Behind The Medical Headlines

IMPROVING DRUG THERAPY FOR RHEUMATOID ARTHRITIS

• Dr E Suresh, Specialist Registrar, Rheumatic Diseases Unit, Western General Hospital, Crewe Road, Edinburgh, Scotland
• Dr CM Lambert, Consultant Rheumatologist, Rheumatic Diseases Unit, Western General Hospital, Crewe Road, Edinburgh, Scotland

Summary

New drug treatments for rheumatoid arthritis have been hailed as ‘blockbuster’ drugs. How much of this hype is justified and how much potential do these drugs have for patients? Suresh and Lambert review the evidence.

Declaration of interests: No conflict of interests declared

Contrary to popular belief, rheumatoid arthritis (RA) does not generally follow a benign course and cases of ‘mild’ or ‘self-limiting’ disease are by far the exception rather than the rule. Rheumatoid arthritis usually leads to irreversible joint damage and disability and is associated with substantial morbidity and increased mortality compared with the general population.¹ Patients with active RA suffer from significant decline in functional capacity and some studies report a 40% work disability rate within five years of the onset of disease.² A real breakthrough in the treatment of this devastating disease would therefore be very welcome news indeed. The recently published Trial of Etanercept and Methotrexate with Radiographic Patient Outcome (TEMPO) study has attracted much media attention and ‘blockbuster’ headlines, which have understandably raised patient demand and expectation for biological therapy.³ But how much of the hype is justified and when should we be diverting scarce healthcare resources to extend the availability of these therapies are key issues?

In this double-blind placebo-controlled study, the combination of the anti-Tumour Necrosis Factor (anti-TNF) drug etanercept (ETN) and methotrexate (MTX) was compared against therapy with each drug alone in 682 patients with established RA. At 52 weeks, 35% of patients who received the combination of ETN and MTX achieved remission (absence of disease activity when measured by a standardised disease activity score), while the remission rates for patients who received MTX or ETN alone were 13% and 16% respectively. Radiographic progression (an indirect measure of structural joint damage) was retarded in 80% of patients who received the combination therapy compared to 68% and 57% in the patients that received ETN and MTX alone respectively. Improvement in functional disability was also better among patients who received the combination. Combination therapy was well tolerated and adverse events were no more common in the combination arm than in either of the monotherapy arms.

Remission, usually defined as <1.6 units of a composite index or Disease Activity Score (DAS), is a tough goal to achieve in RA and an even harder one to maintain. The rate of achieving remission in the combination arm of TEMPO is impressive and higher than some other studies of biological therapies.⁴⁵ However, another recent pivotal study that has attracted much publicity has also demonstrated that it is possible to achieve similar remission rates without recourse to biological agents. The ‘tight control for rheumatoid arthritis’ (TICORA) study⁶ compared routine out-patient management with an intensive strategy comprising liberal use of intra-articular steroids and regular objective assessments of disease activity (based on DAS) for protocol-driven escalation of conventional therapy. The results for remission rates were impressive: 65% versus 16% for intensive versus standard care respectively with similarly favourable outcomes for physical function (based on Health Assessment Questionnaire) and quality of life (based on Short Form 36). Thus, using conventional agents more effectively may achieve similar benefits to biological therapies.

Furthermore, it should be noted that only one-third of the patients who received the ETN and MTX in the TEMPO trial achieved remission, two-thirds had a suboptimal response. Although the numbers of patients receiving the combined therapy who achieved 20%, 50% and 70% improvement in their disease activity (assessed by the criteria devised by the American College of Rheumatology) was much higher at 85%, 69% and 43% respectively, these measures only imply partial response. In other words, these patients had persistently active disease and will probably suffer further functional decline and structural damage. This is a reminder that RA is a chronic disease with a course measured in decades, and that long-term success depends upon sustainable therapeutic benefit. All too often the benefits of treatment reported in clinical trials of RA are transient and their impact on long-term outcome minimal. However, two recent studies confirm the longer-term benefit of controlling active disease either with conventional (FIN-RACo)⁷ or biological therapy.⁸

Patients recruited to the TEMPO trial had long-standing disease with mean disease duration of about six years. This raises the issue of the optimal timing for biological use and whether such drugs should be used much earlier in the course of inflammatory arthritis. There are two persuasive reasons why this may be the case. First, we now have convincing data that biological agents can halt radiographic progression in RA and therefore prevent structural damage and disability,⁹ so why wait for damage? Second, and perhaps more controversially, there is some evidence that a ‘therapeutic window’ exists before the disease becomes persistent and when its biology may be fundamentally altered. Indirect evidence to support this hypothesis comes from several studies that have demonstrated better medium and long-term clinical, radiological and functional outcome with early intervention. Similarly, studies in which disease modifying therapy has been delayed for even as little as eight to nine months suggest that long-term outcome is compromised.¹⁰

We have alluded briefly to a few of the challenges to improving medical therapy for RA. This includes the use of biological therapies and of optimising combination regimes utilising our improved understanding of mechanisms of drug action and interactions. At approximately £8–10k/per annum/patient, funding for biological therapies is another major challenge but it is clear that a strong health economic argument may be proposed on the basis of their ability to reduce long-term disability. Our enthusiasm to heed the results of the TEMPO and similar trials and to increase the use of biological therapy for RA must, of course, be tempered with caution. These drugs are associated with an increased susceptibility to infection, particularly TB, and their effect upon the development of malignancy, particularly of the lymphoproliferative system, is not yet clear.

The last decade has witnessed biological therapies emerge from ‘bench to bedside’ and there can be no doubt that they represent the most important advance in therapeutics for RA since the pioneering work that led to the discovery of cortisone by Hench and Kendall in 1949. It is no coincidence that the two great British pioneers of anti-TNF therapy, Professors Maini and Feldman from the Kennedy Institute in London, were similarly honoured with the prestigious Lasker Award for Clinical Medical Research in 2003. Biological therapy represents a major breakthrough in therapy for RA, for the first time offering the chance of halting radiographic progression and structural damage. And that’s big news.

References

1. Pincus T, Callahan LF, Sale WG et al. Severe functional declines, work disability and increased mortality in seventy five RA patients studied over 9 years. Arthritis Rheum 1984; 27:864–72.
2. Young A, Dixey J, Kulinskaya E et al. Which patients stop working because of rheumatoid arthritis? Results of five years’ follow up in 732 patients from the early RA study (ERAS). Ann Rheum Dis 2002; 61(4):335– 40.
3. Klareskog L, van der Heijde D, de Jager JP et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double blind randomised controlled trial. Lancet 2004; 363(9410):675–81.
4. Lipsky PE, van der Heijde DMFM, St Clair EW et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343:1594–602.
5. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumour necrosis factor receptor: Fc protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340(4):253–9.
6. Grigor C, Capell H, Stirling A et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364(9430):263–9.
7. Korpela M, Laasonen L, Hannonen P et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease modifying anti-rheumatic drugs. Arthritis Rheum 2004; 50(7):2072–81.
8. Maini R, Breedveld FC, Kalden JR et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 2004; 50(4):1051–65.
9. Breedveld FC, Emery P, Keystone E et al. Infliximab in early active rheumatoid arthritis. Ann Rheum Dis 2004; 63(2):149–55.
10. Tsakonas E, Fitzgerald AA, Fitzcharles MA et al. Consequences of delayed therapy with second-line therapy in rheumatoid arthritis: a 3-year follow up on hydroxychloroquine in early rheumatoid arthritis study. J Rheumatol 2000; 27:623–9.