Effectiveness of mogamulizumab in patients with Mycosis Fungoides or Sézary syndrome: A multicentre, retrospective, real-world French study.

BACKGROUND: Efficacy and safety of mogamulizumab, a monoclonal antibody directed against C-C chemokine receptor 4, were demonstrated in a previous multinational clinical trial conducted in patients with previously treated cutaneous T-cell lymphoma (CTCL): Sézary syndrome (SS) or Mycosis Fungoides (MF). OBJECTIVES: The real-world French OMEGA study aimed to describe effectiveness and tolerability of mogamulizumab in adult patients with CTCL, overall and according to the disease (SS or MF). METHODS: In this retrospective study, patients treated with mogamulizumab for SS or MF were included from 14 French expert centres. The overall response rate (ORR) under treatment was described (primary criterion), as well as treatment use and safety data. RESULTS: The 122 analysed patients (69 SS, 53 MF) were aged 66.6 ± 12.1 years at mogamulizumab initiation, and their median disease duration was 2.5 years (IQR: 1.3-5.6). Prior to treatment start, they received a median of three systemic CTCL therapies (2-5). Overall, 77.8% of patients suffered from advanced disease (Stage IIB-IVB), with frequent blood (B1/B2) involvement (67.5%). Over the treatment period (median: 4.6 months, 2.1-7.2), 96.7% of patients received all the planned mogamulizumab infusions. Among the 109 patients evaluable for effectiveness, ORR was 58.7% (95% CI [48.9-68.1]) overall, 69.5% [56.1-80.8] in SS and 46.0% [31.8-60.7] in MF. Compartmental response in the blood was observed in 81.8% [69.1-90.9] of SS patients. Skin responses were observed in 57.0% [47.0-66.5] of patients overall, 66.7% [52.9-78.6] in SS and 46.0% [31.8-60.7] in MF. The most common serious adverse drug reactions were rash (8.1% of patients) and infusion-related reactions (2.4%) which led to treatment discontinuation in 7.3% and 0.8% of patients, respectively. One patient with SS died from mogamulizumab-related tumour lysis syndrome. CONCLUSIONS: This large French study confirmed the effectiveness and tolerability of mogamulizumab in SS and MF patients in routine medical practice.

Palmoplantar pustulosis and acrodermatitis continua of Hallopeau: demographic and clinical comparative study in a large multicentre cohort.

BACKGROUND: Acral pustular disease within the pustular psoriasis/psoriasis-like spectrum mainly includes palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH). Scarce data argue for a distinction between these two entities, but no study has compared the clinical and epidemiologic characteristics of ACH and PPP. OBJECTIVES: We aimed to perform a comparative description of the epidemiological and clinical characteristics of PPP and ACH in a multicentre retrospective cohort. METHODS: In this multicentre national retrospective cohort study, we compared the epidemiological characteristics, comorbidities and psoriasis characteristics of patients with PPP and ACH. RESULTS: A total of 234 patients were included: 203 (87%) with PPP, 18 (8%) with ACH and 13 (6%) with both, according to 2017 ERASPEN criteria. As compared with ACH, PPP was associated with female sex, smoking activity and higher median BMI (P = 0.01, P = 0.02 and P = 0.05 respectively). A family background of psoriasis was more frequent in PPP than ACH. Age of onset of palmoplantar disease was similar between PPP and ACH patients, median age 44 and 48 years respectively. Peripheral joint inflammatory involvement was the only rheumatic disease associated with ACH. The association with another psoriasis type was similar in PPP and ACH (57.6% and 61.1% respectively). CONCLUSION: Our study confirms in a large PPP cohort the predominance of females and a high prevalence of smoking and elevated body mass index but also shows an association of these features in PPP as compared with ACH. In addition, it highlights peripheral arthritis as the only arthritis endotype associated with ACH. Increased knowledge of the immunogenetic backgrounds underlying these two entities is warranted to better stratify pustular psoriasis or psoriasis-like entities for precision medicine.

International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg-1 per day starting dose of oral corticosteroids to treat bullous pemphigoid.

BACKGROUND: European guidelines propose a 0·5 mg kg-1 per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients. METHODS: In a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0·5 mg kg-1 per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0·1 mg kg-1 per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score. RESULTS: In total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80·9 (SD 9·1) years. Control of disease activity was achieved at day 21 in 119 patients [62·6%, 95% confidence interval (CI) 55·3-69.5]; 18 of 24 patients (75%, 95% CI 53·3-90·2), 75 of 110 patients (68·8%, 95% CI 59·2-77·3) and 26 of 56 patients (46.4%, 95% CI 33·0-60·3) had mild, moderate and severe BP, respectively (P = 0·0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82·6% (95% CI 76·3-87·4) corresponding to 90·9%, 83·0% and 80·0% rates in patients with mild, moderate and severe BP, respectively (P = 0·5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively. CONCLUSIONS: A 0·5 mg kg-1 per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.

Epidemiological changes in cutaneous lymphomas: an analysis of 8593 patients from the French Cutaneous Lymphoma Registry.

BACKGROUND: Primary cutaneous lymphomas (PCLs) are a heterogeneous group of T-cell (CTCL) and B-cell (CBCL) malignancies. Little is known about their epidemiology at initial presentation in Europe and about potential changes over time. OBJECTIVES: The aim of this retrospective study was to analyse the frequency of PCLs in the French Cutaneous Lymphoma Registry (GFELC) and to describe the demography of patients. METHODS: Patients with a centrally validated diagnosis of primary PCL, diagnosed between 2005 and 2019, were included. RESULTS: The calculated incidence was unprecedently high at 1·06 per 100 000 person-years. The number of included patients increased yearly. Most PCL subtypes were more frequent in male patients, diagnosed at a median age of 60 years. The relative frequency of rare CTCL remained stable, the proportion of classical mycosis fungoides (MF) decreased, and the frequency of its variants (e.g. folliculotropic MF) increased. Similar patterns were observed for CBCL; for example, the proportion of marginal-zone CBCL increased over time. CONCLUSIONS: Changes in PCL frequencies may be explained by the emergence of new diagnostic criteria and better description of the entities in the most recent PCL classification. Moreover, we propose that an algorithm should be developed to confirm the diagnosis of PCL by central validation of the cases.

Efficacy and safety of TNF blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of Hallopeau.

BACKGROUND: Palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are rare variants of psoriasis. Knowledge of the efficacy of biologics is scarce. OBJECTIVES: To evaluate the real-life efficacy of tumour necrosis factor blockers and ustekinumab in PPP and in ACH. METHODS: A multicentre retrospective descriptive study was conducted in 19 dermatology departments, including all patients with PPP or ACH seen from 2014 to 2016 who received one of the studied biologics. The data were collected by a standardized document. Factors associated with complete clearance (CC) were analysed by multivariate analysis, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 92 patients included, 50 received adalimumab, 44 ustekinumab, 36 etanercept and 31 infliximab. Improvement and CC were observed in 83.9% and 20.0% patients receiving infliximab, 75.0% and 38.6% ustekinumab, 57.1% and 20.0% etanercept and 60.4% and 29.2% adalimumab. We found no significant difference in CC rates or duration of treatment among the biological treatments (P = 0.18 and P = 0.10, respectively). On multivariate analysis, CC with etanercept was associated with the ACH form and not smoking [OR = 9.5 (95% CI 1.1-82.7), P = 0.04 and 0.1 (0.01-0.9), P = 0.04]; with ustekinumab, male sex and absence of obesity [6.0 (1.3-28.6), P = 0.02 and 4.7 (1.0-22.7), P = 0.05]; with adalimumab, the ACH form [11.9 (2.7-52.3), P = 0.001]; and with infliximab, obesity [5.6 (1.1-29.4), P = 0.04]. CONCLUSIONS: We found no difference in efficacy between TNF blockers and ustekinumab and among the three different TNF blockers in real life for PPP or ACH, which reveals the heterogeneity of clinical response to biologics in pustular psoriasis as compared with plaque psoriasis.

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.

[Erythroderma revealing IPEX syndrome]. / Érythrodermie révélatrice d'un syndrome IPEX.

BACKGROUND: Primary immunodeficiencies are rare and frequently life-threatening conditions in the first year of life. They may present with isolated skin manifestations and the absence of other clinical signs may delay diagnosis and management of the disease. Herein we describe a case of IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome) that illustrates this situation. PATIENTS AND METHODS: A 2.5-month-old boy was seen with a psoriasiform eruption. Despite applications of topical steroids, skin lesions progressed to severe exfoliative ichtyosiform erythroderma. A skin biopsy showed keratinocyte necrosis with a dense, epidermotropic, lymphocytic CD8+ infiltrate. The infant presented increased serum IgE and eosinophilia. He developed an enteropathy with severe and profuse diarrhea, septicemia and hypovolemic shock that led to sudden cardiac arrest. DNA analysis revealed a mutation in the FOXP3 gene, confirming IPEX syndrome. A favorable outcome was achieved following allogeneic bone marrow transplant. DISCUSSION: IPEX syndrome is characterized by early secretory enteropathy with profuse diarrhea, dermatitis and diabetes mellitus. Onset usually occurs within the first weeks or months of life, and the natural course of the disease is often lethal. Cutaneous manifestations appear to be mostly eczematiform, psoriasiform or ichthyosiform. These may be the first sign of the disease and a common inflammatory skin disorder may be wrongly diagnosed. The severity of the lesions and their limited response to topical steroids should alert the clinician. CONCLUSION: The early onset of severe cutaneous manifestations with persistent lesions and poor response to topical steroids should lead to an early skin biopsy. If histopathological changes show a cytotoxic lymphocytic infiltrate with keratinocyte necrosis, a diagnosis of primary immunodeficiency must be considered enabling rapid intitation of specific management.

Rapid desensitization to Adalimumab is associated with decreased basophil sensitivity

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Sex- and age-adjusted prevalence estimates of five chronic inflammatory skin diseases in France: results of the « OBJECTIFS PEAU ¼ study.

BACKGROUND: There are few population-based studies assessing the prevalence of skin diseases. OBJECTIVES: To estimate the prevalence of five chronic skin inflammatory diseases, i.e. atopic dermatitis (AD), psoriasis, alopecia areata (AA), vitiligo and hidradenitis suppurativa (HS) in France, using validated self-diagnostic questionnaires. METHODS: Population-based study using a representative sample of the French general population aged more than 15 years and sampling with replacement design. All participants were asked (ii) to fill in a specific questionnaire including socio-demographic characteristics, (ii) to declare if they have been diagnosed with one or more skin problem or skin diseases during their life, and (iii) to fill in five validated self-reported questionnaires for AD, psoriasis, AA, vitiligo and HS. RESULTS: A total of 20.012 adult participants responded to the questionnaire of whom 9760 were men (48.8%) and 10.252 (51.2%) were women. We identified a prevalence of 4.65% for AD (931 individuals), 4.42% for psoriasis (885 individuals), 1.04% for AA (210 individuals), 0.46% for vitiligo (93 individuals) and 0.15% for HS (29 individuals), respectively. LIMITATIONS: Questionnaire-based study and possible disease misclassifications. CONCLUSION: This is the largest population-based study aiming to estimate the prevalence of five chronic skin inflammatory diseases.

Mucosal melanoma: clinical, histological and c-kit gene mutational profile of 86 French cases.

BACKGROUND: Mucosal melanomas are rare and highly aggressive tumours. Few studies evaluated mucosal melanomas of locations other than the head and neck region, and other than those of the Asian population. OBJECTIVES: The objective of this study was to analyse the clinical and histological features, as well as the mutational status of c-kit and b-raf gene of mucosal melanoma in any localization in a French series. METHODS: We investigated clinical (sex, age, performance status, survival, treatment of the patients and lack of pigmentation of the tumours) and histopathological features (ulceration, Breslow's index, mitotic rate), as well as the mutational status of c-kit and b-raf of 86 mucosal melanomas diagnosed in 15 years in four French University Hospitals. RESULTS: Most melanomas affected women (72%) and the genital region (46.5%). A fifth of melanomas were amelanotic. 81% of melanomas had a Breslow's index ≥1, whereas all glans melanomas, and most vulvar melanomas had a Breslow index ≤1 mm. Overall survival was 54% at 3 years; 11.6% of the 43 tested mucosal melanomas were c-kit-mutated while the 15 tested genital melanomas were not. The c-kit gene mutation did not influence the overall survival. Age ≥ 50, amelanotic type and performance status ≥1 were not poor prognostic factors in our series. CONCLUSION: This study confirmed that mucosal melanomas are rare and could be difficult to diagnose being often amelanotic and in hidden sites. Most melanomas were thick at the diagnosis, but glans and vulvar melanomas were thinner probably because of their greater visibility. The frequency of the c-kit mutation varied depending on the initial tumour site. In our series, the prognosis was poor, independently from c-kit mutations and the patient's general health and age. The presence of metastasis at diagnosis was associated with a worse prognosis indicating the importance of an early diagnosis.

[Morel-Lavallée syndrome and post-traumatic nodular fat necrosis: Two post-traumatic complications mimicking cellulitis]. / Syndrome de Morel-Lavallée et cytostéatonécrose : deux complications post-traumatiques simulant une dermo-hypodermite infectieuse.

BACKGROUND: Dermal and subcutaneous inflammation following direct trauma is initially evocative of soft-tissue infection. However, two differential diagnoses must be considered: Morel-Lavallée syndrome and post-traumatic nodular fat necrosis. PATIENTS AND METHODS: Case 1: a 51-year-old woman fell off her motorbike and had dermabrasions on her right and left tibial ridges that rapidly developed into dermo-hypodermitis of the entire limb. There was no improvement after 3 weeks of antibiotics. The patient was apyretic. She had a soft, non-inflammatory tumefaction on the inner aspect of her left knee. Ultrasound revealed subcutaneous collection in both legs. The surgeons confirmed a diagnosis of Morel-Lavallée syndrome and drained the two collections. Progress was good and the patient healed without major consequences. Case 2: following a fall on her stairs, a 40-year-old woman presented dermabrasions and haematomas on her left leg. Antibiotic therapy failed to prevent the progression of dermo-hypodermitis. The patient remained apyretic and there was no inflammatory syndrome. A CT scan showed thickening of a subcutaneous fat and fluid collection, resulting in diagnosis of post-traumatic nodular fat necrosis. Management was surgical and the outcome was good. DISCUSSION: These two cases show two post-traumatic cutaneous complications: Morel-Lavallée syndrome and post-traumatic nodular fat necrosis. Morel-Lavallée syndrome occurs after tangential trauma next to richly vascularized tissue. Post-traumatic nodular fat necrosis is defined as necrosis of adipocytes. In both cases, diagnosis is confirmed by imagery (Ultrasonography, tomography). CONCLUSION: Our two case reports show that inflammatory presentation of both Morel-Lavallée syndrome and post-traumatic nodular fat necrosis can lead to diagnostic and therapeutic errors while a surgical procedure is necessary since tissue necrosis can occur.

Comparative histological analysis of drug-induced maculopapular exanthema and DRESS.

BACKGROUND: Cutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized. OBJECTIVES: To study the cutaneous histopathological changes associated with MPE, sMPE and DRESS. METHODS: A retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013. RESULTS: The number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Numerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

High prevalence of psychiatric disorders in patients with skin-restricted lupus: a case-control study.

BACKGROUND: Psychiatric disorders have been extensively documented in patients with systemic lupus erythematosus (SLE). However, the prevalence of psychiatric disorders in patients with skin-restricted lupus (SRL) remains unknown, although SRL is more common than SLE. OBJECTIVES: To assess current and lifetime prevalence of Axis I psychiatric disorders among outpatients with SRL and to examine the factors associated with psychiatric disorders among such patients. METHODS: A multicentre case-control study involving outpatients with SRL and controls matched for sex, age and education level. The Mini International Neuropsychiatric Interview was used for psychiatric evaluation. RESULTS: We evaluated 75 patients and 150 controls. Of these, 49% of patients vs. 13% of controls fulfilled the criteria for at least one current psychiatric disorder (P < 0·001). The following disorders were significantly more frequent among patients than controls: current and lifetime major depressive disorder (9% vs. 0%, P < 0·001 and 44% vs. 26%, P = 0·01), generalized anxiety disorder (23% vs. 3%, P < 0·001 and 35% vs. 19%, P = 0·03), panic disorder (7% vs. 0%, P = 0·004 and 21% vs. 3%, P < 0·001), current suicide risk (24% vs. 7%, P = 0·003), alcohol dependence (7% vs. 0%, P = 0·004) and lifetime agoraphobia (20% vs. 9%, P = 0·01). Lupus duration and lupus past treatment by thalidomide were significantly higher among patients with current psychiatric disorders. CONCLUSIONS: This study demonstrates a high prevalence of several psychiatric disorders (anxiety, depression, suicide risk, alcohol dependence) in patients with SRL.

[Natural history of portal cavernoma without liver disease. A single centre retrospective study of 32 cases]. / Évolution naturelle des cavernomes portaux non liés à une hépatopathie. Étude rétrospective monocentrique de 32 observations.

PURPOSE: Portal cavernoma follows a chronic occlusion of the portal vein. The long-term consequences of portal cavernoma are not well known. The objective of this study was to report the aetiology of the portal cavernoma and its natural course after excluding liver diseases causes. METHODOLOGY: A single centre retrospective study based on the data collected from the radiology department of the Clermont-Ferrand hospital was conducted from 2000 to 2011. All the patients for whom an imagery found a portal cavernoma have been looked for excluding the patients having a liver disease whatever the aetiology and the Budd-Chiari syndrome. RESULTS: Thirty-two cases (18 women and 14 men) were selected. The mean age at diagnosis was 54.2 years and the mean follow-up period was 5.4 years. The discovery of a portal cavernoma was incidental for 8 cases. An aetiology was found for 24 cases: it was an haematological aetiology in 15 cases (10 myeloproliferative syndromes, 2 antiphospholid syndromes, 1 thalassemia major, 1 hyperhomocysteinemia, 1 prothrombin gene mutation), a general aetiology in 2 cases (1 coeliac disease, 1 pancreatic neoplasia), and a local inflammation in 7 cases. A dysmorphic aspect of the liver was noticed on medical imaging for 11 out of the 32 cases. A liver biopsy was performed in 4 patients and was normal for all of them. Sixteen patients developed oesophageal varices, 4 patients developed ascites, 3 developed asymptomatic biliary compression by the portal cavernoma, and the patient who had been followed for the longest time (15 years) developed an encephalopathy. CONCLUSION: In addition to its underlying etiology, the prognosis of portal is mainly related to the occurrence of oesophageal varices that may develop during the follow-up of the patients.

Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.

Trichodysplasia spinulosa (TS) is a rare skin disease, caused by a specific polyomavirus, occurring in immunocompromised patients. The pathophysiological mechanisms of TS are not yet fully understood. By using polymerase chain reaction and skin biopsy immunostaining we report evidence, in a paediatric case, of follicular keratinocytes being the primary target of trichodysplasia spinulosa-associated polyomavirus.