Vacuolar Interface Dermatitis as a Histologic Reaction Pattern of Sjögren's Syndrome: A Case Report.

Sjögren's syndrome (SS) has been widely known for its dry mouth and dry eyes presentation. Extraglandular disease manifestations may be protean and pose a challenge for clinicians, especially when the typical known manifestations are absent. Skin involvement of SS is variable, and cutaneous signs and symptoms may be the initial presentation of this syndrome. Vacuolar interface dermatitis has been linked to dermatomyositis and systemic lupus erythematosus, but rarely to SS. Herein, we present the case of an 87-year-old man who presented for widespread itchy erythematous scaly plaques that were refractory to topical corticosteroids as well as discontinuation of possible offending medications. A biopsy demonstrated vacuolar interface dermatitis in the setting of strongly positive anti-SSA. Hydroxychloroquine treatment was effective in resolving the plaques.

Navigating patients with atopic dermatitis or chronic spontaneous urticaria during the COVID-19 pandemic.

A rapid spread of different strains of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented pandemic. Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the medical body has encountered major obstacles concerning disease management at different levels. Even though patients infected with this virus mainly present with respiratory symptoms, it has been associated with a plethora of well-documented cutaneous manifestations in the literature. However, little investigations have been conducted concerning COVID-19 and its impact on skin disorders mediated by type 2 inflammation leaving multiple dermatologists and other specialists perplexed by the lack of clinical guidelines or pathways. This review focuses on the effects of this pandemic in patients with skin disorders mediated by type 2 inflammation, specifically atopic dermatitis and chronic spontaneous urticaria. In addition, it will provide clinicians a guide on treatment and vaccination considerations for this stated set of patients.

Characterizing the presence of neutrophil extracellular traps in neutrophilic dermatoses.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of multiple inflammatory dermatoses. However, characterization of NETs in neutrophilic dermatoses was performed on very limited number of patients; this limitation precluded definitive conclusions. In this case series of 57 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different entities of neutrophilic dermatoses (17 with pyoderma gangrenosum, 37 with Sweet's syndrome and three with subcorneal pustular dermatosis). NETs were identified by double immunofluorescence on formalin-fixed paraffin-embedded skin biopsies using antibodies against elastase and citrullinated histone 3. Percentages of neutrophils showing NETs were high across all three entities (62.9% in PG, 48.5% in SS and 37.8% in subcorneal pustular dermatosis). The differences in mean percentages were significant between entities, with PG showing significantly superior percentage of NETs compared with SS. In our series, 15.8% of neutrophilic dermatoses were associated with malignancies, 10.5% with autoimmune diseases and 73.7% were idiopathic. Percentages of NETs were not statistically different between aetiologies. These findings suggest that NETs are abundantly produced in the various entities and different aetiologies of neutrophilic dermatoses. In comparison with SS, the superior percentage of NETs in PG is clinically mirrored in its greater ulceronecrotic nature.

Investigating the presence of neutrophil extracellular traps in septal and lobular cutaneous panniculitides.

BACKGROUND: Panniculitides are a heterogeneous group of inflammatory dermatoses involving the subcutaneous fatty tissue. Histologically, they are classified into septal and lobular panniculitis, according to the predominant localization of the inflammatory infiltrate. Neutrophils are frequently found in panniculitis, mainly at the early stages. Here, we investigated whether neutrophils contribute to various types of cutaneous panniculitis by releasing neutrophil extracellular traps (NETs). MATERIALS AND METHODS: Formalin-fixed paraffin-embedded skin biopsies from 25 patients with panniculitis were included in the study. Our cohort was divided into n = 10 erythema nodosum (septal panniculitis) and n = 15 lobular panniculitis, including n = 7 lupus panniculitis, n = 1 pancreatic panniculitis, n = 1 Weber-Christian disease, n = 1 deep fungal infection, n = 2 lipodermatosclerosis, and three cases did not have an identified etiology. The presence of neutrophils and NETs was assessed by double immunofluorescence using antibodies against elastase, a neutrophilic marker, and citrullinated histone 3, a marker of NETs. RESULTS: The mean percentages (±SEM) of elastase-positive neutrophils showing NETs were 44% ± 3% in erythema nodosum and 43% ± 7% in lobular panniculitis. The difference was not statistically significant and reflects the implication of NETs not only in severe scarring lobular panniculitis but also in benign non-scarring self-remitting reactive inflammation such as erythema nodosum. In tissues, NETs were located in the interlobular septa in erythema nodosum and in the inflamed fat lobules in lobular panniculitis. CONCLUSIONS: NETs are massively present in septal and lobular subtypes of panniculitides, suggesting their involvement in tissue damage.

SuPAR, a potential inflammatory mediator in psoriasis pathogenesis.

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild-moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.

Update on the use of dapsone in dermatology.

Dapsone (4,4'-diaminodiphenylsulfone) is the only remaining sulfone used in anthropoid therapeutics and is commercially available as an oral formulation, an inhaled preparation, and a 5% or 7.5% cream. Dapsone has antimicrobial effects stemming from its sulfonamide-like ability to inhibit the synthesis of dihydrofolic acid. It also has anti-inflammatory properties such as inhibiting the production of reactive oxygen species, reducing the effect of eosinophil peroxidase on mast cells and down-regulating neutrophil-mediated inflammatory responses. This allows for its use in the treatment of a wide variety of inflammatory and infectious skin conditions. Currently in dermatology, the US Food and Drug Administration (FDA)-approved indications for dapsone are leprosy, dermatitis herpetiformis, and acne vulgaris. However, it proved itself as an adjunctive therapeutic agent to many other skin disorders. In this review, we discuss existing evidence on the mechanisms of action of dapsone, its FDA-approved indications, off-label uses, and side effects.

Loss of ferrochelatase is protective against colon cancer cells: ferrochelatase a possible regulator of the long noncoding RNA H19.

BACKGROUND: Ferrochelatase (FECH) is the last enzyme of the heme biosynthesis pathway. Deficiency in FECH was associated with many diseases, including protoporphyria. Correlation studies showed that variations of FECH expression was detected in human carcinomas and more specifically in colon cancer. Nevertheless, the potential role of FECH in colon cancer carcinogenesis in vitro was not depicted yet. METHODS: A small interfering RNA (siRNA) was used to knockdown FECH in human Caco-2 colon cancer cells. The effect of FECH down-regulation on the cellular proliferation, the migration and the expression of target genes was assessed in cancer cells and compared to human normal fibroblasts. RESULTS: Following FECH down-regulation, our results demonstrated that the proliferation of Caco-2 cells was not affected. Furthermore, the migration of cancer and normal cells was affected, only when an additional stress factor (H2O2) was applied to the medium. The expression of twist, snail, hypoxia induced factor (HIF-1α) and vascular endothelial growth factor (VEGF) was reduced in Caco-2 cells. Conversely, VEGF and HIF-1α expression were upregulated by up to 2 folds in control fibroblasts. Interestingly, the pro-carcinogenic long noncoding RNA (LncRNA) H19 was 70% down-regulated in Caco-2 cells upon FECH down regulation whereas no effect was observed in normal fibroblasts. CONCLUSIONS: In conclusion, we showed that loss of FECH is protective against colon cancer tumorigenesis in vitro and this effect could possibly be mediated through inhibition of H19.

Investigating the presence of neutrophil extracellular traps in cutaneous lesions of different subtypes of lupus erythematosus.

Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, little is known about the implication of NETs in cutaneous lupus. In this case series of 30 patients, we compared the amounts of neutrophils producing NETs in cutaneous lesions of different subtypes of lupus (5 with discoid lupus or DLE, 5 with subacute cutaneous lupus or SCLE, 11 with acute cutaneous SLE, 7 with lupus panniculitis and 2 with chilblains). Immunofluorescence was performed on formalin-fixed paraffin-embedded skin biopsies using antibodies against neutrophilic granules (elastase, myeloperoxidase, PR-3 proteins and citrullinated histone 3). Dihydroethidium staining was performed to detect reactive oxygen species (ROS), known inducers of NETs. NETs were detected in the different subtypes of cutaneous lupus as well as in cutaneous lesions of SLE. The amounts of neutrophils producing NETs were significantly higher in lupus panniculitis (49%), acute cutaneous SLE (41%) and DLE (32%), in comparison with SCLE (5%) and chilblains (0%). This suggests that NETs might be associated with more tissue damage and scarring. ROS were observed in the different cutaneous subtypes of lupus independent of NETs.

Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease.

BACKGROUND AND OBJECTIVES: Behçet's disease (BD) is a multi-system inflammatory disorder that can cause vasculitis. Here we questioned whether Neutrophils in BD cause vasculitis via releasing Neutrophil Extracellular Traps (NETs), a process called NETosis. METHODS: Circulating neutrophils were isolated from a cohort of Middle Eastern BD patients with an active disease and healthy volunteers. The percentage of NETs release was monitored in neutrophils stimulated or not with BD serum, and treated or not with Colchicine, Dexamethasone, Cl-amidine or N-Acetyl Cysteine (NAC). The mRNA expression levels of PAD4 (a key enzyme in NETosis) was also assessed. The effect of NETs on the proliferation and cell death of endothelial cells was investigated using an in vitro co-culture model. The presence of NETs in skin tissues of BD patients was examined using immunolabeling of NETs associated proteins. RESULTS: Circulating Neutrophils from BD patients were more prone to release NETs in vitro and expressed higher levels of PAD4 compared to healthy volunteers. Spontaneous NETs formation in BD neutrophils was inhibited by Colchicine and Dexamethasone, two drugs used to treat BD. NETs formation was also inhibited by Cl-amidine, a specific PAD4 inhibitor, and by NAC, a ROS inhibitor. Interestingly, serum from BD patients stimulated circulating neutrophils from healthy volunteers to release more NETs and increased their mRNA PAD4 expression. Moreover, endothelial cells cultured in the presence of NETs from BD patients showed a decrease in proliferation and an increase in apoptosis and cell death. Finally, NETosis was predominantly identified around affected blood vessels in biopsies of vasculitis from BD patients. CONCLUSION: Our results provide evidence on the implication of NETosis in the pathophysiology of BD especially in inducing vasculitis.

SuPAR, an emerging biomarker in kidney and inflammatory diseases.

Soluble urokinase plasminogen activator receptor (suPAR) is a circulating form of a physiological and pathophysiological important cell surface receptor, implicated in inflammation. Recent studies showed that suPAR is a promising biomarker, useful for diagnosis, assessment and prognosis of several diseases. This review summarises the majority of preliminary studies and analyses the significance and the clinical application of suPAR in various clinical conditions. SuPAR seems to have a significant value in the diagnosis as well as prognosis of many diseases; nonetheless, it merits large-scale studies to set cut-off values that help physicians in following up their patients and accordingly tailor their treatment plans.

CHILD syndrome: A modified pathogenesis-targeted therapeutic approach.

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.

Scabies in the age of increasing drug resistance.

Scabies is an infestation of the skin by the mite Sarcoptes scabiei. It manifests with pruritic erythematous papules and excoriations, in addition to the pathognomonic burrows. Multiple drugs can be used for treatment, but resistance to conventional therapy is increasing throughout the years. This paper will review the mechanisms of resistance proposed in the literature and some of the potential solutions to this problem.

FOXI2: a possible gene contributing to ectodermal dysplasia.

Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia.

Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3.

Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway.

Retinoids: a journey from the molecular structures and mechanisms of action to clinical uses in dermatology and adverse effects.

Retinoids are a class of compounds derived from vitamin A or having structural and/or functional similarities with vitamin A. They are classified into three generations based on their molecular structures. Inside the body, retinoids bind to several classes of proteins including retinoid-binding proteins and retinoid nuclear receptors. This eventually leads to the activation of specific regulatory regions of DNA - called the retinoic acid response elements - involved in regulating cell growth, differentiation and apoptosis. Several clinical trials have studied the role of topical and systemic retinoids in disease, and research is still ongoing. Currently, retinoids are used in several fields of medicine. This paper aims to review the structure, mechanisms of action, and adverse effects of retinoids, as well as some of their current uses in Dermatology.

Experience and challenges for biologic use in the treatment of moderate-to-severe psoriasis in Africa and the Middle East region.

The incidence of psoriasis in Africa and the Middle East (AfME) is high as in other regions and represents a significant problem for both dermatologists and patients. Psoriasis co-morbidities such as obesity, cardiovascular disease and psoriatic arthritis (PsA) are also particularly common in these regions and may be under-recognized and under-treated. Despite this, regional guidelines to aid physicians on the appropriate use of biologic agents in their clinical practice are limited. A group of expert dermatologists from across the AfME region were surveyed to help establish best practice across the region, alongside supporting data from the literature. Although biologics have significantly improved patient outcomes since their introduction, the results of this survey identified several unmet needs, including the lack of consensus regarding their use in clinical practice. Discrepancy also exists among AfME physicians concerning the clinical relevance of immunogenicity to biologics, despite increasing data across inflammatory diseases. Significant treatment and management of challenges for psoriasis patients remain, and a move towards individualized, tailored care may help to address these issues. The development of specific local guidelines for the treatment of both psoriasis and PsA could also be a step towards understanding the distinct patient profiles in these regions.

Genetics of inherited cardiocutaneous syndromes: a review.

The life of a human being originates as a single cell which, under the influence of certain factors, divides sequentially into multiple cells that subsequently become committed to develop and differentiate into the different structures and organs. Alterations occurring early on in the development process may lead to fetal demise in utero. Conversely, abnormalities at later stages may result in structural and/or functional abnormalities of varying severities. The cardiovascular system and skin share certain developmental and structural factors; therefore, it is not surprising to find several inherited syndromes with both cardiac and skin manifestations. Here, we will review the overlapping pathways in the development of the skin and heart, as well as the resulting syndromes. We will also highlight several cutaneous clues that may help physicians screen and uncover cardiac anomalies that may be otherwise hidden and result in sudden cardiac death.

High prevalence of metabolic syndrome in patients with psoriasis in Lebanon: a prospective study.

BACKGROUND: Psoriasis is a chronic inflammatory disease that affects not only the skin but also other organs as well. Genetic factors play an important role in individual predisposition. Lately, a positive association has been confirmed between psoriasis and metabolic syndrome (MBS), in western as well as in Middle Eastern countries. AIM: Assess the prevalence of MBS in Lebanese patients with psoriasis and the differential effect according to types and disease severity. METHODS: This was a case-control study including 150 psoriasis patients and 150 age- and gender-matched controls admitted to the dermatology clinics at the American University of Beirut-Medical Center, a tertiary care center in Beirut. Psoriasis severity was assessed by the Psoriasis Area Severity Index (PASI). Blood samples were collected from fasting subjects and tested for glucose, HDL cholesterol, triglycerides, and C-reactive protein (CRP). Multivariate binary logistic regression models were built to assess the relationship between MBS and psoriasis, after adjustment for smoking as a possible confounding variable. RESULTS: Patients with psoriasis were two times more likely to have MBS as compared to controls (35.3% vs 18.0%, P < 0.001) with an odds ratio (OR) of 2.4. All components of MBS were more prevalent in psoriasis patients than in controls. PASI score was greater in patients with MBS than those without MBS (10.5 ± 11.5 vs. 7.0 ± 8.1, P = 0.05). MBS prevalence tended to be higher in the inverse type than in others (52.2% versus 32.3%; P = 0.06) and in patients with nail pitting versus those without (45.3% vs. 28.2%; P = 0.03). CONCLUSIONS: This was the first study to assess the prevalence of MBS in Lebanese subjects with psoriasis and, to our knowledge, the first study that showed a higher likelihood of MBS in patients with inverse psoriasis and with nail pitting.

Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient's skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.