Description:
Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disorder that is characterized by inflammation of synovial joints causing progressive erosion of cartilage and bone. There are three objectives in the treatment of RA: disruption of the disease process, maintaining function and prevention of long term disability. Drug treatment recommended by the American College of Rheumatology includes treatment with disease modifying anti-rheumatic drugs (DMARDS) within three months of diagnosis.  Methotrexate is the most commonly prescribed DMARD and is generally the standard that new treatments are measured by. 

Abatacept is a targeted biological agent that is a novel fusion protein which modulates the T cell co-stimulatory signal. It inhibits T-cell activation and interrupts the process that leads to the inflammation experienced in RA. Studies have indicated that patients with severe RA receiving abatacept with at least one other DMARD showed statistically significant improvement in tender, swollen joints compared with patients receiving placebos.

Policy:   
Orencia IV are considered MEDICALLY NECESSARY when one of the following criteria is met along with specific diagnosis criteria:

• Physician attests that the patient or caregiver is not competent or is physically unable to administer the Orencia product FDA labeled for self-administration.
• Patient has experienced severe hypersensitivity reactions (e.g., anaphylaxis, angioedema, bronchospasm, or hypotension) to Orencia within the past 6 months and requires administration and direct monitoring by a healthcare professional.

Coverage of abatacept (Orencia) is provided when the FDA-approved indications below are met and there has been a trial and failure of preferred therapy.
Abatacept is considered MEDICALLY NECESSARY for the treatment of moderately to severely active rheumatoid arthritis (RA) when all of the following criteria are met:

• Individual is 18 years of age or older
• The drug is being used to reduce signs and symptoms, induce major clinical response, inhibit the progression of structural damage and improve physical function
• The individual has had an inadequate response to a trial of one or more non-biologic (methotrexate, leflunomide, sulfasalazine)
• The individual has had an inadequate response to a trial of TWO or more biologic TNF antagonist or oral Janus Kinase Inhibitor
• The drug may be used alone or in combination with non-biologic DMARDs
• The drug is not used in combination with a biologic DMARD (for example, TNF antagonist) 

Abatacept is considered MEDICALLY NECESSARY for the treatment of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) when all of the following criteria are met:

• Individual meets age requirement as follows:
  • IV: Children ≥ 6 years and Adolescents
  • SubQ: Children ≥ 2 years and Adolescents
• The drug is being used to reduce signs and symptoms of the disease
• The individual has had an inadequate response to a trial of one or more non-biologic (methotrexate, leflunomide)
• The individual has had an inadequate response to a trial of TWO or more biologic TNF antagonist or oral Janus Kinase Inhibitor
• The drug may be used alone or in combination with MTX
• The drug is not used in combination with a biologic DMARD (e.g., TNF antagonist) 

Abatacept is considered MEDICALLY NECESSARY for the treatment of active adult psoriatic arthritis when all of the following criteria are met: 

• The individual has had an inadequate response to a trial of TWO or more biologic TNF antagonists or oral Janus Kinase Inhibitor
• One of the following:
  •  Actively inflamed joints 
  • Dactylitis 
  • Enthesitis 
  • Axial disease 
  • Active skin and/or nail involvement 
• It may be used with or without non-biologic DMARDS. 

Abatacept is considered MEDICALLY NECESSARY for the treatment of acute graft versus host disease (aGVHD) when all of the following criteria are met: 

• Used for prophylaxis of acute graft versus host disease (aGVHD)
• Patient is 2 years of age or older
• Patient will receive hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor
• Recommended antiviral prophylactic treatment for Epstein-Barr Virus (EBV) reactivation (e.g., acyclovir) will be administered prior to Orencia and continued for six months after HSCT
• Used in combination with both of the following:
  • Calcineurin inhibitor (e.g., cyclosporine, tacrolimus)
  • Methotrexate

Abatacept is considered NOT MEDICALLY NECESSARY for an individual with any of the following:

• Use of abatacept in combination with TNF antagonists or other biologic RA therapy, such as anakinra (Kineret^®_, Amgen, Thousand Oaks, CA)
• Tuberculosis or other active serious infections or a history of recurrent infections
• Individual has not had a tuberculin skin test (TST) or Centers for Disease Control and Prevention (CDC)-recommended equivalent test to evaluate for latent tuberculosis.

Abatacept is considered investigational/unproven therefore considered NOT MEDICALLY NECESSARY for all other indications, including, but not limited to, the treatment of: ankylosing spondylitis, Crohn's disease, giant cell arteritis and Takayasu's arteritis, graft versus host disease (GVHD), lupus nephritis, multiple sclerosis, psoriasis vulgaris, scleroderma, systemic lupus erythematosus, Type 1 diabetes, ulcerative colitis and uveitis.

Dosage:

Intravenous Administration for Adult RA (2.1)

Body Weight of Patient                          Dose                      Number of Vials

Less than 60 kg                                      500 mg                               2

60 to 100 kg                                           750 mg                               3

More than 100 kg                                 1000 mg                               4

Subcutaneous Administration for Adult RA (2.1)

• Administer by subcutaneous injection once weekly with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, administer a single intravenous infusion (as per body weight categories above), followed by the first 125 mg subcutaneous injection given within a day of the intravenous infusion.
• Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Juvenile Idiopathic Arthritis (2.2)

• Pediatric patients weighing less than 75 kg receive 10 mg/kg intravenously based on the patient’s body weight. Pediatric patients weighing 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen, not to exceed a maximum dose of 1000 mg.

Rationale:
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 evidence available to support the use of abatacept as first line therapy.

Adult Rheumatoid Arthritis (RA)
Evidence of abatacept's clinical benefit in the management of adult rheumatoid arthritis is primarily based on results of multiple randomized clinical trials in adults with the disease. Additionally, several long-term follow-up studies assessing the safety and efficacy of abatacept have been published.

Genovese and colleagues (2005) evaluated the safety and efficacy of abatacept in a randomized, double-blind, phase three trial of adults at least 18 years of age with active RA and an inadequate response to at least three months of a TNF antagonist (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders [ATTAIN] trial). 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 three 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 that the clinical effectiveness of abatacept and an acceptable safety profile in those with RA and an inadequate response to anti-TNF alpha therapy was demonstrated.

Kremer and colleagues (2005) in a 12 month, multicenter, randomized, double-blind, placebo-controlled study investigated the safety, efficacy, and immunogenicity of abatacept in individuals with active RA despite treatment with MTX. A total of 339 subjects meeting selection criteria were randomly assigned to receive either 2 mg/kg abatacept (n = 105), 10 mg/kg abatacept (n = 115), or placebo (n = 119). Concomitant therapy of MTX was also administered. Study results reported included that a greater percentage of individuals treated with 10 mg/kg abatacept met the ACR 20% improvement criteria (achieved an ACR20 response) at one year as compared with the percentage who received placebo (62.6% vs 36.1%; P < 0.001). In addition, greater percentages of individuals treated with 10 mg/kg abatacept achieved ACR50 responses (41.7% vs 20.2%; P < 0.001) and ACR70 responses (20.9% vs 7.6%; P = 0.003) as compared to those who received a placebo. Adverse events were comparable between the groups and no significant formation of neutralizing antibodies was noted. The authors concluded that abatacept was associated with sustained and significant clinical reduction in disease activity and improvements in physical function.

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 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 2008, Kremer and colleagues reported on a two year follow-up of this study. Individuals who received placebo during year one were switched to abatacept and those taking abatacept continued with it. The authors noted that those who continued to take abatacept at two years maintained their ACR response rates.

The progression of structural damage after two years of abatacept treatment was assessed in an open label extension of the AIM trial (Genant, 2008). 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, one year and two years. Following two 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% vs. 56%).

Kremer and colleagues (2011) reported three year results of the AIM study. Individuals who had been randomized to either abatacept or placebo (+MTX) during the one-year double-blind period of the AIM study received open-label abatacept (+MTX) in the long-term extension (LTE). Safety was assessed in those who received one or more dose of abatacept, regardless of randomization group. Efficacy was assessed for those randomized to abatacept who entered the LTE. A total of 433 and 219 subjects were randomized and treated with either abatacept or a placebo, respectively; 378 and 161 entered the LTE. At year three, 440 of the 539 remained in the trial. No unexpected safety events were observed and by year three, incidence rates of adverse and serious adverse events were 249.8/100 and 15.1/100 "patient-years", respectively. At year three, 84.8%, 63.4% and 37.5% of the subjects achieved ACR criteria of 20, 50 and 70, respectively, as compared to 82.3%, 54.3% and 32.4% respectively at year one. The authors concluded that their data supported the long-term use of abatacept in individuals with an inadequate response to MTX.

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 one 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 (2009) 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 treated 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.

Bathon and colleagues (2011) assessed two-year outcomes of the previously noted study. Of 459 subjects who completed year one, 433 (94.3%) completed year two. Physical function and ACR were maintained through year two in the original abatacept plus methotrexate group, with 55.2% in remission at two years. After abatacept was introduced in the methotrexate-alone group, additional subjects achieved remission. Less radiographic progression was noted at two years in the original abatacept plus methotrexate group than with the methotrexate-alone group. There were no new safety issues noted and similar rates of serious adverse events, serious infections and autoimmune events were seen in years one and two. The authors concluded "these data support the safety and efficacy of abatacept at an early stage of the RA disease continuum."

Schiff and colleagues (2008) evaluated the safety and efficacy of abatacept or infliximab versus placebo in a multicenter, randomized, double blind, and placebo controlled trial titled: A Trial for Tolerability, Efficacy and Safety in Treating Rheumatoid Arthritis (ATTEST 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 six months. Secondary endpoints included reduction in DAS28 (ESR) with infliximab versus placebo at six months. Additional secondary endpoints at six months and one year included a mean reduction in DAS28 (ESR) with abatacept vs infliximab. Study results included a 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."

Schiff and colleagues (2011) assessed the clinical response and tolerability to abatacept in individuals with RA previously treated with infliximib or abatacept in the long-term extension (LTE) of the ATTEST trial. Subjects having been randomized to abatacept, placebo or infliximab who completed the one-year double-blind period were eligible to receive abatacept 10 mg/kg in the open-label LTE. Of the 431 subjects randomly assigned to abatacept (n = 156), infliximab (n = 165) or placebo (n = 110), a total of 344 (79.8%) remained on abatacept at year two. At years one and two, 19.7% and 26.1% of abatacept and 13.3% and 28.6% of infliximab-to-abatacept subjects achieved disease activity score 28-defined remission (< 2.6). Abatacept was generally well tolerated over the two-year study period and was consistent with the double-blind experience, with no increase in adverse event incidence following the switch to abatacept. These authors indicated that abatacept provides sustained responses and consistent safety, suggesting that switching from infliximab to abatacept was well tolerated.

In long term extensions of the previously noted ATTAIN trial (Genovese, 2005), the safety and efficacy of abatacept were followed-up over two year (Genovese, 2008) and five year (Genovese, 2012) periods in individuals with RA who had inadequate response to anti-TNF therapy. Safety and efficacy were found to be consistent from six months to five years. Genovese and colleagues (2012) reported that a total of 317 individuals (218 double blind abatacept, 99 double blind placebo) entered the LTE and 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the double blind period. ACR responses with abatacept at six months were maintained over five years. Among those who received abatacept for five years and had available data at year five, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of individuals remaining on treatment at year five; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. The authors concluded that efficacy was maintained and safety was consistent from six months to five y ears and the benefit of switching to abatacept after failing anti TNF therapy in this difficult to treat population was demonstrated.

An Agency for Healthcare Research and Quality (AHRQ) (Donahue, 2012) updated review examined the comparative effectiveness of corticosteroids, oral DMARDs, and biologic DMARDs, including abatacept, in the treatment of individuals with RA. Limited head-to-head comparative evidence does not support one therapy over another for adults with RA. Network meta-analyses from placebo-controlled trials of biologics suggest some differences, including higher odds of reaching ACR50 response, but the strength of evidence was low. Mixed treatment comparisons found no significant differences in disease activity with tocilizumab, abatacept, adalimumab, golimumab, infliximab, and rituximab (strength of evidence is low). Evidence was insufficient to assess comparative risk of serious adverse events among biologic DMARDs. Combinations of biologic DMARDs have higher rates of serious adverse events than biologic DMARD monotherapy.

In April 2012, the ACR updated their 2008 recommendations for the use of DMARDs and biologic agents in the treatment of RA, following the same methodology used to develop the 2008 recommendations. The 2012 revision updates the following areas:

1. Indications for DMARDs and biologic agents (including new agents not covered in 2008)
2. Switching between DMARD and biologic therapies
3. Use of biologic agents in high-risk individuals (those with hepatitis, congestive heart failure [CHF], and malignancy)
4. Screening for TB in individuals starting or currently receiving biologic agents
5. Vaccination in individuals starting or currently receiving DMARDSor biologic agents (Singh, 2012)

For each final recommendation, the strength of evidence was assigned using a three-level method from the American College of Cardiology. A key assumption for clinical scenarios state the recommendations focus on "common patients, not exceptional cases" and vary with each person with RA. Indications for starting, resuming, adding, or switching DMARDs or biologic agents address use in early RA (disease duration less than six months), and for initiating and switching between DMARDs and biologic agents in established RA (disease duration greater than or equal to six months or meeting the 1987 ACR RA classification criteria). The 2012 guideline algorithm recommends initiating treatment using non-biologic DMARD combination-therapy (including two or more DMARDs/double and triple therapy) for the majority of individuals with early RA with moderately or highly active disease and poor prognostic features (Level of Evidence: A-B, except for MTX and leflunomide: C), or, moving to a biologic agent with or without MTX (Level of Evidence: B) if each option fails to control the disease. When switching from DMARDs to biologics, physicians should use either an anti-TNF biologic or a non-TNF biologic if an individual has moderate or high disease activity after three months of MTX treatment or DMARD combination therapy (Level of Evidence: A-C).

The 2012 updated recommendations for use of biologic agents in high-risk individuals otherwise qualifying for RA management strategy with a history of hepatitis, malignancy, or congestive heart failure are as follows (Level of Evidence: C [i.e., data were derived from consensus opinion of experts, case studies, or standards of care]):

• In persons with RA and untreated chronic hepatitis B, or with treated chronic hepatitis B with Child-Pugh class B and higher disease, the panel recommends not using any biologic agent.
• Persons may be treated with a TNF agent (or any biologic agent) if their treatment for solid malignancies or non-melanoma skin cancer was more than five years prior to starting or resuming any biologic agent.
• Use of a TNF antagonist is not recommended in persons with CHF, NYHA class III or IV and who have an ejection fraction of 50% or less.

The 2012 ACR panel recommendation for TB screening and use of vaccines considers the current CDC recommendations along with an increased awareness of the risk of preventable infections in individuals with RA who are starting or currently receiving DMARDs or biologic agents: 

• Screen for latent TB infection (LTBI) with a TST or interferon-y release assay (IGRA) as the initial test in all individuals with RA starting biologic agents, regardless of risk factors for LTBI (Level of Evidence: C). An algorithm for TB screening prior to initiation of biologic agents includes recommendations for screening if the initial TST or IGRA is "positive" or the individual is being treated for latent TB (Level of Evidence: B).
• For vaccination management, physicians should refer to the vaccine instructions and CDC recommendations for dosing and timing based on age and risk factors. All killed (pneumococcal, influenza intramuscular, and hepatitis B), recombinant (human papillomavirus [HPV] vaccine for cervical cancer) and live attenuated (herpes zoster) vaccinations should be administered before starting a DMARD or a biologic agent. If not previously done, vaccination with indicated pneumococcal (killed), influenza intramuscular (killed), hepatitis B (killed), and HPV vaccine (recombinant) should be undertaken in RA patients already taking a DMARD or a biologic agent. Vaccination with herpes zoster vaccine in RA patients already taking a DMARD is recommended but is not recommended in patients taking a biologic agent (Level of Evidence: C for all vaccination recommendations) (Singh, 2012).

Polyarticular Juvenile Idiopathic Arthritis (JIA) 
The FDA approval of abatacept for use in reducing signs and symptoms of moderately to severely active polyarticular juvenile RA in individuals age six 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 children and adolescents age six to 17 years with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were enrolled. Criteria for enrollment 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. Clinical assessments were completed prior to drug administration at all visits. 

In Period A (open-label, lead-in), subjects received 10 mg/kg (maximum 1000 mg per dose) of abatacept intravenously on days one, 15, 29, and monthly thereafter. Response was assessed according to the ACR Pediatric definition of improvement, defined as greater than or equal to 30% improvement in at least three of the six JIA core set variables and greater than or equal to 30% worsening in not more than one of the six 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 six months or until disease flare. Disease flare was defined as worsening of 30% or more in at least three of the six JIA core response variables and at least 30% worsening in not more than one of the six 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, 2011). 

Ruperto and colleagues (2010a) studied health-related quality of life (HRQOL) in children and adolescents with JIA treated with abatacept in periods A and B of the previously reported on trial. HRQOL assessments performed included a parent-administered 50 item Child Health Questionnaire (CHQ) used to assess physical, social and emotional aspects in children plus physical and psychosocial summary scores, and also parent-administered pain, sleep, and daily activity assessments. A total of 190 subjects from period A and 122 from period B were analyzed. In period A, there were improvements demonstrated across all of the CHQ domains (greatest improvement was in pain and discomfort) with abatacept. At the end of period B, children treated with abatacept had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement was seen with pain and sleep. For daily activity participation, an additional 2.6 school days per month and 2.3 parents' usual activity days per month were gained in period A responders with abatacept, and additional gains were made in period B (1.9 vs 0.9 [P = 0.033] and 0.2 vs -1.3 [P = 0.109] school days per month and parents' usual activity days per month, respectively, in abatacept- versus placebo-treated subjects). A significant study limitation was that HRQOL assessments were parent or caregiver reported evaluations. The authors concluded that the results of this study demonstrated that abatacept provided significant and meaningful improvements in HRQOL. 

Ruperto and colleagues (2010b) described results from the third phase (Period C) of their long-term, open-label double-blind, controlled, randomized withdrawal trial. A total of 153 (90%) of the 170 children completing the open-label lead-in phase (Period A) entered the open-label long term extension (LTE). All children in the LTE phase were treated with 10 mg/kg abatacept administered intravenously every four weeks, with or without methotrexate. Efficacy results were based on data obtained from the 153 participants who entered the open-label LTE phase and reflect greater than or equal to 21 months (589 days) of treatment. By day 589, 90%, 88%, 75%, 57%, and 39% of those treated with abatacept during the double-blind and LTE phases achieved responses according to the ACR Pediatric 30 % (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 improvement criteria, respectively. Similar response rates were observed by day 589 among those previously treated with a placebo. Among children who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who advanced directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. The authors concluded that the results of this study suggest that abatacept is a promising treatment of JIA in children and adolescents.

In 2011, the ACR issued recommendations for the treatment of JIA which included initiation of abatacept as a treatment approach in certain individuals with history of JIA of five or more joints who have previously received a TNF antagonist inhibitor for four months or who have received more than one TNF antagonist inhibitor sequentially. Abatacept was also recommended for certain individuals with JIA who have received methotrexate and a TNF antagonist inhibitor.

Other Proposed Uses 
There has been interest in the use of abatacept for treatment of non FDA approved conditions, including but not limited to Crohn's disease and ulcerative colitis (Sandborn, 2012), lupus nephritis (Wofsy, 2012), scleroderma (Ong, 2010), systemic lupus erythematosus (Merrill, 2010), ankylosing spondylitis (Song, 2011), and type 1 diabetes (Orban, 2011). In addition, a search of Clinical Trials.gov revealed clinical trials for other conditions, including: acute GVHD, giant cell arteritis and Takayasu's arteritis, multiple sclerosis, psoriasis vulgaris, and uveitis. Published evidence regarding the use of abatacept for these conditions is lacking or limited and further investigation in large randomized controlled clinical trials is needed.

Definitions: 

• Ankylosing spondylitis: A chronic disease that causes inflammation of the joints between the spinal bones and the joints between the spine and pelvis.
• Biologic DMARDs: A class of drugs thought to work by targeting components of the immune system by blocking specific immune cytokines, blocking other cytokines, binding with cytokines suppressing Il-12 and IL-23, or by directly suppressing lymphocytes; includes the anti-CD20 monoclonal antibodies (e.g., rituximab), interleukin-1 receptor antagonists (IL-1Ra) (e.g., anakinra), interleukin-6 (IL-6) receptor antagonists (e.g., tocilizumab), interleukin-(IL)-12 and IL-23 antagonists (e.g., ustekinumab), selective co-stimulation modulators (e.g. abatacept), and the tumor necrosis factor (TNF) antagonists (inhibitors).
• 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.
• Interferon gamma (IFN- γ) release assay (IGRA): A test that aids in detecting Mycobacterium tuberculosis infection, both latent infection and infection manifesting as active tuberculosis that may be used for surveillance purposes and to identify persons likely to benefit from treatment. FDA-approved IGRAs include the 1) QuantiFERON-TB Gold test (GFT-G), 2) QuantiFERON-TB Gold In-Tube test (QFT-GIT), and the 3) T-SPOT.TB test (T-Spot).
• Nonbiologic DMARDs: A class of drugs, also referred to as synthetic DMARDs, thought to work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory conditions, although their exact mechanisms of action are unknown. Drugs in this class include azathioprine, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline, organic gold compounds, penicillamine, and sulfasalazine.
• Psoriatic arthritis: A form of arthritis that can affect any joint within the body, either in a single joint or in the same joint on both sides of the body.
• Scleroderma: A systemic disorder of connective tissue characterized by induration and thickening of the skin, abnormalities of the blood vessels, and fibrotic degenerative changes in various body organs
• Systemic lupus erythematosus: A chronic multi-system autoimmune disease which can range from mild, single organ disease to severe, multiple-organ disease, which can lead to organ failure.
• Tumor Necrosis Factor (TNF) antagonists: A class of biologic DMARDs designed to neutralize inflammatory cytokines that target specific pathways of the immune system and either enhance or inhibit immune response. Drugs in this class include adalimumab (Humira®, Abbott Laboratories, North Chicago, IL), certolizumab pegol (Cimzia^®, UCB, Inc., Smyrna, GA), etanercept (Enbrel^®, Immunex Corporation, Thousand Oaks, CA), golimumab (Simponi™, Centocor Ortho Biotech Inc., Horsham, PA), and infliximab (Remicade®, Centocor Ortho Biotech Inc., Horsham, PA).

References:

1. Bathon J, Robles M, Ximenes AC, et al. Sustained disease remission and inhibition of radiographic progression in methotrexate-naïve patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes. Ann Rheum Dis. 2011; 70(11):1949-1956.
2. 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.
3. 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.
4. Genovese MC, Schiff M, Luggen M, et al. Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. Ann Rheum Dis. 2008; 67(4):547-554.
5. Genovese MC, Schiff M, Luggen M, et al. Longterm safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy. J Rheumatol. 2012; 39(8):1546-1554.
6. Hampton T. Trials reveal promising options for treating juvenile rheumatoid arthritis. JAMA. 2008; 299(1):27-28.
7. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005; 52(8):2263-2271.
8. 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.
9. Kremer JM, Genant HK, Moreland LW, et al. Results of a two-year follow up study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. Arthritis Rheum. 2008; 58(4):953-963.
10. Kremer JM, Russell AS, Emery P, et al. Long-term safety, efficacy and inhibition of radiographic progression with abatacept treatment in patients with rheumatoid arthritis and an inadequate response to methotrexate: 3-year results from the AIM trial. Ann Rheum Dis. 2011; 70(10):1826-1830.
11. 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.
12. 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.
13. Mease P, Genovese MC, Gladstein G, et al. Abatacept in the treatment of patients with psoriatic arthritis: Results of a six-month, multicenter, randomized, double-blind, placebo-controlled, phase II trial. Arthritis Rheum. 2011; 63(4):939-948.
14. Merrill JT, Burgos-Vargas R, Westhovens R, et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2010; 62(10):3077-3087.
15. Ong VH, Denton CP. Innovative therapies for systemic sclerosis. Curr Opin Rheumatol. 2010; 22(3):264-272.
16. Orban T, Bundy B, Becker DJ, et al; Type 1 Diabetes TrialNet Abatacept Study Group. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011; 378(9789):412-419.
17. Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician. 2005; 72(6):1037-1047.
18. Ruperto N, Lovell DJ, Li T, Paediatric Rheumatology International Trials Organisation (PRINTO); Pediatric Rheumatology Collaborative Study Group (PRCSG). Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2010a; 62(11):1542-1551.
19. 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.
20. Ruperto N, Lovell DJ, Quartier P, et al; Paediatric Rheumatology International Trials Organization; Pediatric Rheumatology Collaborative Study Group. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheum. 2010b; 62(6):1792-1802.
21. Sandborn WJ, Colombel JF, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology. 2012; 143(1):62-69.
22. Schiff M, Keiserman M, Codding C, et al. Clinical response and tolerability to abatacept in patients with rheumatoid arthritis previously treated with infliximab or abatacept: open-label extension of the ATTEST Study. Ann Rheum Dis. 2011; 70(11):2003-2007.
23. 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.
24. 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.
25. Song IH, Heldmann F, Rudwaleit M, et al. Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study. Ann Rheum Dis. 2011; 70(6):1108-1110.
26. 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.
27. 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.
28. Wofsy D, Hillson JL, Diamond B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 2012; 64(11):3660-3665.
29. Abatacept Monograph. Revised January 1, 2009. American Hospital Formulary Service®. Available at: http://www.ashp.org/ahfs/. Accessed on March 8, 2013.
30. Abatacept (systemic). In: DrugPoints® System [electronic version]. Truven Health Analytics, Greenwood Village, CO: Thomson Healthcare. Updated June 29, 2012. Available at: http://www.micromedexsolutions.com. Accessed on March 08, 2013.
31. 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.
32. Beukelman T, Patkar NM, Saag KG, et al. 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res (Hoboken). 2011; 63(4):465-482.
33. Centers for Disease Control (CDC) and Prevention. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection - United States, 2010; 59(No. RR 5):1-28. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf. Accessed on March 08, 2013.
34. Donahue KE, Jonas DE, Hansen RA, et al. Drug therapy for rheumatoid arthritis in adults: an update. Comparative Effectiveness Review No. 55. Agency for Healthcare Research and Quality. AHRQ Publication No. 12-EHC025-EF. June 1, 2012. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1044&pageaction=displayproduct. Accessed on March 8, 2013.
35. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Abatacept for Treating Adults With Giant Cell Arteritis and Takayasu's Arteritis. NLM Identifier: NCT00556439. Last updated on August 27, 2012. Available at: http://clinicaltrials.gov/ct2/show/study/NCT00556439. Accessed on March 13, 2013.
36. National Institute of Allergy and Infectious Diseases (NIAID). A Cooperative Clinical Study of Abatacept in Multiple Sclerosis (ACCLAIM). NLM Identifier: NCT01116427. Last updated on November 5, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT01116427. Accessed on March 13, 2013.
37. National Institute of Health; Bristol-Myers Squibb. Phase I Study of BMS-188667 (CTLA4Ig) in Patients With Psoriasis Vulgaris. NLM Identifier: NCT00306878. Last updated on April 11, 2011. Available at: http://www.clinicaltrials.gov/ct2/show/study/NCT00306878?term=psoriasis+vulgaris+abatacept&rank=1. Accessed on March 13, 2013.
38. National Institute of Health; Emory University. Safety and Tolerability Trial of Abatacept-based Immunosuppression for Prevention of Acute Graft Versus Host Disease (aGVHD) During Transplant. NLM Identifier: NCT01012492. Last updated on November 12, 2009. Available at: http://clinicaltrials.gov/ct2/show/study/NCT01012492. Accessed on March 13, 2013.
39. National Institute of Health; Oregon Health and Science University. Abatacept in the Treatment of Uveitis. NLM Identifier: NCT01279954. Last updated on August 31, 2012. Available at http://clinicaltrials.gov/ct2/show/NCT01279954. Accessed on March 13, 2013.
40. Orencia [Product Information], Princeton, NJ. Bristol-Myers Squibb; December 2011. Available at:   http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125118s0138lbl.pdf. Accessed on March 08, 2013.
41. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012; 64(5):625-639.
42. Pollard L, Choy E. Rheumatoid arthritis: Non-tumor necrosis factor targets. Curr Opin Rheumatol. 2005;17(3):242-246.
43. Ruderman EM, Pope RM. The evolving clinical profile of abatacept (CTLA4-Ig): A novel co-stimulatory modulator for the treatment of rheumatoid arthritis. Arthritis Res Ther. 2005;7 Suppl 2:S21-S25.

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2013 Forward