Efficacy and safety of infliximab in patients with ankylosing spondylitis over a two-year period.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 9, September 15, 2008, pp 1270 –1278 DOI 10.1002/art.24001 © 2008, American College of Rheumatology ORIGINAL ARTICLE Efﬁcacy and Safety of Inﬂiximab in Patients With Ankylosing Spondylitis Over a Two-Year Period JÜRGEN BRAUN,1 ATUL DEODHAR,2 BEN DIJKMANS,3 PIET GEUSENS,4 JOACHIM SIEPER,5 PAUL WILLIAMSON,6 WEICHUN XU,6 SUDHA VISVANATHAN,6 DANIEL BAKER,6 NEIL GOLDSTEIN,6 DÉSIRÉE VAN DER HEIJDE,7 AND THE ANKYLOSING SPONDYLITIS STUDY FOR THE EVALUATION OF RECOMBINANT INFLIXIMAB THERAPY STUDY GROUP Objective. To assess safety and efﬁcacy of inﬂiximab in patients with ankylosing spondylitis (AS) through 102 weeks. Methods. Patients (n ⴝ 279) with active AS were randomized to either group 1 (n ⴝ 78; placebo through week 24 and then inﬂiximab 5 mg/kg from weeks 24 through 96) or group 2 (n ⴝ 201; inﬂiximab 5 mg/kg through week 96). The primary efﬁcacy end point at week 24 (>20% improvement in the ASsessment in Ankylosing Spondylitis International Working Group criteria [ASAS20]) was assessed with an intent-to-treat analysis of observed data. Results. More patients in group 2 than group 1 achieved the ASAS20 response at week 24 (61.2% versus 19.2%; P < 0.001). By week 102, groups 1 and 2 were similar with regard to ASAS20 response (72.1% versus 73.9%); ASAS40 responses at week 102 were 45.9% versus 59.4%. No new safety issues were discerned. Conclusion. Inﬂiximab demonstrated sustained efﬁcacy and safety over 2 years in this large cohort of patients with active AS. Ankylosing spondylitis (AS) is an immune-mediated rheumatic disease characterized by inﬂammatory back pain due to sacroiliitis, spondylitis, and enthesitis. Traditional therapies for AS may have limited efﬁcacy for some patients (1–3). Owing to the pivotal role of tumor necrosis factor ␣ (TNF␣) in AS pathogenesis (4,5), drugs targeting TNF␣ have emerged as alternatives for patients with unremitting disease (6 –9). Inﬂiximab 5 mg/kg administered every 6 weeks was evaluated in 279 patients with AS in the Ankylosing Spondylitis Study for the Evaluation of Recombinant Inﬂiximab Therapy (ASSERT), and was found to be well tolerated and signiﬁcantly more effective than placebo in improving signs and symptoms of disease through week 24 (8). In an ASSERT substudy involving 266 patients with evaluable magnetic resonance imaging (MRI) data, patients treated with inﬂiximab showed signiﬁcant decreases in spinal inﬂammation versus placebo (10). The ASSERT study continued through 102 weeks; the 2-year safety and efﬁcacy ﬁndings are presented. ClinicalTrials.gov identiﬁer: NCT00207701. 1 Jürgen Braun, MD: Rheumazentrum Ruhrgebiet, Herne, Germany; 2Atul Deodhar, MD: Oregon Health and Science University, Portland; 3Ben Dijkmans, MD, PhD: VU University Medical Centre and Jan van Breemen Institution, Amsterdam, The Netherlands; 4Piet Geusens, MD: University Hasselt, Hasselt, Belgium and University Hospital, Maastricht, The Netherlands; 5Joachim Sieper, MD: Universitaetsklinikum Benjamin Franklin, Free University of Berlin, Berlin, Germany; 6Paul Williamson, MD, Weichun Xu, PhD, Sudha Visvanathan, PhD, Daniel Baker, MD, Neil Goldstein, MD: Centocor, Inc., Malvern, Pennsylvania; 7Désirée van der Heijde, MD, PhD: Leiden University Medical Center, Leiden, The Netherlands. Drs. Braun, Dijkmans, and Geusens have received research support from Centocor and have received consulting fees or honoraria (less than $10,000 each) from Centocor and the Schering-Plough Research Institute. Dr. Deodhar has received research support from Centocor and has received speaking fees and honoraria (more than $10,000 each) from Centocor and Genentech. Dr. Sieper has received research support from Centocor, has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Schering-Plough, Abbott, and Wyeth, and gave expert testimony for Schering-Plough and received a fee. Drs. Williamson, Xu, Visvanathan, and Baker own stock in Johnson & Johnson, of which Centocor is a subsidiary, and are employees of Centocor. Dr. Goldstein is a paid consultant for Centocor. Dr. van der Heijde has received research support from Centocor, has received consultant fees, speaking fees, and/or honoraria (less than $10,000 each) from Abbott, Amgen, Centocor, Schering-Plough, UCB, Wyeth, Roche, Pﬁzer, Chugai, and Novartis, and in 2002 gave expert testimony at the FDA hearing on inhibition of structural damage and received a fee from Centocor. Address correspondence to Jürgen Braun, MD, Rheumazentrum Ruhrgebiet, Landgrafenstr 15, 44652 Herne, Germany. E-mail: firstname.lastname@example.org. Submitted for publication January 16, 2008; accepted in revised form May 19, 2008. INTRODUCTION 1270 Two Years of Inﬂiximab in Ankylosing Spondylitis 1271 Figure 1. Patient treatment and disposition. PATIENTS AND METHODS Patients. Patient eligibility for the ASSERT study has been previously described (8). Brieﬂy, study participants had AS according to the modiﬁed New York criteria (11) for at least 3 months prior to screening, a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ⱖ4 (range 0 –10; a combined assessment of fatigue, spinal pain, joint pain, enthesitis, and morning stiffness), and a spinal pain assessment score ⱖ4 on a visual analog scale (VAS; range 0 –10 cm) (8). Institutional review boards/ independent ethics committees reviewed and approved the study protocol. All patients provided written informed consent. Study protocol. In this double-blind, placebo-controlled study, patients were randomly assigned (3:8) to 1 of 2 groups (8). Patients in group 1 (the placebo/inﬂiximab group) received placebo through week 24 and inﬂiximab as an induction regimen at weeks 24, 26, and 30, followed by dosing every 6 weeks. Patients in group 2 (the inﬂiximab 5 or 7.5-mg/kg group) received inﬂiximab (5 mg/kg) through week 96 (with a placebo infusion at week 26 to maintain the blind). Starting at week 36, patients in group 2 with a BASDAI score ⱖ3 at both the current and prior visits could increase the dose of inﬂiximab to 7.5 mg/kg. In both groups, infusions were given at weeks 0, 2, and 6, and then every 6 weeks through week 96 (see exceptions in Figure 1). Efﬁcacy evaluations. Clinical response assessments were performed prior to any study agent infusion at weeks 0, 2, 6, 12, 18, 24, and 30, and then every 6 weeks through week 102. The primary study end point was achievement of ⱖ20% improvement (and an absolute improvement from baseline of at least 10 units on a scale of 0 –100) in at least 3 of 4 assessment domains of the ASsessment in Ankylosing Spondylitis International Working group cri- teria (ASAS20) (12) at week 24 (8): patient’s global assessment, spinal pain, physical function according to the Bath Ankylosing Spondylitis Functional Index (BASFI), and morning stiffness (the average of the last 2 questions of the BASDAI). These ASAS20 responders also must not have had deterioration from baseline (i.e., worsening ⱖ20%, and an absolute worsening ⱖ10 units on a scale of 0 –100) in the potential remaining assessment domain. ASAS20 response was also assessed at week 102. The proportions of patients achieving partial remission (i.e., a score ⬍20 on a scale of 0 –100 mm in each of the 4 ASAS domains described above) and meeting the ASAS40 (12) and ASAS5/6 (13) response criteria were also determined. Disease activity was also evaluated using the BASDAI (14), a night pain VAS, and C-reactive protein (CRP) level. Physical function was evaluated using the BASFI (score range 0 –10; includes 8 questions relating to the patient’s function and 2 relating to the patient’s ability to cope with everyday life) (15). Range of motion was assessed using the Bath Ankylosing Spondylitis Metrology Index (BASMI; an aggregate score of patient mobility assessments, including tragus-to-wall, lumbar ﬂexion [Schober test], cervical rotation, lumbar side ﬂexion, and intermalleolar distance, assessed on a scale from 0 –2 for each assessment and then summed for the aggregated 0 –10 score) (16) and chest expansion (the difference between the circumference of the chest in maximal inspiration and that in maximal expiration). Other joint assessments included the total swollen joint (17) and enthesis (18) indices. Quality of life was assessed with the Short Form 36 (SF-36) health survey questionnaire (19). Safety evaluations. Safety assessments, including documentation of adverse events, infections, and infusion reactions, were made at each visit. Samples for clinical laboratory tests were collected at weeks 0, 2, 6, 12, 18, 24, 26, and 30, and then every 6 weeks through week 102. Serum samples were collected for assessment of antinuclear an- 1272 Braun et al tibodies (ANAs) and antibodies to inﬂiximab (20) at weeks 0, 24, 54, 78, 96 (antibodies to inﬂiximab only), and 102. Samples positive for ANAs were also tested for antibodies to double-stranded DNA (dsDNA). Statistical analyses. The sample size justiﬁcation for the ASSERT study was provided previously (8). Efﬁcacy analyses were based on randomized treatment groups, and patients who received ⱖ1 study infusion were included in safety analyses by actual treatment received. The proportion of ASAS20 responders (primary end point) was analyzed using the Cochran-Mantel-Haenszel chi-square test stratiﬁed by screening CRP level (within normal range versus ⱖ3 times the upper limit of normal). Analyses for the primary end point at week 24 utilized an intent-to-treat (ITT) analysis, and subsequent analyses of ASAS20 data through week 102 utilized observed data. With the exception of partial remission, all other efﬁcacy analyses did not employ stratiﬁcation by CRP level, and as supportive analyses, they generally included only patients with a nonmissing outcome. The proportions of patients with ASAS20 and ASAS40 responses in addition to achievment of partial remission were determined by ITT analyses with last observation carried forward (LOCF) methodology. Continuous measures were analyzed using an analysis of variance on the van der Waerden normal scores. All statistical tests were 2-sided and performed at ␣ ⫽ 0.05 with no statistical adjustments for multiple comparisons. All analyses and summaries were conducted using SAS software, version 8.2 (SAS Institute, Cary, NC). Baseline patient and disease characteristics. Overall, 279 patients were randomized to either placebo followed by inﬂiximab (78 patients) or inﬂiximab 5 or 7.5 mg/kg (201 patients). Most patients had signiﬁcant AS disease activity (Table 1). One hundred six (52.7%) of 201 patients escalated the inﬂiximab dose from 5 to 7.5 mg/kg at week 36 or later (Figure 1). Sixty-one (78.2%) patients who were randomized to placebo and 166 (82.6%) randomized to inﬂiximab completed the study through 102 weeks. Figure 2. The proportion of patients achieving A, ⱖ20% improvement in the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS20), or B, partial remission, observed data. Open circles represent the placebo/inﬂiximab 5-mg/kg group, open squares represent the inﬂiximab 5-mg/kg group, and solid squares represent the inﬂiximab 5 or 7.5-mg/kg group. For A, the numbers of patients contributing data at weeks 2, 6, 12, 18, 24, 36, 54, 78, and 102 are as follows. Placebo/ inﬂiximab: 76, 76, 75, 75, 75, 72, 67, 64, and 61, respectively; inﬂiximab 5 mg/kg: 95, 95, 94, 93, 92, 91, 84, 82, and 80, respectively; inﬂiximab 5-7.5 mg/kg: 106, 105, 105, 106, 106, 106, 92, 87, and 85, respectively. For B, the numbers of patients contributing data at weeks 2, 6, 12, 18, 24, 36, 54, 78, and 102 are as follows. Placebo/inﬂiximab: 76, 76, 75, 75, 75, 72, 67, 64, and 61, respectively; inﬂiximab 5 or 7.5 mg/kg: 201, 200, 199, 199, 198, 197, 176, 169, and 165, respectively. Efﬁcacy. To provide an appropriate frame of reference, the previously reported week 24 efﬁcacy data are presented along with the week 102 data (Table 1 and Figures 2 and 3). Despite signiﬁcant differences for most efﬁcacy parameters at week 24, the treatment groups were generally comparable by week 102, indicating sustained beneﬁt of inﬂiximab through 1.5 or 2 years of therapy. ASAS20 responders. At week 24, 61.2% of inﬂiximabtreated patients achieved an ASAS20 response versus 19.2% of placebo-treated patients (P ⬍ 0.001; CochranMantel-Haenszel chi-square test, stratiﬁed by screening CRP level). As of week 36, following crossover from placebo to inﬂiximab at week 24, ASAS20 response was similar between treatment groups, with ⬎70% of patients in each group achieving ASAS20 response at week 102 (Figure 2A). The proportions of patients achieving partial remission were similar between the treatment groups from weeks 36 through 102 (Figure 2B). Consistent results were observed when employing ITT with LOCF methodology in the ASAS20 response and partial remission analyses (data not shown). Among the 201 patients randomized to inﬂiximab 5 mg/kg, 95 (47.3%) achieved and maintained ASAS20 response to inﬂiximab 5 mg/kg throughout the 2-year period. The remaining 106 (52.7%) patients escalated to 7.5 mg/kg at week 36 or later. The percentage of patients achieving an ASAS20 response increased from 34.0% to 60.0% from weeks 2 to 102 among patients who qualiﬁed for dose escalation, but the overall percentage with improvement at week 102 was ⬃30% lower than in patients who did not require dose escalation (of whom 89% achieved an ASAS20 response). Of note, the majority of ASAS20 nonresponders at week 102 (38 [63.3%] of 60) had at least 1 ASAS20 response during the 2-year study. Among patients RESULTS 4.0 (2.0, 5.0) 15.0 (12.0, 20.0) 2.5 (1.5, 4.0) 45.0 (30.0, 60.0) 8.8 (5.5, 14.0) 99.5 (79.0, 112.0) 3.0 (2.0, 4.0) 8.0 (3.0, 15.0) 0.0 (0.0, 1.0) 6.6 (4.8, 8.1) 1.5 (0.7, 3.2) 28.8 (23.8, 33.7) 47.6 (37.6, 54.9) 4.0 (2.0, 6.0) 15.0 (12.0, 20.5) 3.0 (1.5, 4.0) 47.0 (30.0, 60.0) 10.0 (5.3, 13.0) 102.0 (74.0, 120.0) 3.0 (2.0, 4.0) 8.0 (2.0, 16.0) 0.0 (0.0, 1.0) 6.7 (4.7, 7.9) 1.7 (0.7, 3.3) 30.1 (24.9, 36.2) 45.0 (33.7, 55.5) Inﬂiximab 5 mg/kg (n ⴝ 201) 0.8 (⫺1.9, 6.0) 2.0 (⫺2.6, 7.5) 0.0 (⫺1.0, 0.0) 0.0 (⫺1.0, 1.0) 0.4 (⫺0.2, 1.0) 0.0 (⫺7.0, 5.0) 0.3 (⫺1.0, 2.7) 0.0 (⫺9.0, 7.0) 0.0 (⫺25.0, 42.9) ⫺3.0 (⫺8.0, 0.0) 0.0 (0.0, 1.0) ⫺0.3 (⫺1.7, 0.9) 0.0 (⫺31.7, 25.0) Placebo (n ⴝ 78) 8.3 (2.5, 17.7) 2.3 (⫺3.6, 11.9) ⬍ 0.001 0.547 10.2 (3.9, 17.1) 2.7 (⫺2.9, 8.8) ⫺1.0 (⫺2.0, 0.0) ⫺0.5 (⫺2.0, 1.0) 0.5 (0.0, 1.0) 6.0 (0.0, 19.0) 1.5 (⫺0.3, 3.5) 8.0 (⫺3.0, 19.0) 33.3 (⫺16.7, 100.0)† ⫺4.0 (⫺13.0, 0.0) 0.0 (⫺1.0, 0.0) ⫺3.3 (⫺5.8, ⫺1.2) ⫺58.8 (⫺78.9, 0.0)† 0.019 0.013 0.749 ⬍ 0.001 0.011 0.045 0.037 0.800 0.019 ⬍ 0.001 ⬍ 0.001 ⫺1.0 (⫺1.0, 0.0) ⫺0.5 (⫺2.0, 0.7) 0.5 (⫺0.3, 1.0) 5.0 (⫺2.0, 15.0) 2.0 (⫺0.3, 4.5) 3.5 (⫺5.0, 12.0) 16.7 (⫺16.7, 66.7) ⫺3.0 (⫺9.0, 0.0) 0.0 (⫺1.0, 0.0) ⫺2.9 (⫺5.6, ⫺0.8) ⫺68.7 (⫺85.2, ⫺16.7) Placebo/inﬂiximab (n ⴝ 78) P 12.4 (4.8, 19.5) 2.4 (⫺2.8, 10.4) ⫺1.0 (⫺2.0, 0.0) ⫺1.0 (⫺3.0, 0.0) 1.0 (0.0, 2.0) 10.0 (0.0, 19.0) 2.2 (⫺1.0, 5.0) 9.0 (⫺2.0, 20.0) 34.8 (0.0, 100.0)† ⫺4.0 (⫺10.0, 0.0) 0.0 (⫺1.0, 0.0) ⫺4.0 (⫺6.4, ⫺1.8) ⫺64.5 (⫺84.9, ⫺20.0)† Inﬂiximab 5 or 7.5 mg/kg (n ⴝ 201) Week 102 Inﬂiximab 5 mg/kg (n ⴝ 201) Week 24 * Values are the median (interquartile range) baseline value or change from baseline, except for chest expansion and CRP level, which are the median (interquartile range) percent change from baseline. BASMI ⫽ Bath Ankylosing Spondylitis Metrology Index; VAS ⫽ visual analog scale; CRP ⫽ C-reactive protein; SF-36 ⫽ Short-Form 36 health assessment questionnaire; PCS ⫽ physical component summary; MCS ⫽ mental component summary. † Actual mean ⫾ SD values for chest expansion at week 102 were 4.4 ⫾ 2.4 and 4.4 ⫾ 1.9 for the placebo/inﬂiximab and inﬂiximab 5 or 7.5-mg/kg groups, respectively; and for CRP level were 1.0 ⫾ 1.3 and 0.7 ⫾ 0.8 for the placebo/inﬂiximab and inﬂiximab 5 or 7.5-mg/kg groups, respectively. BASMI (0–10) Tragus-to-wall, cm Lumbar ﬂexion, cm Cervical rotation, degrees Lumbar side ﬂexion, cm Intermalleolar distance, cm Chest expansion, cm Mander enthesis index, 0–90 Swollen joint index, 0–44 Night pain, 0–10 VAS CRP level, mg/dl SF-36 summary score PCS score MCS score Placebo (n ⴝ 78) Baseline Table 1. Summary of baseline and median change or median percent change in randomized patients from baseline to weeks 24 and 102 in additional clinical outcomes* Two Years of Inﬂiximab in Ankylosing Spondylitis 1273 1274 Figure 3. Mean ⫾ SD values over time for A, the Bath Ankylosing Spondylitis Functional Index (BASFI), B, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and C, the Bath Ankylosing Spondylitis Metrology Index (BASMI). Open circles represent the placebo/inﬂiximab 5-mg/kg group, solid squares represent the inﬂiximab 5 or 7.5-mg/kg group. The numbers of patients contributing BASFI data at weeks 2, 6, 12, 18, 24, 36, 54, 78, and 102 are as follows. Placebo/inﬂiximab: 76, 76, 75, 75, 75, 72, 67, 64, and 61, respectively; and inﬂiximab 5 or 7.5 mg/kg: 201, 201, 199, 199, 198, 197, 176, 169, and 166, respectively. The numbers of patients contributing BASDAI data at weeks 2, 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 96, and 102 are as follows. Placebo/inﬂiximab: 76, 76, 75, 75, 75, 73, 72, 72, 70, 67, 65, 65, 65, 64, 62, 61, 63, and 61, respectively; inﬂiximab 5 or 7.5 mg/kg: 201, 200, 199, 199, 198, 197, 197, 190, 188, 176, 178, 174, 172, 169, 168, 168, 167, and 165, respectively. The numbers of patients contributing BASMI data at weeks 24, 54, 78, and 102 are as follows. Placebo/inﬂiximab: 76, 75, 67, 64, and 61, respectively; inﬂiximab 5 or 7.5 mg/kg: 199, 176, 168, and 166, respectively. randomized to inﬂiximab, 47 (39.2%) and 31 (25.8%) of 120 patients who achieved an ASAS20 response at week 24 had BASDAI scores ⱖ3 and ⱖ4, respectively, for 2 consecutive visits after week 24. In an assessment of ASAS20 response among patients receiving inﬂiximab 7.5 mg/kg for ⱖ12 weeks following dose escalation (n ⫽ 91), 43 (47.3%) achieved an ASAS20 response following dose escalation. Ninety of these patients had ASAS20 response data at week 24 (41 achieved response and 49 did not). Interestingly, 31 (75.6%) of 41 Braun et al patients were among those achieving an ASAS20 response at week 24, while 12 (24.5%) of 49 were not ASAS20 responders at week 24, indicating that patients not responding to inﬂiximab 5 mg/kg by week 24 had a lower likelihood of responding to a higher dose of inﬂiximab than patients who initially responded but then lost response. Similar ﬁndings were observed when assessing this subgroup for a BASDAI score ⬍2 following dose escalation. While only 9 (8.7%) of the 104 patients who escalated the inﬂiximab dose and had BASDAI data at week 24 achieved a BASDAI ⬍2, 8 (32.0%) of 25 patients who had a BASDAI ⬍3 at week 24 achieved a BASDAI ⬍2 following escalation to inﬂiximab 7.5 mg/kg, versus only 1 (1.3%) of 79 with a BASDAI ⱖ3 at week 24. ASAS40 and ASAS5/6 response criteria. At week 102, 98 (59.4%) of 165 patients receiving inﬂiximab 5 mg/kg followed by 5 or 7.5 mg/kg achieved an ASAS40 response, versus 28 (45.9%) of 61 patients receiving placebo/inﬂiximab 5 mg/kg. Respective ﬁndings employing ITT and LOCF methodology were 105 (52.2%) of 201 versus 33 (42.3%) of 78. Similarly, 90 (54.5%) of 165 inﬂiximab 5 or 7.5-mg/kg patients versus 29 (47.5%) of 61 placebo/inﬂiximab patients achieving ASAS40 response at week 102 also met the ASAS5/6 criteria at week 102. Quality of life. Median changes from baseline to week 24 in the physical component summary (PCS) score of the SF-36 were 10.2 and 0.8 for the inﬂiximab and placebo groups, respectively (P ⬍ 0.001). Following crossover to active treatment at week 24, placebo/inﬂiximab patients had a substantial and sustained increase in quality of life. Median changes from baseline to week 102 for the inﬂiximab 5 or 7.5-mg/kg and placebo/inﬂiximab groups were 12.4 and 8.3, respectively, for the PCS score, and 2.4 and 2.3, respectively, for the mental component summary score. Physical function. Median changes in BASFI score at week 24 were –1.7 and 0.0 for the inﬂiximab and placebo groups, respectively (P ⬍ 0.001). At week 36, following crossover from placebo to inﬂiximab, the median change from baseline was –1.3. At week 102, further improvement was observed in the inﬂiximab 5 or 7.5-mg/kg group (⫺2.5), whereas improvement in the placebo/inﬂiximab group was comparable to that achieved at week 24 in the inﬂiximab 5 or 7.5-mg/kg group (⫺1.9) (Figure 3A). Notably, 46.8% of patients in the inﬂiximab 5 or 7.5-mg/kg group maintained ⱖ2 units of improvement from baseline in BASFI score at week 24. At week 102, 80.9% of these patients maintained this response. Disease activity. At week 24, 49.0% of patients in the inﬂiximab group achieved a BASDAI score ⬍3 (indicating low disease activity) versus 18.7% of patients in the placebo group (P ⬍ 0.0001). At week 102, the placebo/inﬂiximab group began to approach the degree of beneﬁt observed in the inﬂiximab 5 or 7.5-mg/kg group, with 59.0% and 61.8% of patients in these groups, respectively, achieving a BASDAI score ⬍3 (Figure 3B). Median improvement in night pain from baseline to week 24 was signiﬁcantly greater in the inﬂiximab group (⫺2.9) versus placebo (⫺0.3; P ⬍ 0.001). At week 102, the median improvement from baseline in night pain in the placebo/inﬂiximab group approached that observed in the Two Years of Inﬂiximab in Ankylosing Spondylitis 1275 Table 2. Summary of safety ﬁndings in treated patients through week 102* Inﬂiximab through 102 weeks Weeks Average weeks of Followup Treatment Patients with any adverse event Patients with any serious adverse event Patients with any malignancy Patients with any infection Patients with any serious infection Patients with any infusion reaction† Infusions with any infusion reaction Patients with serious infusion reactions Possible delayed hypersensitivity reaction‡ Possible anaphylactic reaction§ Patients with antibodies to inﬂiximab Infusion reactions by antibody-toinﬂiximab status Positive Negative Inconclusive Patients with lupus erythematosus syndrome Patients with newly positive ANA titers ⱖ1:40 Patients with newly positive ANA titers ⱖ1:320 Patients with newly positive anti-dsDNA Placebo (n ⴝ 76) Placebo/5 mg/ kg (n ⴝ 74) 5 or 7.5 mg/kg (n ⴝ 201) Combined (n ⴝ 275) 0–24 24–102 0–102 - 25.3 18.3 57 (75.0) 2 (2.6) 0 (0.0) 29 (38.2) 0 (0.0) 7 (9.2) 10/260 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) - 70.2 60.1 72 (97.3) 15 (20.3) 1 (1.4) 60 (81.1) 3 (4.1) 9 (12.2) 14/869 (1.6) 2 (2.7) 1 (1.4) 0 (0.0) 5/63 (7.9) 94.2 84.2 196 (97.5) 34 (16.9) 2 (1.0) 158 (78.6) 8 (4.0) 43 (21.4) 78/3,388 (2.3) 0 (0.0) 0 (0.0) 0 (0.0) 18/176 (10.2) 87.8 77.7 268 (97.5) 49 (17.8) 3 (1.1) 218 (79.3) 11 (4.0) 52 (18.9) 92/4,257 (2.2) 2 (0.7) 0 (0.0) 0 (0.0) 23/239 (1.0) - 3/5 (60.0) 1/7 (14.3) 4/51 (7.8) 2 (2.7) 11/18 (61.1) 4/15 (26.7) 21/143 (14.7) 2 (0.9) 14/23 (60.9) 5/22 (22.7) 25/194 (12.9) 4 (1.4) 8/73 (11.0) 40/67 (59.7) 119/193 (61.7) 159/260 (61.2) 1/73 (1.4) 17/67 (25.4) 74/193 (38.3) 91/260 (35.0) 0/73 (0.0) 14/67 (20.9) 63/193 (32.6) 77/260 (29.6) * Values are the number (percentage) of patients. ANA ⫽ antinuclear antibodies; anti-dsDNA ⫽ antibodies to double-stranded DNA. See Patients and Methods for detailed deﬁnitions of adverse events. † Any adverse event that occurred during, or within 1 hour after, study drug infusion. ‡ An adverse event of myalgia and/or arthralgia with fever and/or rash occurring 1–14 days after an infusion of study drug. § An adverse event of anaphylactoid reaction, laryngeal edema, pharyngeal edema, or a symptom complex characterized by urticaria and/or angioedema with bronchospasm, circulatory failure, myocardial ischemia, arrhythmia, hypotension, or dyspnea occurring within 24 hours following the start of study drug infusion. inﬂiximab 5 or 7.5-mg/kg group (⫺3.3 and ⫺4.0, respectively). The median percent reductions in CRP at week 102 were comparable between groups: 64.5% and 58.8% for the inﬂiximab 5 or 7.5-mg/kg and placebo/inﬂiximab groups, respectively. Range of motion. Median changes from baseline to week 24 in BASMI score were ⫺1.0 for the inﬂiximab group versus 0.0 for placebo (P ⫽ 0.019). At week 102, median changes from baseline in BASMI were –1.0 for both the inﬂiximab 5 or 7.5-mg/kg group and the placebo/ inﬂiximab group (Table 1, Figure 3C). Approximately 63% of patients in both treatment groups achieved an improvement ⱖ1 unit in BASMI score at week 102. Respective median percent changes from baseline in chest expansion for the inﬂiximab and placebo groups were 16.7% and 0.0% at week 24 (P ⫽ 0.037) and 34.8% and 33.3% at week 102 (Table 1). Safety. The average lengths of followup for treatment with placebo, placebo/inﬂiximab, and inﬂiximab 5 or 7.5 mg/kg were 25.3 weeks, 70.2 weeks, and 94.2 weeks, respectively (Table 2). Adverse events. Through week 102, 97.5%, 97.3%, and 75.0% of patients in the inﬂiximab 5 or 7.5-mg/kg, placebo/inﬂiximab, and placebo groups, respectively, had adverse events. The most frequently reported adverse event was upper respiratory tract infection (48.7% of inﬂiximab-treated patients). Among the 106 patients who escalated the inﬂiximab dose from 5 to 7.5 mg/kg, 87.7% experienced an adverse event during the study. Similarly, their most common event was upper respiratory tract infection (31.1%). Serious adverse events were reported for similar proportions of patients across the treatment groups. Through week 102, the most frequently reported serious adverse event was arthritis, occurring in 5 (1.8%) of the 275 inﬂiximab-treated patients. Only 1 case of arthritis occurred after dose escalation to inﬂiximab 7.5 mg/kg. No patient died during the 102-week study. A patient with lung cancer (diagnosed after escalation to inﬂiximab 7.5 mg/kg) was discontinued from the study, and subsequently died due to ventricular ﬁbrillation during chemotherapy for the tumor. Two additional malignancies were diagnosed during the study: squamous cell skin carcinoma 1276 in a placebo/inﬂiximab patient (after crossover to inﬂiximab), and breast cancer in an inﬂiximab-treated patient (after escalation to 7.5 mg/kg). One placebo/inﬂiximab patient developed nonseminoma testicular carcinoma after study completion (not included in Table 2). Eleven patients had a serious infection: 3 (4.1%) placebo/inﬂiximab (following crossover to inﬂiximab) and 8 (4.0%) inﬂiximab 5 or 7.5-mg/kg (4 after escalation to 7.5 mg/kg). Pneumonia was the most frequently reported serious infection, occurring in 3 (1.5%) inﬂiximab-treated patients (2 after escalation). There were no serious infections in placebo patients through week 24. There were also no reports of tuberculosis or serious opportunistic infections; however, 2 patients (placebo/inﬂiximab) had results of puriﬁed protein derivative (PPD) testing convert to positive ﬁndings. One patient had no clinical or radiographic evidence of active tuberculosis, but due to the positive PPD conversion latent tuberculosis was suspected, and the patient received prophylactic treatment with isoniazid. This patient completed study treatment. The PPD conversion in the second patient was noted 48 days after the week 48 inﬂiximab infusion, during patient hospitalization for a suspected lupus-like syndrome. Treatment was not speciﬁed, and the patient discontinued the study agent due to other adverse events. Three patients had oral Candida infections. Several superﬁcial fungal infections were reported in inﬂiximab-treated patients, including fungal dermatitis in 15 (5.5%) and moniliasis in 13 (4.7%) patients in the combined inﬂiximab group. One inﬂiximab patient had herpes zoster. Serious neurologic events occurred in 1 (1.3%) placebo patient (myelitis), 1 (1.4%) placebo/inﬂiximab patient (coma and convulsions), and 3 (1.5%) inﬂiximab 5 or 7.5-mg/kg patients (hemiparesis, neuroma, optic neuritis). Optic neuritis was reported after dose escalation to inﬂiximab 7.5 mg/kg. The patient with hemiparesis (unrelated to study agent) was subsequently noted to have had a cerebrovascular accident with slight left-sided sensorimotor loss from which he recovered. All of these neurologic events had resolved at the time of the last followup visit. One patient in the placebo/inﬂiximab group had a possible delayed hypersensitivity reaction (1 week after crossover to inﬂiximab) reported as fever and myalgia. This patient had antibodies to inﬂiximab and discontinued study agent infusions at week 30 due to bronchospasm and receipt of etanercept. Neither possible anaphylactic reactions nor congestive heart failure were reported. Autoantibodies (ANA and anti-dsDNA). Among patients who were negative for ANA at baseline, newly positive ANAs (titer ⱖ1:40) were detected in 8 (11.0%) placebo patients, 40 (59.7%) placebo/inﬂiximab patients, and 119 (61.7%) inﬂiximab patients. For newly positive ANAs (titer ⱖ1:320), respective occurrences were 1 (1.4%), 17 (25.4%), and 74 (38.3%) patients. Among patients who were negative for anti-dsDNA at baseline, newly positive ﬁndings were detected in no patients who received placebo only, 14 (20.9%) patients in the placebo/inﬂiximab group, and 63 (32.6%) patients in the inﬂiximab 5 or 7.5-mg/kg group. Four patients had lupus erythematosus syndrome (Table 2): 2 in the placebo/inﬂiximab group (after crossover to Braun et al inﬂiximab) and 2 in the inﬂiximab 5 or 7.5-mg/kg group. In the placebo/inﬂiximab group, 1 patient had severe arthralgia of multiple joints after crossover that resulted in study agent discontinuation (arthralgia resolved), and another had swelling and pain of ﬁnger joints after crossover. This patient completed study treatment, at which time the swelling had resolved, but the pain was ongoing. In the inﬂiximab group, 1 patient had drug-induced systemic lupus erythematosus (SLE) during treatment with the 5-mg/kg dose (resolved without treatment, and the patient completed treatment with inﬂiximab 5 mg/kg followed by 7.5 mg/kg), and a second patient discontinued treatment with inﬂiximab 7.5 mg/kg due to pleurisy, pericarditis, pulmonary embolism (resolved), and SLE and antiphospholipid syndrome (ongoing at time of discontinuation). Two patients had uveitis after escalation to inﬂiximab 7.5 mg/kg. Immunogenicity and infusion reactions. Through week 24, 6 (3.0%) of 199 inﬂiximab patients with appropriate samples had antibodies to inﬂiximab. Through week 102, the incidences of antibodies to inﬂiximab were 5 (7.9%) of 63, 5 (6.0%) of 83, and 13 (14.0%) of 93, respectively, for placebo/inﬂiximab 5-mg/kg treatment (weeks 24 –102), inﬂiximab 5-mg/kg treatment (weeks 0 –102), and inﬂiximab 7.5-mg/kg treatment (weeks 36 –102). For the placebo/inﬂiximab group (weeks 24 –102), 7 (11.1%) of 63 patients were antibody negative, versus 7 (8.4%) of 83 for the inﬂiximab 5-mg/kg group (weeks 0 –102) and 8 (8.6%) of 93 for the inﬂiximab 7.5-mg/kg group (weeks 36 –102). Among the 7 patients who were antibody positive at week 24, 6 were positive and 1 was negative at week 102. The majority of patients who were antibody negative at week 24 (n ⫽ 68) were classiﬁed as inconclusive at week 102 (n ⫽ 52). Seven patients were antibody negative at week 24 but positive at week 102. The majority of patients who were classiﬁed as antibody inconclusive at week 24 (n ⫽ 163) had the same status at week 102 (n ⫽ 142). Of the patients classiﬁed as inconclusive at week 24, 10 were antibody positive and 11 were antibody negative at week 102. Infusion reactions occurred in 7 (9.2%) placebo patients, 9 (12.2%) placebo/inﬂiximab patients, and 43 (21.4%) inﬂiximab 5 or 7.5-mg/kg patients. The respective numbers of infusions with an infusion reaction were 10 (2.6%), 14 (1.6%), and 78 (2.3%). Similar ﬁndings were observed in patients who escalated the inﬂiximab dose to 7.5 mg/kg; i.e., 12 (11.3%) of these 106 patients had an infusion reaction and 23 (2.7%) of the 863 infusions were associated with an infusion reaction. Two (2.6%) patients in the placebo/inﬂiximab group had serious infusion reactions after crossover to inﬂiximab (bronchospasm in 1 patient and bronchospasm, orbital edema, ﬂushing, and vertigo in the other). Seven patients discontinued study agent due to infusion reactions. Among patients with samples for antibody to inﬂiximab determinations, 4 patients who were classiﬁed as antibody positive and 1 who was classiﬁed as antibody negative discontinued due to an infusion reaction. Through week 102, patients positive for antibodies to inﬂiximab had the highest occurrence of infusion reactions (Table 2). Two Years of Inﬂiximab in Ankylosing Spondylitis Laboratory abnormalities. Very few patients had a markedly abnormal change in hematology laboratory values. Markedly abnormal increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (deﬁned as ⬎75 IU/liter for ALT/AST or ⬎1.5 mg/dl for bilirubin, all in conjunction with an increase of ⱖ100%), occurred in 67 (24.5%), 31 (11.3%), and 6 (2.2%) inﬂiximab patients, respectively. Elevated liver function tests were generally transient, and no clinically signiﬁcant sequelae associated with abnormal liver function were observed. There were no cases of liver failure. Only 1 patient (placebo/inﬂiximab) had concurrent markedly abnormal ALT and bilirubin levels. However, the peak bilirubin was only 1.9 mg/dl. One (1.3%) patient in the placebo/inﬂiximab group had a markedly abnormal ALT elevation. No patient had both an ALT ⱖ3 times the upper limit of normal and a total bilirubin ⱖ2 times the upper limit of normal. DISCUSSION ASSERT was a multicenter, randomized, double-blind, placebo-controlled study of 279 patients with AS. Efﬁcacy and safety ﬁndings through week 24 have been reported (8), as have MRI assessments of spinal inﬂammation (10). In the current evaluation, no new safety ﬁndings were observed with the extension of inﬂiximab treatment (5 or 7.5 mg/kg every 6 weeks) through 2 years, and the improvements in signs and symptoms, physical function, range of motion, and quality of life observed at week 24 were maintained through week 102 among these AS patients receiving inﬂiximab for 2 years. The placebo patients who began inﬂiximab at week 24 (received active treatment for 1.5 years) showed comparable improvement in the signs and symptoms of AS, physical function, and quality of life. These clinical efﬁcacy ﬁndings are important given the severity of disability that can occur in patients with AS who are treated with nonsteroidal antiinﬂammatory drugs alone (21–23), and are consistent with previous reports of open-label inﬂiximab treatment of 70 AS patients, in whom inﬂiximab therapy produced rapid and signiﬁcant improvements in the BASDAI score that were durable through 1 (24), 2 (25), and 3 (26) years of therapy. BASFI scores clearly indicate that inﬂiximab treatment resulted in continuous improvement in physical function over time. Axial metrology is also an important tool reﬂecting the potential of inﬂiximab to effectively treat AS. In our evaluation of the BASMI, ⬃63% of patients receiving inﬂiximab achieved an improvement ⱖ1 unit in BASMI score at week 102. Starting with the week 36 infusion, patients initially randomized to receive inﬂiximab 5 mg/kg who had a BASDAI score ⱖ3 at both the current and prior visits could increase the inﬂiximab dose to 7.5 mg/kg. The clinical efﬁcacy data derived from this trial following dose escalation provide no rationale for increasing the inﬂiximab dose in patients with AS based on the escalation criteria employed. Speciﬁcally, among the subgroup of patients whose inﬂiximab dose was escalated from 5 to 7.5 mg/kg at 1277 week 36 or later, ⬃30% fewer patients achieved the ASAS20 at each time point versus inﬂiximab-treated patients not escalating the dose. Antibodies to inﬂiximab developed in patients requiring dose escalation, but the increase to 7.5 mg/kg could not compensate for the accelerated inﬂiximab clearance induced by the antibodies formed against inﬂiximab. These ﬁndings of reduced efﬁcacy in conjunction with antibody to inﬂiximab development in AS patients are consistent with a previous evaluation in 8 men with AS (only 2 were receiving concomitant disease-modifying antirheumatic drugs) (27). Findings in our study may also be partly the result of some patients at each measurement period having received an increased dose for only a short period of time, because dose escalation could have occurred at any point from week 36 onward. Data derived from inﬂiximab clinical trials have indicated that antibody development was lower among rheumatoid arthritis and Crohn’s disease patients receiving immunosuppressant therapies such as 6-mercaptopurine/azathioprine or methotrexate (28). Because methotrexate has not shown efﬁcacy in AS, combination therapy was not evaluated in this study. However, in light of the above antibody ﬁndings, it is of interest that 2 recent studies showed no better efﬁcacy of inﬂiximab in combination with methotrexate in patients with AS (29,30). Also related to the antibody to inﬂiximab data, it could be useful to assess whether reductions in the interval between inﬂiximab doses may be more appropriate than increasing the dose in nonresponders. Further analyses are necessary to make ﬁrm conclusions about the role of antibodies to inﬂiximab in patients with AS. As noted, inﬂiximab 5 or 7.5 mg/kg every 6 weeks demonstrated a favorable safety proﬁle in this 2-year study of patients with AS. In the evaluation of safety data, it is important to note the variable lengths of followup for patients receiving placebo (25.3 weeks), placebo followed by inﬂiximab (70.2 weeks), and inﬂiximab 5 or 7.5 mg/kg (94.2 weeks). As was observed through week 24 (8), adverse events related to the respiratory system were the most frequently reported through week 102. Serious infections were uncommon, and there were no reports of active tuberculosis or serious opportunistic infections. Three patients had malignancies, but none had lymphoma. One of these patients (with lung cancer) died from an arrhythmia during chemotherapy after study withdrawal. Taken together, these long-term ﬁndings indicate that inﬂiximab has beneﬁcial efﬁcacy and is safe in patients with active AS over 2 years. ACKNOWLEDGMENTS The authors wish to thank Michelle Perate, MS and Mary Whitman, PhD, of Centocor, Inc., for writing support. AUTHOR CONTRIBUTIONS Dr. Braun had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Braun, Williamson, Baker, van der Heijde. 1278 Acquisition of data. Braun, Deodhar, Dijkmans, Sieper, Baker, van der Heijde. Analysis and interpretation of data. Braun, Deodhar, Dijkmans, Geusens, Sieper, Xu, Visvanathan, Baker, Goldstein, van der Heijde. Manuscript preparation. Braun, Deodhar, Dijkmans, Geusens, Sieper, Visvanathan, Baker, Goldstein, van der Heijde. Statistical analysis. Williamson, Xu. Braun et al 15. 16. REFERENCES 1. Miceli-Richard C, Dougados M. NSAIDs in ankylosing spondylitis. Clin Exp Rheumatol 2002;20 Suppl 28:S65– 6. 2. Braun J, Sieper J. Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, antiTNF␣ therapy and other novel approaches. Arthritis Res 2002; 4:307–21. 3. Van der Horst-Bruinsma IE, Clegg DO, Dijkmans BA. Treatment of ankylosing spondylitis with disease-modifying antirheumatic drugs. Clin Exp Rheumatol 2002;20 Suppl 28:S67– 70. 4. Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, et al. 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