Long-term treatment of rheumatoid arthritis with tumour necrosis factor {alpha} blockade: outcome of ceasing and restarting biologicals

M. H. Buch, H. Marzo-Ortega, S. J. Bingham and P. Emery

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 {alpha} (TNF-{alpha}) 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-{alpha} blockade. Consequently, several questions arose regarding their long-term management, the most important being whether they would flare when anti-TNF-{alpha} 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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FIG. 1 (A) Weeks to flare after first infliximab course. (B) Responses to first and second courses of infliximab.

 
Of the 17 patients, 15 were re-infused with commercially supplied drug and two chose alternative treatments. No infusion reactions or toxicity were observed with re-exposure to infliximab. The mean ACRn at 2 yr of the ATTRACT study and 9 months after re-introduction (on stable therapy) is summarized in Fig. 1B. Fifteen of the 17 patients were re-established on infliximab therapy at 3 mg/kg every 8 weeks (one patient's results are not included as treatment stopped due to attempted pregnancy). On re-establishing therapy, the ACR response on infliximab was comparable in 12/14 patients and worse in only two. No adverse reactions were observed.

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-{alpha} 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.

References

  1. Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 1999;354:1932–9.[CrossRef][ISI][Medline]
  2. Lipsky PE, Van der Heijde D, St Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594–602.[Abstract/Free Full Text]
  3. National Institute of Clinical Excellence. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis. Technology Appraisal Guidance, March 2002, No. 36. London: National Institute of Clinical Excellence.
Accepted 28 May 2003