Phase 2B randomized study of nemolizumab in adults with moderate-to-severe atopic dermatitis and severe pruritus

Background: Nemolizumab targets the IL-31 receptor a subunit involved in atopic dermatitis (AD) pathogenesis. Objective: We sought to evaluate a new dosing strategy of nemolizumab in patients with AD. Methods: We performed a 24-week, randomized, double-blind, multicenter study of nemolizumab (10, 30, and 90 mg) subcutaneous injections every 4 weeks versus placebo, with topical corticosteroids in adults with moderate-to-severe AD, severe pruritus, and inadequate control with topical treatment (n 5 226). The Eczema Area and Severity Index (EASI), the peak pruritus (PP) numeric rating scale (NRS), and the Investigator’s Global Assessment (IGA) were assessed. Standard safety assessments were performed. Results: Nemolizumab improved EASI, IGA, and/or NRS-itch scores, with the 30-mg dose being most effective. Nemolizumab (30 mg) reduced EASI scores versus placebo at week 24 (268.8% vs 252.1%, P 5 .016); significant differences were observed by week 8 (P <_ .01). With significant improvement (P 5 .028) as early as week 4, IGA 0/1 rates were higher for 30 mg of nemolizumab versus placebo at week 16 (33.3% vs 12.3%, P 5 .008) but not week 24 because of an increased placebo/topical corticosteroid effect (36.8% vs 21.1%, P 5 .06). PP-NRS scores were improved for 30 mg of nemolizumab versus placebo at week 16 (268.6% vs 234.3%, P <.0001) and week 24 (267.3% vs 235.8%, P <.0001), with a difference by week 1 (P _4-point decrease) were greater for 30 mg of nemolizumab versus placebo at week 16 (P <_ .001) and week 24 (P <_ .01). Nemolizumab was safe and well tolerated. The most common adverse events were nasopharyngitis and upper respiratory tract infection. Conclusions: Nemolizumab resulted in rapid and sustained improvements in cutaneous signs of inflammation and pruritus in patients with AD, with maximal efficacy observed at 30 mg. Nemolizumab had an acceptable safety profile. (J Allergy Clin Immunol 2020;145:173-82.

Clinical and Serological Characterization of Orf-Induced Immunobullous Disease

Importance: Ecthyma contagiosum, or orf, is a viral zoonotic infection caused by Poxviridae. Although human orf infection is considered to follow a self-limited course, various immunological reactions may be triggered, including immunobullous diseases. In the majority of the latter cases, the antigenic target remained enigmatic. Objective: To characterize the predominant autoantigen in orf-induced immunobullous disease and further describe this clinical entity. Design, Setting, and Participants: This multicenter case series sought to provide detailed clinical, histopathological and immunological characteristics of a patient with orf-induced pemphigoid. Based on this index patient, serological analyses were conducted of 4 additional patients with previously reported orf-induced immunobullous disease. Immunoblotting with extracellular matrix and a recently established indirect immunofluorescence assay for detection of serum anti-laminin 332 IgG were performed. Exposures: The disease course and clinical characteristics of orf-induced immunobullous disease were observed. Main Outcomes and Measures: Orf-induced immunobullous disease is primarily characterized by anti-laminin 332 autoantibodies, predominant skin involvement, and a self-limiting course. The study provides further details on epidemiological, clinical, immunopathological, diagnostic, and therapeutic aspects of orf-induced immunobullous disease. Results: In all 5 patients, IgG1 and/or IgG3 autoantibodies against laminin 332 were identified. The α3, β3, and γ2 chains were recognized in 2, 4, and 1 patient(s), respectively. Conclusions and Relevance: In this case series, laminin 332, a well-known target antigen in mucous membrane pemphigoid, was a major autoantigen in orf-induced immunobullous disease, even though predominant mucosal lesions were lacking in this autoimmune blistering disease. Orf-induced anti-laminin 332 pemphigoid is proposed as distinct clinical entity

Perspective to precision medicine in scleroderma

Systemic sclerosis (SSc) is a rare and heterogeneous disease with no relevant environmental trigger or significant responsible gene. It has been and will continue to be difficult to identify large enough patients to conduct classic population-based epidemiologic exposure/non-exposure studies with adequate power to ascertain environmental and genetic risk factors for these entities. The complexity of pathogenesis and heterogeneity are likely to require personalized/precision medicine for SSc. Since several potential drugs are currently available for specific patients if not whole SSc, classification of SSc seems to form the foundation for a better therapeutic strategy. To date, SSc has been classified based on the extent/severity of the affected area as well as some disease markers, including the autoantibody profile. However, such an analysis should also lead to improvements in the design of appropriately stratified clinical trials to determine the effects and prediction of targeted therapies. An approach based on drug response preclinically conducted using patients’ own fibroblasts in vitro, can provide a precise disease marker/therapeutic selection for clinical practice. Because scleroderma dermal fibroblasts have a persistent hyper-productive phenotype occurring not only in person, but also in cell culture conditions. Thus, an accumulating approach based on disease markers ensures progression and de-escalation to re-establish a better life with a personally optimized drug environment after the onset of SSc

B cell depletion reduces the development of atherosclerosis in mice

B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell–depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti–oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell–derived IFN-γ secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody–mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation

Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study

BACKGROUND: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD). OBJECTIVE: To assess the long-term safety and efficacy of dupilumab in patients with AD. METHODS: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated. RESULTS: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life. LIMITATIONS: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks. CONCLUSION: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD

Plos Med

Background The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level

Counter regulatory B cell functions during autoimmune and inflammatory diseases

La reconnaissance des antigènes du soi et du non soi par les lymphocytes B et T est à l'origine des maladies auto-immunes et inflammatoires. Les anticorps et les auto-anticorps produits par les plasmocytes dérivés des lymphocytes B sont utiles à des fins diagnostiques, mais contribuent également à la physiopathologie de ces maladies. La déplétion des lymphocytes B au cours des maladies auto-immunes chez l'homme a recentré l'attention sur les rôles des lymphocytes B comme modulateurs de la fonction des lymphocytes T, en plus de leur rôle de cellules productrices d'anticorps. L'utilisation d'anticorps anti-CD20 chez la souris révèle le rôle fondamental des lymphocytes B comme adjuvants cellulaires pour l'activation des lymphocytes T CD4+ in vivo (lymphocytes B effecteurs) mais également le rôle régulateur inattendu d'une sous-population de lymphocytes B spléniques CD1dhighCD5+ qui produit de l'interleukine 10 (lymphocytes B10). Le rôle de ces lymphocytes B effecteurs est montré dans un modèle chez la souris NOD (Non Obese Diabetic) alors que le rôle des lymphocytes B régulateurs est montré dans un modèle murin d'eczéma de contact. Au cours de l'encéphalite auto-immune expérimentale, la déplétion précoce des lymphocytes B aggrave les signes neurologiques tandis que la déplétion tardive des lymphocytes B les améliore, reflétant la dualité fonctionnelle des lymphocytes B au cours des maladies inflammatoiresAutoimmunity results from abnormal B and T cell recognition of self antigens, which leads to autoantibody production in many cases. Autoantibodies produced by B cell-derived plasma cells provide diagnostic markers for autoimmunity, but also contribute significantly to disease pathogenesis. The therapeutic benefit of depleting B cells in mice and humans has refocused attention on B cells and their role in autoimmunity beyond autoantibody production. B cells specifically serveas cellular adjuvants for CD4+ T cell activation, while regulatory B cells, including those that produce IL-10 (B10 cells), function as negative regulators of inflammatory immune responses. The role of effector B cells is shown in the non obese diabetic mouse model (NOD) whereas the role of regulatory B cells is demonstrated in a contact dermatitis model. During experimental autoimmune encephalomyelitis, early B cell depletion makes the disease worst whereas B cell depletion after disease onset improves clinical symptoms, reflecting counter regulatory B cell functions during autoimmunit

B Cell Modulation Strategies in Autoimmune Diseases: New Concepts

B cells are major effector cells in autoimmunity through antibody production, T cell help and pro-inflammatory cytokine production. Major advances have been made in human B cell biology knowledge using rituximab and type II new anti-CD20 antibodies, anti-CD19 antibodies, anti-CD22 antibodies, autoantigen specific B cell depleting therapy (chimeric antigen receptor T cells), and B cell receptor signaling inhibition (Bruton’s tyrosine kinase inhibitors). However, in certain circumstances B cell depleting therapy may lead to the worsening of the autoimmune disease which is in accordance with the existence of a regulatory B cell population. Current concepts and future directions for B cell modulating therapies in autoimmune diseases with a special focus on pemphigus are discussed

Lésions cutanées digitales du lupus érythémateux aigu disséminé (à propos de 50 cas)

But : mieux caractériser cliniquement et histologiquement les lésions cutanées digitales au cours du lupus érythémateux aigu disséminé (LEAD). Matériel et méthodes : il s'agit d'une étude monocentrique, rétrospective concernant 50 patients consécutifs ayant un LEAD. Pour être inclus, les patients devaient remplir les critères révisés de LEAD selon l'American College of Rheumatology et avoir des lésions cutanées des doigts. Les caractéristiques cliniques et histologiques de ces lésions étaient systématiquement analysées. Résultats : les lésions des doigts étaient fréquemment douloureuses (50%) et/ou érosives (36%). Une atteinte palmaire à type d'acropulpite était notée dans 70% des cas. Dis huit patients (36%) étaient adressés par des médecins non-dermatologues pour une suspicion clinique de vascularite des doigts. Seulement 1 patient avait une vascularite de type vascularite urticarienne hypocomplémentémique. Quarante six patients (92%) avaient des lésions cutanées spécifiques de lupus : 5 lupus érythémateux aigus (10%), 5 lupus érythémateux subaigus (10%), 21 lupus discoides (42%), avec des formes très atrophiques déformantes ou papulo-squameuses dont 6 avec des atteintes unguéales associées et 15 lupus engelures (30%). Deux patients avaient des lésions d'erythema elevatum diutinum et un patient des lésions de pseudo maladie de Degos. Conclusion : ces résultats illustrent la tendance à surestimer cliniquement la vascularite des doigts au cours du LEAD et soulignent la nécessité d'une confrontation anatomoclinique rigoureuse pour permettre un diagnostic précis et une prise en charge thérapeutique adaptéeObjective : to help better characterize the digital lesions of systemic lupus erythematosus (SLE) with respect to clinical course and histologic features. Material and methods : the clinical charts of 50 patients suffering from SLE according to the American College of Rheumatology revised criteria with digital lesions and available histology sections followed at a single institution were retrospectively analysed. Results : digital lesions in SLE were frequently painful (50%) and/or ulcerated (36%). Finger-pulp inflammation was noted in 70% of cases. Prior to biopsy, lesions were clinically misinterpreted by non dermatologists as vasculitis in 36%. Only one patient had vasculitis classified as hypocomolementic urticarial vasculitis. Fourty six patients (92%) had specific lesions of lupus : 21 discoid lupus erythematosus sometimes very atrophic or papulo-squamous with nail involvement in 6 cases, 5 acute lupus erythematosus, 5 subacute lupus erythematosus. Three patients had erythema elevatum diutinum and one had Degos's disease like lesion. Conclusions : these results highlight the tendency to overestimate clinically the prevalence of cutaneous vasculitis in the setting of SLE and emphasize the need for clinical and pathological confrontation in order to reach accurate diagnosis and proper managementPARIS12-CRETEIL BU Médecine (940282101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF