Trial of Spesolimab for Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity. RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

Congenital liquified subcutaneous fat necrosis in a newborn: an unusual case.

Subcutaneous fat necrosis of the newborn is a self-limited disorder of the panniculus that arises in the first six weeks of life. Some differential diagnoses may be difficult such as bacterial cellulitis or erysipelas. The prognosis is usually favorable but there are serious complications for which the patient must be regularly monitored, especially hypercalcemia. We report a case of a full-term newborn with a liquidated area of subcutaneous fat necrosis. A surgical incision was performed because of the discomfort and the lack of regression. Hypercalcemia and nephrocalcinosis appeared afterward. A set of clinical, biological, and histological arguments allows the diagnosis of subcutaneous fat necrosis. Follow-up to early detection and to manage such complications is necessary.

miRNA implication in the pathogenesis and the outcome of Tunisian endemic pemphigus foliaceus.

Pemphigus foliaceus (PF) is a bullous autoimmune skin disease diagnosed through sera and skin analyses. PF severity is associated with maintained anti-Dsg1 sera levels and its prognosis is unpredictable. MicroRNA (miRNA), dynamic regulators of immune function, have been identified as potential biomarkers for some autoimmune diseases. This study aimed to assess the miRNA expression of miR-17-5p, miR-21-5p, miR-146a-5p, miR-155-5p and miR-338-3p using quantitative real-time PCR in peripheral blood mononuclear cells (PBMC) and lesional skin samples from untreated and treated PF patients (both remittent and chronic) over 3 months. Overall, miRNA expression was significantly higher in PBMC than in biopsy samples. Blood miR-21 expression was increased in untreated patients compared to controls and had a diagnostic value with an AUC of 0.78. After 6 weeks, it decreased significantly, similar to anti-Dsg1 antibodies and the PDAI score. In addition, a positive correlation was observed between cutaneous miR-21 expression and the disease activity score. Conversely, cutaneous expressions of miR-17, miR-146a and miR-155 were significantly higher in treated chronic patients compared to remittent ones. The cutaneous level of miR-155 positively correlated with pemphigus activity, making it a potential predictive marker for patients' clinical stratification with an AUC of 0.86.These findings suggest that blood miR-21 and cutaneous miR-155 can be used as supplemental markers for PF diagnosis and activity, respectively in addition to classical parameters.

Clinical Characteristics and Outcomes of Generalized Pustular Psoriasis Flares.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, neutrophilic skin disease that can become life-threatening if flares are untreated. There are limited data describing the characteristics and clinical course of GPP disease flares with current treatment options. OBJECTIVE: The aim of the study was to describe the characteristics and outcomes of GPP flares using historical medical information from patients enrolled in the Effisayil™ 1 trial. METHODS: Investigators collected retrospective medical data characterizing patients' GPP flares prior to clinical trial enrollment. Data on overall historical flares were collected, as well as information on patients' typical, most severe, and longest past flares. This included data on systemic symptoms, flare duration, treatment, hospitalization, and time to clearance of skin lesions. RESULTS: In this cohort (N = 53), patients with GPP experienced a mean of 3.4 flares per year. Flares were painful, associated with systemic symptoms, and often triggered by stress, infections, or treatment withdrawal. Resolution of flares was longer than 3 weeks in 57.1%, 71.0%, and 85.7% of documented (or identified) typical, most severe, and longest flares, respectively. GPP flares led to patient hospitalization in 35.1%, 74.2%, and 64.3% of patients for their typical, most severe, and longest flares, respectively. For the majority of patients, pustules took up to 2 weeks to clear for a typical flare and 3-8 weeks to clear for the most severe and longest flares. CONCLUSION: Our findings highlight that current treatment options are slow to control GPP flares and provide context for assessing the efficacy of new therapeutic strategies in patients with a GPP flare.

Bullous Pemphigoid Associated With Dipeptidyl Peptidase-4 Inhibitors: A Case Report and Review of Current Evidence.

Dipeptidyl peptidase-4 inhibitors (DPP-4i), or gliptins, are a widely used glucose-lowering agents. A growing amount of evidence pointed to a possible role of DPP-4i in the induction of bullous pemphigoid (BP), which is an auto-immune skin blistering disease that mainly affects the elderly. In this article we discuss a case of DPP-4i associated BP and we provide an updated review of the current knowledge regarding this emerging entity. Use of DPP-4i, particularly vildagliptin, was found to significantly increase the risk of BP. BP180 would be in the center of the aberrant immune response. DPP-4i induced BP is thought to be associated with male gender, mucosal involvement, and milder inflammatory phenotype especially in Asian population. Generally, patients may not remit fully after DPP-4i withdrawal only and require either topical or systemic glucocorticoid courses.

Pustular psoriasis of pregnancy: Clinical and genetic characteristics in a series of eight patients and review of the literature.

Pustular psoriasis of pregnancy (PPP) can lead to life-threatening complications. The objective of this study is to report clinical and genetic spectrum, prognostic factors and management options. A retrospective study was designed including eight PPP patients. Clinical data were collected, and performed genetic and statistical analysis to identify factors associated with fetal complications, resistance to treatment and post-partum flare extension. A systematic review of the literature was also carried out. Eight Tunisian patients, with a mean age of 23 ± 3.3 years, were included. They presented 14 flares (F) during pregnancies and one flare after delivery. Additional GPP flares outside pregnancy periods were noted in 2/8 of patients. The mean duration of PPP flares was 16.66 ± 7.8 weeks. The first flare occurred at a gestational age of 26 ± 5 weeks. Only 2/8 studied patients presented a homozygous mutation c.80 T > C (p.L27P) in IL36RN gene. Used treatments were topical steroids (n = 12F), systemic steroids (n = 5F), ciclosporin (n = 1F), UVB (n = 1F) and acitretin (in post-partum n = 6F). Complications were oligoamnios (n = 2), intra-uterine growth retardation (n = 1), fetal death in utero (n = 1), prematurity (n = 3), low weight at birth (n = 2). A significant association was found between (i) occurrence of fetal complications and early gestational age at the onset (p = 0.036), (ii) resistance to topical steroids and body surface affected area (p = 0.008), (iii) presence of mutation c.80 T > C in PPP flares and low serum levels of calcium (p = 0.01). Our systematic review of the literature identified 39 patients with 41 flares of PPP. Only 7/39 patients presented a causative mutation in IL36RN and CARD14 genes. PPP is characterized by a phenotypic heterogeneity and can be associated to IL36RN mutations. Its early onset can be associated with fetal complications. Systemic steroids and cyclosporine remain the most used therapies.

Mutations in SULT2B1 Cause Autosomal-Recessive Congenital Ichthyosis in Humans.

Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism.

Hymenal polyps in two infants.

Pathological conditions of the hymen are rare in everyday medical practice. Hymenal polyps are polypoid formations originating from the hymenal rim and are benign and disappear spontaneously within a few weeks of onset. We report two cases of hymenal polyps in two infants.

Diffuse dermal angiomatosis of the breast with adjacent fat necrosis: a case report and review of the literature.

Diffuse dermal angiomatosis (DDA) is a type of reactive skin angioproliferation. Clinically, this rare disorder presents as red-violet purpuric papules and/or plaques (some with a greater tendency towards necrosis and ulceration), which can be localized in any body area, but is most often seen in the upper and lower extremities. Localization in the breast commonly presents with severe intractable breast pain and characteristic reticular violaceous erythematous plaques with central ulcerations. Histological examination is fundamental for the diagnosis and is characterized by varied patterns of lobular or diffuse hyperplasia of endothelial cells at the extravascular level. The condition is associated with various underlying conditions, many of which result in local tissue ischemia. In this report, we present a patient with DDA with an underlying mass lesion of the breast, which proved to be an adjacent fat necrosis. Various treatments have proven beneficial, including revascularization, oral corticosteroids, smoking cessation, and isotretinoin. In this case, our patient benefited from secondary excision of the affected area.

Paucisymptomatic Dermoid Cyst with Fatal Outcome.

Dermoid cysts of the central nervous system can cause devastating complications because of the mass effect of meningitis due to sinus tract. We report the case of a 5-month-old girl who presented with a crusted lesion of the occipital region of the scalp. Clinical examination noted skin abnormalities suggestive of occult dysraphism. Magnetic resonance imaging (MRI) was recommended, however, 40 days after this evaluation, and before the MRI could be performed, the girl presented with neurologic complications. Unfortunately, the diagnosis of dermoid cyst was made after the onset of severe complications that led to her death. The findings in this case emphasize the importance of more prompt MRI evaluation, particularly in cases where cranial or spinal dysraphism is suspected to have any connection to the skin as a pit or tract. Should we perform an urgent MRI for any cutaneous sign of dysraphism to avoid a dramatic evolution?

Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans.

Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.

EPIMAG: International Cross-Sectional Epidemiological Psoriasis Study in the Maghreb.

BACKGROUND: Psoriasis is a common skin disorder that is characterized by red plaques covered with silvery scales and is associated with considerable psychosocial impact. It has been described in several studies worldwide, but specific data from the Maghreb (Algeria, Morocco and Tunisia) are unavailable. OBJECTIVES: To characterize the frequency of new psoriasis cases and to describe the epidemiological and clinical profile of psoriasis in the Maghreb. METHODS: A psoriasis working group for the Maghreb initiated the EPIMAG international multicentre cross-sectional observational epidemiological study coupled with a 2-week psoriasis screening study via medical consultation. Data were collected via questionnaires. RESULTS: The total analysis population included 373 pre-existing and 326 new psoriasis cases, described by 261 participating investigators. The frequency of new psoriasis cases was 10.26/1,000 in Algeria, 15.04/1,000 in Morocco and 13.26/1,000 in Tunisia, and thus 12.08/1,000 in the Maghreb. In all 699 psoriasis subjects, the mean age was 46 years, the mean BMI was 26.6, and 55.7% of subjects were men. Two thirds of the subjects had never smoked, and 85.0% had never consumed alcohol. Half had brown skin, and 28.6% had a family history of psoriasis. Three quarters had localized psoriasis, 85.8% had plaque psoriasis, coupled with pruritus in over 70.0% of cases. Flares or outbreaks were most often triggered by stress (79.4%) and change of season (43.1%). The majority of subjects used topical therapy, and the investigators considered overall treatment efficacy to be partial in over half of the cases. Among patients with pre-existing psoriasis, secondary analyses showed that 73.2% had severe psoriasis, and that quality of life was severely affected in 40.1% of cases. The mean number of missing school or work days over 6 months was 3.2 (±12.1) days. CONCLUSIONS: Our study provides novel information relative to psoriasis epidemiology and characterization in the Maghreb and highlights the need to improve psoriasis screening and management in the region. The data will help optimize psoriasis management, to ensure appropriate national health care policies.