Background: ORAL Surveillance (NCT02092467; a post-authorization safety study of the JAK inhibitor tofacitinib at doses of 5 or 10 mg twice daily [BID] vs TNF inhibitors [TNFi]) found higher incidence of major adverse cardiovascular (CV) events (MACE), malignancies (excl non-melanoma skin cancer [NMSC]), venous thromboembolism (VTE), and all-cause mortality with tofacitinib vs TNFi (Figure 1).^[1] At the start of the study, 31% of patients were ≥65 years old (y/o) and 48% had ever smoked (i.e., current or past; >91% of these had smoked >10 years).^[1,2] Age ≥65 y/o and ever smoking were recently identified as differential risk factors for these safety outcomes with tofacitinib vs TNFi, and in patients that were <65 y/o and never smokers, increased risk was not detected for tofacitinib vs TNFi.^[2]

Objectives: To provide a practical framework for individualized benefit/risk assessment and clinical decision-making for treatment with tofacitinib by describing the risk of safety outcomes with tofacitinib vs TNFi in ORAL Surveillance in the four composites of age (≥ or <65 y/o) and smoking (ever or never).

Methods: Patients with rheumatoid arthritis aged ≥50 y/o and with ≥1 additional CV risk factor received tofacitinib 5 mg (N=1,455) or 10 mg (N=1,456) BID, or TNFi (N=1,451). Proportion and incidence rates (IR, 95% CIs) of patients with MACE, malignancies (excl NMSC), VTE, and all-cause mortality for combined tofacitinib dose and TNFi, and hazard ratios (HR, 95% CIs) and numbers needed to harm with combined tofacitinib doses vs TNFi were estimated for the four possible composites of age and smoking history.

Results: Demographic and baseline disease characteristics per age and smoking composite are shown in Table 1 and was similar in the treatment arms (not shown). Risk of MACE (Figure 1A) was increased with tofacitinib vs TNFi in patients with both risk factors, i.e., ‘≥65 y/o and ever smokers’, however, no risk increase was detected in patients with no or one differential risk factor. Occurrence of malignancies (excl NMSC) with tofacitinib vs TNFi (Figure 1B) was increased in patients who ever smoked, and particularly in patients that in addition were ≥65 y/o. Chance of VTE (Figure 1C) and all-cause mortality (Figure 1D) was similar with tofacitinib vs TNFi in patients that were <65 y/o and never smokers, while risk was increased in patients that had at least one of the risk factors (i.e., ≥65 y/o or ever smokers).

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Conclusion: This post hoc analysis of ORAL Surveillance indicates that age and history of smoking, alone or in combination, have variable impact on risk of different safety outcomes with tofacitinib vs TNFi. MACE seems to be increased with tofacitinib vs TNFi in patients that are ≥65 y/o and ever smokers. Ever smoking seems to be particularly important for risk of malignancies (excl NMSC) and older age increases its impact on risk with tofacitinib vs TNFi. However, either older age or ever smoking seem to be associated with increased risk of VTE and all-cause mortality with tofacitinib vs TNFi. Although limited by low numbers of events in some of the analyses, the data give insight on the association between age and smoking, and the risk of important safety outcomes with tofacitinib vs TNFi. The results provide a practical framework for individualized benefit/risk assessment and clinical decision-making on treatment with tofacitinib.

REFERENCES: [1] Ytterberg et al. N Engl J Med 2022; 386: 316–26.

[2] Kristensen LE et al. Ann Rheum Dis. 2023 Jul;82(7):901-910.

Acknowledgements: NIL.

Disclosure of Interests: Jose L. Rivas Pfizer, Pfizer, Lars Erik Kristensen Pfizer, AbbVie, Amgen, Galapagos, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Pfizer, AbbVie, Amgen, Galapagos, UCB, Gilead, Biogen, BMS, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Novo, UCB, Eli Lilly, Novartis and AbbVie, Maya Buch AbbVie, Galapagos, Gilead Sciences, Pfizer Inc, Boehringer Ingelheim, AbbVie, Galapagos, Gilead Sciences, Pfizer Inc, Gilead, Arne Yndestad Pfizer, Pfizer, Min H Zhang Pfizer, Pfizer, Ivana Vranic Pfizer, Pfizer.