Anti-TNF therapy and malignancy in patients with rheumatoid arthritis : studies on cancer incidence, recurrence and survival

Tumor necrosis factor inhibitors (TNFi) have become a backbone treatment of rheumatoid arthritis (RA). TNF has multiple and incompletely understood functions in tumor biology, and cancer is considered a potential adverse event of TNFi treatment. The overarching aim of this thesis was to investigate the risk-benefit balance in RA-patients treated with TNFi, focusing on skin cancer, breast cancer progress and post-cancer survival. To put the risks into context we also contrasted RA-patients never treated with biological drugs (biologics-naive) to the general population. We used data from medical files, national health and census registers and the RA quality of care register, to define clinically relevant subsets of RA and cancer-related outcomes among them. In study I we investigated the risk of malignant melanoma and all-site cancer in TNFi-treated RA-patients (1998-2010), biologics-naive RA-patients, and matched general population comparators. We detected a 50% increased risk of invasive malignant melanoma, but no increased risk of in situ melanoma or all-site cancer among TNFi-treated compared to biologics-naive RA-patients. In study II we investigated the risk of non squamous cell cancer (SCC, 1998-2011) and basal cell cancer (BCC, 2004-2011) in TNFi-treated RA-patients, biologics-naive RA-patients, and matched general population comparators. We found a 20% increase in risk of in situ SCC among TNFi-treated compared to biologics-naive RApatients, but no increased risk of BCC. In biologics-naive RA-patients, we detected a doubled risk of SCC, and a 20% increased risk of BCC compared to the general population. In study III we investigated the risk of breast cancer recurrence in 120 female RApatients who started TNFi treatment (1999-2010) on average a decade after diagnosis of breast cancer. As comparator we used 120 biologics-naive RA-patients with a history of breast cancer, matched on sex, age, year and cancer stage at diagnosis, and residency. We found no difference in risk of recurrent breast cancer and all-cause mortality between the two groups, after adjusting for breast cancer related prognostic factors. In study IV we investigated the clinical stage at diagnosis, and post-cancer survival of cancers developing during or after TNFi treatment (1999-2007), compared to cancers among biologics-naive RA-patients. We used both a matched and an unmatched approach. No major differences in cancer stage at diagnosis or in postcancer survival were observed among TNFi-treated RA-patients, compared to biologics-naive RA-patients with cancer. Pauline Raaschou 2014 LIST OF SCIENTIFIC PAPERS I. Pauline Raaschou, Julia F Simard, Marie Holmqvist, Johan Askling, For the ARTIS study group. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population-based prospective cohort study from Sweden. BMJ 2013 Apr; 346, fl939 II. Pauline Raaschou, Julia F Simard, Charlotte Asker-Hagelberg, Johan Askling for the ARTIS study group. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of squamous cell and basal cell skin cancera nationwide populationbased prospective cohort study from Sweden In manuscript III. Pauline Raaschou, Thomas Frisell, Johan Askling for the ARTIS study group TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis -a nationwide cohort study. ARD Online First, published on August 8, 2014 as 10.1136/annrheumdis-2014-205745 IV. Pauline Raaschou, Julia F Simard, Martin Neovius, Johan Askling, For the ARTIS study group Does cancer that occurs during or after anti-TNF therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologics. Arthritis & Rheumatism 2011 Jul; 63(7): 1812-22 Pauline Raaschou 2014 CONTENTS