ORAL Surveillance risk groups narrow again

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Two types of patients have been identified as sources of excess harm in tofacitinib versus TNFi study.

A post-hoc analysis of the ORAL Surveillance data has identified two subpopulations based on age and smoking status with different relative risk for adverse outcomes with tofacitinib vs TNF inhibitors.

Patients who were 65 years and older or had ever smoked had a greater risk of safety outcomes if they were taking tofacitinib versus taking TNFi. Patients taking tofacitinib who’d never smoked and were under 65 had no increased risk compared with those taking TNFi.

“These easily identifiable and clinically practical subpopulations with different relative risk versus TNFi … can better guide individualised benefit/risk assessment and clinical decision-making on treatment with tofacitinib,” wrote the authors in the Annals of the Rheumatic Diseases.

Age and smoking have been consistently identified in previous analyses as independent risk factors across safety outcomes in the ORAL Surveillance study.

For the current analysis, patients aged at least 65 years or an “ever smoker” (current or past smoker) were categorised “high risk”. Patients under 65 who had never smoked were “low risk”.

Safety outcomes considered were malignancies (excluding non-melanoma skin cancer), major adverse cardiovascular events (MACE), myocardial infarction, venous thromboembolism (VTE) and all-cause death.

Patients in the high-risk category were at increased risk of safety outcomes with tofacitinib versus TNFi, with hazard ratios ranging from 1.41 (for MACE) to 5.19 (for VTE).

In the low-risk category, there was no increased risk in safety outcomes for patients taking tofacitinib versus TNFi, with hazard ratios of around 1 for all safety outcomes.

In the ORAL Surveillance study, characterised by a risk-enriched population of rheumatoid arthritis patients required to be at least 50 years old and to have at least one cardiovascular risk factor, the high-risk patients accounted for around 65% of the total cohort, and 82% of the adverse safety outcomes.

The researchers sought to validate the low absolute risk of safety outcomes observed in the ORAL Surveillance low-risk group against low-risk patients in tofacitinib development programs involving patients with RA, psoriatic arthritis and ulcerative colitis.

The greater number of patients in the RA tofacitinib program (around 8000) vs the ORAL Surveillance study (around 3000 for combined tofacitinib doses), allowed increased precision of risk estimates. So it was reassuring that the absolute risks for the various safety outcomes in the low-risk group in the RA tofacitinib program were similar to those in the low-risk ORAL Surveillance cohort.

Absolute risks of safety outcomes among low-risk patients in the PsA and UC tofacitinib programs were also similar to those of low-risk patients in ORAL Surveillance and the RA tofacitinib programs.

“Moreover,” wrote the authors, “the magnitude of the absolute risk in the low-risk group was low also in relation to published rates in randomised controlled trials and their [long term extensions] in RA populations treated with TNFi and other biologics.”

The same research group had previously reported on history of atherosclerotic cardiovascular disease (ASCVD) as another differentiating risk factor.

“However, whereas the combination of age and smoking is capable of differentiating risk across major outcomes, history of ASCVD is specific for MACE. These are all factors that need to be considered in an individualised benefit/risk assessment.”

Ann Rheum Dis 2023, 17 March

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