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International Journal of Molecular... Jul 2023Atopic dermatitis represents a complex and multidimensional interaction that represents potential fields of preventive and therapeutic management. In addition to the... (Review)
Review
Atopic dermatitis represents a complex and multidimensional interaction that represents potential fields of preventive and therapeutic management. In addition to the treatment armamentarium available for atopic dermatitis, novel drugs targeting significant molecular pathways in atopic dermatitis biologics and small molecules are also being developed given the condition's complex pathophysiology. While most of the patients are expecting better efficacy and long-term control, the response to these drugs would still depend on numerous factors such as complex genotype, diverse environmental triggers and microbiome-derived signals, and, most importantly, dynamic immune responses. This review article highlights the challenges and the recently developed pharmacological agents in atopic dermatitis based on the molecular pathogenesis of this condition, creating a specific therapeutic approach toward a more personalized medicine.
Topics: Humans; Dermatitis, Atopic; Precision Medicine; Biological Products
PubMed: 37511138
DOI: 10.3390/ijms241411380 -
The Journal of Allergy and Clinical... Dec 2023Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes.
OBJECTIVE
We sought to systematically synthesize the benefits and harms of AD systemic treatments.
METHODS
For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna).
RESULTS
The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain.
CONCLUSIONS
Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.
Topics: Humans; Dermatitis, Atopic; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Eczema; Asthma; Treatment Outcome
PubMed: 37678577
DOI: 10.1016/j.jaci.2023.08.029 -
Actas Dermo-sifiliograficas 2023Pruritus is the main symptom of many dermatologic and systemic diseases. Atopic dermatitis, psoriasis, contact dermatitis, urticaria, lichen simplex chronicus, mycosis... (Review)
Review
Pruritus is the main symptom of many dermatologic and systemic diseases. Atopic dermatitis, psoriasis, contact dermatitis, urticaria, lichen simplex chronicus, mycosis fungoides, scars, autoimmune diseases, kidney or liver diseases among others are all associated with itch that may require different approaches to management. Although antihistamines seem to be the first line of therapy, in reality their role is limited to urticaria and drug-induced reactions. In fact, the pathophysiologic mechanisms of each of the conditions covered in this review will differ. Recent years have seen the emergence of new drugs whose efficacy and safety profiles are very attractive for the management of pruritus in clinical practice. Clearly we are at a critical moment in dermatology, in which we have the chance to be more ambitious in our goals when treating patients with pruritus.
Topics: Humans; Dermatology; Pruritus; Dermatitis, Atopic; Urticaria; Skin Neoplasms
PubMed: 37003460
DOI: 10.1016/j.ad.2023.03.004 -
The Journal of Allergy and Clinical... Apr 2024Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and... (Review)
Review
Type 2 inflammation is characterized by overexpression and heightened activity of type 2 cytokines, mediators, and cells that drive neuroimmune activation and sensitization to previously subthreshold stimuli. The consequences of altered neuroimmune activity differ by tissue type and disease; they include skin inflammation, sensitization to pruritogens, and itch amplification in atopic dermatitis and prurigo nodularis; airway inflammation and/or hyperresponsiveness, loss of expiratory volume, airflow obstruction and increased mucus production in asthma; loss of sense of smell in chronic rhinosinusitis with nasal polyps; and dysphagia in eosinophilic esophagitis. We describe the neuroimmune interactions that underlie the various sensory and autonomic pathologies in type 2 inflammatory diseases and present recent advances in targeted treatment approaches to reduce type 2 inflammation and its associated symptoms in these diseases. Further research is needed to better understand the neuroimmune mechanisms that underlie chronic, sustained inflammation and its related sensory pathologies in diseases associated with type 2 inflammation.
Topics: Humans; Inflammation; Dermatitis, Atopic; Pruritus; Sinusitis; Asthma
PubMed: 37634890
DOI: 10.1016/j.jaci.2023.08.017 -
The Journal of Allergy and Clinical... Oct 2023Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
BACKGROUND
Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia.
OBJECTIVES
This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition.
METHODS
The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period.
RESULTS
Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation.
CONCLUSIONS
Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.
Topics: Adult; Humans; Janus Kinase Inhibitors; Dermatitis, Atopic; Histamine; Neoplasms; Janus Kinase 1
PubMed: 37343845
DOI: 10.1016/j.jaci.2023.06.004 -
The British Journal of Dermatology Oct 2023Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial.
BACKGROUND
Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) with a fully human noncytotoxic, nondepleting anti-OX40L monoclonal antibody (amlitelimab; SAR445229; KY1005) is a novel way to modulate persistent inflammation.
OBJECTIVES
To assess the safety and efficacy of amlitelimab over 16 weeks in adults with AD in a phase IIa double-blind placebo-controlled study.
METHODS
The study was conducted at 19 hospitals in Germany, Poland, Spain and the UK. Eligible patients with moderate-to-severe AD were randomized (1 : 1 : 1) to low-dose intravenous (IV) amlitelimab (200 mg), high-dose IV amlitelimab (500 mg) or placebo, followed by three maintenance doses (50% of loading dose) at 4, 8 and 12 weeks, with safety follow-up to week 36. The co-primary endpoints were the incidence of treatment-emergent adverse events (all patients who received ≥ 1 dose of the study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set).
RESULTS
Between 13 December 2018 and 12 May 2020, 89 patients were randomly assigned to low- (n = 29) or high-dose amlitelimab (n = 30) or placebo (n = 29), of whom 88 proceeded to treatment [37 women (42%), 51 (58%) men; mean (SD) age 33.6 (11.9) years]. Amlitelimab was generally well tolerated with an unremarkable safety profile; no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI from baseline to week 16 was -80.12% [95% confidence interval (CI) -95.55 to -64.68; P = 0.009 vs. placebo] and -69.97% (95% CI -85.04 to -54.60; P = 0.07 vs. placebo) for the low- (n = 27) and high-dose (n = 27) amlitelimab groups, respectively, vs. -49.37% (95% CI -66.02 to -32.72) for placebo (n = 24). Numerically greater reductions in EASI were observed for amlitelimab vs. placebo from weeks 2 to 16.
CONCLUSIONS
Novel targeting of OX40L-expressing APCs with amlitelimab was well tolerated and resulted in clinically meaningful improvements in AD.
Topics: Adult; Male; Humans; Female; Dermatitis, Atopic; Treatment Outcome; Antibodies, Monoclonal; Injections, Subcutaneous; Germany; Antineoplastic Agents; Double-Blind Method; Severity of Illness Index
PubMed: 37463508
DOI: 10.1093/bjd/ljad240 -
Journal of Cutaneous Medicine and... 2023Hand eczema is a chronic condition that affects an estimated 14.5% of the general population. It has severe quality of life ramifications in those that struggle with it,... (Review)
Review
Hand eczema is a chronic condition that affects an estimated 14.5% of the general population. It has severe quality of life ramifications in those that struggle with it, including days missed from work or school, productivity loss and impaired work functioning. For years, the standard of care included topical moisturizing creams, topical steroids and more recently systemic agents. As new therapeutic targets emerge and recent advances are being developed, it is now more possible than ever that hand eczema can be managed via the underlying mechanisms. A review of the literature was conducted to identify current treatment options for hand eczema and chronic hand eczema. The terms 'hand eczema', 'hand dermatitis' were used to search PubMed, CENTRAL and Embase. To identify new therapies still undergoing investigation, we used the terms 'hand eczema', 'hand dermatitis', 'atopic dermatitis', and 'vesicular eczema of hands and/or feet' to search Clinicaltrials.gov for all studies until December 2022. There were 56 ongoing clinical trials identified for pharmacological treatments for hand eczema on Clinicaltrials.gov from 2000 - 2022, with 16 that are new or ongoing. These included studies for dupilumab, ruxolitinib, delgocitinib (LEO124249), gusacitinib (ASN002), AFX 5931, and roflumilast (ARQ-252). Two major classes of drugs emerging for the treatment of hand eczema include IL-4/IL-13 inhibitors and JAK inhibitors. With the increase in efficacy seen with these new drugs, we are also noting improved adverse effect profiles, making them attractive options to add to a clinician's management toolbox for patients with hand eczema.
Topics: Humans; Quality of Life; Eczema; Dermatitis, Atopic; Hand; Steroids; Treatment Outcome
PubMed: 37496489
DOI: 10.1177/12034754231188325 -
The Journal of Investigative Dermatology Aug 2023Immunologically targeted therapies have revolutionized the treatment of inflammatory dermatoses, including atopic dermatitis and psoriasis. Although immunologic... (Review)
Review
Immunologically targeted therapies have revolutionized the treatment of inflammatory dermatoses, including atopic dermatitis and psoriasis. Although immunologic biomarkers hold great promise for personalized classification of skin disease and tailored therapy selection, there are no approved or widely used approaches for this in dermatology. This review summarizes the translational immunologic approaches to measuring treatment-relevant biomarkers in inflammatory skin conditions. Tape strip profiling, microneedle-based biomarker patches, molecular profiling from epidermal curettage, RNA in situ hybridization tissue staining, and single-cell RNA sequencing have been described. We discuss the advantages and limitations of each and open questions for the future of personalized medicine in inflammatory skin disease.
Topics: Humans; Dermatitis, Atopic; Precision Medicine; Dermatology; Psoriasis; Skin Diseases; Biomarkers
PubMed: 37341663
DOI: 10.1016/j.jid.2023.04.005 -
Health Technology Assessment... Jan 2024Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus).
OBJECTIVES
To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib).
DATA SOURCES
Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review.
METHODS
A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources.
RESULTS
Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost.
CONCLUSIONS
The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations.
FUTURE WORK AND LIMITATIONS
The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42021266219.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in ; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.
Topics: Child; Adult; Adolescent; Humans; Child, Preschool; Dermatitis, Atopic; Cyclosporine; State Medicine; Treatment Outcome; Cost-Benefit Analysis; Eczema; Antibodies, Monoclonal; Purines; Heterocyclic Compounds, 3-Ring; Sulfonamides; Pyrazoles; Pyrimidines; Azetidines
PubMed: 38343072
DOI: 10.3310/LEXB9006 -
Nature Medicine Dec 2023Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology... (Randomized Controlled Trial)
Randomized Controlled Trial
Toll-like receptor-driven and interleukin-1 (IL-1) receptor-driven inflammation mediated by IL-1 receptor-associated kinase 4 (IRAK4) is involved in the pathophysiology of hidradenitis suppurativa (HS) and atopic dermatitis (AD). KT-474 (SAR444656), an IRAK4 degrader, was studied in a randomized, double-blind, placebo-controlled phase 1 trial where the primary objective was safety and tolerability. Secondary objectives included pharmacokinetics, pharmacodynamics and clinical activity in patients with moderate to severe HS and in patients with moderate to severe AD. KT-474 was administered as a single dose and then daily for 14 d in 105 healthy volunteers (HVs), followed by dosing for 28 d in an open-label cohort of 21 patients. Degradation of IRAK4 was observed in HV blood, with mean reductions after a single dose of ≥93% at 600-1,600 mg and after 14 daily doses of ≥95% at 50-200 mg. In patients, similar IRAK4 degradation was achieved in blood, and IRAK4 was normalized in skin lesions where it was overexpressed relative to HVs. Reduction of disease-relevant inflammatory biomarkers was demonstrated in the blood and skin of patients with HS and patients with AD and was associated with improvement in skin lesions and symptoms. There were no drug-related infections. These results, from what, to our knowledge, is the first published clinical trial using a heterobifunctional degrader, provide initial proof of concept for KT-474 in HS and AD to be further confirmed in larger trials. ClinicalTrials.gov identifier: NCT04772885 .
Topics: Humans; Hidradenitis Suppurativa; Dermatitis, Atopic; Interleukin-1 Receptor-Associated Kinases; Treatment Outcome; Skin; Double-Blind Method; Severity of Illness Index
PubMed: 37957373
DOI: 10.1038/s41591-023-02635-7