JAK inhibitors in rheumatoid arthritis
Janus kinases (JAKs) are a family of tyrosine kinases that function as “intracellular switches” in the signalling processes of the type I/II cytokines and certain growth factors, following engagement with their receptors. There are four members of the JAK family: JAK1, JAK2, JAK3, and tyrosine kinase 2.
Many Type I/II cytokines are implicated in rheumatoid arthritis (RA) pathogenesis. Blocking these key cytokines by targeting JAK pathways offers a new approach to RA treatment. In contrast to biologic therapies, which are large proteins that require injecting and are incapable of penetrating the lipid bilayer cell membrane, JAK inhibitors are small molecules that are orally available and can cross the cell membrane to block activity of one or more cytoplasmic JAKs. They are non-immunogenic and have a shorter half-life than biologics, with the advantage of more rapid reversal of any drug-related adverse events.
Clinical data and efficacy
There are two JAK inhibitors currently FDA/EMA approved for the treatment of active RA: tofacitinib, the first JAK inhibitor to be approved, which selectively inhibits JAK1 and JAK3; and baricitinib, a selective JAK1/2 inhibitor. Both tofacitinib and baricitinib have undergone extensive clinical trials and demonstrate rapid improvements in symptoms and signs when used in combination with concomitant methotrexate, other conventional disease modifying anti-rheumatic drugs (cDMARDs), or as monotherapy, with benefits reported as early as 2 weeks. Both agents inhibit structural damage progression. Remarkably, in methotrexate inadequate responders, the combination of methotrexate and baricitinib 4 mg once daily has demonstrated superiority for American College of Rheumatology criteria (ACR20) response and Disease Activity Score (DAS28-CRP) reduction over standard of care biologic adalimumab used with background methotrexate.
It has been proposed that more selective JAK1 inhibitors may reduce dose-limiting toxicity, even though inhibition of JAK2 and JAK3 may contribute to efficacy. Other JAK inhibitors in development include the selective JAK1 inhibitors filgotinib and upadacitinib, with confirmed efficacy in phase III trials.
Risk for adverse events
Overall, the absolute risk for serious adverse events appears comparable to that of biologic agents. The most striking difference between tofacitinib and baricitinib versus existing therapies is an increased risk for herpes zoster infection, most markedly in patients of East Asian ethnicity.
JAK inhibitors can also cause anemia and cytopenia, but this is rarely of clinical significance at the approved doses. JAK inhibitors are also associated with increases in serum levels of cholesterol, but without alteration to the low-density lipoprotein:high-density lipoprotein ratio.
More controversially, venous thrombotic events (VTE) have been observed in trials within expected frequencies for an RA population. However, in a recent safety study requested by the FDA, tofacitinib at the high 10 mg bd dose, but not the approved 5 mg bd dose, demonstrated an association with VTE. In baricitinib trials there was an imbalance in VTE events in the placebo-controlled period between the placebo and 4 mg once daily baricitinib regime, although this imbalance was not observed when placebo patients were switched to the active comparator. It is unclear at present whether this is a class effect, and if so, what the mechanism is, but caution should be exercised in patients with a thrombotic history. There is no association with cardiovascular events.
The place of JAK inhibitors in the contemporary management of RA
Contemporary recommendations for RA management suggest consideration of a JAK inhibitor as a treatment option in patients with cDMARD- or biologic-refractory RA. In my own practice, and as more general experience has grown in the clinic, JAK inhibitors are increasingly being positioned after cDMARD failure.
Many patients express a preference for oral over injectable drugs, and report that they value the rapid onset of benefit. I undertake routine blood monitoring tests in exactly the same way as for patients taking methotrexate and, in addition, I check fasting blood lipids after 12 weeks of treatment with a JAK inhibitor. If levels are raised above thresholds indicated by NICE recommendations, I consider addition of a statin.
To conclude, JAK inhibitors have the convenience of oral delivery with rapid onset of a biologic-like efficacy with a favorable overall benefit:risk profile.
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