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Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f1939 (Published 08 April 2013) Cite this as: BMJ 2013;346:f1939
  1. Pauline Raaschou, consultant in clinical pharmacology12,
  2. Julia F Simard, assistant professor1,
  3. Marie Holmqvist, resident1,
  4. Johan Askling, professor and consultant in rheumatology13
  5. for the ARTIS Study Group
  1. 1Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, SE-171 76, Stockholm, Sweden
  2. 2Clinical Pharmacology Unit, Department of Medicine Solna, Karolinska Institutet
  3. 3Rheumatology Unit, Department of Medicine Solna, Karolinska Institutet
  1. Correspondence to: P Raaschou pauline.raaschou{at}karolinska.se
  • Accepted 6 March 2013

Abstract

Objectives To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis.

Design Population based cohort study.

Setting Prospectively recorded data from national clinical, health, and demographic registers in Sweden 2001-10.

Patients with rheumatoid arthritis treated (n=10 878) or not (n=42 198) with TNF inhibitors and matched general population comparators (n=162 743).

Main outcome measures The primary outcome was first invasive melanoma in people without any history of invasive cancer of any type. Hazard ratios were estimated using Cox regression, comparing non-biological drug treated rheumatoid arthritis patients with the general population comparator and TNF inhibitor treated rheumatoid arthritis patients with those not treated with biological drugs. Secondary outcomes included in situ melanomas, second primary melanomas, and all site cancer.

Results 113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100 000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n=3 v 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs.

Conclusion Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons.

Footnotes

  • Contributors: PR, JFS, MH, and JA all contributed to the acquisition and analysis of the data and the drafting of the manuscript. JA is the guarantor.

  • The ARTIS Study Group comprises Eva Baecklund, Lars Coster, Helena Forsblad, Nils Feltelius, Pierre Geboreck, Lennart Jacobsson, Lars Klareskog, Staffan Lindblad, Solbritt Rantapaa-Dahlqvist, Tore Saxne, and Ronald van Vollenhoven.

  • Funding: This study was supported by public grants from the Swedish Cancer Society, the Swedish Research Council, Stockholm County Council, and the Swedish Foundation for Strategic Research. The ARTIS Study Group conducts scientific analyses using data from the Swedish biologics register ARTIS run by the Swedish Society for Rheumatology. For the maintenance of this register, the Swedish Society for Rheumatology has received funding, independent of the conduct of these scientific analyses, from Merck, BMS, Pfizer, Abbott Laboratories, SOBI, UCB, and Roche. These entities had no influence on the data collection, statistical analyses, manuscript preparation, or decision to submit. They were allowed to comment on the findings before submission, although all final decisions resided with the investigators.

  • All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: JA has received research grants from Pfizer and Astra-Zeneca as part of a public-private research consortium (COMBINE, www.combinesweden.se) and speakers’ honorariums from Merck; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: The study was approved by the ethics committee at Karolinska Institutet.

  • Data sharing: No additional data available.

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