Background: Biological and targeted synthetic DMARDs (b/tsDMARDs) have demonstrated efficacy and acceptable safety profiles in clinical trials, supported by post-authorization observational data. Ongoing safety concerns regarding Janus kinase inhibitors (JAKi) highlight the importance of identifying patient-level risk factors for adverse events. Sex-related differences in biological and clinical characteristics may also affect safety outcomes, but evidence addressing sex-specific risks in patients with rheumatoid arthritis is limited.

Objectives: To assess the potential impact of sex on the occurrence of malignancies, infections and cardiovascular events among patients with rheumatoid arthritis (RA), using real-world data from the JAK-pot collaboration.

Methods: Adult patients with RA starting JAKi, TNFi or bDMARDs with other mechanisms of action (OMA) from 12 registers across Europe and Québec were included. Registers with less than 10 adverse events reported were excluded from the analysis to avoid possible bias. Adverse events of interest were categorized into: all infections and serious infections, major adverse cardiovascular events (MACE), venous thromboembolism (VTE), and malignancies, stratified in “non-melanoma skin cancer (NMSC)” and “malignancy excluding NMSC”. Adverse events were attributed to a given treatment if these occurred while on therapy or during an event-specific risk window after discontinuation until loss to follow-up, death, or study end, whichever came first. The risk windows were 5 years for malignancies, 6 months for cardiovascular events (MACE and VTE), and 3 months for infections. Chained equations using random forest were used to impute missing data. Incidence rates (IR) per 100 patient-years (PY) and per 1000 PY with 95% confidence intervals (CI) were computed. Cumulative hazards were plotted by sex to assess time from therapy start until the occurrence of the first adverse event. Poisson regression was used to obtain adjusted incidence rate ratios (aIRR) with 95% CI, and Cox regression for adjusted hazard ratios (aHR). The following covariates were used for adjustment: age, disease duration at treatment start, line of treatment, obesity, seropositivity, DAS28-CRP, smoking, and prior history of the adverse event.

Results: A total of 36,912 RA patients initiated 47,816 treatments with TNFi, JAKi and OMA (54%, 20.3% and 25.7%, respectively) between 2013 and 2024, and were included for analysis. Patients were mostly females (78.1%) andinitiated therapy at a mean age of 58.6 years. The median number of previous b/tsDMARD was 1, TNFi were mostly used as 1 ^st line treatments, while JAKi and OMA were more frequently used in second or later treatment lines. Overall, males seemed to have a later onset of RA and thus a shorter disease duration at treatment start. In addition, males were more commonly overweight/obese compared to females (66.3% vs 56.2%), smokers (53.7% vs 32.3%) and had a history of cardiovascular disease (17.8% vs 8.2%). A total of 6046 infections (1207 serious), 680 malignancies (169 NMSC), 301 MACE and 184 VTE were reported.

IRs and crude IRRs (male vs female) were higher among males for all events of interest, except for infections and NMSC (Figure 1). While the incidence of all infections was significantly lower among male patients (aIRR=0.87 [95% CI: 0.81 to 0.93]), males had a significantly higher incidence of serious infections (aIRR=1.29 [95% CI: 1.12 to 1.48]), MACE (aIRR=1.85 [95% CI: 1.41 to 2.42]), and malignancies excl. NMSC (aIRR=1.46 [95% CI: 1.16 to 1.83]). No differences were found for VTE, all malignancies nor NMSC (Figure 1). Fully adjusted Cox analyses were consistent with these results: males had a decreased risk for all infections (aHR=0.85 [95% CI: 0.79 to 0.91]) but increased risk for other adverse events (Figure 2). The adjusted hazard ratios were statistically higher among males for serious infections (aHR=1.29 [95% CI: 1.13 to 1.49]), MACE (aHR=1.82 [95% CI: 1.38 to 2.40]), and cancer (excl. NMSC) (aHR=1.44 [95% CI: 1.15 to 1.81]). No significant differences in the risk of VTE nor NMSC were observed between females and males. No sex and treatment interaction was detected in either of the two approaches.

Conclusions: In this large real-world study, encompassing data from 12 RA registers with all currently available b/tsDMARDs, sex-specific differences in safety profiles were observed: males had a significantly lower risk for infections compared to females, but in contrast, a greater risk for serious infections, MACE, and malignancies (excl. NMSC). Further studies are warranted to explore underlying mechanisms of the observed sex-specific differences across different adverse event endpoints. Awareness of these differences may support more individualized risk–benefit assessment in routine clinical practice, contributing to more personalized treatment strategies.

Figure 1.

Incidence rates of adverse events of interest stratified by sex and incidence rate ratios for male vs female participants (crude and adjusted by age, disease duration, line of treatment, obesity, seropositivity, DAS28-CRP at baseline, smoking and past history of the adverse event)

Figure 2.

Cumulative hazard of adverse events of interest stratified by sex

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Lucia Otero Varela: None declared, Ben Meuleman: None declared, Denis Mongin: None declared, Benoît Gilbert: None declared, Romain Guemara: None declared, Louis Coupal: None declared, Denis Choquette: None declared, Catalin Codreanu: None declared, Ruth Fritsch-Stork: None declared, Roberto F. Caporali: None declared, Doreen Huschek: None declared, Kimme Hyrich AbbVie, Pfizer, BMS, Florenzo Iannone Abbvie, Alfasigma, Amgen, Astra-Zeneca, Csl-Vifor, GSK, Janssen, Novartis, Lilly, UCB, Abbvie, Amgen, Astra-Zeneca, GSK, Janssen, Lilly, UCB, Tore K. Kvien Grunenthal, Janssen, Sandoz, AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, Dan Nordström Pfizer, UCB, BMS, Lilly, MSD, Novartis, Pfizer, UCB, BMS, MSD, UCB, Karel Pavelka AbbVie, Eli Lilly, Sandoz, UCB, Medac, Pfizer, Manuel Pombo-Suarez: None declared, Sella Aarrestad Provan: None declared, Ziga Rotar Abbvie, Pfizer, Eli Lilly, SOBI, Novartis, Astra Zeneca, Stada., Anja Strangfeld AbbVie, AlfaSigma, Janssen, Lilly, Pfizer, Takeda, UCB., Unconditional grant to my institution for the RABBIT register with equal parts from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Galapagos/Alfasigma, Hexal, Lilly, MSD, Viatris, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, and UCB., Nina Trokovic: None declared, Jakub Závada Abbvie, Elli-Lilly, Sandoz, Novartis, Egis, UCB, Sanofi, AstraZeneca, Sobi, Abbvie, Novartis, AstraZeneca, Glaxo, Sizheng Steven Zhao Novartis, UCB, AlfaSigma, AbbVie, Novartis, UCB, AlfaSigma, Delphine S Courvoisier: None declared, Axel Finckh AbbVie, Alfasigma, Astra Zeneca, Eli-Lilly, Pfizer, UCB, AbbVie, Alfasigma, Eli-Lilly, Galapagos, Pfizer,, Carlos Sánchez-Piedra: None declared, Kim Lauper AbbVie (paid to the institution), Pfizer, Novartis (all paid to the institution), AbbVie, Eli-Lilly, Galapagos, Pfizer, Alfasigma (all paid to the institution).