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.

Nemolizumab is associated with a rapid improvement in atopic dermatitis signs and symptoms: subpopulation (EASI ≥ 16) analysis of randomized phase 2B study.

BACKGROUND: Nemolizumab is a humanized anti-IL-31 receptor blocker in phase 3 for atopic dermatitis (AD). OBJECTIVE: Analyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs placebo (SC q4wk plus loading dose) in moderate-to-severe AD. METHODS: Post hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate-to-severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP-NRS), Investigator's Global Assessment (IGA), changes in sleep and responders with ≥ 4-point improvement on PP-NRS. RESULTS: There was a significantly greater itch relief apparent by Day 2 (-22.8% vs -12.3% PP-NRS; P = 0.005) which continued to improve through week 16 (-68.5% vs -30.9% PP-NRS; P < 0.001). At week 16, PP-NRS ≥ 4-point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (-26.6% vs -9.0%; P < 0.001) which further improved till week 16 (-76.0% vs -36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (-68.6% vs. -42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab-treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002). Nemolizumab was safe and well-tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events. CONCLUSIONS: Nemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.

Actinic cheilitis: a systematic review of treatment options.

Actinic cheilitis is a premalignant condition that can progress to squamous cell carcinoma with a higher propensity for metastasis than cutaneous squamous cell carcinoma. Optimal treatment for actinic cheilitis has not been established, and evidence-based estimates of clinical cure in the dermatology literature are limited. Here, we review and synthesize outcome data published for patients with actinic cheilitis after treatment with various modalities. A systematic review was conducted in MEDLINE, Embase and the Cochrane library for English, French and German-language studies and references of included articles from inception to 20 January 2020. Studies were included if they reported on at least six patients with biopsy-proven actinic cheilitis. After quality appraisal, results of studies with the strongest methodology criteria were synthesized. 18 studies of 411 patients (published 1985 to 2016) were included. The majority of the studies were case series. Carbon dioxide laser ablation and vermilionectomy were associated with the most favourable outcomes with fewest recurrences. Chemical peel and photodynamic therapy were associated with higher recurrence. Adverse effects generally resolved in the weeks following treatment and cosmetic outcomes were favourable overall. In conclusion, there is a lack of high-quality comparative studies evaluating different treatment options for actinic cheilitis. The included publications used various outcome measures; however, the majority reported on the recently defined core outcome sets. These results suggest that both carbon dioxide laser ablation and vermilionectomy are effective treatments for actinic cheilitis. Prospective head-to-head studies are needed to compare these treatment modalities and to assess patient preferences.

Chronic graft-versus-host disease and inhibition of interleukin-17: proof of concept in humans.

Psoriasiform chronic graft-versus-host disease (GvHD) is a rare clinical presentation recently described after allogeneic haematopoietic stem cell transplantation. It is characterized by the combination of clinical and pathological characteristics of psoriasis together with pathological features of chronic GvHD. As described for psoriasis, psoriasiform chronic GvHD is characterized by the infiltration of T helper 17 CD8+ T cells producing both interferon-γ and interleukin-17. However, no data are available about the efficacy of interleukin-17 blockade in the treatment of patients with psoriasiform chronic GvHD. What's already known about this topic? Psoriasiform chronic graft-versus-host disease (GvHD) is a rare clinical presentation with a poor durable response to steroids. Animal models and human data suggest that psoriasiform GvHD could be induced through interleukin-17 production by donor T cells. What does this study add? We describe the first case of a patient with psoriasiform GvHD and persistent improvement on treatment with secukinumab, an anti-interleukin-17A antibody.

Rituximab is an effective treatment in patients with pemphigus vulgaris and demonstrates a steroid-sparing effect.

BACKGROUND: Corticosteroids (CS) with or without adjuvant immunosuppressant agents are standard treatment for pemphigus vulgaris (PV). The efficacy of adjuvant therapies in minimizing steroid-related adverse events (AEs) is unproven. OBJECTIVES: To utilize data collected in a French investigator-initiated, phase III, open-label, randomized controlled trial to demonstrate the efficacy and safety of rituximab and seek approval for its use in PV. METHODS: This was an independently conducted post hoc analysis of the moderate-to-severe PV subset enrolled in the Ritux 3 study. Patients were randomized to rituximab plus 0·5 or 1·0 mg kg-1 per day prednisone tapered over 3 or 6 months, or 1·0 or 1·5 mg kg-1 per day prednisone alone tapered over 12 or 18 months, respectively (according to disease severity). The primary end point was complete remission at month 24 without CS (CRoff) for ≥ 2 months, and 24-month efficacy and safety results were also reported. RESULTS: At month 24, 34 of 38 patients (90%) on rituximab plus prednisone achieved CRoff ≥ 2 months vs. 10 of 36 patients (28%) on prednisone alone. Median total cumulative prednisone dose was 5800 mg in the rituximab plus prednisone arm vs. 20 520 mg for prednisone alone. Eight of 36 patients (22%) who received prednisone alone withdrew from treatment owing to AEs; one rituximab-plus-prednisone patient withdrew due to pregnancy. Overall, 24 of 36 patients (67%) on prednisone alone experienced a grade 3/4 CS-related AE vs. 13 of 38 patients (34%) on rituximab plus prednisone. CONCLUSIONS: In patients with moderate-to-severe PV, rituximab plus short-term prednisone was more effective than prednisone alone. Patients treated with rituximab had less CS exposure and were less likely to experience severe or life-threatening CS-related AEs. What's already known about this topic? Pemphigus vulgaris (PV) is the most common type of pemphigus. Corticosteroids, a standard first-line treatment for PV, have significant side-effects. Although their effects are unproven, adjuvant corticosteroid-sparing agents are routinely used to minimize steroid exposure and corticosteroid-related side-effects. There is evidence that the anti-CD20 antibody rituximab is effective in the treatment of patients with severe recalcitrant pemphigus and in patients with newly diagnosed pemphigus. What does this study add? This study provides a more detailed analysis of patients with PV enrolled in an investigator-initiated trial. Rituximab plus prednisone had a steroid-sparing effect and more patients achieved complete remission off prednisone. Fewer patients experienced grade 3 or grade 4 steroid-related adverse events than those on prednisone alone. This collaboration between academia and industry, utilizing independent post hoc analyses, led to regulatory authority approvals of rituximab in moderate-to-severe PV.

[Association of borderline tuberculoid leprosy and tuberculosis: A case report and review of the literature]. / Association d'une lèpre borderline tuberculoïde et d'une tuberculose : un cas et revue de la littérature.

INTRODUCTION: In metropolitan France, nearly 20 new cases of leprosy are diagnosed each year. The incidence of tuberculosis in France is 8/100,000 inhabitants and there are very few accounts of association of these two mycobacteria. Herein we report a case of co-infection with borderline tuberculoid (BT) leprosy and disseminated tuberculosis diagnosed in metropolitan France. PATIENTS AND METHODS: A male subject presented with diffuse painless infiltrated erythematous plaques. The biopsy revealed perisudoral and perineural lymphohistiocytic epithelioid cell granuloma as well as acid-alcohol-fast bacilli on Ziehl staining. PCR was positive for Mycobacterium leprae, confirming the diagnosis of leprosy in the BT form. The staging examination revealed predominantly lymphocytic left pleural effusion, right-central necrotic adenopathy without histological granuloma, negative screening for BK, a positive QuantiFERON-TB™ test, and a positive intradermal tuberculin reaction. The clinical and radiological results militated in favour of disseminated tuberculosis. Combined therapy (rifampicin, isoniazid, ethambutol and pyrazinamide) together with clofazimine resulted in regression of both cutaneous and extra-cutaneous lesions. This rare co-infection combines leprosy, often present for several years, and tuberculosis (usually pulmonary) of subsequent onset. The pathophysiological hypothesis is that of cross-immunity (with anti-TB immunity protecting against subsequent leprosy and vice versa), supported by the inverse correlation of the two levels of prevalence and by the protection afforded by tuberculosis vaccination. In most cases, treatment for TB and leprosy improves both diseases. Patients presenting leprosy should be screened for latent tuberculosis in order to avoid reactivation, particularly in cases where corticosteroid treatment is being given.

[Cutaneous plasmacytosis with Darier's sign in a woman of European origin]. / Plasmocytose cutanée avec signe de Darier chez une femme d'ascendance européenne.

INTRODUCTION: Cutaneous plasmacytosis is a rare skin condition first described in 1976 and it is seen mainly in patients of Asian descent. Patients usually present with multiple reddish-brown macules and nodules chiefly on the trunk and face, with clusters of well-differentiated plasma cells in the dermis. The aetiopathogenesis and nosological features of this entity remain obscure. We report herein a case of cutaneous plasmacytosis in a European middle-aged woman with presence of Darier's sign. PATIENTS AND METHODS: A 56-year-old woman of European descent presented with asymptomatic hyperpigmented patches affecting the dorsal aspect of her trunk for at least two years. Darier's sign was present in some episodes. Cutaneous biopsy showed a moderately dense interstitial and perivascular infiltrate containing numerous well-differentiated mature plasma cells affecting the entire dermal surface. Kappa and lambda immunochemistry demonstrated polyclonal plasma cell infiltrates with absence of light-chain restriction. Immunohistochemical examination was negative for HHV-8 and Treponema pallidum spirochetes. Laboratory findings revealed hypergammaglobulinaemia with no monoclonal bands being detected on immunofixation. A diagnosis of cutaneous plasmacytosis was made. In the absence of systemic involvement initial management consisted of clinical surveillance. DISCUSSION: The characteristic clinico-pathological features of CP allowed diagnosis of this skin condition in our patient, although it is very rarely reported in patients of European descent. The main differential diagnoses were ruled out, namely plasmacytic infiltrates related to infections and marginal B-cell lymphoma.

Human orf complicated by epidermolysis bullosa acquisita.

Orf is a DNA parapoxvirus transmitted to humans by contact with infected goats and sheep. Many complications have been reported after orf infection, including erythema multiforme. A few cases of autoimmune bullous dermatosis complicating orf disease have been reported to date. They are usually characterized by tense blister eruptions with or without mucosal involvement; linear deposition of C3, IgG and/or IgA along the basement membrane; and negativity of indirect immunofluorescence analysis and enzyme-linked immunosorbent assay (ELISA) (performed in four of 11 reported cases). These analyses have targeted antigens of bullous pemphigoid, mucous membrane pemphigoid or epidermolysis bullosa acquisita, except one case of mucosal pemphigoid with antilaminin-332 antibodies. We describe the case of a patient who presented with an ulceration on his finger 10 days after direct contact with a lamb during Eid al-Adha. Four weeks later he developed a severe tense blistering eruption associated with mucous membrane erosions. Indirect immunofluorescence analysis using the patient's serum revealed circulating antibasement membrane IgG that bound the dermal side of salt-split skin. ELISA was positive for recombinant immunodominant NC1 domain of type VII collagen. We finally diagnosed epidermolysis bullosa acquisita complicating probable human orf infection.

Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients.

BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.

[Sarcoid-like granulomatosis associated with eosinophilic fasciitis]. / Fasciite de Shulman associée à un infiltrat granulomateux sarcoïdosique.

BACKGROUND: Eosinophilic fasciitis (EF) is a rare condition characterized by swelling of the extremities, sclerodermatous evolution and frequent hypereosinophilia. Hematological disorders, including aplastic anemia, solid tumors and autoimmune diseases, may be associated with EF. EF is usually not associated with granulomatous diseases. CASE REPORT: Herein we describe the case of an 80-year-old man with symmetrical swelling and sclerosis of the legs, typical of EF, associated with skin and lymph node granulomas. Oral prednisone treatment resulted in complete clinical remission. DISCUSSION: Association of EF and granulomatous disease is uncommon. Our case highlights the possible association of EF with sarcoidosis-like reactions.

Cutaneous presentation of adult T-cell leukemia/lymphoma (ATLL). Single-center study on 37 patients in metropolitan France between 1996 and 2016.

INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a hematological malignancy associated with chronic HTLV-1 infection. AIM: To describe skin lesions in ATLL. METHODS: A descriptive, retrospective study between 1996 and 2016, including all patients diagnosed with ATLL at Saint-Louis Hospital (Paris, France). RESULTS: Thirty-seven ATLL patients were included. Fifteen patients (41%) had a cutaneous localization of the disease, which was present from the beginning of the disease for two thirds of them. ATLL types in patients with cutaneous localization of the disease were as follows: lymphoma, n=5, chronic, n=4, smoldering, n=4, acute, n=2. Half the patients had 2 or more cutaneous manifestations. The cutaneous localizations observed were as follows: nodulotumoral (n=8), plaques (n=7), multipapular (n=6), macular (n=4), purpuric (n=2). Among the 15 patients with cutaneous localization, median overall survival was significantly shorter in the acute and lymphoma types compared to the smoldering and chronic types (8.7 months vs. 79 months, P=0.003). DISCUSSION: ATLL is a hematologic malignancy with variable expression that is diagnosed only very rarely in metropolitan France, but that should be sought in patients from countries with high HTLV-1 prevalence in the event of a chronic eruption with patches, papules, plaques and/or tumors. The chronic and smoldering types are relatively indolent, whereas the acute and lymphoma forms have a poor prognosis.

Efficacy and comparison of antimalarials in cutaneous lupus erythematosus subtypes: a systematic review and meta-analysis.

BACKGROUND: The antimalarials (AMs) hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated variable cutaneous response rates in cutaneous lupus erythematosus (CLE). OBJECTIVES: We sought to assess the global cutaneous response rates to HCQ and CQ, with respect to CLE subtypes, based on previously published studies. METHODS: We performed a systematic review and meta-analysis of studies published in MEDLINE, Embase and the Cochrane Library between 1965 and December 2015. The proportions of responders to AMs according to CLE subtypes were extracted from individual studies and pooled using random-effects or fixed models. The odds ratio (OR) was used as the measure of association to compare the response rates between CLE subtypes and AMs. RESULTS: Among 1990 courses of treatment with AMs from 31 included studies, the overall response rate to AMs was 63% [95% confidence interval (CI) 55-70], with important statistical heterogeneity across the included studies. HCQ had a higher overall efficacy than CQ, but this was not significant (OR 1·48, 95% CI 0·98-2·23). The response rate to AMs was different between CLE subtypes, ranging from 31% (95% CI 20-44) for chilblain lupus to 91% (95% CI 87-93) for acute CLE. The response was significantly higher for acute CLE than for subacute CLE and intermittent CLE. In case of failure of monotherapy with AM, the combination of quinacrine with HCQ or CQ seemed effective, whereas too little data were available to assess the efficacy of the switch to another AM agent. CONCLUSIONS: Wide discrepancies in cutaneous response to AMs are observed between CLE subtypes. A specific therapeutic approach considering CLE subtypes may improve CLE management.