The relationship between cancer and medication exposures in systemic lupus erythaematosus: a case–cohort study S Bernatsky, 1 L Joseph, 2 J-F Boivin, 1 C Gordon, 4 M Urowitz, 5 D Gladman, 5 P R Fortin, 5 E Ginzler, 6 S-C Bae, 7 S Barr, 8 S Edworthy, 8 D Isenberg, 9 A Rahman, 9 M Petri, 10 G S Alarco ´n, 11 C Aranow, 12 M-A Dooley, 13 R Rajan, 14 J-L Se ´ne ´cal, 15 M Zummer, 16 S Manzi, 17 R Ramsey-Goldman, 18 A E Clarke 2 1 Division of Clinical Epidemiology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; 2 Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada; 3 Department of Rheumatology, University of Birmingham, UK; 4 Division of Health Care & Outcomes Research, Toronto Western Research Institute, Toronto, Ontario, Canada; 5 Division of Rheumatology, Department of Medicine, SUNY Health Science Center at Brooklyn, New York, USA; 6 Department of Internal Medicine, Division of Rheumatology, Hanyang University College of Medicine and the Hospital of Rheumatic Diseases, Seoul, Korea; 7 Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; 8 Centre for Rheumatology Research - Department of Medicine, University College London, UK; 9 Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA; 10 Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, Alabama, USA; 11 Department of Medicine, Columbia University, New York, USA; 12 Department of Medicine, Thurston Arthritis Research Center, The University of North Carolina at Chapel Hill, North Carolina, USA; 13 Department of Oncology, McGill University Health Centre, Montreal, Quebec, Canada; 14 Division of Rheumatology, Centre Hospitalier de l’Universite de Montreal, Department of Medicine, University of Montreal School of Medicine, Montreal, Quebec, Canada; 15 Department of Rheumatology, Maisonneuve- Rosemont Hospital, Montreal, Quebec, Canada; 16 Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 17 Division of Rheumatology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA Correspondence to: Dr Sasha Bernatsky, Division of Clinical Epidemiology, McGill University Health Centre, 687 Pine Avenue West, V-Building, Montreal, Que ´bec H3A 1A1, Canada; sasha.bernatsky@mail. mcgill.ca Note: AEC and RRG made equal contributions as senior authors Accepted 7 May 2007 Published Online First 31 May 2007 ABSTRACT Objective: To examine if, in systemic lupus erythaema- tosus (SLE), exposure to immunosuppressive therapy (cyclophosphamide, azathioprine, methotrexate) increases cancer risk. Methods: A case–cohort study was performed within a multi-site international SLE cohort; subjects were linked to regional tumour registries to determine cancer cases occurring after entry into the cohort. We calculated the hazard ratio (HR) for cancer after exposure to an immunosuppressive drug, in models that controlled for other medications (anti-malarial drugs, systemic gluco- corticoids, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin), smoking, age, sex, race/ethnicity, geographic location, calendar year, SLE duration, and lupus damage scores. In the primary analyses, exposures were treated categorically (ever/never) and as time- dependent. Results: Results are presented from 246 cancer cases and 538 controls without cancer. The adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI 0.50–1.36). Age >65, and the presence of non-malignancy damage were associated with overall cancer risk. For lung cancer (n = 35 cases), smoking was also a prominent risk factor. When looking at haemato- logical cancers specifically (n = 46 cases), there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02–5.15). Conclusions: In our SLE sample, age >65, damage, and tobacco exposure were associated with cancer risk. Though immunosuppressive therapy may not be the principal driving factor for overall cancer risk, it may contribute to an increased risk of haematological malignancies. Future studies are in progress to evaluate independent influence of medication exposures and disease activity on risk of malignancy. In many types of systemic autoimmune diseases, including systemic lupus erythaematosus (SLE), there is increasing evidence that cancer (particu- larly haematological and lung cancers) contributes to both morbidity and mortality. 1–4 The most definitive data regarding cancer risk in SLE was generated from our recent large, multi-centre, international cohort study (9547 patients at 23 centres). 1 This confirmed a slight increased risk for all cancers combined, and a striking increased risk for haematological malignancies, where the standardised incidence ratio (SIR) estimate was 2.75 (95% CI 2.13–3.49). The data also suggested an increased risk of lung cancer (SIR 1.37, 95% CI 1.05–1.76). Is this cancer susceptibility caused by immuno- suppressive drugs? Despite case reports, data from animal models of lupus, 5 and studies of organ transplant recipients, 67 there is no convincing evidence of this relationship in SLE. 8–13 In fact, in our cohort study, the highest SIRs occurred in the first year of SLE duration, suggesting that cancer risk is not completely explained by cumulative exposure to immunosuppressive drugs. Our objective, therefore, was to determine if, in SLE, exposure to immunosuppressive drugs (speci- fically cyclophosphamide, azathioprine, and meth- otrexate) increases the overall risk of cancer. We also performed separate analyses for haematologi- cal cancer and for lung cancer, given the particular increased risk of these two cancer types. 14 METHODS We conducted a case–cohort study within the previously mentioned multi-site SLE cohort, 4 with the participation of 15 collaborating centres in North America, Europe and Asia. These centres represented two research networks, the Systemic Lupus International Collaborating Clinics (SLICC) and the Canadian Network for Improved Outcomes in Systemic Lupus. Included were three centres from Montreal; one centre from each of Toronto, and Calgary; two New York City sites; one centre each from Pittsburgh, Chicago, Baltimore, Chapel Hill North Carolina, and Birmingham Alabama; and one centre each from London, UK, Birmingham, UK, and Seoul, Korea. We used the case–cohort study design for optimal flexibility and efficiency; in this design, exposure and covariate information is collected from all cases, and a random representative sample of the cohort (‘‘subcohort’’; in our case, 10% of the full cohort), which is the source for controls. All of our study subjects were patients with definite SLE (according to American College of Rheumatology (ACR) 14 15 or clinical criteria). Cancer cases were ascertained by regional cancer registry linkages. Cases refer to invasive cancers discovered after entry into the lupus cohort at each centre; the index time for each risk (case–control) set was the date of the case’s cancer occurrence. The controls Extended report 74 Ann Rheum Dis 2008;67:74–79. doi:10.1136/ard.2006.069039