Nemolizumab with concomitant topical therapy in adolescents and adults with moderate-to-severe atopic dermatitis (ARCADIA 1 and ARCADIA 2): results from two replicate, double-blind, randomised controlled phase 3 trials.

BACKGROUND: Nemolizumab, an interleukin (IL)-31 receptor subunit α antagonist, inhibits the IL-31 pathway of itch and skin inflammation in atopic dermatitis. Two international phase 3 studies were done to assess the efficacy and safety of nemolizumab in atopic dermatitis. In this Article we report results for the 16-week initial treatment period of both trials. METHODS: ARCADIA 1 and ARCADIA 2 were identical 48-week randomised, double-blind, placebo-controlled phase 3 trials in adult and adolescent participants (aged ≥12 years) with moderate-to-severe atopic dermatitis, associated pruritus, and inadequate response to topical steroids. Participants were enrolled from 281 clinics, hospitals, and academic centres in 22 countries across both trials, and were randomly assigned (2:1) to receive nemolizumab 30 mg subcutaneously (baseline loading dose 60 mg) or matching placebo once every 4 weeks with background topical corticosteroids (TCS) with or without topical calcineurin inhibitors (TCI; ie, TCS-TCI background treatment). Randomisation was done via interactive response technology and stratified by baseline disease and pruritus severity. Study staff and participants were masked throughout the study, with outcome assessors masked until database lock. Coprimary endpoints at week 16 post-baseline were Investigator's Global Assessment (IGA) success (score of 0 [clear skin] or 1 [almost clear skin] with a ≥2-point improvement from baseline) and at least 75% improvement in Eczema Area and Severity Index score from baseline (EASI-75 response). Outcome rates were compared between groups with the Cochran-Mantel-Haenszel test adjusting for randomisation strata. The key secondary endpoints were the proportion of participants with Peak Pruritus Numerical Rating Scale (PP-NRS) score improvement of at least 4 points at weeks 1, 2, 4, and 16; PP-NRS score below 2 at weeks 4 and 16; Sleep Disturbance Numerical Rating Scale score improvement of at least 4 points at week 16; EASI-75 response plus PP-NRS score improvement of at least 4 points at week 16; and IGA success plus PP-NRS score improvement of at least 4 points at week 16. Efficacy analyses were done on an intention-to-treat basis; safety analyses included all participants who received one dose of nemolizumab or placebo. Both studies are completed (ClinicalTrials.gov: ARCADIA 1, NCT03985943 and ARCADIA 2, NCT03989349). FINDINGS: Between Aug 9, 2019, and Nov 2, 2022, 1728 participants were enrolled across both trials: 1142 were allocated to nemolizumab plus TCS-TCI (620 in ARCADIA 1 and 522 in ARCADIA 2) and 586 to placebo plus TCS-TCI (321 in ARCADIA 1 and 265 in ARCADIA 2). ARCADIA 1 included 500 (53%) male participants and 441 (47%) female participants, and ARCADIA 2 included 381 (48%) male participants and 406 (52%) female participants. Mean age ranged from 33·3 (SD 15·6) years to 35·2 (17·0) years across the treatment groups. Both trials met the coprimary endpoints; at week 16, a greater proportion of participants receiving nemolizumab plus TCS-TCI versus placebo plus TCS-TCI had IGA success (ARCADIA 1: 221 [36%] of 620 vs 79 [25%] of 321, adjusted percentage difference 11·5% [97·5% CI 4·7-18·3], p=0·0003; ARCADIA 2: 197 [38%] of 522 vs 69 [26%] of 265, adjusted difference 12·2% [4·6-19·8], p=0·0006) and an EASI-75 response (ARCADIA 1: 270 [44%] vs 93 [29%], adjusted difference 14·9% [7·8-22·0], p<0·0001; ARCADIA 2: 220 [42%] vs 80 [30%], adjusted difference 12·5% [4·6-20·3], p=0·0006). Significant benefits were observed with nemolizumab for all key secondary endpoints including improvement in itch, as early as week 1, and sleep improvement by week 16. The safety profile was similar between nemolizumab plus TCS-TCI and placebo plus TCS-TCI. In the safety sets, 306 (50%) of 616 participants (ARCADIA 1) and 215 (41%) of 519 participants (ARCADIA 2) who received nemolizumab plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in six [1%] and 13 [3%], respectively); and 146 (45%) of 321 (ARCADIA 1) and 117 (44%) of 263 (ARCADIA 2) who received placebo plus TCS-TCI had at least one treatment-emergent adverse event (serious treatment-emergent adverse events in four [1%] and three [1%], respectively). Ten serious treatment-emergent adverse events possibly related to nemolizumab were reported in five (1%) participants in ARCADIA 2. No deaths occurred. INTERPRETATION: Nemolizumab plus TCS-TCI was efficacious and showed statistically and clinically significant improvements in inflammation and itch in adults and adolescents with moderate-to-severe atopic dermatitis. Nemolizumab might offer a valuable extension of current therapies if approved. FUNDING: Galderma.

Coencapsulation of Immunosuppressive Drug with Anti-Inflammatory Molecule in Pickering Emulsions as an Innovative Therapeutic Approach for Inflammatory Dermatoses.

Psoriasis is an inflammatory skin disease characterized by epidermal and immune dysfunctions. Although efficient, current topical treatments display adverse effects, including skin atrophy and burning sensation, leading to poor patient adherence. To overcome these downsides, pickering emulsions were formulated in which the calcitriol-containing dispersed phase was stabilized with either cyclosporin A- or tacrolimus-loaded poly(lactic-co-glycolic) acid nanoparticles. This study aimed to investigate their biological effects on lymphocytes and epidermal cells and their effectiveness in an imiquimod-induced psoriasis-like mouse model. Results showed that both emulsions significantly inhibited nuclear factor of activated T cell translocation in T lymphocytes as well as their IL-2 production, cell activation, and proliferation. In keratinocytes, inhibition of nuclear factor of activated T cell translocation decreased the production of IL-8 and TNF-α. Topical application of emulsions over skin biopsies ex vivo showed accumulation of rhodamin B-coupled poly(lactic-co-glycolic) acid nanoparticles throughout the epidermis by immunofluorescence and significantly decreased the antigen-presenting capacity of Langerhans cells in relation to a reduced expression of activation markers CD40, CD86, and HLA-DR. Using an imiquimod-induced psoriasis model in vivo, pickering emulsions significantly alleviated psoriasiform lesions potentially attributed to the decreased cutaneous expression of T-cell markers, proinflammatory cytokines, chemokines, and specific epidermal cell genes. Altogether, pickering emulsion might be a very efficient formulation for treating inflammatory dermatoses.

Real-life efficacy of immunotherapy for Sézary syndrome: a multicenter observational cohort study.

Background: Sézary syndrome is an extremely rare and fatal cutaneous T-cell lymphoma (CTCL). Mogamulizumab, an anti-CCR4 monoclonal antibody, has recently been associated with increased progression-free survival in a randomized clinical trial in CTCL. We aimed to evaluate OS and prognostic factors in Sézary syndrome, including treatment with mogamulizumab, in a real-life setting. Methods: Data from patients with Sézary (ISCL/EORTC stage IV) and pre-Sézary (stage IIIB) syndrome diagnosed from 2000 to 2020 were obtained from 24 centers in Europe. Age, disease stage, plasma lactate dehydrogenases levels, blood eosinophilia at diagnosis, large-cell transformation and treatment received were analyzed in a multivariable Cox proportional hazard ratio model. This study has been registered in ClinicalTrials (SURPASSe01 study: NCT05206045). Findings: Three hundred and thirty-nine patients were included (58% men, median age at diagnosis of 70 years, Q1-Q3, 61-79): 33 pre-Sézary (9.7% of 339), 296 Sézary syndrome (87.3%), of whom 10 (2.9%) had large-cell transformation. One hundred and ten patients received mogamulizumab. Median follow-up was 58 months (95% confidence interval [CI], 53-68). OS was 46.5% (95% CI, 40.6%-53.3%) at 5 years. Multivariable analysis showed that age ≥ 80 versus <50 (HR: 4.9, 95% CI, 2.1-11.2, p = 0.001), and large-cell transformation (HR: 2.8, 95% CI, 1.6-5.1, p = 0.001) were independent and significant factors associated with reduced OS. Mogamulizumab treatment was significantly associated with decreased mortality (HR: 0.34, 95% CI, 0.15-0.80, p = 0.013). Interpretation: Treatment with mogamulizumab was significantly and independently associated with decreased mortality in Sézary syndrome. Funding: French Society of Dermatology, Swiss National Science Foundation (IZLIZ3_200253/1) and SKINTEGRITY.CH collaborative research program.

Pasteurella bettyae Infections in Men Who Have Sex with Men, France.

Pasteurella bettyae is a gram-negative bacillus sporadically involved in human infections; its main reservoirs are cats and dogs. A recent publication suggests the possibility of sexual transmission leading to genital infections in men who have sex with men. We report 9 cases in France of genital infection among this population.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX.

OBJECTIVES: Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and safety of targeted therapies. METHODS: Multicentre retrospective study including patients with genetically proven VEXAS syndrome who had received at least one targeted therapy. Complete response (CR) was defined by a clinical remission, C-reactive protein (CRP) ≤10 mg/L and a ≤10 mg/day of prednisone-equivalent therapy, and partial response (PR) was defined by a clinical remission and a 50% reduction in CRP levels and glucocorticoid dose. RESULTS: 110 patients (median age 71 (68-79) years) who received 194 targeted therapies were included: 78 (40%) received Janus kinase (JAK) inhibitors (JAKi), 51 (26%) interleukin (IL)-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) tumour necrosis factor (TNFα) blockers and 12 (6%) other targeted therapies. At 3 months, the overall response (CR and PR) rate was 24% with JAKi, 32% with IL-6 inhibitors, 9% with anti-IL-1 and 0% with TNFα blockers or other targeted therapies. At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors. Survival without treatment discontinuation was significantly longer with JAKi than with the other targeted therapies. Among patients who discontinued treatment, causes were primary failure, secondary failure, serious adverse event or death in 43%, 14%, 19% and 19%, respectively, with JAKi and 46%, 11%, 31% and 9%, respectively, with IL-6 inhibitors. CONCLUSIONS: This study shows the benefit of JAKi and IL-6 inhibitors, whereas other therapies have lower efficacy. These results need to be confirmed in prospective trials.

IFNα induces CCR5 in CD4+ T cells of HIV patients causing pathogenic elevation.

BACKGROUND: Among people living with HIV, elite controllers (ECs) maintain an undetectable viral load, even without receiving anti-HIV therapy. In non-EC patients, this therapy leads to marked improvement, including in immune parameters, but unlike ECs, non-EC patients still require ongoing treatment and experience co-morbidities. In-depth, comprehensive immune analyses comparing EC and treated non-EC patients may reveal subtle, consistent differences. This comparison could clarify whether elevated circulating interferon-alpha (IFNα) promotes widespread immune cell alterations and persists post-therapy, furthering understanding of why non-EC patients continue to need treatment. METHODS: Levels of IFNα in HIV-infected EC and treated non-EC patients were compared, along with blood immune cell subset distribution and phenotype, and functional capacities in some cases. In addition, we assessed mechanisms potentially associated with IFNα overload. RESULTS: Treatment of non-EC patients results in restoration of IFNα control, followed by marked improvement in distribution numbers, phenotypic profiles of blood immune cells, and functional capacity. These changes still do not lead to EC status, however, and IFNα can induce these changes in normal immune cell counterparts in vitro. Hypothesizing that persistent alterations could arise from inalterable effects of IFNα at infection onset, we verified an IFNα-related mechanism. The protein induces the HIV coreceptor CCR5, boosting HIV infection and reducing the effects of anti-HIV therapies. EC patients may avoid elevated IFNα following on infection with a lower inoculum of HIV or because of some unidentified genetic factor. CONCLUSIONS: Early control of IFNα is essential for better prognosis of HIV-infected patients.

The treatment for HIV, known as antiretroviral therapy (ART), does not cure HIV but enables individuals to live longer, healthier lives. In this study, we compared immune responses between elite controllers (ECs), who control their HIV infection without any treatment, and ART-treated and untreated patients. We demonstrate that IFNα, a small protein crucial in controlling immune system, is excessively produced at the onset of HIV infection and at levels that persist, resulting in poor HIV control without therapy. We show a mechanism for lack of control of HIV by IFNα. While inhibiting HIV, IFNα also simultaneously increases the HIV co-receptor, CCR5, thereby facilitating virus entry into the target cell. This is avoided by ECs which we hypothesize is associated with a lower infectious inoculum of HIV.

Early elevated IFNα is a key mediator of HIV pathogenesis.

BACKGROUND: A complete understanding of the different steps of HIV replication and an effective drug combination have led to modern antiretroviral regimens that block HIV replication for decades, but these therapies are not curative and must be taken for life. "Elite controllers" (ECs) is a term for the 0.5% of HIV-infected persons requiring no antiretroviral therapy, whose status may point the way toward a functional HIV cure. Defining the mechanisms of this control may be key to understanding how to replicate this functional cure in others. METHODS: In ECs and untreated non-EC patients, we compared IFNα serum concentration, distribution of immune cell subsets, and frequency of cell markers associated with immune dysfunction. We also investigated the effect of an elevated dose of IFNα on distinct subsets within dendritic cells, natural killer cells, and CD4+ and CD8 + T cells. RESULTS: Serum IFNα was undetectable in ECs, but all immune cell subsets from untreated non-EC patients were structurally and functionally impaired. We also show that the altered phenotype and function of these cell subsets in non-EC patients can be recapitulated when cells are stimulated in vitro with high-dose IFNα. CONCLUSIONS: Elevated IFNα is a key mediator of HIV pathogenesis.

Currently, HIV infection is not curable, but infected individuals can manage their condition by taking daily doses of antiretroviral therapy. Some individuals, known as elite controllers (ECs), control their infection without antiretroviral treatment, and studying how their immune system responds to HIV exposure could lead to a potential cure for others. Here, we compare immune cell responses between ECs and untreated non-ECs. We find that IFNα, a small protein with an important role in controlling white blood cell activity, is produced in excess in immune cells from non-ECs compared with ECs during early infection. This insight provides an important clue for the future development of a targeted cure for HIV.

Overview of Neutrophilic Biology, Pathophysiology, and Classification of Neutrophilic Dermatoses.

Neutrophilic dermatoses are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. These conditions present with a wide range of clinical manifestations, including pustules, bullae, abscesses, papules, nodules, plaques, and ulcers. The classification of neutrophilic dermatoses is based on the localization of neutrophils in the skin. The pathogenic mechanisms of neutrophilic dermatoses involve autoinflammation, neutrophilic dysfunction, clonal somatic mutation and differentiation of the myeloid precursors as encountered in myeloid neoplasm.

Two cases of dupilumab-responsive Kimura disease.

Kimura disease (KD) is a rare, chronic angiolymphoproliferative inflammatory disease appearing to be mostly restricted to the skin and soft tissue. Cutaneous involvement of KD includes head and/or neck nodules showing suggestive histological features, frequently associated with an atopic dermatitis-like or prurigo-like presentation. KD is challenging to treat, with high rate of recurrence using current therapeutic strategies. Evidence for involvement of a T-helper type 2 (Th2) immune response in KD pathogenesis has been found in previous studies. Consequently, this study aimed to determine the efficacy and safety of dupilumab, a human monoclonal antibody that inhibits signalling of key Th2 cytokines, interleukin (IL)-4 and IL-13, within a single-centre cohort of patients with cutaneous KD. Two adults with a diagnosis of refractory (failure of at least one treatment line) cutaneous-restricted KD based on clinical, biological, histological, molecular and imaging findings received dupilumab for KD, and showed dramatic response with a good safety profile.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Neutrophilic dermatosis and hidradenitis suppurativa in patients with Behçet's disease: A neutrophilic disease in the spectrum of autoinflammatory syndromes.

BACKGROUND: Association of neutrophilic dermatosis (ND), hidradenitis suppurativa (HS) and Behçet's disease (BD) and shared efficacy of TNFα axis blockade suggests common physiopathology. OBJECTIVES: To investigate the clinical features and therapeutic response of ND and HS associated with BD. METHODS: We identified 20 patients with ND or HS associated with BD among 1462 patients with BD. RESULTS: We analysed 20 (1.4%) patients diagnosed with ND or HS associated with BD: 13 HS, 6 pyoderma gangrenosum (PG), and 1 SAPHO. Our 6 PG cases over 1462 BD patients accounts for 400/100 000 prevalence. Thirteen had bipolar aphthosis, 6 vascular, 5 neurologic, and 4 ocular involvements. All PG occurred on limbs and had typical histology with constant dermal neutrophilic infiltrate. All HS had the classical axillary-mammary phenotype. Sixty-nine percent (69%) of HS were Hurley 1 stage. Treatment consisted mainly in colchicine (n = 20), glucocorticoids (n = 12), and anti-TNFα (n = 9). Interesting results with complete or partial responses were obtained with anti-TNFα (9 cases), ustekinumab (3 cases) and tocilizumab (1 case) to treat refractory ND or HS associated with BD. CONCLUSION: PG seems overrepresented in patients with BD. Biotherapies such as anti-TNFα, ustekinumab and tocilizumab appear to be promising to treat refractory ND or HS associated with BD.

Evidence of inter- and intra-keloid heterogeneity through analysis of dermal fibroblasts: A new insight in deciphering keloid physiopathology.

Keloid scars are hypertrophic and proliferating pathological scars extending beyond the initial lesion and without tendency to regression. Usually, keloids are considered and treated as a single entity but clinical observations suggest heterogeneity in keloid morphologies with distinction of superficial/extensive and nodular entities. Within a keloid, heterogeneity could also be detected between superficial and deep dermis or centre and periphery. Focusing on fibroblasts as main actors of keloid formation, we aimed at evaluating intra- and inter-keloid fibroblast heterogeneity by analysing their gene expression and functional capacities (proliferation, migration, traction forces), in order to improve our understanding of keloid pathogenesis. Fibroblasts were obtained from centre, periphery, papillary and reticular dermis from extensive or nodular keloids and were compared to control fibroblasts from healthy skin. Transcriptional profiling of fibroblasts identified a total of 834 differentially expressed genes between nodular and extensive keloids. Quantification of ECM-associated gene expression by RT-qPCR brought evidence that central reticular fibroblasts of nodular keloids are the population which synthesize higher levels of mature collagens, TGFß, HIF1α and αSMA as compared to control skin, suggesting that this central deep region is the nucleus of ECM production with a centrifuge extension in keloids. Although no significant variations were found for basal proliferation, migration of peripheral fibroblasts from extensive keloids was higher than that of central ones and from nodular cells. Moreover, these peripheral fibroblasts from extensive keloids exhibited higher traction forces than central cells, control fibroblasts and nodular ones. Altogether, studying fibroblast features demonstrate keloid heterogeneity, leading to a better understanding of keloid pathophysiology and treatment adaptation.

IFNα induces CCR5 in CD4+ T-cells, causing its anti- HIV inefficiency and its subsequent pathogenic elevation, partially controlled by anti-HIV therapy.

Like EC, we find that ART-treated patients control serum IFNα concentration and show few immune cell alterations enabling a healthy but fragile medical status. However, treatment interruption leads to elevated IFNα reflecting virus production indicating that like EC, ART does not achieve a virological cure. The immune system becomes overwhelmed by multiple immune cell abnormalities as found in untreated patients. These are chiefly mediated by elevated IFNα inducing signaling checkpoints abnormalities, including PD1, in cytotoxic immune cells. Importantly, during acute infection, elevated IFNα correlated with HIV load and we found that IFNα enhances CCR5, the HIV coreceptor in CD4+ T-cells, impairing its anti-viral response and accounting for the pathogenic vicious cycle: HIV → IFNα ↗ → infected CD4+ T-cells ↗ →HIV ↗. This study opens immunotherapeutic perspectives showing the need to control IFNα in order to convert ART patients into EC.