https://orcid.org/0000-0002-1645-5582
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Abstract
Purpose
Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level.
Patients and Methods
In the Cancer Registry of Norway, we identified all cases aged 18–85 with a first primary cutaneous melanoma diagnosed in 2007–2015 (n=12,106). These were matched to population controls from the Norwegian National Registry 1:10 (n=118,564), on sex and year of birth using risk set sampling. Information on prescribed drugs (2004–2015) was obtained by linkage to the Norwegian Prescription Database (NorPD). Conditional logistic regression was used to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for associations between use of immunomodulating drugs (immunosuppressants and corticosteroids) and melanoma risk, adjusted for ambient UVR and other drug use.
Results
Compared with ≤1 prescription, use of ≥8 prescriptions of immunosuppressants was associated with increased risk of melanoma (RR 1.50, 95% CI 1.27, 1.77). Similar associations were found for subgroups of immunosuppressants: drugs typically prescribed to organ transplant recipients (OTRs) (RR 2.02, 95% CI 1.35, 3.03) and methotrexate (RR 1.27, 95% CI 1.04, 1.55). Similar results were found for high levels of cumulative doses and across all histological subtypes. Use of corticosteroids was not associated with melanoma risk.
Conclusion
We found a positive association between use of immunosuppressants and melanoma risk, with the highest risk seen for drugs prescribed to OTRs. Knowledge about this risk increase is important for physicians and users of these drugs, for intensified surveillance, awareness and cautious sun exposure.
Abbreviations
All are defined in full at their first instance in the text: ATC, anatomical therapeutic chemical; CI, confidence interval; CRN, Cancer Registry of Norway; DDD, defined daily doses; ICD-O-3, International Classification of Diseases of Oncology 3rd edition; ICD-10, International Classification of Diseases 10th Revision; NM, nodular melanoma; NorPD, Norwegian Prescription Database; OTR, organ transplant recipient; PIN, personal identification number; RR, rate ratio; SSM, superficial spreading melanoma; UVR, ultraviolet radiation.
Data Sharing Statement
The data are available as presented in the paper. According to Norwegian legislation, our approvals to use the data for the current study do not allow us to distribute or make the data directly available to other parties.
Ethics Approval
The study is approved by the Norwegian Data Protection Authority and the Regional Committee for Medical and Health Research Ethics. The study is also approved by the national registries contributing with data; CRN, the National Registry, NorPD and the Medical Birth Registry. The linkage key for the 11-digit PINs was stored and governed by a third party unavailable to the research team. All data management and analyses were conducted on data with no individual person identified. This case-control study utilized only data from nationwide population-based registers and thus did not include a recruitment process for patients, who were not involved in either the design or conduct of the study. Thus, the research question and outcome measures were not informed by any specific patient priorities, experiences or preferences. Rather, their formulation was based upon our own priorities for patient benefit and result interpretation. All results are distributed on a group level, without any possibilities for individual identification.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
Øystein Karlstad participates in two Post-Authorization Safety Studies (PASS) unrelated to the submitted work. The studies are on an antidiabetic drug and an anti-psoriasis drug and have been imposed by the European Medicines Agency (EMA). The studies are funded by the marketing authorization holders (Novo Nordisk and Leo Pharma) and are conducted according to the EnCePP Code of Conduct for scientific independence and transparency. The authors report no other potential conflicts of interest related to this work.