model biologics indications

7/23/2019 Model Biologics Indications

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AMERICAN COLLEGE OF RHEUMATOLOGY

Position Statement

SUBJECT: Model Biologics Indications

PRESENTED BY: Committee on Rheumatologic Care

FOR DISTRIBUTION TO: Members of the American College of Rheumatology

Medical Societies

Members of CongressHealth Care Organizations/Third Party Carriers

Managed Care Entities

This policy addresses the indications for the class of drugs known as biologics. These biologics include

disease modifying anti-rheumatic drugs (DMARDs) used to treat many types of rheumatic conditions.

Each of these molecules has been approved by the FDA for specific rheumatic diseases based on theavailable peer-reviewed evidence . In addition, off label use of biologics for certain rheumatic

diseases are widely accepted and are included in this statement. ACR promotes early, equalaccess to the following biologic therapies:

Adalimumab (Humira), certolizumab pegol (Cimzia ), etanercept (Enbrel), golimumab (Simponi ),and infliximab (Remicade) inhibit the cytokine Tumor Necrosis Factor (TNF)-.

Anakinra (Kineret), rilonacept (Arcalyst) and canakinumab (Ilaris) work as antagonists to thecytokine IL-1.

Abatacept (Orencia) inhibits T-cell co-stimulation.

Rituximab (Rituxan) is a B-cell depleting therapy, whereas belimumab (Benlysta) is a B-lymphocytestimulator (BLyS)-specific inhibitor.

Tocilizumab (Actemra) is an interleukin-6 receptor inhibitor.

Denosumab (Prolia) is a RANK ligand inhibitor.

Pegloticase (KrystexxaTM) is a modified urate oxidase enzyme specific toward uric acid.

AMA CPT Copyright Statement

CPT codes, descriptions and other data only are copyright 2010 American Medical Association

(or such other date of publication of CPT). All Rights Reserved.

Region Applicable:

All Regions as applicable

Indications and Limitations of Coverage and/or Medical Necessity


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A. Coverage for medication is based on the patients condition, the appropriateness of the dose androute of administration, based on the clinical condition and the standard of medical practice

regarding the effectiveness of the drug for the diagnosis and condition.

B. The following established ICD-9, CPT and drugs will be allowed for therapy and service whencriteria are met as indicated: The foll owing codes for treatments and procedures applicable to

this policy are included below for in formational pur poses. I nclusion or exclusion of aprocedure, diagnosis or device code(s) does not consti tute or imply member coverage or

provider reimbursement policy. Please refer to the memberscontract benefi ts in effect at the

time of service to determine coverage or non-coverage of these services as it appl ies to an

individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

J0129J0135

abatacept, 10 mg (Orencia)adalimumab, 20 mg (Humira)

J0718J1438

certolizumab pegol, 1 mg (Cimzia)etanercept, 25 mg, administered under the direct supervision of a physician (not for usewhen drug is self-administered) (Enbrel)

J1745J9310J3262

J0638J2793

J0490J0897J2507

infliximab, 10 mg (Remicade)rituximab, 100 mg(Rituxan)tocilizumab (Actemra)

canakinumab (Ilaris)rilonacept (Arcalyst)

belimumab (Benlysta)denosumab (Prolia)

pegloticase (Krystexxa)

J3590*no

specificcode

anakinra (Kineret)

CPT Codes

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug);subcutaneous or intramuscular (Humira, Enbrel, Cimzia, Simponi, Orencia SQ)

96374 Therapeutic, prophylactic, or diagnostic; intravenous push (Boniva)96401 Chemotherapy, antineoplastic; subcutaneous or intramuscular (Prolia)

96413 Chemotherapy administration, intravenous infusion technique; up to 1hour, single or initial substance/drug

+96415 - each additional hour (list separately in addition to code for primary

procedure)

ICD-9 Diagnosis

099.3 Reactive Arthritis135 Sarcoidosis136.1 Behcets syndrome274.00 Gouty arthropathy, unspecified274.01 Acute gouty arthropathy


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274.02 Chronic gouty arthropathy without mention of tophus (tophi)274.03 Chronic gouty arthrocopy with tophus (tophi)

277.31 Familial Mediterranean Fever (Periodic Fever (CAPS, Muckle-Wells syndrome, FCAS)359.79 Inflammatory myopathy NOS361.19 Pseudocyst retina364.3 Uveitis NOS

370.52 Cogans syndrome379.00 Scleritis and episcleritis379.05 Scleritis with corneal involvement446.4 Granulomatosis with polyangiitis (GPA)446.5 Temporal arteritis555.9 Crohns disease NOS

556.9 Ulcerative colitis, unspecified696.0 Psoriatic arthropathy

696.1 Psoriasis NOS705.83 Hidradenitis suppurativa710.0 Systemic Lupus Erythematosus710.1 Scleroderma

710.2 Sjogrens syndrome710.3 Dermatomyositis710.4 Polymyositis714.0-714.2 Rheumatoid arthritis714.30 or 714.89uvenile idiopathic arthritis714.31 Polyarticular juvenile rheumatoid arthritis acute

714.9 Unspecified inflammatory polyarthritis716.59 Unlisted polyarthropathy or polyarthritis

720.0-720.9 Ankylosing spondylitis725 Polymyalgia rheumatica733.01 Senial Osteoporosis (post-menopausal osteoporosis)

733.09 Steroid-induced Osteoporosis

When services are Investigational/Not Medically Necessary:For the procedure codes listed above, when criteria are not met and for all other diagnosis not listedabove; or when the code describes a procedure indicated in the Policy section as Investigational/Not

Medically Necessary.

Policy Statement

I. Abatacept (Orencia)

A. Abataceptis medically necessaryand has an FDA-approved indicationfor the treatment

of:

1. Adult Rheumatoid Arthritis: reducing signs and symptoms, inducing majorclinical response, inhibiting progression of structural damage, and improving

physical function in adult patients with moderately to severely active RA.Abatacept may be used as monotherapy or concomitantly with DMARDs otherthan TNF antagonists.


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2. Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms in pediatricpatients 6 years of age and older with moderately to severely active polyarticular

JIA. Abatacept may be used as monotherapy or concomitantly with methotrexate.

B. Special considerations for abatacept:

1.

Patients should be tested for latent tuberculosis before and during therapy.Treatment for latent tuberculosis infection should be initiated prior to therapy.

2. Concomitant use with TNF antagonists increases the risk of infection.

3.

Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,Human Papilloma and Herpes Zoster vaccines are recommended.

4. During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and HumanPapilloma are recommended vaccines. Live attenuated vaccines such as HerpesZoster vaccines are not recommended during therapy.

C.

Off-label use of abataceptmay include but is not limited to:

1. Systemic Lupus Erythematosus

2. Sjogrens Syndrome3.

Vasculitides

4. Psoriatic Arthritis5. Ankylosing Spondylitis6. JIA all ages and all subtypes

7. Autoinflammatory Diseases8. Undifferentiated Polyarthritis9.

Undifferentiated Spondyloarthritis10. Reactive Arthritis

11.

Ankylosing Spondylitis

12. 12. Uveitis

D. Dosage and administration (IV administration):

1. Abatacept is administered as an intravenous infusion. Following the initialadministration, Orencia should be given at 2 and 4 weeks after the firstinfusion, then every 4 weeks thereafter.

2. A dose of 500 mg per infusion is recommended for adults with a body weight of100 kg.

5. For children > 6 years old and < 75 kg, recommended dose is 10 mg/kg per

infusion.6. For children > 6 years old and > 75 kg, dosage is according to body weight as

follows:

75-100 kg: dose is 750 mg

>100 kg: dose is 1,000 mg


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E. Dosage and administration (SQ administration):

1.

Abatacept may be administered by subcutaneous injection instead of infusion.

2. The recommended dose is 125mg by subcutaneous injection weekly.

II. Adalimumab (Humira)

A. Adalimumabis medically necessaryand has an FDA-approved indicationfor the

treatment of:

1. Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing major

clinical response, inhibiting the progression of structural damage, and improvingphysical function in adult patients with moderately to severely active disease.

2. Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderately

to severely active polyarticular juvenile idiopathic arthritis in patients 4 years ofage and older.

3. Psoriatic Arthritis (PsA): reducing signs and symptoms of active arthritis,inhibiting the progression of structural damage, and improving physical function.

4. Ankylosing Spondylitis (AS): reducing signs and symptoms in patients withactive disease.

5. Crohns Disease: reducing signs and symptoms and inducing and maintaining

clinical remission in adult patients with moderately to severely active Crohnsdisease who have had inadequate response to conventional therapy. Reducingsigns and symptoms and inducing clinical remission in these patients if they havealso lost response to or are intolerant to infliximab.

6.

Plaque Psoriasis: the treatment of adult patients with moderate to severe chronic

plaque psoriasis who are candidates for systemic therapy or phototherapy, andwhen other systemic therapies are less appropriate.

B. Special considerations with adalimumab:

1. Patients should be tested for latent tuberculosis before and during therapy.

Treatment for latent tuberculosis infection should be initiated prior to therapy.

2. Monitor HBV carriers during and several months after therapy. If reactivationoccurs then stop drug and begin anti-viral therapy.

3. Concomitant use of anti-TNF- therapy with anakinra and abatacept increasesthe risk of infection.


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4. Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,Human Papilloma and Herpes Zoster vaccines are recommended.

5. During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and HumanPapilloma are recommended vaccines. Live attenuated vaccines such as Herpes

Zoster vaccines are not recommended during therapy.

6. Treatment not recommended in patients with NYHA class III/IV with ejectionfraction 50% or less.

C. Off-label use of adalimumabmay include but is not limited to the following conditions:

1. Undifferentiated Polyarthritis

2. Undifferentiated Spondyloarthropathy3. Sarcoidosis4. Myositis

5. Behets Disease6. Uveitis

7.

Adult-Onset Stills Disease8. Reactive Arthritis

9. JIA all ages and all subtypes10. Autoinflammatory Diseases

D.

Dosage and administration:

1. Adalimumab is administered by subcutaneous injection.2. In RA, PsA, and AS the recommended dose is 40 mg every other week.3. In RA, some patients not taking concomitant methotrexate may derive additional

benefit from increasing the dosing frequency of adalimumab to 40 mg everyweek.

4.

In Crohns Disease, the recommended initial dosage is 160 mg, then 80 mg 2weeks later, and then 40 mg every other week.

5. In Plaque Psoriasis, the recommended initial dosage in 80 mg, then 40 mg every

other week.6.

For children with JIA who weigh 15 kg to 30 mg, recommended dose is 40 mgevery other week.

III.

Anakinra (Kineret)

A. Anakinrais medically necessaryand has an FDA-approved indicationfor the treatment

of:

1.

Rheumatoid Arthritis (RA): reducing signs and symptoms and slowing theprogression of structural damage in moderately to severely active RA, in patients

18 years of age or older who have failed one or more disease modifyingantirheumatic drugs (DMARDs). Anakinra can be used alone or in combinationwith DMARDs other than TNF blocking agents.

B. Special considerations with anakinra:


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1. Concomitant use with TNF antagonists increases the risk of infection.

C.

Off-label use of anakinramay include but is not limited to:

1. Adult-Onset Stills Disease2.

Periodic Febrile Syndromes

3.

Gout4. Autoinflammatory Diseases5. Juvenile Idiopathic Arthritis

D. Dosage and administration:

1. In RA the recommended dose of anakinra is 100 mg/day administered by

subcutaneous injection.2. In RA patients who have severe renal insufficiency (creatinine clearance < 30

ml/min) a dose of 100 mg every other day should be considered.

IV.

Belimumab (Benlysta)

A. Belimumabis medically-necessaryand has an FDA-approved indicationfor the

treatment of:

1. Systemic Lupus Erythematosus (SLE): adult patients with active, autoantibody-positive, SLE who are receiving standard therapy.

B. Special Considerations for belimumab:

1. Live vaccines should not be given concurrently with belimumab

D.


1. Belimumab is an intravenous infusion delivered over 1 hour.2. Belimumab must be reconstituted and diluted prior to administration.

3. For SLE the dosing is 10mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter.

V. Canakinumab (Ilaris)

A. Canakinumabis medically necessaryand has an FDA-approved indicationfor thetreatment of Cryopryin-Associated Periodic Syndromes (CAPS), in adults and children 4

years of age and older including:

1.

Familial Cold Autoinflammatory Syndrome

2. Muckle-Wells Syndrome

B. Special considerations with canakinumab:

1.

Live vaccines should not be given concurrently with canakinumab.

C. Off-label use of canakinumab may include but is not limited to:


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1. Systemic Juvenile Idiopathic Arthritis


2. Canakinumab is administered by subcutaneous injection every 8 weeks.

3.

For CAPS patients with body weight greater than 40 kg, the recommended dose

is 150 mg.4. For CAPS patients with body weight between 15 kg and 40 kg, the recommended

dose is 2 mg/kg.

5. For children 15 to 40 kg with an inadequate response, the dose can be increasedto 3 mg/kg.

VI. Certolizumab pegol (Cimzia )

A. Certolizumab pegolis medically necessaryand has an FDA-approved indicationfor thetreatment of:

1. Rheumatoid Arthritis (RA): moderately to severely active RA.

2. Crohns Disease: reducing signs and symptoms of Crohns disease andmaintaining clinical response in adult patients with moderately to severely activedisease who have had an inadequate response to conventional therapies.

B. Special considerations with certolizumab pegol:

1. Patients should be tested for latent tuberculosis before and during therapy.Treatment for latent tuberculosis infection should be initiated prior to therapy.

2. Monitor HBV carriers during and several months after therapy. If reactivation

occurs then stop drug and begin anti-viral therapy.




6. Treatment not recommended in patients with NYHA class III/IV with ejection

fraction 50% or less.

C. Off-label use of certolizumab pegolmay include but is not limited to the followingconditions:

1. Undifferentiated Polyarthritis2. Undifferentiated Spondyloarthropathy3. Sarcoidosis

4. Myositis


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5. Behets Disease6. Uveitis

7. Adult-Onset Stills Disease8. Reactive Arthritis9. JIA

10. Autoinflammatory Diseases


1. Certolizumab pegol is administered by subcutaneous injection.2. In RA the recommended dose is 400 mg initially and at weeks 2 and 4, followed

by 200 mg every other week.

3. In RA, for maintenance dosing, 400 mg every 4 weeks can be considered.4. In Crohns Disease, the recommended initial dosage is 400 mg, then repeated in

2 weeks. Maintenance dosage is 400 mg every 4 weeks.

VII. Denosumab (Prolia)

A.

Denosumabis medically necessaryand has an FDA-approved indicationfor thetreatment of:

1. Osteoporosis (OP): postmenopausal women with OP at high risk of fracture.

B.

Special considerations for denosumab:

1. Hypocalcemia must be corrected prior to initiating denosumab. Adequatelysupplement patients with calcium and vitamin D

C. Off-label use of denosumabmay include but is not limited to:

1.

Men with OP2. Women and men with low bone mass and at high risk of fracture


1. Denosumab is given as a 60mg single subcutaneous injection once every 6months.

VIII.

Etanercept (Enbrel)

A. Etanerceptis medically necessaryand has an FDA-approved indicationfor the

treatment of:

1. Rheumatoid Arthritis (RA): reducing signs and symptoms, inducing majorclinical response, inhibiting the progression of structural damage, and improving

physical function in patients with moderately to severely active RA. Enbrel canbe initiated in combination with methotrexate or used alone.

2. Juvenile Idiopathic Arthritis (JIA): reducing signs and symptoms of moderatelyto severely active polyarticular JIA in patients ages 2 and older.


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3. Psoriatic Arthritis (PsA): reducing signs and symptoms, inhibiting theprogression of structural damage of active arthritis, and improving physical

function. Enbrel can be used in combination with methotrexate in patients whodo not respond adequately to methotrexate alone.

4. Ankylosing Spondylitis (AS): reducing signs and symptoms in patients with

active AS.

5. Plaque Psoriasis: treating adult patients with chronic moderate to severe plaquepsoriasis who are candidates for systemic therapy or phototherapy.

B. Special considerations with etanercept:







6.

Treatment not recommended in patients with NYHA class III/IV with ejectionfraction 50% or less.

C. Off-label use of etanerceptmay include but is not limited to:

1. Undifferentiated Polyarthritis2. Undifferentiated Spondyloarthropathy

3. Sarcoidosis4. Myositis5. Behet Disease

6. Uveitis7.

Adult-Onset Stills Disease

8.

Reactive Arthritis9. JIA all ages and all subtypes



1. Etanercept is administered by subcutaneous injection.

2. In RA, AS, and PSA the recommended dose is 50 mg per week. 50 mg once weekly or 25 mg twice weekly.


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3. In JIA the recommended dose for pediatric patients ages 2 to 17 years is0.8mg/kg per week (up to a maximum of 50 mg per week).

4. In Plaque Psoriasis, the recommended dosage is 50 mg twice a week for 3months, and the 50 mg once week maintenance.

IX. Golimumab (Simponi )

A. Golimumabis medically necessaryand has an FDA-approved indicationfor thetreatment of:

1. Rheumatoid Arthritis (RA): moderately to severely active RA in adults, incombination with methotrexate.

2. Psoriatic Arthritis (PsA): active PsA in adults alone in or combination with

methotrexate.

3. Ankylosing Spondylitis (AS): active AS in adults.

B.

Special considerations with golimumab:



2. Monitor HBV carriers during and several months after therapy. If reactivation

occurs then stop drug and begin anti-viral therapy.

3.

Concomitant use of anti-TNF- therapy with anakinra and abatacept increasesthe risk of infection.

4. Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,

Human Papilloma and Herpes Zoster vaccines are recommended.


6.

Treatment not recommended in patients with NYHA class III/IV with ejectionfraction 50% or less.

C. Off-label use of golimumabmay include but is not limited to the following conditions:

1. Undifferentiated Polyarthritis2. Undifferentiated Spondyloarthropathy

3.

Sarcoidosis4.

Myositis

5. Behets Disease6. Uveitis7. Adult-Onset Stills Disease

8. Reactive Arthritis9.

Juvenile Idiopathic Arthritis



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1.

Golimumab is administered by subcutaneous injection.

2. In RA, PsA, and AS the dose is 50 mg every month.

X. Infliximab (Remicade)

A. Infliximabis medically necessaryand has an FDA-approved indicationfor the treatmentof:

1. Rheumatoid Arthritis (RA): in combination with methotrexate to reduce signsand symptoms, inhibit progression of structural damage, and improve physicalfunction in moderately to severely active RA in combination.

2. Psoriatic Arthritis (PsA): reducing signs and symptoms of active arthritis,inhibiting the progression of structural damage, and improving physical function.

3. Ankylosing Spondylitis (AS): reducing signs and symptoms in active AS.

4. Adult Crohns Disease: reducing signs and symptoms and inducing andmaintaining clinical remission in adult patients with moderately to severely

active Crohns disease who have had an inadequate response to conventionaltherapy. Reducing the number of enterocutaneous and rectovaginal fistulas and

maintaining fistula closure in adult patients with fistulizing Crohns disease.

5.

Pediatric Crohns Disease: reducing signs and symptoms and inducing andmaintaining clinical remission in pediatric patients with moderately to severely

active Crohns disease who have had an inadequate response to conventionaltherapy.

6. Ulcerative Colitis: reducing signs and symptoms, inducing and maintainingclinical remission and mucosal healing, and eliminating corticosteroid use in

patients with moderately to severely active ulcerative colitis who have had an

inadequate response to conventional therapy.

7. Plaque Psoriasis: treatment of adult patients with chronic severe plaque psoriasis

who are candidates for systemic therapy and when other systemic therapies aremedically less appropriate.

B. Special considerations with infliximab:

1. Patients should be tested for latent tuberculosis before and during therapy.Treatment for latent tuberculosis infection should be initiated prior to therapy.




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5. During therapy, Pneumococcal, Influenza intramuscular, Hepatitis B, and HumanPapilloma are recommended vaccines. Live attenuated vaccines such as Herpes

Zoster vaccines are not recommended during therapy.

6. Treatment not recommended in patients with NYHA class III/IV with ejectionfraction 50% or less.

C. Off-label use of infliximabmay include but is not limited to:

1. Undifferentiated Polyarthritis

2. Undifferentiated Spondyloarthropathy3. Sarcoidosis4. Myositis

5. Behet Disease6. Uveitis

7.

Adult-Onset Stills Disease8. Reactive Arthritis

9. Juvenile Idiopathic Arthritis10. Autoinflammatory Diseases


1. In RA the recommended dose of infliximab is 3 mg/kg given as an intravenousinfusion followed with additional similar doses at 2 and 6 weeks after the first

infusion then every 8 weeks thereafter.2. In RA, for patients who have an incomplete response, consideration may be

given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks.

3.

In AS the recommended dose is 5 mg/kg given as an intravenous infusionfollowed with additional similar doses at 2 and 6 weeks after the first infusion,

then every 6 weeks thereafter.4. In PSA the recommended dose is 5 mg/kg given as an intravenous infusion

followed with additional similar doses at 2 and 6 weeks after the first infusionthen every 8 weeks thereafter.

5. In Crohns disease, the recommended dosage: Induction: 5 mg/kg week 0, 2 and

6. Maintenance: 5 mg/kg every 8 weeks. May be increased up to 10 mg/kg.6. In Ulcerative Colitis, the recommended dosage: Induction: 5 mg/kg week 0, 2

and 6. Maintenance: 5 mg/kg every 8 weeks.7.

In Plaque Psoriasis, the recommended dosage: Induction: 5 mg/kg week 0, 2 and

6. Maintenance: 5 mg/kg every 8 weeks.

XI.

Pegloticase (KrystexxaTM

)

A.

Pegloticaseis medically-necessaryand has an FDA-approved indicationfor the

treatment of:

1. Chronic Gout: adults patients refractory to conventional therapy

B. Special considerations for pegloticase:


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1. Patients at higher risk for G6PD deficiency should be screened due to risk of

hemolysis and methemoglobinemia.

2. Exercise caution when using in patients with congestive heart failure.

C.


1. Pegloticase is given as an intravenous infusion over no less than 120 minutes

2. Pegloticase should not be administered as an intravenous push or bolus. 3. Adult patient dosing is 8mg intravenously every 2 weeks.

XII. Rilonacept (Arcalyst)

A. Rilonaceptis medically necessaryand has an FDA- approved indicationfor thetreatment of Cryoprin-Associated Periodic Syndromes (CAPS), in adults and children over

the age of 12 years including:1. Familial Cold Auto-Inflammatory Syndrome

2. Muckle-Wells Syndrome

B.

Special considerations with rilonacept:

1. Live vaccines should not be given concurrently with rilonacept.

2. IL-1 blocking agents (i.e. anakinra, canakinumab) increased risk of seriousinfection.

3.

TNF- inhibitors increased risk of serious infection.

C.


1. Patients 12 to 17 years: A loading dose of 4.4 mg/kg, up to 320 mg, injectedsubcutaneously. Administer as two separate injections on the same day if thedose exceeds a maximum single injection volume of 2 ml. Maintenance dose is2.2 mg/kg, up to 160 mg, injected subcutaneously once a week.

2. Patients 18 years and older: A loading dose of 320 mg (4 ml) administered as two160 mg (2 ml) subcutaneous injections in separate sites on the same day.

Maintenance dose is 160 mg injected subcutaneously once a week.

XIII. Rituximab (Rituxan)

A.

Rituximabis medically necessaryand has an FDA-approved indicationfor the treatment

of:

1.

Rheumatoid Arthritis (RA): in combination with methotrexate to reduce signs

and symptoms and to slow the progression of structural damage in adult patientswith moderately-to severely-active RA who have had an inadequate response toone or more TNF antagonist therapies.


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2. Granulomatosis with Polyangiitis (GPA; formerly Wegeners Granulomatosis):adult patients in combination with glucocorticoids

3. Microscopic Polyangiitis (MPA): adults patients in combination withglucocorticoids

B.

Special considerations for rituximab:

1.

Patients should be tested for latent tuberculosis before and during therapy.Treatment for latent tuberculosis infection should be initiated prior to therapy.

2.

Monitor HBV carriers during and several months after therapy. Rituximab shouldbe discontinued if reactivation occurs.

3. Rituximab should be discontinued if progressive multifocal leukoencephalopathyoccurs.

4. Pneumocystis jiroveci pneumonia prophylaxis is recommended for patients with

GPA and MPA during treatment and for at least 6 months following the lastrituximab infusion.



7. Rituxan therapy should be considered first line for any patient with prior treatedlymphoproliferative malignancy, skin melanoma, nonmelanoma skin cancer, or

solid malignancy within the last 5 years.

C. Off-label use of rituximabmay include but is not limited to:

1. Systemic Lupus Erythematosus

2. Cutaneous Lupus, all subtypes3.

Juvenile Idiopathic Arthritis

4. Vasculitides5. Sjogrens Syndrome6. Autoinflammatory Diseases

7. Polymyositis8. Dermatomyositis (juvenile and adult onset)

D.


1. Rituximab is administered as an intravenous infusion.2. In RA, the recommended dose is two 1000 mg infusions separated by 2 weeks.

Subsequent courses should be administered every 24 weeks or based on clinicalevaluation, but no sooner than every 16 weeks

3. In GPA and MPA the recommended dose is 375mg/m2once weekly for 4 weeks.


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XIV. Tocilizumab (Actemra)

A. Tocilizumabis medically necessaryand has an FDA-approved indicationfor thetreatment of :

1. Rheumatoid Arthritis (RA): adult patients with moderately to severely active RAwho have had an inadequate response to one or more TNF-antagonist therapies.

2. Systemic Juvenile Idiopathic Arthritis (SJIA): patients 2 years of age and olderwith active SJIA.

B. Special considerations for tocilizumab:



2.

Use with caution in patients who may be at increased risk of gastrointestinalperforation.

3. Laboratory monitoring is recommended due to potential consequences oftreatment-related changes in neutrophils, platelets, lipids, and liver function tests.

4.

Prior to initiating therapy, Pneumococcal, Influenza intramuscular, Hepatitis B,Human Papilloma and Herpes Zoster vaccines are recommended.


C.

Off-label use of tocilizumabmay include but is not limited to:

1. Systemic Juvenile Idiopathic Arthritis all ages

2. Polyarticular Juvenile Idiopathic Arthritis


1.

Tocilizumab is given as a 60-minute single intravenous drip infusion

2. Tocilizumab may be given as a monotherapy or in combination withmethotrexate.

3. In RA, the recommended starting dose is 4 mg/kg followed by an increase to 8

mg/kg based on clinical response.4. In SJIA, the recommended dose for patients less than 30kg is 12mg/kg every 2

weeks5. In SJIA, the recommended dose for patients 30kg or more is 8mg/kg every 2

weeks

Rationale


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FDA-Approved Indications

Abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), belimumab (Benlysta), canakinumab(Ilaris), certolizumab pegol (Cimzia), denosumab (Prolia), etanercept (Enbrel), golimumab (Simponi),infliximab (Remicade), pegloticase (Kyrstexxa), rituximab (Rituxan), and tocilizumab (Actemra) belong

to a class of drugs known as Biologic Response Modifiers (BRMs). Adalimumab, certolizumab pegol ,etanercept , golimumab , and infliximab are in the class of BRMs that inhibit the cytokine Tumor

Necrosis Factor (TNF)-. Anakinra, rilonacept and canakinumab work as antagonists to the cytokine IL -1. Abatacept is an inhibitor of T-cell co-stimulation. Rituximab is a B-cell depleting therapy, whereas

belimumab is a B-lymphocyte stimulator (BLyS)-specific inhibitor. Tocilizumab is an interleukin-6

receptor inhibitor. Denosumab is a RANK ligand inhibitor. Pegloticase is a modified urate oxidaseenzyme specific toward uric acid. Each has been approved by the FDA for use in specific indications

based on the available peer-reviewed evidence (please see medically necessary policy statement for list ofindications).

1-14A mechanism should exist where patients demonstrating a favorable response to a specific

biologic medication are allowed to continue that same agent even if the patient transitions to a differentmedical/prescription benefit plan.

Off-Label Use

Many autoimmune rheumatic diseases have severe multisystem manifestations, including internal organinvolvement and premature death. Unfortunately, for many of these conditions, standard (FDA approved)therapies do not exist, or are only effective in a subset of patients. The rarity of some of these conditions

presents a barrier to performing large scale studies required for regulatory approval. However, valuableinformation is obtained in the published clinical reports of biologic DMARD therapies for many less

common but disabling autoimmune conditions. When successful treatment options have been clearlydocumented in peer-reviewed journals, patients should receive the opportunity to benefit from theseeffective therapies. The following references are examples as new information will continue to be

published.

References are provided for the anti-TNF agents as a class for off-label use in UndifferentiatedSpondyloarthropathy, Sarcoidosis, Myositis, Behcets, Uveitis, and Reactive Arthritis.

15-43Additional

references for the off-label use of anakinra44-51, abatacept52-53, canakinumab54, denosumab55-56, rituximab57-

76, and tocilizumab77-78 are listed below. A mechanism should exist where the rheumatologist or an NP/PAguided by a rheumatologist can engage in a peer-to-peer review with a benefit provider representative to

appeal any negative decision on the use of biologic agents. The benefit provider representative shouldhave an accredited-Rheumatology or Immunology education background.

Biologic Molecule Description

Biologic Response Modifiers (BRMs), also called biologic agents, are a class of drugs created by living

cell cultures and are used to treat a number of diseases. These drugs target specific pathways of theimmune system. The United States Food and Drug Administration (FDA), the division of the U.S.Department of Health and Human services charged with ensuring the safety and effectiveness of newdrugs before they can go on the market, has approved several BRMs. The following molecular

descriptions are taken from the agents U.S.-approved Prescribing Information.

Remicade (infliximab) is a chimeric (part mouse, part human) monoclonal antibody that blocks activity ofa key biologic response mediator called tumor necrosis factor (TNF) alpha. The action of Remicade isto bind to and neutralize TNF- on the cell membrane and in the blood supply and to destroy TNF-


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producing cells, thus inhibiting inflammation. Remicade is supplied as a sterile, white lyophilizedpowder for intravenous infusion. It is an infusible medication that has been approved for home IV

therapy, hospital outpatient administration or physician office administration.

Enbrel (etanercept) is a dimeric fusion protein that binds specifically to tumor necrosis factor (TNF) andblocks its interaction with cell surface TNF receptors. Enbrel is supplied as white, preservative-free,

lyophilized powder for single-use parenteral administration after reconstitution with 1 ml of the suppliedsterile bacteriostatic water for injection, as a prefilled glass syringe and as a prefilled autoinjector glasssyringe. It is intended for use under the guidance and supervision of a physician. Patients may self-injectonly if their physician determines that it is appropriate and with medical follow-up, as necessary, after

proper training in reconstitution and injection technique.Humira (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for the human tumor

necrosis factor and acts by blocking the interaction between TNF- and p55 and p75 receptors. It issupplied in a single-use, 1 ml prefilled glass syringe and a prefilled autoinjector syringe as a sterile,

preservative-free solution for subcutaneous administration. Humira is intended for use under the guidanceof a physician. Patients may self-inject only if their physician determines that it is appropriate and with

medical follow-up, as necessary, after proper training in injection technique.

Simponi (golimumab) is a human IgG1 monoclonal antibody specific for human TNF- that exhibitsmultiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. Simponi is suppliedeither as a single dose prefilled syringe or a single dose prefilled autoinjector. Simponi does not contain

preservatives.

Cimzia (certolizumab pegol) is a recombinant, humanized antibody to Fab fragment, with specificity for

human TNF- , conjugated to an approximately 40kDa polyethylene glycol (PEG2MAL40K). The Fabfragment is manufactured inE. coliand is subsequently subjected to purification and conjugation toPEG2MAL40K, to generate certolizumab pegol. Cimzia is supplied as either a sterile, white, lyophilized

powder for solution or as a sterile, solution in a single-use prefilled 1 ml glass syringe for subcutaneousinjection. Each single-use vial provides approximately 200 mg certolizumab pegol. Each prefilled syringe

delivers 200 mg of certolizumab pegol. No preservatives are present. A patient may self-inject Cimzia if a

physician determines that it is appropriate, with medical follow-up, as necessary, after proper training insubcutaneous injection technique.

Kineret (anakinra) is a recombinant form of human interleukin-1 receptor antagonist, which functions to

block the pro-inflammatory interleukin-1 cytokine, which plays a role in inflammation and celldestruction. Kineret is supplied in single-use preservative-free, 1 ml prefilled glass syringes with 27 gaugeneedles. Patients or care providers should not be allowed to administer Kineret until he/she has

demonstrated a thorough understanding of procedures and an ability to inject the product.

Ilaris (canakinumab) is a recombinant, human anti-human-IL-1 monoclonal antibody that belongs to theIgG1/ isotype subclass. It is expressed in a murine Sp2/0-Ag14 cell line and comprised of two 447- (or

448-) residue heavy chains and two 214-residue light chains, with a molecular mass of 145157 Daltons

when deglycosylated. Both heavy chains of canakinumab contain oligosaccharide chains linked to theprotein backbone at asparagine 298 (Asn 298). Ilaris is supplied as a 180 mg white lyophilized powder for

solution for subcutaneous injection. Reconstitution with 1 ml of preservative-free Sterile Water forInjection is required prior to subcutaneous administration of the drug, resulting in a total volume of 1.2 ml

reconstituted solution. The reconstituted Ilaris is a clear to slightly opalescent, colorless to a slightbrownish yellow tint, essentially free from particulates, 150 mg/ml solution.

Arcalyst (rilonacept) is a dimeric fusion protein consisting of the ligand-binding domains of theextracellular portions of the human interleukin-1 receptor component (IL-R1) and IL-1 receptor accessory


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protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Arcalyst blocks IL-1 beta signalingby acting as a soluble decoy receptor that binds IL-1beta and prevents its interaction with cell surface

receptors. Arcalyst also binds IL-1alpha and IL-1 receptor antagonist (IL-1ra) with reduced affinity.Arcalyst is supplied in sterile, single use 20 ml glass vials that contain 220 mg of Arcalyst as a white tooff-white preservative-free lyophilized powder. Reconstitution with 2.3 ml of preservative-free SterileWater for Injection is required prior to subcutaneous administration of the drug. The reconstituted

Arcalyst is a viscous, clear, colorless to pale yellow, essentially free from particulates, 80 mg/ml solution.

Orencia (abatacept) is a soluble fusion protein that consists of the extracellular domain of humancytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3domains) portion of human immunoglobulin G1 (IgG1). Orencia acts as a selective costimulationmodulator. It inhibits T cell activation by binding to CD80 and CD86, thereby blocking interaction with

CD28. Orencia is supplied as a sterile, white, preservative-free, lyophilized powder for parenteraladministration. Following reconstitution with 10 ml of Sterile Water for Injection, USP, the solution of

Orencia is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of Orenciaprovides 250 mg abatacept, 500 mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium

chloride for administration.

Rituxan (rituximab) is a genetically engineered chimeric murine/human monoclonal AgG, kappa antibodydirected against the CD20 antigen. CD20 is expressed on the majority of B-cells, but the antigen is notfound on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. B cells are

believed to play a role in the pathogenesis of RA and associated chronic synovitis. Administration ofRituxan results in a rapid and sustained depletion of circulating and tissue-based B cells. Rituxan is asterile, clear, colorless, preservative-free liquid concentrate for intravenous administration. It is supplied

at a concentration of 10 mg/ml in either 100 mg (10 ml) or 500 mg (50 ml) single-use vials.

Actemra (tocilizumab) is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonalantibody of the immunoglobulin IgG1 subclass with a typical H2L2polypeptide structure. Each lightchain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are

linked intra- and inter-molecularly by disulfide bonds. Actemra has a molecular weight of approximately

148kDa. Actemra is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at aconcentration of 20 mg/ml. Actemra is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available containing 80 mg/4 ml, 200 mg/10 ml, or 400 mg/20 ml of Actemra. Injectablesolutions of Actemra are formulated in an aqueous solution containing disodium phosphate dodecahydrate

and sodium dihydrogen phosphate dehydrate (as a 15 mmol/L phosphate buffer), polysorbate 80 (0.5mg/ml), and sucrose (50 mg/ml).

Prolia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human RANKligand (RANKL). Denosumab has an approximate molecular weight of 147 kDa and is produced in

genetically engineered mammalian (Chinese hamster ovary) cells. Prolia is a sterile, preservative-free,clear, colorless to pale yellow solution. Each 1 mL single-use prefilled syringe of Prolia contains 60 mg

denosumab (60mg/mL solution), 4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for

Injection (USP), and sodium hydroxide to a pH of 5.2.

Krystexxa (pegloticase) is a uric acid specific enzyme which is a PEGylated product that consists ofrecombinant modified mammalian urate oxidase (uricase) produced by a genetically modified strain of

Escherichia coli. Uricase is covalently conjugated to monomethoxypoly(ethylene glycol) [mPEG] (10kDa molecular weight). The cDNA coding for uricase is based on mammalian sequences. Each uricasesubunit has a molecular weight of approximately 34 kDa per subunit. The average molecular weight of

pegloticase (tetrameric enzyme conjugated to mPEG) is approximately 540 kDa. Krystexxa is a sterile,clear, colorless solution containing 8 mg/mL pegloticase in phosphate-buffered saline.


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Krystexxa concentrations are expressed as concentrations of uricase protein. Each mL of Krystexxacontains 8 mg of uricase protein (conjugated to 24 mg of 10 kDa mPEG), 2.18 mg Disodium Hydrogen

Phosphate Dihydrate (Na2HPO42H2O), 8.77 mg Sodium Chloride (NaCl), 0.43 mg Sodium DihydrogenPhosphate Dihydrate (NaH2PO42H2O), and Water for Injection to deliver 8 mg of pegloticase (asuricase protein).

Benlysta (belimumab) is a human IgG1 monoclonal antibody specific for soluble human B lymphocytestimulator protein (BLyS, also referred to as BAFF and TNFSF13B). Belimumab has a molecular weightof approximately 147 kDa. Belimumab is produced by recombinant DNA technology in a mammaliancell expression system. Benlysta is supplied as a sterile, white to off-white, preservative-free, lyophilized

powder for intravenous infusion. Upon reconstitution with Sterile Water for Injection, USP, [see Dosageand Administration (2.3)] each single-use vial delivers 80 mg/mL belimumab in 0.16 mg/mL citric acid,

0.4 mg/mL polysorbate 80, 2.7 mg/mL sodium citrate, and 80 mg/mL sucrose, with a pH of 6.5.

Definitions

Induction:treatment designed as a first step toward treatment of a given condition.

Juvenile idiopathic arthritis (JIA):A chronic, inflammatory arthritis occurring in children less than 16years of age which causes joint pain, swelling and stiffness and in some children, systemic symptoms.

The subtypes include: systemic, oligoarticular persistent, oligoarticular extended, polyarticular-rheumatoid factor negative, polyarticular-rheumatoid factor positive, enthesitis-related arthritis and

psoriatic arthritis.

Monoclonal antibody:monoclonal antibodies are produced by a single clone of cells and are of

exceptional purity and specificity.

Refractory:resistant to ordinary treatment.

Rheumatoid Arthritis (RA):a chronic inflammatory disease characterized by symmetrical jointinvolvement, which causes pain, swelling, stiffness, and loss of function in the joints.

Seronegative:producing a negative reaction to serological tests.

Spondyloarthropathy:the spondyloarthropathies (SpA) are a heterogeneous set of disorders which

include ankylosing spondylitis, psoriatic arthritis, enteropathic arthritis and reactive arthritis characterizedby axial and peripheral joint involvement and frequent association with the HLA B27 antigen.

Tumor Necrosis Factor (TNF):a naturally occurring cytokine that is involved in normal inflammatoryand immune responses.


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References

Package Inserts

1. Actemra [package insert]. South San Francisco, CA: Genentech; 2012.

2.

Arcalyst [package insert]. Tarrytown, NJ: Regeneron; 2012.3. Benlysta [package insert]. Rockville, MD: Human Genome Sciences, Inc; 2012.4. Cimzia [package insert]. Smyrna, GA: UCB, Inc; 2012.5. Enbrel [package insert]. Thousand Oaks, CA: Amgen; 2012.6. Humira [package insert]. North Chicago, IL: Abbott Laboratories; 2012.7. Ilaris [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2012.

8. Kineret [package insert]. Stockholm, Sweden: Biovitrum; 2012.9. Krystexxa

TM[package insert]. East Brunswick, NJ: Savient Pharmaceuticals, Inc.; 2012

10.Orencia [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2012.11.

Prolia [package insert]. Thousand Oaks, CA: Amgen; 2012.

12.Remicade [package insert]. Horsham, PA: Janssen Biotech, Inc; 2012.13.Rituxan [package insert]. South San Francisco, CA: Genentech; 2012.

14.

Simponi [package insert]. Horsham, PA: Janssen Biotech, Inc; 2012.

TNF-Antagonists

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16.Scheinfeld N. Treatment of coincident seronegative arthritis and hidradenitis supprativa withadalimumab. J AM Acad Dermatol 2006;55:163-164.

17.Brandt J, Haibel H, Reddig J, Seiper J, Braun J. Successful short-term treatment of severeundifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonalantibody infliximab. J Rheumatol 2002;29:118-22.

18.Thielen AM, Barde C, Saurat JH, Laffitte E. Refractory chronic cutaneous sarcoidosis responsive

to dose-escalation of TNF-alpha antagonists. Dermatology 2009;219:59-62.19.

Cruz BA, Reis DD, Araujo CA. Refractory retinal vasculitis due to sarcoidosis successfullytreated with infliximab. Rheumatol Int 2007;1181-1183.

20.Baughman RP, Drent M, Kavuru M, Judson MA, et al. Infliximab therapy in patients with

chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802.21.Riley P, McCann LJ, Maillard SM, Woo P, et al. Effectiveness of infliximab in the treatment of

refractory juvenile dermatomyositis with calcinosis. Rheumatology 2008;47:877-80.22.Callejas-Rubio JL, Ortego-Centeno N, Lopez-Perez L, Benticuaga MN. Treatment of therapy-

resistant sarcoidosis with adalimumab. Clin Rheumatol 2006;25:596-597.

23.Khanna D, Liebling MR, Louie JS. Etanercept ameliorates sarcoidosis arthritis and skin disease. JRheumatol 2003;30:1864-1897.

24.Efthimiou P, Schwartzman S, Kage LJ. Possible role for tumour necrosis factor inhibitors in the

treatment of resistant dermatomyositis and polymyositis: a retrospective study of eight patients.Ann Rheum Dis 2006;65:1233-6.

25.Hengstman GJ, van der Hoogen FH, Barrera P, Netea MG, et al. Successful treatment ofdermatomyositis and polymyositis with anti-tumor-necrosis-factor-alpha; preliminary

observations. Eur Neurol 2003;50:10-5.26.Adams AB, Kazim M, Lehman TH. Treatment of orbital myositis with adalimumab. J Rheumatol

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27.Sprott H, Glatzel M, Michel BA. Treatment of myositis with etanercept (Enbrel), a recombinanthuman soluble fusion protein of TNF-alpha type II receptor and IgG1. Rheumatology

2004;43:524-6.28. Iwata S, Saito Y, Yamaoko K, Tsujimura S. Effects of anti-TNF-alpha antibody infliximab in

refractory entero-Behcets disease. Rheumatology 2009;48:1012-1013.29.Sfikakis PP, Markomichelakis N, Alpsoy E, Assaad-Khalil S, et al. Anti-TNF therapy in the

management of Bechets diseasereview and basis for recommendations. Rheumatology2007;46-:736-741.

30.Callejas-Rubio, Luis-Jose; Sanchez-Cano, Daniel; et al. Adalimumab Therapy for RefractoryUveitis: A Pilot Study. Journal of Ocular Pharmacology and Therapeutics. 2008 (6): 24.

31.Guignard S; Gossec; et al. Efficacy of tumour necrosis factor blockers in reducing uveitis flares inpatients with spondylarthropathy: a retrospective study. Ann Rheum Dis. 2006;65: 1631-1634.

32.Hale, Sarah; Lightman, Sue. Anti-TNF therapies in the management of acute and chronic uveitis.Cytokine. 2006; 33: 231-237.

33.Panagiotis G., Theodossiadis; Markomichelakes N., Nikolaos; et al. Preliminary Evidence for anEmerging Approach in the Treatment of Ocular Inflammation. Retina, The Journal of Retinal and

Vitreous Diseases.2007 (4): 399-413.34.Rudwaleit, M; Rodevand, E; et al. Adalimumab effectively reduces the rate of anterior uveitis

flares in patients with active anklyosing spondylitis: results of a prospective open-label study.Ann Rheum Dis. 2009;68: 696701.

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Sieper, Joachim; Koenig S Andrew; et al. Analysis of uveitis rates across all etanercept

ankylosing spondylitis clinical trials. Ann Rheum Dis 2010;69:226-299.36.Sobrin, Lucia; Kim C. Eva; et al. Infliximab Therapy for the Treatment of Refractory Ocular

Inflammatory Disease. Arch Ophthalmol. 2007;125(7):895-900.

37. Suhler, EB. Infliximab Therapy for Refractory Uveitis: 2-Year Results of a Prospective Trial.Arch Ophthalmol. June 2009;127: 819-822.

38. Simonini G, Taddio A, Cattalini M; et al. Prevention of flare recurrences in childhood-refractorychronic uveitis: an open-label comparative study of adalimumab versus infliximab. Arthritis CareRes. 2011 (4): 612-618.

39.Schafranski MD. Infliximab for reactive arthritis secondary to Chlamydia trachomatis infection.

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Gill H, Maiithia V. Successful use of infliximab in the treatment of Reiters syndrome: a casereport and discussion. Clin Rheumatol 2008;27:121-3.

41.Gaylis N. Infliximab in the treatment of an HIV positive patient with Reiters syndrome. J

Rheumatol 2003;30:407-11.42.Meador R, Hsia E, Kitumnuaypong T, Schumacher HR. TNF involvement and anti-TNF therapy

of reactive and unclassified arthritis. Clin Exp Rheumatol 2002;20(6 Suppl 28):S130-4.43.Ruperto N, Lovell D, Cuttica R; et al. A randomized, placebo-controlled trial of infliximab plus

methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis

Rheum. 2007 (9): 3096-106.44.Ruperto N, Lovell D, Cuttica R; et al. Long-term efficacy and safety of infliximab plus

methotrexate for the treatment of polyarticular course juvenile rheumatoid arthritis: findings from

an open-label treatment extension. Ann Rheum Dis. 2010 (4): 718-722.45. Larnot L, Bukovac LT, Vidovic; et al. The head to head comparison of etanercep and infliximab

in treating children with juvenile idiopathic arthritis. Clin Exp Rheumatol. 2011 (1): 131-139.46. Otten MH, Prince FH, Twilt M; et al. Tumor necrosis factor-blocking agents for children with

enthesitis-related arthritisdata from the Dutch arthritis and biologicals in children register, 1999-2010. J Rheumatol. 2011 (10): 2258-2263. Otten, M, Prince F, Ten Cate R, et al. Tumor necrosisfactor (TNF)-blocking agents in juvenile psoriatic arthritis: are they effective? Ann Rheum Dis. 2011(2): 337-340.

Anakinra


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47.Mitroulis I, Papadopoulos VP, Konstandinidis T, Ritis K. Anakinra suppresses familialMediterranean fever in a colchicine-resistant patient. Neth J Med 2008;66:489-491.

48.Gaelotti C, Tran TA, Franchi-Aabella S, Fabre M, et al. IL1-RA agonist (anakinra) in thetreatment of multi-focal castleman disease: a case report. J Pediatr Hematol Oncol 2008;30:920-924.

49.Debiais S, Maillot F, Luca L, Buret J, et al. Efficacy of anakinra in case of refractory Stills

disease. J Clin Rheumatol 2008;14:357-358.50.Singh D, Huston KK. IL-1 inhibition with anakinra in a patient with refractory gout. J Clin

Rheumatol 2009;15:366.51.McGonagle D, Tan AL, Shankaranarayana S, Madden J, et al. Management of treatment

resistant-inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis2007;66:1683-1684.

52. .53. Quartier P, Allantaz F, Cimaz R, et al. A multicenter, randomized, double-blind, placebo-

controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onsetjuvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011 (5): 747-754.

54. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy insystemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter

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rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study.

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Abatacept

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Denosumab

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63.Fizazi K, Carducci M, Smith M, Damio R, et al. Denosumab versus zoledronic acid fortreatment of bone metastases in men with castration-resistant prostate cancer: a randomized-

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patient with systemic onset juvenile idiopathic arthritis refractory to TNF alpha antagonists.Journal of Clinical Rheumatology 2009;15: 363-5.

68.Narvaez J, Diaz-Torne C, Juanola X, et.al. Rituximab therapy for refractory systemic-onsetjuvenile idiopathic arthritis. Ann Rheum Dis 2009;68: 607-8.

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Stone JH, Merkel PA, Seo P, Spiera R, Langford CA, Hoffman GS, et al. Rituximab VersusCyclophosphamide for Induction of Remission in ANCA-Associated Vasculitis: A RandomizedControlled Trial (RAVE). Arthritis Rheum 2009 (abstract supplement)

74.Keogh KA, Wylam ME, Stone JH, Specks U. Induction of remission by B lymphocyte depletion

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Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U. Rituximab forrefractory Wegener's granulomatosis: report of a prospective, open-label pilot trial. Am J RespirCrit Care Med. 2006 Jan 15;173(2):180-7.

76.Seo P, Specks U, Keogh KA. Efficacy of rituximab in limited Wegener's granulomatosis withrefractory granulomatous manifestations. J Rheumatol. 2008 Oct;35(10):2017-23.

77.Taylor SR, Salama AD, Joshi L, Pusey CD, Lightman SL. Rituximab is effective in the treatment

of refractory ophthalmic Wegener's granulomatosis. Arthritis Rheum. 2009 May;60(5):1540-7.78. Isaksen K,Jonsson R,Omdal R.Anti-CD20 treatment in primary Sjogrens syndrome. Scan J

Immunol 2008;68:554-564.79.Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study.

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