Classification of PTEN germline non-truncating variants: a new approach to interpretation.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) encompasses distinct syndromes, including Cowden syndrome resulting from PTEN pathogenic variants. Missense variants account for 30% of PHTS cases, but their classification remains challenging. To address these difficulties, guidelines were published by the Clinical Genome Resource PTEN Variant Curation Expert Panel. METHODS: Between 2010 and 2020, the Bergonie Institute reference laboratory identified 76 different non-truncating PTEN variants in 166 patients, 17 of which have not previously been reported. Variants were initially classified following the current guidelines. Subsequently, a new classification method was developed based on four main criteria: functional exploration, phenotypic features and familial segregation, in silico modelling, and allelic frequency. RESULTS: This new method of classification is more discriminative and reclassifies 25 variants, including 8 variants of unknown significance. CONCLUSION: This report proposes a revision of the current PTEN variant classification criteria which at present rely on functional tests evaluating only the phosphatase activity of PTEN and apply a particularly stringent clinical PHTS score.The classification of non-truncating variants of PTEN is facilitated by taking into consideration protein stability for variants with intact phosphatase activity, clinical and segregation criteria adapted to the phenotypic variability of PHTS and by specifying the allelic frequency of variants in the general population. This novel method of classification remains to be validated in a prospective cohort.

Activity of apremilast in a patient with severe pemphigus vulgaris: case report.

Introduction: Although the treatment for pemphigus vulgaris (PV) has been revolutionized by the use of rituximab combined with corticosteroids, new effective therapies with a better safety profile are needed. Observation: A 67-year-old woman was diagnosed with severe mucosal PV, which was initially misdiagnosed as atypical Behçet's disease. Following an unsuccessful colchicine treatment, significant improvement was observed upon the introduction of apremilast: reduced pain, fewer lesions, and a stabilized weight. The discontinuation of apremilast led to a rapid relapse. Retrospective analysis through anti-Dsg3 ELISA indicated a gradual decrease in antibody levels during the apremilast treatment. Discussion: Apremilast, a phosphodiesterase 4 inhibitor approved for psoriasis and Behçet's disease's related oral ulcers treatment, demonstrated its efficacy in this PV case. This is the second case report highlighting the effectiveness of apremilast for PV treatment. Apremilast's ability to upregulate cyclic adenosine monophosphate (cAMP) levels appears to contribute to the stabilization of keratinocyte adhesion. Conclusion: Apremilast may be a promising therapeutic option for the treatment of pemphigus, with an innovative mechanism of action, no induced immunosuppression, and good tolerance. It could be a good alternative to steroids, in the treatment regimen of steroids combined with rituximab.

Extensive buruli ulcer in a patient returning from Mali and Senegal.

no abstract requested for correspondance items.

Lichen planus pemphigoides with predominant mucous membrane involvement: a series of 12 patients and a literature review.

Background: Lichen planus pemphigoides (LPP), an association between lichen planus and bullous pemphigoid lesions, is a rare subepithelial autoimmune bullous disease. Mucous membrane involvement has been reported previously; however, it has never been specifically studied. Methods: We report on 12 cases of LPP with predominant or exclusive mucous membrane involvement. The diagnosis of LPP was based on the presence of lichenoid infiltrates in histology and immune deposits in the basement membrane zone in direct immunofluorescence and/or immunoelectron microscopy. Our systematic review of the literature, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, highlights the clinical and immunological characteristics of LPP, with or without mucous membrane involvement. Results: Corticosteroids are the most frequently used treatment, with better outcomes in LPP with skin involvement alone than in that with mucous membrane involvement. Our results suggest that immunomodulators represent an alternative first-line treatment for patients with predominant mucous membrane involvement.

Efficacy and Safety of Rilzabrutinib in Pemphigus: PEGASUS Phase 3 Randomized Study.

TRIAL DESIGN: Pemphigus is a rare but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. METHODS: Adults (aged 18-80 years) were randomized 1:1 to 400 mg rilzabrutinib (n = 65) or placebo (n = 66) twice daily (with CS ≤ 0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/pemphigus foliaceus. RESULTS: The primary endpoint of complete remission from week 29 to week 37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13 of 54 (24%) rilzabrutinib versus 10 of 55 (18%) placebo patients with PV (P = .45). Secondary endpoints showed numerical but nonsignificant improvements with rilzabrutinib (vs placebo) in reduced CS use, prolonged complete remission duration, and faster time to first complete remission. CONCLUSIONS: Overall, rilzabrutinib was well-tolerated, with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support Bruton tyrosine kinase inhibition as a viable therapeutic approach for pemphigus.

S2k guidelines on diagnosis and treatment of linear IgA dermatosis initiated by the European Academy of Dermatology and Venereology.

INTRODUCTION: Linear IgA dermatosis (LAD) is a rare subepidermal autoimmune bullous disease (AIBD) defined by predominant or exclusive immune deposits of immunoglobulin A at the basement membrane zone of skin or mucous membranes. This disorder is a rare, clinically and immunologically heterogeneous disease occurring both in children and in adults. The aim of this project is to present the main clinical features of LAD, to propose a diagnostic algorithm and provide management guidelines based primarily on experts' opinion because of the lack of large methodologically sound clinical studies. METHODS: These guidelines were initiated by the European Academy of Dermatology and Venereology (EADV) Task Force Autoimmune Bullous Diseases (AIBD). To achieve a broad consensus for these S2k consensus-based guidelines, a total of 29 experts from different countries, both European and non-European, including dermatologists, paediatric dermatologists and paediatricians were invited. All members of the guidelines committee agreed to develop consensus-based (S2k) guidelines. Prior to a first virtual consensus meeting, each of the invited authors elaborated a section of the present guidelines focusing on a selected topic, based on the relevant literature. All drafts were circulated among members of the writing group, and recommendations were discussed and voted during two hybrid consensus meetings. RESULTS: The guidelines summarizes evidence-based and expert opinion-based recommendations (S2 level) on the diagnosis and treatment of LAD. CONCLUSION: These guidelines will support dermatologists to improve their knowledge on the diagnosis and management of LAD.

Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome.

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

Sustained Remission Without Corticosteroids Among Patients With Pemphigus Who Had Rituximab as First-Line Therapy: Follow-Up of the Ritux 3 Trial.

Importance: The Ritux 3 trial demonstrated the short-term efficacy and safety of first-line treatment with rituximab compared with a standard corticosteroid regimen in pemphigus. No data on the long-term follow-up of patients who received rituximab as first line are available. Objective: To assess the long-term efficacy and safety of the Ritux 3 treatment regimen. Design, Setting, and Participants: This 7-year follow-up study of the Ritux 3 trial included patients with pemphigus from 25 dermatology departments in France from January 1, 2010, to December 31, 2015. Exposure: Patients were initially randomized in the rituximab plus prednisone group or prednisone-alone group. Main outcomes and measures: The primary outcome was the 5- and 7-year disease-free survival (DFS) without corticosteroids, assessed by Kaplan-Meier curves. Secondary outcomes were occurrence of relapse, occurrence of severe adverse events (SAEs), and evolution of antidesmoglein (Dsg) antibody enzyme-linked immunosorbent assay values to predict long-term relapse. Results: Of the 90 patients in the Ritux 3 trial, 83 were evaluated at the end of follow-up study visit (44 in the rituximab plus prednisone group; 39 in the prednisone-alone group) with a median (IQR) follow-up of 87.3 (79.1-97.5) months. Forty-three patients (93%) from the rituximab plus prednisone and 17 patients (39%) from the prednisone-alone group had achieved complete remission without corticosteroids at any time during the follow-up. Patients from the rituximab group had much longer 5- and 7-year DFS without corticosteroids than patients from the prednisone-alone group (76.7% and 72.1% vs 35.3% and 35.3%, respectively; P < .001), and had about half the relapses (42.2% vs 83.7%; P < .001). Patients who received rituximab as second-line treatment had shorter DFS than patients treated as first line (P = .007). Fewer SAEs were reported in the rituximab plus prednisone group compared with the prednisone-alone group, 31 vs 58 respectively, corresponding to 0.67 and 1.32 SAEs per patient, respectively (P = .003). The combination of anti-Dsg1 values of 20 or more IU/mL and/or anti-Dsg3 values of 48 or more IU/mL yielded 0.83 positive predictive value and 0.94 negative predictive value to predict long-term relapse. Conclusions and Relevance: In this secondary analysis of the Ritux 3 trail, first-line treatment of patients with pemphigus with the Ritux 3 regimen was associated with long-term sustained complete remission without corticosteroid therapy without any additional maintenance infusion of rituximab.

Omalizumab in the treatment of bullous pemphigoid resistant to first-line therapy: a French national multicentre retrospective study of 100 patients.

BACKGROUND: Interest in the use of omalizumab to treat bullous pemphigoid (BP) in the event of resistance or contraindication to conventional therapies is currently based on limited evidence. OBJECTIVES: To assess the effectiveness and safety of omalizumab in BP and to identify predictive factors in response to treatment. METHODS: We conducted a French national multicentre retrospective study including patients with a confirmed diagnosis of BP treated with omalizumab after failure of one or several treatment lines. We excluded patients with clinically atypical BP, as per Vaillant's criteria. The criteria for clinical response to omalizumab were defined according to the 2012 international consensus conference. Anti-BP180-NC16A IgE enzyme-linked immunosorbent assay was performed on sera collected before initiating omalizumab, when available. RESULTS: Between 2014 and 2021, 100 patients treated in 18 expert departments were included. Median age at diagnosis was 77 years (range 20-98). Complete remission (CR) was achieved in 77% of patients, and partial remission in an additional 9%. CR was maintained 'off therapy' in 11.7%, 'on minimal therapy' in 57.1%, and 'on non-minimal therapy' in 31.2%. Median time to CR was 3 months (range 2.2-24.5). Relapse rate was 14%, with a median follow-up time of 12 months (range 6-73). Adverse events occurred in four patients. CR was more frequently observed in patients with an increased serum baseline level of anti-BP180-NC16A IgE (75% vs. 41%; P = 0.011). Conversely, urticarial lesions, blood total IgE concentration or eosinophil count were not predictive of CR. Patients with an omalizumab dosage > 300 mg every 4 weeks showed a similar final outcome to those with a dosage ≤ 300 mg every 4 weeks, but control of disease activity [median 10 days (range 5-30) vs. 15 days (range 10-60); P < 0.001] and CR [median 2.4 months (range 2.2-8.2) vs. 3.9 months (range 2.3-24.5); P < 0.001] were achieved significantly faster. CONCLUSIONS: We report the largest series to date of BP treated by omalizumab and confirm its effectiveness and safety in this indication. Serum baseline level of anti-BP180-NC16A IgE may predict response to treatment.

The association between air pollution and the severity at diagnosis and progression of systemic sclerosis-associated interstitial lung disease: results from the retrospective ScleroPol study.

OBJECTIVE: To investigate the association of air pollution exposure with the severity of interstitial lung disease (ILD) at diagnosis and ILD progression among patients with systemic sclerosis (SSc)-associated ILD. METHODS: We conducted a retrospective two-center study of patients with SSc-associated ILD diagnosed between 2006 and 2019. Exposure to the air pollutants particulate matter of up to 10 and 2.5 µm in diameter (PM10, PM2.5), nitrogen dioxide (NO2), and ozone (O3) was assessed at the geolocalization coordinates of the patients' residential address. Logistic regression models were used to evaluate the association between air pollution and severity at diagnosis according to the Goh staging algorithm, and progression at 12 and 24 months. RESULTS: We included 181 patients, 80% of whom were women; 44% had diffuse cutaneous scleroderma, and 56% had anti-topoisomerase I antibodies. ILD was extensive, according to the Goh staging algorithm, in 29% of patients. O3 exposure was associated with the presence of extensive ILD at diagnosis (adjusted OR: 1.12, 95% CI 1.05-1.21; p value = 0.002). At 12 and 24 months, progression was noted in 27/105 (26%) and 48/113 (43%) patients, respectively. O3 exposure was associated with progression at 24 months (adjusted OR: 1.10, 95% CI 1.02-1.19; p value = 0.02). We found no association between exposure to other air pollutants and severity at diagnosis and progression. CONCLUSION: Our findings suggest that high levels of O3 exposure are associated with more severe SSc-associated ILD at diagnosis, and progression at 24 months.

S2k guidelines on the management of paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Paraneoplastic pemphigus (PNP), also called paraneoplastic autoimmune multiorgan syndrome (PAMS), is a rare autoimmune disease with mucocutaneous and multi-organ involvement. PNP/PAMS is typically associated with lymphoproliferative or haematological malignancies, and less frequently with solid malignancies. The mortality rate of PNP/PAMS is elevated owing to the increased risk of severe infections and disease-associated complications, such as bronchiolitis obliterans. OBJECTIVES: These guidelines summarize evidence-based and expert-based recommendations (S2k level) for the clinical characterization, diagnosis and management of PNP/PAMS. They have been initiated by the Task Force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology with the contribution of physicians from all relevant disciplines. The degree of consent among all task force members was included. RESULTS: Chronic severe mucositis and polymorphic skin lesions are clue clinical characteristics of PNP/PAMS. A complete assessment of the patient with suspected PNP/PAMS, requiring histopathological study and immunopathological investigations, including direct and indirect immunofluorescence, ELISA and, where available, immunoblotting/immunoprecipitation, is recommended to achieve a diagnosis of PNP/PAMS. Detection of anti-envoplakin antibodies and/or circulating antibodies binding to the rat bladder epithelium at indirect immunofluorescence is the most specific tool for the diagnosis of PNP/PAMS in a patient with compatible clinical and anamnestic features. Treatment of PNP/PAMS is highly challenging. Systemic steroids up to 1.5 mg/kg/day are recommended as first-line option. Rituximab is also recommended in patients with PNP/PAMS secondary to lymphoproliferative conditions but might also be considered in cases of PNP/PAMS associated with solid tumours. A multidisciplinary approach involving pneumologists, ophthalmologists and onco-haematologists is recommended for optimal management of the patients. CONCLUSIONS: These are the first European guidelines for the diagnosis and management of PNP/PAMS. Diagnostic criteria and therapeutic recommendations will require further validation by prospective studies.

Severe Scabies: A French Multi-centre Study Involving 95 Patients with Crusted and Profuse Disease and Review of the Literature.

The aim of this multi-centre French retrospective study was to identify severe, i.e. crusted and profuse, scabies patients. Records were retrieved from 22 Dermatology or Infectious Diseases departments in the Ile-de-France from January 2009 to January 2015 to characterize epidemiology, demography, diagnosis, contributing factors, treatment features, and outcomes in severe scabies. A total of 95 inpatients (57 crusted and 38 profuse) were included. A higher number of cases was observed among elderly patients (>75 years), mostly living in institutions. Thirteen patients (13.6%) reported a history of previously treated scabies. Sixty-three patients (66.3%) had been seen by a previous practitioner for the current episode (up to 8 previous visits). Initial misdiagnosis (e.g. eczema, prurigo, drug-related eruptions, psoriasis) was documented in 41 patients (43.1%). Fifty-eight patients (61%) had already received 1 or more previous treatments for their current episode. Forty percent received corticosteroids or acitretin for an initial diagnosis of eczema or psoriasis. Median time from the onset of symptoms to the diagnosis of severe scabies was 3 months (range 0.3-22). Itch was present in all patients at diagnosis. Most patients (n=84, 88.4%) had comorbidities. Diagnostic and therapeutic approaches varied. Complications occurred in 11.5% of cases. To date, there is no consensus for diagnosis and treatment, and future standardization of is required for optimal management.

Une lésion labiale inhabituelle.

A 75 years old patient presented with a papular easily bleeding lesion of the lower lip that had been growing for two months. He was known for alcoholic cirrhosis complicated with hepatocellular carcinoma treated since one year. A working diagnostic hypothesis of benign vascular lesion was proposed. Microscopic examination showed a neoplastic dermal proliferation that had been fully excised, made of lobules segregated by thin fibrous septae. The neoplastic architecture was trabecular and delineating spaces forming pseudo-rosettes. Tumour cells were monomorphic, cuboidal or cylindric with abundant eosinophilic and granulous cytoplasm and centered by a lone nucleus that often contained a prominent nucleolus. Some spaces were filled with a brownish-greenish pigmented material. Immunohistochemical study showed that tumour cells were positive with the hepatocyte paraffin 1 antibody as well as cytokeratin 8 antibody. Chromogranin A and synaptophysin stainings were negative. Thus we concluded to a lip metastasis from the previously known hepatocellular carcinoma. Skin metastasis arise in around 3% of cases of hepatocellular carcinoma. They account for less than 1% of all cutaneous metastasis. Overall appearance of cutaneous metastasis of hepatocellular carcinoma is associated with a poor prognosis and an aggravated risk of metastasis to other locations and organs and a median overall survival of less than 5 months. Since incidence of hepatocellular carcinoma is rising pathologists might face more frequently in years to come to cutaneous metastasis whose varied clinical presentations make a diagnostic challenge.

Impaired social cognition and fine dexterity in patients with Cowden syndrome associated with germline PTEN variants.

PURPOSE: Cowden syndrome (CS) is an autosomal dominant disease related to germline PTEN variants and is characterised by multiple hamartomas, increased risk of cancers and frequent brain alteration. Since the behaviour of patients with CS sometimes appears to be inappropriate, we analysed their neuropsychological functioning. METHODS: This monocentric study was conducted between July 2018 and February 2020. A standardised neuropsychological assessment, including an evaluation of social cognition, executive functions, language and dexterity, as well as a cerebral MRI were systematically proposed to all patients with CS. Moreover, PTEN variants were identified. RESULTS: Fifteen patients from 13 families were included, with six non-sense (40%), three missense (20%), five frameshift (33.3%) and one splice site (6.6%) variant types. Twelve patients (80%) had altered social cognition: 10 patients had an abnormal modified Faux-Pas score and 5 had Ekman's facial emotions recognition impairment. Nearly all patients (93%) had impaired dexterity. Cerebral MRI showed various cerebellar anomalies in seven patients (46.7%). CONCLUSION: Altered social cognition and impaired fine dexterity are frequently associated with CS. Further studies are needed to confirm these results and to determine whether dexterity impairment is due to the effect of germline PTEN variants in the cerebellum.