Upadacitinib Outperforms 4 JAK Inhibitors in Atopic Dermatitis Meta-Analysis

A recent meta-analysis shows upadacitinib’s short term efficacy may be preferential for short-term efficacy versus 4 other oral Janus Kinase (JAK) inhibitors for atopic dermatitis, although direct comparison studies are still warranted.1

These findings on JAK inhibitor use resulted from a study conducted to compare oral upadacitinib therapy to 4 other JAK inhibitors, or JAKis: abrocitinib (100 or 200 mg), baricitinib (2 or 4 mg), and ivarmacitinib (4 or 8 mg).

Investigator Najib Babul, PharmD, MBA, a drug development consultant from Cinergen, and colleagues described indirect comparisons made via Bayesian network meta-analysis (BNMA) as helpful for comparisons of medication efficacy. However, previous studies had chiefly focused on biologics and others had information gaps due to a general exclusion of various data on different atopic dermatitis drugs.

“To address these gaps, we conducted a Bayesian network meta-analysis (BNMA) evaluating the short-term efficacy of four JAK inhibitors (abrocitinib, upadacitinib, baricitinib, and ivarmacitinib) as monotherapy for moderate-to-severe AD,” Babul and colleagues wrote.1 “The study aimed to rank their comparative efficacy, identify the most effective regimen across EASI-75, IGA-AD 0/1, and Itch NRS ≥ 4 endpoints, and inform evidence-based clinical decision-making.”

Analysis Details

The investigators, in accordance with PRISMA 2020 guidelines, conducted a systematic review conducted and registered in PROSPERO evidence drawn from various phase 2 and phase 3 randomized, double-blind, placebo-controlled trials. These studies would be evaluating oral JAK inhibitors for the treatment of moderate-to-severe atopic dermatitis, and the investigators’ searches involved the Embase, PubMed, Cochrane Library, and ScienceDirect databases.

In the early portion of their study, through August 2025, they conducted their search for trials. This was also supplemented by a manual screening of reference lists along with relevant congress abstracts, with Babul and coauthors seeking to ensure inclusion of all eligible research. In their review, they looked at data on baricitinib at doses of 2 mg and 4 mg, abrocitinib at 100 mg and 200 mg, upadacitinib at 15 mg and 30 mg, and ivarmacitinib at 4 mg and 8 mg. Age eligibility criteria were noted by the investigators as consistent with criteria implemented in the pivotal clinical development programs for each of these drugs.

Research related to abrocitinib included the JADE MONO-1 study (NCT03349060), JADE MONO-2 (NCT03575871), and a phase 2b analysis (NCT02780167), with patients evaluated being aged 12 years and older. Data on upadacitinib’s use were derived from MEASURE UP-1 (NCT03569293) and MEASURE UP-2 (NCT03607422). These 2 studies included participants between the ages of 12 - 75 years.

The BREEZE-AD1 (NCT03334396), BREEZE-AD2 (NCT03334422), and BREEZE-AD5 (NCT03435081) studies were used to look at baricitinib, and all of these trials were limited to adults aged 18 years or older. For ivarmacitinib, Babul et al used a phase 3 study (NCT04875169) that enrolled adolescents and adults between 12 - 75 years of age. In terms of primary efficacy outcomes, they looked for patient attainment of at least a 75% improvement from baseline in the Eczema Area and Severity Index (EASI-75) at 12 - 16 weeks.

Additionally, they looked at participants’ Investigator’s Global Assessment scores of clear or almost clear (IGA-AD 0/1). They also looked for a reduction of at least 4 points on the itch numeric rating scale, also known as the Itch NRS. Effects of therapies were estimated by the investigators via Bayesian hierarchical models, with odds ratios (ORs) being generated with corresponding 95% credible intervals (CrIs). Comparative ranking across these 4 drugs was determined through the use of surface under the cumulative ranking curve (SUCRA) probabilities.

Comparisons of 4 JAK Inhibitors

In total, there were 9 randomized controlled trials. These studies were made up of 4261 individuals who had met the criteria for involvement. Across all endpoints examined by Babul and colleagues, upadacitinib 30 mg consistently had the strongest level of efficacy in those with atopic dermatitis. In their assessment of EASI 75 scores, the OR was 12.3 (95% CrI, 7.9–18.7). IGA-AD 0/1 response, on the other hand, yielded an OR of 18.9 (95% CrI, 12.0–29.7). Positive shifts in pruritus severity, defined by a ≥4-point reduction in trial participants’ Itch NRS scores, was also shown to be the greatest with upadacitinib 30 mg treatment, with an OR of 11.1 (95% CrI, 7.2–17.5).

This dose was followed in overall efficacy by upadacitinib 15 mg. Then, Babul and coauthors found abrocitinib 200 mg had the next best efficacy, followed by ivarmacitinib 8 mg. In contrast, they found baricitinib at both the 2 mg and 4 mg doses had been consistently in the lowest treatment ranking positions. They reinforced such data via SUCRA analyses. Upadacitinib 30 mg attained probabilities ranging from 97% - 98%, which the investigators note suggests an increased likelihood of being the most effective option across the different endpoints.

Overall, the investigative team concluded upadacitinib, especially at the 30 mg dose and followed by the 15 mg dose, allows for the most robust short-term improvements in both patients’ level of skin clearance and their level of itch among these 4 oral JAKis.

“These findings support a provisional efficacy preference for upadacitinib in managing moderate-to-severe [atopic dermatitis] unresponsive to biologic or topical therapies,” they wrote.1

A variety of limitations were also noted in this analysis, with the team citing the lack of head-to-head trials among the 4 aforementioned medications, requiring reliance on indirect, placebo-controlled comparisons. They also noted variability in baseline characteristics. Examples of baseline severity differences include IGA-AD and EASI scores.

For trials such as Measure Up 1, IGA-AD severity among 3 cohorts at baseline ranged from 125-131, whereas in JADE MONO-1, for example, baseline severity among 3 cohorts involved ranged from 31-64. Other baseline characteristic differences were referenced such as patients' ages between studies as well as different geographic locations, background use of topicals, and washout rules among those evaluated.

Outcome timing across studies was also highlighted, along with additional constraints such as the inability to assess publication bias, baseline severity differences, the short-term only focus on efficacy, and the lack of quality-of-life outcomes included due to inconsistent reporting and measurement. Overall, the investigators acknowledgements underscored the need for longer-term and more standardized future research.

References

1. Babul A, Mehta D, Babul N, et al. Upadacitinib Leads in Efficacy: A Bayesian Network Meta-Analysis of Four JAK Inhibitors in Moderate-To-Severe Atopic Dermatitis. Int J Dermatol. 2026 Jan 5. doi: 10.1111/ijd.70228. Epub ahead of print. PMID: 41489415.

2. Zhao Y, Gooderham M, Zhang J. Ivarmacitinib for Moderate to Severe Atopic Dermatitis in Adults and Adolescents: A Phase 3 Randomized Clinical Trial. JAMA Dermatol. 2025 Jul 1;161(7):688-697. doi: 10.1001/jamadermatol.2025.0982. PMID: 40305055; PMCID: PMC12044538.