CD4+ T-cell Subsets and Cytokine Signature in Pemphigus Foliaceus Clinical Stratification beyond the th1/Th2 Paradigm.

BACKGROUND: T helper interplay and cytokines monitoring in auto-immune skin disorders such as Pemphigus Foliaceus [PF] may play a central role in predicting the clinical stratification of the pathology. OBJECTIVES: In order to assess the CD4+ T cell imbalance, [i] this study aims to assess the related immune cells [Th1, Th2, Th17, and Treg cells] as well as the related cytokines [IL-1ß, IFNγ, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL- 22, TNF-ß, and TNFα] in peripheral blood, and [ii] their respective transcription factors in the lesioned skin of PF endemic patients during the clinical course. METHODS: Peripheral blood of 22 PF patients was analyzed by flow cytometry to assess the functional associations of Th cell subpopulations and their characteristic cytokines by multiplex bead assay of 14-plex cytokines. Skin mRNA expression of their associated transcription factors was analyzed using the TaqMan detection system. RESULTS: Our findings revealed that the CD4+ T cell subtypes in PF patients compared to Healthy Controls [HC] were characterized by [i] a similar Th1/Th2 ratio and increased Th17/Treg ratio and [ii] significantly higher plasma levels of Th-17 specific cytokines; IL- 6, IL-8, IL-17A. Higher percentages in Th17 and Treg subtypes and a significant increase in plasma IL-17F levels were maintained in relapsing PF patients, arguing the pivotal role of Th17 cells in PF pathogenesis. Furthermore, our findings pointed out the major contribution of the pro-inflammatory cytokine IL-6. Indeed, in addition to being involved in the initial stages of disease development, IL-6 seems to also be involved in the maintenance of the pathophysiological process, probably through its effect on Th17 differentiation. The skin-relative mRNA expression levels of FOXP3 and TBET were significantly higher in relapsing PF patients compared to de novo PF patients. CONCLUSION: Our results highlight the central role played by Th17 lymphocytes and their related pro-inflammatory cytokines during the clinical course of the disease, reversing the Th1/Th2 dichotomy in PF.

Unraveling the role of the vitamin D-VDR pathway in pemphigus vulgaris from Tunisian patients.

Vitamin D dysregulation has been recognized as a factor that may cause or aggravate autoimmunity. Vitamin D deficiency was found to be common in pemphigus vulgaris (PV) in different populations. This study aimed to investigate the vitamin D-VDR pathway in PV in the Tunisian population. A serological study was carried out to determine the vitamin D status in newly diagnosed PV patients. CYP27B1, CYP24A1 and VDR mRNA expression was assessed using quantitative real-time PCR in peripheral blood mononuclear cells (PBMC) from untreated newly diagnosed and treated PV patients. In addition, a genetic study was accomplished on VDR polymorphisms to investigate the changes in VDR gene expression. Overall, the serological study confirmed the hypovitaminosis D in newly diagnosed PV patients. Vitamin D-VDR pathway gene expression showed downregulation of CYP27B1 and CYP24A1 mRNA in first-discovery patients compared to healthy controls, while VDR mRNA was highly expressed in newly diagnosed PV patients. Moreover, CYP27B1, CYP24A1 and VDR mRNA were significantly upregulated in chronic disease severity groups compared to mild disease groups. The genetic study showed low VDR gene expression in carriers of FokI > CC genotype, which was more frequent among PV patients, and FokI > C-TaqI > C-ApaI > A-polyA > A16 haplotype, suggesting that the VDR gene polymorphisms testing can provide useful information for PV treatment decision-making. In conclusion, our findings underline the impact of vitamin D-VDR pathway disruption in the PV pathophysiology in Tunisian patients.

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.

Direct medical cost related to the management of pemphigus: A pilot Tunisian study.

INTRODUCTION: Pemphigus is a therapeutically challenging disease with high morbidity and economic burden. First-line prescription of rituximab remains limited in Tunisia due to its high cost. Systemic steroids remain the standard of care but are associated with a major risk of morbidities and higher treatment costs. AIM: To assess the direct medical costs of pemphigus in Tunisia. METHODS: Retrospective estimation of direct medical costs during the 18 months following the diagnosis using the "bottom-up approach" in the Dermatology Department of Hedi Chaker Hospital, Sfax, Tunisia. RESULTS: Total medical costs were estimated at 38745.7 €, with an average cost of 1 210 € per patient and per year: paraclinical investigations (46%), medical treatment (30%), hospitalization (21%) and outpatient visits (3%). The average cost was the highest in the age group of 15-24 years (1553 €). Treatment costs related to corticosteroid-induced morbidity were estimated at 1208 €. CONCLUSIONS: The management of pemphigus in Tunisia needs to be adapted to take into account the health economic analysis in order to reduce overall disease costs and the burden of steroid-induced morbidities.

Characteristics of DRESS Syndrome in the Elderly: A Comparative Study of 55 Patients.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare drug reaction characterized by a skin rash, eosinophilia, and organ involvement. Objective: Our purpose is to focus on the clinical and epidemiological characteristics of DRESS in the elderly and to identify the incriminated drugs. Methods: This is a retrospective study including patients, hospitalized for DRESS with a RegiSCAR ≥4. The population was divided into 2 groups according to age: 65 years or older (G1) and <65 years (G2). The statistical study was performed using the comparative and multivariate analysis. Results: We included 55 patients (30.9% G1 and 69.1% G2). Skin manifestations were comparable in both groups. Lymphadenopathy was less common in G1 with a statistically significant difference (P = 0.012). Renal impairment was more frequent in the elderly with a statistically significant result (P = 0.005). DRESS in the elderly group was significantly associated with the occurrence of sepsis (P = 0.008). Allopurinol was the most common culprit associated with DRESS in G1 (P = 0.001). Relapses and recurrences were comparable in both groups (P = 0.71). Conclusions: DRESS in the elderly is associated with a high risk of complications, mainly kidney involvement and sepsis. Allopurinol is the most incriminated drug.

Follicular Basaloid Hamartoma and Associated Cutaneous Tumors: Clinical, Histopathological and Dermoscopic Aspects.

Background: Basaloid follicular hamartoma is an uncommun benign neoplasm of the hair follicule. The linear form of basaloid follicular hamartoma can be associated with basal cell carcinoma.OBJECTIVE: We report a case of a patient with multiple basal cell carcinomas developing on a congenital lesion allowing the diagnosis of basaloid follicular hamartoma on histopathology. Methods: Each lesion was evaluated by two dermatologists. All biopsy specimens were routinely stained with hematoxylin-eosin. Results: A 76 year-old-man consulted our dermatology departement for erythematous papules spread over the left lower limb. The lesion had been evolving since birth with flesh-colored to pinkish papules following Blaschko's lines from the root of the thigh to the foot. Three months before consultation, the papules increased in size leading to nodules with sometimes an ulcerated center. Dermoscopy under polarized mode displayed for ulcerated lesions (A) yellow-brownish crusts and ulceration surrounded by blue-grey ovoid nests, subtle short white streaks, brown dots and linear/arborising vessels. For nodular lesions (B), dermoscopic features are white pinkish hue, dotted and linear vessels, brown dots, blue-grey structureless areas and white prominent shiny streaks. There were some more erythematous inflamed and eroded areas in the background with a reversed honeycomb white network on dermoscopy (C), polymorphous vessels, whitish scales, ulcerations and milia-like cysts. The background lesion showed varied dermoscopic structures on a flesh colored slightly pinkish bottom (D). Histolopathology concluded for lesions A to an infiltrating and nodular basal cell carcinoma, (B) and (C) to fibroepithelioma of Pinkus and (D) to basaloid follicular hamartoma. Conclusion: Several case reports have documented dermoscopic features of a solitary basaloid follicular hamartoma. However, further studies are required to specify any reproducible features.

Inverted Follicular Keratosis: A Retrospective Study Over 10 Years.

Inverted follicular keratosis (IFK) is a rare benign tumour of the follicular infundibulum characterized by exo-endophytic growing. Generally, the diagnosis of IFK is histopathologically made because clinical differentiation from other lesions is difficult. We present a retrospective series with thirteen patients with histologically confirmed IFK to evaluate the epidemiological, clinical and histopathologic characteristics of IFK. The mean age of the patients at the time of the excision was 53 years with extremes ranging from 19 to 82 years. The sex ratio M/F was 3.3. The lesions affected the face in nine patients mainly the moustache, followed by the scalp in three cases and the arm in one case, and 92% of the localizations are sun-exposed. The diagnosis was never clinically evoked. The lesion had a pink colour in ten cases and was pigmented in two cases and hypopigmented in one case. More than half of the lesions (53%) had a keratotic centre. Histopathological examination showed endophytic intradermal proliferation of basaloid cells with a variable degree of squamoid differentiation. Horn cysts were present in all cases. According to our series, the IFK occurs predominantly in young men, in the face and more specifically in the moustache. Dermoscopy may suggest the diagnosis of the IFK. In fact, a histopathological examination is the gold standard for the diagnosis of the IFK and helps differentiate these benign tumours from possible malignant neoplasms.

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.

Trichofolliculoma: A Case Series.

Trichofolliculoma (TF) is a rare benign adnexal follicular tumor, described as hamartoma with follicular differentiation according to some authors. It typically appears during adulthood on the face or scalp as an isolated nodule with protrusion of central tufted hairs. We present a retrospective series of eleven patients with histologically confirmed TF to evaluate epidemiological, clinical, and histopathologic characteristics. The mean age at excision was 46 years with extremes ranging from 20 to 75 years. The sex ratio M/F was 0.37. Clinical presentation was a papule or nodule with an average diameter of 6,7mm (2-15 mm), firm with central pit in 54 percent and visible emerging vellus hairs in 18 percent of cases only. The localization was on the face in seven cases (63.6%) and only four cases were located outside the face (scalp [n=2], sub mammary fold [n=1] and shoulder [n=1]). Histologically, a cystically dilated hair follicle containing keratinous material with several mature and immature branched follicular structures is described in all cases. According to our series, TF occurs predominantly in women without age predilection, in the face. Central tufted hairs are only found in a minority of cases corresponding histologically to many secondary vellus hair follicles. In fact, histopathological examination is the gold standard for the diagnosis because clinical diagnosis could be challenging. Histology and dermoscopy may vary according to the age of the lesion. To date, only few case series have been published.

Whitish patches on the buccal mucosa: Role of dermoscopy.

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.

Late onset of flesh-colored papules of the neck.

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.

Role of chemical exposure in the incidence of vitiligo: a case-control study in Tunisia.

Vitiligo is a multifactorial dermatosis with many etiological hypotheses that have been suggested for its occurrence. To our knowledge, few epidemiological studies are available on vitiligo induction factors and particularly on the role of exposure to chemicals in the onset of the disease has been found. Therefore, there is need to investigate the relationship between vitiligo and chemical exposures in order to understand this mysterious disease. We conducted a case-control study of patients with vitiligo whose diagnosis was made by a specialist in dermatology. The total study period was of 6 months extending from 1 July to 31 December 2019. The minimum sample size was determined as 46 cases and 92 controls. The control group was gender, age, and professional status matched to the vitiligo group. In the binary logistic regression model, household chemicals/colored toothpaste use, a history of a repeated antibiotic use, and an occupational exposure to phenol/catechol derivatives were significantly associated with vitiligo (three to fourfold increase). Our results suggest that chemical factors play a key role in the occurrence of vitiligo. Therefore, prevention of this dermatosis requires the identification of exposure to the incriminated chemicals in any patient followed for vitiligo. The earlier the diagnosis of 'chemical' or chemically aggravated vitiligo, the better the prognosis for this disease.

Lichenoid lesions around the anus: An unusual site of Hailey-Hailey disease.

The anal region is an unusual site of Hailey-Hailey disease. It manifests with lichenoid lesions with crusted erosions around the anus. It should be differentiated from condylomata acuminata, extramammary Paget disease, and bowenoid papulosis.

Evaluation of X chromosome inactivation in endemic Tunisian pemphigus foliaceus.

BACKGROUND: Almost 5% of the world's population develops an autoimmune disease (AID), it is considered the fourth leading cause of disability for women, who represent 78% of cases. The sex ratio when it comes to the most prevalent AID varies from 9:1 in systemic lupus erythematosus (SLE) to 13:1 in endemic Tunisian pemphigus foliaceus (PF). METHODS: To test the potential involvement of skewed x-inactivation in the pathogenesis of Tunisian PF, we analyzed the methylation status of a highly polymorphic CAG repeat in the androgen receptor gene and evaluated the x chromosome inactivation (XCI) patterns in peripheral blood-leukocyte-derived DNA samples of female patients with PF (n = 98) compared to healthy control (HC) subjects (n = 150), as well as female patients with SLE (n = 98) were enrolled as a reference group. RESULTS: XCI status was informative for 50 of the 98 PF patients (51%) and 70 of the 150 HC women (47%). Extremely skewed XCI patterns were more frequent in PF and SLEwomen than HC, but the difference was statistically significant only in women with SLE. No statistical difference was observed in XCI patterns between PF and SLE patients. PF phenotype-XCI correlation analysis revealed that (i) skewed XCI patterns may be involved in the disease's subtype and (ii) it was more pronounced in the endemic group than the sporadic one. Furthermore, preferential XCI showed an increase in heterozygote genotypes of PF's susceptibility polymorphisms in immunity-related X genes (FOXP3, AR, and TLR7) in PF patients compared to HC. CONCLUSION: Our results suggest that skewed XCI could lead to hemizygosity of X-linked alleles that might unmask X-linked deleterious alleles.

Acral blisters in neonates: Three rare and benign diseases.

Exclusive acral involvement in neonatal pemphigus is unusual. Blisters in neonatal bullous pemphigoid, affecting 2%-3% of newborns of mothers with gestational pemphigoid, can be located in the trunk, limbs and acral areas. Unlike neonatal bullous pemphigoid, which can appear up to 5 days after birth, neonatal pemphigus is often revealed at birth. They are benign diseases in newborns. There is no correlation between the disease severity in babies and mothers. Neonatal risk is dominated by the side effects of corticosteroid therapy.

Gingival Recession: An Unusual Oral Presentation of Morphea "en coup de sabre".

A 21-year-old woman presented with a 13-year history of a linear lesion on the lip. She experienced no pain and only had an esthetic complaint. Her personal and family history was otherwise unremarkable. She had no history of photosensitivity, Raynaud's phenomenon, arthralgias, dry eyes, fever, trauma, or exposure to irradiation.