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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Objective

Treatment of ankylosing spondylitis (AS) with infliximab, an anti–tumor necrosis factor α monoclonal antibody, was shown to be efficacious in patients with active disease during a 3-month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1-year period.

Methods

This study was an open, observational, extension study of a 3-month, randomized, placebo-controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12-week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

Results

At week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent-to-treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31–63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36–67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in ∼70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study.

Conclusion

Infliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.

Ankylosing spondylitis (AS) is a common chronic, inflammatory, rheumatic disease (1) with a definite genetic predisposition. Most AS patients carry the HLA–B27 antigen. The sacroiliac joints, entheses, and spine are the areas most frequently involved in AS. A hallmark of the disease is chronic inflammatory back pain. During the course of AS, many young patients develop inflammation of the spine as well as a progressive ankylosis of the spine, resulting in restricted mobility, disability, and decreased quality of life (2–4). Patients with a severe disease course have higher rates of withdrawal from the labor force because of the AS (5, 6).

For decades, AS has been treated mainly with nonsteroidal antiinflammatory drugs (NSAIDs). In contrast to rheumatoid arthritis (RA), disease-modifying antirheumatic drugs (DMARDs) are currently not approved for the treatment of AS (7). None of the few studies of DMARDs in AS has demonstrated efficacy in axial disease. While methotrexate was found to have limited efficacy in a few studies of AS patients in which no control group was used (8, 9), sulfasalazine was shown to be efficacious in the treatment of peripheral arthritis in controlled trials (10, 11).

In a recent randomized, placebo-controlled, 3-month trial, we showed that infliximab is significantly superior to placebo for the treatment of many of the manifestations of AS (12), including disease activity, function, spinal motility, peripheral arthritis, enthesitis, and quality of life. These results show that infliximab is effective for the short-term treatment of severe AS, but long-term treatment data are sparse (13). In the present study, we report the findings of an open-label, 1-year extension study that followed the 3-month, placebo-controlled phase. The primary focus of this 1-year study was the long-term efficacy and safety of infliximab in the treatment of AS.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients.

The eligibility criteria and the study design of the 3-month, randomized, controlled phase of the study have been reported previously (12). Seventy patients were enrolled in the study between July 2000 and October 2000. Patients were eligible for the study if they had AS (14) that was clinically classified as active based on a score of ≥4 on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (15) and a score of ≥4 on a 10-cm visual analog scale (VAS) for pain in the spine. Concomitant DMARDs and oral corticosteroids were withdrawn at least 4 weeks before screening. Patients were allowed to take NSAIDs, but the dosage could not be increased over the baseline level during the course of the trial. However, the dosage could be reduced, and dosage reductions were recorded.

Study protocol.

Patients were randomly assigned to receive placebo or infliximab. For this open extension study (phase B), 65 of the 69 patients (1 of the 70 patients initially enrolled was not treated) continued to participate in the study. Patients were examined at weeks 14 and 18 and every 6 weeks thereafter; at week 22 patients were contacted by telephone.

Infliximab was administered intravenously at a dosage of 5 mg/kg at week 12 of the original randomized, controlled trial, and every 6 weeks thereafter. At week 14, an additional infusion was administered to patients who had received placebo during the initial 3-month study (phase A). This dose was given before regular dosing intervals were begun to ensure that adequate blood levels were attained with the standard 5-mg/kg intravenous infliximab regimen (hereafter referred to as the placebo/infliximab group). In order to maintain the blind criteria for phase A, subjects who had received 5 mg/kg of infliximab intravenously during phase A received a dummy infusion of placebo at week 14 (hereafter referred to as the infliximab/infliximab group).

Essex Pharma (Munich, Germany) provided the study medication. All patients gave their written informed consent for the study. The study protocol was approved by the local ethics committees.

Study end points.

The core set of end points recently proposed by the Assessment in Ankylosing Spondylitis (ASAS) Working Group (16, 17) was used to measure the clinical benefit of infliximab therapy in AS. The following validated instruments were also used. The BASDAI, which is based on 6 questions relating to fatigue, spinal pain, peripheral arthritis, enthesitis, and morning stiffness (both quantitative and qualitative), was used to measure disease activity (15). The Bath Ankylosing Spondylitis Functional Index (BASFI), which is based on 10 questions about daily functioning, was used to measure physical function (18). A 10-cm VAS (where 10 = very bad and 0 = very good) was used to measure pain in the spine. Patient's and physician's global assessments were also performed. The Bath Ankylosing Spondylitis Metrology Index (BASMI) (19), which is used to grade mobility of the spine and hip by measuring the distance from the tragus to the wall, lumbar flexion, cervical rotation, lumbar side flexion, and intermalleolar distance on a scale of 1–10, was evaluated in each patient by the same rheumatologist. The Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s) (20), which consists of the sum of 3 scores (range of scores 2–12) for radiographic features in the sacroiliac joints, lumbar spine, and cervical spine (each scored 0–4) using the New York criteria, was used to evaluate radiographic changes.

In addition, 20% improvement and partial remission criteria recently proposed by the ASAS group (17) were assessed. According to these criteria, 20% improvement is defined as an improvement of at least 20% and an absolute improvement of at least 10 units (on a scale of 0–100) in at least 3 of the following 4 domains: patient's global assessment, pain, function (represented by the BASFI score), and inflammation (represented by the mean of the 2 morning stiffness–related BASDAI VAS scores). Furthermore, there must be an absence of deterioration, which is defined as worsening of not more than 20% and net worsening of not more than 10 units (on a scale of 0–100), in the potential remaining domain. Partial remission was defined as a score of <20 (on a scale of 0–100) in each of the 4 domains. Analogous to the RA response criteria, a 50% improvement was defined as improvement of at least 50% and an absolute improvement of at least 20 (on a 0–100-mm VAS scale) in at least 3 of the 4 domains according to the ASAS criteria, together with an absence of deterioration in the remaining domain.

Assessments of health-related quality of life were performed using the Short-Form 36 (SF-36) health survey (21). The individual aspects of the instrument were grouped as physical component and mental component summary scores, each of which was assigned a mean ± SD of 50 ± 10 on the basis of US population data (21). The scoring algorithm of the Medical Outcome Trust (22) was used to check and to calculate the SF-36 scores, as well as to handle single missing items on this questionnaire. All outcome measures were evaluated every 6 weeks, except for weeks 36 and 48, when the BASFI, the physician's global assessment, the BASMI, and the SF-36 were not performed.

The primary efficacy measure was the response rate, that is, a minimum of 50% improvement in the BASDAI score between baseline and week 24 as well as week 54. The secondary end point parameters analyzed were improvements in scores on the VAS for spinal pain, the BASFI, the BASMI, the SF-36, and the ASAS response criteria, as well as improvements in levels of serum C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR).

Serologic studies.

Serum levels of antinuclear antibodies (ANAs) were measured at the laboratories of each participating study site. ANA titers were determined by indirect immunofluorescence at all study sites. A clinically relevant, positive ANA titer was defined as 2 titer steps above the cutoff level of 1:160. ANA titers were measured at baseline, week 30, and week 54. At these time points, patients in the placebo/infliximab group had received 18 weeks (week 30) and 42 weeks (week 54) of treatment with infliximab, and patients in the infliximab/infliximab group had received 30 weeks and 54 weeks of treatment, respectively. Anti–double-stranded DNA (anti-dsDNA) and antihistone antibodies were measured by enzyme-linked immunosorbent assay.

Statistical analysis.

The evaluation of efficacy was based on an intent-to-treat analysis (ITT). Patients who withdrew were counted as nonresponders for every missing visit. Therefore, in phase B, the ITT results were also based on data for 69 patients. Furthermore, every significant increase in the NSAID dosage from baseline was considered to be a nonresponse in phase A. This criterion was also applied to phase B. Every patient with a significant increase in the NSAID dosage at ≥2 followup visits was counted as a nonresponder for these visits.

In patients who tolerated the treatment well, the results of an ITT analysis were more likely to be conservative. For this reason, an efficacy analysis of completers was performed. Baseline and last visit data for patients who discontinued were compared with those for the 54 patients who completed the study. For all patients who withdrew, the difference between their last valid BASDAI score and the mean score for all completers at that visit was computed to evaluate whether missed visits occurred randomly with respect to disease activity (23). The mean of these differences and the corresponding 95% confidence intervals (95% CIs) are given below. The scoring method of Wilson was used to generate the 95% CIs of the response rates.

Response rates were compared by Fisher's exact test, and the means were compared by one-way analysis of covariance, with the baseline value as the covariate, or by the nonparametric Mann-Whitney unpaired U test. For comparisons between visits, the paired t-test was used. All comparisons were 2-sided. A significance level of 5% was used. No adjustment for repeated significance testing was done. Statistical analyses were performed with SPSS software (release 10.0.7; SPSS, Chicago, IL).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Fifty-four of the 69 patients (78%) completed 54 weeks of study; 15 patients (22%) did not. One of the 70 patients who were initially enrolled was excluded because the radiographic criteria were not fulfilled. Eleven of the 69 patients (16%) failed to complete the study because of adverse events. Two patients (2.9%) discontinued because of lack of efficacy, and 2 discontinued because of noncompliance (Figure 1).

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Figure 1. Randomization, reasons for treatment discontinuation, and numbers of patients who completed the 1-year trial of infliximab therapy for ankylosing spondylitis. Seventy patients were initially enrolled, 1 of whom did not receive an infusion of study medication. Fifty-four patients continued to receive therapy for 54 weeks. Fifteen patients discontinued the study, 11 because of adverse events, 2 because of lack of efficacy, and 2 because of noncompliance.

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There were no significant differences in the baseline characteristics between the 2 treatment groups (Table 1). Furthermore, patients who discontinued from the study prematurely had comparable disease activity at baseline (data not shown). Patients who did not complete the trial had more disease activity at their last visit than did patients who completed the trial (mean differences in BASDAI scores 1.6 [95% CI 0.6–2.5] for the infliximab/infliximab group and 3.2 [95% CI 1.9–4.4] for the placebo/infliximab group).

Table 1. Baseline characteristics of the ankylosing spondylitis study patients, by treatment group*
CharacteristicInfliximab/infliximab group (n = 34)Placebo/infliximab group (n = 35)
  • *

    No statistically significant between-group differences were found for any of these baseline variables by the nonparametric Mann-Whitney unpaired U test. See Patients and Methods for a description of the study groups. BASRI-s = Bath Ankylosing Spondylitis Radiology Index for the spine.

  • The highest and lowest 5% of the values are not included in the analysis.

Sex, no. (%) males/females23 (68)/11 (32)22 (63)/13 (37)
Age, mean ± SD years40.6 ± 8.039.0 ± 9.1
Disease duration, mean ± SD years16.4 ± 8.314.9 ± 9.3
HLA–B27 positive, no. (%)31 (91)27 (88)
No. of swollen joints (68 assessed), mean ± SD0.9 ± 4.11.3 ± 5.2
No. of enthesitic regions (12 assessed), mean ± SD1.7 ± 3.32.0 ± 3.2
History of anterior uveitis, no. (%)17 (50)15 (43)
Radiologic score for the spine (by BASRI-s), mean ± SD6.5 ± 2.56.6 ± 2.9

An ITT efficacy analysis was conducted with the data for all 69 patients. Patients who discontinued prematurely were counted as nonresponders. An analysis of the 54 patients who completed the study was conducted. All questionnaires were completed at all time points, except for the missing visits by patients who withdrew and by 1 patient who had simply missed a visit.

Efficacy of infliximab.

ITT analysis.

The magnitude of improvement in disease activity, as determined by analysis of each clinical outcome assessed, was sustained up to week 54 in both groups. The ITT primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% CI 31–63) and 51% of patients in the placebo/infliximab group (95% CI 36–67) achieved a 50% improvement in BASDAI scores (Figure 2a). According to the ASAS Working Group criteria, 18% of the infliximab/infliximab group (95% CI 8–34) and 17% of the placebo/infliximab group (95% CI 8–33) were in partial remission after treatment with infliximab for 54 weeks and 42 weeks, respectively (Figure 2c).

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Figure 2. Response to treatment, as measured by a, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores at the 50% improvement level, b, the Assessment of Ankylosing Spondylitis (ASAS) criteria for 20% improvement, c, the ASAS criteria for partial remission, and d, the mean BASDAI scores. Only the 54 patients who completed week 54 of study are shown. Intent-to-treat analyses were performed on the data shown in a–c.

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Of the placebo/infliximab-treated patients, who switched from placebo to infliximab at week 12, 43% demonstrated 50% improvement at week 24 (95% CI 28–59) (Figure 2a). This rate was similar to that in the infliximab/infliximab group at week 12 (53% of patients; 95% CI 37–69). The 50% BASDAI improvement response rates were similar in the two treatment groups when comparisons were made of the scores obtained at the same durations of infliximab treatment.

No patient in the infliximab/infliximab group showed an increase in disease activity between week 12 and week 54. Only 3 patients in the placebo/infliximab group showed an increase in disease activity between week 24 and week 54. An increase in disease activity was defined as an increase in the BASDAI score of >2 at week 12 for the infliximab/infliximab group and at week 24 for the placebo/infliximab group (Table 2).

Table 2. Scores on individual components of the BASDAI at baseline, week 12, and week 54, by treatment group*
BASDAI componentBaseline (n = 54)Infliximab/infliximab group (n = 24)Placebo/infliximab group (n = 30)
Week 12Week 54Week 24Week 54
  • *

    All comparisons between baseline and weeks 12, 24, and 54 were significantly different (P < 0.05), by Student's paired t-test. See Patients and Methods for a description of the study groups. BASDAI = Bath Ankylosing Spondylitis Disease Activity Index.

Fatigue6.94.53.33.92.9
Spinal pain7.93.73.13.73.2
Peripheral joint pain5.22.41.93.02.2
Entheseal pain6.02.82.32.72.6
Morning stiffness6.52.81.42.72.2

During phase A, a significant number of infliximab-treated patients (19 of 33; 57%) reduced their use of NSAIDs by 50%, with 48% (16 of 33) discontinuing NSAID use altogether. In comparison, fewer placebo-treated patients were able to reduce their use of NSAIDs by 50% (19%; P = 0.004), and even fewer were able to stop taking NSAIDs (13%; P = 0.02). During the 1-year observation period, patients continued to further reduce the intake of NSAIDs. Accordingly, at week 54, 72% of the infliximab/infliximab patients and 67% of the placebo/infliximab patients had reduced their NSAID dosage by >50% of their respective baseline levels, and 59% of the patients in both groups had completely stopped taking NSAIDs.

Levels of both acute-phase reactants decreased in the placebo/infliximab group. These decreases were sustained until week 54 in both treatment groups (Table 3). Approximately half of the patients in each group had a history of acute anterior uveitis (Table 1). Within the 6 months preceding the study, 3 of the 69 patients (4%) had ≥1 episode of anterior uveitis, whereas only 1 patient had a new episode of anterior uveitis while receiving infliximab treatment from the time of study initiation until the end of the trial (not statistically significant).

Table 3. Clinical and biologic variables in the 54 AS patients who completed the study, at baseline and at weeks 12, 24, and 54*
VariableInfliximab/infliximab group (n = 24)Placebo/infliximab group (n = 30)P, week 12
BaselineWeek 12Week 24Week 54BaselineWeek 12Week 24Week 54
  • *

    Only data for ankylosing spondylitis (AS) patients who completed week 54 were analyzed. Except for the C-reactive protein (CRP) level and the erythrocyte sedimentation rate (ESR), values are the mean ± SD. BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing Spondylitis Metrology Index; VAS = visual analog scale; SF-36 = Short Form 36 health survey.

  • Placebo/infliximab versus infliximab/infliximab at week 12, by analysis of covariance at week 12.

  • The highest and lowest 5% of the values are not included in the analysis.

  • §

    Placebo/infliximab versus infliximab/infliximab at week 12, by nonparametric Mann-Whitney unpaired U test.

Overall assessment, VAS         
 Patient7.1 ± 1.93.3 ± 2.32.5 ± 1.82.8 ± 2.36.7 ± 1.96.1 ± 2.13.3 ± 1.82.9 ± 1.8<0.0001
 Physician6.6 ± 1.42.7 ± 2.12.6 ± 1.72.1 ± 1.56.1 ± 1.75.6 ± 1.63.1 ± 1.42.3 ± 1.4<0.0001
No. of swollen joints (68 assessed)0.6 ± 4.70.2 ± 2.50.0 ± 1.00.0 ± 1.61.6 ± 5.71.4 ± 4.50.0 ± 0.00.0 ± 0.40.31§
No. of enthesitic regions (12 assessed)1.8 ± 3.50.5 ± 0.90.5 ± 1.20.2 ± 0.82.0 ± 3.31.8 ± 2.80.6 ± 1.60.3 ± 0.80.05§
Bath AS Indexes         
 BASDAI6.6 ± 1.23.3 ± 2.02.8 ± 1.82.4 ± 1.96.3 ± 1.45.6 ± 1.93.2 ± 1.72.6 ± 1.7<0.0001
 BASFI5.6 ± 1.73.4 ± 2.22.9 ± 1.72.6 ± 2.04.9 ± 2.04.7 ± 2.33.2 ± 2.23.3 ± 2.40.0001
 BASMI3.8 ± 2.02.9 ± 2.12.8 ± 2.12.3 ± 1.93.6 ± 2.13.6 ± 2.02.7 ± 1.82.4 ± 2.00.0019
CRP, median (range) mg/liter24 (8–68)6 (0–55)5 (0–12)4 (0–18)15 (1–74)15 (1–75)6 (1–12)4 (0–15)0.001§
ESR, median (range) mm/hour27 (10–78)5 (1–14)6 (1–34)6 (1–50)22 (3–88)26 (4–88)8 (1–80)8 (2–70)0.001§
Health-related quality of life (SF-36 score), %         
 Physical component29.6 ± 5.841.0 ± 10.041.0 ± 7.941.6 ± 10.129.0 ± 7.829.3 ± 8.639.9 ± 10.539.6 ± 11.00.001
 Mental component38.0 ± 11.244.3 ± 10.547.7 ± 11.148.8 ± 10.044.9 ± 12.348.5 ± 10.649.3 ± 9.052.0 ± 8.60.96
Analysis of completers.

In the analysis of patients who completed the study, the response rates according to the 50% improvement criteria were higher in the infliximab/infliximab group (67%; 95% CI 47–82) than in the placebo/infliximab group (60%; 95% CI 42–75). The mean BASDAI scores showed continuous improvement. In all 54 patients who completed the study, the mean BASDAI scores decreased significantly between weeks 0 and 54 (mean ± SD 3.0 ± 1.8 at week 54; P = 0.01 versus baseline). The same trends were observed with the BASFI and BASMI scores as well as for peripheral arthritis and enthesitis (Table 3).

At baseline, 20 of the 54 patients in both study groups (37%) had peripheral arthritis. At week 54, only 2 patients still had peripheral arthritis (3.7%). At baseline, 25 patients (46%) had peripheral enthesitis, 10 in the infliximab/infliximab group and 15 in the placebo/infliximab group. At week 54, there were still 7 patients who had enthesitis (2 in the infliximab/infliximab group and 5 in the placebo/infliximab group; 13%).

Thirty-nine of the 54 patients who completed the study (72%) had elevated CRP levels (>10 mg/liter) at baseline; the other 15 patients (28%) had low-to-normal CRP levels at baseline. Among patients with elevated CRP levels, 29 showed 50% improvement in the BASDAI scores (74%), while only 5 patients (33%) with low CRP levels reached this level of improvement (P = 0.01).

Of the 48 HLA–B27–positive patients, 33 were classified as responders (69%), while all 5 HLA–B27–negative patients were classified as nonresponders (P = 0.005). In contrast, neither sex nor the degree of radiologic changes in the spine (differentiated according to BASRI-s scores above and below 6) influenced the response to treatment (24, 25).

Treatment with infliximab significantly improved the quality of life in both groups, as measured by the SF-36 (Table 3).

Safety of infliximab.

Adverse events.

Infliximab infusions were generally well tolerated. Most treatment-related adverse events were mild to moderate in severity (Table 4). Two serious adverse events of clinical concern occurred during phase A of the study: systemic tuberculosis and allergic bronchiocentric granulomatosis of the lung in 2 patients who received infliximab. Both patients recovered, the first received tuberculostatic therapy and the second received corticosteroids for 2 weeks.

Table 4. Drug-related adverse events*
 Phase APhase BTotal
Placebo only (n = 35)Infliximab only (n = 34)Placebo/infliximab (n = 35)Infliximab/infliximab (n = 30)
  • *

    Values are the number of patients who experienced at least 1 adverse event in each category.

  • Only the adverse events that occurred in at least 4 patients are shown.

  • Patient with serious adverse events who discontinued the study.

  • §

    Increased transaminase levels.

Most frequent drug-related adverse events     
 Upper respiratory tract infection633214
 Headache134210
 Liver function abnormal/elevated transaminase levels01539
 Sinusitis00235
 Herpes simplex00404
 Pharyngitis00134
 Rhinitis00134
 Diarrhea00404
 Total77241654
All serious drug-related adverse events     
 Allergic granulomatosis01001
 Tuberculosis01001
 Leukopenia01001
 Possibly ANA-associated symptoms (peripheral arthritis)00033
 Hepatitis00101
 Liver function abnormalities§00011
 Lupus-like rash00101
 Total03249

Sixteen of the 70 patients initially enrolled in the study discontinued; 4 of them were noncompliant with the protocol or had insufficient efficacy. One patient was excluded because radiographic criteria were not met. The remaining 11 patients discontinued due to adverse events that were possibly associated with infliximab. Six of these patients experienced serious adverse events (Table 4). No deaths were reported.

Detection of ANAs.

At baseline, no patients in the placebo group and 1 patient in the infliximab group were ANA positive. After 30 weeks, 4 patients in the infliximab/infliximab group (13%) and none in the placebo/infliximab group were ANA positive. At week 54, 3 of the 4 patients were still ANA positive and continued to participate in the study. Between weeks 24 and 54, another 5 patients in the infliximab/infliximab group and 8 patients in the placebo/infliximab group became ANA positive. Thus, 17 of 69 patients (25%) had developed ANAs after 42 and 54 weeks, respectively, of infliximab treatment in both groups. Only 3 ANA-positive patients had musculoskeletal symptoms, such as polyarthritis of the wrists, proximal interphalangeal joints, and metacarpophalangeal joints. All symptoms resolved in 2 patients after discontinuation of infliximab therapy and with temporary treatment with methylprednisolone. One patient has developed chronic polyarthritis.

Anti-dsDNA titers were assessed in 12 ANA-positive patients. Slightly-to-moderately elevated titers were found in 4 of them: 1 had symptoms of arthritis (as described above) and 3 were asymptomatic. Two patients in whom antihistone antibodies were detected were also asymptomatic.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

This open extension of a randomized, placebo-controlled, multicenter study (12) was conducted to investigate the efficacy and safety of, and durability of response to, infliximab therapy in patients with active AS. The results showed clear and lasting benefit. The efficacy of infliximab on a short-term basis has recently been substantiated by a followup study using magnetic resonance imaging of the spine (25).

In the open extension phase reported herein, all efficacy end points were confirmed by statistically significant responses for multiple additional measures of efficacy, including mean BASDAI, BASFI, and BASMI scores. We have shown for the first time that in AS patients, efficacy was maintained over 54 weeks and, importantly, the majority (78%) of the patients were still receiving infliximab therapy after 1 year. Strikingly, the analysis of patients who completed the study showed ongoing improvements in the mean BASDAI scores over this period. This finding is especially encouraging in light of the fact that the percentage of patients with a history of anterior uveitis was quite high in our study population, possibly indicating more severe disease in these patients (26).

Infliximab provides quantifiable benefits consistent with improvement in pain and disease activity, as well as physical function and the more objective metrologic measure, the BASMI score. The improvement in mobility of the spine, which was not previously thought to be sensitive to change over the short term (17), shows that the loss of functioning caused by spinal inflammation is reversible with effective antiinflammatory therapy. However, it is not yet known if the remaining deficits, which are possibly related to spinal ankylosis and muscular fibrosis, can be improved by infliximab therapy.

Therapeutic benefit was demonstrated in most subgroups, but patients without definite CRP elevations and those negative for HLA–B27, which represent only a minority of the patients in this trial, did not respond to the same degree. This suggests that there may be a different biologic basis for the disease in this subgroup. There is no straightforward explanation for the finding that HLA–B27–negative patients responded less well. Nevertheless, genetic and immunologic differences between B27-positive and B27-negative subjects have been reported (27, 28). Taken together, it seems possible that both parameters might help to identify patients who are less likely to benefit from infliximab therapy.

The discontinuation rate of 22% in this trial is comparable to the rates reported in the Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) trial (29) and the A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT) trial (30). Eleven of the patients who discontinued the study did so because of side effects attributed to infliximab (16%). Abnormal findings on liver function tests were minor and transient, and only 1 patient withdrew from the study because of hepatic abnormalities. This patient had been taking both diclofenac and infliximab, and recovered without sequelae after both drugs were discontinued.

ANAs were reported as adverse events in 3 of 69 patients (4.3%), 1 of whom had ANAs that were deemed to be unrelated to infliximab therapy. Because there is no internationally accepted definition of lupus-like disease, in the absence of both anti-dsDNA antibodies and specific lupus symptoms, we prefer to describe the clinical and laboratory features observed in these patients as ANA-associated symptoms. Such symptoms occurred in 3 patients during the study and remitted within a few weeks of withdrawal of infliximab. However, the overall sample size of this trial was small and, thus, may have contributed to errors in estimating the accurate rate of occurrence of ANAs.

Other serious adverse events occurring in the placebo-controlled phase of this study have been previously described in more detail (12). The overall safety experience with infliximab in this patient population was similar to that described with long-term infliximab treatment in other trials (31). Rare and potentially severe side effects can occur with infliximab; therefore, careful screening and monitoring of patients is recommended (7).

Thus far, both infliximab and etanercept, which are tumor necrosis factor α–blocking agents, have been tested in patients with spondylarthropathies. While infliximab and etanercept have been shown to be effective in RA and psoriatic arthritis, only infliximab works in Crohn's disease (30), whereas etanercept does not (32). In contrast, both agents are effective in reducing joint symptoms in patients with colitis (33, 34), but gut inflammation may flare in patients who take etanercept (35). The reasons for this difference are not entirely clear, but these observations call into question the role of the gut in the pathogenesis of the spondylarthropathies (36).

In conclusion, a beneficial clinical response to infliximab was demonstrated in patients with AS throughout a 1-year period of observation. Patients with active AS despite NSAID therapy experienced clinical improvement with infliximab. The profile of adverse events was consistent with that of previous trials of infliximab in Crohn's disease and RA. This study underscores a pathogenetic role of tumor necrosis factor α in AS and portends a paradigm shift in the expectations for pharmacotherapy of AS. Infliximab has significant beneficial effects on disease activity and function and, importantly, on quality of life in AS patients. Further studies are needed to assess the efficacy of infliximab on structural changes, as assessed by magnetic resonance imaging and radiographic techniques. The continued observation of this AS cohort, including comparisons of radiographs of the spine taken before and after infliximab therapy at 2 years, is ongoing. Patients with AS should be treated by clinicians who are experienced in the management of potent biologic regimens.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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