Evaluating risk of emboli
The incidence of VTE is about two times higher among people with RA, compared with the general population, Dr. Strand said, with research suggesting the majority of risk resides among people with a previous event. However, she added, an emerging profile of thromboembolic events associated with JAK inhibitors is “considered a class effect by the FDA.”
One exception in the JAK inhibitor class could be tofacitinib (Xeljanz), which might carry less risk because “most of the data with tofacitinib are quite good,” Dr. Weinblatt said. One study presented at ACR 2018, for example, showed a similar VTE rate between tofacitinib and TNF inhibitors.
Nevertheless, the FDA issued a boxed warning in July 2019 about elevated risks of blood clots and death at a higher dose of tofacitinib. The concerns stem from an open-label, endpoint-driven study mandated by the FDA to explore major adverse cardiac events. “There was a clinically important and statistically significant occurrence of pulmonary embolism and VTE, and an increase in mortality in the 10-mg dose group as opposed to the anti-TNF therapies,” Dr. Weinblatt said. As a result, the FDA requested patients on the 10-mg twice-daily dose be transitioned to the 5-mg twice-daily dose.
The package labeling for the JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq) feature warnings about increased risk for thromboembolic events. Furthermore, the labeling for filgotinib, a JAK inhibitor in development that received a complete response letter from the FDA in August 2020, is expected to carry the same warning.An unanswered question remains on why this class of agents potentially increases risk of thromboembolism. “We’re all uncomfortable because there is no known mechanism of JAK inhibition that should lead to this,” he added. Another unresolved issue is whether or not patients prescribed a JAK inhibitor should also be prescribed an anticoagulant.
Anti-TNF adverse events
Infections, primarily reactivation of tuberculosis and an increased risk for fungal disease, are concerns with the anti-TNF agents. However, the risk is not restricted to this class. “Greater risk of infection is seen with all our immune-modulating therapies,” Dr. Weinblatt said.
Rare adverse events include demyelinating syndromes, hematologic toxicity, and a worsening of heart failure in some cases.
“Despite a concern about malignancy, the only defined cancer reported over 22 years of use was skin cancer,” he said. “It took more than a decade of ongoing registry data for skin cancer to be identified. It was not noted in randomized, placebo-controlled trials.”
Potential pregnancy concerns
When it comes to risk during reproduction, “there is a clear difference,” Dr. Weinblatt said. “We know anti-TNF therapy can be used safely in pregnant women. We know they can conceive on them and maintain them during pregnancy. They can also breastfeed on them.”
“Frankly, I’m not so ‘gung ho’ on TNF inhibitor safety in pregnancy and lactation with exception of certolizumab, which doesn’t result in high levels of antibody in the placenta or the mother’s milk,” Dr. Strand said.
The 2020 ACR Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases states that all anti-TNF therapies can be used during pregnancy and lactation, Dr. Weinblatt said. “Although I agree certolizumab has the best safety profile, all of them can be used.”
“The same is not true with the jakinibs,” he added, pointing to warnings that women of reproductive age should use contraception while on JAK inhibitors and for 4 weeks after stopping treatment.
However, Dr. Strand defended the pregnancy risk with JAK inhibitors. She cited two publications, including a 2016 study where researchers evaluated the safety of tofacitinib during pregnancy in women with rheumatoid arthritis and psoriasis. “There was only one possible deformity, a pulmonary stenosis,” Dr. Strand said. “Essentially, the majority of patients delivered healthy babies. There was very little difference from what we know occurs in RA otherwise.”
A 2018 study assessed pregnancy outcomes with tofacitinib among people with ulcerative colitis, “again showing the majority of patients had normal deliveries.”
“There just aren’t enough data,” Dr. Weinblatt said. “Perhaps in 5 years, we will reach same conclusion with the jakinibs.”