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BackgroundPeople 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.ObjectivesTo examine the contribution of NSAIDs in the development of a wide range of comorbidities in people with and without OA.MethodsThis 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.ResultsThe 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.ConclusionUse 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.AcknowledgementsWe 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 InterestsSubhashisa 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

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes not only joint pain but also bone destruction resulting in impairment of quality of life. Tumor necrosis factor inhibitors have improved prognosis of patients with rheumatoid arthritis dramatically, especially in combination with methotrexate, however, the optimal dose of the concomitant methotrexate is unclear.ObjectivesTo evaluate the efficacy and safety of adalimumab in combination with reduced dose of methotrexate in patients with early RA with inadequate response to methotrexate.MethodsThe MIRACLE study was a multinational, randomized, open-label study in patients with RA with inadequate response to methotrexate conducted in Asia. It compared low dose and high dose methotrexate upon starting adalimumab. Methotrexate-naive patients with RA with a disease duration of less than two years started methotrexate at 6 to 8 mg/week and increased it to the maximum tolerable dose by week 12. Patients who have not achieved remission according to simplified disease activity index (SDAI) despite methotrexate ≥ 10 mg/week at week 24 were randomised to the maximum tolerable dose of methotrexate group (10 to 25 mg/week) or the reduced dose group (6 to 8 mg/week) and started to receive subcutaneous adalimumab 40 mg every other week. The primary endpoint was non-inferiority in the achievement of SDAI remission at week 48 in the reduced dose group compared with the maximum tolerable dose group with a non-inferiority margin of -15% based on two-sided 90% confidence interval. (NCT03505008)ResultsA total of 300 patients were enrolled in the study. Among them, 291 started methotrexate and were included in the analysis. The mean age was 57.7±15.2 years, female was 74.6%, and the mean disease duration from the diagnosis of RA was 21.1±56.2 days. Anti-CCP antibody was positive in 211 (73.0%) and the mean SDAI at study enrollment was 26.5±12.4. At week 24, with the mean dose of methotrexate of 12.6±2.9 mg/week, 108 patients (37.1%) achieved remission according to SDAI and continued MTX monotherapy. 134 patients (46.0%) were randomised and started adalimumab with 68 patients in the maximum tolerable dose group and 66 patients in the reduced dose group. At week 48, the remission achievement rates were 38.4 % and 44.8 %, respectively, with the adjusted risk difference of the reduced dose group to the maximum tolerable dose group of 6.4% (-7.0% to 19.8%, 90% CI), which met the criterion for noninferiority. No significant difference was found in health assessment questionnaire disability index ≤0.5 (59.1% vs 62.0%, respectively, p=0.72) and in radiological remission rates (Δmodified total Sharp score ≤0.5, 66.3% vs 62.0 %, respectively, p=0.59). Adverse drug reactions tended to be more frequent in the maximum tolerable dose group than in the reduced dose group (22.1% vs 9.1%, respectively, p=0.06).ConclusionThe MIRACLE randomised study demonstrated that, in patients with inadequate response to methotrexate, the efficacy of adalimumab with reduced dose of concomitant methotrexate was not inferior to that with maximum tolerable dose of methotrexate with better safety profile.Disclosure of InterestsHiroya Tamai Speakers bureau: Eisai, Grant/research support from: Eisai, Kei Ikeda Speakers bureau: AbbVie, Eisai, Eli Lilly, Novartis, Gilead, Asahi-Kasei, Grant/research support from: Mitsubishi-Tanabe, Toshiaki Miyamoto: None declared, Hiroaki Taguchi: None declared, Chang-Fu Kuo: None declared, Kichul Shin: None declared, Shintaro Hirata Speakers bureau: AbbVie, Asahi-Kasei, Astellas, Ayumi, Bristol Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Kyorin, Novartis, Pfizer, Sanofi, Tanabe-Mitsubishi, UCB, Paid instructor for: AbbVie, Mitsubishi-Tanabe, Consultant of: AbbVie, Astellas, Bristol Myers Squibb, Eisai, Gilead, Ily Lilly, Grant/research support from: AbbVie, Asahi-Kasei, Eisai, Otsuka, Sanofi, Shionogi, Chugai, Pfizer, Tanabe-Mitsubishi, Eli Lilly, UCB, yutaka okano: None declared, Shinji Sato Speakers bureau: AbbVie, Eisai, Grant/research support from: AbbVie, Eisai, Hidekata Yasuoka Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Daiichi-Sankyo, Eisai, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer-Ingelheim, Bayer, Glaxo Smith Kline, Paid instructor for: AbbVie, Consultant of: AbbVie, Asahi Kasei, Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, In Ah Choi Speakers bureau: Abbvie, Eisai, Sung-Hwan Park: None declared, Meng-Yu Weng Paid instructor for: Novartis, Eli Lilly, ChuGai, Abbvie, Consultant of: Abbvie, Masataka Kuwana Speakers bureau: Astellas, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Mitsubishi-Tanabe, Consultant of: Boehringer-Ingelheim, Kissei, Mochida, Grant/research support from: AbbVie, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, MBL, Nippon Shinyaku, Ono Pharmaceuticals, Mitsubishi-Tanabe, Yun Jong Lee Grant/research support from: Yuhan, Tomonori Ishii Speakers bureau: Chugai, Mitsubishi-Tanabe, Glaxo Smith Kline, Pfizer, Eli Lilly, Janssen, AbbVie, Eisai, Astellas, Jinhyun Kim: None declared, Hideto Kameda Speakers bureau: AbbVie, Pfizer, Consultant of: AbbVie, Grant/research support from: AbbVie, Eisai, Toshihisa Kojima Speakers bureau: AbbVie, Pfizer, Eisai, Grant/research support from: AbbVie, Han Joo Baek: None declared, Ping-Ning Hsu: None declared, Chun-Ming Huang Paid instructor for: Abbvie, Pfizer, Tien-Tsai Cheng Paid instructor for: Abbvie, Grant/research support from: Abbvie, Wan-Yu Sung: None declared, Takehiro Taninaga Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Masahiko Mori Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Hideaki Miyagishi Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Yasunori Sato Speakers bureau: Eisai Co., Ltd. Kowa Company, Ltd., Consultant of: MOCHIDA PHARMACEUTICAL CO., LTD, Tsutomu Takeuchi Speakers bureau: Astellas, AbbVie, Ayumi, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo Smith Kline, Janssen, Mitsubishi-Tanabe, Nippon-kayaku, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Asahi Kasei, AbbVie, Ayumi, Boehringer-Ingelheim, Chugai, Eisai, Eli Lilly, Mitsubishi-Tanabe, Sanofi, UCB, Yuko Kaneko Speakers bureau: Asahi Kasei, Astellas, Ayumi, Bristol Myers Squibb, Chugai, Eisai, Elli Lilly, Mitsubishi-Tanabe, Novartis, UCB, Grant/research support from: AbbVie, Chugai, Eisai, Mitsubishi-Tanabe, UCB.

BackgroundOsteoarthritis (OA) patients are more likely to have other comorbidities (Swain, Sarmanova et al. 2020). Improving the understanding of comorbidity profiles of OA patients may lead to improvement in their clinical care.ObjectivesTo identify sub-groups in patients diagnosed with hip OA using patterns of comorbidity.MethodsRoutinely-collected data of individuals ≥18 years with an incident diagnosis of hip OA (baseline/time of diagnosis), with at least 1 year of follow-up in SIDIAP (Information System for Research in Primary Care, a primary case database from Spain) were collected from January 1st 2006 to June 31st 2020. Those with soft-tissue disorders or other bone/cartilage diseases at the same joint in the year prior/after baseline were excluded. Comorbidities associated with OA in the literature and present in ≥1% of the study population were included. Clusters of comorbidities were identified at baseline using latent class analysis (LCA), a soft clustering method that classifies individuals according to the distribution of their measured items. The number of clusters or sub-groups within the study population was decided by comparing goodness of fit parameters (CAIC, BIC, ABIC) and log-likelihood changes of models from 2 to 8 clusters. The selected model was externally evaluated by a survival analysis assessing 10 years mortality within each cluster, where the weight of the posterior probability was used as a probability of sampling weight.ResultsWe identified 94,720 individuals with an incident diagnosis of hip OA, 56.3% women and 43.7% men, with a mean age (SD) of 67.2 (13.1) years. We selected the LCA model with 5 clusters that could be described as: healthier (lower prevalence of all comorbidities than average in the cohort), multimorbidity (higher prevalence of all comorbidities, multiple comorbidities), back/neck pain plus mental health (B/N-mental), cardiovascular disease (CVD), and metabolic syndrome (MetS) (Figure 1). Cox regression (HR [95CI%]) showed higher mortality risk for multimorbidity (3.76 [3.70-3.83]), CVD (1.56 [1.53-1.59]) and MetS (4.56 [4.35-4.78]), compared to healthy. No difference was observed for B/N-mental cluster.Figure 1.Distribution of comorbidities within each cluster using latent class analysis. Clusters were described as Healthier, Multimorbidity, B/N-mental, CVD and MetS. Black horizontal lines represent the prevalence of the comorbidity before the clusterization. Abbreviations: Healthier, lower prevalence of all comorbidities; Multimorbidity, higher prevalence of all comorbidities; B/N-mental, back/neck pain plus mental health disorders; CVD, cardiovascular disease; Met, metabolic syndrome; Bhp, benign prostate hypertrophy; Chd, chronic heart disease; Chf, chronic heart failure; Ckd, chronic kidney disease; Copd, chronic obstructive pulmonary disease; Gbs, gall bladder stone; Gerd, gastroesophageal reflux disease; Ibd, inflammatory bowel disease; Ovd, other vessel diseases; Substance, substance abuse.ConclusionClustering of co-morbidities in hip OA patients at the time of diagnosis has the potential to detect sub-groups of hip OA patients who might require additional care.References[1]Swain, S., A. Sarmanova, C. Coupland, M. Doherty and W. Zhang (2020). “Comorbidities in Osteoarthritis: A Systematic Review and Meta-Analysis of Observational Studies.” Arthritis Care Res (Hoboken) 72(7): 991-1000.AcknowledgementsWe 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 InterestsNone declared