Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial

• Published in: Annals of the rheumatic diseases Vol. 82; no. 3; pp. 331 - 343
• Main Authors: Curtis, Jeffrey R, Yamaoka, Kunihiro, Chen, Yi-Hsing, Bhatt, Deepak L, Gunay, Levent M, Sugiyama, Naonobu, Connell, Carol A, Wang, Cunshan, Wu, Joseph, Menon, Sujatha, Vranic, Ivana, Gómez-Reino, Juan J
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.03.2023; Elsevier Limited; BMJ Publishing Group
• Subjects: antirheumatic agents; Antirheumatic Agents - therapeutic use; Arteriosclerosis; arthritis, rheumatoid; Arthritis, Rheumatoid - chemically induced; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - epidemiology; Cancer therapies; Cardiovascular disease; Cardiovascular diseases; Drug dosages; Humans; Lung cancer; Lung Neoplasms - chemically induced; Lung Neoplasms - epidemiology; Lymphoma; Malignancy; Medical screening; Melanoma; Patients; Population studies; Pyrroles - adverse effects; Rheumatoid Arthritis; Risk Factors; Skin cancer; Skin Neoplasms; Surveillance; TNF inhibitors; Treatment Outcome; Tumor necrosis factor; tumor necrosis factor inhibitors; Tumor Necrosis Factor Inhibitors - therapeutic use; Tumor necrosis factor-TNF; Tumors; arthritis, rheumatoid; cardiovascular diseases; tumor necrosis factor inhibitors; antirheumatic agents
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/ard-2022-222543

ObjectivesTo evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).MethodsIn an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores.ResultsIRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments.ConclusionsRisk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer.Trial registration numbers NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661