Methotrexate and Leflunomide combination in RA/PsA: Is it safe? Save

I asked the EULAR twitter sphere how they feel about combination of Methotrexate (MTX) and Leflunomide (LEF). The opinions are differing so far, with 50% reporting prescribing this combination often while 50% are worried of side effects. In my practice, I have used it as a last resort in some cases with careful monitoring of side effects. Several abstracts presented this year are providing further data to help us make up our minds in RA and PsA.

In OP0195, Albuquerque and colleagues evaluated effects of the long-term use of combined MTX and LEF. To do so, they analysed data from the REAL observational cohort of 1115 RA patients. Twenty five percent had received MTX+LEF and 16% were receiving it at the time of the analysis. Over a cumulative time on MTX + LEF combination therapy of 24.5 months the authors did not observe differences in mean scores for liver fibrosis (FIB-4 & APRI). The authors also did not find significant correlation between the cumulative time of exposure to MTX + LEF and the fibrosis scores. However, current exposure to MTX + LEF was associated in multivariate analyses with higher ALT levels (adjustment on multiple parameters including diabetes although BMI did not seem to be one of them).

This is a slightly different story in PsA. You might have heard of the COMPLETE PsA trial, published in 2022, a RCT comparing MTX monotherapy and MTX + LEF. While the study showed greater improvement in disease activity according to PASDAS, MTX + LEF was also associated with higher risk of adverse events. In fact, the latest EULAR recommendations for PsA treatment do not recommend using the combination due to the low efficacy to safety ratio. In OP0106, Peeters and colleagues report the long-term outcomes of the COMPLETE PsA trial. Drug survival (tolerability) of combo MTX + LEF at 12 and 24 months follow-up was 35% and 27% vs. 46% and 33% for MTX monotherapy, respectively (ns). Reasons for discontinuation were inefficacy (26%) and tolerability (74%). The time to bDMARD initiation did not differ across groups.

Finally, in the observational registry study from Steinz and colleagues, presented in OP0192, amongst 5,500+ patients, 55% responded inadequately to MTX first line and 46% subsequently were prescribed >1 csDMARDs; 4% of which (n=19) received MTX + LEF. Interestingly, in this analysis, the average survival of an add-on csDMARD strategy (regardless of csDMARD added) was almost 2 times inferior to those who switched for another DMARD. Interestingly, LEF demonstrated significantly lower survival rates in both switch and add-on scenarios.

Overall, while the liver data seems reassuring, these studies do not commonly support the combination of MTX+LEF in RA or PsA patients due to low tolerance. I will definitely keep this combination in my therapeutic arsenal as a last resort in populations who need escalation and can’t receive bio/tsDMARDs.