Summary
Background
Interleukin (IL)‐31 affects the inflammatory response, is involved in epidermal barrier disruption in atopic dermatitis (AD) and plays a key role in pruritus. Nemolizumab, a ...humanized monoclonal antibody against IL‐31 receptor A, reduced pruritus in patients with AD after a 16‐week administration period.
Objectives
To examine the long‐term effectiveness and safety of nemolizumab in patients aged ≥ 13 years with AD and inadequately controlled moderate‐to‐severe pruritus.
Methods
In two long‐term phase III studies, nemolizumab 60 mg every 4 weeks (Q4W) was administered subcutaneously, concomitantly with topical treatments. Study‐JP01 patients received double‐blind nemolizumab or placebo for 16 weeks, and then entered a 52‐week extension period in which all patients received nemolizumab (nemolizumab/nemolizumab and placebo/nemolizumab groups). Study‐JP02 patients received nemolizumab for 52 weeks. Both studies included an 8‐week follow‐up period.
Results
Study‐JP01 nemolizumab/nemolizumab and placebo/nemolizumab, and Study‐JP02 nemolizumab groups comprised 143, 72 and 88 patients, respectively. In the nemolizumab/nemolizumab group, there were clinically meaningful improvements from the start of treatment to week 68 in the pruritus visual analogue scale (66% decrease) and Eczema Area and Severity Index (78% decrease). Quality of life (QoL) indicators improved after the first nemolizumab dose; improvements were maintained during the follow‐up period. The long‐term safety profile was consistent with previous studies, with no unexpected late‐onset adverse events.
Conclusions
Nemolizumab 60 mg Q4W with concomitant topical treatments in patients with AD and inadequately controlled moderate‐to‐severe pruritus produced a continuous improvement in pruritus, signs of AD, and QoL for up to 68 weeks, with a favourable safety profile.
What is already known about this topic?
Pruritus, a characteristic symptom of atopic dermatitis (AD), causes distress to patients, reducing quality of life and affecting sleep and daily activities.
Nemolizumab (plus topical agents) has previously been shown to reduce pruritus associated with AD to a greater extent than placebo over 16 weeks.
As patients with AD suffer from repeated phases of relapse and remission, it is important to extend the periods of relief from pruritus and rash.
What does this study add?
Data from two long‐term (≥ 52 weeks) phase III studies confirmed that nemolizumab plus topical agents increased or maintained effectiveness through the study duration, with continuous improvement after week 16.
Acute itchiness or flare of AD were rarely observed during the 8‐week follow‐up period.
The results support the long‐term use of nemolizumab with concomitant topical agents in patients with AD and inadequately controlled moderate‐to‐severe pruritus.
Linked Comment: S. Barbarot. Br J Dermatol 2022; 186:608.
Plain language summary available online
Mast cells and basophils share some functions in common and are generally associated with T helper 2 (Th2) immune responses, but taking basophils as surrogate cells for mast cell research or vice ...versa for several decades is problematic. Thus far, their in vitro functions have been well studied, but their in vivo functions remained poorly understood. New research tools for their functional analysis in vivo have revealed previously unrecognized roles for mast cells and basophils in several skin disorders. Newly developed mast cell‐deficient mice provided evidence that mast cells initiate contact hypersensitivity via activating dendritic cells. In addition, studies using basophil‐deficient mice have revealed that basophils were responsible for cutaneous Th2 skewing to haptens and peptide antigens but not to protein antigens. Moreover, human basophils infiltrate different skin lesions and have been implicated in the pathogenesis of skin diseases ranging from atopic dermatitis to autoimmune diseases. In this review, we will discuss the recent advances related to mast cells and basophils in human and murine cutaneous immune responses.
Summary
Background
Baricitinib, an oral selective Janus kinase 1 and 2 inhibitor, effectively reduced atopic dermatitis (AD) severity in a phase II study with concomitant topical corticosteroids.
...Objectives
To evaluate the efficacy and safety of baricitinib in patients with moderate‐to‐severe AD who had an inadequate response to topical therapies.
Methods
In two independent, multicentre, double‐blind, phase III monotherapy trials, BREEZE‐AD1 and BREEZE‐AD2, adults with moderate‐to‐severe AD were randomized 2 : 1 : 1 : 1 to once‐daily placebo, baricitinib 1 mg, 2 mg, or 4 mg for 16 weeks.
Results
At week 16, more patients achieved the primary end point of Validated Investigator's Global Assessment of AD (0, 1) on baricitinib 4 mg and 2 mg compared with placebo in BREEZE‐AD1 N = 624; baricitinib 4 mg 16·8% (P < 0·001), 2 mg 11·4% (P < 0·05), 1 mg 11·8% (P < 0·05), placebo 4·8%, and BREEZE‐AD2 N = 615; baricitinib 4 mg 13·8% (P = 0·001), 2 mg 10·6% (P < 0·05), 1 mg 8·8% (P = 0·085), placebo 4·5%. Improvement in itch was achieved as early as week 1 for 4 mg and week 2 for 2 mg. Improvements in night‐time awakenings, skin pain and quality‐of‐life measures were observed by week 1 for both 4 mg and 2 mg (P ≤ 0·05, all comparisons). The most common adverse events in patients treated with baricitinib were nasopharyngitis and headache. No cardiovascular events, venous thromboembolism, gastrointestinal perforation, significant haematological changes, or death were observed with any baricitinib dosage.
Conclusions
Baricitinib improved clinical signs and symptoms in patients with moderate‐to‐severe AD within 16 weeks of treatment and induced rapid reduction of itch. The safety profile remained consistent with prior findings from baricitinib clinical development in AD, with no new safety concerns.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic heterogeneous inflammatory skin disease with few approved therapies for patients with moderate‐to‐severe disease.
What does this study add?
These two phase III trials show that baricitinib, an oral inhibitor of Janus kinase 1 and 2, significantly improved clinical signs and symptoms of AD compared with placebo within the first 16 weeks of treatment.
Baricitinib may represent a first‐in‐class oral treatment option for adult patients with moderate‐to‐severe AD.
Linked Comment: Drucker. Br J Dermatol 2020; 183:199–200.
Plain language summary available online
Summary
Background
Ustekinumab, a fully human monoclonal antibody against interleukin‐12/23, may potentially be effective for severe atopic dermatitis (AD) treatment.
Objectives
To evaluate efficacy ...and safety of ustekinumab 45 mg and 90 mg in patients with severe AD.
Methods
In this randomized, placebo‐controlled, phase II study, Japanese patients (aged 20–65 years) with severe or very severe AD entered a 12‐week double‐blind treatment period during which they received (1 : 1 : 1) ustekinumab 45 mg, 90 mg or placebo subcutaneous injections at weeks 0 and 4, with follow‐up until week 24. The primary efficacy end point was percentage change from baseline in Eczema Area and Severity Index (EASI) score at week 12. Major secondary efficacy end points included the proportion of patients achieving EASI 50, EASI 75, Investigator's Global Assessment score 0–1, change from baseline Atopic Dermatitis Itch Scale and Dermatology Life Quality Index.
Results
A total of 79 patients were randomized ustekinumab 45 mg (n = 24), 90 mg (n = 28), placebo (n = 27). Ustekinumab treatment showed nonsignificant improvement in least square mean change from baseline EASI score at week 12 45 mg: –38·2%, 95% confidence interval (CI) –21·02–19·51; P < 0·94 and 90 mg: –39·8%, 95% CI –21·84–17·14; P < 0·81 vs. placebo (–37·5%). A nonsignificant improvement in major secondary efficacy end points was observed in both ustekinumab groups vs. placebo. The most common treatment‐emergent adverse events were nasopharyngitis and worsened AD (higher in placebo vs. ustekinumab groups).
Conclusions
Ustekinumab 45 mg and 90 mg did not demonstrate meaningful efficacy in Japanese patients with severe AD. The treatment was generally well tolerated.
What's already known about this topic?
There are reports suggesting the involvement of T helper 17 cells in the pathogenesis of atopic dermatitis (AD).
Several case studies have reported therapeutic benefits of ustekinumab in patients with severe AD, while a few studies have failed to show the benefits.
What does this study add?
Ustekinumab 45 mg and 90 mg did not demonstrate meaningful efficacy in Japanese patients with severe AD.
Ustekinumab treatment was generally well tolerated in Japanese patients with severe AD.
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Linked Comment: Samuel and Reynolds. Br J Dermatol 2017; 177:339–341
Summary
Background
The cytokine interleukin‐31 (IL‐31) is considered to be responsible for the development of pruritus in humans. At present, no available evidence has been provided on the safety and ...efficacy of blocking the IL‐31 signal in humans for the amelioration of pruritus in atopic dermatitis (AD). CIM331 is a humanized antihuman IL‐31 receptor A (IL‐31RA) monoclonal antibody, which binds to IL‐31RA to inhibit subsequent IL‐31 signalling.
Objectives
To assess the tolerability, safety, pharmacokinetics and preliminary efficacy of CIM331 in healthy Japanese and white volunteers, and Japanese patients with AD.
Methods
In this randomized, double‐blind, placebo‐controlled phase I/Ib study, CIM331 was administered in a single subcutaneous dose. The primary outcomes were safety and tolerability; the exploratory analysis was efficacy.
Results
No deaths, serious adverse events (AEs) or discontinuations due to AEs were reported in any part of the study. No dose‐dependent increase in the incidence of AEs occurred in any part of the study. In healthy volunteers, all AEs occurred once in the placebo groups, and increased creatine phosphokinase was more common in the CIM331 groups. In patients with AD, CIM331 reduced pruritus visual analogue scale score to about −50% at week 4 with CIM331 compared with −20% with placebo. CIM331 increased sleep efficiency and decreased the use of hydrocortisone butyrate.
Conclusions
A single subcutaneous administration of CIM331 was well tolerated in healthy volunteers and patients with AD. It decreased pruritus, sleep disturbance and topical use of hydrocortisone. CIM331 may become a novel therapeutic option for AD by inhibiting IL‐31.
What's already known about this topic?
Interleukin‐31 (IL‐31) has been implicated in the induction of pruritus, the major symptom of atopic dermatitis (AD).
What does this study add?
This is the first human trial to investigate whether inhibition of IL‐31 signalling ameliorates pruritus in AD.
Single subcutaneous administration of CIM331, a humanized antihuman IL‐31 receptor A monoclonal antibody, was well tolerated in healthy volunteers and patients with AD.
CIM331 markedly improved pruritus in patients with AD.
Plain language summary available online
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