乌鸦传媒視頻

The targeted synthetic disease-modifying antirheumatic drugs (DMARDs) known as Janus kinase inhibitors or "jakinibs" are emerging as a new therapeutic option for patients with inadequate response to conventional synthetic DMARDs and established biologics such as tumor necrosis factor (TNF) inhibitors. Their safety profile, however, is still under investigation.

As small, orally delivered, and rapid-acting molecules, JAK1, JAK2, and JAK3 inhibitors intervene in the immune signaling pathway by targeting tyrosine enzymes and downregulating the JAK-STAT pathway. As non-selective agents, they have the advantage of suppressing several inflammatory cytokines, including interferon alpha and beta, and interleukins 2, 4, 7, 9, 15, 21, and 22.

These inhibitors are considered a breakthrough since the introduction of biologics because they are not limited to antagonizing a single target, and their oral route of administration could influence patient preference and minimize drug discontinuation rate over those seen with parenterally delivered drugs. "They may be the preferred option for patients who have a phobia about needles," said Elizabeth Volkmann, MD, of UCLA Medical Center in Los Angeles. In addition, they may ultimately cost less than biologics with complicated chemical structures.

How soon they become early-line therapy is not clear. "It's always hard to predict the time frame in which an agent will be utilized in the treatment algorithm, but JAK inhibitors have already found a place in treating those who fail one or more biologics," Mark C. Genovese, MD, of Stanford University Medical Center in California, told 乌鸦传媒視頻. "And, increasingly, I think we'll see these drugs used earlier, even in front of other biologics such as TNF inhibitors."

Genovese noted that several clinical trials have shown a combination of a JAK inhibitor plus methotrexate to be more effective than comparator use of methotrexate plus the TNF inhibitor adalimumab (Humira).

In the JAK 1/JAK 2 inhibitor tofacitinib (Xeljanz) monotherapy (as first- or second-line treatment) and combination therapy with a DMARD (as second- or third-line treatment) has effectively reduced disease activity and improved health-related quality of life, with benefits sustained during long-term therapy. Tofacitinib monotherapy has inhibited progression of structural damage in methotrexate-naïve patients, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months.

Newer jakinibs also look promising. In a randomized, double-blind, placebo- and active-controlled trial of patients with an inadequate response to methotrexate, the JAK1/2 inhibitor baricitinib (Olumiant) was associated with significant clinical improvements over placebo and adalimumab. An increased American College of Rheumatology (ACR) 20 score response rate at week 12 was observed with baricitinib versus adalimumab (70% and 61%, respectively). Furthermore, baricitinib proved superior to adalimumab in the mean Disease Activity Score 28-joint count/C reactive protein (DAS28-CRP) achieved at week 12. Adverse events were similar. The drug, however, was associated with a reduction in neutrophil count, early transient increases in lymphocyte count, and modest increases in platelet count.

Tested in the upadacitinib, a JAK1 newcomer, proved superior both to placebo and adalimumab in RA. Low disease activity based on DAS28-CRP was seen in 45% of patients receiving upadacitinib versus 29% receiving adalimumab and 14% receiving placebo at week 12, respectively.

Findings also demonstrated the superiority of upadacitinib over adalimumab on secondary endpoints. At week 12, 45% of upadacitinib patients achieved ACR50 versus 29% of patients receiving adalimumab. Upadacitinib was also superior to adalimumab in pain reduction, measured by the Patient's Assessment of Pain, and improvements in physical function, measured by the Health Assessment Questionnaire-Disability Index at week 12.

Most recently, 乌鸦传媒視頻 reported on a phase III study presented at ACR 2018 that found upadacitinib superior to placebo and comparator adalimumab for RA. This new agent is currently being tested in phase 3 trials of psoriatic arthritis and Crohn's disease, and is being investigated to treat ulcerative colitis, ankylosing spondylitis, atopic dermatitis, lupus, and giant cell arteritis.

Are different jakinibs more effective and safer than others? "So far, there have been no head-to-head trials between different JAK inhibitors so we can't make direct comparisons of their individual efficacy," said Genovese, whose group is involved in several trials.

As for risks, "At our institution we haven't observed differences in safety profile between individual JAK inhibitors or other biologics, whether in terms of cardiovascular problems, cancer, or infection," Volkmann said.

But because jakinibs have been variously associated with increased risk of herpes zoster, thrombotic events, and changes in lipid and hematological status, researchers are investigating more selective versions. New JAK1- and JAK3-specific agents are expected to minimize JAK2 inhibition, thereby limiting the associated impact on hemoglobin, lymphocyte, and neutrophil counts.

Among these, the novel JAK1-specific inhibitor filgotinib demonstrated rapid efficacy as monotherapy in the phase IIb trial, having previously proven beneficial in combination with methotrexate in DARWIN 1.

Peficitinib and decernotinib are two new selective inhibitors of JAK3 that have proven effective in reducing the signs and symptoms of RA and obtaining significant ACR score response rates in patients with inadequate response to conventional synthetic DMARDs. Safety signals were acceptable.

In a phase II decernotinib at a range of dosages was tested against placebo in biologic-naive RA patients who had failed DMARDs. ACR20 responses for the highest dosages ranged from 61% to 65.9% compared with 29.3% for placebo. Some serious infections and liver enzyme elevations were noted, but there were no cytopenias and no effects on serum creatinine level.

Two (RAJ3 and RAJ4) of peficitinib, which inhibits both JAK1 and 3, have shown the efficacy of this agent in RA patients failing conventional therapy. A phase III randomized placebo-controlled, reported by Yoshiya Tanaka, MD, PhD, and colleagues at the American College of Rheumatology meeting, 2018, found that peficitinib monotherapy at two different daily doses significantly reduced RA symptoms with acceptable safety and tolerability and no emergent safety signals versus other JAK inhibitors. Its efficacy was similar to that of etanercept (Enbrel), used on safety control group.

Safety remains top of mind among researchers and clinicians. While to date no increased risk of malignancy in RA has emerged with tofacitinib, which has been in use the longest, experience is still limited even for this older jakinib, and extended follow-up studies must carefully evaluate long-term risk for this and other JAK inhibitors.

"Our understanding of the safety aspect of these agents will evolve as we do more trials with more agents," Genovese said.