Methotrexate is currently the most widely used disease modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis and is generally considered the ‘gold standard’ therapy. Not only is it typically the first-line DMARD treatment but, if it fails and biologics are required, it is also the most common concomitant therapy given alongside biologics. 

However, there is a growing patient population for whom methotrexate is contraindicated. Unfortunately, the comorbidities that most commonly result in a patient not being able to take methotrexate - including diabetes, hypertension and renal disease - are currently on the rise. Consequently, research interest has recently shifted towards finding effective alternatives to methotrexate. 

The most common alternatives include hydroxychloroquine, sulfasalazine and leflunomide. In particular, new research interest has arisen in leflunomide and results suggest the drug may be more effective than previously believed.  

A recent study conducted by Katerina Chatzidionysiou from the Department of Rheumatology at Karolinska University Hospital in Stockholm (Sweden) in association with international colleagues has generated novel and somewhat unexpected results.  

The aim of the study was to compare the effectiveness and safety of rituximab alone or in combination with either methotrexate or leflunomide. The authors analysed anonymised datasets from 10 European registries submitted with baseline, 3-, 6-, 9- and 12-month clinical data from patients who had started rituximab. According to the collated data, 1,195 patients were treated with rituximab + methotrexate, 177 with rituximab + leflunomide, and 505 with rituximab alone. 

Results showed that significantly more patients achieved a European League Against Rheumatism (EULAR) good response at 6 months when treated with rituximab + leflunomide (29.1%) compared with rituximab + methotrexate (21.1%) and rituximab alone (19.3%; p=0.02 and p=0.01, respectively), and similar results were observed at 12 months. 

Adverse events occurred in 10.2%, 13.2% and 13.9% of patients on rituximab + leflunomide, rituximab + methotrexate and rituximab alone, respectively.

The authors concluded that these results show that leflunomide is an effective and safe alternative to methotrexate as a concomitant treatment with rituximab. Moreover, better results were obtained by the combination of rituximab and leflunomide than rituximab and methotrexate, raising the possibility of a synergistic effect of leflunomide and rituximab.

These results are important for two reasons. Firstly, they show that leflunomide is a safe and effective concomitant therapy with at least some biologics, a particularly important issue for those patients who cannot take methotrexate. Secondly, the analysis appears to suggest that leflunomide might in fact be more effective than methotrexate in the general patient population, when given alongside rituximab. These results require further follow-up with randomized clinical trials; however, their statistical significance clearly hints at a real phenomenon. If further studies confirm the effectiveness of leflunomide, doctors are likely to increase their appreciation and possible use of this drug.