Trends 2003;15(Suppl C):8-13.

2. Mount C, Featherstone J. Rheumatoid arthritis market. Nat Rev Drug Discov 2005;4(1):11-2.

3. Weycker D, Yu EB, Woolley JM, Oster G. Retrospective study of the costs of care during the first year of therapy with etanercept or infliximab among patients aged > or =65 years with rheumatoid arthritis. Clin Ther 2005;27(5):646-56.

Abstracts (relevant economic evaluations excluded because they were abstracts)

1. Badia X, Serrano D, Magaz S. A cost-minimisation analyse for studying the efficiency of biologic therapies (BT) in rheumatoid arthritis (RA): overview for the Spanish setting [abstract]. Value Health 2004;7(6):663.

2. Badia X, Serrano D, Magaz S. Assessing intangibles in biologic therapies for rheumatoid arthritis (RA): a willingness to pay (WTP) study in Spanish patients [abstract]. Value Health 2004;7(6):669.

3. Barbieri M, Wong JB, Drummond MF. The cost-effectiveness of infliximab for severe rheumatoid arthritis [abstract]. Value Health 2001;4(6):485.


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4. D'Souza AO, Crivera C, Coyle JJ. Economic analysis of novel disease-modifying anti-rheumatic drugs (DMARDS) for rheumatoid arthritis (RA) patients in a managed care setting [abstract]. Value Health 2003;6(3):222.

5. De Portu S, Ferraccioli G, Sarzi-Purrini P, Fiocco U, Montecucco C, Valesini A, et al. A comparison of cost of infliximab and etanercept in the treatment of rheumatoid arthritis in Italy: results of the IERI Study Group [abstract]. Value Health 2004;7(6):665.

6. Huse DM, Doyle J. First-year costs associated with novel disease-modifying drugs in the treatment of patients with rheumatoid arthritis [abstract]. Value Health 2002;5(6):180.

7. Igarashi A, Fukuda T, Tsutani K, Miyasaka N. Economic evaluation of self-injection vs ambulatory care of anti-rheumatoid biologics (etanercept) in Japan [abstract]. Value Health 2004;7(3):240-1.

8. Lopatriello S, Berto P. Etanercept versus infliximab plus methotrexate in rheumatoid arthritis: a cost-effectiveness analysis from the Italian NHS perspective [abstract]. Value Health 2003;6(6):725.

9. Malone DC. Cost-effectiveness analysis of etanercept monotherapy versus infliximab plus methotrexate in the treatment of rheumatoid arthritis [abstract]. Arthritis Rheum 2001;44(9 Suppl):S322.

10. Singh A, Wanke LA, Malone DC, Ortmeier BG. Cost-efficacy comparison of adalimumab and etanercept in the treatment of rheumatoid arthritis [abstract]. Arthritis Rheum 2003;48(9 Suppl):S461.

11. Spalding JR, Hay JW. Cost-effectiveness of tumor necrosis factor alpha (TNF-alpha) inhibitors as first-line agents in rheumatoid arthritis [abstract]. Value Health 2004;7(3):241.


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APPENDIX 13: Economic Review—Study Characteristics

Table 1: Characteristics of health technology assessments Jointly Reviewed Studies HTA TX Year

Author(s) Choi122

200131 Schering-Plough NICE submission (IFX) Jobanputra IFX

ETN 200232

Wyeth NICE submission (ETN) Choi122 Jobanputra32 Kulp IFX

ETN 200430 Nuijten130 Barton33 Kobelt113 Kobelt114

Gulácsi IFX 200419

Lyseng-Williamson134

Barton IFX ETN 200433 Jobanputra32

Jobanputra32 Choi122 Choi123 Yazdani127 Ollendorf125

Kristenesen

IFX ETN 200218

Nuijten130

Maini238

Lipsky41 Moreland143 Moreland62

Ward239

Coyle IFX ETN 200634

Maetzel240


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Table 2: Characteristics of reviews Jointly Reviewed Studies

Review TX Year Pharmaceutical Funding/Authorship Author(s)

Fautrel241 Kobelt113 Nuijten130 Ollendorf125 Wong116 Wong242 Wong243

Lyseng-Williamson and Foster IFX 2004134 Adis International

Limited

Wong244 Kavanaugh245 Kobelt113 Marra246 Van vollenhoven247

Nahar IFX 2003135 not specified

Wong116 Brennan117 Choi123 Choi122 Hernandez-Cruz248 Kobelt114 Nuijten130

Lyseng-Williamson and Plosker ETN 2004136 Adis International

Limited

Ollendorf125 Brennan117 Choi122 Jobanputra32 Kobelt113 Kobelt114

Bansback IFX ETN 2005137 none

Wong116 Brennan249 Choi123 Kavanaugh245 Huse250 Malone251 Malone252 Malone253 Malone254 Nuijten130 Ollendorf125 Rubio-Terres36

Emery IFX ETN 2004138 Wyeth

Yelin128 Brennan117 Choi123 Choi122 Jobanputra32 Kobelt114 Kobelt113 Nuijten130

Merkesdal IFX ETN 2004139 not specified

Wong116 Emery140 Strand142 Kalden141

Rubio-Terres IFX MTX LEF

200136 Aventis Pharma

Lipsky41


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Table 3: Characteristics of individual economic evaluations

Study TX Population Origin Trial (cohort) Time

Horizon Pharmaceutical

Funding, Authorship Model

Bansback120 ADM ETN IFX

Sweden

Weinblatt 2003 (ARMADA) Keystone Van de Putte Weinblatt 1999 Moreland Maini (ATTRACT) Crnkic Geborek 2002

6 months Abbott Laboratories Monte Carlo

Barbieri115 IFX+MTX UK

Maini (ATTRACT) Lipsky Wong (ARAMIS)

lifetime Schering-Plough Markov

Brennan117 ETN UK Moreland Young (ERAS) lifetime Wyeth Laboratories Monte Carlo

Chiou121

IFX ETN ANA ADM

US

Maini (ATTRACT) Cohen 2002 Weinblatt 1999 Klareskog (TEMPO) Weinblatt 2003 (ARMADA) Bresnihan Lipsky 2000 1998 (ATTRACT)

1 year not specified decision-sensitivity analysis

Choi123

ETN LEF MTX (up to 15 mg weekly) SSZ no second line agent

US

Smolen Strand Bathon Emery

6 months none decision-analysis

Choi122 ETN ETN+MTX US

Weinblatt Moreland Tugwell O’Dell

6 months none decision-analysis

Gilbert129 IFX or ETN US PharMetrics Patient-Centric Database

1 year Abbott Laboratories Inc

predictive model for dose escalation and comparison of annual costs

Kavanaugh131 IFX US ATTRACT 1 year Centocor

change in HRQOL and employability by HAQ

Kobelt113 IFX UK

Maini (ATTRACT) Young (ERA) Ebenhardt (Lund)

10 years Schering-Plough Markov


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Table 3: Characteristics of individual economic evaluations

Study TX Population Origin Trial (cohort) Time

horizon Pharmaceutical

Funding, Authorship Model

Kobelt114 ETN or IFX Sweden Crnkic (SSATG) 1 year

Reumatikerförbundent Österlund & Kock Foundations King

Gustav V 80 year fund

improvement versus year before treatment

Kobelt118 ETN+MTX Sweden Kareskog (TEMPO)

2 to 10 years Wyeth Research Markov

Kosinski47 ETN MTX US

Bathon (Subanalysis of ERA trial)

1 year Immunex Corporation &

Wyeth Ayerst laboratories

multiple regression models

Nuijten130 ETN The Netherlands van Jaarsveld 1 year Wyeth Netherlands &

Wyeth-Ayerst decision-analysis

Ollendorf125 LEF US

PharMetrics Integrated Outcomes Database

1 year Aventis Pharmaceutical Inc

GLM (generalized log-linear regression modelling techniques)

Ollendorf126 LEF IFX US

PharMetrics Patient-Centric Database

1 year Bristol-Myers Squibb cost analysis of dose escalation

Rubio-Terres124

LEF+MTX IFX+MTX Spain

Aventis Pharmaceuticals; Lipsky, 2000

6 months Aventis Pharma, SA cost-minimization analysis

Slothuus132 IFX Denmark RA patients from Odense University Hospital

NA not specified

double-bounded & contingent ranking

Sorensen133 ETN or IFX Denmark Based on the 2000 Danish national health survey

5 years

Danish Centre for Evaluation and Health

Technology Assessment (DACEHTA)

sensitivity analysis

Welsing119 LEF ETN The Netherlands

Hartman Moreland , Weinblatt Cohen

5 years not specified Markov

Wong116 IFX US

Maini (ATTRACT) Wolfe and Fries (ARAMIS)

lifetime Schering-Plough Markov

Yazdani127 LEF US

PharMetrics Integrated Outcomes Database

6 months Aventis Pharmaceuticals Inc

intention to treat, sensitivity analysis

Yelin128 ETN US RAPOLO RAPANEL 1 year Amgen Inc, Wyeth

Research & NIH sensitivity analysis

NA=not applicable.


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APPENDIX 14: Economic Review Results

Table 1: Results of health technology assessments HTA TX Conclusions

Jobanputra31,32 IFX ETN

IFX and ETN shown to be clinically effective for treatment of RA; inconclusive whether there is enough cost offset due to effective delay of disease progression to make therapies cost-effective

Kulp30 IFX ETN evaluation largely followed Jobanputra HTA including use of Birmingham Preliminary Model (BPM)

Gulácsi19 IFX IFX likely to be cost-effective therapy in Hungarian health care system; evaluation recommended use of Hungarian data to compare with international findings on effectiveness and costs

Barton33 IFX ETN

presented updated simulation of cost-effectiveness of IFX and ETN to include reduced health care resource utilization due to improved radiographic progression

Kristenesen18

IFX ETN

use of ETN or IFX should be second-line strategy after traditional DMARDs fail; recommendation based largely on medication costs of anti-TNFα therapies

Coyle34 IFX ETN

ETN and IFX+MTX more effective than baseline therapy for treatment of RA; authors could not find scenario where ETN or IFX+MTX cost-effective from health care system perspective, compared with gold for treatment of RA

Table 2: Results of reviews

Review TX Conclusions

Lyseng-Williamson and Foster134 IFX IFX resulted in acceptable cost-utility ratios; long-term studies need to include benefit of delay of radiographic progression due to IFX

Nahar135 IFX cost-effectiveness of IFX sensitive to modelling of long-term effects and costs of therapy; more long-term observation and direct comparisons with other biologic therapies needed

Lyseng-Williamson and Plosker136 ETN ETN may be cost-effective for DMARD-naïve and DMARD-resistant RA patients; more long-term studies need to be completed using societal perspective

Bansback137 IFX ETN

anti-TNFα therapies likely to be cost-effective; needs to be more research on long-term cost-effectiveness of drugs and which drugs comparatively more cost-effective

Emery138 IFX ETN IFX and ETN likely to be cost-effective, with evidence suggesting ETN more cost-effective in short run

Merkesdal139 IFX ETN

RA treatment with ETN or IFX may not be cost-effective for population; specific subgroups need to be identified in which biologics are cost-effective therapies

Rubio-Terres36 IFX+MTX LEF

LEF monotherapy slightly more effective than IFN+MTX with respect to ACR20 response rate; LEF equivalent with respect to ACR50 response; 1-year cost of IFN+MTX more expensive than LEF by factor of 8.24; cost per patient of 1-year treatment with LEF or with IFX+MTX estimated to be €1,893 and €15,604 respectively


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Table 3: Results of individual economic evaluations

Study TX Base Comparator Outcome Weighting

Time Horizon Rate of Discount Conclusions

Bansback120 ADA ADA+MTX ETN ETN+MTX IFX+MTX

traditional DMARDs transformation from HAQ-Di to HUI-3

6 months 3% (costs) 3% (benefits)

ADA is a CE treatment for moderate RA. On the basis of these findings, one cannot be certain about which TNF antagonist is the most cost-effective.

Barbieri115 IFX+MTX MTX HAQ and VAS lifetime 6% (costs) 1.5% (benefits)

IFX may be a cost-effective treatment in patients with severe active treatment-resistant RA

Brennan117 ETN intramuscular gold; LEF; CSA

regression HAQ versus EQ-5D

lifetime 6% (costs), 1.5% (effect)

ETN should be considered cost-effective when compared against traditional DMARDs in UK setting

Chiou121 monotherapies: ADA ETN; combination therapies: ADA+MTX Anakinra+MTX ETN+MTX IFX+MTX

Anakinra ACR20, 50, 70, HAQ

1 year no discounting Biologic response modifiers are cost-effective for RA patients who fail traditional DMARD therapy. ETN (monotherapy or with MTX) appears to be the most cost-effective. There needs to be more research on switching rules for biologics.

Choi123 ETN; LEF; MTX; SSZ;

no second line agent ACR20; ACR70WR

6 months no discounting The most efficacious option, ETN, cost $41,900 per ACR20 and $40,800 per ACR70WR with SSZ and MTX, respectively.

Choi122 ETN; ETN+MTX

CSA+MTX; MTX, HCQ, SSZ

ACR20, ACR70WR

6 months no discounting The most efficacious options, ETN, cost $41,900 per ACR2001

Gilbert129 IFX+MTX ETN predictive model for dose escalation and comparison of annual costs

1 year no discounting The difference in treatment costs may be attributed to the higher rate of dose escalation among the IFX group.

Kavanaugh131 IFX+MTX MTX HAQ; van der Heijde modified Sharp; SF-36

1 year no discounting Clinically important improvements in HAQ scores result in improved HRQOL, fewer missed days from work, and lower total health care costs.


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Time Horizon

Rate of Discount Conclusions

Kobelt113 IFX+MTX MTX EQ-5D 10 years 3% in Sweden, 6% in UK (costs); 3% in Sweden, 1.5% in UK (effect)

1 to 2 years of treatment with IFX and MTX, compared with MTX alone, will lead to offsets in direct and indirect costs

Kobelt114 ETN or IFX DMARDs EQ-5D 1 year no discounting anti-TNF treatments found to be cost-effective; no conclusion could be reached as to whether infliximab or etanercept is more cost-effective

Kobelt118 ETN ETN+MTX

MTX EQ-5D and HAQ 2 to 10 years

3% (costs) 3% (effects)

combination treatment with ETN+MTX appears cost-effective compared with MTX alone in patients such as those included in TEMPO trial

Kosinski47 ETN MTX HAQ, SF-36 1 year no discounting patients in ETN group enjoyed significantly better physical health status than patients in MTX group, through 3rd month of treatment

Nuijten130 ETN IFX NA (cost-cost study)

1 year no discounting total medical costs substantially lower for ETN, mostly because of additional costs associated with outpatient visits for IFX

Ollendorf125 ETN or IFX LEF Charlson index 1 year no discounting by deferring use of costly biologic agents, use of LEF associated with reduced RA-related utilization and costs relative to ETN and IFX

Ollendorf126 IFX+MTX (cost analysis, no comparator)

- 1 year no discounting dose escalation associated with increase in total RA-related medical costs; small cost offset for non-RA medical costs

Rubio-Terres124 LEF+MTX IFX+MTX ACR20, ACR50 1 year no discounting cost per patient of 6-month treatment with LEF+MTX or with IFX+MTX estimated to be €2,823 and €11,489 respectively.

Slothuus132 IFX - willingness to pay - - positive WTP for relief from symptoms of RA through use of infliximab

Sorensen133 ETN or IFX 1st drug

prescribed after failure with DMARDs

budget impact 5 years no discounting introduction of TNFα inhibitors into treatment of patients with RA poses considerable financial burden on health care system


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Time Horizon

Rate of Discount Conclusions

Welsing119 LEF; ETN usual care ACR20, ACR50, ACR70

5 years 4% (cost), 4% (effects)

expected effect of treatment strategies that include ETN on disease activity and QALYs larger than expected effect of usual treatment or LEF treatment in RA patients satisfying indication for TNF blocking agents in the Netherlands

Wong116 IFX+MTX MTX Visual analogue scale

lifetime 3% (costs), 3% (effect)

IFX should be preferred and cost-effective for patients with active refractory rheumatoid arthritis; clinical benefit of less physical impairment should result in lowered future direct and indirect costs that partly offset cost of IFX

Yazdani127 ETN LEF comorbid condition 6 months no discounting LEF-treated patients accrued lower charges during 6 months after initiation of therapy than did patients in ETN group

Yelin128 ETN DMARDs HAQ, employment 1 year not applicable among RA patients who had been employed at the time of diagnosis, those from ETN trial more likely to be currently employed


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Table 4: Summary of cost-utility data in 2004 Canadian dollars — health technology assessments

Study Strategy QALYs Direct Costs

Total Costs

ICER (direct costs)

ICER (total costs)

no anti-TNF 0.73 - $31,563 - -

ETN 0.95 - $61,692 - $140,789

IFX 0.85 - $54,193 - $195,084 Jobanputra31,32

ETN versus IFX - - - - $76,522 Kulp30 presented only Jobanputra,32 Choi,121 and Nuijten130 findings Gulácsi19 presented only Jobanputra32 findings

DMARDs 10.46 - $34,384 - -

ETN 10.73 - $88,351 - $199,878

IFX 10.61 - $75,115 - $271,539 Barton33*

ETN versus IFX - - - - $110,302 Kristenesen18 budget impact analysis: not cost-effectiveness or cost utility

baseline 0.09 - $9,200 - -

ETN before gold 0.36 - $48,400 - $144,700

ETN after gold 0.34 - $41,200 - $125,700 IFX+MTX before gold 0.34 - $37,900 - $113,000

Coyle34

IFX+MTX after gold 0.31 - $30,900 - $97,800

*QALYs estimated for lifetime.


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Table 5: Cost-utility data from individual studies in 2004 Canadian dollars

Study Pharmaceutical Funding/Authorship Strategy QALYs‡ Direct

Costs Total Costs

ICER (direct costs)

ICER (total costs)

MTX (Sweden) 4.42 $29,197 $171,889 - -

IFX+MTX (Sweden) 4.65 $36,670 $163,280 dominant dominant

MTX (UK) 3.69 $27,579 $82,513 - - Kobelt113 Schering-Plough

IFX+MTX (UK) 4.03 $42,111 $90,600 $42,741 $23,784

base case - - $86,751 -

HAQ <0.6 - - $256,108 -

HAQ 0.6 to <1.1 - - $123,283 -

HAQ 1.1 to <1.6 - - $121,539 -

HAQ 1.6 to <2.1 - - $74,269 -

Kobelt114 Reumatiker Vörbundent

HAQ ≥2.1

only incremental

QALYs reported-

- - $85,825 -

MTX - - - - Barbieri115 Schering-Plough

IFX+MTX

only incremental

QALYs reported

- - - $73,121 (1 yr) $53,040 (lifetime)

MTX 9.11 $115,618 $439,327 - - Wong116 Schering-Plough

IFX+MTX 9.40 $124,519 $442,195 $30,694 $9,890

DMARD 5.87 $19,643 - - - Brennan117 Wyeth

ETN 7.53 $77,325 - $34,749 -

MTX 3.08 - $324,352 - -

ETN 3.23 - $361,386 - $246,890 Kobelt118 Wyeth

ETN+MTX 3.46 - $352,701 - $74,603

usual care 2.86 $8,093 $18,295 - -

LEF 2.93 $10,118 $19,451 $33,745 $19,254

LEF to TNF* 2.99 $40,816 $48,551 $438,540 $415,718

TNF 3.00 $74,025 $80,827 $439,542 $416,877

Welsing119 NS

TNF to LEF† 3.01 $74,213 $80,973 $18,819 $14,560 DMARD 1.18 $99,261 $139,435 - - ADM 1.66 $136,408 $178,403 $78,486 $82,332 ADM+MTX 2.31 $174,851 $215,891 $66,918 $67,684 ETN 2.05 $160,321 $202,894 $70,386 $73,151 ETN+MTX 2.10 $163,255 $204,297 $69,893 $70,840

Bansback120 Abbott

IFX+MTX 1.84 $155,947 $202,256 $86,398 $95,749 ANA 0.5733 $14,472 - - - ETN 0.6421 $15,238 - $11,127 - ADM 0.5842 $15,305 - $76,407 - Anakinra+MTX 0.5772 $14,999 - - - ETN+MTX 0.6919 $15,754 - $6,687 - ADM+MTX 0.6608 $15,757 - $9,067 -

Chiou121 NS

IFX+MTX 0.5949 $16,683 - $95,139 -

*compared with LEF; †compared with TNF; ‡QALY estimation varied according to study timeframe; NS=not specified

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