Methotrexate in Polymyalgia Rheumatica: Kernel of Truth or Curse of Tantalus?

In Greek mythology, King Tantalus, a son of Zeus, was a mortal favored by the gods. Invited to share ambrosiafood of the godsTantalus committed some unspecified breach of protocol, leading swiftly to his downfall. The unfortunate king was consigned to the lower world, there to undertake his punishment: eternal immersion in water up to his neck. More diabolically, whenever Tantalus tilted his head to drink, the water drained away. Although luscious fruit hung above him on trees, whenever he extended his arms to grasp it, winds blew the branches beyond reach. From Tantalus's name comes the English verb tantalize. In this issue, readers must decide whether Caporali and colleagues' randomized, double-blind, placebo-controlled trial of methotrexate in polymyalgia rheumatica (1) reveals a kernel of truth about methotrexate or bespeaks the curse of Tantalus: a desirable result placed just beyond the reach of those who would grasp it. Few treatment responses in medicine rival the improvement in polymyalgia rheumatica wrought by prednisone. Regrettably, in some patients, repeated treatment courses necessitated by flare-ups engender long-term frustrations (and side effects) whose intensity may surpass even the exhilaration of those first days of prednisone therapy. Eventually, because of adverse glucocorticoid effects, some patients wonder whether the prescribed treatment is not closer to punishment than panacea. Rheumatologists have long sought a drug that would allow them to control polymyalgia rheumatica with less prednisone. Methotrexate has been their main hope. Research on the potential efficacy of methotrexate's steroid-sparing effects in polymyalgia rheumatica and a related disorder, giant-cell arteritis, has been frustratingly inconclusive. In polymyalgia rheumatica, some studies have hinted at efficacy, yet the only previous randomized, controlled trial was negative (2). In 1 randomized trial studying giant-cell arteritis, Jover and coworkers (3) found that the combination of methotrexate and prednisone decreased glucocorticoid use and was more effective than prednisone alone for disease control. In contrast, another giant-cell arteritis trial by Hoffman and associates (4), which enrolled more than twice the number of patients and used higher methotrexate doses, was negative. The reasons for these disparate results are unknown (5), but a careful reading of the 2 studies provides a glimmer of hope for methotrexate. Jover and coworkers (3) observed a steroid-sparing effect of methotrexate only after 1 year of treatment. In contrast, Hoffman and associates (4) terminated follow-up after 12 months because of many treatment failures in the methotrexate group. Yet an interesting finding emerged from a secondary analysis in Hoffman and associates' study: In the methotrexate group, fewer disease flare-ups presented as polymyalgia rheumatica (4). These threads of data have sustained hope for methotrexate and paved the way for Caporali and colleagues' study in this issue (1). Caporali and colleagues (1) randomly assigned 72 patients with newly diagnosed polymyalgia rheumatica to receive prednisone (25 mg/d, tapered to 0 mg/d within 24 weeks) plus either oral methotrexate (10 mg/wk) or placebo. Thirty-six patients were randomly assigned to each group. The principal outcome measures were the proportion of patients no longer taking prednisone, the number of disease flare-ups, and the cumulative prednisone doses at 76 weeks. From the outset, the authors' decisions about the study design reflected optimism. Several design features placed the trial at risk for missing modest but potentially important methotrexate effects. To justify a relative small sample size, for example, the investigators assumed a very large effect size (a doubling of the percentage of patients no longer taking prednisone in the methotrexate group). Furthermore, compared with doses now used to treat many inflammatory diseases (6, 7), the dosage of methotrexate used (10 mg/wk) was low. Finally, plans for measuring the primary outcomes were unusually stringent: The protocol specified stopping methotrexate therapy at 48 weeks, yet the authors did not assess the primary outcomes until 7 months later (week 76). Nevertheless, at first glance, the study results are tantalizing indeed. Patients in the methotrexate group were more successful in discontinuing prednisone therapy, had fewer disease flare-ups, and required a lower cumulative prednisone dose. Several issues, however, militate against full acceptance of methotrexate plus prednisone as a new standard of care. First, for unclear reasons, the prednisone-only group fared surprisingly poorly in this trial. In only 76 weeks of follow-up, 73% had disease flare-ups (the authors expected a flare-up rate of 60%). Second, patients in the methotrexate group had fewer flare-ups during weeks 48 to 76 (when they were not taking methotrexate) than they did during weeks 24 to 48 (while they were still taking the drug): 4 flare-ups versus 10. Although this finding may be explained by chance, the suggestion of a sustained effect after withdrawal of methotrexate strains biological plausibility and has little precedent in rheumatologic disease. Third, given the background of inconsistent results in previous studies, we should be cautious about acting on the conclusions from this trial (or any single trial). The only other randomized, controlled trial in polymyalgia rheumatica showed no effect of methotrexate (2). Using a dosage only 2.5 mg/wk higher, Caporali and colleagues observed important clinical effects. We should accept with caution the implication that an additional 2.5 mg of methotrexate per week could effect such dramatically different outcomes until this finding is confirmed by other investigations. Fourth, although the between-group comparison of cumulative glucocorticoid doses was statistically significant in favor of methotrexate, its clinical significance is not clear. The methotrexate group took less prednisone (83.5 g vs. 96.6 g) but did not have less steroid-related morbidity. The mean reduction in daily prednisone dosage in the methotrexate group amounted to just over 1 mg/d. Even in a substantially longer study, one would not expect measurable clinical benefits from such a small dose reduction. Finally, Caporali and colleagues' study confirms that methotrexate is much less effective than prednisone itself and begs the question: Is the potential bother of methotrexate really worth it? Most patients in both groups (besides 2 in the methotrexate group) achieved disease control within 4 weeks. This effect is due to prednisone. Indeed, during the first 24 weeks, when all patients were taking prednisone, the number of disease flare-ups did not differ between groups (7 in the methotrexate group vs. 8 in the placebo group). After prednisone was withdrawn, 15 disease flare-ups (in 10 patients) occurred in the methotrexate group over only 24 weeks. Given these findings and the failure of methotrexate to ameliorate prednisone-associated morbidity, the advantage of adding methotrexate to prednisoneas opposed to simply continuing prednisone at the lowest effective doseis unclear. This is particularly true if the lowest effective dose of prednisone is 5 mg or less. This trial raises several tantalizing questions: Would a higher dose of methotrexate have had a more convincing effect? Alternatively, might a higher dose of methotrexate have caused more adverse events (for example, gastrointestinal intolerance) that decreased its tolerability? Would longer follow-up have demonstrated not only a reduction in cumulative prednisone dosage but also a decrease in steroid-associated morbidity? Or might additional time have eroded the effect of methotrexate, particularly if the drug were withdrawn (as in this protocol)? What is the bottom line here? Is this truth or the curse of Tantalus? I favor the latter. If there is a kernel of truth to the claim that methotrexate is effective in polymyalgia rheumatica, it is small and does not yet warrant acceptance of this therapy as the standard of care. In my own practice, I will consider using methotrexate in patients with polymyalgia rheumatica who do not tolerate even low doses of glucocorticoids. Even then, I will caution them about the high risk for disease flare-ups after stopping prednisone therapy. Although the trial by Caporali and colleagues contributes meaningfully to the conversation about the role of the steroid-sparing effects of methotrexate in polymyalgia rheumatica, it does not slake our thirst for an effective alternative to prednisone.