
Persistent clinical response to the anti-TNF-
antibody infliximab in patients with ankylosing spondylitis over 3 years
J. Braun1,2,
X. Baraliakos1,
J. Brandt1,
J. Listing3,
A. Zink3,
R. Alten4,
G. Burmester5,
E. Gromnica-Ihle6,
H. Kellner7,
M. Schneider9,
H. Sörensen8,
H. Zeidler10 and
J. Sieper2,3
1 Rheumatology Medical Center Ruhrgebiet, Herne, Ruhr-University Bochum, 2 University Medicine Berlin, Campus Benjamin Franklin, Herne, 3 German Rheumatism Research Center, Berlin, 4 Schlosspark Clinic, Berlin, 5 Charité Hospital, Humboldt University, Berlin, 6 Berlin-Buch Hospital, Berlin, 7 Ludwig Maximilians University, Munich, 8 Immanuel Hospital, Berlin, 9 Heinrich Heine University, Düsseldorf and 10 Medical University, Hannover, Germany.
Correspondence to: J. Braun, Rheumazentrum Ruhrgebiet, Landgrafenstr. 15, 44652 Herne, Germany. E-mail: J.Braun{at}Rheumazentrum-Ruhrgebiet.de
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Abstract
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Objective. Infliximab, a monoclonal antibody against tumour necrosis factor
(TNF-
), is approved in Europe for the treatment of patients with active ankylosing spondylitis (AS) who have responded inadequately to conventional therapy. This report provides analyses from a 3-yr extension study, as a follow-up to both the 1- and 2-yr open label extensions of the original 3-month randomized controlled trial of infliximab in patients with AS.
Methods. Of the 49 patients with AS who completed the second year of the study, 46 continued treatment with infliximab 5 mg/kg every 6 weeks up to week 156. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index, the Bath AS Metrology Index, patient's and physician's global assessments, quality of life (Short Form-36), C-reactive protein (CRP) and erythrocyte sedimentation rate were assessed throughout the study period.
Results. The improvement of signs and symptoms observed in the majority of the patients during the first and second year was sustained throughout the third year of the study. Forty-three patients (62% of the 69 patients enrolled at baseline and 93% of the patients who started the third year) completed week 156. In the intention-to-treat analysis, an ASAS 5 out of 6 and ASAS 40% response was seen by 46% and 50% of the patients, respectively. The scores for other efficacy assessments were similar to the values observed at weeks 54 and 102. Median CRP levels remained low (1.5 mg/l at week 156). There were no relevant side-effects and no discontinuation because of drug-related adverse events during the third year of the study.
Conclusions. Patients with AS receiving infliximab for 3 yr showed a durable clinical response without loss of efficacy. Long-term infliximab treatment was well tolerated by patients in this study.
KEY WORDS: Ankylosing spondylitis, Infliximab, TNF-
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Introduction
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Ankylosing spondylitis (AS), the prototype of the spondyloarthritides, is a chronic inflammatory disease with a prevalence of 0.11.1% [14], a substantial burden of disease [5] and definite direct and indirect costs [68]. It affects both sexes, although it affects men at a higher rate than women, and it usually starts in the third decade of life.
Inhibition of the proinflammatory cytokine tumour necrosis factor
(TNF-
) has demonstrated efficacy in patients with active AS [912]. In a 12-week, double-blind, placebo-controlled study of 69 patients with active AS, we reported significant improvement in signs and symptoms for patients treated with infliximab [10]. This response was maintained for up to 2 yr in an open-label extension phase of the study, during which all patients were treated continuously with infliximab infusions of 5 mg/kg every 6 weeks [11, 12].
Here we report the results of the third-year extension of the study, which represents the longest systematic follow-up of patients receiving anti-TNF-
therapy for AS.
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Methods
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Patients and study protocol
The study design of the 12-week, randomized, placebo-controlled phase of the study [10] and the 1- and 2-yr extension study [11, 12] were reported previously. Briefly, 69 patients with severe AS were randomly assigned to receive placebo or infliximab 5 mg/kg. Beginning at week 12, patients initially assigned to placebo were eligible to receive infliximab 5 mg/kg. Disease activity at baseline was assessed by using the Bath AS Disease Activity Index (BASDAI [13]) score. The main inclusion criterion at baseline was a BASDAI >4 and spinal pain >4 [on a numerical rating scale (NRS) ranging from 0 to 10]. Concomitant disease-modifying anti-rheumatic drugs (DMARDs) and oral corticosteroids were not permitted during the entire study period. Use of non-steroidal anti-inflammatory drugs (NSAIDs) was permitted, and dosages of NSAIDs were allowed to be reduced but not increased during the study.
After completing the second year of the study [12], patients who chose to participate in the 156-week extension of the study received open-label infusions of infliximab 5 mg/kg every 6 weeks, beginning with the week-108 infusion. Study medication was manufactured by Centocor and was packaged and labelled for the study by Essex Pharma (Munich, Germany).
Eight centres participated in the third-year extension, all of which had patients who participated in the study throughout the entire 3 yr. The local independent ethics committees approved the original study protocol and the third-year extension. All patients who chose to participate in the third year of the study provided written informed consent.
Assessments
The disease status was assessed by using validated parameters for disease activity (BASDAI), function (Bath AS Functional Index; BASFI [14]) and metrology (Bath AS Metrology Index; BASMI [15]). These parameters range between 0 and 10 points on a 10-item NRS. Patient and physician global disease assessments and patient assessments of spinal pain were also measured using a NRS ranging from 0 to 10. Health-related quality of life was assessed using the Short Form (SF)-36 questionnaire [16]. Peripheral arthritis was assessed by counting the number of swollen joints (overall SF-36, 64 joints). Other reasons for joint pain, tenderness or swelling had to be excluded on a clinical basis and, if indicated, by imaging procedures (e.g. due to a meniscal lesion). The scoring algorithm of the Medical Outcome Trust [17] was used to calculate the SF-36 physical and mental component summary scores.
The primary outcome parameter was a 50% improvement from baseline in BASDAI score at the end of the third year. Treatment response was also assessed by using the Assessments in AS (ASAS) Working Group criteria [18], as described recently in more detail [10]. These improvement criteria for the efficacy of treatment in patients with AS consist of four domains: patient's global assessment, pain, function (represented by the BASFI score) and morning stiffness (represented by the mean of the two morning stiffness scales of the BASDAI). Furthermore, the recently proposed criteria for assessment of short-term improvement after anti-TNF-
therapy in patients with AS were applied [19], which include the ASAS 40% and ASAS 5 out of 6 criteria for improvement. To meet the ASAS 5 out of 6 criteria, a 20% improvement in any five of the following six domains is required: the four domains used for ASAS 40%, the acute phase reactants [assessed as C-reactive protein (CRP)] and spinal mobility (assessed as BASMI score). Partial remission was defined as a score
2 (on a scale of 010) in each of the ASAS 40% domains.
Statistical analysis
We used both an intention-to-treat (ITT) analysis, which included data for all patients who were enrolled at the beginning of the study, and an analysis of patients who started the third year. In the ITT analysis, data for all patients who were randomly assigned to treatment and who fulfilled the inclusion criteria (n = 69, Fig. 1) were included. Because an ITT analysis tends to underestimate the treatment effect in long-term trials, we applied a slightly modified version of this method. Five patients who discontinued the study for personal reasons after the first and second years (Fig. 1) were included in the analysis of the third year with their last outcome while on treatment. The other 21 patients who discontinued treatment were considered to be BASDAI and ASAS non-responders for every missing visit.
For the completer analysis, only data for the 46 patients who decided to participate in the third year of the study were included (Fig. 1). To calculate the means of the different parameters for the third-year study population, data for the last observation was carried forward to the end-point for patients who discontinued prematurely. To compare mean differences between time points (week 0 vs week 156, week 54 vs week 156), a paired t-test was applied. In the case of skewed distributions [CRP and erythrocyte sedimentation rate (ESR)] the corresponding non-parametric test (Wilcoxon test) was used. The McNemar test was used to compare frequencies between different points in time. A recently proposed non-parametric dropout test was applied to investigate if the dropouts could be considered as a random sample from the ITT study population with respect to selected parameters [20].
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Results
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The results of the 3-month placebo-controlled phase [10] and the first- [11] and second-year extensions [12] of this study have been reported previously. Fifty-four patients (78%) completed the study after 54 weeks and 49 (71%) completed after 102 weeks. Forty-six patients (67%) chose to continue the study for the third year. Sixty-one per cent of the patients who participated in the third year of the study were men, the mean age was 40.9 yr, the mean weight was 73.9 kg, and 40/46 (87%) were HLA-B27-positive. Forty-three patients (62% of the original 69 patients) completed the entire 156-week extension, representing 93% of the patients who started the third year. Three patients (two women, one man) withdrew from the study during the third year, because of personal reasons (planning pregnancy) but not because of adverse events or inefficacy (Fig. 1).
Efficacy
ITT analysis
Throughout the 3 yr of the study, response rates remained stable for the whole population in the ITT analysis. Compared with baseline, 47.1% of the patients in the infliximab group and 42.9% of the patients in the placebo/infliximab group achieved a 50% improvement in the BASDAI score at week 156, while this level of improvement was achieved by 41 and 49%, respectively, at week 102 (Fig. 2a) [12]. Furthermore, comparable levels of response for ASAS 40% criteria and ASAS 5 out of 6 criteria were observed at each time point throughout the entire 3 yr of follow-up among the 69 patients whose data were included in the ITT analysis (Fig. 2b).

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FIG. 2. (a) Efficacy of infliximab therapy in the ITT population as assessed by at least 50% improvement in the BASDAI. (b) Efficacy of infliximab therapy in the ITT population as assessed by at least 40% improvement in the criteria of the ASAS working group and at least 20% improvement in the ASAS 5 out of 6 criteria.
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Analysis of the third-year study population
Compared with baseline, 28 out of 46 patients (61%) showed a reduction of at least 50% in the BASDAI score, which was similar to the response levels at week 54 (63%) and at week 102 (58%). The BASDAI 50% response was consistent over the entire third year of the study, 27 patients achieving at least 50% improvement at each assessment point. Forty-nine (94%), 44 (85%) and 42 (91%) of the patients in each year achieved at least 20% improvement in BASDAI at weeks 54, 102 and 156, respectively. Twenty-two patients achieved at least a 70% reduction from baseline in BASDAI score at weeks 54 and 102 (41% and 45% of the patients who completed the first and second year, respectively), while 18 patients (39%) achieved this level of response at week 156.
Persistence of clinical response, as measured by the BASDAI, was similar to the results obtained for the other clinical assessments (Table 1). At week 156, there was a statistically significant reduction from baseline in patient and physician global disease assessments, BASDAI score, spinal pain, BASFI score, BASMI score, CRP, ESR and the physical and mental component summary scores of the SF-36 (P
0.002). Changes between week 102 and week 156 were not significant (Table 1), except for a statistically significant decrease in the CRP and ESR (P = 0.04 and 0.05, respectively). The individual parameters of the BASDAI remained as low as at week 54 and 102 (Table 2a). Of the patients who were included in the third year of the study, 27 patients (59%), 29 patients (63%) and 28 patients (61%) showed low disease activity (BASDAI score <3) at week 54, 102 and 156, respectively. The individual components of the BASMI are provided in Table 2b. Mean BASDAI, BASFI and BASMI scores are shown in Fig. 3.
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TABLE 1. Assessment of response for all clinical parameters after 54, 102 and 156 weeks of therapy for all 46 patients who participated in the third year
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FIG. 3. Completer analysis of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) over the study period of 3 yr.
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At week 156, 15 patients (33%) achieved partial remission, four more than the number that had achieved this end-point at week 54 (Fig. 4). Of the patients who participated in the third year, 21 (45.7%) had enthesitis at baseline and 8 (17.4%) had enthesitis at week 156. Eight patients (17.4%) had peripheral arthritis at week 156, which was fewer than the number observed at baseline [14 patients (30.4%)], but was more than the number observed at week 54 [one patient (2.2%)] and week 102 [five patients (10.9%)] (Table 3). While 46% of the patients had a history of anterior uveitis and 8% had had a flare of anterior uveitis within the last year before inclusion in the study, only one patient reported a flare of anterior uveitis during the third year of treatment.
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TABLE 3. Partial remission, enthesitis and arthritis for the 46 patients who participated in the third year of the study at baseline and weeks 54, 102 and 156
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By the beginning of the third year of treatment, 23 of the original 69 patients had discontinued participation in the study. The disease characteristics of these patients at study entry were similar to those who remained in the study (Table 4). At their last visit, the patients who discontinued had, on average, higher values for BASDAI and CRP than those who participated in the third-year extension study. For this reason, results for the overall study population are based on an ITT analysis (Fig. 2a and b).
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TABLE 4. Disease characteristics at baseline and at the visit of discontinuation for all patients whose data were not included in the 3-yr analysis (n = 23)
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Adverse events
During the third year of this study, 44 patients (96%) reported at least one adverse event (Table 5). The most frequently reported events were upper respiratory tract infections (37%), diarrhoea (22%) and rhinitis (20%).
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TABLE 5. Summary of the adverse events occurring during the third year, as reported for all 46 patients who participated in the third year of the study
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Six patients (13%) reported serious adverse events (SAE). Three of these SAEs were clinically relevant: one patient was hospitalized for a muscle biopsy due to muscle pain, one patient was hospitalized for a rehabilitation procedure, and one patient was hospitalized because of persistent obstipation. None of these SAEs was considered to be related to infliximab, and none was given as a reason for discontinuation from the study. The other three SAEs included two women who discontinued infliximab because they were planning a pregnancy and one man who discontinued infliximab because he was planning a pregnancy with his partner.
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Discussion
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The results of this open-label, extension study confirm that the clinical efficacy and safety of infliximab observed after 3 months [10], 1 yr [11] and 2 yr [12] in patients with severe AS continued for up to 3 yr. The BASDAI 50% improvement was found to be similar throughout the entire observation period, with high proportions of patients fulfilling this response criterion at week 54 (63%), week 102 (58%) and week 156 (61%). Strikingly, all clinical assessments of disease activity (BASDAI, enthesitis and swollen joint count), functional ability (BASFI), metrology (BASMI), quality of life (SF-36) and laboratory parameters (CRP and ESR) showed persistence of the clinical response over the 3-yr treatment period. There was even a small, though not statistically significant, increase in the percentage of patients reaching remission in the third year. Taken together, these results indicate that the clinical improvement observed in patients with AS receiving infliximab maintenance therapy can persist without loss of efficacy.
The long-term persistence of response observed in this study is of special interest because none of the patients was receiving concomitant immunosuppression with DMARDs, such as methotrexate or glucocorticoids. Thus, although they were not measured directly, antibodies inhibiting infliximab did not seem to play a role in curtailing the clinical response in this population of patients with AS receiving a regular maintenance dosing regimen of infliximab 5 mg/kg every 6 weeks. This is in contrast to observations made in patients with Crohn's disease who, when treated with infliximab at irregular intervals, had an increased incidence of antibodies to infliximab, allergic reactions and loss of efficacy, events which occurred less frequently in patients receiving concomitant steroids or other immunosuppressive agents [21].
The observation that only one flare of anterior uveitis was observed in the third year deserves comment because an incidence rate of <3% is clearly less than what could have been expected from this cohort on the basis of earlier experience and reports from the literature [22]. Although the total numbers are small, it seems that infliximab may prevent flares of uveitis associated with AS.
With regard to safety, although based on a small cohort of patients, the adverse event rates observed in this study are in concordance with the known safety profile of infliximab. Overall, infliximab was well tolerated by all patients who participated in the third year of this study. Interestingly, there were no patients who dropped out of the study during the third year because of drug-related adverse events. Furthermore, there were no serious infections, including tuberculosis, no reports of lupus-like syndrome, and no infusion reactions. The overall discontinuation rate (7%) during the third year of the study was lower than that observed during the first year of the study (22%) and similar to that of the second year (6%). This is less than the reported 17% withdrawal rate for the second year of the ATTRACT trial, the large randomized controlled study of infliximab in combination with methotrexate in patients with rheumatoid arthritis [23], possibly reflecting the strong efficacy of infliximab in AS and the younger study population with less comorbidity. In conclusion, there were no major infection associated or other serious adverse events in this third year of the trial. However, this doesn't exclude that treatment with anti-TNF-
agents may rarely cause infection-related side-effects, as recently discussed [24].This study represents the longest treatment period described in the literature on the efficacy and safety of an anti-TNF agent in patients with AS. According to the study protocol, patients who complete the third year of the study and agree to continue participation will have their treatment stopped to determine if long-term remission can be induced. In case of relapse, treatment with infliximab will be restarted for another 2 yr, giving a total observation period of 5 yr. These results, along with the data from other studies, will increase our long-term experience with efficacy and safety of infliximab in patients with severe AS.
J. Braun and J. Sieper have held consultancies and received research honoraria, speaker's honoraria and grants/research support from Centocor, Schering-Plough, Essex, Wyeth and Abbott. H. Zeidler has received speaker's honoraria from Essex. G. Burmester has held consultancies for Centocor, Essex, Wyeth and Abbott; has received honoraria from Centocor, Essex, Wyeth and Abbott; has been a member of a speaker's bureau for Centocor, Essex, Wyeth and Abbott; and has received grants/research support from Centocor, Essex and Abbott. The other authors have declared no conflicts of interest.
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Submitted 3 November 2004;
revised version accepted 1 February 2005.