Dear Editor,
Low-dose methotrexate is commonly prescribed for inflammatory disorders, and remains the cornerstone treatment for rheumatoid arthritis. Studies have reported an increased risk of melanoma with methotrexate exposure,1,2 but the evidence is inconclusive. To investigate the effect of methotrexate on incident cutaneous melanoma risk, we performed a secondary analysis of data from the ASpirin in Reducing Events in the Elderly (ASPREE) trial, a large primary prevention trial of daily aspirin.
Details of the trial methods have been published else-where.3 Briefly, 19,114 adults aged ≥70 years (≥65 years in Hispanic and African-American minority groups in the United States of America), who were free of cardiovascular disease, dementia and physical disability and had a life expectancy of at least 5 years were randomised to daily aspirin or placebo. Baseline medication use and self-reported indication was recorded and confirmed at in-person visits. During the trial, suspected cancer diagnoses, including in-situ and invasive melanoma, were adjudicated and confirmed by an expert panel.
In this analysis, methotrexate exposure was defined as use at baseline, and the outcome was cutaneous melanoma (in situ or invasive) occurring after randomisation, over a median follow-up of 4.7 years. Cox-proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) comparing exposed and unexposed participants. As a question of aetiological association was investigated in this study, cause-specific hazard ratios were estimated.4 Censoring occurred at time of melanoma event, death, or latest time point of contact, including medical record review.
Participant characteristics are shown in Table 1. At baseline, 196 individuals reported methotrexate use. This remained relatively constant, with 95% reporting ongoing use during their first annual visit, and 88% at their second annual visit. Self-reported indications included “rheumatoid arthritis”/“arthritis”(72%), “psoriasis”(4%), unknown (14%) and “other”(10%).
Table 1.
Baseline characteristics of all participants by methotrexate exposure status and incident melanoma events during the trial
| MTX-exposed, n = 196 n (%) |
MTX-unexposed, n = 18,918 |
|
|---|---|---|
| Age (years) | ||
| Median | 74 | 74 |
| Sex | ||
| Male | 75 (38) | 8257 (44) |
| Female | 121 (62) | 10661 (56) |
| Randomised trial arm | ||
| Aspirin, 100 mg daily | 104 (53) | 9421 (50) |
| Placebo | 92 (47) | 9497 (50) |
| Past history of melanoma† | ||
| Yes | 8 (4) | 677 (4) |
| No | 186 (96) | 18164 (96) |
| Family history of melanoma‡ | ||
| Yes | 6 (3) | 583 (3) |
| No | 190 (97) | 18334 (97) |
| Past history of cancer§ | ||
| Yes | 35 (18) | 3625 (19) |
| No | 159 (81) | 15216 (80) |
| Country | ||
| Australia | 183 (93) | 16520 (87) |
| USA | 13 (7) | 2398 (13) |
| Incident melanoma events during ASPREE | ||
| 8 (4) | 358 (2) | |
MTX (methotrexate), USA (United States of America).
Past personal history of melanoma data missing for 79 participants.
Family history of melanoma data missing for one participant.
Past history of cancer data missing in 22 participants and unknown in 57 participants.
During follow-up, 366 incident melanoma events occurred. Eight of the 196 methotrexate-users (4%) developed a melanoma, compared to 358 of 18,918 (2%) in the unexposed group. Methotrexate use was associated with an increased risk of incident melanoma, (HR 2.22, 95%CI 1.10 – 4.47, p = 0.03) and this remained after adjusting for age at randomisation, sex, past melanoma history, family melanoma history and intervention arm (HR 2.29, 95%CI 1.14 – 4.62, P = 0.02).
Our results suggest that methotrexate use in older individuals is associated with a more than two-fold increase in melanoma risk, consistent with a previous Australian study of 459 rheumatoid arthritis patients, which found a 3-fold increase in melanoma risk compared to the general population.1 Similarly, a Swedish study also found a small but significant increased risk amongst methotrexate users, and this risk was preserved only in women older than 70 years at commencement of use in a subgroup analysis.2 Another case-control study involving psoriasis patients found no greater history of methotrexate use in patients with, compared to without melanoma, although comparability with our predominantly rheumatoid arthritis-based usage cohort is limited.5
It has been suggested that methotrexate may have photosensitising properties.6 Similar to Buchbinder et al,1 we observed a heightened melanoma risk, which could be related to the higher levels of ambient ultra-violet radiation (UVR) in Australia, where the majority of participants were enrolled, and its possible immunomodulatory effects or interaction with methotrexate.7 An important consideration is also the intrinsic effect that underlying inflammatory disorders have in driving malignancy risk. We could not assess for confounding by indication as most participants were taking methotrexate for rheumatoid arthritis/arthritis.
Limitations of our study include the low number of melanoma events, lack of data around past methotrexate use, and data on specific melanoma risk factors such as sun exposure and naevus count. Residual confounding bias might exist as we did not consider methotrexate as a time-dependent exposure. Strengths include the large sample size, and the fact that all melanoma events were confirmed through adjudication.
Our results provide further impetus to examine the possible effects that methotrexate has on melanoma risk. Such findings have important clinical implications for risk assessment and skin cancer surveillance strategies.
ACKNOWLEDGEMENTS
We acknowledge the ASPREE Cancer Endpoint Adjudication Committee who reviewed and confirmed all cancer events. M.Y is supported by an Australian Government Research Training Program Scholarship. The ASPREE trial was supported by a grant (U01AG029824) and the extension study (ASPREE-XT) is supported by a grant (U19AG062682) from the National Institute on Aging and the National Cancer Institute at the National Institutes of Health, by grants (334047 and 1127060) from the National Health and Medical Research Council of Australia, and by Monash University and the Victorian Cancer Agency.
Footnotes
Conflicts of Interest: None.
Ethics approval status: Reviewed and approved by Monash University Human Research Ethics Committee. Project ID: 26001.
Clinical Trials Registration: clinicaltrials.gov identifier: NCT01038583, first posted: December 24, 2009.
REFERENCES
- 1.Buchbinder R, Barber M, Heuzenroeder L et al. Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis. Rheum 2008; 59: 794–9. [DOI] [PubMed] [Google Scholar]
- 2.Polesie S, Gillstedt M, Sönnergren HH et al. Methotrexate treatment and risk for cutaneous malignant melanoma: a retrospective comparative registry-based cohort study. Br. J. Dermatol 2017; 176: 1492–9. [DOI] [PubMed] [Google Scholar]
- 3.ASPREE Investigator Group. Study design of ASPirin in Reducing Events in the Elderly (ASPREE): A randomized, controlled trial. Contemporary Clinical Trials 2013; 36: 555–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Andersen PK, Geskus RB, de Witte T et al. Competing risks in epidemiology: possibilities and pitfalls. Int. J. Epidemiol 2012; 41(3): 861–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Polesie S, Gillstedt M, Paoli J et al. Methotrexate treatment for patients with psoriasis and risk of cutaneous melanoma: a nested case-control study. Br. J. Dermatol 2020; 183(4): 684–91. [DOI] [PubMed] [Google Scholar]
- 6.Chahidi C, Morliere P, Aubailly M et al. Photosensitization by methotrexate photoproducts. Photochem. Photobiol 1983; 38(3): 317–22. [DOI] [PubMed] [Google Scholar]
- 7.Bernard JJ, Gallo RL, Krutmann J. Photoimmunology: how ultraviolet radiation affects the immune system. Nat. Rev. Immunol 2019; 19(11): 688–701. [DOI] [PubMed] [Google Scholar]