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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To assess safety and efficacy of infliximab in patients with ankylosing spondylitis (AS) through 102 weeks.

Methods

Patients (n = 279) with active AS were randomized to either group 1 (n = 78; placebo through week 24 and then infliximab 5 mg/kg from weeks 24 through 96) or group 2 (n = 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.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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 α (TNFα) in AS pathogenesis (4, 5), drugs targeting TNFα 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.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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 ≥4 (range 0–10; a combined assessment of fatigue, spinal pain, joint pain, enthesitis, and morning stiffness), and a spinal pain assessment score ≥4 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 ≥3 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).

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Figure 1. Patient treatment and disposition.

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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 ≥20% 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 criteria (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 ≥20%, and an absolute worsening ≥10 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 antibodies (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 ≥1 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 ≥3 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 α = 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).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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.

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*
 BaselineWeek 24Week 102
Placebo (n = 78)Infliximab 5 mg/kg (n = 201)Placebo (n = 78)Infliximab 5 mg/kg (n = 201)PPlacebo/infliximab (n = 78)Infliximab 5 or 7.5 mg/kg (n = 201)
  • *

    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)4.0 (2.0, 6.0)4.0 (2.0, 5.0)0.0 (−1.0, 0.0)−1.0 (−1.0, 0.0)0.019−1.0 (−2.0, 0.0)−1.0 (−2.0, 0.0)
 Tragus-to-wall, cm15.0 (12.0, 20.5)15.0 (12.0, 20.0)0.0 (−1.0, 1.0)−0.5 (−2.0, 0.7)0.013−0.5 (−2.0, 1.0)−1.0 (−3.0, 0.0)
 Lumbar flexion, cm3.0 (1.5, 4.0)2.5 (1.5, 4.0)0.4 (−0.2, 1.0)0.5 (−0.3, 1.0)0.7490.5 (0.0, 1.0)1.0 (0.0, 2.0)
 Cervical rotation, degrees47.0 (30.0, 60.0)45.0 (30.0, 60.0)0.0 (−7.0, 5.0)5.0 (−2.0, 15.0)< 0.0016.0 (0.0, 19.0)10.0 (0.0, 19.0)
 Lumbar side flexion, cm10.0 (5.3, 13.0)8.8 (5.5, 14.0)0.3 (−1.0, 2.7)2.0 (−0.3, 4.5)0.0111.5 (−0.3, 3.5)2.2 (−1.0, 5.0)
 Intermalleolar distance, cm102.0 (74.0, 120.0)99.5 (79.0, 112.0)0.0 (−9.0, 7.0)3.5 (−5.0, 12.0)0.0458.0 (−3.0, 19.0)9.0 (−2.0, 20.0)
Chest expansion, cm3.0 (2.0, 4.0)3.0 (2.0, 4.0)0.0 (−25.0, 42.9)16.7 (−16.7, 66.7)0.03733.3 (−16.7, 100.0)34.8 (0.0, 100.0)
Mander enthesis index, 0–908.0 (2.0, 16.0)8.0 (3.0, 15.0)−3.0 (−8.0, 0.0)−3.0 (−9.0, 0.0)0.800−4.0 (−13.0, 0.0)−4.0 (−10.0, 0.0)
Swollen joint index, 0–440.0 (0.0, 1.0)0.0 (0.0, 1.0)0.0 (0.0, 1.0)0.0 (−1.0, 0.0)0.0190.0 (−1.0, 0.0)0.0 (−1.0, 0.0)
Night pain, 0–10 VAS6.7 (4.7, 7.9)6.6 (4.8, 8.1)−0.3 (−1.7, 0.9)−2.9 (−5.6, −0.8)< 0.001−3.3 (−5.8, −1.2)−4.0 (−6.4, −1.8)
CRP level, mg/dl1.7 (0.7, 3.3)1.5 (0.7, 3.2)0.0 (−31.7, 25.0)−68.7 (−85.2, −16.7)< 0.001−58.8 (−78.9, 0.0)−64.5 (−84.9, −20.0)
SF-36 summary score       
 PCS score30.1 (24.9, 36.2)28.8 (23.8, 33.7)0.8 (−1.9, 6.0)10.2 (3.9, 17.1)< 0.0018.3 (2.5, 17.7)12.4 (4.8, 19.5)
 MCS score45.0 (33.7, 55.5)47.6 (37.6, 54.9)2.0 (−2.6, 7.5)2.7 (−2.9, 8.8)0.5472.3 (−3.6, 11.9)2.4 (−2.8, 10.4)

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.

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Figure 2. The proportion of patients achieving A, ≥20% 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.

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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.

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ASAS20 responders.

At week 24, 61.2% of infliximab-treated patients achieved an ASAS20 response versus 19.2% of placebo-treated patients (P < 0.001; Cochran-Mantel-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 randomized to infliximab, 47 (39.2%) and 31 (25.8%) of 120 patients who achieved an ASAS20 response at week 24 had BASDAI scores ≥3 and ≥4, respectively, for 2 consecutive visits after week 24.

In an assessment of ASAS20 response among patients receiving infliximab 7.5 mg/kg for ≥12 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 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 ≥3 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 ≥2 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 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 ≥1 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).

Table 2. Summary of safety findings in treated patients through week 102*
 Placebo (n = 76)Infliximab through 102 weeks
Placebo/5 mg/kg (n = 74)5 or 7.5 mg/kg (n = 201)Combined (n = 275)
  • *

    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.

Weeks0–2424–1020–102-
Average weeks of    
 Followup25.370.294.287.8
 Treatment18.360.184.277.7
Patients with any adverse event57 (75.0)72 (97.3)196 (97.5)268 (97.5)
Patients with any serious adverse event2 (2.6)15 (20.3)34 (16.9)49 (17.8)
Patients with any malignancy0 (0.0)1 (1.4)2 (1.0)3 (1.1)
Patients with any infection29 (38.2)60 (81.1)158 (78.6)218 (79.3)
Patients with any serious infection0 (0.0)3 (4.1)8 (4.0)11 (4.0)
Patients with any infusion reaction7 (9.2)9 (12.2)43 (21.4)52 (18.9)
Infusions with any infusion reaction10/260 (2.6)14/869 (1.6)78/3,388 (2.3)92/4,257 (2.2)
Patients with serious infusion reactions0 (0.0)2 (2.7)0 (0.0)2 (0.7)
Possible delayed hypersensitivity reaction0 (0.0)1 (1.4)0 (0.0)0 (0.0)
Possible anaphylactic reaction§0 (0.0)0 (0.0)0 (0.0)0 (0.0)
Patients with antibodies to infliximab-5/63 (7.9)18/176 (10.2)23/239 (1.0)
Infusion reactions by antibody-to-infliximab status    
 Positive-3/5 (60.0)11/18 (61.1)14/23 (60.9)
 Negative-1/7 (14.3)4/15 (26.7)5/22 (22.7)
 Inconclusive-4/51 (7.8)21/143 (14.7)25/194 (12.9)
Patients with lupus erythematosus syndrome 2 (2.7)2 (0.9)4 (1.4)
Patients with newly positive ANA titers ≥1:408/73 (11.0)40/67 (59.7)119/193 (61.7)159/260 (61.2)
Patients with newly positive ANA titers ≥1:3201/73 (1.4)17/67 (25.4)74/193 (38.3)91/260 (35.0)
Patients with newly positive anti-dsDNA0/73 (0.0)14/67 (20.9)63/193 (32.6)77/260 (29.6)
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 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 ≥1:40) 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 ≥1:320), 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 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).

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 ≥100%), 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 ≥3 times the upper limit of normal and a total bilirubin ≥2 times the upper limit of normal.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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 ≥1 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 ≥3 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 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.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

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.

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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

The authors wish to thank Michelle Perate, MS and Mary Whitman, PhD, of Centocor, Inc., for writing support.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
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