Janus Kinase inhibitors in AD: a safety overview

The previous article in this special supplement provided an important overview of the pathophysiology and pivotal efficacy data of Janus kinase inhibitors (JAKis) in atopic dermatitis (AD). While efficacy is paramount to the clinician’s decision-making approach to disease management, there is also a need to consider therapies that can be used in the long-term without causing irreversible end organ damage or high levels of adverse effects leading to treatment discontinuation.

First generation JAKis approved for the treatment of rheumatoid arthritis (RA) such as tofacitinib have exhibited a number of adverse events including severe infections, venous thromboembolism and malignancies, which have resulted in black box warnings¹. Due to safety concerns with first generation JAK inhibitors, likely as a result of JAK2 and JAK3 inhibition, interest has shifted to the more selective JAK1 inhibitors with the aim of achieving a more tolerable safety profile ^2,3.  Upadacitinib and abrocitinib have greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2. Overall, the safety profile of the JAK1 inhibitors in the phase III AD studies, at the 16 week follow up timepoint, is reassuring (Table 1). These newer JAKis do not appear to have the same side effect profile as the first generation JAK inhibitors. As such, both compounds were recently approved for the treatment of adults and adolescents ≥ 12 years of age with refractory moderate-to-severe AD who are not adequately controlled with systemic treatments (e.g., steroid or biologic) or when use of those therapies is inadvisable.^4,5

Table 1. Summary of adverse events associated with systemic JAKis for the treatment of AD over short-term trials adapted from Wood et al., 20226
AE, adverse event; SAE, serious adverse event; VTE, venous thromboembolism; URTI, upper respiratory tract infection; CPK, creatine phosphokinase; NR, not reported

Importantly, upadacitinib and abrocitinib have been studied in a relatively younger and healthier AD population, which is very different from an older RA population who may have numerous underlying comorbidities, risk factors and possibly be taking concomitant immunosuppressive therapies. As a result, neither the indirect comparison across trials with differing patient populations nor the comparison of different JAKis with varying pharmacological characteristics and clinical profiles are recommended.

The Measure Up 1 and Measure Up 2 studies were 16-week replicate pivotal phase III studies designed to assess the safety and efficacy of upadacitinib vs placebo in moderate-to-severe AD patients. Eligible patients were adolescents (aged 12-17 years) and adults (aged 18-75 years) with moderate-to-severe atopic dermatitis (≥10% of body surface area affected by atopic dermatitis, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator’s Global Assessment for Atopic Dermatitis [vIGA-AD] score of ≥3, and Worst Pruritus Numerical Rating Scale score of ≥4). The most frequently reported treatment-emergent adverse events (≥5% in any treatment group in either study) were acne (all but one were mild-moderate in severity, and usually managed via topical therapies or no intervention),⁷ upper respiratory tract infection, nasopharyngitis and headache. The incidence of serious adverse events and adverse events leading to discontinuation of the study drug were low and balanced across treatment arms⁸. No deaths and few adverse events of special interest were reported in either study. The incidence of serious infections was less than 1% in all treatment groups; a few cases of opportunistic infections were reported, and the incidence was similar between treatment groups. All opportunistic infections reported were cases of eczema herpeticum (three patients in the upadacitinib 15 mg cohort, three patients in the upadacitinib 30 mg cohort, and four patients in the placebo cohort). The incidence of herpes zoster infection was higher in the active arms than the placebo arm. However, no cases of herpes zoster led to discontinuation of study drug. The incidence of anemia, neutropenia, and lymphopenia were observed to be transient. A few cases of malignancies excluding nonmelanoma skin cancer were noted, but none was deemed to be associated with the treatment. No cases of active tuberculosis, adjudicated gastrointestinal perforation, venous thromboembolic events, or major adverse cardiovascular events were reported in either of the upadacitinib cohorts. The Measure Up trials provided efficacy and safety data out to 16 weeks and more recently, 52-week efficacy and safety data demonstrated an overall consistency with the 16-week data for both doses of upadacitinib (Table 2).⁹

Table 2. Treatment-emergent adverse events and exposure-adjusted event rates during upadacitinib administrationa; adapted from Guttman-Yasky, E. et al, 2021
aCombined data from Measure Up 1 and Measure Up 2 studies (safety population). bOne death (myocardial infarction related to COVID-19 infection) occurred on study Day 399 (28 days after last study drug dose) in a 67-year-old man treated with UPA 30 mg in Measure Up 1; the patient had multiple cardiovascular disease risk factors. AE, adverse event; CPK, creatine phosphokinase; PBO, placebo; PY, patient-year; TEAE, treatment-emergent AE; UPA, upadacitinib; URTI, upper respiratory tract infection; cEczema herpeticum or Kaposi’s varicelliform eruption
CPK, creatine phosphokinase; GI, gastrointestinal; HZ, herpes zoster; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer; PBO, placebo; PY, patient-year; TB, tuberculosis; UPA, upadacitinib

Recent studies have also published safety data on other JAKis showing adverse event rates over an average duration of 24 or more weeks.^10-12 In an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study to evaluate the long-term safety of abrocitinib 200 mg and 100 mg, total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure 

was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 patients (maximum 108 weeks)¹⁰. Results from this study demonstrated that dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). A transient and dose-dependent reduction in platelet count was observed; 2/2718 patients (200 mg group) had confirmed platelet counts of < 50 × 10³/mm³ at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200 mg and 100 mg groups, respectively. The IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were observed to be < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200 mg group.

To date, the long-term safety data for newer JAK inhibitors up to 52 weeks of treatment is consistent across the published literature of the JAK inhibitor class with no new safety signals being reported. The upadacitinib 52-week data looking at the exposure-adjusted adverse event rates (per 100 patient-years) remained stable between 16 and 52 weeks of exposure (Table 2). Longer term data up to 5 years will be available in the near future, and which, when combined with real world experience, may enhance physician comfort with prescribing new generation JAKis for their AD patients.

Screening and monitoring considerations with JAKis in AD

Before initiating therapy with JAKis, it is important to ensure that key vaccinations are up to date including prophylactic zoster vaccination in agreement with current immunization guidelines ⁹. Clinicians should also assess for signs and symptoms of infection, screen for TB or latent TB by performing a TB skin test or QuantiFERON^®-TB Gold and order a chest x-ray. It is important to verify the pregnancy status of female patients of childbearing age. Clinicians should also screen for risks factors for VTEs including birth control use, prothrombotic status, past history or family history of deep vein thrombosis/pulmonary embolism. Finally, baseline bloodwork should include CBC, aspartate transaminase/alanine transaminase (AST/ALT), renal function, lipid profile and hepatitis serology.

Despite an acceptable safety profile, monitoring is required with JAKis. It is recommended to see patients for follow up a few months after initiating JAKi therapy to check clinical response, side effects and to repeat basic bloodwork which would include CBC, liver enzymes and lipid profile (Table 3). 

Table 3. Key monitoring considerations with JAKis for the treatment of AD

Conclusion

JAK inhibitors have revolutionized the treatment landscape for moderate-to-severe atopic dermatitis. As novel small molecules with a unique mode of action involving the blocking of the JAK-STAT pathway, JAKis are highly, rapidly efficacious and have demonstrated a tolerable safety profile in the AD population. The side effects associated with JAKi use are largely minor, highly predictable and can be readily identified through regular monitoring and easily managed with no long term sequelae observed out to >1 year in adults and adolescents with moderate-to-severe atopic dermatitis.