No significant differences in the incidence rates of invasive cutaneous malignant melanoma in biologic-naïve patients and biologic-exposed patients with rheumatoid arthritis (RA) taking tumor necrosis factor inhibitors (TNFis) were detected by researchers combining data from several large biologic registers included in the European League Against Rheumatism Registers and Observational Drug Studies (RODS).1

Conflicting reports of the association between conventional synthetic and biologic disease modifying antirheumatic drugs (DMARDs) and increased risk of malignancy, including melanoma, have been published.2   Researchers thus sought to determine comparative rates of invasive melanoma in patients with RA receiving various DMARDs to those in the general population in Europe.

High Yield Data Summary

  • No significant increases in age and sex standardized incidence ratios of invasive melanoma were found between biologic-naïve patients and patients exposed to TNFis, RTX, ABT or TOC

Inclusion into this pooled analysis required patients with RA to be prospectively enrolled into one of the participating European biologic registers.  Patients with a prior history of invasive melanoma were excluded from data analysis to prevent possible confounding by the appearance of recurrent melanoma. 

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Separate cohorts of patients were created, including patients who were biologic-naïve, patients treated with TNFis, rituximab (RTX), tocilizumab (TOC), and abatacept (ABT).  

Mean length of follow-up or exposure times to either TNFis, biologic, and synthetic DMARDs were not differentiated in the cohorts based on prior studies that did not show an association between melanoma rates and exposure times.3

In those patients who were biologic-naïve at time of registry enrollment, exposure time started at point of registration, and subsequently censored at first occurrence of invasive melanoma, patient death, end of follow-up, or the date of receiving a first biologic drug, whichever event occurred first.

In those patients in the TNFi cohort, prior exposure to biologic drugs, with the exception of anakinra, was not permissible. An ‘ever-exposed’ approach was defined, and used in the primary analysis to contribute to total follow-up time from the first dose of TNFi drug after registry inclusion until occurrence of invasive melanoma, death, or end of follow-up period. 

These exposure definitions were also applied to those patients included in the RTX, TOC, and ABT cohorts. 

A general population register specific to each country was used as reference, and was stratified to age, sex, and calendar year. This data was used to generate standardized incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma. Pooled SIR and incidence rate ratios (IRRs) were then used to compare the biologic and biologic-naïve cohorts, accounting for the varying sizes of the registries into account.

A total of 130 315 patients with RA, mean age of 58 years, from 11 registers contributed to 579 983 patient-years statistically analyzed in this study.  Across all treatment groups, the incidence of invasive melanoma was slightly higher in patients with RA compared to the corresponding country-specific general populations. 

The pooled SIR for invasive histology-confirmed cutaneous melanoma  for the biologic-naïve cohort was 1.1 (95% confidence interval [CI] 0.9 to 1.4). The corresponding pooled SIR for the TNFi cohort was 1.2 (95% CI 0.99 to 1.6). The pooled SIR for the RTX cohort was 1.3 (95% CI 0.6 to 2.6).

Summary and Clinical Applicability

Analysis of pooled data from several large European registries did not confirm findings from prior studies that suggested there was an increased risk of melanoma in patients with RA who were treated with TNFis.  

No significant increases in age and sex standardized incidence ratios of invasive melanoma were found between biologic-naïve patients and patients exposed to TNFi, RTX, ABT, or TOC. 

“We detected no systematic heterogeneity between the country-specific SIRs… [and] conclude that this large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi[s],” the authors concluded.

Limitations and Disclosures

Smaller sample sizes of the subcohorts of TNFi-exposed patients have to be noted. Additionally, “the SIR for melanoma risk in TNFi-treated patients was numerically higher, although not statistically different, when limited to countries with linkage to cancer registries [raising] the possibility that ascertainment of melanoma cases was incomplete in other registries,” the authors cautioned.

Individual registries were funded by AbbVie, BMS, MSD, Pfizer, Roche, UCB. These companies were not involved, however, in the planning of this research, the statistical analyses, or the interpretation of the results.

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1.   Mercer LK, Askling J, Raaschou P, et al. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers. Ann Rheum Dis. 2016; Published online ahead of print June 15, 2016. doi:10.1136/annrheumdis-2016-209285

2.   Dreyer L, Mellemkjaer L, Andersen AR, et al. Incidences of overall and site specific cancers in TNFalpha inhibitor treated patients with rheumatoid arthritis and other arthritides—a follow-up study from the DANBIO Registry. Ann Rheum Dis 2013;72: 79–82.

3.   Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from SwedenBMJ 2013;346:f1939.