Background/Purpose:  Methotrexate (MTX) and anti-TNF drugs have been hypothesized to increase the risk of a first non-melanoma skin cancer (NMSC). Among patients with prior NMSC, it is unknown what impact use of these medications has on a second NSMC.

Methods: We performed a cohort study using Medicare data from 2006-2011. We identified Caucasian patients with rheumatoid arthritis (RA) and a first recorded NMSC on the basis of a diagnostic code for NMSC and related surgical procedure within 60 days according to a validated algorithm. We assessed for MTX, anti-TNF, abatacept, and rituximab use before and after the initial NMSC diagnosis. Hydroxychloroquine and sulfasalazine (HCQ/SSA) were assessed as comparator therapies. We excluded individuals with HIV, organ transplant, xeroderma pigmentosa, albinism, and psoriasis. Follow-up began at the latest of either ≥1 year after the first NMSC surgery or a 6-month period without an NMSC diagnosis after surgery. The primary outcome was a second NMSC. Drug exposure was categorized as never, current, or recently discontinued after the start of follow-up. We adjusted for exposure to these drugs prior to incident NMSC. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals, adjusted for age, sex, latitude, urban or nursing home residence, and covariates assessed at baseline including comorbidities, glucocorticoids, actinic keratosis, and number of dermatology visits.

Results: 5994 individuals with RA had a first NMSC; 847 developed a second NMSC. Baseline actinic keratoses were more common in those with a second NMSC (65.2% vs 53.2%). Other baseline characteristics were similar. Current exposure to MTX was associated with a significantly increased risk of a second NMSC (Table 1). When stratified by concomitant exposure to anti-TNFs, SSA, or HCQ as background therapies, MTX use was consistently associated with a numerically but not statistically significant increased risk of a second NMSC. Risk of a second NMSC increased with longer duration of MTX exposure relative to no MTX exposure. Use of an anti-TNF, abatacept, or rituximab were not associated with an increased risk of second NMSC compared to those not using each agent,  with the exception of short-term anti-TNF use (HR 1.46, 95%CI 1.01-2.10).

Conclusion: Current MTX use increased the risk of a second NMSC among those with a prior NMSC. This association was not observed with anti-TNF drugs, rituximab, or abatacept.

Table 1: Impact of Current MTX on recurrent NMSC