Identification of two tofacitinib subpopulations with different relative risk versus TNF inhibitors: an analysis of the open label, randomised controlled study ORAL Surveillance

• Published in: Annals of the rheumatic diseases Vol. 82; no. 7; pp. 901 - 910
• Main Authors: Kristensen, Lars Erik, Danese, Silvio, Yndestad, Arne, Wang, Cunshan, Nagy, Edward, Modesto, Irene, Rivas, Jose, Benda, Birgitta
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.07.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Age; Aged; Antirheumatic Agents; Arthritis; Arthritis, Rheumatoid - drug therapy; Cardiovascular disease; Cardiovascular diseases; Clinical decision making; Decision making; Humans; Hypertension; Inflammatory bowel disease; Malignancy; Melanoma; Middle Aged; Myocardial infarction; Patients; Psoriatic arthritis; Rheumatoid Arthritis; Risk assessment; Risk Factors; Skin cancer; Smoking; Subpopulations; Surveillance; Therapeutics; Thromboembolism; TNF inhibitors; Treatment Outcome; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor Inhibitors - adverse effects; Tumor necrosis factor-TNF; Tumors; Ulcerative colitis; United States > US; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Arthritis; Therapeutics
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard-2022-223715

ObjectivesBased on primary results from ORAL Surveillance, an event-driven clinical trial of risk-enriched patients, identify subpopulations with different relative risk (ie, ‘high-risk’ and ‘low-risk’) with tofacitinib versus tumour necrosis factor inhibitors (TNFi).MethodsPatients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg two times a day or TNFi. Prior analyses had identified age and smoking as risk factors of particular interest across safety outcomes. Hazard ratios (HRs) and incidence rates were evaluated by age and smoking individually and in combination. Results were validated across tofacitinib development programmes.Results‘Age ≥65 years or ever smoker’ defined a group (‘high-risk’) with increased risk of malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events, myocardial infarction, venous thromboembolism and all-cause death with tofacitinib (combined doses) versus TNFi (HRs 1.41–5.19). In patients ‘aged <65 years and never smokers’ (’low-risk’), there was no detectable risk increase with tofacitinib versus TNFi (HRs ≈1.0) up to 6 years of follow-up, and absolute risk remained low and was corroborated across tofacitinib rheumatoid arthritis, psoriatic arthritis and ulcerative colitis programmes with up to 10 years of observation.ConclusionsThis posthoc analysis of ORAL Surveillance identified two tofacitinib subpopulations with different relative risk versus TNFi. High risk was confined to patients defined by distinct risk factors age ≥65 years or smoking, and these differentiating risk factors accounted for the excess risk observed with tofacitinib versus TNFi. These findings can guide individualised benefit/risk assessment and clinical decision-making on treatment with tofacitinib.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, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.