The contribution of itch and skin severity improvements to the Dermatology Life Quality Index in patients with atopic dermatitis in baricitinib phase III trials

Abstract

With data from three monotherapy baricitinib phase III randomized clinical trials (RCTs), we conducted a posthoc mediator analysis to assess whether changes in itch or skin severity mediated the treatment effect over placebo on changes in health‐related quality of life. In this analysis, baricitinib demonstrated significant improvement in the Dermatology Life Quality Index for which itch mediated approximately half of the changes at weeks 4 and 16.

dear editor, Baricitinib, an oral, selective Janus kinase (JAK)1/JAK2 inhibitor, is approved in several countries for the treatment of moderate‐to‐severe atopic dermatitis (AD) in adults who are candidates for systemic therapy. With data from three monotherapy baricitinib phase III randomized clinical trials (RCTs), ¹ , ² we conducted a post hoc mediator analysis to assess whether changes in itch or skin severity mediated the treatment effect over placebo in health‐related quality of life (HRQoL).

This analysis included data from BREEZE‐AD1 (NCT03334396), BREEZE‐AD2 (NCT03334422) and BREEZE‐AD5 (NCT03435081). Detailed methods of the RCTs have been published. ¹ , ² The RCTs were double‐blind, parallel‐group, placebo‐controlled trials of adults with moderate‐to‐severe AD with inadequate or intolerable responses to topical therapy. Patients were randomly allocated to once‐daily placebo, baricitinib 2 mg or baricitinib 4 mg in BREEZE‐AD1 and BREEZE‐AD2; and to placebo, baricitinib 1 mg or baricitinib 2 mg in BREEZE‐AD5. Here, we focus on data from the arms receiving placebo, baricitinib 2 mg and baricitinib 4 mg. Because BREEZE‐AD1 and BREEZE‐AD2 were twin studies conducted at the same time in Europe, Asia, Latin America and Australia, data from these studies were pooled together for the mediator analysis. The BREEZE‐AD5 study was conducted in North America, and its data are presented separately.

Patients were aged ≥18 years and had a ≥ 1‐year history of AD. At screening and baseline, patients were required to have an Eczema Area and Severity Index (EASI) score ≥ 16, a validated Investigator’s Global Assessment for AD (vIGA‐AD™) score ≥ 3, and body surface area of involvement ≥10%, as derived from the EASI assessment. ¹ , ²

Itch was measured by change from baseline in a numerical rating scale (NRS) with ranges from 0 (no itch) to 10 (worst itch imaginable). We assessed the weekly average in itch NRS, skin severity with EASI, and the Dermatology Life Quality Index (DLQI).

This post hoc analysis was based on data from the first 16 weeks of treatment. We assessed the least‐squares mean change from baseline to week 4 or week 16. The multiple mediation model used change in DLQI from week 4 or 16 as the dependent variable, and treatment (baricitinib 2 mg, baricitinib 4 mg or placebo) as the independent variable. ³ Itch and EASI at weeks 4 or 16 were the mediators. The total treatment effect over placebo for changes in DLQI that could be accounted for by either itch or EASI was the indirect or mediation effect. The total treatment effect over placebo that could not be accounted for by the indirect effect was the direct effect (Figure 1a). Data were censored after patients discontinued the study drug or received rescue therapy. We imputed missing data with a modified last observation carried forward analysis. Analyses were conducted with R 3·6·3 and R package lavaan (version 0·6–5) for mediator analysis. ⁴

Figure 1.

(a) Schematic of the mediator model for the Dermatology Life Quality Index (DLQI). (b) The percentage of DLQI accounted for by indirect mediators [itch and Eczema Area and Severity Index (EASI)] and direct effects. BARI, baricitinib; PBO, placebo. [Colour figure can be viewed at wileyonlinelibrary.com]

Patients ranged in age from 35 to 40 years, and 34–53% were women. Across the RCTs, the baseline mean (SD) values were approximately 7 (2) for itch NRS; 27 (11) to 34 (13) for EASI; 41% (23%) to 54% (23%) for body surface area; and 14 (7) to 15 (7) for DLQI. Approximately half of the patients had a vIGA score of 3, and Scoring Atopic Dermatitis ranged from a mean of 64 (13) to 68 (13).

As reported previously, baricitinib 2 mg and 4 mg demonstrated significantly greater improvement (P < 0·05) than placebo for most post‐baseline analyses with DLQI, itch and EASI. ¹ , ² For the mediator analyses investigating the impact of baricitinib 2 mg or 4 mg over placebo on DLQI, with itch and EASI as mediators at weeks 4 or 16, the indirect effect of the mediator variables on the outcome, or how improvement in itch or EASI impacts the improvement in DLQI, ranged from 43% to 52% for itch and 21% to 36% for EASI. The direct effect, representing all of the other effects of baricitinib on DLQI, ranged from 12% to 33% (Figure 1b).

In this analysis, baricitinib demonstrated significant improvement in DLQI, for which itch mediated approximately half of the changes at weeks 4 and 16. This study underscores the importance of itch improvement in HRQoL for patients with AD and suggests that itching has a greater impact on HRQoL than visible skin findings for patients with AD undergoing treatment.

Author contributions

Gil Yosipovitch: Conceptualization (lead); methodology (equal); supervision (equal); visualization (lead); writing – review and editing (equal). Kim Papp: Conceptualization (equal); investigation (equal); methodology (equal); supervision (equal); writing – review and editing (equal). Seth Forman: Investigation (equal); methodology (equal); writing – review and editing (equal). George Han: Conceptualization (equal); investigation (equal); supervision (equal); visualization (equal); writing – review and editing (equal). Jill S. Waibel: Conceptualization (equal); investigation (equal); supervision (equal); visualization (equal); writing – review and editing (equal). Maria J Rueda: Conceptualization (lead); funding acquisition (lead); supervision (lead); visualization (equal); writing – original draft (equal). Luna Sun: Formal analysis (equal); methodology (equal); validation (equal); visualization (equal); writing – original draft (equal). Yun‐Fei Chen: Conceptualization (equal); formal analysis (equal); funding acquisition (equal); methodology (equal); writing – original draft (equal). Orin Goldblum: Conceptualization (equal); funding acquisition (equal); methodology (equal); writing – review and editing (equal). Evangeline Pierce: Conceptualization (equal); methodology (equal); visualization (equal); writing – review and editing (equal). Jonathan I Silverberg: Conceptualization (lead); investigation (equal); methodology (equal); supervision (equal); visualization (equal); writing – review and editing (equal).

Supporting information

Appendix S1 Funding sources, Conflicts of interest and Data availability statement.