Patients with active rheumatoid arthritis treated with tofacitinib had higher risks of major adverse cardiovascular events (MACE) and cancer compared with those treated with the TNF inhibitors adalimumab and etanercept, reported researchers of the Oral Rheumatoid Arthritis Trial (ORAL) Surveillance clinical trial.

Their results are published in The New England Journal of Medicine.

The targeted, synthetic, disease-modifying anti-rheumatic drug (DMARD) tofacitinib selectively inhibits Janus kinase (JAK) 1, JAK 2, and JAK 3, and was approved by the FDA for the treatment of rheumatoid arthritis at doses of 5 mg twice daily or 11 mg once daily.

“During drug development, increases in serum lipid levels and the incidence of cancers, including lymphoma, were observed, which prompted the FDA to require a prospective, head-to-head safety trial comparing tofacitinib with TNF inhibitors,” wrote Stephen R. Ytterberg, MD, of the Mayo Clinic, Rochester, Minnesota, and fellow ORAL Surveillance researchers.

“This noninferiority trial assessed the hypothesis that the risk of major adverse cardiovascular events (MACE) or cancers, excluding non-melanoma skin cancer, would not be at least 1.8 times higher with tofacitinib (combined doses of 5 mg and 10 mg twice daily) than with a TNF inhibitor in this patient population,” they added.

The ORAL Surveillance trial was conducted at 323 sites in 30 countries. For this randomized, open-label, noninferiority, safety endpoint trial, Ytterberg and colleagues randomized 4,362 patients who had active rheumatoid arthritis despite treatment with methotrexate. Patients ages ≥50 years (mean age: 61.2 years; 78.2% women; 76.9% White; 51.8% never smokers) with at least one additional cardiovascular risk factor were randomized to treatment with tofacitinib (5 or 10 mg twice daily) or a TNF inhibitor. In North America, the TNF inhibitor used was adalimumab (40 mg every 2 weeks); in the rest of the world, etanercept (50 mg once weekly) was used.

The most common cardiovascular risk factors included a history of hypertension (66%), extra-articular disease (36.8%), diabetes (17.4%), fasting HDL <40 mg/dL (12.4%), and coronary heart disease (11.4%).

Mean duration of treatment was approximately 40 months, median follow-up was 4.0 years, and the coprimary endpoints of the study were MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and cancer.

When combined, patients treated with the 5- and 10-mg doses of tofacitinib had a higher incidence of MACE and cancer compared with those treated with a TNF inhibitor (3.4% versus 2.5%, respectively; HR: 1.33; 95% CI: 0.91-1.94), and that of cancer was 4.2% versus 2.9% (HR: 1.48; 95% CI: 1.04-2.09). Thus, the noninferiority of tofacitinib was not shown.

For the combined doses of tofacitinib, the 5.5-year cumulative estimated probability of MACE was 5.8%, compared with 4.3% with a TNF inhibitor, and the cumulative estimated probability of nonfatal MI was 2.2% and 0.7%, respectively.

Ytterberg and colleagues conducted subgroup analyses and found that the incidence of MACE was higher in patients age 65 years or older, higher with both doses of tofacitinib compared with a TNF inhibitor in these patients, and higher in patients in North America compared with the rest of the world, which researchers noted was possibly due to increased risk factors in North American patients.

In 5.5 years of follow-up, the estimated cumulative probability of cancers in patients treated with both doses of tofacitinib was 6.1%, compared with 3.8% in those treated with a TNF inhibitor. Similar to the incidence of MACE, cancer incidence was also higher in patients ≥65 years old compared with those younger and higher in North American patients.

Adverse events occurred in 91.6% of patients treated with the 5-mg dose of tofacitinib and in 92.3% of those treated with the 10-mg dose, compared with 90.1% in those treated with a TNF inhibitor. The corresponding incidence of serious adverse events were 24.1%, 26.8%, and 21.1%, respectively. Infections and infestations were the most common adverse and serious adverse events. The most common adverse events included upper respiratory tract infections, bronchitis, and urinary tract infections, while pneumonia was the most common serious adverse event.

The incidence of opportunistic infections such as herpes zoster and tuberculosis, all herpes zoster (serious and non-serious), and non-melanoma skin cancer were all higher in patients treated with tofacitinib compared with those treated with a TNF inhibitor. For example, serious infections occurred in 9.7% of patients treated with 5-mg tofacitinib, and in 11.6% of those treated with the 10-mg dose, compared with 8.2% of those treated with a TNF inhibitor. And serious and nonserious herpes zoster infections occurred in 12.4% and 12.2%, versus 4.0% of these patients, respectively.

Efficacy was similar in all three treatment groups. Patients demonstrated improvements from month 2, which were sustained throughout the study.

For clinicians, then, what is the bottom line based on these results?

“In patients with rheumatoid arthritis who have an incomplete response to methotrexate and have active disease, a TNF inhibitor will be preferred to tofacitinib for a new start, especially in persons 65 years of age or older. If patients strongly prefer or are only willing to take an oral DMARD and if the patient is 50 to 64 years of age, a detailed patient–provider discussion of the risks associated with tofacitinib as compared with TNF inhibitors and shared decision making are needed before choosing tofacitinib as the treatment option. JAK inhibitors are among important oral treatment options for rheumatoid arthritis,” wrote Jasvinder A. Singh, MD, MPH, of the Veterans Affairs Medical Center and the University of Alabama at Birmingham, both in Birmingham, Alabama, in his accompanying editorial.

These results are not applicable, however, to patients younger than 50 years, those age 50 or older with no cardiovascular risk factors, and those with disease that is refractory to treatment with a TNF inhibitor or who experience unacceptable side effects, he added.

“Treating rheumatoid arthritis with an effective DMARD is critically important. The use of DMARDs to treat rheumatoid arthritis reduces pain; improves function, quality of life, and productivity; reduces joint destruction and disability; and decreases systemic inflammation. The increase in risk with tofacitinib as compared with TNF inhibitors must be balanced against patient preferences for oral medication,” Singh concluded.

Study limitations include its open-label design, high rates of treatment discontinuation, lack of other control groups, and the use of adalimumab in North America and etanercept in other parts of the world.


This study was supported by Pfizer.

Ytterberg serves as a member of Data and Safety Monitoring for Corbus Pharmaceuticals, and is a Steering Committee Chair for Pfizer Inc.

Singh is a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organization that develops outcome measures in rheumatology and receives arms-length funding from 8 companies and serve on the FDA Arthritis Advisory Committee. Singh also is the chair of the Veterans Affairs Rheumatology Field Advisory Committee; editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. Singh previously served as a member of the following committees: the American College of Rheumatology’s (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, and as Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and co-chair of the ACR Criteria and Response Criteria subcommittee.



Liz Meszaros, Deputy Managing Editor, BreakingMED™

Kaiser Health News

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