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How does the safety of oral JAK inhibitors compare with that of dupilumab in patients with atopic dermatitis (AD)?

To find out, a group of dermatologists and immunologists with Harvard Medical School and Massachusetts General Hospital conducted a population-based cohort study that ultimately included data from 14,716 patients. Of these, 942 were treated with oral JAK inhibitors (upadacitinib, abrocitinib, and baricitinib), and 13,774 with dupilumab.

Treatment with oral JAK inhibitors was not associated with an elevated risk of mortality, malignancies, major adverse cardiovascular events, venous thromboembolism, renal events, or serious gastrointestinal events. On average, however, patients who received oral JAK inhibitors showed significantly higher risks of developing various significant if less serious conditions -- including skin and tissue infection (HR 1.35, 95% CI 1.07-1.69), herpes infection (herpes simplex: HR 1.64, 95% CI 1.03- 2.61; herpes zoster: HR 2.51, 95% CI 1.14-5.52), acne (HR 2.09, 95% CI 5 1.54-2.84), cytopenia (anemia: HR 1.83, 95% CI 1.39-2.41; neutropenia: HR 4.02, 95% CI 1.91- 8.47; thrombocytopenia: HR 1.76, 95% CI 1.08-2.89), and hyperlipidemia (HR 1.45, 95% CI 1.09-1.92).

The risk of ophthalmic complications was higher in those receiving dupilumab (HR 1.49, 95% CI 1.03-2.17).

The study appears in . The following paper excerpts were edited for length and clarity.

What was the impetus for this investigation?

Dupilumab was the first biologic approved by the FDA for moderate-to-severe AD. JAK inhibitors have since emerged as a promising option for AD treatment based on their capacity to modulate AD-related cytokines. One topical JAK inhibitor (ruxolitinib) is currently approved for mild-to-moderate AD, while three oral JAK inhibitors (upadacitinib, abrocitinib, and baricitinib) are approved for moderate-to-severe AD.

The safety of dupilumab has been established in both adults and children; its main side effects have been conjunctivitis and injection-site reactions. Dupilumab therapy has primarily focused on atopic disorders, while JAK inhibitors have broader applications across immune and inflammatory diseases, including rheumatoid arthritis and psoriasis.

Clinical trials investigating oral JAK inhibitors for AD have reported both mild and transient side effects such as headache and nausea, as well as more concerning complications, including serious and opportunistic infections, herpes infections, nasopharyngitis, acne, anemia, and elevated cholesterol levels, among others.

Despite the greater efficacy that oral JAK inhibitors have demonstrated over other systemic treatments in clinical trials for AD, many clinicians remain conservative in prescribing them for AD because of safety concerns that arose after the FDA placed boxed warnings on all approved JAK inhibitors. These concerns have persisted in the dermatology community even though the AEs that triggered the FDA warning came primarily from rheumatologic indications rather than dermatologic ones.

The current study's objective was to add new data to the safety profile of oral JAK inhibitors for patients with AD. Dupilumab was selected as the active comparator because of its place as the primary systemic treatment for AD.

What were the key safety findings for JAK inhibitors?

No major safety signals emerged for major adverse cardiovascular events, venous thromboembolism, renal events, or malignancies that have been problematic in patients treated with JAK inhibitors for other diseases.

Infections commonly reported after initiating therapy with JAK inhibitors include nasopharyngitis, pneumonia, urinary tract infection, cellulitis, and herpes.

Only sporadic cases of malignant neoplasms have been reported in clinical trials of JAK inhibitors for AD. These cases were mostly nonmelanoma skin cancer, and none were determined to be directly related to the medications used in the study.

What are the potential clinical implications for dermatologists?

According to the research team, the current findings can serve as reassurance that JAK inhibitors, when used to treat AD, did not seem to confer any risk for malignancies or the other serious AEs that led to the FDA warning.

In the meantime, increased susceptibility to infections remains a significant potential hurdle with JAK inhibitor therapy compared with dupilumab. For example, acne has been reported as one of the most frequent treatment-emergent AEs. These AEs typically do not lead to treatment discontinuation, but regular monitoring for these complications is recommended.

What does the future hold for JAK inhibitors and patients with AD?

This study only provided the outcomes within a 2-year follow-up. Certain chronic outcomes, such as neoplasms, may not manifest within this observational period.

Considering the recent approval of JAK inhibitors for AD and the limited two year tracking period of this study, there remains the possibility that diseases with longer latency periods may not yet have materialized in trials.