Introduction

Deuruxolitinib is an orally available small molecule inhibitor of Janus kinases that is used to treat severe alopecia areata. Deuruxolitinib is associated with a low rate of transient and usually mild elevations in serum aminotransferase levels during therapy but has not been linked to cases of clinically apparent acute liver injury.

Background

Deuruxolitinib (dew rux” oh li’ ti nib) is an orally available, specific inhibitor of Janus-associated kinases (greater inhibition of JAK1, JAK2, and TYK2 relative to JAK3) that is used to treat moderate-to-severe alopecia areata. Alopecia areata is an autoimmune disorder that is characterized by hair loss resulting in patches and even complete baldness of the scalp, along with thinning or loss of eyebrows and eyelashes. It is believed to be an autoimmune condition. The Janus kinases are critical steps in immune activation that transmit signals for different cytokine receptors and promote expression of genes involved in production of proinflammatory cytokines. Inhibitors of JAK kinases have been used to treat several autoimmune diseases including alopecia areata. In two large randomized controlled trials, deuruxolitinib was found to decrease or reverse hair loss in adults with alopecia areata. Deuruxolitinib was approved for this use in the United States in 2024, the third small molecule JAK inhibitor approved as therapy for alopecia areata, after baricitinib (in 2022) and ritlecitinib (in 2023). Deuruxolitinib is available in tablets of 8 mg under the brand name Leqselvi. The recommended dose is 8 mg twice daily. Current indications are severe alopecia areata (as defined by 50% hair loss or greater) in adults. Common side effects are headache, acne, rash, nasopharyngitis, fatigue, weight gain, skin and soft tissue infections, and herpes virus reactivation. Deuruxolitinib can also cause anemia, lymphopenia, neutropenia, thrombocytopenia, hyperlipidemia, and creatine kinase elevations. Potential severe adverse events may include reactivation of fungal, viral, and opportunistic infections such as tuberculosis, hepatitis B, herpes simplex, and herpes zoster. Other JAK inhibitors have been linked to a higher rate of all-cause mortality and rarely to venous and arterial thromboses and to malignancies and major atherosclerotic cardiovascular and cerebrovascular events (myocardial infarction, stroke, and cardiovascular death).

Hepatotoxicity

In the prelicensure clinical trials in alopecia areata, serum aminotransferase elevations occurred in less than 1% of deuruxolitinib-treated subjects and there were no instances of ALT or AST elevations accompanied by symptoms or jaundice. The elevations were typically mild and transient and did not lead to dose adjustments or discontinuations. In prelicensure studies in alopecia areata, there were no instances of liver related severe adverse events or drug induced liver injury. Since approval of deuruxolitinib, there have been no published reports of hepatotoxicity associated with its use, but clinical experience with it has been limited.

Finally, deuruxolitinib is an immune modulatory agent and has the potential of causing reactivation of viral infections including hepatitis B. Other JAK inhibitors have been implicated in rare instances of reactivation of hepatitis B, although the episodes were usually asymptomatic and self-limited in course. The risk of reactivation of hepatitis B in patients with HBsAg or with anti-HBc without HBsAg who are treated with deuruxolitinib has not been defined as patients with these viral markers were excluded from the preregistration trials.

Likelihood score: E* (unlikely cause of idiosyncratic clinically apparent liver injury but is a potential cause of reactivation of hepatitis B).

Mechanism of Injury

The mechanism by which deuruxolitinib might cause liver injury is not known. It is metabolized in the liver, largely via CYP 2C9 and to a lesser extent by 3A4. High levels can arise in patients who are slow metabolizers by CYP 2C9 and the product label recommends testing patients for CYP 2C9 metabolized status before its use. Furthermore, coadministration of deuruxolitinib with moderate or strong inhibitors of CYP 2C9 can lead to marked elevations in plasma levels and such agents should not be used. Finally, concurrent use of inducers of CPY 2C9 or 3A4 can lead to lower plasma levels and possible loss of effect and should not be avoided. The pharmacokinetics of deuruxolitinib are not affected by mild-to-moderate liver impairment (Child-Pugh A or B), but its use is not recommended in patients with severe impairment (Child-Pugh C).

Outcome and Management

Serum aminotransferase elevations are uncommon during deuruxolitinib therapy, and routine monitoring of liver tests is not recommended in the product label. If aminotransferase elevations above 5 times the upper limit of normal (ULN) arise, deuruxolitinib therapy should be interrupted, at least temporarily, until levels fall into the normal or near normal range. Elevations above 20 times the ULN or any elevations accompanied by symptoms or jaundice should lead to permanent discontinuation.

Because of its potential to cause reactivation of hepatitis B, routine blood screening for HBsAg and anti-HBc before starting therapy with deuruxolitinib is appropriate. Patients with HBsAg in serum should be treated prophylactically during therapy using an oral antiviral agent with activity against HBV such as entecavir or tenofovir. An alternative approach, which is also appropriate for patients with anti-HBc without HBsAg, is to monitor patients carefully for HBV DNA and initiate antiviral therapy if HBV DNA becomes detectable in serum.

Drug Class: Dermatologic Agents, Protein Kinase Inhibitors

Other Drugs for Alopecia areata: Baricitinib, Ritlecitinib