pm 4.50 hochberg

Evidence-Based Care of Women with Rheumatoid Arthritis

Marc C. Hochberg, MD, MPH

Professor of Medicine and Epidemiology and Public Health

Head, Division of Rheumatology & Clinical Immunology

University of Maryland School of Medicine

Baltimore, MD

Disclosures

• Dr. Hochberg receives research support from the National Institutes of Health

• He has served as a consultant to the following commercial entities:– Abbott Laboratories, Amgen, Astra-Zeneca

Pharmaceutical Co., Bristol Myers Squibb Company, CORRONA, Genentech/Roche, Merck & Co. Inc., NicOx S.A., Novartis Pharma AG, Pfizer Inc., Pozen Inc., Theralogix LLC and UCB Inc.

“So much to do; so little time.”

The White Rabbit, “Alice in Wonderland”

Slide provided by Daniel E. Furst, M.D.

Rheumatoid Arthritis (RA)

• A chronic, systemic inflammatory disorder that principally affects the synovial joints

• Characterized by a proliferative response in the synovial membrane leading to bone and cartilage destruction and joint deformity

Hochberg MC, et al: Rheumatoid arthritis. Mosby/Elsevier, Philadelphia, 2009.

Who is Affected by RA?

• Most commonly presents between the ages of45 and 64 years1

• Overall lifetime risk of RA2

– 3.6% for women– 1.7% for men

• For women with a first-degree relative with RA, lifetime risk of RA approaches 18%2

1. Silman AJ and Hochberg MC. In: Rheumatoid Arthritis; 2010, 1st ed. 2. Crowson CS, et al. Arthritis Rheum. 2011;63:633-639.

Common Articular Features• Additive, symmetric

inflammatory arthritis– Typically involves small

joints of the hands (PIPs, MCPs), wrists, elbows, shoulders, knees, ankles, and feet (MTPs)

– DIPs, hips and spine usually spared

DIP, distal interphalangeal; MCP, metacarpophalangeal; MTP, metatarsophalangeal; PIP, proximal interphalangeal.

Characteristic Deformities

• Ulnar deviation

• Swan-neck deformity

• Boutonniere deformity

Extra-articular ManifestationsAffected tissue or organ

Comments

Infections Association with RA due to disease, medications; important implications for vaccination

Cardiovascular Pericarditis, endocarditis, myocarditis, MI; association due to underlying inflammatory disease, medications, reduced exercise, genetics

Nervous system Depression; PML (rare but often fatal in immunosuppressed; more common with biologics such as rituximab)

Skin Subcutaneous nodules

Pulmonary Pulmonary nodules; interstitial lung disease

Eyes Scleritis, episcleritis, retinal vasculitis

Other Secondary Sjogren’s syndrome, anemia, thrombocytosis, vasculitis, diabetes, GI bleeding, cancer (e.g., lymphoma)

GI, gastrointestinal; MI, myocardial infarction; PML, progressive multifocal leukoencephalopathy.

Natural History of RA: Any Gender Differences?

• Baseline measures of disease activity slightly higher in women1

– Higher swollen/tender joint count– Higher scores for pain and fatigue– Worse physician and patient global assessment of

disease activity

• No gender differences in treatment response2

1. Sokka T, et al. Arthritis Res Ther. 2009;11:R7. 2. Kristensen LE, et al. Rheumatology. 2008;47:495-499.DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.

Management of RA: 2012

• Early correct diagnosis

• Prompt initiation of traditional DMARDs– Methotrexate alone– Triple therapy (MTX, SSZ, HCQ)

• Appropriate use of biological DMARDs– Anti-TNF agents as 1st line biologics– What to use in inadequate responders?

Saag KG, et al. Arthritis Rheum. 2008;59:762-784.

DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine; TNF, tumor necrosis factor.

Early Diagnosis of RA

• Prompt referral of patients with 1 or more swollen joints (“early arthritis”) by the PCP to a rheumatologist

• Evaluation by the rheumatologist to determine correct diagnosis

• Apply 2010 ACR/EULAR Classification Criteria to identify those with early arthritis who do not have another diagnosis

Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

*Aletaha D et al: Arthritis Rheum 2010;62:2569-81.Aletaha D, et al. Arthritis Rheum. 2010;62:2569-2581.

2010 ACR/EULAR RA Classification Criteria

• Classification as ‘definite RA’ based on:– Confirmed presence of synovitis in at least

one joint– Absence of an alternative diagnosis better

explaining the synovitis

2010 ACR/EULARClassification Criteria for RA

JOINT DISTRIBUTION (0-5)1 large joint 0

2-10 large joints 1

1-3 small joints (large joints not counted) 2

4-10 small joints (large joints not counted) 3

>10 joints (at least one small joint) 5

SEROLOGY (0-3)Negative RF AND negative ACPA 0

Low positive RF OR low positive ACPA 2

High positive RF OR high positive ACPA 3

SYMPTOM DURATION (0-1)<6 weeks 0

≥6 weeks 1

ACUTE PHASE REACTANTS (0-1)Normal CRP AND normal ESR 0

Abnormal CRP OR abnormal ESR 1

≥6 = definite RA

What if the score is <6?

Patient might fulfill the criteria…

Prospectively over time (cumulatively)

Retrospectively if data on all four domains have been adequately recorded in the past


Classification Tree

*Aletaha D et al: Arthritis Rheum 2010;62:2569-81.

• >10 joints (≥1 small joint)– Positive serology or duration ≥6 wks or abnormal acute

phase reactant (APR)

• 4-10 small joints– Positive serology (if low titer, then duration ≥6 wks or

abnormal APR)

• 1-3 small joints– Positive serology and duration ≥6 wks or abnormal APR (if

low titer, then duration ≥6 wks and abnormal APR)

• 2-10 large joints (no small joints)– Positive serology and duration ≥6 wks and abnormal APR


*Aletaha D et al: Arthritis Rheum 2010;62:2569-81.

Classification Criteria in Practice


Rationale for Early Institution of Traditional DMARDs

• Early onset of functional limitation and reduced health-related quality of life

• Early onset of joint damage– Rate of progression of joint damage is

greater in early c/w late disease


RA: Typical Course

• Damage occurs early in most patients • 50% show joint space narrowing or

erosions in the first 2 years

• Disease activity and damage are associated with functional limitation and work disability– By 10 years, 50% of young working

patients are “work disabled”


Critical Elements of Management: Staging RA

• Assess disease activity • AM stiffness, synovitis (#P/T and swollen joints),

pain, ESR and/or CRP

• Document the degree of damage • Joint space narrowing and erosions on imaging• Functional status (HAQ-DI)

• Document extra-articular manifestations • Nodules, sicca symptoms, vasculitis

• Assess prior Rx responses and side effects

Imaging Tools for Assessing Early Joint Damage

• Plain radiographs– Views of hands and feet at baseline visit– Low sensitivity for early erosive disease

• Ultrasound (gray scale and power Doppler)– Tenosynovitis common– Correlates with active disease

• Magnetic resonance imaging– Gadolinium enhancement for synovitis


Grayscale and Power Doppler Ultrasound Images of Synovial Hypertrophy in RA

Brown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.

Brown AK, et al. Nat Rev Rheumatol. 2009;5:698-706.

Grayscale and Ultrasonography Images of Joint Erosion in RA

MRI in Early RA

Mak W, et al. J Musculoskel Med. 2009;26:478-486.

Approaches to Traditional DMARD Therapy

• Single agent (MTX as anchor drug)– Leflunomide or SSZ in patients with a

contraindication to MTX

• Triple therapy (MTX, SSZ, HCQ)– More efficacious than MTX alone at 6 months1

– More efficacious than MTX with either SSZ or HCQ after 2 years2

1. O’Dell J, et al. N Engl J Med. 1996;334:1287-1291. 2. O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.

DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine.

O’Dell J, et al. Arthritis Rheum. 2002;46:1164-1170.

ACR, American College of Rheumatology; HCQ, hydroxychloroquine; MTX, methotrexate; SSZ, sulfasalazine.

Triple DMARD Therapy in RA:

ACR Responses at 2 Years

Treat to Target (T2T)

• Treatment should be targeted at achieving a state of clinical remission– A state of low disease activity may be an

acceptable alternative goal, particularly in patients with established disease

• Therapy should be adjusted at least every 3 months, as needed

• Decisions should be based on validated composite measures of disease activity

Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637.

T2T Treatment Goals and Decision Points

Goal DAS-28 CDAI SDAI

Low Disease Activity

≤ 3.2 ≤ 10 ≤ 11

Clinical Remission

≤ 2.6 ≤ 2.8 ≤ 3.3

Smolen JS, et al. Ann Rheum Dis. 2010;69:631-637.

CDAI, Clinical Disease Activity Index; DAS-28, Disease Activity Score-28; SDAI, Simplified Disease Activity Index.

ACR/EULAR Definition of Remission in RA

• Patient must satisfy all of the following:– Tender joint count ≤ 1– Swollen joint count ≤ 1– C-reactive protein ≤ 1 mg/dl– Patient global assessment ≤ 1 (0-10 scale)

• Patient must have an SDAI score ≤ 3.3

Felson DT, et al. Ann Rheum Dis. 2011;70:404-413.

ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; SDAI, Simplified Disease Activity Index.

Options for Inadequate Response to Methotrexate

• Add additional traditional DMARDs– Azathioprine, cyclosporin, leflunomide,

sulfasalazine + hydroxychloroquine

• Add biologic DMARD– TNF inhibitors are agents of choice for

initial biologic therapy in patients with RA

DMARD, disease-modifying antirheumatic drug; TNF, tumor necrosis factor.


IL- 6

Pro-inflammatory cytokines targeted hitherto:

•TNF/ INF, ETN, ADA, GO, CP

•IL-1/ Anakinra

CTLA-4Ig / abatacept

Anti-CD20 / rituximab

Current Biological Targets in RA

IL-6 receptor/ tocilizumab

Smolen JS, et al. Nature Rev Drug Disc. 2003;2:473-488.

ADA, adalimumab; CP, certolizumab pegol; CTLA-4, cytotoxic T-lymphocyte antigen 4; IL, interleukin; INF, interferon; ETN, etanercept; GO, golimumab; TNF, tumor necrosis factor.

Anti-TNF Therapy in Early RA: Swefot Trial

• 487 patients with early RA enrolled

• 145 achieved LDA with MTX

• 258 randomly assigned to either infliximab or SSZ + HCQ added to MTX

van Vollenhoven RF, et al. Lancet 2009;374:459-466.

HCQ, hydroxychloroquine; LDA, low disease activity; MTX, methotrexate; RA, rheumatoid arthritis; SSZ, sulfasalazine; TNF, tumor necrosis factor.

Swefot Trial Results

Response MTX + SSZ + HCQ MTX + Infliximab RR (95% CI)

EULAR Good 32 (25%) 50 (39%) 1.59 (1.10, 2.30)

EULAR Good or Moderate

64 (49%) 77 (60%) 1.22 (0.98, 1.53)

ACR 20 37 (28%) 54 (42%) 1.48 (1.06, 2.08)

ACR 50 19 (15%) 32 (25%) 1.71 (1.02, 2.86)

ACR 70 9 (%) 15 (12%) 1.69 (0.77, 3.73)

• Frequency of adverse events similar between groups

van Vollenhoven RF, et al. Lancet 2009;374:459-466.

ACR, American College of Rheumatology; EULAR, European League Against Rheumatism; HCQ, hydroxychloroquine; MTX, methotrexate; RR, relative risk; SSZ, sulfasalazine.

Treatment of Early Aggressive RA (TEAR) Study of Traditional vs Newer Biologics

• 755 patients with early RA ( 3 years) – MTX naïve; ≥ 4 TJC/SJC; RF+ or CCP+ or 2 erosions

• Baseline characteristics– DAS 5.8; 90% RF+; pred 42%; prior DMARD 24%

• Treatment arms– Initial combination therapy with triple DMARDs or MTX/ETN (n=376)

or MTX monotherapy (n=379) for 24 weeks– If DAS >3.2 with MTX alone, step up to triple therapy or MTX/ETN

• 28% achieved LDA on MTX alone

• Study endpoints– Primary: DAS28 from weeks 48-102– Secondary: ACR20/50/70, Xray, QOL, DAS remission

• Completers analysis: 63% @ 2 yrs

Moreland L, et al. ACR 2009; Abstract 1895.

DMARD, disease-modifying antirheumatic drug; ETN, etanercept; MTX, methotrexate; RF, rheumatoid factor.

TEAR Study Results

Conclusion: Early benefits to aggressive therapy, but similar outcomesat 2 years regardless of treatment regimen

Treatment DAS28 at week 102

ACR20(6 months)

ACR50(6 months)

ACR70(6 months)

Initial MTX/ ETN (IE) 3.0 +/- 1.4 63.6% 35.5% 13.1%

Initial Triple DMARD (IT) 2.9 +/- 1.4 64.0% 38.6% 11.4%

Step-up MTX/ETN (SE) 3.1 +/- 1.4 45.2% 22.1% 3.2%

Step-up triple DMARD (ST) 2.8 +/- 1.3 47.7% 21.5% 4.7%

Week 0 Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Week 84 Week 96 Week 102

DA

S2

8

0

1

2

3

4

5

6IE

SE

IT

ST

Step-up to multipleDMARD at Week24 if DAS28 ≥ 3.2

Moreland L, et al. ACR 2009; Abstract 1895.

Initiation of a Biologic DMARD

• Choice of agent is based on the shared decision of the patient and rheumatologist

• TNF inhibitors are the biologic DMARDs of choice for patients with an inadequate response to traditional DMARDs

• Response rates generally similar across anti-TNF agents• Safety considerations– Cases of tuberculosis reactivation reported for TNF-blocking agents– Tuberculosis reactivation risk lower with etanercept (soluble TNF

receptor) than with anti-TNF monoclonal antibodies

Nam JL, et al. Ann Rheum Dis. 2010;69:976-986. Saillot C, et al. Ann Rheum Dis. 2011:70:266-271.


Numbers Needed to Treat with Biologic DMARDs to Achieve ACR Responses

Response @ 6 months NNT (95% CI)

ACR 20 3.2 (2.4, 4.0)

ACR 50 4.2 (3.6, 4.8)

ACR 70 7.7 (6.7, 10.0)

Nam JL, et al. Ann Rheum Dis. 2010;69:976-986.

Response @ 12 months NNT (95% CI)

ACR 20 3.0 (2.6, 3.6)

ACR 50 3.7 (3.2, 4.2)

ACR 70 5.9 (5.0, 6.7)

ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; NNT, number needed to treat.

Cost-Effectiveness of TNF Inhibitors in RA

van der Velde G, et al. Arthritis Care Res. 2011;63:65-78.

*Defined as incremental cost-effectiveness ratio (ICER) < $100,000 per quality-adjusted life year.DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.

Cost-effective* • In patients with an inadequate response to MTX

Not cost-effective • As initial therapy • In MTX- or traditional DMARD-

naïve patients

Options for Inadequate Responders to TNF Inhibitors

• Switch to another TNF inhibitor• Switch to another biologic DMARD with a

different mechanism of action– Abatacept– Rituximab– Tocilizumab

• Response rates generally similar between biologic DMARDs

Bergman GJD, et al. Semin Arthritis Rheum. 2010:39:425-441. Saillot C, et al. Ann Rheum Dis. 2011:70:266-271.


Numbers Needed to Treat for ACR 50 Response

Biologic DMARD NNT (95% CI)

Abatacept 4 (3-5)

Certolizumab pegol 4 (3-5)

Golimumab 6 (4-13)

Rituximab 5 (4-10)

Tocilizumab 5 (3-8)

Kristensen LE, et al. Scand J Rheumatol. 2010;iFirst:1-7.

ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; NNT, number needed to treat.

Role of Glucocorticoids in RA Management

• Low-dose glucocorticoids effective for:– Alleviating signs and symptoms– Reducing functional limitation– Slowing radiographic progression

• EULAR recommends that dose should be tapered as rapidly as possible– No good data, however, on the optimal schedule

for tapering to prevent disease flare

Gorter SL, et al. Ann Rheum Dis. 2010;69:1010-1014.

RA and Menopausal Status• Contraception, fertility issues, and hormone therapy

managed by GYN and/or primary care providers

Premenopause • Recommend contraception during DMARD therapy• No evidence of interaction between oral contraceptives

and RA

Preconception • Discontinue DMARDs at least 2 menstrual cycles before trying to conceive

Pregnancy • Expect improvement in RA symptoms during pregnancy followed by postpartum flare

• Avoid antirheumatic drugs with contraindications in pregnancy (next slide)

Postmenopause • Refer for hormone therapy at the discretion of the primary care provider or gynecologist

McNaughton S, et al. J Nurse Pract. 2008;4:370-376.

Antirheumatic Drug Risks During PregnancyDrug class

FDA Pregnancy Category

Clinical Recommendations

Corticosteroids C First-trimester use associated with increased risk of oral cleft Increased risk of adrenal insufficiency

Nonbiologic DMARDs

Sulfasalazine B No increased risk of congenital malformations Combine with folate supplements

Azathioprine D Can be continued to maintain remission during pregnancy

Methotrexate X Contraindicated in pregnancy Discontinue 3–6 months before conception

Leflunomide X Contraindicated during pregnancy Discontinue use 2 years before pregnancy

Antimalarials C HCQ is compatible with pregnancy Risk for retinal toxicity and ototoxicity higher for chloroquine than for HCQ

Biologic DMARDs

TNF inhibitors B Anti-TNF antibodies not transferred to embryo/fetus in first trimester of

pregnancy

Abatacept C No human pregnancy data available Discontinue 10 weeks before planned pregnancy

Rituximab C Reversible B-cell depletion or lymphopenia in the neonate Long half-life; discontinue 1 year before planned pregnancy

Tocilizumab C No human pregnancy data available Discontinue 10 weeks before planned pregnancy

DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine; TNF, tumor necrosis factor.

Hazes JMW, et al. Rheumatology. 2011;50:1955-1968.

Management of RA: Summary (I)

• Early referral to rheumatology and diagnosis are of paramount importance

• Traditional DMARDs should be initiated promptly after diagnosis of RA

• MTX is considered the DMARD of choice (anchor drug)

• Triple therapy can be considered as an alternative approach

DMARD, disease-modifying antirheumatic drug; MTX, methotrexate.

Management of RA: Summary (II)

• Patients with an inadequate response to MTX should be treated with a TNF inhibitor– Step up therapy using other traditional DMARDs

can be considered

• Patients with an inadequate response to one TNF inhibitor may be – Switched to another TNF inhibitor, or – Treated with a biologic DMARD with a different

mechanism of action

DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; TNF, tumor necrosis factor.

Thank you

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