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Rheumatoid arthritis treatments in the real world

A way forward?
Study
Results
Comment

The real world is sceptical about clinical trials, and whether the results of trials transfer into clinical practice. Complaints vary. One complaint is that randomised trials do not recruit patients like ours, and exclude too many patients, making patients in trials unlike those in the real world. Another is that patients in trials are somehow coerced into remaining on treatments when in real life adverse events or lack of efficacy make them discontinue treatment. Or trials are not long enough when patients may have daily treatment for many years. The real cynics think that clinical trials are a stitch up between industry and government.

Whatever the reason, cynicism and caution are justified. A new treatment may have been used by only a few thousand patients (typically about 1,500, though that is rising). That is too few to be confident of safety, especially if older, or sicker patients, or those on other medicines are being treated than those included in clinical trials.

A way forward?


Take new treatments for rheumatoid arthritis as an example. A NICE review ( Bandolier 99) had information on about 1,000 patients given etanercept, and about 630 given infliximab. The treatments were effective within the limits of the trials, but only a small proportion used the licensed doses, and those for only 24-30 weeks, not long when the treatment may be used for years. And these biological treatments are innovative. We have no experience of treating patients with monoclonal antibodies for many years.

So what would you do? A guess at a way forward would be to create strict treatment protocols, defining who should be treated, and how, but leaving the clinical decision of who to treat with what to the doctor and patient. Without exception every patient treated would be monitored, at set times, and with defined criteria of what to measure. Adverse events would be recorded, and reasons for stopping treatment.

That, of course, is similar to what the British Society for Rheumatologists and other bodies have proposed. But in Sweden they already have the results [1], and describe how an academic unit can work with non-teaching institutions to do good real world research.

Study


In the University Hospital of Lund in southern Sweden, a clinical treatment protocol was adapted to monitor new treatments in rheumatoid arthritis. Six non-teaching hospitals also used the protocol, so that coverage of patients with rheumatoid arthritis in southern Sweden was complete.

There were strict eligibility criteria, including a proper diagnosis of rheumatoid arthritis, failure to respond to or tolerate at least two disease-modifying drugs including methotrexate. Though not approved by the European Medicines Agency at the time (1999-2000), Swedish law allowed use of several treatments on an individual patient basis.

For etanercept, infliximab and leflunomide initial doses were according to licence, with changes as necessary. Assessments were mandated before treatment started, and at 3, 6 and 12 months, and 3-6 months thereafter.

Results


Of 369 patients treated, 166 were on etanercept, 135 on infliximab and 103 on leflunomide. Some (33) tried two treatments and one all three. Patients on the TNF-antagonists etanercept and infliximab were similar, but those on leflunomide were older, had more severe joint damage, were more often treated with monotherapy and had somewhat lower inflammatory activity as judged by ESR values.

After 12 months of treatment with etanercept, about 60% of patients had an ACR20 response, 40% an ACR50 response and about 18% an ACR70 response (as judged from graphs in the paper). Figure 1 shows that these results were similar to those of a trial of the licensed dose at six months. After 20 months, 79% of patients who began treatment were still using it.

Figure 1: Etanercept results from RCT and protocol



After 12 months of treatment with infliximab, about 60% of patients had an ACR20 response, 40% an ACR50 response and about 18% an ACR70 response (as judged from graphs in the paper). Figure 2 shows that these results were similar to that of trials of similar doses and dose intervals at about six months. After 20 months, 75% of patients who began treatment were still using it.

Figure 2: Infliximab results from RCT and protocol



After 12 months of treatment with leflunomide, about 20% of patients had an ACR20 response, 20% an ACR50 response and about 10% an ACR70 response (as judged from graphs in the paper). After 20 months, 22% of patients who began treatment were still using it.

Adverse events were well reported, especially deaths, life-threatening, and serious adverse events. For the TNF-antagonists five myocardial infarctions occurred, there were some episodes of serious bacterial infection, and there were three lymphomas and one case of acute myeloid leukaemia.

Comment


This real-world study provided significant information about treating patients with rheumatoid arthritis using new therapies. The amount of information in terms of patient numbers multiplied by duration of treatment was, for the TNF-antagonists, about equal or more than that from clinical trials. Results on efficacy were similar to clinical trials. The adverse events recorded confirmed those seen in clinical trials, and reminded us that they could be serious.

Most important was the model. It shows that high-quality monitoring of new treatments can be done without the intervention of manufacturers, who may be biased. There was no industrial sponsorship for this study. There's no reason why similar schemes could not be put in place for most new introductions. It requires some thinking in advance about what is required, cooperation of doctors, and some good information technology.

Reference:

  1. P Geborek et al. Etanercept, infliximab, and leflunomide in established rheumatoid arthritis: clinical experience using a structured follow up programme in southern Sweden. Annals of Rheumatic Disease 2002 61: 793-798.
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