"Tight control" in the management of rheumatoid arthritis - optimising outcomes

26/09/08: By Dr Peter C Taylor MA, PhD, FRCP

Taken from NRAS magazine, Autumn 2008

Introduction – A rapidly evolving treatment paradigm for rheumatoid arthritis

Many, if not all, readers will have heard of diabetes, a condition in which levels of glucose in the bloodstream are too high because the cells of body tissues are not able to absorb it as efficiently as they should under the influence of the hormone insulin. For many decades now we have known that diabetics need an appropriate diet and treatment to try and lower the blood glucose levels. However, for a long time it was not known how important it was to try and control the blood glucose to the extent that it remained within the normal, or near normal, range. It was believed that normalisation of glucose concentrations might reduce some of the long-term problems associated with diabetes, such as nerve and blood vessel damage. However, it has only been relatively recently that it has been possible to establish that this is indeed the case; so called “tight-control” of glucose levels leads to better long-term outcomes for diabetics. In just the same way, it has emerged in recent years that tight control of inflammation in rheumatoid arthritis (RA) at every stage of the condition also leads to better long term outcomes.

Early identification of patients with RA and in particular, those likely to suffer from more rapid joint damage, is important because of the likely benefit of early intervention with disease-modifying anti-rheumatic drugs (DMARDs) or biologic therapies. As appreciation of the gravity of the social and economic burden imposed by RA has grown, so has the recognition that more favourable clinical outcomes are achieved when inflammation is optimally suppressed. In particular, there is now compelling evidence that intervention with DMARDs early in the course of disease results in improved remission rates, magnitude of clinical benefit, and slowing of damage to joints. In addition, the armamentarium of therapeutics has grown. Of these, biologic therapeutics targeting TNF-α, particularly when used in combination with oral methotrexate, have enjoyed considerable success in suppressing inflammation and markedly inhibiting the progression of joint damage previously thought to be an unavoidable characteristic of RA.

Changing goals of therapy

These advances have led to maturation of therapeutic goals from simply ameliorating symptoms of disease. Several key studies in early RA demonstrate improved outcomes with optimal use of oral DMARDs, either singly or in combination, with a clear demonstration that significantly improved efficacy need not be at the expense of unacceptable side effects. Studies with biologic anti-TNFs have further improved the expectation for magnitude of improvement. Using strategies designed to intensively suppress joint inflammation, with either conventional DMARDs or biologic anti-TNF-α therapies in combination with methotrexate, remission has become an achievable goal for a proportion of patients.

Measuring disease activity

A prerequisite for knowing whether or not inflammation associated with RA is adequately controlled is to have the tools to measure such inflammation. Your rheumatologist may do this in a number of ways. These include asking you questions about your health, examining the joints and counting the number that are swollen or tender as well as blood tests of inflammation such as the ESR and CRP. You may also be asked to indicate your recent level of overall well-being on a scale of 0-100 by marking a point on a 100mm straight line. The disease activity score (DAS) is a composite measure of disease activity based on the number of swollen and tender joint counts, the ESR or CRP and an optional patient global health assessment (measured on a 100mm scale). The numerical score is worked out by mathematical formula with the aid of a calculator.

The concept of “tight disease control”

In a clinical trial conducted in Glasgow called the TIght COntrol for Rheumatoid Arthritis (TICORA) trial, routine outpatient care was compared with a strategy of individualized intensive outpatient treatment, according to the patient’s DAS assessed at monthly review. The patients assigned to the “tight control” arm of the trial were treated with standard oral disease modifying anti-rheumatic drugs (DMARDs) with the rapid addition of additional DMARDs if the DAS failed to improve by a set amount, together with steroid joint injections and/or intramuscular steroid as required. After a year, remission rates were significantly greater in the intensive therapy group at 65% vs 16%. Similarly, X-ray outcomes were superior in the intensive therapy group. Interestingly, when the group treated with a “tight control” protocol reverted to standard care after 18 months, the initial benefits were lost.

In another Dutch clinical trial (the BeST study) of a protocol-driven approach to management of RA from first presentation, four different treatment strategies were compared. Three of these strategies involved initial intervention with conventional DMARDs and the fourth comprised initial treatment with the anti-TNF agent infliximab together with once weekly methotrexate. The treatment goal for each strategy was to obtain a low level of DAS. Patients were monitored every 3 months, and the drug therapy adjusted by a pre-set algorithm to a more intensive regimen if intervention up to that point had failed to achieve the target DAS. Alternatively, if a patient achieved an adequate response at this level for 6 consecutive months, regardless of which of the 4 strategic arms was being applied, drugs were tapered in a predetermined manner to a maintenance dose of a single therapy. Prednisolone and infliximab were always the first drugs to be taken to zero.

Of 120 patients initially assigned to infliximab plus methotrexate, 77 achieved very low disease activity and 67 were able to discontinue infliximab after 9 months with a sustained low disease activity. After 3 years, a median of 26 months after infliximab discontinuation, 61 out of these 67 patients still had a persistent low disease activity. Of these 45 were on methotrexate monotherapy and 16 in drug-free clinical remission.

Conclusions

The promising results of these studies:

  • Emphasise the importance of early referral for suspected RA.
  • The value of regular clinical review and protocol driven treatment adjustment with a view to achieving “tight control” of the disease activity score (DAS).
  • Suggest a rationale for future treatment of many more patients with anti-TNF agents at the earliest stages of RA particularly where patients present with poor prognostic features.

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