Leflunomide, a new disease-modifying anti-rheumatic drug and the never ending rheumatoid arthritis story

The standard approach to the therapy of rheumatoid arthritis (RA) has been revised during the last decade. Traditionally a treatment pyramid [1, 2] was used but this has been challenged [3–9]. In particular, the original philosophy which fostered a ‘wait and see [with or without non‐steroidal anti‐inflammatory drugs (NSAIDs)]’ attitude has been taken apart and replaced by the demand ‘Treat now, not later!’ [10]. As a result, disease‐modifying anti‐rheumatic drugs (DMARDs) are now initiated more as early in the disease course as possible, i.e. as soon as an accurate diagnosis is made [10–12]. Many issues are unresolved, including: (a) the definition of ‘early RA’, since most studies of so‐called early RA have dealt with patients who had the disease for 1, 2 or even more years [13]; (b) how to reduce the period between onset of symptoms and presentation to a rheumatologist [13–15]; (c) the non‐specific nature of inflammatory polyarthritis at early stages [16, 17]; (d) uncertainty about the long‐term impact of early intervention; (e) relatively small, i.e. 20% improvements that are viewed as significant achievements from therapy [18, 19]. Despite these queries, the value of early therapy is now accepted, especially as the risks of therapies with DMARDs in very early disease are low compared with the risk of the disease itself [20] and even compared with the risks of treatment with conventional NSAIDs [21–23]. Modern therapeutic approaches include either a step‐up approach, using conventional DMARDs such as sulphasalazine, methotrexate or anti‐malarials at the highest doses necessary followed by combination therapy [24, 25] and/or new therapies alone or in combination with other DMARDs; or, alternatively, a step‐down approach starting with combination therapy [26]. Two of the variables that best correlate with long‐term outcome are the numbers of swollen joints and the levels of C‐reactive protein (CRP) [27–29]. The ideal situation in the therapy of RA would be to achieve or come close to remission [30]. Thus, the real therapeutic need is to aim for ‘zero swollen joints and zero increase in CRP’. How will rheumatologists achieve this? Currently employed DMARDs, even if applied early in the course of RA, have a limited drug‐survival span either due to toxicity or insufficient efficacy. Thus, in the majority of patients, DMARDs have to be stopped and exchanged for others within a few years [31–33]. Interestingly, all DMARDs have a responder rate of 40–70% of patients, who may then respond to the next DMARD at approximately the same proportion, i.e. at least 30% non‐response (this is true even with the new successful agents). Moreover, once effective to the degree of a defined minimal response or above, this response may wear off and patients again become non‐responders. Thus, during the lifetime of the disease, the patients may receive up to 10 courses of different DMARDs or their combinations. However, the number of DMARDs is limited. Thus, once most or all DMARDs have been applied, rheumatologists have been traditionally forced to re‐apply previously ineffective drugs hoping that now they may be better effective, albeit in the context of combination therapy. As RA patients are in need of new therapeutic options, fortunately several new compounds have been licensed in the European Union, namely leflunomide [34] and the tumour necrosis factor (TNF)‐blocking agents [35, 36]; other substances are on the horizon. Thus, new agents expand the rheumatologists' armamentarium to combat the most crippling joint disease. One such new compound is leflunomide. Leflunomide is an isoxazole derivative which exerts its effects, after metabolic opening of the isoxazole ring, via its active metabolite A77 1726. Leflunomide appears to have several effects of immunological relevance. Its major target is dihydro‐orotate‐dehydrogenase (DHODH), a key enzyme of the de novo pyrimidine synthesis, with subsequent inhibition of RNA and DNA synthesis [37]. This leads to disproportionate availability of nucleotides in activated T cells [38] and subsequently to reversible cell cycle arrest [38], presumably by activation of p53 [39, 40]. This effect is mainly exerted upon activated T cells which are important elements in the pathogenesis of RA [41]. Leflunomide may also inhibit the proliferation of B cells and the production of antibodies [42]. In line with the effects on B and/or helper T cells is the significant reduction of rheumatoid factor levels in RA patients treated with leflunomide [34]. In addition, leflunomide inhibits the activation and gene expression of nuclear factor (NF) κB [43]. NFκB is a ubiquitous transcription factor which is activated by a variety of inflammatory stimuli such as TNF‐α and interleukin‐1 (IL‐1), usually via induction of degradation of its inhibitor IκB [44]; the subsequent translocation of NFκB to the nucleus leads to the activation of a variety of genes including those for various cytokines and metalloproteinases. The NFκB‐activating cytokines TNF‐α and IL‐1 are crucially important in the pathogenesis of the joint destruction seen in RA [41, 45–47]. These cytokines are also responsible for the induction of the acute phase response [48]. The degree of this acute phase response is associated with disease activity, radiographic progression and outcome of RA [27, 28, 49]. The observation that leflunomide rapidly reduces the acute phase response in patients with RA [34] supports the findings on its effects upon TNF‐α‐mediated signal transduction pathways. Thus, in RA, leflunomide may act at several levels all relevant to the pathogenesis of the disease: at the T‐cell level, at the B‐cell level and at the level of pro‐inflammatory cytokines. Clinically, short‐ and intermediate‐term studies indicate that the efficacy of leflunomide is comparable to that of sulphasalazine and methotrexate [34, 50], whilst in the long term, leflunomide appears to be superior to sulphasalazine at 2 g/day [51]. Moreover, leflunomide may be an effective compound for combination therapy, since it led to quite significant improvements in methotrexate non‐responders in whom it was added on top of a relatively high median dose of methotrexate in an open study [52]. In two patients it even led to clinical remission. Consequently, further controlled studies of combinations of leflunomide (with sulphasalazine as well as methotrexate) are underway. Importantly, leflunomide retards radiographic disease progression to a similar degree as sulphasalazine and methotrexate, as early as after 6 months of therapy [34, 50]. This effect appears to be sustained in the longer term, and results in retardation of radiographic erosions [53]. Leflunomide is as efficacious in patients with relatively early disease (<2 yr duration) as in those with longer‐standing RA and it has similar efficacy in DMARD‐naive patients as in those previously treated with one or more DMARD [34, 54]. Leflunomide shares liver toxicity with methotrexate and sulphasalazine [34, 50], and there may be added hepatic toxicity if it is combined with methotrexate [52]. Leflunomide can also induce nausea, diarrhoea, alopecia and mild weight loss. All these side‐effects tend to decrease in frequency with continued use. On the other hand, life‐threatening events, such as pneumonitis, as seen with methotrexate, or rapid‐onset agranulocytosis, as seen with sulphasalazine, were not observed in the clinical studies which comprised over 1000 patients treated for up to 3 yr, although leucocytopenia, potentially progressing into agranulocytosis, may occur, particularly when leflunomide is combined with methotrexate. More than 80 000 patients have now been treated in the USA and these events appear to be rare; no case of pneumonitis has been observed to our knowledge. Critical evaluation of rare reports on vasculitis did not provide unequivocal evidence for an association with leflunomide [54]. However, whereas the drug may be beneficial in some forms of vasculitis [55], it may not be an effective compound for the vasculitis associated with RA [34, 54]. It is notable for the rheumatological community that these clinical trials of leflunomide have not only been interesting and important but have also expanded our knowledge on the efficacy of sulphasalazine and methotrexate in a large patient cohort studied in the short and intermediate term. The emphasis has been particularly on radiographic progression and the accrued database is invaluable as a research tool. So where do we go from here? Leflunomide is an efficacious agent, but it will not cure RA nor does it—at least as a monotherapy—lead to a high proportion of complete remissions; in this respect it is no different from other compounds. The TNF‐blocking agents are new promising biologicals, but even these agents, when used in monotherapy, have led to relatively few complete remissions [35, 36]. On the other hand, leflunomide combined with methotrexate and TNF blockers combined with methotrexate showed a significant and sustained improvement in many patients [52, 56–58]. Thus, it is relevant to consider whether the combination of leflunomide with a TNF‐α‐blocking compound would be a particularly effective therapy and such combinations clearly need to be studied. The future for patients with RA appears more promising than it has ever been since the first DMARD was prescribed in the 1920s. Not only has our understanding of the pathogenesis of the disease and its clinical manifestations improved, but DMARDs are used more effectively at higher doses and in combinations. Furthermore, changes in diagnostic and treatment paradigms have meant that novel compounds and therapeutic principles have become a therapeutic reality. Hopefully, all these achievements will really change the prognosis of our patients while we are waiting for even better strategies that eventually may lead to the cure of RA. Correspondence to: J. S. Smolen, Department of Rheumatology, Internal Medicine III, Vienna General Hospital, University of Vienna, Waehringer Guertel 18–20, A‐1090 Vienna, Austria.