Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK
Correspondence to: P. Emery, Academic Unit of Musculoskeletal Disease, 1st Floor, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. E-mail: p.emery{at}leeds.ac.uk
SIR, Infliximab, a chimeric monoclonal antibody, has demonstrated effective suppression of disease and prevention of the progression of structural damage in rheumatoid arthritis (RA) in its phase III randomized study (ATTRACT study) [1, 2]. Two anti-tumour-necrosis factor (TNF-
) drugs, infliximab and etanercept, have recently been approved by the National Institute of Clinical Excellence [3].
With a large number of patients at a single centre for the ATTRACT study [1], the follow-up of our patients represents a special cohort of patients with RA who have received 2 yr of TNF- blockade. Consequently, several questions arose regarding their long-term management, the most important being whether they would flare when anti-TNF-
treatment ceased and, if so, did the maintenance of response depend on the previous dose and response? Finally, the practical question of whether the drug could be restarted safely and effectively was addressed. This is of particular relevance because of concerns regarding the development of human anti-chimeric antibodies when infliximab treatment is interrupted. This study provides new insights into the strategy of long-term therapy with infliximab. This observational study was in accordance with our local ethics committee guidelines.
In the ATTRACT study, patients on methotrexate were randomized to placebo or one of four active treatment infliximab regimens (either 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks). Fifty to sixty per cent of patients on infliximab achieved the primary end-point of an ACR (American College of Rheumatology) 20 response. On completion of the ATTRACT study after 24 months, patients were continued on methotrexate alone. Subsequent relapse was defined as a 20% or greater deterioration in swollen and tender joint count and three out of the five other ACR criteria (composite score). On relapse, patients were recommenced on infliximab at the licensed dose of 3 mg/kg at weeks 0, 2 and 6, and then 8-weekly. The outcome was assessed 9 months after re-induction. Details of baseline disease activity before the ATTRACT study and at 2 yr on infliximab were collected to calculate ACRn (i.e. the ACRn response at the end of 2 yr). The 9-month ACRn after re-introduction of infliximab was assessed.
Of 24 patients who received infliximab as part of the ATTRACT study in Leeds, six dropped out on medical grounds or due to lack of efficacy, one died and 17 entered the 2-yr extension phase. All 17 flared after therapy was ceased at 2 yr. Mean time to flare varied between 13.5 and 15 weeks for the four treatment groups. Patients on the 10 mg/kg dose flared later than those in the 3 mg/kg group (not significant) (Fig. 1A). There was no relationship between time taken to flare and the degree of previous response.
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This study primarily addressed the question of whether anti-TNF treatment for RA needs to be continued in the long term in a group of patients with established RA. A special group of responding patients had received 2 yr of infliximab therapy, three-quarters of them receiving a dose (maximum 10 mg/kg 4-weekly) higher than that licensed. These patients should have had the best chance of a profound modification of the underlying inflammatory disease. In the event, all relapsed, albeit with a slight delay in those who had previously received a higher dose of drug. According to infliximab's pharmacokinetic profile, this would be approximately 6 weeks after clearance of the drug.
Other questions were answered by the study namely despite concerns regarding intermittent therapy, all those patients resuming therapy after a prolonged gap did so without adverse reactions. Furthermore, the response was comparable, although these patients were started with an induction regime, which gives a higher dose for the first 6 months. For this reason the assessments were made at 9 months in the stable phase.
In conclusion, in established RA, responding patients require ongoing therapy to maintain their response in the long term. Hence, anti-TNF- therapy provides immunosuppression rather than immunomodulation. It is noted that the drug can be restarted after an interval of several months without observed problems.
The authors have declared no conflicts of interest.
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