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  1. S. Swain1,
  2. A. Kamps2,
  3. J. Runhaar3,
  4. A. Dell’Isola4,
  5. A. Turkiewicz4,
  6. D. E. Robinson5,
  7. V. Y. Strauss5,
  8. C. Mallen6,
  9. C. F. Kuo7,
  10. C. Coupland8,
  11. M. Doherty1,
  12. A. Sarmanova9,
  13. D. Prieto-Alhambra5,
  14. M. Englund4,
  15. S. M. A. Bierma-Zeinstra3,
  16. W. Zhang1
  17. on behalf of FOREUM OA Comorbidity Consortium
  1. 1University of Nottingham, Academic Rheumatology, Nottingham, United Kingdom
  2. 2Erasmus MC University Medical Center Rotterdam, 3. Department of General Practice, Rotterdam, Netherlands
  3. 3Erasmus MC University Medical Center Rotterdam, Department of General Practice, Rotterdam, Netherlands
  4. 4Lund University, Department of Clinical Sciences Lund, Lund, Sweden
  5. 5University of Oxford, NDORMS, Oxford, United Kingdom
  6. 6Keele University, School of Medicine, Keele, United Kingdom
  7. 7Chang Gung Memorial Hospital, Division of Rheumatology, Allergy and Immunology, Taiwan, Taiwan, Republic of China
  8. 8University of Nottingham, Department of Primary Care, Nottingham, United Kingdom
  9. 9University of Bristol, Musculoskeletal Research Unit, Bristol Medical School, Bristol, United Kingdom


Background People with osteoarthritis (OA) are at higher risk of developing a wide array of comorbidities. Whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) contributes to the increased risk of some incident comorbidities remains unknown.

Objectives To examine the contribution of NSAIDs in the development of a wide range of comorbidities in people with and without OA.

Methods This observational cohort study used the UK primary care Clinical Practice Research Datalink (CPRD) GOLD containing data on 20+ million people covering 937 practices. We identified 259,000 people with incident OA and 259,000 age (±2 years), sex, and practice matched controls at 1:1 ratio. Controls were assigned the same index date (the date of first diagnosis of OA) as cases for the start of follow-up. Both cases and controls were further divided into two groups according to NSAID prescriptions at any time after the index date. This allowed us to examine both the main effect of each exposure and interaction between OA and NSAID exposure after the index date. People with an NSAID prescription before the index date were excluded from the study. NSAID exposure was defined as at least two prescriptions within 90 days. Exposure status of each participant was assessed every six months as yes/no until the end of the study/outcome of interests/death/last data available, whichever came first. Comorbidities were grouped into 9 categories as cancer, cardiovascular disease (CVD), endocrine, psychological, renal, gastrointestinal (GI), genitourinary, hepatic, and neurological conditions. Propensity scores for the prescription of NSAIDs were calculated using a logistic regression model including age, sex, body mass index (BMI), musculoskeletal and pain related conditions covariates. The propensity score adjusted time varying exposure analysis was undertaken using a multivariate COX model and hazard ratio (HR) and 95% confidence intervals were calculated. Proportional hazard assumption was tested using Schoenfeld test. Smoking, alcohol, ever prescription of proton pump inhibitors (PPIs) and other comorbidities were included in the adjusted model. The additional contribution of NSAIDs and OA towards the incident comorbidity was estimated using addictive interaction methods. We also investigated the individual risk across non-selective, and COX-2 selective NSAIDs.

Results The mean age was 59.4±12.8 years in people with OA and 60.2±12.8 years for controls with 57.7% being female. Nearly two thirds of people with OA were prescribed NSAIDs as defined, compared to one third in the control population. People with OA and exposed to NSAIDs had highest risk of developing psychological (1.51; 1.43,1.60), CVD (1.38; 1.33,1.43), cancer (1.34; 1.25,1.44), GI (1.25; 1.16,1.34) and renal (1.17; 1.11,1.24) comorbidities after adjusting for all the covariates and PPI drugs, compared to the non-OA and non-NSAID group. (Figure 1) Interaction between OA and NSAID was significant for cancer, GI, renal, hepatic, and neurological outcomes. Within people with OA, non-selective NSAIDs increased the risk of CVD (1.25; 1.20,1.30), cancer (1.11; 1.04,1.19), endocrine (1.15; 1.10,1.19), renal (1.19; 1.13,1.26) and psychological (1.21; 1.15,1.28) comorbidities, whereas COX-2 selective NSAIDs increased risk of incident CVD (1.34; 1.25,1.44), endocrine (1.13; 1.04,1.21), renal (1.25; 1.14,1.37), and psychological (1.21; 1.09,1.34) comorbidities.

Figure 1.

Hazard ratio of developing different comorbidities (reference group: no OA and no NSAIDs) OA- Osteoarthritis; NSAIDS- Non-steroidal anti-inflammatory drugs.

Conclusion Use of NSAIDs among people with OA is associated with increased risk of a wide variety of comorbidities. Non-selective and COX-2 selective NSAIDs are both associated with increased risk of cardiovascular, renal, and psychological comorbidities.

Acknowledgements We thank the Patient Research Participants (PRP) members Jenny Cockshull, Stevie Vanhegan, and Irene Pitsillidou for their involvement since the beginning of the project. We would like to thank the FOREUM for financially supporting the research.

Disclosure of Interests Subhashisa Swain: None declared, Anne Kamps: None declared, Jos Runhaar: None declared, Andrea Dell’Isola: None declared, Aleksandra Turkiewicz: None declared, Danielle E Robinson: None declared, Victoria Y Strauss: None declared, Christian Mallen: None declared, Chang-Fu Kuo: None declared, Carol Coupland: None declared, Michael Doherty Consultant of: Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Grant/research support from: Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Aliya Sarmanova: None declared, Daniel Prieto-Alhambra Speakers bureau: paid speaker services from Amgen and UCB Biopharma., Consultant of: His department has received advisory or consultancy fees from Amgen, Astellas, AstraZeneca, Johnson, and Johnson, and UCB Biopharma, Grant/research support from: Prof. Prieto-Alhambra’s research group has received grant support from Amgen, Chesi-Taylor, Novartis, and UCB Biopharma., Martin Englund: None declared, S.M.A. Bierma-Zeinstra: None declared, Weiya Zhang Speakers bureau: Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium, Consultant of: Consultant of: Grunenthal for advice on gout management,

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