JAK inhibitors have significant impact in psoriatic arthritis, but safety concerns remain

Despite some safety concerns, Janus kinase, or JAK, inhibitors, are carving out a place as important treatment options for a number of autoimmune diseases, including psoriatic arthritis.

JAK inhibitors were first approved by the FDA for rheumatoid arthritis, with tofacitinib (Xeljanz, Pfizer) receiving approval in 2012, followed by baricitinib (Olumiant, Eli Lilly & Co.) in 2018 and upadacitinib (Rinvoq, Abbvie) in 2019. Eventually, data from several phase 3 trials prompted the FDA to also greenlight two of these JAK inhibitors — tofactinib in 2017 and upadacitnib in 2021 — for treatment of PsA.

However, JAK inhibitors’ arrival on the market has not been without controversy, especially in light of data linking these therapies to an increased risk for cardiovascular events and cancer.

Finding their place

The FDA approval of tofacitinib, the first JAK inhibitor approved for PsA, came on the heels of the publication of two phase 3 trials — OPAL Broaden and OPAL Beyond — in The New England Journal of Medicine in 2017.

In OPAL Broaden, results showed that tofacitinib was beneficial in patients with active PsA who had had an inadequate response to a conventional synthetic disease-modifying antirheumatic drug. Building on these data, in OPAL Beyond, researchers found that tofacitinib also yielded positive results in patients who had had an inadequate response to at least one TNF inhibitor. In both trials, ACR20 response rates and improvement in Health Assessment Questionnaire-Disability Index scores were significantly greater with tofacitinib when compared with placebo.

Notably, OPAL Broaden also included an active control arm in which patients received adalimumab (Humira, Abbvie). Clinical improvements were comparable in the tofacitinib and adalimumab arms, but there was no planned analysis of noninferiority or superiority of the two treatments.

In an editorial accompanying the publication of the two trials, Robert A. Colbert, MD, PhD, and Michael M. Ward, MD, both from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the NIH, noted that these trials suggest that tofacitinib “also has a place in the arsenal of drugs for the treatment of psoriatic arthritis.”

“Tofacitinib may find a place alongside TNF inhibitors and phosphodiesterase-4 inhibitors,” they wrote. “Although more head-to-head comparisons will be useful, other factors, such as cost, convenience, safety and the extent of skin disease, will be considerations in treating patients and improving outcomes.”

Similarly, FDA approval of upadacitinib hinged on two phase 3 trials. In SELECT PsA 1, which was published in NEJM in 2021, the treatment proved superior to placebo at 12 weeks, with data also showing a higher dose of upadacitinib outperforming adalimumab, in patients with PsA who had had an inadequate response to a nonbiologic disease-modifying antirheumatic drug. SELECT-PsA 2, which was presented at the EULAR Annual Congress in 2021, further showed that upadacitinib maintained its efficacy out to 56 weeks.

Aside from the data supporting their bid for approval, Wells noted, studies have shown that JAK inhibitors have significant benefits across the board in PsA.

“In both RA and PsA, JAK inhibitors work fast and help with tender joints and swollen joints. In PsA, of course, they also help with skin and nail psoriasis, and we now have data showing they help with genital and scalp psoriasis as well,” Wells said. “This has been amazing. These drugs have had an impact on everything.”

Additional advantages

Though backed by promising data, the relative newness of JAK inhibitors for treatment of PsA raises the question of where they fall on the spectrum of available therapies.

“They are first-line therapy for me,” Alvin F. Wells, director of the Rheumatology and Immunology Center in Franklin, Wisconsin, and adjunct assistant professor at Duke University Medical Center, told Healio. He noted that some of the other drugs commonly used in PsA, such as methotrexate and sulfasalazine, are not specifically approved for the condition. “In my practice, we do evidence-based medicine, which involves drugs the FDA has approved.”

However, the advantages of JAK inhibitors extend beyond their efficacy, according to Wells.

“One of the biggest benefits is the convenience of taking a pill vs. a shot or an infusion,” Wells said. “Additionally, you don’t need to have other concomitant drugs. For instance, if a patient is on an anti-TNF drug, they should also be on background methotrexate and other drugs that help prevent immunogenicity or a reaction against the medication. That’s unnecessary with JAK inhibitors.”

JAK inhibitors also appear to have an edge in terms of onset of action when compared with some other therapies, such as TNF inhibitors.

“They work a lot faster. In clinical trials, you have some people who are on TNF inhibitors and achieve a response in 2 weeks. The data on JAK inhibitors show that they work within a week,” Wells said.

Moreover, Wells noted, when compared with TNF inhibitors specifically, JAK inhibitors have greater impacts on pain and the skin as well. They also have demonstrated beneficial effects from a gastrointestinal perspective.

“Some patients with PsA have bile disease, which JAK inhibitors control as well,” Wells said.

Safety concerns

JAK inhibitors clearly have advantages, but recent data have raised questions about their safety as well.

When the FDA granted approval of tofacitinib for RA in 2012, the agency required a postmarketing study to evaluate the drug’s long-term effects on CV disease, cancer and serious infections.

Interim data from the safety-endpoint study — the ORAL Surveillance trial — prompted the FDA to approve a boxed warning about the increased risk for blood clots and death with the 10 mg dose of tofacitinib. The agency then issued a safety alert in February 2021 regarding preliminary data from the study showing an increased risk for serious heart-related events and cancer with tofacitinib when compared with TNF inhibitors among older patients. Most recently, in September 2021, the FDA required that warnings about these increased risks be added to two other JAK inhibitors, including baricitinib and upadacitinib, although they were not evaluated in the study.

In January, the open-label, noninferiority ORAL Surveillance trial was published in NEJM. The study randomly assigned patients with active RA, despite MTX, aged 50 years or older and with at least one additional CV risk factor to tofacitinib 5 mg or 10 mg twice daily or a TNF inhibitor. As indicated in the FDA safety communications, results revealed increased risks for major adverse CV events and cancers with the combined tofacitinib doses, as compared with TNF inhibitors, and the noninferiority of tofacitinib was not shown. Efficacies of tofacitinib and TNF inhibitors were similar.

These data, however, may require greater context, according to Wells.

“Right now, for PsA, the guidelines say start with a prescription dose of an NSAID, and if we indeed talk about prescribing an NSAID, the side effects are not much different than those observed with JAK inhibitors,” Wells told Healio. “They can cause heart attacks, stroke, gastrointestinal bleeds and renal insufficiency. And, if you look at the data with NSAIDs, up to 14% of patients can have one of those side effects.”

Consequently, Wells noted that pieces may be missing from the puzzle.

“The researchers showed that more side effects occurred with the JAK inhibitors than with the TNF inhibitors, but I would love to see them compare them with NSAIDs with the same study population — people aged older than 50 with the same CV risk factors — because I wouldn’t even put them on an NSAID,” Wells said. “There almost should have been a third comparator in there. I keep coming back to NSAIDs because that’s where the ACR and Group for Research and Assessment of Psoriasis and Psoriatic Arthritis recommend starting with treatment of PsA.”

Considering the future

Although other JAK inhibitors are approved around the world, physicians may be limited to just tofacitinib and upadacitinib, at least in the short term, due to the current safety concerns. However, their place in the treatment armamentarium is solid and likely to improve, according to Wells.

“I think that the insurance companies, particularly Medicare, are going to find that if you have a pill that works the same or even better, it’s going to be a lot cheaper than an infusion medication. Right now, you have to try NSAIDs and a TNF inhibitor before a JAK inhibitor, but I think we’re going to see them moving up earlier on the treatment scale,” Wells said.

Importantly, amid the controversy, physicians should remember that these therapies work very well, according to Wells.

“JAK inhibitors have been my go-to medications for treating across the spectrum of autoimmune diseases, whether that’s autoimmune hair loss, autoimmune arthritis or autoimmune skin disease. These JAK inhibitors impact all of those, they work quickly and the side effect profile is acceptable and is no different than what we’ve seen with other drugs.”

References

FDA. FDA approves boxed warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-boxed-warning-about-increased-risk-blood-clots-and-death-higher-dose-arthritis-and. Published July 26, 2019. Accessed April 1, 2022.

Colbert RA, et al. N Engl J Med. 2017;doi:10.1056/NEJMe1709907.

Gladman D, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615977.

Mease P, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615975.

Mease PJ. Upadacitinib in patients with psoriatic arthritis refractory to biologic disease-modifying antirheumatic drugs: 56-week data from the phase 3 SELECT-PsA 2 study. Presented at: EULAR 2021 Virtual Congress; June 2-5, 2021 (virtual meeting).

Ytterberg SR, et al. N Engl J Med. 2022;doi: 10.1056/NEJMoa2109927.