Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib

Sandra Ferreira; Emma Guttman-Yassky; Tiago Torres


Am J Clin Dermatol. 2020;21(6):783-798. 

In This Article


Despite being a highly prevalent disease, until recently, AD lacked efficacious, safe, long-term therapy options for moderate-to-severe disease. Now, though, it is somewhat challenging to keep up with the extremely fast pace of developments in AD. Recent evidence unveiling the molecular underpinnings of AD, in association with the huge unmet need for effective and safe medications, and strong industry motivation in producing novel agents, has led to multiple therapeutic agents being tested for this skin disease. In fact, a much-needed paradigm shift in AD treatment seems to be finally on the verge. Increasing knowledge of its pathogenesis has allowed the development of new small-molecule agents that inhibit multiple cytokines at once by targeting their intracellular signaling pathways, such as the JAK-STAT pathway. In fact, JAK inhibitors are emerging as an exciting class of therapies in the field of dermatology.

Data from phase II and phase III studies demonstrated significant efficacy with an acceptable safety profile of both selective JAK1 inhibitors, upadacitinib and abrocitinib, vs placebo for the treatment of moderate-to-severe AD. Therefore, it is not surprising that both agents were granted breakthrough therapy designation by the Food and Drug Administration in AD.

Upadacitinib and abrocitinib demonstrated fast clinical improvement in study endpoints with each dose regimen evaluated, with especially strong efficacy at the highest doses. These drugs also showed meaningfully improved IGA and EASI75 dose–response outcomes compared with placebo.

A clear dose response was observed with upadacitinib for the primary endpoint and most secondary endpoints, including EASI50, EASI75, EASI90, and IGA 0/1, which were statistically significantly higher with each dose regimen compared with placebo.[74] Upadacitinib 30 mg was associated with the highest decrease in EASI and appeared to exhibit the best benefit/risk profile. One-half of patients receiving 30 mg daily achieved an EASI90 response and an IGA 0/1 score at week 16. In fact, these outcomes are considerably high for a systemic monotherapy in this population.[74] Noteworthy, an EASI100 response, which was not previously reported before this study, was defined and reported for the first time with upadacitinib, being more frequently observed in the 15- and 30-mg groups vs placebo at week 16. Other endpoints, such as pruritus and SCORAD, BSA, and POEM scores, were also shown to improve from baseline at week 16.

Regarding abrocitinib, data from phase II–III studies have demonstrated that 200- and 100-mg doses of once-daily oral abrocitinib were associated with great improvement in the signs and symptoms of AD, with a fast onset of action for disease severity and pruritus. Approximately 40% and 24–30% of patients achieved IGA 0/1 with 200 and 100 mg of abrocitinib, respectively, thereby highlighting its efficiency in the short term.

Noteworthy, in both studies, the proportion of patients achieving IGA 0/1 with the highest dose of abrocitinib was ~ 38–44% (vs 8–9% for placebo), which is similar to the percentage of patients achieving this endpoint with dupilumab (40% vs 8–10% for placebo) after 16 weeks of treatment.[10] Clinical efficacy has also been demonstrated by ~ 60% and ~ 40% of patients achieving EASI75 with 200 and 100 mg of abrocitinib, respectively.

Regarding pruritus, for all doses of upadacitinib, a reduction in pruritus was observed as early as week 1 and improvement in the extent and severity of skin lesions as early as week 2. Similarly, abrocitinib rapidly (within 1 day) and significantly improved pruritus vs placebo regardless of the baseline peak pruritus NRS score. Interestingly, in the JADE COMPARE study, reduction in itch severity was statistically superior for the 200-mg abrocitinib dose compared with dupilumab and numerically higher, for the 100-mg abrocitinib dose compared with dupilumab. As itching aggravates the quality of life of patients with AD, including loss of sleep and suicidal ideation, relief of pruritus may be especially important. This improvement in pruritus with a JAK1 blockage may have been mediated by inhibiting IL-31 and factors that directly prompt itching in sensory neurons.[49] The effectiveness observed with upadacitinib and abrocitinib may reflect the fact that JAK1 inhibition aims further cytokine pathways implicated in chronic AD, beyond just Th2 and Th22 cytokines,[40,82] differentiating from dupilumab.

There was considerable diminution of serum levels of Th2 (absolute eosinophil count, CCL17/18/26) and Th22 (IL-22-associated markers) with upadacitinib (15 and 30 mg) as early as week 2, implying that upadacitinib may have early and strong effects on AD's characteristic Th2 and Th22 axes. Molecular meliorations were also noticed and were correlated with clinical improvement.

Although efficacy appeared to stabilize within the 16-week period (except EASI100, which was still increasing with upadacitinib), further information on longer term efficacy and safety will be yielded by the ongoing trials. The safety profiles of both drugs were acceptable, and exhibit a dose-dependent pattern. An unprecedented efficiency was demonstrated with the upadacitinib 30-mg regimen, and, although small dose-dependent anomalies were observed in hemoglobin, neutrophils, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and creatinine phosphokinase over time, they were not regarded as clinically relevant. The increased occurrence of acne was unexpected, though, none of those AEs were severe. Although mild to moderate in most patients, acne may have a potential negative impact on a patient's quality of life, already impacted by AD. It is difficult to postulate a mechanism explaining the increased occurrence of acne that should be further studied in future trials. Overall, based on the phase IIb data, there was no registration of dose-limiting safety AEs or unexpected safety findings that would prevent further investigation of upadacitinib in AD.

Abrocitinib was also well tolerated through week 12, which was demonstrated by its safety profile. Gastrointestinal AEs were the only treatment-related AEs occurring considerably more often in patients receiving abrocitinib than those given placebo; however, these events were mostly mild. Changes in platelet counts do not appear to represent a significant clinical safety risk in most patients, and were manageable and reversible. The mechanism that leads to changes in platelet counts with abrocitinib treatment is not known. However, it could be a pharmacologic effect of abrocitinib, potentially mediated by the inhibition of JAK1 and downstream inhibition of thrombopoietin production or by the inhibition of Ashwell-Morrell receptors and downstream effects on platelet production. For this reason, laboratory monitoring of this parameter is advisable during abrocitinib treatment.

Anomalous laboratory findings, including transient augments in creatinine phosphokinase and liver enzymes, along with lipid and hematologic anomalies are attributed to JAK inhibitors.[83–87] Janus kinase 1 blockage has also been demonstrated to increase total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides.[83–87] Whether these lipid anomalies occur because of a reaction to inflammation or as a consequence of the mechanism of action of these biologic agents requires further investigation, including the assessment of long-term cardiovascular risks. Of note, in the JADE COMPARE study, a broader proportion of patients in the abrocitinib 200-mg group experienced AEs (61.9%) compared with the other treatment arms, abrocitinib 100 mg, dupilumab, and placebo arms (50.8, 50, and 53.4%, respectively).

Most JAK inhibitors are associated with hematologic abnormalities such as neutropenia, anemia, and thrombocytopenia.[83–87] Janus kinase 2 is implicated in signaling via erythropoietin and other colony-stimulating factors, thus contributing widely to neutropenia and anemia events.[43] Nevertheless, inhibition of JAK1 is also associated with hematologic issues, which may be explained by the inhibition of IL-6 signaling or the presence of a residual JAK2 inhibitory effect.[84–87]

Importantly, JAK inhibitors such as tofacitinib, ruxolitinib, and baricitinib have been associated with an increased risk of thromboembolic AEs, especially at higher dosage, which may be serious and life threatening, and thereby these drugs may not be suitable for patients at risk for these events.[88] However, only one AE of pulmonary embolism was reported in a patient treated with abrocitinib 200 mg in phase IIb study, which was not considered related to treatment. There were no thromboembolic AEs reported for both selective JAK1 inhibitor agents in all the other trials. Noteworthy, the observational study by Verden et al.[88] suggests that there may indeed be a general effect of JAK inhibitors on thromboembolic disorders, although there is ongoing incertitude about its accurate nature. While thromboembolic-related AEs as a whole may not be a class-wide problem with JAK inhibitor agents, pulmonary thrombosis is a potential issue for the class, and portal vein thrombosis may be a potential risk for ruxolitinib.[88] Perhaps, the selective JAK1 antagonism over JAK2 and JAK3 may yield a more favorable thromboembolic AE profile.