Tacrolimus therapy in rheumatoid arthritis

D. W. McCarey, H. A. Capell and R. Madhok

Centre for Rheumatic Diseases, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK

Correspondence to: R. Madhok. E-mail: gcl103{at}clinmed.gla.ac.uk

Our understanding of the pathogenesis of rheumatoid arthritis (RA) has recently improved significantly and this has been paralleled by the availability of highly effective agents directed against TNF-{alpha} as well as the more effective use of existing agents, often in combination. However, a sizeable proportion of patients are unresponsive to these therapeutic approaches. Furthermore the long-term consequences of continued TNF-{alpha} blockade are not known. It is therefore critically important for us to continue to develop new therapeutic strategies that target the broad range of cell types that we consider to be important in the initiation and perpetuation of inflammatory synovitis. Rather than focusing narrowly on the targeting of specific effector molecules such as TNF-{alpha}, there is a strong case to be made for improving our capability further upstream in the inflammatory cascade, for example in T-cell inhibition.

For some time now it has been clear that the T cell has a critical role in the pathogenesis of RA [1]. At the tissue level, T-cell infiltrates are prominent in RA synovitis [2]. Further circumstantial evidence is provided by the fact that antigen-specific T-cell responses in animal models of RA, such as collagen-induced arthritis, are of pivotal importance [3]. Indeed, autoreactive T cells directed at various antigens have been identified in patients with RA [4, 5]. Finally, the strongest known genetic link with RA is the susceptibility epitope found in HLA DR1 and HLA DR4 [6], the MHC-II complex being critical to antigen presentation to CD4+ T cells [7].

This body of evidence has supported the development of a number of T-cell-suppressive therapies of varying degrees of specificity, such as cyclosporin and leflunomide. These agents are now familiar to us in the clinical setting and have established themselves as useful therapeutic options in the treatment of RA. More recently, with the advent of the biological agents, highly specific T-cell therapies have been developed. Anti-CD4 antibodies have been used in therapeutic trials but, despite reasonable efficacy data, problems with lymphopenia and rash have given rise to concerns regarding the safety of this therapeutic approach [8].

Another novel approach to T-cell suppression has been to block the second, costimulatory signal from the antigen-presenting cell required for optimal T-cell activation. CTLA4Ig is the product of the fusion of cytotoxic T-lymphocyte-associated antigen 4 with the heavy-chain constant region of human IgG1 [9]. Kremer et al. [9] recently published the results of a 6-month, double-blind, randomized, placebo-controlled study of CTLA4Ig in addition to pre-existing methotrexate therapy. Patients receiving the higher dose of CTLA4Ig (10 mg/kg intravenously on days 1, 15 and 30, and monthly thereafter for a total of 6 months) derived significant benefit from 2 months onwards. The ACR20 response was 60% and the ACR50 response was 36.5%. The drug was tolerated well and no significant excess of adverse events was noted. This provides further evidence that T-cell-suppressive therapy is potentially effective and safe in the treatment of RA.

In this issue of Rheumatology, Yocum et al. report a long-term safety trial for another T-cell-suppressive agent [10]. Tacrolimus is an orally available, T-cell-specific, immunomodulatory and anti-inflammatory drug that has been proposed as a therapeutic agent in RA. Previously known as FK-506, it is a macrolide calcineurin inhibitor which down-regulates the synthesis of inflammatory cytokines such as TNF-{alpha} and interferon {gamma} (IFN-{gamma}) by activated T-cells [11] and, as such, is closely related to cyclosporin. Tacrolimus is established in the field of transplantation in the prevention of allograft rejection and has also been studied in the context of inflammatory bowel disease [12, 13]. A number of studies of tacrolimus in the treatment of RA have now been performed and the results suggest that it may have a useful role as a disease-modifying agent [14–17]. The present study from the Tacrolimus RA Study Group seeks to address concerns regarding the safety of the drug in the context of RA [10].

A small pilot study by Gremillion et al. [14] published in 1999 was the first to show a benefit of tacrolimus therapy in RA. Twelve patients with active RA who had failed on serial DMARDs were treated in an open-label study. Unfortunately, only seven of the 12 patients tolerated the drug, almost certainly due to the wide dose range that was employed: 2–6 mg/day. The main reason given for withdrawal from the study was gastrointestinal upset, although no effect on creatinine or blood pressure was observed. The response in the patients who did tolerate the drug was, however, encouraging. All of the patients who completed the study achieved an ACR20 response while five of seven achieved an ACR50 response. Very significant improvements were noted both in tender and swollen joint counts.

It was not until 2002 that the first more rigorous trial of tacrolimus in RA was published, by Furst et al. [15]. This was designed as a phase II, double-blind, randomized, placebo-controlled, dose-ranging study comparing 1, 3 and 5 mg/day of tacrolimus with placebo. Two hundred and sixty-eight patients were enrolled in the study and discontinued previous DMARDs at least 4 weeks prior to initiation of the study drug. The study drug was administered for 6 months and the prespecified primary endpoints were ACR20 response and change in tender and swollen joint counts. The results of the trial indicated a fairly narrow therapeutic window for tacrolimus in RA. A clear dose–response effect was observed when considering the ACR20 response, with 15.5, 29, 34.4 and 50% response rates in the 0, 1, 3 and 5 mg/day groups respectively. ACR50 response rates in the same groups were rather disappointing at 1.4, 14.5, 17.2 and 14.1% respectively, perhaps suggesting a plateau in efficacy at or above 3 mg/day. Unfortunately, there was very clear evidence of dose-dependent toxicity, with a significant (≥40%) rise in creatinine observed in 28.1% of the patients who received the highest dose. There was also evidence of a significant increase in diastolic blood pressure in the higher dose groups, although the absolute increases observed were small. Taken together, the efficacy and safety data suggested to the investigators that the optimal therapeutic dose of tacrolimus in RA appeared to lie somewhere between 1 and 3 mg/day.

A phase III study which followed this has recently been published [16]. This was a trial of similar design, comparing tacrolimus monotherapy at doses of 2 and 3 mg/day with placebo in 464 patients, many of whom rolled over into the present long-term safety study. Once more there was evidence of superiority over placebo and, arguably, a dose–response effect. ACR20 response rates were lower in this study, at 13.4, 21.4 and 32% in the placebo, 2 mg/day and 3 mg/day groups respectively. One reason for these disappointing response rates may be the high dropout rate in the study, with only 46.9% of tacrolimus-treated patients completing 6 months of therapy on the study. Analysis of the ACR component scores is informative, with much clearer evidence of improvement in swollen and tender joint counts (median decrease of 30% in each score) than in the subjective patient global score (median decrease of 13.6%) in the 3 mg/day tacrolimus group, suggesting a greater benefit in terms of suppression of synovitis rather than in general patient well-being. Overall, it appeared that tacrolimus was fairly effective in patients in whom the drug was tolerated.

Safety and tolerability data from this study were generally reassuring. A similar number of patients withdrew in each group due to adverse events (18 in the placebo group, 21 in the 2 mg/day group and 20 in the 3 mg/day group), although there were slightly more serious adverse events noted in the tacrolimus-treated than in the placebo-treated patients. As with previous studies of tacrolimus and in view of the known toxicity profile of its close relation, cyclosporin, attention was closely focused on hypertension and impairment in renal function. Effects on blood pressure appeared modest, with no clear evidence of dose-dependent toxicity. Increases in creatinine were common in tacrolimus-treated patients (29.1% of patients experienced ≥40% increase from baseline in the higher dose group); however, absolute levels of creatinine remained largely acceptable. One other common adverse event was tremor. The authors rightly point out that all these and other adverse events occurred at much lower rates in this trial than in transplantation trials, as might reasonably be expected with the lower dose of drug used.

One other trial of tacrolimus in RA was published at the end of last year by Kremer et al. [17]. This differed from the other studies in that tacrolimus was investigated as an adjunctive therapy in patients already established on methotrexate therapy. Patients were enrolled in the study if they had active disease despite ongoing oral methotrexate therapy and were simply treated on an open-label basis with the addition of tacrolimus 3 mg/day. As might be expected in an open-label trial, the response rates were higher than in other studies: ACR20, ACR50 and ACR70 response rates were 52.5, 28.8 and 13.8% respectively. Renal toxicity was less pronounced than may have been expected, with modest elevations in creatinine, which were reversible on discontinuation of the drug, and no significant effect on blood pressure was observed.

The present study represents the largest single investigation of the safety of tacrolimus therapy in RA to date [10]. Yocum et al. allowed 311 patients from their placebo-controlled trial [16] to roll over into this study and, in addition, recruited 585 new patients. This long-term safety study was designed as a 12-month, open-label assessment of the tolerability and safety of tacrolimus therapy in RA, using a dose of 3 mg/day with no additional DMARD therapy allowed. Of the initial 896 patients, 489 patients (54.6%) managed to complete the full year's treatment, giving a fairly large cohort for the study of the safety of this drug in RA. Around a fifth of patients withdrew due to adverse events and one in eight withdrew due to lack of efficacy. Only 2.7% of patients experienced serious adverse events, these being very varied, as detailed in the paper. One patient died during the study from pneumonia and renal failure, although the authors conclude that this was unrelated to the study drug. Clearly, longer-term surveillance is required to establish that there is no excess mortality associated with this therapy in RA. Once again, renal impairment was a common finding in this study and as many as 40% of patients experienced an increase of ≥30% in creatinine levels from baseline, although the absolute level of creatinine rarely gave cause for concern. Although hypertension was reported as an adverse event in 9.2% of patients, the mean systolic and diastolic blood pressures differed little, if at all, at the end of the study compared with baseline. As with other studies previously, drug-induced hyperglycaemia was rarely encountered.

Efficacy data from an open trial such as this must always be interpreted with caution. ACR20, ACR50 and ACR70 response rates in this trial are comparable to other studies, at 38.4, 18.6 and 9% respectively. It is interesting to note that they are a good deal lower than the results obtained by Kremer et al. in the trial of tacrolimus in combination with methotrexate. Once more it was observed that if a patient tolerated the drug well, he or she had a good chance of obtaining clinical benefit.

Tacrolimus is undoubtedly an effective T-cell-suppressive agent. Trial data so far indicate that it is effective to a degree in treating active synovitis in RA. The relative lack of a subjective benefit to the patient is, however, of concern. This will undoubtedly contribute to problems with tolerability and compliance and, together with concerns regarding toxicity, may limit the utility of this therapy in the clinic. Despite a lesser degree of renal impairment and hypertension than may have been anticipated, we must proceed with caution in using this drug outwith the confines of the clinical trial and in patients with a greater burden of comorbidity.

Tacrolimus may now be considered a realistic therapeutic option in the treatment of active RA. Its efficacy in monotherapy does, however, seem somewhat limited and perhaps the little evidence that we have regarding its use in combination with methotrexate may suggest to us that it is more attractive as a component for use in combination DMARD therapeutic strategies.

The authors have declared no conflict of interest.

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