Patients with rheumatoid arthritis treated with tofacitinib (Xeljanz) are more likely to develop infections than are those who take a tumor necrosis factor inhibitor (TNFi), results of an industry-sponsored randomized controlled trial suggest.
The Janus kinase (JAK) inhibitor tofacitinib and TNFi biologics are common RA treatments that, along with factors including age, disease activity, and comorbidities, can put patients with RA at increased risk for infections.
Dr. Deepak L. Bhatt
“In this secondary analysis of the ORAL Surveillance trial, infections were increased with tofacitinib, compared with TNFi,” study coauthor Deepak L. Bhatt, MD, MPH, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, both in Boston, explained in an interview.
As reported in Annals of the Rheumatic Diseases, Dr. Bhatt and colleagues performed a subanalysis of the final dataset from the phase 3b/4 open-label safety trial of tofacitinib in RA conducted between March 2014 and July 2020, in 345 study locations worldwide.
Study participants were 50 years of age or older with moderate to severe RA who were taking methotrexate but having inadequate symptom control. They had at least one cardiovascular risk factor such as being a current smoker or having hypertension, past heart attack, family history of coronary heart disease, high cholesterol, diabetes mellitus, or extra-articular RA. Patients with current or recent infection, clinically significant laboratory abnormalities, or pregnancy, were excluded from the study.
In the study, 1,455 participants received oral tofacitinib 5 mg twice per day; 1,456 received oral tofacitinib 10 mg twice per day; and 1,451 were treated with subcutaneous TNFi (40 mg subcutaneous adalimumab [Humira] injection every 2 weeks in the United States, Puerto Rico, and Canada; and 50 mg subcutaneous etanercept [Enbrel] injection every week in all other countries. Participants continued their prestudy stable dose of methotrexate if clinically indicated.
The researchers calculated incidence rates and hazard ratios for infections, overall and by age (50-64 years, compared with 65 years and older). They calculated probabilities of infection using Kaplan-Meier estimates and identified infection risk factors through Cox modeling.
They found higher infection rates, serious infection events (SIEs), and nonserious infections (NSIs) with tofacitinib than with TNFi, including:
- Patients taking tofacitinib 5 mg (HR, 1.17; 95% confidence interval, 0.92-1.50) and 10 mg (HR, 1.48; 95% CI, 1.17-1.87) were at greater risk for SIEs.
- Patients older than 65 who were taking tofacitinib 10 mg had increased IRs and HRs for all infections and for SIEs, compared with those aged 50-64.
- The probability of a SIE rose from month 18 onward in participants taking tofacitinib 5 mg, as well as before month 6 in those taking tofacitinib 10 mg.
- In both tofacitinib groups, the probability of NSI increased before month 6.
The most common risk factors for SIEs were higher age, baseline opioid use, history of chronic lung disease, and time-dependent oral corticosteroid use. Risk factors for NSIs were female sex, history of chronic lung disease or infection, history of smoking, as well as time-dependent higher Disease Activity Score in 28 joints and C-reactive protein score.
‘Best information to date’
Michael George, MD, MSCE, assistant professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, welcomed the study’s results.
Dr. Michael George
“This study provides the best information to date on the risk of infection with the JAK inhibitor tofacitinib, compared to a TNF inhibitor,” Dr. George, who was not involved in the study, said in an interview. “It is rare to have such a large randomized trial with an active comparator focused on safety. This is a major strength.
“Being able to quantify the amount of increased risk will help with shared decision-making when counseling patients,” he added.
Data are not definitive
Dr. George said that, while the small overall risk may not be clinically meaningful for younger, healthier patients, trying biologics such as TNFi before tofacitinib may be optimal for high-risk patients who are older or have comorbidities.
Dr. Bhatt agreed.
“In deciding on appropriate therapies for RA (or other conditions where tofacitinib is used), it is important for the prescribing physician to explain the risks to the patient and weigh them against the potential benefits,” he advised.
Dr. Bhatt noted that increased infection is not the first risk that’s been linked with tofacitinib.
“ORAL Surveillance was designed primarily to assess cardiovascular safety and showed higher rates of cardiovascular events such as myocardial infarction and pulmonary embolism, as well as cancer, with tofacitinib,” he explained.
He recommended further related research.
“Randomized trials are needed to determine the best ways to treat conditions such as RA while trying to minimize cardiovascular, cancer, and infectious risks,” he said.
The study was sponsored by Pfizer. All authors reported financial involvements with Pfizer; most have financial involvements with other pharmaceutical companies as well; four authors are employees of Pfizer and three are also stockholders in the company. Dr. George reported involvements with the pharmaceutical industry.