The development of randomised clinical trials in the treatment of rheumatoid arthritis over 20 years (1991 – 2011) in a single centre

Porter, Duncan (2013) The development of randomised clinical trials in the treatment of rheumatoid arthritis over 20 years (1991 – 2011) in a single centre. MD thesis, University of Glasgow.

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Rheumatoid Arthritis (RA) is the commonest inflammatory polyarthritis in the UK, and is associated with significant symptoms, disability and premature mortality. Treatment options in 1980 were restricted to corticosteroids, non-steroidal anti-inflammatory drugs, and a small number of disease modifying anti-rheumatic drugs (DMARDs). There had been few large, well conducted randomised controlled studies such that our knowledge about the relative efficacy and safety of the drugs available was very limited. Trial design also left much to be desired, with inadequate methods of randomisation and/or concealment of allocation being commonplace. There was no consensus about which outcome measures ought to included in trials, and no composite measures of outcome had yet been developed or validated. The limited evidence base and restricted therapeutic armamentarium was reflected in the poor outcome of the disease for many patients: remission was rare, and patients often experienced increasing disability, orthopaedic intervention, work-related unemployment and premature mortality.

Within 20 years, the prognosis for patients with newly diagnosed RA has dramatically improved. Modern management results in the majority of patients achieving low disease activity or even remission. The studies incorporated into this thesis have played an important role in the evolution of these management strategies. Early studies focussed on building the evidence base for the use of DMARD monotherapy, demonstrating that sulfasalazine and methotrexate were both safe and effective treatments. The Sulfasalazine-Auranofin trial contributed to the downfall of auranofin, a drug that is no longer manufactured. Contrary to early concerns, methotrexate was proven to be well tolerated, even in the socially deprived population of Greater Glasgow, and this drug had become the DMARD of first choice in the management of RA. DMARD monotherapy, however, is usually not sufficient to maintain good disease control in the long term. The Gold-Hydroxychloroquine study was one of the first studies to investigate the role of combination DMARD therapy in a well conducted, double blind randomised controlled trial (RCT). The results were negative, but a follow up trial demonstrated the superiority of stepping up to Methotrexate-Sulfasalazine combination therapy when compared to sequential monotherapy in the MASCOT study. The West of Scotland Early RA corticosteroid trial was a double blind RCT investigating the role of low dose oral corticosteroids in addition to sulfasalazine therapy. It failed to demonstrate any benefit of low dose steroids, a finding that is at odds with a growing literature that has established corticosteroids as a proven disease modifying therapy.

The strategy trials (Tight Control of RA [TICORA] and Triple Therapy in Early RA [TEAR] studies) have been the most influential studies to have been performed in Glasgow. They did not primarily address the issue of whether a drug is effective or whether one drug is more effective than another. Rather, they sought to test a hypothesis drawn from observations in other biologic models (principally Type I Diabetes Mellitus): namely, that i) using currently available DMARDs ‘tight control’ can be achieved if patients are reviewed frequently, their disease assessed formally (using the disease activity score), and their treatment escalated if their disease remained active; ii) that the achievement of tight control would lead to improved outcomes. The studies provided strong evidence that dramatic improvements in symptom control, disability and radiographic progression can be achieved by pursuing this strategy of ‘Tight Control’. National and international clinical guidelines, and international consensus statements have embraced the results of TICORA (and subsequent confirmatory studies), such that regular, frequent assessment of the patient, use of composite measures of disease activity and the adoption of a ‘treat-to-target’ therapeutic strategy have become accepted as ‘best practice’ throughout the world.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: M.D. presented by published work. The electronic version of this thesis has been edited and some or all third party copyright material removed.
Keywords: Rheumatoid arthritis; clinical trial
Subjects: R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation > Immunology
Supervisor's Name: Iain, Prof. McInnes
Date of Award: 2013
Depositing User: Dr Duncan Porter
Unique ID: glathesis:2013-3854
Copyright: Copyright of this thesis is held by the author
Date Deposited: 13 Mar 2013 12:13
Last Modified: 18 May 2022 10:58

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