Abatacept (Orencia^®, Bristol-Myers Squibb Company, Princeton, NJ) is a selective costimulation modulator which inhibits T cell (T lymphocyte) activation. Activated T lymphocytes are implicated in the development of rheumatoid arthritis (RA) and are found in the synovium of individuals with RA. This document addresses the indications for the use of abatacept.

Note: Please see the following document for information on additional drugs which may be used in the treatment of rheumatoid RA:

• DRUG.00002 Tumor Necrosis Factor Antagonists
• DRUG.00041 Rituximab (Rituxan^®)
• DRUG.00043 Tocilizumab (Actemra^®)

Medically Necessary: 

Abatacept is considered medically necessary for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease modifying anti-rheumatic drugs (DMARDs), such as methotrexate (MTX), or a tumor necrosis factor (TNF) antagonist. Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists.

Abatacept is considered medically necessary for reducing signs and symptoms in individuals 6 years of age or older with moderately to severely active polyarticular juvenile idiopathic arthritis who have had an inadequate response to one or more DMARDs, such as MTX, or a TNF antagonist. It may be used as monotherapy or concomitantly with MTX.

Not Medically Necessary:

Abatacept is considered not medically necessary for an individual with any of the following:

1. Currently receiving TNF antagonists or for use concomitantly with other biologic RA therapy, such as anakinra (Kineret^®,Amgen, Thousand Oaks, CA);
2. Tuberculosis or other active serious infections or a history of recurrent infections;  
3. Individual has not had a tuberculin skin test (TST) or Centers for Disease Control (CDC)-recommended equivalent to rule out latent tuberculosis. 

Investigational and Not Medically Necessary:

Abatacept is considered investigational and not medically necessary for all other indications.

Abatacept was first approved on December 23, 2005 by the U.S. Food and Drug Administration (FDA) for reducing signs and symptoms, inducing major clinical response, slowing the progression of structural damage, and improving physical function in adults with moderately to severely active RA who have had an inadequate response to one or more DMARDs, such as MTX, or a TNF antagonist. Abatacept may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. Subsequently, the label was updated with the FDA approved indication "for reducing signs and symptoms in pediatric patients six years and older with moderately to severely active polyarticular JIA" and by the removal of the requirement of an inadequate response to one or more DMARDs, such as MTX, or a TNF antagonist in adult RA. However, the majority of clinical trials for abatacept were conducted in individuals (pediatric and adult) who had an inadequate response to one or more DMARDS. There is insufficient published peer reviewed medical literature available to support the use of abatacept as first line therapy.

Genovese and colleagues (2005) evaluated the safety and efficacy of abatacept with a randomized, double-blind, phase 3 trial in adults at least 18 years of age with active RA and an inadequate response to at least three months of a TNF antagonist (also known as anti–TNF alpha therapy). From December 10, 2002 to June 2, 2004, 258 individuals were randomly assigned and treated with abatacept and 133 were randomly assigned and received a placebo. At the time of randomization, subjects had to have increased C-reactive protein levels, at least 10 swollen joints and at least 12 tender joints. They also had to have been taking an oral DMARD or anakinra for at least 3 months with a stable dose for at least 28 days. Use of oral corticosteroids, but no more than 10 mg of prednisone or its equal per day was allowed if there had been a stable dose for at least 28 days. Dose changes of the background DMARDS were not allowed except to avoid adverse effects. Abatacept or placebo was administered on days 1, 15, and 29 and every 28 days thereafter for 6 months. Anti–TNF alpha therapy was discontinued prior to randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed. After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, a greater number of subjects in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group. The authors concluded results showed evidence that abatacept is clinically effective and has an acceptable safety profile in those with RA and an inadequate response to anti–TNF alpha therapy.

In a phase III, double-blind, randomized, placebo controlled trial (the AIM study), Kremer and colleagues (2006), studied abatacept in individuals with active RA who had an inadequate response to MTX. Six hundred fifty two adults were randomized in a 2:1 ratio to receive a monthly administration of abatacept at 10mg/kg or placebo, while continuing the background DMARD, most often MTX. Efficacy was assessed with measurements of American College of Rheumatology (ACR) 20, 50, and 70 which refer to the percentage of improvement (20%, 50%, and 70%, respectively) in tender and swollen joint counts. After 1 year of treatment, ACR 20, 50, and 70 response rates were significantly higher in the abatacept group than the placebo group (80% vs. 60%, 53.3 vs. 33.8, and 26.7% vs. 12% respectively, p<.001). The study also showed that abatacept significantly slowed radiographic progression of joint damage.

In "the abatacept study of safety in use with other RA therapies (ASSURE trial)", Weinblatt and colleagues (2006) studied the safety of abatacept in individuals who had been receiving traditional nonbiologic or biologic DMARDs. This was a one year, multicenter, randomized, double blind trial in which treatment consisting either of abatacept or placebo was administered on days 1, 15, and 29 and every four weeks after for 14 total doses. All study subjects were required to continue to receive their background RA therapies consisting of biologic DMARDS, non biologic DMARDS, or both. A total of 1, 456 subjects were randomized and 1, 441 received at least 1 dose of study medication. The frequency of adverse events in the abatacept and placebo groups were similar; however, when evaluated according to background therapy, serious adverse events occurred more often in the subgroup receiving abatacept with a biologic agent (22.3%) than in the other subgroups (11.7-12.5%). The authors concluded that abatacept in combination with synthetic DMARDS improved physical function and were well tolerated; however, abatacept in combination with biologic background therapies was associated with increased serious adverse events.

Westhovens and colleagues (2006) assessed the safety and efficacy of abatacept in individuals with early RA with poor prognostic factors who had not previously been treated with MTX. In this double blind, phase IIIb study, 509 individuals with RA for two years or less were randomized to receive abatacept plus methotrexate (n=256), or placebo plus methotrexate (n=253) for one year. At one year, a significantly greater number of abatacept plus methotrexate teated subjects achieved disease remission (41.4% vs 23.3%) and the frequency of adverse events was comparable between both groups. The authors concluded that the combination of abatacept plus methotrexate was more effective than methotrexate alone, but noted the study may have been limited by its short term duration of one year.

In an open label extension of the AIM trial, Genant and colleagues (2008) assessed the progression of structural damage after 2 years of abatacept treatment. Five hundred thirty nine individuals were treated with abatacept in the open-label period (378 initially randomized to abatacept and 161 to placebo). A high retention rate was maintained, with 90% of the subjects who entered the extension completing two years. Radiographic assessment of the hands and feet was performed at baseline, 1 year and 2 years. Following 2 years of treatment with abatacept, 50% of subjects had no progression of structural damage, 56% of those treated with abatacept had no progression during the first year compared with 45% of those treated with placebo. In the second year of treatment with abatacept more individuals had no progression than in the first year (66% versus 56%).

Schiff and colleagues (2008) evaluated the safety and efficacy of abatacept or infliximab vs placebo in a multi-center, randomized, double blind, and placebo controlled trial. A total of 431 individuals with RA and an inadequate response to MTX were randomized in a 3:3:2 ratio to abatacept (approximately 10 mg/kg every 4 weeks, n = 156), infliximab (3 mg/kg every 8 weeks, n = 165), or placebo (every 4 weeks, n = 110) by intravenous infusion. At randomization, individuals had active disease despite background MTX. Similar clinical demographics and clinical characteristics were present at baseline between groups. The primary endpoint of the study was to evaluate a reduction in disease activity, measured by Disease Activity Score 28 (based on erythrocyte sedimentation rate levels; DAS28 (ESR) with abatacept versus placebo at 6 months. Secondary endpoints included reduction in DAS28 (ESR) with infliximab versus placebo at 6 months. Additional secondary endpoints at 6 months and 1 year included a mean reduction in DAS28 (ESR) with abatacept vs infliximab. Study results demonstrated included reduction in DAS28 (ESR) at day 197 which was significantly greater with abatacept vs placebo, reduction in DAS28 (ESR) at day 197 was greater in the infliximab vs placebo groups, and also a greater reduction in DAS28 (ESR) at day 365 with abatacept vs infliximab. The authors concluded abatacept and infliximab both offer clinical improvements to those with an inadequate response to MTX; however, abatacept had a relatively more acceptable safety and tolerability profile than the infliximab group.

Schiff and colleagues (2009) reported on "the six month safety and efficacy of abatacept in patients with RA who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: ARRIVE trial". In this international open label trial, the safety, tolerability and efficacy of abatacept in RA subjects who had failed anti- TNF therapy and were either switched directly to abatacept or after completing a washout were assessed. A total of 1046 (449 washout, 597 direct switch) with similar baseline characteristics between groups were evaluated. At six months, adverse events and discontinuations due to adverse events were comparable in both groups and there were no opportunistic infections. There were also similar clinically meaningful improvements seen in both groups at six months. The authors conclusions included: "these results demonstrate the acceptable safety and tolerability and clinically meaningful efficacy benefits of abatacept in patients with an inadequate response to anti-TNF therapy, a population representative of those encountered in clinical practice."

The FDA approval of abatacept for use in reducing signs and symptoms of moderately to severely active polyarticular juvenile RA in individuals 6 years and older was based on a three-part study including an open-label extension in children with polyarticular JIA. Ruperto and colleagues (2008) reported on the study which was conducted at 45 pediatric rheumatology centers in Europe, Latin America, and the USA. One hundred ninety subjects aged 6 to 17 years of age with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated. Enrollment criteria included at least five active joints (those with swelling or limited range of motion, accompanied by either pain or tenderness) and active disease (at least two active joints and two joints with limited range of motion). All DMARDS, except methotrexate, were withdrawn and not given during the trial. At study entry, 74% of subjects were receiving MTX and remained on a stable dose of MTX. Those not receiving MTX did not initiate MTX treatment during the study. Clinical assessments were completed prior to drug administration at all visits. Six core ACR pediatric response variables were assessed: the number of active joints, number of active joints with limited range of motion, physician's global assessment of disease severity, parent's global assessment of their child's overall wellbeing, functional ability with the validated translated version of the Childhood Health Assessment Questionnaire (CHAQ) disability index (0-3 point scale), and the erythrocyte sedimentation rate. In Period A (open-label, lead-in), subjects received 10 mg/kg (maximum 1000 mg per dose) of abatacept intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed according to the ACR Pediatric definition of improvement, 6 defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. At the end of Period A, 122 subjects who had improved by 30% according to ACR pediatric definitions were randomized into the double-blind phase (Period B) and received either abatacept or placebo for 6 months or until disease flare. Disease flare was defined as worsening of 30% or more in at least 3 of the 6 JIA core response variables and at least 30% worsening in not more than 1 of the 6 variables. Improvement was defined as an improvement of 30% or more in at least three of six ACR core response variables and at least 30% worsening in not more than one variable. Improvements were also defined by 50%, 70%, and 90% improvements in the ACR pediatric criteria. At the conclusion of Period A (at day 113), two-thirds of the 190 enrolled subjects had improved by 30% or more according to ACR pediatric response criteria. Similar proportions of subjects with different disease subtypes improved by 30% or more. During the double-blind randomized withdrawal phase (Period B), abatacept treated subjects experienced significantly fewer disease flares compared to those treated with placebo (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among individuals continuing on abatacept was less than one third than that for those withdrawn from abatacept treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among subjects who received abatacept throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR responders has remained consistent for 1 year (Product Information, 2008).

The American College of Rheumatology (ACR) (2008) issued recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in RA. For each final recommendation, the strength of evidence was assigned using the methods of the American College of Cardiology (i.e. level of evidence A, data were derived from multiple RCTs or meta-analyses). Recommendations issued for abatacept state: "The TFP (Task Force Panel) recommends the use of abatacept in patients for whom methotrexate in combination with DMARDs or sequential administration of other nonbiologic DMARDs led to an inadequate response, and with at least moderate disease activity and features of a poor prognosis (level A evidence for high disease activity)." According to the ACR, these recommendations are intended to provide guidance based on clinical evidence rather than be used in a prescriptive manner.

RA is a chronic inflammatory and progressive disease characterized by symmetrical joint involvement, which causes pain, swelling, stiffness, and loss of function in the joints. If left untreated it may lead to joint destruction and progressive disability. The disease affects approximately 2.1 million Americans usually striking people between the ages of 20 and 60, and people in their mid to late fifties are especially vulnerable. RA is three times more common in women than in men

JIA (formerly known as juvenile RA) is a form of RA in children that generally occurs prior to the age of 16, favors one or more large joints and can interfere with normal bone growth

Polyarticular JIA is a form of JIA affecting five or more joints. It often affects the same joints on both sides of the body (symmetrical arthritis). Girls are more frequently affected by polyarticular JIA than boys. In teenagers, it often resembles RA.

Clinical studies support the safety and efficacy of abatacept for the treatment of RA and polyarticular JIA when used as described in the FDA approved indications.

Important Limitations of Use (Orencia Production Information, 2009):

• Abatacept should not be administered concomitantly with TNF antagonists.
• Abatacept is not recommended for use concomitantly with other biologic RA therapy, such as anakinra.

Medical Management Information: 

Product Information Warnings and Precautions (Orencia Product Information, 2009) 

• Concomitant use with a TNF antagonist can increase the risk of infections and serious infections
• Hypersensitivity, anaphylaxis, and anaphylactoid reactions
• Individuals with a history of recurrent infections or underlying conditions predisposing to infections may experience more infections
• Discontinue if a serious infection develops
• Screen for latent TB infection prior to initiating therapy. Those testing positive should be treated prior to initiating abatacept
• Live vaccines should not be given concurrently or within 3 months of discontinuation
• Individuals with juvenile idiopathic arthritis should be brought up to date with all immunizations prior to abatacept therapy
• Based on its mechanism of action, abatacept may blunt the effectiveness of some immunizations
• Individuals with COPD may develop more frequent respiratory adverse events

Disease modifying anti-rheumatic drugs (DMARDs): a variety of medications which work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including RA, ankylosing spondylitis, and psoriatic arthritis

Tumor Necrosis Factor (TNF) antagonists: a class of drugs (including, but not limited to infliximab, etanercept, and adalimumab) designed to neutralize inflammatory cytokines

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above in those instances described in the Position Statement as not medically necessary

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, and for all other diagnoses not listed

Peer Reviewed Publications: 

1. Genant HK, Peterfy CG, Westhovens R, et al. Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial. Ann Rheum Dis. 2008; 67(8):1084-1089.
2. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005; 353(11):1114-1123.
3. Hampton T. Trials reveal promising options for treating juvenile rheumatoid arthritis. JAMA. 2008; 299(1):27-28.
4. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006; 144(12):865-876.
5. Lutt JR, Deodhar A. Rheumatoid arthritis: strategies in the management of patients showing an inadequate response to TNF alpha antagonists. Drugs. 2008; 68(5):591-606.
6. Massarotti EM. Clinical and patient-reported outcomes in clinical trials of abatacept in the treatment of rheumatoid arthritis. Clin Ther. 2008; 30(3):429-442.
7. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005; 72(6):1037-1047.
8. Ruperto N, Lovell DJ, Quartier P, et al. Paediatric Rheumatology International Trials Organization; Pediatric Rheumatology Collaborative Study Group. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet. 2008; 372(9636):383-391.
9. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008; 67(8):1096-1103.
10. Schiff M, Pritchard C, Huffstutter JE, et al. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Ann Rheum Dis. 2009; 68(11):1708-1714.
11. Weinblatt M, Combe B, Covucci A, et al. Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum. 2006; 54(9):2807-2816.
12. Westhovens R, Robles M, Ximenes AC, et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009; 68(12):1870-1877.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Abatacept (systemic). In: DrugPoints^® System [Internet database]. Greenwood Village, CO: Thomson Healthcare. Last modified January 04, 2010. Available at: http://www.thomsonhc.com. Accessed on March 18, 2010.
2. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2010^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2010.
3. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002; 46(2):328-346.
4. Bristol-Myers Squibb, BMS-188667 in Children and Adolescents with Juvenile Rheumatoid Arthritis. NLM Identifier: NCT00095173. Last updated on September 28, 2009. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00095173?term=NCT00095173&rank=1. Accessed on March 18, 2010.
5. Orencia [Product Information], Princeton, NJ. Bristol-Myers Squibb; August 2009. Available at: http://packageinserts.bms.com/pi/pi_orencia.pdf. Accessed on March 18, 2010.
6. Saag KG, Teng GG, Patkar NM. American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59(6):762-784.

Orencia
Polyarticular juvenile idiopathic arthritis (JIA)
Rheumatoid Arthritis

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.