Ankylosing Spondylitis AS M45. Psoriatic Arthritis PSA L405, M070, M071, M073. Systemic Lupus Erythematosus SLE M320, M321, M328, M329

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1 Appendix 1. Diagnosis codes according to International Classification of Disease version 10 (ICD 10) used to define rheumatoid arthritis (RA) and related diseases Diagnosis Abbreviation ICD 10 Rheumatoid Arthritis RA M05, M060, M062, M063, M068, M069, M123 Juvenile Idiopathic Arthritis JIA M08, M09 Ankylosing Spondylitis AS M45 Psoriatic Arthritis PSA L405, M070, M071, M073 Systemic Lupus Erythematosus SLE M320, M321, M328, M329

2 Appendix 2. Definitions, ICD codes and source of potential confounders used for statistical adjustments. Potential confounder Definition Source Country of birth Family history of melanoma Education level Co-morbidity ICD 7 Nordic; Other (including missing, 0.01%) Melanoma in biological parents, siblings or children 9 yrs (including missing, 12%); >9yrs National Population Register National Cancer Register The Multi-generation Register The Swedish Register of Education NMSC in situ 191 National Cancer register COPD Ischemic heart disease Diabetes mellitus, type 1&2 ICD 10 J41-J44 I20-I25 E10-E14 Surgical procedure codes Knee replacement surgery Hip replacement surgery NGB, , 8426 NFB, , 8419 NMSC= Non Melanoma Skin Cancer, Includes squamous cell carcinoma (97%) as well as other types of non-melanoma skin cancer (3%) but not basal cell carcinoma; COPD=Chronic obstructive pulmonary disease. The National Population Register, the National Cancer Register, and the National Inpatient and are described in the section Data sources, participants and variables. The Multi-generation Register contains all individuals registered in Sweden at any time since 1961 and those who were born in 1932 or later (index persons), with information on their biological parents. The register coverage of index persons is virtually complete and the share of index persons with links to both parents is above 80% 32. The Swedish Register of Education is updated annually and provides information on graduation and educational background data from 1985 and onwards 32. Less than 15% of our study population had missing/incomplete data on education.

3 Supplementary table A. Seminal studies of melanoma risk in rheumatoid arthritis (RA)-patients exposed to non-biologic DMARDs or biologics. Study, year of publication Setting and design Study time period RA study population Drug treatment Average follow-up N melanomas Relative risk of melanoma in patients with RA Gridley, 1993 Sweden; N=11683 Not specified (prebiologic era) 8,6 yrs 12 SIR: 0.9 ( ) Mellemkjaer, 1996 Denmark; Populationbased N=20699* Not specified (prebiologic era) 7,1 yrs 37 SIR: 1.1 ( ) Thomas, 2000 Scotland; N=7080 No specified (prebiologic era) 5,3 yrs 2 (men) 26 (women) SIR: 0.3 ( ) men 1.2 ( ) women Askling, Sweden; a) n=3703 and b) n=4160 (TNFi) a) biologics-naive b) TNFitreated a) 3,6-5,6yrs b) 2,3 yrs a) 124 b) 1 a) SIR: RA 1.2 ( ) and 0.9 ( ) b) HR: TNFi-treated versus biologics naive: 0.3 ( ) Setoguchi, 2006 US & Canada; Pooled RA : N=8458, 65 yrs and older Biologicstreated**: 14% MTX-treated: 86% Not stated 29 SIR RA, including biologicstreated: 2.3 ( ) Wolfe & Michaud, 2007 US N=13001; Biologicstreated**: 41%; MTX-treated: 57% Not stated 22 a) SIR RA, including biologics-treated: 1.7 ( ) b) RR TNFi and anakinra versus biologics-naive RA: 2.3 ( ). Abásolo, 2008 Spain N=789 Non-biological DMARDs 3,9 yrs 1 SIR: 3.8 ( ) Buchbinder, 2008 Australia; 1986 (latest) N= 458 Non-biologcal DMARDs, 100% MTXtreated 9.3 yrs 7 SIR: 3.0 ( ) Hellgren, 2010 Sweden Populationbased case-control N=6745 Unselected incident RA 0-10 yrs 11 RR 1.0 ( ) Perkins 2012 Review and Meta-analysis ,351,061 Person-yrs Non-biological DMARDs SIR 1.0 ( ) SIR= Standardized Incidence Ratio vs. the general population cancer incidence RR= Relative Risk HR= Hazard Ratio DMARD=disease-modifying antirheumatic drug, TNFi=Tumor Necrosis Factor inhibitor, MTX= Methotrexate, GenPop=General Population, Inc=Incident, Prev=Prevalent *Cohort includes patients with rheumatoid arthritis, juvenile rheumatoid arthritis and unspecified rheumatoid arthritis. ** Anakinra or (predominantly) TNFi-treated

4 Supplementary Table B. Hazard ratios (HR) and 95% confidence intervals (CI) of invasive melanoma in rheumatoid arthritis RA- patients initiating TNFi as first biologic (n=10,878, 38 melanomas), compared with 3 different definitions of rheumatoid arthritis patients not treated with biological drugs, and HR of invasive melanoma in the three s compared to the general population (GenPop). Biologics-naïve RA Comparator N patients N invasive melanoma s HR (95% CI) * TNFi vs. biologicsnaive comparator HR (95% CI) ** Biologics-naive comparator vs. GenPop comparator 1. DMARD «switchers» 4, ( ) 0.3 ( ) 2. «Stable» MTX users 27, ( ) 1.2 ( ) 3. First ever DMARD newstarter 8, ( ) 1.3 ( ) DMARD= Disease-Modifying Antirheumatic Drug. MTX=Methotrexate. * Stratified for inclusion-year and adjusted for sex, age, country of birth, personal history of non melanoma skin cancer in situ, family history of melanoma, education level and co-morbidities during follow-up (diabetes mellitus, ischemic heart disease, chronic obstructive pulmonary disease and joint surgery). ** Stratified for inclusion-year and adjusted for sex and age. 1. RA-patients with two or more visits listing RA in the Outpatient Register , initiating a new non-biologic DMARD after July 1st 2006, as noted in the Prescribed Drug Register which started in July (July 1 st July 1 st 2006 serving as baseline period). This definition is supposed to reflect RA-patients with unsatisfactory disease control, who change medical therapy, e.g., a new-user design. 2. RA-patients with two or more visits listing RA in the Outpatient Register , with two consecutive dispensings of methotrexate within 6 months as noted in the Prescribed Drug Register which started in July. This is supposed to reflect RA patients stable on methotrexate treatment. 3. RA-patients registered in the Swedish Rheumatology Quality register with new-onset RA (incident RA) who were followed from the initiation of their first non-biologic DMARD after RA diagnosis.

5 Supplementary Table C. Baseline predictors of invasive melanoma. Hazard Ratios (HR) and 95% confidence intervals (CI) of melanoma in TNFi-treated rheumatoid arthritis (RA)-patients in relation to characteristics at the start of TNFi. TNFi-treated RA (n=10,878) with HR (95% CI) treatment start between Male (vs. female) 2.2 ( ) Age (per year) 1.0 ( ) RA duration (per year) 1.0 ( )* Rf seropositive (75%) 1.0 (ref) Rfseronegative (15%) 1.2 ( ) Rf unknown/missing data (10%) 0.9 ( ) MTX (68%) 1.0 (ref) Non-biologic DMARD other than MTX 0.5 ( ) (8%) No non-biologic DMARD/missing data 0.4 ( ) (24%) Rf= Rhematoid factor; MTX= Methotrexate; DMARD=Disease-Modifying Antirheumatic Drug. Covariates were assessed within a two month interval from start of TNFi-therapy. For sex and age, there were no missing data. For RA duration 2% had missing data. *P=0.9