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

Tumor necrosis factor i nhibitors (TNFi) h ave 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 investiga te 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 - naïve) to th e 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 o f malignant melanoma and all - site cancer in TNFi - treated RA - patients (1998 - 2010), biologics - naïve RA - patients, and matched general population comparators. We detected a 50% increased risk of invasive malignant melanoma, but no increased risk of in situ mel anoma or all - site cancer among TNFi - treated compared to biologics - naïve RA - patients.

In study II we investigated the risk of non squa mous cell cancer (SCC, 1998 - 2011 ) and b asal cell cancer (BCC, 2004 - 2011 ) in TNFi - treated RA - patients, biologics - naïve RA - pa tients, and matched general population comparators. We found a 20% increase in risk of in situ SCC among TNFi - treated compared to biologics - naïve RA - patients, but no increased risk of BCC. In biologics - naïve 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 RA - patients who started TNFi treatment (1999 - 2010) on average a decade after diagnosis of breast cancer. As comparator we used 120 biologics - naïve 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 g roups, 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 - naïve RA - patients. We used both a matched and an unmatched approach. No major differences in cancer stage at diagnosis or in post - cancer survival were observed among TNFi - treated RA - patients, compared to biologics - naïve RA - patients with cancer.

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.
https://doi.org/10.1136/bmj.f1939.

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 cancer- a nationwide population-based prospective cohort study from Sweden. [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. Ann Rheum Dis. 2015 Dec;74(12):2137-43.
https://doi.org/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.
https://doi.org/10.1002/art.30247.