Plasma cell-directed therapies induce profound clinical and durable responses in patients with severe or relapsed/refractory scleromyxedema.

BACKGROUND: Scleromyxedema (SM) is a rare skin disorder related to monoclonal gammopathy. High dose intravenous immunoglobulins (HDIVIg) are usually used as a frontline therapy with initial efficacy. However, some patients evolve with relapse, refractory state or severe extra-cutaneous complications such as dermato-neuro syndrome (DNS) or cardiac involvement. The objective of the study is to evaluate the use of anti-plasma cell treatment in these patients in order to obtain a deep and durable dermatological and haematological response. METHODS: We report here eight patients treated with HDIVIg together with anti-plasma cell therapy including: lenalidomide and dexamethasone (n = 5); bortezomib, cyclophosphamide and dexamethasone (n = 1); daratumumab, lenalidomide and dexamethasone (n = 2). RESULTS: Combination of HDIVIg with a treatment targeting the monoclonal component led to a high level of haematological remission and drastically improved skin response with an acceptable safety profile in all patients. Moreover, HDIVIg was reduced and stopped in 4 of the 7 patients who achieved complete remission. CONCLUSIONS: The association of lenalidomide and dexamethasone with HDIVIg could improve the treatment of relapsed or severe SM.

Neutrophilic dermatoses.

Neutrophilic dermatoses (ND) are a group of inflammatory skin conditions characterized by a neutrophilic infiltrate on histopathology with no evidence of infection. ND are classified based upon the localization of neutrophils within the skin and clinical features. Recent findings suggest that ND are due to two main mechanisms: i) a polyclonal hereditary activation of the innate immune system (polygenic or monogenic); or ii) a clonal somatic activation of myeloid cells such as encountered in myelodysplastic syndrome or VEXAS syndrome. ND belong to internal medicine as a great number of patients with ND suffer from an underlying condition (such as hematological malignancy, inflammatory bowel disease, auto-immune and auto-inflammatory diseases). ND are diagnoses of exclusion and physicians should always consider differential diagnoses, particularly skin infections. Here, we review the pathophysiology and classification of the main ND (i.e., subcorneal pustular dermatosis (Sneddon-Wilkinson Disease) and Intercellular IgA dermatoses, aseptic pustulosis of the folds, Sweet syndrome, neutrophilic eccrine hidradenitis, pyoderma gangrenosum, erythema elevatum diutinum, neutrophilic urticarial dermatosis and neutrophilic panniculitis), their clinical and histopathological features, and we highlight the investigations that are useful to identify ND-associated diseases and to exclude the differential diagnoses.

[Dupilumab-related blepharoconjunctivitis: Recommendations of the CEDRE group. Atopic dermatitis, conjunctivitis and dupilumab: Which management approach?] / Blépharo-conjonctivites sous dupilumab : recommandations du groupe CEDRE. Dermatite atopique, conjonctivites et dupilumab : quelle prise en charge ?

Dupilumab is a recombinant monoclonal IgG4 type antibody which inhibits IL4 and IL13 signaling. It is indicated in moderate to severe atopic dermatitis (AD) in adults and adolescents over 12 years of age. Its side effects include conjunctivitis and blepharoconjunctivitis, affecting between 4.7% and 28% of patients depending on the study. The incidence of conjunctivitis in patients treated with dupilumab for AD appears to be higher than placebo in clinical studies. This increase was not observed in patients treated with dupilumab for asthma or sinonasal polyposis. The risk factors for conjunctivitis in patients with AD are disease severity, pre-existence of conjunctivitis and low concentrations of dupilumab, but the pathophysiology of this disease is poorly understood. A literature search carried out in April and May 2020 showed an increase in the number of publications on the subject, but there are currently no official joint dermatologist-ophthalmologist recommendations for prevention and management. The objective of this article is to provide an overview of the status of this subject, to address the main questions raised by this type of conjunctivitis and to suggest a course of action for starting and continuing treatment with dupilumab in patients with AD, according to the recommendations of the French Ophthalmologist/Dermatologist group CEDRE.

Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

Treatment of Eosinophilic Annular Erythema: Retrospective multicenter study and literature review.

BACKGROUND: Eosinophilic annular erythema (EAE) is a rare eosinophil-related skin disease which typically manifests with annular erythematous plaques and severe pruritus. Besides the diagnosis, the treatment of EAE is challenging since relevant published data are sparse. METHODS: The aim of this study was to assess the underlying diseases, treatments and outcomes of patients with EAE. To this end, we conducted a retrospective multicenter study and a systematic review of the MEDLINE database. RESULTS: We included 18 patients with EAE followed in 8 centers. The MEDLINE database search yielded 37 relevant publications reporting 55 cases of EAE with 106 treatment sequences. The most common and efficient treatments included topical or systemic corticosteroids, hydroxychloroquine and dapsone. In refractory patients, a combination of systemic corticosteroids with hydroxychloroquine was associated with 88% of complete clinical response. DISCUSSION: To improve the management of EAE patients, we discuss the following treatment strategy: in topical steroid-resistant patients, hydroxychloroquine can be given as first-line systemic treatment. Dapsone, hydroxychloroquine or systemic corticosteroids are second-line options to consider. Last, monoclonal antibodies or JAK inhibitors targeting type 2 inflammation could represent promising last-resort options in refractory patients.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.