Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugsA one-year randomized placebo-controlled study.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 54, No. 9, September 2006, pp 2807–2816 DOI 10.1002/art.22070 © 2006, American College of Rheumatology 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 M. Weinblatt,1 B. Combe,2 A. Covucci,3 R. Aranda,3 J. C. Becker,3 and E. Keystone4 patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%). Conclusion. Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy. Objective. To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving >1 traditional nonbiologic and/or biologic diseasemodifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study. Methods. This was a 1-year, multicenter, randomized, double-blind, placebo-controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo. Results. The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of T cells play a fundamental role in the upstream initiation and perpetuation of the pathologic immune response in rheumatoid arthritis (RA), resulting in downstream inflammation and destruction (1). Following antigen recognition, T cells require a costimulatory signal for full activation, with one of the best characterized pathways being the engagement of CD80/86 on antigen-presenting cells with CD28 on T cells (2). Following the normal immune response, endogenous CTLA-4 down-regulates CD28-mediated T cell activation by binding to CD80/86 with higher avidity than CD28 (3). The important role of T cells in the immune response in RA makes T cell activation a rational therapeutic target for treatment of this disease. Abatacept is a fully human soluble fusion protein that consists of the extracellular domain of human CTLA-4 linked to the modified Fc portion of human IgG1. Abatacept is the first in a new class of agents for Supported by Bristol-Myers Squibb. 1 M. Weinblatt, MD: Brigham and Women’s Hospital, Boston, Massachusetts; 2B. Combe, MD: Hopital Lapeyronie, Montpellier, 3 France; A. Covucci, MSc, R. Aranda, MD, J. C. Becker, MD: Bristol-Myers Squibb, Princeton, New Jersey; 4E. Keystone, MD: Mount Sinai Hospital, Toronto, Ontario, Canada. Drs. Weinblatt and Keystone have received consultancies and/or honoraria (less than $10,000) from Bristol-Myers Squibb, Abbott, Amgen, Wyeth, Centocor, and Genentech. Dr. Combe has received consultancies and/or honoraria (less than $10,000) from Briston-Myers Squibb, Abbott, and Sanofi. Drs. Aranda and Becker own stock and/or stock options in Bristol-Myers Squibb. Address correspondence and reprint requests to M. Weinblatt, MD, Rheumatology and Immunology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: mweinblatt@ partners.org. Submitted for publication February 15, 2006; accepted in revised form June 9, 2006. 2807 2808 WEINBLATT ET AL the treatment of RA that selectively modulates the CD80/86:CD28 costimulatory signal required for full T cell activation. Abatacept, a selective costimulation modulator, has previously demonstrated efficacy, safety, and tolerability in combination with methotrexate (MTX) in clinical trials of patients in whom the response to MTX was inadequate (4,5). Furthermore, a trial of abatacept on a background of disease-modifying antirheumatic drugs (DMARDs) in patients with an inadequate response to anti–tumor necrosis factor (anti-TNF) therapy recently demonstrated a significant efficacy benefit of abatacept in this unique RA patient population (6). The Abatacept Study of Safety in Use with Other RA Therapies (ASSURE trial) was designed to assess the safety of abatacept compared with placebo in patients with active RA during 1 year of abatacept treatment added to a background of treatment with ⱖ1 of the traditional nonbiologic and/or biologic DMARDs currently approved for the treatment of RA. This trial was designed to assess the safety of abatacept in patients with RA who would be encountered in clinical practice. PATIENTS AND METHODS Role of the funding source. Bristol-Myers Squibb was involved in the design of the study (conducted between December 17, 2002 and June 21, 2004) and collection and analysis of the data. Patients. The study group comprised men and women at least 18 years of age who met the 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria for the diagnosis of RA (7) and the 1991 ACR criteria for RA functional classes I, II, III, or IV (8). Patients had to have active disease despite receiving background DMARDs and/or biologic therapy, warranting additional therapy at the discretion of the investigator. To qualify for this study, the average score for the patient’s global assessment of disease activity, as assessed by visual analog scale (VAS) measurements obtained at the time of screening and randomization (day 1), was required to be ⱖ20 mm. Patients were required to have been receiving ⱖ1 biologic and/or nonbiologic DMARD approved for RA for at least 3 months, and at a stable dose for at least 28 days prior to day 1 of the trial. Patients with stable medical conditions such as congestive heart failure (CHF), asthma, chronic obstructive pulmonary disease (COPD), and diabetes mellitus were included. Patients were excluded if they had unstable or uncontrolled renal, endocrine, hepatic, hematologic, gastrointestinal, pulmonary, cardiac, or neurologic diseases, or any autoimmune disorder other than RA as the main diagnosis. Other exclusion criteria were active or chronic recurrent bacterial infections unless treated and resolved, active herpes zoster infection within the previous 2 months, hepatitis B or hepatitis C virus infection, and active or latent tuberculosis (as assessed via chest radiography and tuberculin testing) unless appropriately treated. Pregnant or nursing women were also excluded. Study protocol. This was a 1-year, multinational, multicenter, randomized, double-blind, 2-arm, parallel-dosing trial. Eligible patients were randomized 2:1 to receive abatacept (at a fixed dose approximating 10 mg/kg) or placebo by intravenous infusion. The fixed dosing regimen was based on the following body weight range: 500 mg for patients with a body weight ⬍60 kg, 750 mg for patients with a body weight of 60–100 kg, and 1 gram for patients with a body weight ⬎100 kg. Patients completing the double-blind phase of the study were allowed to enter a long-term, open-label extension phase during which all patients received a fixed dose of abatacept approximating 10 mg/kg. The study was carried out in accordance with the ethical principles of the Declaration of Helsinki and was approved by institutional review boards. All patients gave informed consent before undergoing any screening procedure. Treatment administration. Medication (abatacept or placebo) was administered via a 30-minute intravenous infusion on days 1, 15, and 29, and every 4 weeks thereafter, for a total of 14 doses. Concomitant medications. All patients were required to continue to receive their background RA therapies (biologic DMARDs, nonbiologic DMARDs, or a combination of both) at study entry. For the purposes of the study, approved biologic and nonbiologic DMARDs included the following: MTX, hydroxychloroquine, leflunomide, gold, azathioprine, anakinra, etanercept, infliximab, and adalimumab. Stable, low-dose oral corticosteroids (10 mg/day or less) and/or stable doses of nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin (acetylsalicylic acid [ASA]), were allowed. During the first 3 months of the trial, adjustments in background RA therapy (nonbiologic DMARDs, biologic DMARDs, or corticosteroids) were not allowed except for decreases in dose due to toxicity. Analgesics that did not contain ASA or NSAIDs were permitted to be administered to patients who were experiencing pain that was not adequately controlled by baseline and study medications. Additional analgesics or NSAIDs that were not part of background RA therapy were not permitted within the 12 hours preceding the patient’s global assessment of disease activity on days 1, 85, 169, and 253. After the first 3 months (days 86–365), adjustments in background RA therapy were permitted, including the withdrawal or addition of nonbiologic DMARDs, biologic DMARDs, or corticosteroids. Patients were permitted to adjust the dosage of existing DMARDs or add additional DMARDs; however, dose modification of the study medication was not permitted. Therapies that were prohibited during the study included mycophenolate mofetil, cyclosporine, other calcineurin inhibitors, D-penicillamine, cyclophosphamide, and apheresis (immunoadsorption columns). Safety. Overall assessments. The primary objective of the ASSURE trial was to evaluate the safety of abatacept in patients with active RA, including those with comorbid conditions, during 1 year of abatacept treatment added to a background of ⱖ1 of the traditional biologic and/or nonbiologic DMARDs approved for RA. All patients who received at least 1 dose of study medication were evaluated for the occurrence of adverse events (AEs), serious adverse events (SAEs), discontinuations due to AEs, death, clinically significant changes THE ASSURE TRIAL in vital signs, physical examination abnormalities, and clinical laboratory test abnormalities. Adverse and serious adverse events. An AE was defined as any new or worsening illness, sign, symptom, or clinically significant laboratory test abnormality noted by the investigator or patient during the course of the study, regardless of causality. Intensity was rated by the investigator on a scale of 1 (mild) to 4 (very severe). An SAE was defined as an AE that met any of the following criteria: was fatal, was lifethreatening, resulted in hospitalization, resulted in persistent or significant disability or incapacity, was a malignancy, was a congenital anomaly or birth defect, resulted in an overdose or drug dependency, or was deemed an important medical event, as determined by the investigator. The severity of AEs (including infections) was assessed by the investigator. Prespecified infusion events. Prespecified infusion events represented a collection of AE terms (mostly representative of hypersensitivity reaction) selected from the Medical Dictionary for Regulatory Activities codes for a possible association with an infusion reaction. Acute infusional events were described as AEs occurring within 1 hour of the start of infusion. Periinfusional events were described as AEs occurring within 24 hours of the start of infusion. Prespecified autoimmune events. Autoimmune disorders of interest (including systemic lupus erythematosus, multiple sclerosis, and psoriasis) were identified according to a predefined list of terms and definitions. Clinical outcome measures. Three patient-reported components of the ACR core data set (9) were exploratory secondary efficacy objectives in this study. These measures have been shown to discriminate the efficacy of study treatments compared with that of placebo as effectively as composite ACR response measures (10). Physical function was assessed using the Disability Index of the Health Assessment Questionnaire (HAQ) (11). Patient’s global assessment of disease activity, patient’s global assessment of pain, and physician’s global assessment of disease activity were all assessed using a 100-mm VAS. Statistical analysis. Data were assessed for all patients treated with either abatacept or placebo in order to ascertain the safety and patient- and physician-reported benefit of abatacept in the overall population (all patients, regardless of background therapy) of this study. Furthermore, data from each treatment group were assessed according to background therapy (nonbiologic DMARDs versus biologic DMARDs) to determine whether differences in the effects of abatacept between these patient populations would be evident. Safety analyses were based on a data set containing all available assessments from all patients who received at least 1 infusion of study medication (treated patients). The study was powered to detect AEs occurring at a rate of 0.2%. No formal tests were planned to compare AE incidence rates between treatment groups. Exploratory efficacy analyses were performed on the 4 clinical outcome measures. For each of these measures, descriptive statistics, including the median percent improvement from baseline, the mean percent improvement from baseline, and the mean change from baseline, were provided for all time points. A post hoc analysis was used to assess each efficacy outcome according to background therapy (nonbiologic DMARDs versus biologic DMARDs). 2809 Figure 1. Patient disposition to 1 year. RESULTS Patient disposition and baseline characteristics. Of the 1,456 patients randomized, 1,441 received at least 1 infusion of study medication. A total of 1,231 patients (87.2% of those assigned to abatacept and 82.0% of those assigned to placebo) completed 1 year of doubleblind treatment (Figure 1). The majority of patients were white women. The mean ⫾ SD age for the overall study population was 52.3 ⫾ 11.8 years, and the mean duration of RA was approximately 9.7 ⫾ 8.9 years. Disease duration was typically longer in patients receiving biologic DMARDs than in those receiving nonbiologic DMARDs (11.3 years versus 9.5 years). The treatment groups were similar with respect to demographic characteristics and most baseline disease characteristics, with the exception of the C-reactive protein level, which was slightly higher in the subgroup receiving nonbiologic background therapy (Table 1). Among all patients overall (both the abatacept and placebo groups), the prevalence of comorbidities was as follows: for diabetes mellitus (type 1 or type 2), 6–7%; for type 2 diabetes mellitus, 6%; for asthma, 6%; for COPD, 4%; and for CHF, 1–2%. 2810 WEINBLATT ET AL Table 1. Baseline demographic and clinical characteristics of the patients, according to background therapy* Nonbiologic background therapy Biologic background therapy Parameter Abatacept (n ⫽ 856) Placebo (n ⫽ 418) Abatacept (n ⫽ 103) Placebo (n ⫽ 64) Age, years Female sex, no. (%) White race, no. (%) Disease duration, years Pain, 100-mm VAS Physical function, HAQ DI score Patient’s global assessment, 100-mm VAS Physician’s global assessment, 100-mm VAS C-reactive protein, mg/dl 52.2 ⫾ 11.8 711 (83.1) 718 (83.9) 9.5 ⫾ 8.7 61.1 ⫾ 20.4 1.5 ⫾ 0.6 60.6 ⫾ 19.7 57.8 ⫾ 17.4 1.9 ⫾ 2.4 52.0 ⫾ 12.1 350 (83.7) 348 (83.3) 9.5 ⫾ 9.1 61.3 ⫾ 20.8 1.5 ⫾ 0.7 61.3 ⫾ 20.1 58.3 ⫾ 17.5 2.1 ⫾ 2.6 54.6 ⫾ 11.2 78 (75.7) 100 (97.1) 11.3 ⫾ 8.9 62.2 ⫾ 20.3 1.5 ⫾ 0.6 60.3 ⫾ 19.8 57.4 ⫾ 17.8 1.4 ⫾ 1.9 52.8 ⫾ 11.4 48 (75.0) 59 (92.2) 11.3 ⫾ 9.6 61.5 ⫾ 20.0 1.6 ⫾ 0.6 58.7 ⫾ 17.2 57.6 ⫾ 17.6 1.5 ⫾ 1.9 * Except where indicated otherwise, values are the mean ⫾ SD. The nonbiologic background therapy subgroup was defined as all patients who received a nonbiologic agent at any time during the study or up to 56 days following discontinuation. The biologic background therapy subgroup was defined as all patients who received a biologic agent at any time during the study or up to 56 days following discontinuation. VAS ⫽ visual analog scale; HAQ DI ⫽ Disability Index of the Health Assessment Questionnaire. Background therapy. Results are presented according to background RA therapies (nonbiologic versus biologic DMARDs). The biologic subgroup was defined as all patients who received biologic DMARDs at any point during the course of the study or up to 56 days following discontinuation of study medication. At the time of randomization, the majority of patients were receiving 1 background DMARD (69% of the abatacept group and 65% of the placebo group). Smaller numbers of patients were receiving 2 DMARDs (24% and 29%, respectively) or 3 DMARDs (6% and 5%, respectively), while less than 1% of patients in either group were receiving 4 or more background DMARDs. Concomitant RA medications that were being received by patients in the nonbiologic and biologic subgroups are summarized in Table 2. Of the 959 patients assigned to receive abatacept, 855 (89.2%) received nonbiologic RA therapy (abatacept plus nonbiologic subgroup) and 103 (10.7%) received background biologic RA therapy (abatacept plus biologic subgroup) during the trial. Corresponding numbers of patients assigned to the placebo group who received background nonbiologic or biologic therapy were 417 (86.5%; placebo plus nonbiologic subgroup) and 64 (13.3%; placebo plus biologic subgroup). The most frequently used nonbiologic DMARD was MTX (in the nonbiologic subgroup, 80.7% of patients receiving abatacept and 80.4% of those receiving placebo; in the biologic subgroup, 56.3% of patients receiving abatacept and 56.3% of those receiving placebo). In the biologic subgroup, 87.4% of patients assigned to abatacept and 87.5% of those assigned to placebo were receiving anti-TNF therapy. The most commonly used biologic therapy was etanercept (64.1% and 65.6% of the abatacept and placebo groups, respectively). After month 3, when changes in background DMARDs were permitted, fewer abatacept-treated patients than placebo-treated patients received additional nonbiologic DMARDs (4.3% and 7.7%, respectively), while a similar proportion of patients from the abatacept and placebo groups discontinued additional nonbiologic DMARDs (5.6% and 5.2%, respectively). In terms of background biologic therapy, 0.9% of patients in the abatacept group and 1.9% of those in the placebo group received additional therapy. The proportions of abatacept-treated patients and placebo-treated patients who discontinued additional biologic therapy were 1.1% and 0.6%, respectively. Safety. Overall adverse events and serious adverse events. Overall, the abatacept and placebo groups were similar in terms of the incidence of AEs (90% and 87%, respectively), SAEs (13% and 12%, respectively), and severe or very severe AEs (16% and 15%, respectively). Discontinuations due to AEs were infrequent in both treatment groups, occurring in 5% and 4% of the abatacept and placebo groups, respectively. Five patients (0.5%) in the overall abatacept group and 4 patients (0.8%) in the overall placebo group died during the 1-year, double-blind treatment period. Four of the deaths occurring in the abatacept group (hypertensive heart disease 2 days following the first infusion, coronary THE ASSURE TRIAL 2811 Table 2. Concomitant rheumatoid arthritis medication received by the patients, according to background therapy* Nonbiologic background therapy Biologic background therapy Therapy Abatacept (n ⫽ 856) Placebo (n ⫽ 418) Abatacept (n ⫽ 103) Placebo (n ⫽ 64) Nonbiologic DMARDs Methotrexate Hydroxychloroquine/chloroquine Sulfasalazine Leflunomide Gold Azathioprine Biologic DMARDs Anti–tumor necrosis factor therapy Etanercept Infliximab Adalimumab Anakinra Corticosteroids (oral and/or injectable) 855 (99.9) 691 (80.7) 194 (22.7) 137 (16.0) 106 (12.4) 24 (2.8) 23 (2.7) 0 0 0 0 0 0 613 (71.6) 417 (99.8) 336 (80.4) 123 (29.4) 72 (17.2) 59 (14.1) 10 (2.4) 17 (4.1) 0 0 0 0 0 0 308 (73.7) 81 (78.6) 58 (56.3) 15 (14.6) 11 (10.7) 15 (14.6) 1 (1.0) 3 (2.9) 103 (100) 90 (87.4) 66 (64.1) 20 (19.4) 11 (10.7) 13 (12.6) 77 (74.8) 52 (81.3) 36 (56.3) 7 (10.9) 4 (6.3) 12 (18.8) 1 (1.6) 3 (4.7) 64 (100) 56 (87.5) 42 (65.6) 5 (7.8) 10 (15.6) 10 (15.6) 51 (79.7) * Values are the number (%). The nonbiologic background therapy subgroup was defined as all patients who received a nonbiologic agent at any time during the study or up to 56 days following discontinuation. The biologic background therapy subgroup was defined as all patients who received a biologic agent at any time during the study or up to 56 days following discontinuation. Two patients (1 in the abatacept group and 1 in the placebo group) were not receiving disease-modifying antirheumatic drugs (DMARDs) at any time during the study, or for 56 days following discontinuation, and these patients were protocol violators. atherosclerosis and acute ischemic cardiopathy 13 days following the twelfth infusion, central atherosclerosis and significantly advanced coronary atherosclerosis with focal stenosis 7 days following the thirteenth infusion, and cardiac arrest 29 days following the twelfth infusion) and 3 of the deaths in the placebo group (CHF 55 days following the seventh infusion, cardiopulmonary arrest 37 days following the fourteenth infusion, and cardiac arrest 28 days following the fourteenth infusion) were deemed either unlikely to be related or unlikely to be unrelated to study medication. For the remaining abatacept patient, the cause of death was unknown, because no autopsy was performed. The remaining death in the placebo group was the result of Pneumocystis carinii pneumonia, which was deemed possibly related to the investigational drug by the study investigator, who was blinded to therapy at the time of assessment. This patient had been receiving background RA therapy with MTX, gold salts, prednisone, and chloroquine. A summary of AEs according to treatment subgroup and background therapy is shown in Table 3. Nonbiologic background therapy. Total AEs in the subgroup receiving nonbiologic background therapy occurred at similar rates in the abatacept plus nonbiologic subgroup and the placebo plus nonbiologic subgroup (89.7% and 86.1%, respectively), as did discon- tinuations due to AEs (5.0% and 4.3%, respectively). The most common AE was headache (20.3% of patients in the abatacept plus nonbiologic subgroup versus 13.9% of those in the placebo plus nonbiologic subgroup). Total SAEs occurred at similar rates in the abatacept plus nonbiologic subgroup and the placebo plus nonbiologic subgroup (11.7% and 12.2%, respectively), while discontinuations due to SAEs were more frequent in the abatacept plus nonbiologic subgroup (2.1% and 1.2%, respectively). In a subpopulation of patients receiving background leflunomide (106 patients in the abatacept group and 59 patients in the placebo group), total SAEs occurred more frequently in those receiving abatacept than in those receiving placebo (23.6% versus 15.3%). The most common events were musculoskeletal and connective tissue disorders (8.5% versus 5.1%) and infections/infestations (7.5% versus 5.1%). There was no trend in the particular type of AE associated with the use of abatacept plus background leflunomide. In contrast, the percentage of SAEs in the subpopulations of patients receiving abatacept on a background of MTX and those receiving placebo on a background of MTX was similar (10.6% versus 11.0%), while SAEs occurred less frequently in patients receiving abatacept on a background of sulfasalazine than in those receiving 2812 WEINBLATT ET AL Table 3. Summary of adverse events, serious adverse events, and serious infections, according to background therapy* Nonbiologic background therapy Event Deaths Total adverse events Related adverse events Discontinuations due to adverse events Total serious adverse events Related serious adverse events Discontinuations due to serious adverse events Serious infections Total neoplasms Most common neoplasms† Uterine leiomyoma Fibroadenoma of breast Basal cell carcinoma Most common adverse events‡ Infections Gastrointestinal disorders Nervous system disorders Musculoskeletal and connective tissue disorders Serious infections Respiratory Dermatologic Urinary Gastrointestinal Gynecologic Opportunistic Pneumocystis pneumoniae Candidiasis Other Biologic background therapy Abatacept (n ⫽ 856) Placebo (n ⫽ 418) Abatacept (n ⫽ 103) Placebo (n ⫽ 64) 5 (0.6) 768 (89.7) 473 (55.3) 43 (5.0) 4 (1.0) 360 (86.1) 203 (48.6) 18 (4.3) 0 98 (95.1) 61 (59.2) 9 (8.7) 0 57 (89.1) 36 (56.3) 2 (3.1) 100 (11.7) 18 (2.1) 18 (2.1) 51 (12.2) 10 (2.4) 5 (1.2) 23 (22.3) 5 (4.9) 5 (4.9) 8 (12.5) 3 (4.7) 2 (3.1) 22 (2.6) 27 (3.2) 7 (1.7) 16 (3.8) 6 (5.8) 7 (6.8) 1 (1.6) 1 (1.6) 4 (0.5) 4 (0.5) 3 (0.4) 1 (0.2) 0 3 (0.7) 0 0 2 (1.9) 0 0 0 470 (54.9) 350 (40.9) 304 (35.5) 229 (26.8) 224 (53.6) 148 (35.4) 121 (28.9) 112 (26.8) 67 (65.0) 40 (38.8) 37 (35.9) 28 (27.2) 37 (57.8) 20 (31.3) 23 (35.9) 20 (31.3) 9 (1.1) 5 (0.6) 4 (0.5) 2 (0.2) 0 0 0 0 3 (0.4) 4 (1.0) 1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2) 2 (0.5) 1 (0.2) 1 (0.2) 0 3 (2.9) 0 2 (1.9) 1 (1.0) 0 0 0 0 1 (1.0) 1 (1.6) 0 0 0 0 0 0 0 0 * Values are the number (%). The nonbiologic background therapy subgroup was defined as all patients who received a nonbiologic agent at any time during the study or up to 56 days following discontinuation. The biologic background therapy subgroup was defined as all patients who received a biologic agent at any time during the study or up to 56 days following discontinuation. † Occurring in ⬎0.2% of patients receiving abatacept plus nonbiologic background therapy. ‡ Occurring in ⬎25% of patients in all groups. placebo on a background of sulfasalazine (10.9% versus 12.5%). Biologic background therapy. Among patients receiving biologic background therapy, total AEs were more frequent in those in the abatacept subgroup compared with the placebo subgroup (95.1% versus 89.1%), as were discontinuations due to AEs (8.7% versus 3.1%). In the subpopulation of patients receiving biologic background therapy, the most common AE was headache, and this was reported more frequently in those receiving abatacept than in those receiving placebo (20.4% versus 15.6%). Total SAEs were more frequent in patients receiving abatacept than in those receiving placebo (22.3% versus 12.5%), as were discon- tinuations due to SAEs (4.9% versus 3.1%). In the small subgroup of patients receiving background anakinra (13 patients assigned to receive abatacept and 10 patients assigned to the placebo group), the frequencies of total SAEs were 15.4% and 20.0%, respectively. Infections. Overall incidence of infections. Infections were the most common adverse events reported in both treatment groups (for abatacept, 56.0%; for placebo, 54.1%). The most frequent infections (upper respiratory tract infection and nasopharyngitis) occurred at similar rates in the abatacept and placebo groups (15% for both groups and 10% for both groups, respectively). Fewer than 4% of patients in either treatment group had a severe or very severe infection; however, THE ASSURE TRIAL serious infections (i.e., those that were fatal or lifethreatening, those that resulted in hospitalization, and those that resulted in persistent or significant disability or incapacity) occurred more frequently in the abatacept group (2.9% versus 1.9% in the placebo group). For the majority of patients, the serious infections were treatable and did not result in discontinuation of treatment. All of the serious infections in the abatacept group were bacterial in origin. In patients treated with abatacept during the year-long study period, no infection attributed to an opportunistic microorganism was seen, no cases of tuberculosis were observed, and no fatalities due to infection occurred. Nonbiologic background therapy versus biologic background therapy. Serious infections occurred more frequently in the subpopulation of patients receiving abatacept plus nonbiologic therapy than in those receiving placebo plus nonbiologic therapy (2.6% versus 1.7%) and in patients receiving abatacept plus biologic therapy (5.8% versus 1.6% of patients receiving placebo plus biologic therapy). These infections consisted of single events of cellulitis, intestinal abscess, infective bursitis, and pyelonephritis. In the small subgroup of patients receiving background anakinra, serious infections occurred more frequently with abatacept than with placebo (7.7% versus 0%). Malignancies. Overall incidence of malignancies. The overall incidence of neoplasms (benign, malignant, and unspecified) was 3.5% in both the abatacept group and the placebo group. Neoplasms reported as SAEs occurred in 1.5% of abatacept-treated patients and in 1.0% of placebo-treated patients. Skin carcinomas (primarily basal cell or squamous cell) were reported most commonly. Breast cancer was reported in 1 patient (0.1%) in the abatacept group and in 2 patients (0.4%) in the placebo group. Three lung cancers were reported in the abatacept group (0.3%) compared with none in the placebo group; 2 of the 3 patients with lung cancer had a history of smoking, and 2 patients had short duration (29 and 100 days) of therapy prior to the diagnosis of malignancy. One patient with lung cancer had an abnormal baseline radiograph, and this patient also had a synchronous renal malignancy. There were no reports of lymphoma. Nonbiologic background therapy versus biologic background therapy. The incidence of neoplasms (benign, malignant, and unspecified) was 7% in the group of patients receiving abatacept plus biologic therapy compared with 2% in the group receiving placebo plus biologic therapy. Within the subgroup receiving abatacept plus biologic therapy, there were 3 reports of 2813 malignant cancers (2 basal cell carcinomas and 1 squamous cell carcinoma). None of these 3 malignancies was rated as severe or very severe or resulted in study discontinuation, and each one was considered either unrelated or unlikely to be related to the study drug. Autoimmune events. Prespecified autoimmune events were reported at a similar rate in the 2 treatment groups (3.3% and 3.1% in the abatacept and placebo groups, respectively). Reported events in both treatment groups included keratoconjunctivitis sicca and vasculitis. There were no reports of multiple sclerosis or any other demyelinating disorders. Infusion-related adverse events. The incidences of acute infusion-related (within 1 hour of the start of infusion) and periinfusional (within 24 hours of the start of infusion) events were similar in the abatacept group (acute, 10.0%; periinfusional, 24.3%) and the placebo group (acute, 7.1%; periinfusional, 20.3%). The most frequent of these events were headache and dizziness. Few patients in the abatacept group had a severe acute (0.7%) or periinfusional (1.5%) event. Two patients in each treatment group experienced hypersensitivity reactions within 1 hour of infusion. Overall, prespecified acute infusional or periinfusional events resulted in discontinuation in only a small number of patients (0.6% of patients receiving abatacept and 0.2% of those receiving placebo). Patients with comorbid conditions. The numbers of patients with CHF and asthma were too small to permit conclusions to be drawn. However, the overall frequencies of SAEs and discontinuation due to AEs among patients receiving abatacept and those receiving placebo were generally comparable. Patients with COPD. Among patients with COPD, adverse events were reported in 97.3% of those receiving abatacept (n ⫽ 37) and 88.2% of those receiving placebo (n ⫽ 17). More AEs involving the respiratory system occurred in patients with COPD treated with abatacept than in those treated with placebo (43.2% versus 23.5%), the majority of which were of mild-to-moderate intensity. The most common respiratory AEs among abatacept-treated patients with COPD (occurring with a frequency ⬎5%) were cough, rhonchi, exacerbation of chronic obstructive airway disease, chronic obstructive airway disease, dyspnea, and nasal congestion. Infections were the most common organ system class of events reported as AEs among patients with COPD and occurred with a similar frequency in both the abatacept and placebo groups (59.5% and 58.8%, respectively). In the abatacept group, the most common infection-related AEs (occurring in ⱖ5% of patients) were upper respi- 2814 ratory tract infection, bronchitis, sinusitis, influenza, lower respiratory tract infection, herpes zoster infection, and respiratory tract infection. The pattern and types of infections were similar to those observed in abatacepttreated patients without COPD. Among patients with COPD, more SAEs were reported in those treated with abatacept than in those receiving placebo (27% versus 5.9%). Serious AEs reported for abatacept-treated patients with COPD included intestinal ischemia, colon adenoma, COPD, exacerbated COPD, squamous cell carcinoma of the skin, RA (2 cases), bronchitis, basal cell carcinoma (2 cases), cellulitis, cataract, and eye surgery. These events were more common in patients treated with abatacept than in those treated with placebo. Serious AEs of a respiratory nature were more commonly reported by patients receiving abatacept (10.8%; 1 exacerbation of COPD, 1 worsening of COPD, 1 bronchitis, 1 pneumonia) than by those receiving placebo (0%). Among abatacept-treated patients with COPD who had SAEs, no death occurred. Patients with diabetes mellitus. Among patients with diabetes mellitus, adverse events were reported by 93.8% of those in the abatacept group (n ⫽ 65) and 90.3% of those in the placebo group (n ⫽ 31). Infections were the most common organ system class of events reported as AEs among patients with diabetes mellitus and occurred at a modestly lower frequency in the abatacept group compared with the placebo group (50.8% versus 58.1%). More abatacept-treated patients with diabetes mellitus reported SAEs than did placebotreated patients with diabetes mellitus (21.5% versus 12.9%), and this was driven by increases in SAEs in the Figure 2. Patient- and physician-reported outcomes at 1 year. VAS ⫽ visual analog scale; HAQ DI ⫽ Disability Index of the Health Assessment Questionnaire. ⴱ ⫽ Sixteen patients were excluded from the efficacy analysis due to compliance issues at one center. WEINBLATT ET AL Figure 3. Disability Index of the Health Assessment Questionnaire (HAQ DI) at 1 year, according to background therapy. ⴱ ⫽ Sixteen patients were excluded from the efficacy analysis due to compliance issues at one center. organ system classes of musculoskeletal disorders and injury. Clinical outcome measures. Patient- and physician-reported outcomes. In the overall study population (all patients, regardless of background therapy), mean changes from baseline in patient- and physicianreported disease outcomes (patient’s assessment of pain, patient’s global assessment, and physician’s global assessment) at 1 year were significantly better for abatacept-treated patients (⫺26.3, ⫺27.2, and ⫺33.5, respectively) compared with placebo-treated patients (⫺16.4, ⫺17.4, and ⫺23.6, respectively) (P ⬍ 0.001 for all comparisons). In a post hoc analysis, improvements from baseline in all patient- and physician-reported outcomes were greatest in the group receiving abatacept plus nonbiologic therapy (Figure 2). Physical function. At 1 year, the mean change from baseline in physical function (Disability Index of the HAQ) was greater in patients treated with abatacept compared with those treated with placebo (⫺0.46 versus ⫺0.25; P ⬍ 0.001). Similarly, in a further post hoc analysis, improvements from baseline in physical function were seen in both abatacept treatment subgroups, with the differences between the abatacept and placebo groups being greatest in patients receiving nonbiologic background DMARDs (Figure 3). DISCUSSION Several randomized studies have demonstrated the efficacy of abatacept in patients with active RA. In a THE ASSURE TRIAL phase IIb trial (5), therapy with abatacept plus MTX in patients with an inadequate response to MTX provided significant improvements in terms of the ACR 20% (ACR20), ACR50, and ACR70 criteria (9) compared with placebo at 1 year (for ACR20, 63% versus 36%; for ACR50, 42% versus 20%; for ACR70, 21% versus 8%). A phase III trial in a similar patient population demonstrated similar benefit with abatacept versus placebo (for ACR20, 73% versus 40%; for ACR50, 48% versus 18%; for ACR70, 29% versus 6%) (12), while a further phase III trial of 6 months duration in patients with a current or previous inadequate response to anti-TNF therapy also demonstrated significant benefit with abatacept in this unique patient population (for ACR20, 50% versus 19.5%; for ACR50, 20% versus 4%; for ACR70, 10% versus 2%) (6). In all trials, abatacept provided significant improvement in patients’ physical function and quality of life (5,6,12). The primary end point of the ASSURE trial was to evaluate the safety of abatacept compared with placebo when added to a background of approved synthetic DMARDs and/or biologic DMARDs over the course of 1 year, in a blinded, randomized study. This study revealed overall similarity between the abatacept and placebo groups in their respective frequency of AEs, SAEs, and severe or very severe AEs; furthermore, discontinuations due to AEs were infrequent in both treatment groups. The overall frequency of neoplasms was similar in the abatacept and placebo groups. Lung cancer was the most frequently reported solid malignancy in this study (n ⫽ 3). A causal relationship to abatacept therapy is considered less likely in this group, considering that 2 of these patients had a very short duration of treatment, and 1 patient had an abnormal radiograph at baseline. However, the data are too limited to permit a definitive conclusion, and longerterm observation will be required. There were no reports of lymphoma, tuberculosis (for which patients were screened prior to treatment), or demyelinating disorders. When assessed according to background therapy, the rates of AEs and SAEs were similar in the subgroup receiving abatacept plus nonbiologic background therapy and the subgroup receiving placebo plus nonbiologic background therapy. However, AEs, SAEs, and discontinuations were all most frequent when abatacept was combined with background biologic therapy. It should be noted that the proportion of patients who experienced an SAE was greater among those receiving leflunomide plus abatacept than in those receiving leflunomide plus placebo; however, there was no trend for 2815 any specific organ system class or type of SAE, and the sample size of this group was relatively small. In the subgroup of patients with COPD, respiratory system– related AEs and SAEs were reported in a greater proportion of patients in the abatacept group compared with the placebo group, although the overall number of patients with COPD in this study was small. Nonetheless, the findings in this study indicate that abatacept should be used with caution and with close monitoring of respiratory status in patients with RA and COPD. The ASSURE trial involved 1 year of observation; however, greater clinical experience over longer periods of observation and in larger populations of patients with comorbidities is required to validate these findings. An important finding in this study was the number of serious infections observed when abatacept was combined with other biologic therapies. This confirms the findings of a smaller phase II study in which abatacept (2 mg/kg) in combination with the anti-TNF agent etanercept was associated with a higher rate of serious infections than was etanercept plus placebo after 1 year of double-blind therapy (Weinblatt M, et al: unpublished observations). In contrast, across clinical trials of abatacept in combination with nonbiologic therapy, the reported incidence of serious infections was lower than that reported here for patients receiving abatacept in combination with biologic background therapy. Genovese et al (6) reported that among patients who experienced an inadequate response to anti-TNF therapy, at 6 months the number of serious infections was comparable in patients receiving abatacept plus DMARDs and in those receiving placebo plus DMARDs (2.3% for both). More recently, among a group of patients with an inadequate response to MTX, serious infections in the abatacept group were of a similar magnitude to those in patients with an inadequate response to anti-TNF therapy (3.9% and 2.3%, respectively, for patients receiving abatacept plus MTX and those receiving placebo plus MTX) (12). Although efficacy was not a primary end point of the ASSURE trial, and as such this study was not designed to prospectively assess the efficacy of abatacept between subgroups, the benefit seen with abatacept in terms of physical function and physician- and patientreported pain and global assessment tended to be less in patients receiving background biologic therapy compared with those receiving background nonbiologic therapy. A post hoc analysis was used to assess each efficacy outcome according to background therapy; although post hoc analyses may not be deemed optimal, the lack of clinical benefit seen here in the group of patients 2816 WEINBLATT ET AL receiving abatacept plus biologic therapy is consistent with that seen in the phase II study of abatacept in combination with etanercept. Coupled with the less favorable safety profile seen in patients receiving abatacept on a background of biologic therapy, these findings are consistent with the lack of added benefit and increased rate of infection seen when other biologic agents were used in combination (e.g., etanercept plus anakinra) (13). In that study, patients receiving etanercept plus anakinra had a higher frequency of serious infection compared with those receiving etanercept alone (3.7–7.4% versus 0%), and the number of ACR responders was lower (13). Based on the results of the ASSURE trial and the phase II study evaluating the concomitant use of abatacept and etanercept, a favorable benefit-to-risk ratio with abatacept in combination with other biologic therapies is not apparent; therefore, use of abatacept in combination with biologic therapies is not advised. The safety and tolerability of abatacept in the ASSURE trial was favorable when abatacept was given in combination with nonbiologic DMARDs; the number of good clinical outcomes was also greater in this subgroup over the course of 1 year. Selective costimulation modulation with abatacept is an effective therapy for RA, with an acceptable safety profile when used in combination with a variety of background nonbiologic DMARDs. ACKNOWLEDGMENTS We would like to thank all of the physicians, nurses, study coordinators, and patients for their important contributions to the ASSURE trial. We would also like to thank Claire Smart, PhD, Medicus International, for her editorial assistance. REFERENCES 1. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001;344:907–16. 2. Yamada A, Salama AD, Sayegh MH. The role of novel T cell costimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002;13:559–75. 3. Chambers CA, Allison JP. CTLA-4—the costimulatory molecule that doesn’t: regulation of T-cell responses by inhibition. Cold Spring Harb Symp Quant Biol 1999;64:303–12. 4. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907–15. 5. Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W, 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;52:2263–71. 6. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor ␣ inhibition. N Engl J Med 2005;353: 1114–23. 7. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. 8. Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 1992;35:498–502. 9. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. 10. Pincus T, Strand V, Koch G, Amara I, Crawford B, Wolfe F, et al. An index of the three core data set patient questionnaire measures distinguishes efficacy of active treatment from that of placebo as effectively as the American College of Rheumatology 20% response criteria (ACR20) or the Disease Activity Score (DAS) in a rheumatoid arthritis clinical trial. Arthritis Rheum 2003;48: 625–30. 11. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum 1980;23:137–45. 12. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C, et al. Effects of abatacept in patients with methotrexate-resistant rheumatoid arthritis: a randomized trial. Ann Intern Med 2006;144:865–76. 13. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004;50:1412–9.