Say Goodbye to Methotrexate in PMR? Save

For decades, glucocorticoids (GCs) have formed the backbone of polymyalgia rheumatica (PMR) management. Whilst previously there was a sense that a “low” GC dose with limited duration was used, we now appreciate just how heterogenous the disease course of PMR can be, with many patients experiencing frequent relapses and garnering a subsequent huge GC burden over a number of years. This is a cause of significant concern, especially in this older vulnerable cohort of patients.

Despite mixed results on its clinical efficacy in three previous randomised controlled trials (RCTs)1-3, methotrexate is considered the most widely used GC sparing agent. Prior to the RCTs on interleukin 6 antagonists, its use was perhaps justified by many due to the paucity of alternative positive studies. Moreover, the poor methodological quality and low methotrexate doses of ≤10mg used in the aforementioned trials resulted in much uncertainty.

Therefore the results of the PMR-MODE trial (Abstract 1697) have been highly anticipated.

This 52 week double blinded placebo controlled RCT included 64 recently diagnosed PMR patients who had been treated for less than 8 weeks with GC, and were randomised to either 25mg/week methotrexate or placebo. 56 patients were included in the final analysis and the primary outcome of GC-free remission with a PMR-activity score of <10 at week 52, did not differ significantly between groups – 67% in the placebo group compared to 68% in the methotrexate group.

The secondary outcomes also did not show significant differences between groups, with a median (IQR) cumulative GC dose at 52 weeks of 2081mg (1873-2606) in the placebo group versus 2063mg (1660-2623) in the methotrexate group, and both groups having a relapse incidence rate per patient per year of 1.3.

Although small, this RCT seems to confirm the suspicion we have had for some time – that methotrexate is not an effective GC sparing agent in the management of PMR, and that we should reconsider its position in the therapeutic algorithm of PMR.

This is further emphasised in Abstract 1700, which uses health plan claims data to compare the effectiveness of sarilumab versus methotrexate as a GC sparing agent in patients with PMR. After deriving a comparable cohort, 210 patients initiating sarilumab versus methotrexate were matched. Those able to discontinue GCs within 6 months, was numerically higher for sarilumab (59%) versus methotrexate (35%) users.

Moreover, those in the sarilumab group required fewer median (IQR) days on GCs: 122 (61,195) days compared to  methotrexate 227 (131,287) days, and a numerically lower median (IQR) cumulative dose of GCs: 679mg (440, 1005)  compared to  methotrexate 867mg (523, 1248). Although preliminary results, this study indicates that sarilumab is more effective than methotrexate as a GC sparing agent.

Whilst studies like this on methotrexate would once herald frustration due to the limited therapeutic alternatives, the promising results of interleukin 6 antagonists represent the movement towards more efficacious and meaningful therapies for our patients.

Both of the discussed abstracts (1697 and 1700) will be presented at the abstract session on Sunday 17th November on clinical trials in non-ANCA associated vasculitis.

1. Caporali R, Cimmino MA, Ferraccioli G, et al. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine 2004;141(7):493-500.

2. Van der Veen M, Dinant H, van Booma-Frankfort C, van Albada-Kuipers G, Bijlsma J. Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis? Annals of the Rheumatic Diseases 1996;55(4):218-223.

3. Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. The Journal of Rheumatology 1996;23(4):624-628.