Risk for Malignancy Higher With Tofacitinib vs TNF Inhibitors in RA

Treatment with tofacitinib vs TNF inhibitors resulted in higher risk for malignancies among patients with RA.

In patients with rheumatoid arthritis (RA), risk for malignancies is increased with tofacitinib compared with tumor necrosis factor inhibitors (TNFi), with the incidence highest among those with a history of atherosclerotic cardiovascular disease (HxASCVD), according to study results published in Annals of the Rheumatic Diseases.

Researchers sought to assess the association of malignancies with baseline risk factors and cardiovascular (CV) risk scores with tofacitinib vs TNFi therapy in individuals with RA.

The phase 3b/4 ORAL Surveillance study (ClinicalTrials.gov Identifier: NCT02092467) was conducted between March 2014 and July 2020 among participants aged 50 years and older with moderate to severe RA with at least 1 additional CV risk factor. Patients were randomly assigned 1:1:1 to receive tofacitinib 5 mg twice-daily, tofacitinib 10 mg twice-daily, or a TNFi.

A total of 4362 patients (tofacitinib 5 mg, n=1455; tofacitinib 10 mg, n=1456; and TNFi, n=1451) were included in the study. Exposure to the last trial treatment was 5073.5 patient-years, 4773.4 patient-years, and 4940.7 patient-years, respectively. The duration of treatment was 44.7 months, 42.8 months, and 43.9 months, respectively.

Risk 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.

Results of the study showed that 3.8% (n=164) of the participants reported a malignancy excluding nonmelanoma skin cancer (NMSC) and 1.8% (n=80) reported at least 1 NMSC. Regarding malignancies excluding NMSC, incidence rates were higher with individual and combined doses of tofacitinib compared with TNFi.

The risk for lung cancer, which was the most common form of malignancy reported with tofacitinib use, was higher with tofacitinib 10 mg vs TNFi. In the overall study population, the risk for malignancies, except NMSC, was similar between both doses of tofacitinib and TNFi until month 18, then diverged from month 18 onward for combined tofacitinib doses (hazard ratio [HR], 0.93; 95% CI, 0.53-1.62 from baseline to month 18 and HR, 1.93; 95% CI, 1.22-3.06 from month 18 onward; P for interaction, P =.0469).

Study limitations included the fact that ORAL Surveillance was not powered to evaluate comparisons for malignancy subtypes across the treatment groups; the post hoc analyses for assessing baseline risk factors were exploratory, rather than confirmatory, in nature; and although malignancies were adjudicated centrally for standardization across various investigational sites, different countries may have had different practices with regard to staging and grading of tumors, with no specified screening procedures at baseline.

The study authors concluded, “Risk for malignancies was increased with tofacitinib [vs] TNFi, and incidence was highest in patients with HxASCVD or increasing [CV] risk. This may be due to shared risk factors for [CV] risk and cancer.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Curtis JR, Yamaoka K, Chen Y-H, et al. Malignancy risk with tofacitinib versus TNF inhibitors in rheumatoid arthritis: results from the open-label, randomised controlled ORAL Surveillance trial. Ann Rheum Dis. Published online December 23, 2022. doi:10.1136/ard-2022-222543