New Biologics for the Treatment of Atopic Dermatitis: Analysis of Efficacy, Safety, and Paradoxical Atopic Dermatitis Acceleration.
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ABSTRACT:
SUBMITTER: Qi HJ
PROVIDER: S-EPMC8181104 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The era of biologics for the treatment of moderate-to-severe atopic dermatitis (AD) began in 2017 with the approval of dupilumab, a monoclonal antibody that binds to the α-subunit of the interleukin IL-4 receptor. Until then, only conventional immunosuppressants were available for systemic treatment, of which only cyclosporine is approved for the treatment of severe AD. In the meantime, the therapeutic landscape of AD has been changing rapidly, and additional biologics have been developed which target IL-13, the IL-31 receptor, OX40, and OX40L, among others. Many of these substances have already shown promising results in phase 1, 2, and in some cases also phase 3 trials. In June 2021, tralokinumab, an IL-13 antibody, has been approved in Europe for the treatment of moderate-to-severe AD in adults. In addition to antibody-based therapies, "small molecules" that, e.g., inhibit Janus kinases enrich the armamentarium of systemic AD therapies. With all these agents, not only will many more targeted therapies become available, but also will the complex and heterogeneous pathophysiological processes of this disease be better understood.
| S-EPMC8439107 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, inflammatory cutaneous disease driven by immune dysregulation and skin barrier dysfunction. We are currently experiencing a new era of understanding of the pathogenesis of AD and, as a consequence, a new era of innovation in therapeutics, including small molecules and biologic therapy. Recently, advances in translational research have challenged the traditional AD pathogenesis paradigm of AD being solely a Th2-dominant disease. Other immune pathways seem to play a role in the complex AD pathophysiology, although the clinical relevance of these additional immune pathway abnormalities is unclear. Type 1, type 22, and type 17 pathway activation (with related cytokines/chemokines) have been demonstrated in the skin and blood of AD patients. Type 2 (interleukin [IL]-4, IL-13), IL-31, and type 22 (IL-22) pathway cytokines are increased in AD acute lesions. IL-22 induces both an epidermal hyperplasia at the onset of acute AD and a marked increase in the terminal differentiation S100 genes. This understanding of pathogenesis corresponds to a historic increase in therapeutic development in AD. The extreme clinical heterogeneity and the chronic progression of AD establish the need for newer, safer, and more effective treatments, control the disease, and improve the quality of life of affected patients.
| S-EPMC7875213 | biostudies-literature
Project description:Atopic dermatitis (AD) is a prevalent inflammatory skin disorder affecting all age and ethnic groups. The age-dependent varying appearance and extent of pruritic lesions are accompanied by distinct individual suffering, highlighting the importance of effective treatment options. Over the past years systemic drugs have considerably extended therapeutic approaches of patients with moderate to severe AD, in particular new biologics, most notably dupilumab has appeared as major breakthrough. In addition to monoclonal blockade of IL-4 and IL-13 pathway, more cytokines have been found to play a substantial role in AD pathogenesis, presenting potential targets for new therapy options.
| S-EPMC8648434 | biostudies-literature
Project description:This was a phase II, randomized, placebo-controlled, double-blinded single center study (clinicaltrials.gov: NCT01806662) to investigate safety and efficacy of ustekinumab treatment in moderate-to-severe AD patients. Patients underwent 1:1 randomization using a computer generated subject randomization table by an unblinded pharmacist. to Subjects received subcutaneous ustekinumab or placebo at weeks 0, 4, and 16 with a crossover to the other agent (either ustekinumab or placebo) at weeks 16, 20, and 32 (Figure 1A) to ensure patient retention.
2019-11-20 | GSE140684 | GEO
Project description:Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and recurrent eczematous lesions that significantly impair quality of life. It is a heterogeneous disease affecting both children and adults. The treatment of moderate-to-severe forms of AD is challenging, as topical corticosteroids are often insufficient to achieve disease control or inappropriate and off-label use of immunosuppressants may have significant undesirable side effects. The development of targeted biologic therapies specifically for AD is thus highly desirable. Dupilumab is the only biologic therapy that is Food and Drug Administration approved for the treatment of moderate-to-severe AD in patients 6 years and older, with consistent long-term efficacy and safety trial data. In this article, we review the mechanisms, safety, and efficacy of dupilumab from recent clinical trials, and we review the current data, mechanism of action, clinical efficacy, and limitations of new biologics currently in phase 2 and 3 clinical trials (lebrikizumab, tralokinumab, nemolizumab, tezepelumab, and ISB 830).
| S-EPMC7951162 | biostudies-literature
Project description:Atopic dermatitis (AD) is the most common inflammatory skin disease, but treatment options for moderate-to-severe disease are limited. Ustekinumab is an IL-12/IL-23p40 antagonist that suppresses Th1, Th17 and Th22 activation, commonly used for psoriasis patients. We sought to assess efficacy and safety of ustekinumab in patients with moderate-to-severe AD. In this phase II, double-blind, placebo-controlled study, 33 patients with moderate-to-severe AD were randomly assigned to either ustekinumab (n=16) or placebo (n=17), with subsequent crossover at 16 weeks, and last dose at 32 weeks. Background therapy with mild topical steroids was allowed to promote retention. Study endpoints included clinical (SCORAD50) and biopsy-based measures of tissue structure and inflammation, using protein and gene expression studies. The ustekinumab group achieved higher SCORAD50 responses at 12, 16 (the primary endpoint) and 20 weeks compared to placebo, but the difference between groups was not significant. The AD molecular profile/transcriptome showed early robust gene modulation, with sustained further improvements until 32 weeks in the initial ustekinumab group. Distinct and more robust modulation of Th1, Th17 and Th22 but also Th2-related AD genes was seen after 4 weeks of ustekinumab treatment (i.e. MMP12, IL-22, IL-13, IFN-γ, elafin/PI3, CXCL1 and CCL17; P<.05). Epidermal responses (K16, terminal differentiation) showed faster (4 weeks) and long-term regulation (32 weeks) from baseline in the ustekinumab group. No severe adverse events were observed. Ustekinumab had clear clinical and molecular effects, but clinical outcomes might have been obscured by a profound "placebo" effect, most likely due to background topical glucocorticosteroids and possibly insufficient dosing for AD.
| S-EPMC5502835 | biostudies-literature
Project description:Abrocitinib is a JAK1 selective inhibitor recently approved for the treatment of moderate-to-severe atopic dermatitis in adults. It has demonstrated efficacy and safety in several clinical trials, both in children and adults, in monotherapy, and compared with dupilumab. The expected EASI-75 response rate estimates at week 12 are 62.9% (95% CrI 42.5-79.9%) for abrocitinib 200 mg and 43.0% (95% CrI 24.8-64.0%) for abrocitinib 100 mg. Abrocitinib has shown a faster effect than dupilumab as regards early alleviation of itch. Because of the incomplete target selectivity of JAK inhibitors, when abrocitinib treatment is considered, laboratory screening is necessary, latent tuberculosis must be screened for, active infections are a contraindication, and special caution must be exerted in treating elderly patients and those predisposed to thromboembolic events. Even though recent meta-analyses of clinical trials have not shown that atopic dermatitis, or its treatment with JAK inhibitors or dupilumab, modify the risk of deep venous thrombosis or pulmonary embolism, long-term follow-up studies will better define the safety profile of abrocitinib.
| S-EPMC9960033 | biostudies-literature
Project description:IntroductionCalcineurin inhibitors, novel topical immunomodulators, may constitute a superior alternative for glucocorticosteroids in atopic dermatitis (AD) topical treatment.AimDetermination of efficacy and safety of each topical calcineurin inhibitor (TCI) formulation, 0.3% or 0.1% tacrolimus and 1% pimecrolimus, for the treatment of moderate to severe AD in comparison with glucocorticosteroids.Material and methodsCochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, GREAT database, trials registers and reference lists were searched up to February 2018. Randomised controlled trials of TCI, compared to corticosteroids (TCS), reporting efficacy or safety outcomes were selected. Quality of trials and evidence of each outcome were evaluated according to Cochrane Collaboration recommendations and tools. The primary outcomes were physician's global assessment of improvement and occurrence of adverse events (AEs).ResultsFourteen trials involving 7376 children and adults with AD were included. Calcineurin inhibitors were significantly more effective than various potency TCS, neither least potent to lower mid-strength nor mid-strength to potent TCS (RR = 1.24, 95% CI: 1.06-1.44). The major AEs were skin burning and pruritus, their incidence was higher in TCI treatment (RR = 3.32, 95% CI: 2.90-3.80; RR = 1.59, 95% CI: 1.34-1.80).ConclusionsCalcineurin inhibitors seem to be more effective and contrarily they elicit more AEs than TCS.
| S-EPMC6986278 | biostudies-literature
Project description:BackgroundCurrent therapeutic options for atopic dermatitis (AD) are limited. Janus kinase (JAK) inhibitors may be viable alternatives.ObjectivesTo assess the efficacy and safety of JAK inhibitors for AD treatment.MethodsWe searched PubMed, Embase, the Cochrane Controlled Register of Trials, Web of Science, Global Resource of Eczema Trials database, and ClinicalTrials.gov from inception to September 1, 2020. Randomized clinical trials (RCTs) comparing JAK inhibitors with placebo/vehicle treatment for AD patients were included. The primary study outcomes included (1) the change (%) from the Eczema Area and Severity Index (EASI) baseline expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI), and (2) the Investigator's Global Assessment (IGA) response and safety outcomes expressed as relative risk (RR) and 95% CI.ResultsWe included 14 RCTs published in 13 studies (3,822 patients). Treatment with JAK inhibitors significantly improved IGA response (RR 2.83, 95% CI 2.25-3.56, p < 0.001) and EASI score (WMD -28.82, 95% CI -34.48 to -23.16, p < 0.001). JAK inhibitor treatment achieved the largest improvement in both IGA response (RR 3.59, 95% CI 2.66-4.84, p < 0.001) and EASI score (WMD -42.00, 95% CI -48.64 to -35.36, p < 0.001) by week 4 of treatment. Topical JAK inhibitors were significantly more efficacious than oral inhibitors. Upadacitinib treatment for 4 weeks was most effective in reducing EASI score (WMD -53.92, 95% CI -69.26 to -38.58, p < 0.001), while abrocitinib for 4 weeks led to the most effective IGA response (RR 5.47, 95% CI 2.74-10.93, p < 0.001). There was no difference in the frequency of adverse events (AEs) leading to discontinuation; however, JAK inhibitors use, especially abrocitinib, led to a higher incidence of treatment-emergent AEs (RR 1.25, 95% CI 1.10-1.42, p = 0.001).ConclusionOur results imply that JAK inhibitors are an effective and safe AD treatment. Nevertheless, further trials with longer duration and head-to-head comparisons of different JAK inhibitors are needed.
| S-EPMC9393843 | biostudies-literature
Project description:IntroductionUpadacitinib, an oral selective-JAK1 inhibitor, has been used in clinical trials to treat atopic dermatitis (AD).AimTo evaluate the efficacy and safety of upadacitinib in moderate-to-severe AD.Material and methodsWe searched clinical trials from PubMed, Embase, Cochrane Library databases, and Web of Science. All randomized controlled trials (RCTs) of upadacitinib treatment on patients with moderate-to-severe AD were included. A meta-analysis was performed using the fixed- or random-effects models to calculate pooled standard mean differences or relative risks (SMD or RR, respectively).ResultsCompared with the placebo group, our meta-analysis revealed that upadacitinib was related to a significant decrease in Eczema Area and Severity Index (EASI) scores, and pruritus numeric rating scale (NRS) scores. A higher response rate in Investigator's Global Assessment (IGA) and EASI-75 were also detected in the upadacitinib group. Although patients treated with upadacitinib experienced a higher incidence of adverse events (AEs), these AEs were mild and tolerated. As for serious adverse events (SAEs), there was no difference between the placebo group and the upadacitinib group.ConclusionsThis meta-analysis demonstrated that upadacitinib is a safe and effective treatment for moderate-to-severe AD. Further long-term trials are required for confirmation.
| S-EPMC10809830 | biostudies-literature