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.

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.

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.

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.

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.

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.

Guidelines for the Topical Treatment of Psoriasis Vulgaris in the Levant and Iraq Area.

Psoriasis vulgaris is a common chronic, inflammatory, multisystem disorder that affects approximately 1.5% to 3.4% of the population in the Middle East. The disease has an impact on the quality of life in a significant number of affected patients. The majority of patients (approximately 70%) have mild to moderate psoriasis that is manageable with topical agents, which generally show a high efficacy to safety ratio. Topical agents can be used alone when treating patients with limited disease or may be used as adjunctive therapy for patients with more extensive psoriasis undergoing systemic treatment. Treatment should also be customized to meet individual patients' needs. To optimize the topical treatment of psoriasis in the Levant and Iraq area, dermatology experts from Iraq, Jordan, Lebanon, Palestine, and Syria met and initiated a project to develop guidelines and recommendations for the topical management of psoriasis. The guidelines are based on literature evidence and experts' opinions. We present recommendations for the use of topical corticosteroids, vitamin D analogues, calcineurin inhibitors, tazarotene, salicylic acid, anthralin, and coal tar, as well as combination therapy, based on their efficacy and safety profiles.

Prurigo pigmentosa: a clinicopathologic study of 4 cases from the middle East.

Prurigo pigmentosa (PP) is a rare inflammatory dermatosis originally reported in Japan. Since then, most reports have originated from Asia, and to a lesser extent from Europe. Although the pathogenesis remains unclear, it is now established that PP is linked to ketoacidotic states. Four patients diagnosed with PP were identified from the dermatopathology database at the American University of Beirut Medical Center between January 2009 and December 2013. Clinicopathologic findings in the 4 patients were similar to those previously reported in the literature. The patients were all female with a mean age of 23.5 years. They all presented with itchy erythematous reticulated papulovesicles/plaques leaving variable reticulated brownish patches. Two patients had, in addition, annular lesions arranged en cocarde and pustules, respectively. In 3 patients, the rash was associated with fasting or dieting. The rash had a predilection to the trunk and proximal part of the upper extremities. One patient had intergluteal area involvement. Two biopsy specimens revealed psoriasiform hyperplasia and neutrophilic exocytosis mimicking psoriasis or an impetiginized spongiotic dermatitis. One biopsy specimen exhibited a mild superficial perivascular lymphocytic infiltrate with ballooning and reticular degeneration, a picture mimicking a viral exanthema. Another biopsy specimen exhibited a picture similar to chronic spongiotic dermatitis. Although mostly described in Japan, PP has been described much less frequently in the Middle East region likely due to mis/underdiagnosis. Therefore, increased awareness is necessary especially because fasting is a common religious practice among Arab countries. Further investigations are necessary to better understand the etiopathogenesis of this rare entity.

A homozygous frameshift mutation in the HOXC13 gene underlies pure hair and nail ectodermal dysplasia in a Syrian family.

Pure hair and nail ectodermal dysplasia (PHNED) is a rare genetic disorder characterized by hypotrichosis or complete alopecia, as well as nail dystrophy. Mutations in the type II hair keratin gene KRT85 and the HOXC13 gene on chromosome 12q have recently been identified in families with autosomal-recessive PHNED. In the present study, we have analyzed a consanguineous Syrian family with an affected girl having complete alopecia and nail dystrophy since birth. The family clearly showed linkage to chromosome 12q13.13-12q14.3, which excluded the KRT85 gene. Sequencing of another candidate gene HOXC13 within the linkage interval identified a homozygous frameshift mutation (c.355delC; p.Leu119Trpfs*20). Expression studies in cultured cells revealed that the mutant HOXC13 protein mislocalized within the cytoplasm, and failed to upregulate the promoter activities of its target genes. Our results strongly suggest crucial roles of the HOXC13 gene in the development of hair and nails in humans.

Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis.

Acrodermatitis continua of Hallopeau (ACH) is a rare, chronic, sterile, pustular eruption that predominantly affects the fingertips with nail involvement. While some consider ACH a distinct entity, many believe it to be a variant of pustular psoriasis, especially as cases of ACH progressing to generalized pustular psoriasis (GPP) have been reported. Recently, recessively inherited mutations in the IL36RN gene, which encodes interleukin-36 receptor antagonist (IL-36Ra), have been demonstrated to be the cause of familial GPP, a condition termed DITRA (deficiency of IL-36Ra). Here, we identified a homozygous missense mutation c.338C>T (p.Ser113Leu) in the IL36RN gene in a male patient with ACH, as well as in his sister who had a history of GPP.

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.

Molecular diagnosis of cutaneous leishmaniasis and species identification: analysis of 122 biopsies with varied parasite index.

BACKGROUND: Cutaneous leishmaniasis is endemic in the Middle East and North Africa. Confirming the diagnosis histologically depends on amastigote identification, which varies significantly depending on the inoculum, strain type, host response and disease stage. Accurate histological diagnosis is mandatory for appropriate therapy. METHODS: Skin biopsies from 122 patients from Lebanon, Syria and Saudi Arabia with clinical diagnosis of untreated leishmaniasis were reviewed and clinical data extracted. Cases were classified according to the modified Ridley's parasitic index. DNA was extracted from formalin-fixed paraffin-embedded blocks. Polymerase chain reaction (PCR) was performed using Leishmania-specific ribosomal internal transcribed spacer 1 (ITS1-PCR). Nested ITS1-PCR was performed on cases negative for conventional ITS1-PCR. ITS1-PCR amplicons were digested with HaeIII for subsequent restriction fragment length polymorphism (RFLP) subspeciation. RESULTS: Of 122 cases, 54 (44.3%) showed a parasitic index of 0-1+ (no unequivocal amastigotes). ITS1-PCR (conventional and nested) was positive for all cases as compared with negative control tissue. RFLP identified Leishmania tropica in all cases. Patients with clinically suspected leishmaniasis, whose skin biopsies failed to detect amastigotes represented 44.3% of our cases. CONCLUSIONS: In this study, we describe a rapid and optimized protocol from DNA extraction to leishmaniasis subspeciation. ITS1-PCR showed high sensitivity and specificity in confirming clinically suspected cases.

Cutaneous leishmaniasis mimicking inflammatory and neoplastic processes: a clinical, histopathological and molecular study of 57 cases.

BACKGROUND: Cutaneous leishmaniasis displays considerable variation in its histopathological and clinical presentation. Clinically, it progresses from a papule into a painless ulcerated and crusted nodule/papule. Microscopically, it progresses from sheets of amastigote-filled histiocytes to granulomatous inflammation. METHODS: The study was conducted on 145 skin biopsies from untreated patients with histopathological and/or clinical suspicion of cutaneous leishmaniasis in Lebanon, Syria and Saudi Arabia (1992-2010). The pre-biopsy clinical diagnosis and demographic data were collected. Biopsies were evaluated for the major microscopic pattern, and the parasitic index (PI) was also determined. Diagnosis was confirmed by polymerase chain reaction (PCR) followed by molecular sub-speciation. RESULTS: Of the 145 patients, 125 were confirmed as cutaneous leishmaniasis by PCR. Eighteen cases presented with a pre-biopsy clinical diagnosis other than cutaneous leishmaniasis that ranged from dermatitis to neoplasm. Of the 125 cases, 57 showed a major histopathological pattern other than cutaneous leishmaniasis. Identification of amastigotes was equivocal (PI ≤1) in 38 of the 57 cases. Of interest, all the 18 cases with a pre-biopsy clinical diagnosis other than cutaneous leishmaniasis also showed atypical histopathology for cutaneous leishmaniasis. CONCLUSIONS: The manifestations of cutaneous leishmaniasis are broad and may mimic other inflammatory and neoplastic diseases. Pathologists and dermatologists should be aware of such pitfalls and can utilize PCR to confirm the diagnosis of leishmaniasis.

Identification of two novel mutations in SLC29A3 encoding an equilibrative nucleoside transporter (hENT3) in two distinct Syrian families with H syndrome: expression studies of SLC29A3 (hENT3) in human skin.

BACKGROUND: H syndrome is a rare autosomal recessive genetic disorder which involves the skin and other systemic organs and is caused by mutations in the SLC29A3 gene. OBJECTIVES: To disclose the molecular basis of H syndrome in two Syrian families, and to determine the localization of hENT3 in human skin. METHODS: DNA from two Syrian families with H syndrome was analyzed through direct sequencing, and the expression of hENT3 in normal human skin was investigated by in situ hybridization and immunostaining. RESULTS: We identified two novel mutations in the SLC29A3 gene: a homozygous splice site mutation IVS1+2T>G predicted to cause a splicing error, and a homozygous missense mutation c.1157G>A (p.R386Q) which substituted highly conserved amino acid residue in a transmembrane domain of hENT3. Furthermore, we demonstrate that hENT3 is expressed in histiocytes as well as in endothelium of blood and lymphatic vessels in normal human skin. CONCLUSIONS: Our results further enhance the mutation spectrum of the SLC29A3 gene for this rare genetic disorder, and also suggest potential pathomechanisms for the skin lesions resulting from SLC29A3 mutations.

Livedoid vasculopathy in a patient with lupus anticoagulant and MTHFR mutation: treatment with low-molecular-weight heparin.

Livedoid vasculopathy is characterized by painful purpuric lesions on the extremities which frequently ulcerate and heal with atrophic scarring. For many years, livedoid vasculopathy has been considered to be a primary vasculitic process. However, there has been evidence considering livedoid vasculopathy as an occlusive vasculopathy due to a hypercoagulable state. We present the case of livedoid vasculopathy in a 21-year-old female who had been suffering of painful lower extremity lesions of 3 years duration. The patient was found to be lupus anticoagulant positive and homozygous for methylenetetrahydrofolate reductase C677T mutation. The patient was successfully treated with low-molecular-weight heparin.

Mucocutaneous pseudoepitheliomatous hyperplasia: a review.

Pseudoepitheliomatous hyperplasia, also called pseudocarcinomatous hyperplasia because of its resemblance to well-differentiated squamous cell carcinoma, is a reactive epithelial proliferation that is characterized by prominent irregular hyperplasia of the epithelium with tongue-like epithelial projections into the dermis. This reactive pattern may involve cutaneous or mucosal surfaces and has been described in association with a wide variety of stimuli including infectious, neoplastic, inflammatory, and traumatic among others. In this review, we will discuss the pathophysiology of pseudoepitheliomatous hyperplasia, the histopathological findings that are helpful in its differentiation from squamous cell carcinoma, and the spectrum of conditions that may show this unique feature on microscopic examination.

Livedoid vasculopathy associated with sickle cell trait: significant improvement on aspirin treatment.

Livedoid vasculopathy (LV) is a chronic, recurrent, painful cutaneous disease manifesting as longstanding distal lower extremity ulcers that scar leaving stellate atrophic lesions known as 'atrophie blanche'. A significant number of cases have been associated with thrombophilic abnormalities. In this study, we describe, to the best of our knowledge, the first report of LV only associated with sickle cell trait with significant improvement on aspirin.

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.

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.

Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.

BACKGROUND: Pachydermoperiostosis (PDP) is a rare hereditary disorder characterized by digital clubbing, periostosis, and pachydermia. Pachydermia results in leonine facies, a major cause of cosmetic and functional morbidity in these patients. Its treatment is usually surgical. So far, no medical treatment has been suggested to alleviate this morbidity. OBJECTIVE: We sought to assess the role of botulinum toxin type A (BTX-A) in improving the cosmetic appearance of pachydermia in patients with PDP. METHODS: Three patients with PDP were treated with BTX-A for their leonine facies. A total of 70 to 80 U were used to treat the upper third of the face. Photographs were taken at baseline and at 2 and 6 weeks after the injections. The patients were followed up periodically for at least 6 months. Wrinkle severity was assessed at relaxation using the 4-point facial wrinkle scale at baseline, week 6, and month 6. In addition, a subjective assessment of the improvement of the extent and depth of the facial rhytides/furrows over the upper third of the face was performed by the same investigator at week 6 and month 6. RESULTS: Using the subjective assessment of the improvement of wrinkles, all 3 patients exhibited a fair to excellent response at week 6 that started manifesting 1 week after the BTX-A treatment. All patients demonstrated a residual effect 6 months after the treatment. One patient exhibited a mild exacerbation of his ptosis. LIMITATIONS: Major limitations were the small number of patients and the administration of BTX-A injections and assessment of their response by a single unblinded physician. CONCLUSION: BTX-A is a simple procedure that may be of value in temporarily improving the cosmetic appearance of pachydermia in patients with PDP.