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Rheumatology Advance Access originally published online on January 25, 2006
Rheumatology 2006 45(7):859-862; doi:10.1093/rheumatology/kel015
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Continuation of treatment with infliximab in ankylosing spondylitis: 2-yr open follow-up

L. Gossec, A. Le Henanff, M. Breban1, E. Vignon2, P. Claudepierre3, V. Devauchelle4, D. Wendling5, E. Lespessailles6, L. Euller-Ziegler7, J. Sibilia8, A. Perdriger9, C. Alexandre10 and M. Dougados

Rheumatology B Unit, Cochin Hospital, APHP, Rene Descartes University, Paris and Rheumatology Units, 1 Ambroise Pare Hospital, Boulogne-Billancourt, 2 Lyon-Sud Hospital, Pierre-Benite, 3 Henri Mondor Hospital, Creteil, 4 Cavale Blanche Hospital, Brest, 5 Jean Minjoz Hospital, Besancon, 6 Orleans Regional Hospital, Orleans, 7 Archet Hospital, Nice, 8 Hautepierre Hospital, Strasbourg, 9 Sud Hospital, Rennes and 10 Bellevue Hospital, Saint-Etienne, France.

Correspondence to: Laure Gossec, Rheumatologie B, Hôpital Cochin, 27 rue du fbg St. Jacques, 75014 Paris, France. E-mail: laure.gossec{at}cch.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate the continuation and safety of treatment with infliximab in ankylosing spondylitis (AS) over a 2-yr period.

Methods. This study was an open, observational, 2-yr extension study of an open-label study of three induction infusions of infliximab in refractory AS. The fourth infusion was performed only in case of relapse. Thereafter, infliximab was to be administered as needed according to the rheumatologist's opinion; however, for some patients, infusions were performed systematically.

Results. None of the 50 recruited patients was lost to follow-up. Thirteen patients (26%) interrupted their treatment by infliximab: four for inefficacy, seven for adverse events, of which four were for allergic reactions to the infusion, and two for other reasons. For all of the 46 patients who had had three infusions judged efficacious and well tolerated, a fourth infusion was performed because of a flare of the disease, after a mean interval of 20.3±9.9 weeks (range 7.3–57.9). Over the 24 months, the mean interval between infusions was 11.6±9.0 weeks. This interval was longer when patients were treated only as needed (mean 14.3±12.1 weeks) than systematically (mean 9.8±5.7 weeks). Side-effects were similar to those noted in shorter-term studies; seven patients suffered serious adverse events. There were no deaths, no malignancies and no tuberculosis.

Conclusion. This study confirms the long-term treatment continuation of infliximab in AS, and shows an acceptable safety profile. It appears that for some patients the disease can be controlled with long intervals between infusions; these findings warrant further studies.

KEY WORDS: Ankylosing spondylitis, Infliximab, Treatment continuation, Safety


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Recently several trials have shown that anti-tumour necrosis factor (anti-TNF) drugs are significantly superior to placebo in the treatment of ankylosing spondylitis (AS) [1–3]. In an open-label 6-month trial consisting of an induction treatment of three infliximab infusions [4], we observed that infliximab is very effective for the short-term treatment of severe axial AS, but long-term data are sparse [5–9]. To our knowledge, there are only three published reports of a follow-up longer than 1 yr [10–12].

In the present work, we report the findings of an open-label, 2-yr extension study of our cohort [4]. The primary focus of this 2-yr study was the long-term treatment continuation and safety of infliximab in the treatment of AS.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Study design
An open 18-month extension of a prospective, multicentre, observational, 6-month open-label study [4]. The initial 6-month study was approved by the local ethics committee. All patients gave their written informed consent for the study.

Patients
The eligibility criteria for the 6-month, open-label phase of the study have been reported elsewhere [4]. Briefly, patients were eligible if they had AS according to the modified New York criteria [13] that was classified as clinically active despite non-steroidal anti-inflammatory drug (NSAID) intake, based on a score of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 30/100 [14] and a serum C-reactive protein (CRP) level ≥ 15 mg/l. Patients were required to have a predominantly axial form of AS. Exclusion criteria included pregnancy, present infection or any serious infection within the last 3 months, active malignancy within the previous 5 yr, or any previous anti-TNF-alpha treatment.

Study treatment
Patients were scheduled to receive a loading regimen of infliximab intravenously at a dosage of 5 mg/kg at weeks 0, 2 and 6. Thereafter, infusions were to be repeated as needed: the decision to perform a new infusion (with a maximal frequency of one infusion every 4 weeks) was to be taken according to the patient's status, based on the appearance of a flare but no specific criteria for severity had to be met. The dosage was maintained throughout the study at 5 mg/kg. However, for some patients, at some point during follow-up after the fourth infusion, the infusions became systematic, i.e. they were performed at regular intervals, every 8 weeks for example, and not according to a disease flare. Thus two groups can be individualized a posteriori: patients with infusions only as needed (n = 18) vs patients with at least one infusion performed systematically (n = 19). Patients could modify their NSAIDs as needed, and could receive other disease-modifying anti-rheumatic drugs (DMARDs), steroids and/or intra-articular injections, as indicated.

Evaluation of treatment continuation, efficacy and safety
After the first 6 months, follow-up was performed in each centre according to usual practice. There were no mandatory evaluations. Elements concerning follow-up during this part of the trial were obtained by retrospectively filling in a form based on the complete paper patient file. The form included the dates of each infusion and, where available, BASDAI scores before each infusion [14]. If infliximab was interrupted before 2 yr, reasons for the interruption were noted. Infusion reactions and adverse events were all recorded.

Statistical analysis
The primary endpoint was in the intention to treat analysis of all included patients, the proportion of patients continuing treatment for 2 yr. Secondary endpoints were reasons for treatment interruption and adverse events, and for the completers who continued infliximab treatment for 2 yr, intervals between infusions. Survival analysis with statistical analysis system (SAS) according to the Kaplan–Meier technique was used to describe treatment continuation and duration of intervals between two infusions.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Table 1 gives a description of patients at baseline. Patients (n = 50) were primarily male (n = 37, 76%), with active AS (before the first infliximab infusion: mean BASDAI±S.D. = 58±2).


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  		TABLE 1. Description at baseline of the 50 AS patients

 
Continuation of treatment
No patient was lost to follow-up over the 2-yr period. After 1 yr, treatment continuation was 78% and after 2 yr, 74% (Fig. 1).


Figure 1
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  		FIG. 1 Treatment continuation: percentage of patients still taking infliximab over 2 yr for 50 AS patients (Kaplan–Meier survival analysis).

 
Thirteen patients (26%) interrupted their treatment by infliximab: four for inefficacy (of whom one was switched with success to etanercept) and seven for adverse events. Four of these patients had reactions associated with infusion that led to discontinuation (of whom three were then switched to etanercept). Three patients discontinued treatment for other reasons which the investigator considered to be unrelated to the study treatment (one for a suspicion of multiple sclerosis, which was not confirmed; one for vagal reaction to an infusion; one for gastric ulcer haemorrhage). Two other patients discontinued infliximab for other reasons (one non-compliance and one moved to another country where he continued NSAID therapy).

Interval before the fourth infusion
Among the 49 patients who had received the first three infusions, three discontinued treatment for inefficacy or intolerance before the fourth infusion. In all of the remaining 46 patients a fourth infusion was performed because of a flare. The mean duration of the interval between the third infusion (last infusion of induction) and the fourth infusion (first infusion performed only as needed) was 20.3±9.9 weeks (range 7.3–57.9 weeks).

For the 42 patients who had five infusions, the mean interval between the fourth and fifth infusions was 15.3±9.5 weeks (range 4.0–47.0 weeks).

Intervals between infusions
For the 37 patients who continued infliximab treatment for the 24 months, the mean interval between infusions was 11.6±9.0 weeks (range 6.0–67.2 weeks). However, the interval between infusions was longer if infusions were performed only as needed (mean interval 14.3±12.1 weeks for n = 18 patients) rather than systematically (9.8±5.6 weeks for n = 19 patients).

A BASDAI score before infusions was only available for 174 of the 274 infusions; mean BASDAI was 36±22 (for patients treated as needed 42±21 and for patients treated systematically 33±22).

Safety of infliximab: adverse events
Infliximab infusions were generally well tolerated. Most treatment-related adverse events were mild to moderate in severity. The number of patients experiencing any adverse event was 48 (96%). The most frequently reported adverse events were bronchitis (28%), upper respiratory tract infections (24%), symptoms associated with infusions (24%) and dermatological manifestations (24%) such as pruritis, rash or fungal infection. Over the 2-yr period, six (12%) patients reported a total of seven serious adverse events that were considered to be clinically relevant. The event for one of these patients was considered to be unrelated to the study drug (unilateral hypoacousia). Six serious adverse events (symptoms associated with infusion, n = 4, multiple adenopathies with negative work-up, n = 1, upper-arm infection, n = 1) were considered to be possibly related to the study drug. Four other patients reported surgical procedures or rehabilitation measures that were considered to be irrelevant and unrelated to the study drug.

No deaths, no malignancies and no tuberculosis were reported.

Concomitant DMARDs
Eight patients took a concomitant DMARD during the study period; in the cases it was methotrexate, with a range of 7.5 to 12.5 mg/week orally and a duration of 3 to 19 months. In all, methotrexate was taken for a cumulative total of 83 patient-months (7% of follow-up patient-months).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
This study confirms the long-term continuation of infliximab in AS, and shows an acceptable safety profile. Almost three-quarters of patients were still receiving infliximab therapy after 2 yr; thus, it appears that clinical response to infliximab is durable.

Therapeutic continuation is an indirect measure of efficacy and safety. Due to the study design, we cannot present results of efficacy evaluated with the usual tools (e.g. BASDAI 50). Finally results presented here are closer to ‘real life’ practice than usual trials.

The discontinuation rate of 26% after 2 yr is comparable to the rates reported in the literature: discontinuation concerned, for infliximab, 29% of 69 patients after 2 yr almost unchanged after 3 yr [10, 11], and for etanercept 22% of 257 patients after 2 yr [12]. Treatment continuation is also remarkably similar here after 1 and 2 yr of follow-up. Thus, it appears that when AS patients discontinue infliximab therapy, this happens more frequently during the first months of treatment; this is similar to the results of Braun et al.'s study [10].

The originality of this study is that after induction, patients were retreated only if they had a disease flare. For 19 patients, however, at some point during follow-up after the fourth infusion the infusions became systematic. It seems that the reasons for performing infusions systematically were mainly practical (it is easier to give a patient his next infusion date as he/she leaves the hospital than to organize an urgent infusion when he/she calls because of a painful flare), and in some cases patient pressure or the frequency of flares. It is noteworthy that all the patients who had the three induction infusions and for whom these infusions were evaluated as efficacious and well tolerated, necessitated a fourth infusion. This means that there were no prolonged remissions occurring 2 yr after induction. However, the delay before a fourth infusion was needed was in some cases very long (for seven patients, this delay was longer than six months, and in one case it exceeded 1 yr). Furthermore, during the whole 2-yr period, intervals between infusions were notably longer for patients who were treated only as needed vs those who received systematic infusions. However, one limitation of our results is that the severity of a flare necessitating a new infusion was not pre-defined, and was left to the appreciation of the patients and clinicians. In our study BASDAI was not always evaluated before infusions. However, the indicative mean value of 36 corresponds to 62% of the initial BASDAI; this indicates that patients were apparently re-treated rather often, even in the group treated only as needed. It is possible that if the monitoring had been more rigorous patients could actually have benefited from extra infusions. Whatever the explanation, the observed mean interval between infusions of 14 weeks when patients were treated as needed does result from daily practice in 10 tertiary centres.

The overall safety experience with infliximab in this patient population was similar to that described with infliximab treatment in other trials [5–12]. The most frequent side-effect leading to treatment interruption was allergy or immediate intolerance to the drug. These infusion reactions may have been more frequent because our patients were not taking concomitant immunosuppressive drugs and were treated irregularly [16].

In conclusion, a beneficial clinical response with good continuation rates was demonstrated in patients with AS throughout a 2-yr period of observation. The systematic flare observed after the first three infusions justifies long-term treatment and monitoring in this chronic disabling disease. Additional long-term studies of infliximab in AS are warranted using larger patient groups, in particular to better evaluate the safety/efficacy profile according to the mode of prescription (systematic vs as needed).
Figure 2


   Acknowledgments
 
The authors would like to thank the investigators who participated in the study, support staff who helped with data collection and Schering Plough for supplying the study drugs.

This study was supported by an unrestricted grant from Schering Plough and conducted with an independent research association (ARCR, Association de Recherche Clinique en Rhumatologie) as the promoter. The funding source played no role in the conception of the study, the analysis, the elaboration of the report or the decision to publish.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Brandt J, Haibel H, Cornely D et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346–52.[CrossRef][Web of Science][Medline]
  2. Braun J, Brandt J, Listing J et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002;359:1187–93.[CrossRef][Web of Science][Medline]
  3. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002;346:1349–56.[Abstract/Free Full Text]
  4. Breban M, Vignon E, Claudepierre P et al. Efficacy of infliximab in refractory ankylosing spondylitis: results of a six-month open-label study. Rheumatology 2002;41:1280–5.[Abstract/Free Full Text]
  5. Kruithof E, Van den Bosch F, Baeten D et al. Repeated infusions of infliximab, a chimeric anti-TNFalpha monoclonal antibody, in patients with active spondyloarthropathy: one year follow up. Ann Rheum Dis 2002;61:207–12.[Abstract/Free Full Text]
  6. Maksymowych WP, Jhangri GS, Lambert RG et al. Infliximab in ankylosing spondylitis: a prospective observational inception cohort analysis of efficacy and safety. J Rheumatol 2002;29:959–65.[Abstract/Free Full Text]
  7. Braun J, Brandt J, Listing J et al. Long-term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: an open, observational, extension study of a three-month, randomized, placebo-controlled trial. Arthritis Rheum 2003;48:2224–33.[CrossRef][Web of Science][Medline]
  8. Brandt J, Listing J, Haibel H et al. Long-term efficacy and safety of etanercept after readministration in patients with active ankylosing spondylitis. Rheumatology 2005;44:342–8.[Abstract/Free Full Text]
  9. van der Heijde D, Dijkmans B, Geusens P et al. Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005;52:582–91.[CrossRef][Web of Science][Medline]
  10. Braun J, Brandt J, Listing J et al. Two year maintenance of efficacy and safety of infliximab in the treatment of ankylosing spondylitis. Ann Rheum Dis 2005;64:229–34.[Abstract/Free Full Text]
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  12. Davis JC Jr, van der Heijde DM, Braun J et al. Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks. Ann Rheum Dis 2005;64:1557–62.[Abstract/Free Full Text]
  13. van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8.[Web of Science][Medline]
  14. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91.[Web of Science][Medline]
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Submitted 5 April 2005; revised version accepted 16 December 2005.
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