OBJECTIVES: Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. METHODS: Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. RESULTS: Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). CONCLUSIONS: This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

Arthritis Research UK Centre for Epidemiology Manchester Academic Health Science Centre The University of Manchester Manchester UK

Arthritis Research UK Centre for Epidemiology Manchester Academic Health Science Centre The University of Manchester Manchester UK NIHR Manchester Musculoskeletal Biomedical Research Unit Central Manchester University Hospitals NHS Foundation Trust and University of Manchester Partnership Manchester UK

Clinical Epidemiology Unit Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Clinical Epidemiology Unit Department of Medicine Solna Karolinska Institutet Stockholm Sweden Department of Rheumatology Karolinska University Hospital Stockholm Sweden

Department of Rheumatology Herlev and Gentofte University Hospital Hellerup Denmark The Parker Institute Bispebjerg and Frederiksberg University of Copenhagen Copenhagen Denmark

Department of Rheumatology Teaching Hospital of Lapeyronie and University of Montpellier Montpellier France

Epidemiology Unit German Rheumatism Research Centre Berlin Germany

Epidemiology Unit German Rheumatism Research Centre Berlin Germany Charité University Medicine Berlin Berlin Germany

Institute of Rheumatology Prague Czech Republic 1st Faculty of Medicine Charles University Prague Prague Czech Republic

Rheumatology Department National Center for Rare Systemic Autoimmune Diseases Hôpitaux Universitaires de Strasbourg CNRS Institut de Biologie Moléculaire et Cellulaire Immunopathologie et Chimie Thérapeutique Laboratory of Excellence Medalis Université de Strasbourg Strasbourg France

Rheumatology Department Université Paris Sud AP HP Hôpitaux Universitaires Paris Sud INSERM U1184 Center for Immunology of Viral Infections and Autoimmune Diseases Le Kremlin Bicêtre France

Rheumatology Division University of Geneva Geneva Switzerland

Rheumatology Research Unit Rheumatology Department Instituto de Medicina Molecular Faculdade de Medicina Universidade de Lisboa Lisbon Portugal CHLN Santa Maria Hospital CAML Lisbon Portugal

Rheumatology Unit DIM University of Bari Bari Italy

The DANBIO registry and Copenhagen Center for Arthritis Research Center for Rheumatology and Spine Diseases Rigshospitalet Glostrup and second affiliation Hetland Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

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$a OBJECTIVES: Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. METHODS: Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. RESULTS: Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). CONCLUSIONS: This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

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$a Raaschou, Pauline $u Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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$a Strangfeld, Anja $u Epidemiology Unit, German Rheumatism Research Centre, Berlin, Germany.

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$a Mariette, Xavier $u Rheumatology Department, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, INSERM U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin-Bicêtre, France.

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$a Hyrich, Kimme L $u Arthritis Research UK Centre for Epidemiology, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK. NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester Partnership, Manchester, UK.

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