The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials ...comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.
In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 clear or 1 almost clear on the IGA scores range from 0 to 4, with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI scores range from 0 to 72) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale scores range from 0 to 10) at week 2 and IGA and EASI-75 responses at week 16.
A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.
In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).
Atopic dermatitis (AD) is generally considered a T helper type 2–dominated disease. Pediatric AD is usually less severe than adult AD, but it may present as moderate to severe lesions that are ...inadequately managed by current modalities including emollients/moisturizers, topical corticosteroids (TCSs), topical calcineurin inhibitors (TCIs), and even systemic immunosuppressants (such as cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil). In addition, systemic immunosuppressants are often not recommended for childhood AD by the current guidelines due to their toxicities. Therefore, there is still an unmet need for a safe and effective long-term therapy for pediatric AD patients whose disease is inadequately controlled or who are intolerant to current treatments. The emerging therapeutics for AD focuses on intervening in the inflammatory pathway by targeting specific cytokines/chemokines or their receptors. Monoclonal antibodies against immunoglobulin E (IgE), interleukin (IL)-4 receptor subunit α, IL-5, IL-13, IL-31 receptor subunit α, IL-33, and thymic stromal lymphopoietin (TSLP) have been evaluated clinically for AD. Encouraging results have been reported for many of the biologics, of which the most exciting is dupilumab. Other emerging systemic therapies include small molecules such as baricitinib, abrocitinib, upadacitinib, and tradipitant. Several novel topical agents are under clinical investigation for the treatment of AD, including topical phosphodiesterase 4 (PDE4) inhibitors, Janus kinase (JAK) inhibitors, aryl hydrocarbon receptor (AhR) modulating agents, and transient receptor potential vanilloid subfamily member 1 (TRPV1) antagonists. Accompanied by thorough characterization of different phenotype and endotype subsets, the application of precision medicine could provide new prospects for the optimal treatment of AD.
RNA sequencing also showed reduced expression of JAK-STAT–dependent cytokines and pathways known to be critical to granuloma development and maintenance.5 In this issue, Wang et al6 investigated the ...immunopathogenesis of GA by using single-cell RNA sequencing (scRNAseq) to characterize the tissue microenvironment in GA skin lesions, and found that IFN-γ, oncostatin M (OSM), and, to a lesser degree, IL-21 and IL-15 mediate pathogenic communication between T cells, macrophages, and fibroblasts to drive lesion formation in GA (Fig 1). Because these 4 cytokines signal via the JAK-STAT pathway, Wang et al proposed that GA might respond to JAK inhibition, and reported on the efficacy of an oral JAK inhibitor, tofacitinib, in 5 patients with long-lasting GA and the effect of the treatment on specific targets. Because IFN-γ and OSM both signal via JAK1/2 and appear to be the most proximal drivers of this disease, it is possible that more directed inhibition of JAK1 or JAK1/2 might be more effective by providing more potent inhibition of these cytokines. Previous case reports have also shown that JAK inhibitors might be effective in treating these disorders,1,5 indicating that these disorders may share common pathogenic pathways. ...a clearer understanding of the molecular pathogenesis and immune mechanisms of GA could also be of value in identifying potential novel targeted therapies for these granulomatous disorders.
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic ...predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.
IMP‐3 expression is a poor prognostic factor of melanomas and it promotes melanoma cell migration and invasion by a pathway modulating HMGA2 mRNA expression. We tried to identify other putative ...targets of IMP‐3. We identified putative IMP‐3‐binding RNAs, including AKT1, MAPK3, RB1 and RELA, by RNA immunoprecipitation coupled with next‐generation sequencing. IMP‐3 overexpression increased AKT and RELA levels in MeWo cells. siRNAs against AKT1 and RELA inhibited MeWo/Full‐length IMP‐3 cell migration. IMP‐3 knockdown of A2058 cells decreased AKT1 and RELA expression and lowered migration ability. Co‐transfection of A2058 cells with AKT1‐ or RELA‐expressing plasmids with IMP‐3 siRNA restored the inhibitory effects of IMP‐3 knockdown on migration. HMGA2 did not influence AKT1 and RELA expression in melanoma cells. Human melanoma samples with high IMP‐3 levels also showed high HMGA2, AKT1 and RELA expression. Our results show that IMP‐3 enhances melanoma cell migration through the regulation of the AKT1 and RELA axis.
Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex.
We conducted ...two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults ≥18 years of age and adolescents 12 to <18 years of age, weighing ≥40 kg) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 severe disease) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed.
In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation.
In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).
Background
Ligelizumab, a next‐generation, humanized anti‐immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms ...are inadequately controlled with standard‐of‐care therapy.
Objective
To evaluate the long‐term safety and re‐treatment efficacy of ligelizumab 240 mg in patients who completed the core study and extension study.
Methods
This open‐label, single‐arm, long‐term Phase 2b extension study was designed to assess patients who were previously administered various doses of ligelizumab, omalizumab or placebo in the Phase 2b, dose‐finding core study and who presented with active disease after Week 32. In the extension study, patients received ligelizumab 240 mg subcutaneously every 4 weeks, for 52 weeks and were monitored post‐treatment for 48 weeks.
Results
Overall, ligelizumab was well‐tolerated with no newly identified safety signals. A total of 95.4% (226/237) screened patients received ligelizumab 240 mg in the extension study; 84.1% (190/226) of patients experienced at least one treatment‐emergent adverse event. Most reported events were mild (41.6%) or moderate (35.8%) and mostly unrelated to the study treatment. At Week 12, 46.5% of patients had a complete response increasing to 53.1% after 52 weeks. Following 52 weeks of extension study treatment, 75.8% (95% confidence interval, 69.9, 81.3) of patients had cumulative complete responses. The median time to relapse in complete responders was 38 weeks.
Conclusion
The long‐term safety profile of ligelizumab 240 mg in patients with chronic spontaneous urticaria was consistent with the core study and re‐treatment efficacy was shown.
Trial Registration: ClinicalTrials.gov Identifier: NCT02477332 and NCT02649218.
A total of 226 patients received ligelizumab 240 mg for 52 weeks. Overall, 84.1% of patients experienced at least one TEAE. After 52 weeks of treatment, 53.1% of patients had a complete response and 75.8% of patients had cumulative complete responses. The long‐term safety profile of ligelizumab 240 mg in patients was consistent with the core study and re‐treatment efficacy was shown.Abbreviations: BAS, basophil; CSU, chronic spontaneous urticaria; FcεRI, Fc epsilon receptor 1; IgE, immunoglobulin E; MC, mast cell; MoA, mechanism of action; TEAE, treatment‐emergent adverse event; UAS7, weekly urticaria activity score; UAS7 = 0, complete response; UAS7 ≤ 6, minimal disease activity
Objectives
To determine whether periodontitis is a modifiable risk factor for dementia.
Design
Prospective cohort study.
Setting
National Health Insurance Research Database in Taiwan.
Participants
...Individuals aged 65 and older with periodontitis (n = 3,028) and an age‐ and sex‐matched control group (n = 3,028).
Measurements
Individuals with periodontitis were compared age‐ and sex‐matched controls with for incidence density and hazard ratio (HR) of new‐onset dementia. Periodontitis was defined according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM) codes 523.3–5 diagnosed by dentists. To ensure diagnostic validity, only those who had concurrently received antibiotic therapies, periodontal treatment other than scaling, or scaling more than twice per year performed by certified dentists were included. Dementia was defined according to ICD‐9‐CM codes 290.0–290.4, 294.1, 331.0–331.2.
Results
After adjustment for confounding factors, the risk of developing dementia was calculated to be higher for participants with periodontitis (HR = 1.16, 95% confidence interval = 1.01–1.32, P = .03) than for those without.
Conclusion
Periodontitis is associated with greater risk of developing dementia. Periodontal infection is treatable, so it might be a modifiable risk factor for dementia. Clinicians must devote greater attention to this potential association in an effort to develop new preventive and therapeutic strategies for dementia.
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