JAK inhibitors: Potential additions to chronic hand eczema treatment toolbox

The search for chronic hand eczema (CHE) relief has led to two different Janus kinase (JAK) inhibitors, one topical and the other oral, with both performing well in phase IIb trials reported during the 29th European Academy of Dermatology and Venereology (EADV) Virtual Congress.

A multifactorial skin disorder, CHE limits the ability to work and perform activities of daily living. It can also weigh on the patients’ psychological well-being and socioeconomic capacity. [J Cutan Med Surg 2010;14:267-284; Contact Dermatitis 2011;65:3-12; Dermatol Ther 2019;e12840:1-12]

Topical corticosteroids are commonly used for treatment, but the associated risks of atrophy and cracked skin limit their use, according to presenting author of the first trial Dr Margitta Worm of Charité University Hospital in Berlin, Germany.

Beyond corticosteroids, emollients, and calcineurin inhibitors, topical treatment options with well-documented efficacy and favourable safety profile are sparse, Worm added.

Pan-JAK inhibitor cream

“Delgocitinib is a novel pan-JAK inhibitor blocking all four members of the JAK family (JAK1–3 and tyrosine kinase 2),” having potential anti-inflammatory effects, she said.  

Worm and colleagues evaluated varying doses of delgocitinib cream (1, 3, 8, or 20 mg/g) against a vehicle cream in a randomized trial involving 258 CHE patients (mean age, 46 years; 61 percent female; mean disease duration, 12 years). Treatment was administered twice daily for 16 weeks.

The majority of the population (56 percent) had moderate eczema, while 20 percent had severe and 24 percent had mild. Median Hand Eczema Severity Index (HECSI) score at baseline was 44.5.

Delgocitinib doses of 8 and 20 mg/g exhibited the greatest efficacy. By week 16, 36.5 percent and 37.7 percent of patients in the corresponding dose groups were clear or almost clear of symptoms (Investigator’s Global Assessment for CHE [IGA-CHE] score of 0 or 1) as opposed to only 8 percent in the vehicle group (p=0.0004).

Skin clearance occurred as early as the fourth week in the 8 mg/g group and the sixth week in the 20 mg/g group. Furthermore, all active delgocitinib doses produced significant improvements in HECSI score from baseline to week 16 compared with the vehicle (p<0.05).

Neither safety-related dose response nor safety signals emerged, Worm noted. Most adverse events were mild or moderate in severity and considered to be unrelated to treatment. Nasopharyngitis, eczema, and headache occurred most frequently.

Dual inhibitor anti-inflammatory pill

Meanwhile, some patients with CHE do not respond to topical medications, and they may be prescribed systemic anti-inflammatories. Another team of researchers evaluated the efficacy of a novel oral dual inhibitor of JAK and spleen tyrosine kinase (SYK), gusacitinib, in moderate-to-severe CHE patients in a randomized, placebo-controlled trial.

“SYK–JAK inhibition with gusacitinib modulates Th2, Th22, Th1 and Th17 cytokines, and regulates keratinocyte interleukin-17 mediated signaling and proliferation/differentiation,” according to the presenting author Dr Howard Sofen of Dermatology Research Associates in Los Angeles, US.

“Hence [the drug] can simultaneously target both the immune cells and epithelial cells involved in CHE and other dermatologic and inflammatory conditions,” Sofen added.

In total, 97 patients (average age, 45 years; 70.57 percent female) were randomized to receive once-daily treatment with either placebo or gusacitinib at 40 or 80 mg for 16 weeks. Physician Global Assessment (PGA) was 3 or 4 at baseline, and all patients were refractory to topical or systemic corticosteroids (moderate, high, or ultra-high potency).

At week 16, the modified total lesion severity score (mTLSS) shed down by as much as 69.5 percent with gusacitinib 80 mg. In comparison, there was a relative decrease of 49.0 percent with the 40-mg dose and of 33.5 percent with placebo (p<0.005). Active treatment produced a 66- and 50-percent improvement, respectively, in the mTLSS pruritus subscore.

In addition, more patients in the gusacitinib than in the placebo group achieved PGA 0–1 status by week 16 (31.3 percent with 80 mg and 21.25 percent with 40 mg vs 6.3 percent; p<0.005). This improvement came as early as week 2 in the active treatment groups (p<0.05).

“Gusacitinib plasma concentration increased in a dose-related manner,” Sofen noted.

The drug was well tolerated at both dose levels. Adverse events were typically mild-to-moderate and of short duration. The most common of these were upper respiratory tract infection, headache, nausea, and nasopharyngitis. There were no thromboembolic events or opportunistic infections recorded.

In light of the findings, Sofen believes that gusacitinib represents a potential new oral treatment for patients with moderate-to-severe CHE and other inflammatory dermatological diseases.