Lesional Skin Biopsies Research Articles

Consensus on the diagnostic and therapeutic management of chronic spontaneous urticaria in adults - Brazilian Society of Dermatology.

BackgroundUrticarias are frequent diseases, with 15% to 20% of the population presenting at least one acute episode in their lifetime. Urticaria are classified in acute ( ≤ 6 weeks) or chronic (> 6 weeks). They may be induced or spontaneous.Objectives To verify the diagnostic and therapeutic recommendations in chronic spontaneous urticaria (CSU), according to the experience of Brazilian experts, regarding the available guidelines (international and US).MethodsA questionnaire was sent to Brazilian experts, with questions concerning diagnostic and therapeutic recommendations for CSU in adults.ResultsSixteen Brazilian experts answered the questionnaire related to diagnosis and therapy of CSU in adults and data were analyzed. Final text was written, considering the available guidelines (International and US), adapted to the medical practices in Brazil. Diagnostic work up in CSU is rarely necessary. Biopsy of skin lesion and histopathology may be indicated to rule out other diseases, such as, urticarial vasculitis. Other laboratory tests, such as complete blood count, CRP, ESR and thyroid screening. Treatment of CSU includes second-generation anti-histamines (sgAH) at licensed doses, sgAH two, three to fourfold doses (non-licensed) and omalizumab. Other drugs, such as, cyclosporine, immunomodulatory drugs and immunosuppressants may be indicated (non-licensed and with limited scientific evidence).ConclusionsMost of the Brazilian experts in this study partially agreed with the diagnostic and therapeutic recommendations of the International and US guidelines. They agreed with the use of sgAH at licensed doses. Increase in the dose to fourfold of sgAH may be suggested with restrictions, due to its non-licensed dose. Sedating anti-histamines, as suggested by the US guideline, are indicated by some of the Brazilian experts, due to its availability. Adaptations are mandatory in the treatment of CSU, due to scarce or lack of other therapeutic resources in the public health system in Brazil, such as omalizumab or cyclosporine.

Elevated level of B-cell-activating factor in tissues and serum of patients with vitiligo: a proof of autoimmune theory

Background Several studies strongly supported the involvement of autoimmunity in vitiligo pathogenesis, which proposed the alteration of both humoral and cellular immunity leading to the destruction of melanocytes. B-lymphocyte-activating factor (BAFF) is a member of tumor necrosis factor family that has an important role in peripheral B-cell survival and homeostasis. The increased production of BAFF may lead to autoimmunity. Objective To assess BAFF levels in both serum and tissue in patients with vitiligo to detect its possible role in the disease. Patients and methods The present case–control study included 30 patients with vitiligo and 30 age-matched and sex-matched healthy controls. Overall, 5 ml of blood sample was retrieved, and lesional skin biopsy specimen was obtained from the margin of lesional skin from each patient and site-matched control for estimation of BAFF levels by ELISA. Results A higher level of BAFF was detected in tissues and sera of patients with vitiligo (8.3±5.0 and 1.9±1.0, respectively) compared with healthy controls (1.0±0.3 and 1.1±0.5 with P<0.001 and <0.005, respectively). Significant correlation was found between BAFF levels in either tissue or serum with duration of the disease (r=0.9, P<0.001 and r=0.7, P<0.001, respectively). Moreover, significant correlation was found between BAFF in tissue and BAFF in serum (r=0.7 and P<0.001). Conclusion The present study provides further evidence on the role of BAFF in the pathogenesis of vitiligo.

Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab

IL-23 contributes to the activation, maintenance, and proliferation of TH17cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established. We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point. Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing. Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, β-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180mg of risankizumab, respectively, were graded as experiencing "excellent improvement" versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab. Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4.

Phase 1/2 Trial of Durvalumab and Lenalidomide in Patients with Cutaneous T Cell Lymphoma (CTCL): Preliminary Results of Phase I Results and Correlative Studies

Background: In CTCL, intratumoral T cells are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. To this end, we initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, with mechanisms of action that target the exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Methods: A Phase 1 portion is ongoing to characterize the safety and tolerability of durvalumab and lenalidomide combination. Patients (pts) are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; subsequent planned dose increments of 5 mg) to evaluate safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor micro-environment. We examined the correlation between clinical response and resistance and the following biological factors: PD1 clustering at the single molecule level using super-resolution microscopy, and expression of PD-L1 and ICOS at the tissue level by means of multiplex immunohistochemistry on pre-treatment primary cells (migrated from skin explants), and skin tissue (formalin-fixed and paraffin-embedded) from clinical trial subjects. Results: Six patients (5 males/1female, age 32-57 years) with refractory/advanced CTCL (mycosis fungoides/Sezary syndrome subtype), clinical stage IB (1), IIA (1), IIB (3), IIIA (1) have been enrolled as of July 2018. Duration time on treatment was 4 to 13+ months. Four patients showed improvement of skin disease with 2 patients achieved partial response with > 90% improvement of skin disease by mSWAT. Two patients developed progressive disease. No serious adverse events (AEs) were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), anemia (n=3) chills (n=4), and decreased appetite (n=3). All treatment-related AEs were Grade 1 or 2 in severity. One grade 3 fatigue occurred in one patient. No dose limiting toxicity has been observed to date. Using multispectral microscopy, we analyzed expression panels of several checkpoints: PD1, PD-L1, and ICOS on lesional skin biopsies at baseline. Strong PD-L1 and ICOS expression is observed from non-responders. Detectable levels of PD-L1, but low levels of ICOS is observed in responding patients. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders and no PD1 clustering was observed in T cells from non-responders. Conclusions: Durvalumab/lenalidomide has significant clinical activity in patients with refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion of this trial. Responses were durable and ongoing, and treatment was well tolerated with a low toxicity profile. Dose escalation is planned up to lenalidomide 20 mg daily. Our preliminary results from patients on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. DisclosuresQuerfeld:Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Noninvasive Analysis of High-Risk Driver Mutations and Gene Expression Profiles in Primary Cutaneous Melanoma

Tools that help reduce the number of surgical biopsies performed on benign lesions have the potential to improve patient care. The pigmented lesion assay (PLA) is a noninvasive tool validated against histopathology that helps rule out melanoma and the need for surgical biopsies of atypical pigmented skin lesions. Genetic information is collected using adhesive patches and the expression of two genes, LINC and PRAME, is measured. By using genetic material collected noninvasively and to further validate the PLA, somatic hotspot mutations in genes known to be drivers of early melanoma development (BRAF other than V600E, NRAS, and the TERT promoter) can also be identified. The frequency of these hotspot mutations in samples of early melanoma was 77%, which is higher than the 14% found in nonmelanoma samples (P < 0.0001). TERT promoter mutations were the most prevalent mutation type in PLA-positive melanomas; 82% of PLA-negative lesions had no mutations, and 97% of histopathologically confirmed melanomas were PLA and/or mutation positive (cohort 1, n= 103). Mutation frequencies were similar in prospectively collected real-world PLA samples (cohort 2, n= 519), in which 88% of PLA-negative samples had no mutations. Combining gene expression and mutation analyses enhances the ability to noninvasively detect early cutaneous melanoma.

3-Dimensional Optical Clearing and Imaging of Pruritic Atopic Dermatitis and Psoriasis Skin Reveals Downregulation of Epidermal Innervation

3-Dimensional Optical Clearing and Imaging of Pruritic Atopic Dermatitis and Psoriasis Skin Reveals Downregulation of Epidermal Innervation

Clinical and dermoscopic features associated with lichen planus-like keratoses that undergo skin biopsy: A single-center, observational study.

Lichen planus-like keratoses (LPLK) are benign skin lesions that can mimic malignancy; the clinical and dermoscopic features distinguishing lichen planus-like keratoses from skin tumors have not been extensively studied. The objective of this study was to identify dermoscopic features that may prevent unnecessary biopsies of lichen planus-like keratoses. Retrospective, single-center, observational study of biopsied skin lesions at a tertiary center. We compared 355 lichen planus-like keratoses to 118 non-lichen planus-like keratoses lesions with lichen planus-like keratosis in the differential diagnosis biopsied from August 1, 2015, to December 31, 2016. The investigators were blinded to the diagnosis of the lesions. Lichen planus-like keratoses were most frequently non-pigmented (61.7%), truncal (52.1%), and on sun-damaged skin (69.6%); the majority occurred in Whites (95.5%) and females (62.8%). Dermoscopically, lichen planus-like keratoses were more likely than non-lichen planus-like keratoses to have scale (42.5% vs 31.4%, P=0.03) and orange colour (8.2% vs 0.9%, P=0.01). Among lesions with peppering (n=76; 63 lichen planus-like keratoses and 13 non-lichen planus-like keratoses), coarse±fine peppering (73% vs 38.5%, P=0.02) and peppering as the only feature (34.9% vs 0%, P=0.01) were associated with lichen planus-like keratoses. Lichen planus-like keratoses can be challenging to distinguish from benign and malignant skin tumors. The presence of dermoscopic scale and orange colour may aid in the recognition of lichen planus-like keratosis. Coarse peppering and the presence of peppering as the only dermoscopic feature may further aid the identification of pigmented lichen planus-like keratoses.

Accuracy of tele-consultation on management decisions of lesions suspect for melanoma using reflectance confocal microscopy as a stand-alone diagnostic tool.

Diagnostic accuracy of reflectance confocal microscopy (RCM) as a stand-alone diagnostic tool for suspect skin lesions has not been extensively studied. Primary aim was to measure experts' accuracy in RCM-based management decisions. Secondary aim was to identify melanoma-specific RCM features. The study enrolled patients ≥18years that underwent biopsy of skin lesions clinically suspected to be melanoma. One hundred lesions imaged by RCM were randomly selected from 439 lesions prospectively collected at four pigmented lesion clinics. The study data set included 23 melanomas, three basal cell and two squamous cell carcinomas, 11 indeterminate melanocytic lesions and 61 benign lesions including 50 nevi. Three expert RCM evaluators were blinded to clinical or dermoscopic images, and to the final histopathological diagnosis. Evaluators independently issued a binary RCM-based management decision, 'biopsy' vs. 'observation'; these decisions were scored against histopathological diagnosis, with 'biopsy' as the correct management decision for malignant and indeterminate lesions. A subset analysis of 23 melanomas and 50 nevi with unequivocal histopathological diagnosis was performed to identify melanoma-specific RCM features. Sensitivity, specificity and diagnostic accuracy were 74%, 67% and 70% for reader 1, 46%, 84% and 69% for reader 2, and 72%, 46% and 56% for reader 3, respectively. The overall kappa for management decisions was 0.34. Readers had unanimous agreement on management for 50 of the 100 lesions. Non-specific architecture, non-visible papillae, streaming of nuclei, coarse collagen fibres and abnormal vasculature showed a significant association with melanoma in the evaluation of at least two readers. Reflectance confocal microscopy tele-consultation of especially challenging lesions, based on image review without benefit of clinical or dermoscopy images, may be associated with limited diagnostic accuracy and interobserver agreement. Architectural and stromal criteria may emerge as potentially useful and reproducible criteria for melanoma diagnosis.

Introduction to reflectance confocal microscopy and its use in clinical practice

Reflectance confocal microscopy (RCM) is a novel technology that provides noninvasive, in vivo imaging of the skin at nearly histologic resolution. In 2016, the US Centers for Medicare and Medicaid Services (CMS) established reimbursement codes for RCM image acquisition and for the reading and interpretation of images. The combination of RCM imaging with dermoscopy has improved the accuracy of skin cancer diagnosis while reducing the number of biopsies of benign skin lesions. With that, we are starting to see more dermatologists and dermatopathologists using RCM in clinical practice. This editorial is to serve as an introduction on RCM imaging with a focus on its usefulness in both the diagnosis and management of skin cancers. We end by briefly describing the characteristic RCM features of normal skin to serve as a building block for later cases that will explore both the benefits and drawbacks of incorporating RCM imaging for benign and malignant lesions.

Recurrent tendosynovitis as a rare manifestation of a lipid disorder

A 33-year-old female had suffered from spontaneously recurrent bursitis and tendosynovitis/enthesitis of the patellar and Achilles tendons for about 10 years. The episodes of immobilization increased. Ultrasound imaging of the swollen and painful tendons showed chronic inflammation with neoangiogenesis within the tendons and hypoechoic lesions. Clinical and laboratory tests did not provide evidence for a rheumatic disease. Low density lipoprotein cholesterol was elevated. Biopsies of skin lesions did not confirm the suspicion of cutaneous xanthomas. Genetic testing for familial hypercholesterolemia was negative. Campesterol and sitosterol were elevated 7- to 12-fold and 20- to 38-fold over the upper limit of normal on two occasions. There was no relevant mutation in ABCG5. In ABCG8, we identified a missense mutation c.1267G>A in exon 9 changing glutamic acid 423 into lysine within the transmembrane domain, and an insertion of adenine (c.1487insA) leading to a frameshift and a premature stop codon (Ile497Aspfs*105). The patient had no clinical evidence of premature atherosclerosis. Therapeutic approaches with nonsteroidal antirheumatic drugs, prednisone, statins, and ezetimibe accompanied by a diet poor in plant sterols led to a relief of symptoms. This case report shows that tendon xanthoma along with tendosynovitis, especially on extensor areas, is suspicious for hypercholesterolemia as the underlying cause. The absence of atherosclerotic plaques in the abdominal aorta and in the carotid arteries on ultrasound may suggest that phytosterolemia is not necessarily accompanied by premature vascular disease.

Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: A randomized, double‐blind, placebo‐controlled study

Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study. Chronic spontaneous urticaria patients (18-75years) were randomized to either 300mg omalizumab (n=20) or placebo (n=10) administered s.c. every 4weeks for 12weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages. At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P<0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16). Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.

Real-world performance and utility of a noninvasive gene expression assay to evaluate melanoma risk in pigmented lesions.

About 3 million surgical pigmented skin lesion biopsies are performed each year in the USA alone to diagnose fewer than 200 000 new cases of invasive melanoma and melanoma in situ using the current standard of care that includes visual assessment and histopathology. A recently described noninvasive adhesive patch-based gene expression rule-out test [pigmented lesion assay (PLA)] may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. The main objective of this utility study was to determine the real-world clinical performance of PLA use and assess how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of 330 PLA(-) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3-6 months, were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95 and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50 and 7%, respectively. The PLA alters clinical management of pigmented lesions and shows high clinical performance. The likelihood of positive histopathologic diagnosis of melanoma is higher in PLA results that are positive for both LINC00518 and PRAME.

Paediatric mastocytosis: long-term follow-up of 53 patients with whole sequencing of KIT. A prospective study.

Mastocytosis is a heterogeneous group of clinical disorders characterized by the abnormal accumulation of mast cells. The adult and paediatric forms differ in their clinical and genetic features and outcomes. To describe the clinical evolution of a well-characterized cohort of paediatric mastocytosis (PM), and to analyse the relationship between KIT mutation and the clinical course. This was a prospective cohort study performed at the National Clinical Reference Center for Mastocytosis. Diagnosis was confirmed by identification of KIT mutation on lesional skin biopsy. Mastocytosis subtype, mast cell mediator-related symptoms (MC MRS) and clinical course were recorded. Fifty-three patients with PM and >4years of disease course were enrolled. The mean±SD age at the final evaluation was 13·2±4·8years. The main outcome was the type of KIT mutation as a predictor of evolution and clinical characteristics. Patients presented with maculopapular cutaneous mastocytosis (n=44), diffuse cutaneous mastocytosis (n=6) or mastocytoma (n=3). The mean duration of disease was 12·1years. Substantial or partial cutaneous regression (18 of 53 and 16 of 53), stabilization or aggravation (16 of 53) and complete cutaneous regression (three of 53) were noted. MC MRS mainly regressed (21 of 53). For 22 patients, evolution of MC MRS and evolution of cutaneous lesions were different. No significant association between evolution and KIT mutation or between evolution and type of cutaneous mastocytosis was found. A late onset of the disease (after 2years) is associated with worse evolution. PM is not systematically self-regressive. MC MRS manifestations and cutaneous lesions can persist or increase overtime. KIT mutation is not a predictor of evolution.

A Rare Case of Multicentric Reticulohistiocytosis

Multicentric reticulohistiocytosis (MRH) is a rare, histiocytic disorder that primarily affects the skin and joints. This disease can have systemic involvement of various organ systems and has been associated with underlying malignancy. Middle-aged, Caucasian females are the most commonly affected demographic group in this disease. We present a case of a 56-year-old African American male with debilitating joint pain and a papulonodular rash on his face, chest, arms, and hands. Biopsy of skin lesions confirmed the diagnosis of multicentric reticulohistiocytosis. Histological findings revealed dermal infiltrate composed of glassy histiocytes and giant cells with eosinophilic cytoplasm. The patient was started on 15 mg of methotrexate weekly, 1 mg of folic acid daily, and 60 mg of prednisone daily with mild improvement of skin lesions at one month followup. He expired from other comorbidities before long term treatment could be achieved. The potential for disfiguring skin lesions and debilitating arthropathy emphasizes the importance of early recognition and treatment of MRH. Corticosteroids and methotrexate are recommended for patients with moderate to severe disease and have been shown to be successful in some cases. More studies are needed on patients with MRH to further elucidate the etiology and pathogenesis of this disease.

Paraneoplastic Pemphigus Associated with Lymphoid Leukemia: A Case of Persistent and Refractory Oral Ulcerations

A 53-year-old man was diagnosed with chronic lymphoid leukemia in December 2016 and was subjected to FCR-Lite protocol (cyclophosphamide 249 mg/m2 and fludarabine 33.2 mg/m2) in January 2017. The patient developed exanthema on the skin (torso and lower members), bullous lesions on the feet, and ulcers in the oral mucosa. Initially, the diagnosis was pharmacodermia and mucositis, rendered by oncologists. The dental team prescribed 0.12% alcohol-free chlorhexidine associated with low-level laser therapy for analgesia. The oral lesions have persisted with an increased extension and bleeding in the lips. Therefore, an incisional biopsy of skin lesions was performed and revealed intraepidermal vesicles, which supported the initial hypothesis of pharmacodermia. Due to persistence of the oral lesions, paraneoplastic pemphigus was suggested by the dental team as a diagnostic hypothesis and confirmed after an incisional biopsy and immunofluorescence assay. A 2-week follow-up revealed improvement of oral lesions, and no pain symptoms were reported.

Clinical analysis of four cases of dermatomyositis with painful palmar eruptions complicated by fatal rapidly progressive interstitial lung disease

Objective To firstly report 4 cases of dermatomyositis characterized by painful palmar eruptions complicated by fatal rapidly progressive interstitial lung disease (RP-ILD) in China. Methods Four patients with dermatomyositis with painful palmar eruptions complicated by fatal RP-ILD were enrolled from the Department of Dermatology, Zhongshan Hospital, Fudan University between December 2014 and April 2017, and their clinical and pathological features were analyzed. Results Among these patients, 3 were female and 1 was male. Their age ranged from 47 to 59 years. Of the 4 patients, 3 had no muscular involvement. All of the 4 patients had multiple solid red papules or nodules on the bilateral palms, palmar and lateral surfaces of fingers, which preceded, followed or concurred with the onset of other skin lesions of dermatomyositis. The occurrence of type Ⅰ respiratory failure was preceded by 3 weeks to 5 months of painful palmar eruptions in the 4 patients. Early-stage palmar eruptions were easily misdiagnosed as contact dermatitis, eczema or erythema multiforme. Histopathological examination of the skin lesions on the finger palmar surface showed perivascular infiltration of a few lymphocytes in the dermis, and deposition of varying amounts of mucin-like substances around blood vessels and appendages. Of the 4 patients, 3 showed positive staining for anti-melanoma differentiation-associated gene 5 antibody. Although the 4 patients received anti-inflammatory and immunosuppressive therapies, they all finally died of respiratory failure. Conclusions Dermatomyositis with painful palmar eruptions may indicate the occurrence of fatal RP-ILD, and early biopsy of skin lesions is needed to help to identify the disease. Immunosuppressive treatment should be performed timely to improve the prognosis in these patients. Key words: Dermatomyositis; Lung diseases, interstitial; Skin manifestations; Hand; Pain; Glucocorticoids; Immunosuppressive agents

Cutaneous Manifestations of Mycobacterium kansasii Infection.

Mycobacterium kansasii is a slow-growing member of the nontuberculous mycobacterial species that manifests clinically with pulmonary, cutaneous, or disseminated forms. Most cases of M. kansasii infection occur in immunocompromised hosts including HIV/AIDS, solid-organ transplantation, anti-interferon-γ antibody disorder, or among those with pulmonary disorders such as chronic obstructive pulmonary disease or cystic fibrosis. In this review, we aim to discuss relevant literature regarding the clinical manifestations of this infection with a particular emphasis on the clinical spectrum and treatment of the cutaneous manifestations of this mycobacterial infection. Infection caused by M. kansasii is associated with exposure to contaminated municipal water systems since this organism thrives in human-engineered environments. Chronic or subacute skin lesions may represent the primary source of entry of the organism due to open sores or traumatic injuries. Alternatively, cutaneous lesions may occur secondary to dissemination of the organism to the skin from pulmonary infection. The diagnosis of M. kansasii of the skin and soft tissues should be entertained among immunocompetent or immunocompromised individuals presenting with subacute or chronic lesions. The differential diagnosis of M. kansasii infection includes infections of skin and soft tissues caused by rapidly growing mycobacteria, subcutaneous mycosis, pyogenic bacterial infections, nocardiosis, free-living amoebas, and protothecosis. Cutaneous lesions caused by M. kansasii most commonly manifest in the setting of concomitant pulmonary disease or in the setting of disseminated infection among immunocompromised hosts. When clinicians suspect a cutaneous mycobacterial infection either due to slow-growing mycobacteria such as M. kansasii or due to rapidly growing mycobacteria, obtaining a skin biopsy of chronic nonhealing lesions for histopathologic evaluation and for microbiological assessment is crucial. Mycobacteriology assessment of clinical specimen includes acid-fast bacilli staining, culture in solid/liquid media, and molecular assays for confirmation. Treatment of M. kansasii infection of the skin and subcutaneous tissues follows the same management recommendations as those for the treatment of isolated pulmonary forms or disseminated disease.

Overview of Cutaneous Mycobacterial Infections.

Mycobacterial infections may affect any human organ and produce disseminated disease in immunocompromised individuals. Their most common clinical presentations include pulmonary, cutaneous (skin and soft tissues), and disseminated forms. The skin and soft tissues are frequent targets of affection by mycobacterial pathogens manifesting as localized or diffuse disease. Overall, infections due to Mycobacterium leprae, Mycobacterium ulcerans, and Mycobacterium tuberculosis are the most frequently recognized mycobacterial pathogens involving the skin and soft tissues. Additionally, all mycobacterial species of the nontuberculous group may also produce cutaneous disease. Of these, the most commonly identified organisms causing localized infections of the skin and subcutaneous tissues are the rapidly growing species (Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus complex), Mycobacterium marinum, and M. ulcerans. Since the skin and soft tissues are important protective barriers for environmental pathogens, their disruption often represents the portal of entry of nontuberculous environmental mycobacteria (soil, natural water systems, engineered water networks, etc.). Additionally, some mycobacterial diseases affecting cutaneous structures occur after exposure to infected animals or their products (i.e., Mycobacterium bovis). Mycobacterial infections of the skin and soft tissues may manifest with a broad range of clinical phenotypes such as cellulitis, single or multiple abscesses, subacute or chronic nodular lesions, macules, superficial lymphadenitis, plaques, nonhealing ulcers, necrotic plaques, verrucous lesions, and many other dermatologic manifestations. Geography and environmental exposure play an important role in the epidemiology of cutaneous mycobacterial infections. Mycobacterial infection of the skin and subcutaneous tissue is an important cause of human suffering in terms of morbidity, deformity, dysfunction, and stigma. The diagnosis of cutaneous mycobacterial infections is challenging requiring a low threshold of clinical suspicion for obtaining skin biopsies of cutaneous lesions for acid-fast staining and cultures, and molecular probe assays to detect the presence of mycobacterial pathogens. The choice of antibacterial therapy combinations and length of therapy for cutaneous mycobacterial infections is species-specific.

Involvement of the IL23/Th17 Pathway in the Pathogenesis of Tunisian Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is a rare autoimmune skin disease caused by anti-Dsg1 pathogenic autoantibodies. It is considered as a Th2-mediated disease. Likewise, Th17 cells were recently described in the pathogenesis of the disease but their role is still unclear. We aimed to unravel the eventual implication of the IL23/Th17 pathway in the development of PF. A case-control study was conducted on 115 PF patients and 201 healthy controls using PCR-RFLP and AS-PCR methods. SNPs in IL23R, RORγt, IL17A, IL17F, IL17AR, TNFa, and STAT3 genes were genotyped. mRNA expression of IL23R and RORγt was evaluated using Q-PCR. The frequency of circulating Th17 cells was analyzed by flow cytometry. Genetic associations between IL23R>rs11209026, IL17A>rs3748067, IL17F>rs763780, and TNFa>rs1800629 and the susceptibility to PF were reported. Moreover, we revealed a significant increased frequency of circulating CD4+IL17+ cells as well as higher mRNA levels of RORγt and IL23R in PBMCs of patients. However, no significant increase of RORγt and IL23R mRNA expression was observed in lesional skin biopsies. In spite of the little size of specimens, our results provide converging arguments for the contribution of the IL23/Th17 pathway in the pathogenesis of PF.

Pulsed-dye laser as an adjuvant treatment for discoid lupus erythematosus: a randomized, controlled trial

Purpose: To evaluate the efficacy and safety of pulsed-dye laser (PDL) for discoid lupus erythematosus (DLE) in a double blinded, randomized, controlled fashion.Method: Forty-eight DLE lesions from nine patients were recruited. The lesions on one side of the body were randomized into the treatment group and the other side served as a control. Treatments with the PDL (595 nm) were delivered every four weeks for four consecutive months. The patients were evaluated at weeks 0, 4, 8, 12, 16 and 24. Erythema index (EI) and Texture index (TI) were obtained by Antera3D®. Modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) and physician global assessment (PGA) scores were assessed in every visit. Lesional skin biopsies before and after the PDL treatment were taken from four patients.Results: The lesions treated with the PDL demonstrated significantly more decreases in EI, TI and improvement in PGA scores compared to the control. Though there was improvement of mCLASI in the laser group, the significance difference was not observed. Interestingly, real-time polymerase chain reaction showed a reduction in CXCL-9, 10, IFN-γ, IL-1β, TNF-α and TGF-β. Additionally, post-treatment DLE lesions demonstrated decreased CD3, CD4, CD8 and CXCR3-positive cells.Conclusions: Improvements of DLE can be achieved with PDL.