Seven patients with pustular psoriasis, three with mutations in
IL36RN
, were treated with a monoclonal antibody against interleukin-36 receptor and had amelioration of their skin disease.
A study of families from southern Tunisia affected by general pustular psoriasis uncovered the genetic cause of their disease: a mutation affecting the function of the interleukin-36–receptor ...antagonist.
Psoriasis is a chronic inflammatory skin disease affecting 2 to 3% of persons of European descent.
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Psoriasis vulgaris, the most common form of the disease, accounts for 80% of cases and has a strong, albeit complex, genetic component.
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Numerous chromosomal loci have been implicated in genomewide association studies, but analyses of these loci have yielded only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses.
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–
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The disease follows mendelian transmission in a small minority of families.
Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are characterized by . . .
Several auto-immune diseases have been linked to vitamin D deficiency as a contributing environmental factor. Its pleiotropic effects on the immune system, especially its essential role in ...maintaining immune tolerance, make the vitamin D pathway of great interest. In this study, we focused on Pemphigus foliaceous (PF) in Tunisian population. we aimed to quantify the Serum 25OHD levels using chemiluminescence assay and to analyze the differential expression of the
VDR
,
CYP27B1
and
CYP24A1
genes in the circulating blood cells and lesional skin tissue of PF patients using Q-PCR. A genetic explanation was then sought to explore any direct relationship between tag polymorphisms and the inherited features of PF. Results confirmed a vitamin D hypovitaminosis in Tunisian PF patients. Interestingly, a differential gene expression correlated to the disease stratification was noted. Indeed, at the systemic level, an upregulation of VDR and CYP27B1 genes was observed in healthy controls compared to PF patients. Notably, in lesional skin tissue, the clinical and serological remission phase was correlated with high transcriptional levels of the VDR gene and conversely a drop in expression of the CYP24A1 gene. Genetic analysis indicated the involvement of the most appealing polymorphisms, rs2228570 and poly (A) microsatellite, in PF etiopathogenesis. Indeed, CAC13 haplotype was associated with a higher risk of PF development. Our findings suggest that alterations in the vitamin D-VDR pathway may influence PF physiopathology, making this pathway a potential target for pharmacological modulation, especially for cortico-resistant PF patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionGeneralized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite ...the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.Methods and analysisAt least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.Ethics and disseminationThe study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.Trial registration detailsClinicalTrials.gov identifier: NCT03782792; Pre-results.
An otherwise healthy 63-year-old man from a rural area in Tunisia presented with ulcerated paronychia, with a verrucous lesion at the base of the right thumb. Physical examination revealed seven ...crusty, ulcerated skin lesions on the limbs.
An otherwise healthy 63-year-old man from a rural area in central Tunisia presented with a 1-month history of ulcerated paronychia, with a verrucous lesion at the base of the right thumb (Panel A). He was otherwise asymptomatic and reported having no pain, but physical examination revealed seven crusty, ulcerated skin lesions on the limbs (including a lesion on the left ankle, Panel B). Since the ulcerations and the presence of lesions on the limbs were not consistent with chronic paronychia, a skin smear was obtained. Optical examination of the smear after May–Grünwald–Giemsa staining revealed amastigote forms of the leishmania parasite, . . .
Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, ...acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36–dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants.
These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Morsicatio is caused by chronic self‐inflicted biting of the buccal mucosa that results in clinically whitish plaques. It is frequently confused with other dermatological mucosal disorders. To avoid ...needless invasive procedures, dermoscopy can help with differential diagnosis. Dermoscopy shows whitish and yellowish structureless areas and lines, small erosions, and some white scales. The lack of additional, more specific signs such as Wickham striae is crucial to guide the diagnosis.
Dermoscopy can help to make the right diagnosis in front of whitish patches of the buccal mucosa avoiding unnecessary invasive procedures and inappropriate treatment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
9.
A longstanding tumor with toe deformity Chaima, Kouki; Emna, Bahloul; Fatma, Hammami ...
International journal of rheumatic diseases,
10/2023, Volume:
26, Issue:
10
Journal Article
Peer reviewed
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Papular elastorrhexis is a rare, acquired disorder of elastic tissue, occurring in adolescent females, characterized by flesh‐colored monomorphous papules usually located on the trunk and the ...proximal portion of the extremities. We report a case in an old woman with atypically isolated localization on the neck.
The diagnosis of papular elastorrhexis can be challenging. It belongs to a heterogeneous elastic tissue disorder. Histology remains the main key for diagnosis especially for unusual locations.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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