‘The Great Debate’: JAK inhibitors vs biologics following methotrexate failure in RA
medwireNews: “The Great Debate” of the ACR Convergence 2020 virtual meeting addressed the question of whether Janus kinase (JAK) inhibitors should be given before biologics following an inadequate response to methotrexate in patients with rheumatoid arthritis (RA).
Introducing the topic, Elizabeth Wahl, from the University of Washington in Seattle, USA, said that the 2015 ACR guidelines recommend the use of tumor necrosis factor (TNF) inhibitors before JAK inhibitors following an inadequate response to conventional DMARDs, but “emerging data indicates that [JAK inhibitors] may be more effective than TNF inhibitors for the treatment of RA.” Accordingly, in the 2019 update of the European RA treatment guidelines, EULAR did “not specify a treatment order between biologics or [JAK inhibitors]” in RA patients with high-risk features and an inadequate response to conventional DMARD.
“Do the data support a specific treatment recommendation for these patients?” Wahl asked.
Better short-term efficacy with JAK inhibitors vs biologics
Arguing for the use of JAK inhibitors before biologics, Vibeke Strand, from Stanford University School of Medicine in California, USA, said that “the JAK inhibitor class is an exciting development for rheumatology […] and in RA they should be used early.”
She outlined that the three JAK inhibitors currently approved for RA – tofacitinib, baricitinib, and upadacitinib – have “well established efficacy in RA,” with better responses seen with shorter disease duration. Moreover, phase 3 randomized controlled trials have “indicated equivalency or superiority” of JAK inhibitors relative to the TNF inhibitor adalimumab in patients with an inadequate response to methotrexate, she added.
For instance, the RA-BEAM and SELECT-COMPARE trials suggested better clinical outcomes with baricitinib 4 mg/day and upadacitinib 15 mg/day, respectively, relative to adalimumab, when all treatments were given alongside stable background methotrexate, while ORAL Strategy demonstrated noninferiority of tofacitinib 5 mg twice daily to adalimumab.
Strand said that the “onset of action is rapid,” with ACR20 responses to JAK inhibitors seen as early as week 1, and that ACR20, 50, and 70 responses were sustained at 12–18-month follow-up visits in these trials.
Long-term established effectiveness with TNF inhibitors
Making the case against using JAK inhibitors before TNF inhibitors following methotrexate failure was Michael Weinblatt, from Brigham and Women's Hospital in Boston, Massachusetts, USA. He said that despite the encouraging efficacy results from phase 3 trials of JAK inhibitors, “we have over 22 years of clinical experience” with TNF inhibitors, compared with just 8 years with JAK inhibitors.
Weinblatt pointed out that five TNF inhibitors are currently approved for RA – etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol – with a raft of evidence from many studies supporting their use.
“Importantly, we have a vast number of approved other disease applications with anti-TNF therapy, including ankylosing spondylitis, psoriatic arthritis, [juvenile idiopathic arthritis], uveitis, [and] ulcerative colitis,” he said.
Conversely, of the three JAK inhibitors currently approved by the US FDA, at the time of writing only tofacitinib is recommended for indications other than RA (psoriatic arthritis and ulcerative colitis), whereas baricitinib and upadacitinib are only approved for RA.
Weinblatt also highlighted that in addition to placebo-controlled trials, there are comparative studies of TNF inhibitors versus methotrexate, as well as studies of long-term follow-up, early remission, withdrawal, and dose reduction.
“Anti-TNF therapy offers us the opportunity to lower the dose or modify the interval of dosing in patients in low disease activity or remission,” he said, stressing that this has not been evaluated with the JAK inhibitors.
TNF inhibitors have a well-established safety profile
So how about the safety profiles of TNF inhibitors? “After 22 years of approved use, we know everything bad about these drugs, and there’s no uncertainty,” said Weinblatt. He noted that “bacterial infections are a concern,” along with opportunistic infections, and that TNF inhibitors should be avoided in people with demyelinating syndromes. Weinblatt also said that hematologic toxicity occurs “extremely rarely” with TNF inhibitors, and there are rare cases of lupus-like syndrome, along with worsening of heart failure and skin cancer.
“It took more than a decade of ongoing registry data for skin cancer to be identified,” he stressed, highlighting that “duration of experience is important, particularly with identifying cancer risk.”
Toxicity questions remain with JAK inhibitors
In contrast to the TNF inhibitors, Weinblatt pointed out that there are “several” toxicity questions that remain to be answered with the JAK inhibitors, particularly regarding venous thromboembolism (VTE) risk. In light of study findings suggesting a potentially elevated risk with JAK inhibitor treatment, he said that the FDA has added boxed warnings for deep vein thrombosis, pulmonary embolism, and arterial thrombosis to the labels for tofacitinib, baricitinib, and upadacitinib.
Weinblatt noted that we do not know whether there is “truly an increased risk” or whether the risk differs between the different JAK inhibitors, and that there is “probably” a dose-related association, with higher VTE rates seen with higher doses of JAK inhibitors.
“We’re all uncomfortable because there’s no known mechanism in which JAK inhibition should lead to” increased risk, he stressed.
Weinblatt also pointed out that women are advised to use contraception whilst taking JAK inhibitors, whereas TNF inhibitors can be used during pregnancy and breastfeeding, and that JAK inhibitors are associated with an increased risk for infections, particularly herpes zoster.
Strand agreed that “it’s important to know that there’s an increased risk of herpes zoster” with JAK inhibitors, but she noted that patients can be vaccinated upon starting treatment. Moreover, she stressed that “JAK inhibitors have the shortest half-life of any therapeutic class in rheumatology, meaning that “adverse events can often resolve over a short time frame.”
“There is a need for vaccination and careful history and attention to risk factors for VTEs and [arterial thromboembolism],” as well as “careful surveillance for serious infections and malignancies,” she said.
Convenience and cost considerations
In addition to their favorable response rates and short half-life, Strand emphasized that the convenience of JAK inhibitors is a major draw for patients. “These are oral agents; they are convenient [with] ease for travel,” she said, noting that RA patients are typically “active, working [people], working within or outside the home,” with “high expectations for control of disease.”
Weinblatt, on the other hand, suggested that the dosing schedule of TNF inhibitors may be more convenient for patients.
“Dosing is daily with the [JAK inhibitors], whereas with the anti-TNF therapy “patients can dose weekly to every 8–12 weeks depending on whether they are using the [subcutaneous] or [intravenous] formulation,” he said.
Moreover, he commented that cost is an important consideration. “We so far have not benefited from the use of primarily biosimilar anti-TNFs [in the USA], but in Europe the [annual] cost of adalimumab biosimilar or etanercept biosimilar is about US$ 5000 [€ 4243],” whereas JAK inhibitors in the USA cost $ 50,000–60,000 (€ 42,436–50,923), “so there is a major cost saving with biosimilars,” he said.
So what’s the verdict?
In a poll submitted at the end of the debate, the majority of the audience voted in favor of Weinblatt’s argument that JAK inhibitors should not be used before TNF inhibitors after methotrexate failure in RA, with 69% agreeing with this view, while 31% said that JAK inhibitors should be used before TNF inhibitors.
“We are not there yet [with JAK inhibitors]; it takes a lot to convince people after years and years of safety data [with TNF inhibitors],” summarized Wahl.
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