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ABSTRACT: Blau syndrome is a rare familial autoinflammatory disorder characterized by the triad of granulomatous dermatitis, polyarthritis, and uveitis. Blau syndrome exhibits an autosomal dominant inheritance pattern and can be caused by a gain-of-function mutation in nucleotide-binding oligomerization domain 2 (NOD2), a member of the NOD-like receptor family of pattern recognition receptors. Mutations in NOD2 cause upregulation of inflammatory cytokines and resultant autoinflammation. Because of the rarity of this condition and early onset of symptoms, Blau syndrome may be misdiagnosed as juvenile idiopathic arthritis. We present a case of a 37-year-old male patient with a long-documented history of juvenile idiopathic arthritis and uveitis, who developed an asymptomatic eruption of pink papules on the trunk and upper extremities. A biopsy demonstrated noncaseating, well-formed dermal granulomas with relatively sparse lymphocytic inflammation and Langerhans-type giant cells. Genetic testing confirmed a mutation in NOD2. Based on the patient's clinical history, histologic findings, genetic testing, the diagnosis of Blau syndrome was made.
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Artrite , Proteína Adaptadora de Sinalização NOD2 , Sarcoidose , Sinovite , Uveíte , Humanos , Masculino , Uveíte/genética , Uveíte/diagnóstico , Artrite/genética , Artrite/diagnóstico , Sinovite/genética , Sinovite/patologia , Sinovite/diagnóstico , Adulto , Proteína Adaptadora de Sinalização NOD2/genética , Sarcoidose/genética , Sarcoidose/diagnóstico , Sarcoidose/patologia , Dermatite/genética , Dermatite/patologia , Dermatite/diagnóstico , Biópsia , Doenças Hereditárias AutoinflamatóriasRESUMO
Azadirachta indica, commonly known as neem, has many uses as a natural remedy. We review and discuss the pharmacologic, biologic, and medicinal properties of neem in disease management. We also report a rare clinical case of a 77-year-old man who presented with a hypopigmented rash on the lower back, bilateral flanks, and buttocks after 6 months of repeated application of neem oil to treat persistent arthritis and lower back pain.
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Azadirachta , Masculino , Humanos , Idoso , Glicerídeos/farmacologia , Terpenos/farmacologia , Extratos VegetaisRESUMO
ABSTRACT: Monkeypox (Mpox) is a zoonotic Orthopoxvirus of the Poxviridae family, endemic to Africa. In August 2022, the US government declared it an emergency because of the worldwide spread. Traditionally, Mpox infection spreads through contact with infected animals. However, the 2022 outbreak Centers for Disease Control and Prevention (CDC) data note that 94% of cases had recent male-to-male sexual or close intimate contact, suggesting a novel sexual transmission. In this article, we report a 39-year-old HIV-positive man presenting with a diffuse cutaneous rash, perianal pain, and bloody stool of 2-week duration. A medical history includes intravenous drug use and multiple sexual partners. Physical examination revealed umbilicated, tan-colored, crusted cutaneous papules scattered across the face, trunk, and genital regions. Perianal lesion biopsy showed an acanthotic epidermis with spongiosis, ballooning degeneration of keratinocytes, and the formation of multinucleated syncytial keratinocytes. A dermal superficial/lichenoid mixed inflammatory cell infiltrate with multinucleated giant cells was noted. Perianal lesion polymerase chain reaction (PCR) was positive for Mpox. Colonoscopy revealed a 3-cm circumferential rectal ulcer with gray exudate and necrosis. A rectal ulcer biopsy showed an ulcerated mucosa with acute proctitis and necrosis. There were scattered macrophages with intranuclear inclusion and glassy vacuolization, and Mpox infection was confirmed by immunostaining with a Mpox-specific anti-Vaccinia virus antibody.
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Mpox , Proctite , Estados Unidos , Animais , Humanos , Masculino , Adulto , Úlcera , Proctite/diagnóstico , Anticorpos Antivirais , NecroseRESUMO
ABSTRACT: Most melanocytic tumors are classified as benign or malignant based on clinical morphology, histology, and immunohistochemical (IHC) analysis. A subset of more challenging cases with ambiguous features may require further evaluation with established ancillary diagnostic molecular studies, including fluorescence in situ hybridization and/or single nucleotide polymorphism array, to increase diagnostic certainty. More recently, a diagnostic gene expression-profiling (GEP) assay and an IHC stain for the detection of PRAME (PReferentially expressed Antigen in MElanoma) have been developed. The use of PRAME IHC has been validated in cases of unequivocal and ambiguous melanocytic proliferations via comparing results with fluorescence in situ hybridization and/or single nucleotide polymorphism array. A study comparing performance metrics of PRAME IHC and diagnostic GEP has not been previously published. Herein, we evaluated the use of PRAME IHC in 55 melanocytic tumors with challenging histomorphology by comparing the results with diagnostic GEP and final histomorphologic diagnosis. Intertest agreement occurred in 88% of cases. PRAME IHC supported the final diagnosis in 89% of cases with a sensitivity of 79%, specificity of 95%, and positive predictive value of 88.2%. GEP agreed with the final diagnosis in 88% of cases with a sensitivity of 65%, 97% specificity, and positively predicted melanoma in 91.7% of cases. Because the results of this study align with past publications evaluating the performance metrics of PRAME IHC, showing it to be as sensitive as and more cost effective than all other ancillary molecular tests, we propose the use of PRAME IHC as the optimal first-line diagnostic tool for ambiguous melanocytic proliferations.
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Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Hibridização in Situ Fluorescente , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Expressão Gênica , Antígenos de Neoplasias/genéticaRESUMO
A 61-year-old African-American female with moderately controlled Hailey-Hailey disease (HHD) presents to the emergency department with a rash and fever. One day prior to her presentation, she was started on oral clindamycin for a tooth extraction procedure. Her physical examination shows diffuse erythema on the trunk and extremities with multiple nonfollicular pustules. A punch biopsy of her upper extremity revealed intraepidermal acantholysis, neutrophilic spongiosis, and subcorneal pustules. The perivascular and interstitial superficial dermal infiltrate is mixed and composed of predominantly neutrophils, with lymphocytes and rare eosinophils. These findings suggest a superimposed acute generalized exanthematous pustulosis (AGEP) in the background of HHD. AGEP is a potentially severe cutaneous condition characterized by the abrupt onset of numerous nonfollicular pustules in a background of pruritic edematous erythroderma. To date, only two case reports have described AGEP in patients with HHD. Early diagnosis of AGEP is essential to initiate prompt and aggressive systemic therapy, prompt medication cessation, close monitoring for end-organ damage, and improve overall morbidity and mortality.
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Pustulose Exantematosa Aguda Generalizada , Exantema , Pênfigo Familiar Benigno , Humanos , Feminino , Pessoa de Meia-Idade , Pustulose Exantematosa Aguda Generalizada/tratamento farmacológico , Pustulose Exantematosa Aguda Generalizada/etiologia , Pustulose Exantematosa Aguda Generalizada/diagnóstico , Clindamicina/efeitos adversos , Pênfigo Familiar Benigno/tratamento farmacológico , Exantema/patologia , Pele/patologiaRESUMO
BACKGROUND: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. METHODS: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. RESULTS: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. CONCLUSIONS: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.
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Penfigoide Bolhoso , Humanos , Vesícula/metabolismo , Proteínas do Sistema Complemento , Imunofluorescência , Perfilação da Expressão Gênica , Imunidade Inata , Penfigoide Bolhoso/patologia , RNA Mensageiro , Receptor 4 Toll-Like/metabolismo , Regulação para CimaRESUMO
ABSTRACT: Prototheca species are achlorophyllic algae that are a rare cause of infection in humans. It most commonly causes localized cutaneous disease and rarely disseminated infection. Immunocompromised patients have the highest risk of disseminated protothecosis, with a higher mortality rate than localized cutaneous infections. At the species level, infections caused by Prototheca zopfii are reported less frequently than those caused by Prototheca wickerhamii. The diagnosis can be made using histopathology, culture, and molecular testing. There is no definitive evidence for an effective treatment, which currently consists of antifungals (primarily amphotericin B). With only a handful of cases of disseminated protothecosis reported worldwide that are caused by P. zopfii , we herein present an additional case of a postbone marrow transplant patient in the Midwest of the United States.
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Infecções , Prototheca , Dermatopatias Infecciosas , Humanos , Infecções/diagnóstico , Infecções/etiologia , Infecções/patologia , Dermatopatias Infecciosas/complicações , Antifúngicos/uso terapêuticoRESUMO
ABSTRACT: A 43-year-old woman presented with a palpable, pruritic, minimally painful right vulvar lesion. Physical examination revealed approximately 2.0-cm tender nodule at 70' clock in the right labia majora. Histological sections of the excision specimen showed an unremarkable epidermis with large, well-circumscribed dermal proliferation with extension to the reticular dermis. Within this proliferation are small solid and ductal structures relatively evenly distributed in the sclerotic stroma. The epithelial elements consisted of monomorphous cuboidal cells and assumed round, oval, curvilinear, or have other peculiar geometric shapes, including "comma-like" or "tadpole"-like configurations. The tumor cells were positive for CEA, EMA, and estrogen receptor and negative for progesterone receptor. The clinical presentation and the deep extension of the tumor were similar to the microcystic adnexal carcinoma. Although a syringoma generally presents with multiple lesions and usually involves the superficial dermis, a syringoma with deep extension was favored based on the lack of follicular differentiation, atypia, mitoses, and perineural invasion. Microcystic adnexal carcinoma and syringoma have a morphologic overlap and are misdiagnosed in 30% of the cases. Thus, it is exceptionally important for pathologists to be aware of and be able to distinguish these entities. To the best of our knowledge, this is the first case of a solitary, painful vulvar syringoma with deep extension.
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Neoplasias Cutâneas , Neoplasias das Glândulas Sudoríparas , Siringoma , Neoplasias Vulvares , Feminino , Humanos , Adulto , Siringoma/diagnóstico , Siringoma/patologia , Neoplasias Cutâneas/patologia , Neoplasias Vulvares/diagnóstico , Neoplasias Vulvares/cirurgia , Neoplasias Vulvares/patologia , Erros de Diagnóstico , Neoplasias das Glândulas Sudoríparas/diagnóstico , Neoplasias das Glândulas Sudoríparas/cirurgia , Neoplasias das Glândulas Sudoríparas/patologiaRESUMO
ABSTRACT: A 32-year-old G2P1L1 (5 months pregnant) woman presented with a 3-month history of a slow-growing cystic lesion on her scalp vertex. Similar lesions in the exact location were excised twice in the past with a diagnosis of trichilemmal carcinoma (TC). A biopsy of the scalp lesion showed morphology and immunoprofile consistent with previously diagnosed TC. Staging PET/CT demonstrated a 4.7 cm right upper lobe lung, and a subsequent lung biopsy showed a small, round blue-cell tumor with necrosis, morphologically identical to the prior biopsies from the scalp. Considering the unusual clinical course of TC, a lung biopsy was sent for next-generation sequencing that showed EWSR1-FLI1 (type1) fusion. Additionally, CD99 immunostaining revealed uniform cytoplasmic and membranous staining in the tumor cells. The previous scalp excision specimen was also sent for mutation analysis, which showed EWSR1-FLI1 fusion. In conjunction with clinical history and histological and molecular findings, a definitive diagnosis of primary cutaneous Ewing sarcoma (PCES) with local recurrence and metastasis to the lung was made. We present a case of PCES, which was previously misdiagnosed and treated as TC. This case emphasizes the importance of CD99 in the initial screening of cutaneous small round blue-cell tumors to avoid misdiagnosis from other morphological overlaps. Also, despite its rarity, PCES should be included in the differential diagnosis of small, round, blue cell tumors at cutaneous sites. Our case also exemplifies common biases in medical decision-making, including premature closure and anchoring bias which can result in misdiagnosis or diagnostic delay and associated delay in appropriate management.
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Neoplasias Ósseas , Neoplasias da Mama , Neoplasias Pulmonares , Sarcoma de Ewing , Sarcoma , Adulto , Feminino , Humanos , Gravidez , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Neoplasias Ósseas/diagnóstico , Diagnóstico Tardio , Pulmão/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sarcoma/diagnóstico , Sarcoma de Ewing/genética , Couro Cabeludo/patologia , Neoplasias Pulmonares/secundárioRESUMO
ABSTRACT: A 30-year-old African American woman with a history of interstitial lung disease presented with bilaterally symmetrical, nonpruritic, scaling and fissuring, hyperpigmented, lichenified plaques on her hands and feet. She reported occasional erythema of her face, intermittent erythema, and irritation of her eyes but denied any muscle weakness. A biopsy of the plantar first toe showed hyperkeratosis, striking alternating ortho- and parakeratosis with underlying apoptotic bodies. There was psoriasiform acanthosis without suprapapillary thinning, numerous apoptotic keratinocytes in all layers of the epidermis extending into the corneum that were out of proportion with the minimal interface inflammation. Colloidal iron and Alcian blue stains showed increased dermal mucin deposition. Given the clinical, histopathological, and supportive serological findings (positive anti-KU and anti-SSA), a diagnosis of clinically amyopathic dermatomyositis with mechanic hand/hiker feet (MH/HF) was rendered. The pseudocheckerboard pattern of MH/HF has been previously reported in only 4 patients. The most frequent associations with MH/HF are dermatomyositis and antisynthetase syndrome; however, our patient was negative for antiaminoacyl transfer RNA synthetase antibodies, a required criterion to diagnose antisynthetase syndrome. It is imperative to recognize MH/HF clinically and histopathologically because it may be an early indication of developing dermatomyositis or other connective tissue diseases, which would guide further workup and screening for systemic involvement of the disease, including interstitial lung disease.
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Dermatomiosite , Ceratose , Doenças Pulmonares Intersticiais , Adulto , Feminino , Humanos , Dermatomiosite/complicações , Dermatomiosite/diagnóstico , Ceratose/etiologia , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnósticoRESUMO
Papular-purpuric "gloves and socks" syndrome (PPGSS) is a unique, self-limited dermatosis characterized by edema, erythema, and pruritic petechiae and papules in a distinct "gloves and socks" distribution. This is often accompanied by systemic symptoms, including fever, lymphadenopathy, asthenia, myalgia, and arthralgias. PPGSS has also been described as a manifestation of an underlying immunological mechanism that can be triggered by viral or drug-related antigens. A 32-year-old male developed a painful eruption on the bilateral hands and feet after being diagnosed with influenza B. On examination, scattered papular purpura with occasional overlying scale was noted on the bilateral hands, fingers, feet, toes, volar wrists, and ankles. Histopathologic sections showed a mixed pattern of inflammation with interface and spongiotic changes. A parakeratotic scale with overlying basket-weave orthokeratosis was also seen. Within the epidermis, there was intraepidermal vesicles and Langerhans cell microabscess formation with scattered apoptotic keratinocytes. The underlying dermis showed a superficial perivascular lymphocytic infiltrate with mild edematous changes, and extravasation of red blood cells. Clinicopathologic correlation strongly supported a diagnosis of popular-purpuric gloves and socks syndrome. The influenza virus has never been reported in association with PPGSS; thus, this case outlines an important new variant that clinicians should be familiar with.
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Dermatoses do Pé , Dermatoses da Mão , Influenza Humana , Parvovirus B19 Humano , Púrpura , Adulto , Edema , Dermatoses do Pé/diagnóstico , Humanos , Masculino , Púrpura/diagnósticoRESUMO
ABSTRACT: We report an extraordinary case of primary myelofibrosis with transformation to leukemia cutis. A 64-year-old Caucasian man with a history of JAK2-positive primary myelofibrosis presented with erythematous papulonodules on his right lower extremity. A punch biopsy revealed a normal epidermis with an underlying diffuse dermal infiltrate composed of medium-to-large-sized myeloid cells and leukocytes. Neoplastic cells were immunoreactive for LCA, CD34, CD61, CD117, and CD68 and negative for lysozyme, CD20, CD3, myeloperoxidase, and TdT. These findings were consistent with a diagnosis of leukemia cutis. A concurrent bone marrow biopsy demonstrated a markedly fibrotic, hypercellular marrow without a significant increase in blasts. With no morphologic evidence of bone marrow involvement by acute myeloid leukemia, our case suggests that the patient's primary myelofibrosis transformed to leukemia cutis. Our patient died 2 months after the onset of his skin nodules. Our case demonstrates that leukemia cutis should be included in the differential diagnosis for cutaneous nodular lesions in patients with a history of an advanced-stage hematological malignancy.
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Leucemia Mieloide Aguda/patologia , Infiltração Leucêmica/metabolismo , Mielofibrose Primária/complicações , Neoplasias Cutâneas/patologia , Evolução Fatal , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/diagnósticoRESUMO
BACKGROUND: Patients presenting with a site-specific skin complaint may receive a total body skin examination (TBSE) or a more focused examination. A TBSE may be time-consuming but can potentially detect unsuspected or early stage skin cancers. The purpose of this study was to assess the detection of skin cancers associated with dermatologist-initiated TBSE performed immediately after a focused skin examination on the same patients. METHODS: The dermatology records of patients with biopsy-proven melanoma, basal cell carcinoma (BCC), or squamous cell carcinoma (SCC) during a 2-year period were reviewed. Generalized linear mixed-effects models were used to estimate the odds of a lesion being identified by a dermatologist (rather than the patient or the patient's primary health care provider). RESULTS: A total 1563 biopsy-proven cutaneous malignancies were found on 1010 patients. Of these, 797 cancers (51%) were first identified by a dermatologist on TBSE and 764 (48.9%) by the patient or the referring provider. Among tumors first identified by dermatologists (nâ¯=â¯797), 553 (69%) were BCCs, 220 (28%) were SCCs, and 24 (3%) were melanomas. The mean Breslow depth was 0.53 mm (standard deviation: 0.31 mm) for melanomas found on TBSE versus 1.04 mm (standard deviation: 1.68 mm) if identified by patients or referring providers. BCCs were more likely to be identified by a dermatologist during a TBSE (nâ¯=â¯553 [56%] vs. nâ¯=â¯434 [44%]; odds ratio: 1.79; p < .001). Tumors ultimately diagnosed as SCCs were more often identified by patients or patients' primary care providers (nâ¯=â¯302 [58%]; odds ratio: 0.56; p < .001). However, 220 otherwise undetected SCCs were found during dermatologist-performed TBSE. CONCLUSION: Dermatologist-performed TBSEs identified numerous cutaneous malignancies that might otherwise have remained undiagnosed. Early detection of melanoma or nonmelanoma skin cancer by TBSEs may spare patients significant morbidity and mortality.
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Intraosseous (IO) access provides a potentially lifesaving means of vascular access in settings of trauma and advanced cardiovascular life support in which patients often require prompt and large volumes of fluid resuscitation, blood products, and medications. An additional benefit of IO access is the rare incidence of complications, with many studies reporting rates of less than 1%. The most commonly cited complications include compartment syndrome, osteomyelitis, traumatic bone fracture, and epiphyseal plate damage. To evaluate the dermatologic sequelae, we performed a retrospective chart review spanning 18 consecutive months to identify patients who underwent IO line placement, either at or en route to a large metropolitan level I trauma center in the Midwestern United States. Our review identified a complication rate of 2.7%, with complications including compartment syndrome, needle breakage, and a previously unreported cutaneous complication of traumatic bullae.
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Serviços Médicos de Emergência , Osteomielite , Humanos , Infusões Intraósseas/efeitos adversos , Agulhas , Estudos Retrospectivos , PeleRESUMO
While drug-induced panniculitis is not uncommon in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor therapy, it is rare for CML to initially present as a leukemic panniculitis. We present the case of a 45-year-old male with no relevant prior medical history presenting with 6 months of migratory nodules, 2 months of drenching night sweats, and a 20 pound weight loss. Physical examination showed firm subcutaneous nodules with overlying ecchymoses present on the right lateral thigh and left lower back. Biopsy of a nodule from the right thigh showed a subcutaneous lobular panniculitis involved by a dense infiltrate of neutrophils and granulocyte precursors. Fluorescent in-situ hybridization (FISH) was positive for t(9;22)(q34;q11.2)BCR-ABL1 fusion. A concurrent hemogram revealed a white blood cell count elevation of 600,000 K/µL. Bone marrow biopsy examination showed marked myeloid expansion with an increase in granulocyte precursors and Philadelphia chromosome positivity by FISH, consistent with bone marrow involvement by CML. Herein, we describe this unusual and rare case of CML initially presenting as a neutrophilic panniculitis-like leukemia cutis. Arriving at this challenging diagnosis may be easily missed without clinical and laboratory correlation, which would certainly lead to the patient's not receiving life-saving treatment.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Paniculite/patologia , Pele/patologia , Diagnóstico Diferencial , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Paniculite/diagnósticoRESUMO
Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are Severe Cutaneous Adverse Reactions (SCARS) characterized by fever and mucocutaneous lesions leading to necrosis and sloughing of the epidermis. Conjunctival lesions are reported in 85% of patients. The pathogenesis of SJS/TEN/SCARS is not completely understood. It is hypothesized that IL-13, IL-15 and Granulysin expressed in plasma and skin may play a role. We measured the circulating levels of these cytokines in the plasma using ELISA and their expression in the skin using immunofluorescence microscopy. A total of 12 SJS/TEN skin biopsy samples (8 SJS, 2 SJS/TEN overlap and 2 TEN) were analyzed. Biopsy samples from patients with Lichen Planus (an inflammatory condition of the skin and mucous membranes) served as controls. Studies were also performed in human corneal epithelial cells where expression of these cytokines were measured following a challenge with TNF-α (0, 1, 10 and 100 ng/ml). The intensity of immunofluorescence was measured Using Imaris® software. The results showed significantly increased expression of these cytokines in the skin biopsy samples as measured by the average intensities of IL-13 (6.1 x 133.0 ± 4.231 x 10^8), and Granulysin (4.2 x 123.0 ± 4.231 x 10^8) compared to Lichen planus control (3.0 x 123.0 ±1.62 x 10^5). Increased expression of IL-13 and IL-15 were noted in cell culture studies and in the plasma samples when compared to Normal Human Plasma as controls. It is concluded that IL-13, IL-15 and Granulysin play a role in the pathogenesis of SJS/TEN.