Monkeypox: What the Dermatologist Needs to Know.

Monkeypox, an endemic disease in some African countries, has provoked public health activeness on a global scale that even the World Health Organization (WHO), invoking international health regulations, declared it a public health emergency of international concern (PHEIC). The WHO called attention of member states to exert maximum surveillance over the disease, its patients, and contact persons in order to standardize control measures. A need was directed to provide complete knowledge about the disease, allowing the administration of prior diagnoses as well as isolation and more effective epidemiologic control measures. An updated review on monkeypox emphasized upon having the fundamental aspects of the lesions caused by the disease, and appropriate management of patients upon clinical and epidemiologic evaluation.

New small molecules in dermatology: for the autoimmunity, inflammation and beyond.

OBJECTIVE AND DESIGN: The discovery of new inflammatory pathways and the mechanism of action of inflammatory, autoimmune, genetic, and neoplastic diseases led to the development of immunologically driven drugs. We aimed to perform a narrative review regarding the rising of a new class of drugs capable of blocking important and specific intracellular signals in the maintenance of these pathologies: the small molecules. MATERIALS/METHODS: A total of 114 scientific papers were enrolled in this narrative review. RESULTS: We describe in detail the families of protein kinases-Janus Kinase (JAK), Src kinase, Syk tyrosine kinase, Mitogen-Activated Protein Kinase (MAPK), and Bruton Tyrosine Kinase (BTK)-their physiologic function and new drugs that block these pathways of intracellular signaling. We also detail the involved cytokines and the main metabolic and clinical implications of these new medications in the field of dermatology. CONCLUSIONS: Despite having lower specificity compared to specific immunobiological therapies, these new drugs are effective in a wide variety of dermatological diseases, especially diseases that had few therapeutic options, such as psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, and vitiligo.

Cytokine Profiles Associated With Acute COVID-19 and Long COVID-19 Syndrome.

The duration and severity of COVID-19 are related to age, comorbidities, and cytokine synthesis. This study evaluated the impact of these factors on patients with clinical presentations of COVID-19 in a Brazilian cohort. A total of 317 patients diagnosed with COVID-19 were included; cases were distributed according to clinical status as severe (n=91), moderate (n=56) and mild (n=170). Of these patients, 92 had acute COVID-19 at sample collection, 90 had already recovered from COVID-19 without sequelae, and 135 had sequelae (long COVID syndrome). In the acute COVID-19 group, patients with the severe form had higher IL-6 levels (p=0.0260). In the post-COVID-19 group, there was no significant difference in cytokine levels between groups with different clinical conditions. In the acute COVID-19 group, younger patients had higher levels of TNF-α, and patients without comorbidities had higher levels of TNF-α, IL-4 and IL-2 (p<0.05). In contrast, patients over age 60 with comorbidities had higher levels of IL-6. In the post-COVID-19 group, subjects with long COVID-19 had higher levels of IL-17 and IL-2 (p<0.05), and subjects without sequelae had higher levels of IL-10, IL-6 and IL- 4 (p<0.05). Our results suggest that advanced age, comorbidities and elevated serum IL-6 levels are associated with severe COVID-19 and are good markers to differentiate severe from mild cases. Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 and IL-10 appear to constitute a cytokine profile of long COVID-19, and these markers are potential targets for COVID-19 treatment and prevention strategies.

Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach.

In long coronavirus disease 2019 (long COVID-19), involvement of the musculoskeletal system is characterised by the persistence or appearance of symptoms such as fatigue, muscle weakness, myalgia, and decline in physical and functional performance, even at 4 weeks after the onset of acute symptoms of COVID-19. Muscle injury biomarkers are altered during the acute phase of the disease. The cellular damage and hyperinflammatory state induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may contribute to the persistence of symptoms, hypoxaemia, mitochondrial damage, and dysregulation of the renin-angiotensin system. In addition, the occurrence of cerebrovascular diseases, involvement of the peripheral nervous system, and harmful effects of hospitalisation, such as the use of drugs, immobility, and weakness acquired in the intensive care unit, all aggravate muscle damage. Here, we review the multifactorial mechanisms of muscle tissue injury, aggravating conditions, and associated sequelae in long COVID-19.

Lessons from dermatology about inflammatory responses in Covid-19.

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Blastic plasmacytoid dendritic cell neoplasm: an early presentation.

A blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a cutaneous lymphoma derived from a plasmacytoid dendritic precursor cell that exhibits aggressive clinical behavior. Herein, we report a 46-year-old woman with a complaint of a painless nodule on the back, associated with pruritus. The nodule grew and new growths appeared over six months of evolution. The histopathological examination of one of the left upper limb lesions showed a dense lymphoid cell infiltrate with atypia in the superficial and deep dermis. Immunohistochemistry showed positivity for CD45, S-100 protein, CD123, and TCL 1. About two months after the initial evaluation, the patient was admitted to the Emergency Hospital of Marituba-PA with dyspnea. She progressed to cardiorespiratory arrest and death within 12 hours of admission. There is still no consensus for the treatment of BPDCN. Intensive therapy for acute leukemia can be useful, but allogeneic bone marrow transplantation has a greater chance of long-term survival.

The inflammasome in leprosy skin lesions: an immunohistochemical evaluation.

OBJECTIVE: Leprosy is a chronic infectious disease presenting with a spectrum of clinical manifestations that correspond to the type of immune response that develops in the host. Factors that may be involved in this process include inflammasomes, cytosolic proteins responsible for the activation of caspase 1, IL-1ß and IL-18 secretion, and induction of a type of death called pyroptosis. PATIENTS AND METHODS: We evaluated the expression of inflammasome markers (nucleotide-binding oligomerization domain-like receptor containing pyrin domain 1 [NLRP1], nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 [NLRP3], caspase 1, IL-1ß, and IL-18) by immunohistochemistry in 43 samples of skin lesions of leprosy patients from the groups indeterminate (I) leprosy (13 patients), tuberculoid (TT) leprosy (15 patients), and lepromatous leprosy (LL; 15 patients). RESULTS: The evaluated markers were most upregulated in LL lesions, followed by lesions of TT leprosy and I leprosy. Differences were statistically significant between the I leprosy and LL leprosy forms and between the I leprosy and TT leprosy forms. Positive and significant correlations were found between IL-18 and caspase 1 in LL (r=0.7516, P=0.0012) and TT leprosy (r=0.7366, P=0.0017). In I leprosy, correlations were detected between caspase 1 and IL-1ß (r=0.6412, P=0.0182), NLRP1 and IL-18 (r=0.5585, P=0.473), NLRP3 and IL-18 (r=0.6873, P=0.0094), and NLRP1 and NLRP3 (r=0.8040, P=0.0009). CONCLUSION: The expression of inflammasome markers in LL lesions indicates the ineffectiveness of this protein complex in controlling the infection. Caspase 1 may be involved in the pyroptotic cell death in the lepromatous form of the disease. Inflammasomes may act together in the initial phase of I leprosy; this phenomenon may influence the clinical outcome of the disease.

Carcinoma de células escamosas cutâneo-invasivo - relato de caso / Invasive cutaneous squamous cell carcinoma - Case report

O carcinoma de células escamosas cutâneo é resultante da proliferação maligna dos queratinócitos. Costuma surgir da evolução de lesões precursoras, mas pode crescer espontaneamente na pele normal ou cronicamente inflamada. O carcinoma de células escamosas invasivo corresponde à segunda forma mais comum de câncer da pele não melanoma e representa 20% de todas as neoplasias cutâneas. Este trabalho relata um caso clínico de carcinoma de células escamosas cutâneo, rapidamente progressivo e com metástases regionais, que mesmo com a ressecção completa e esvaziamento ganglionar, apresentou pouca resposta terapêutica e evoluiu a óbito.

Cutaneous squamous cell carcinoma (SCC) results from malignant proliferation of keratinocytes. It usually arises from the development of precursor lesions, however it may grow spontaneously on normal or chronically inflamed skin. Invasive SCC is the second most common type of non-melanoma skin cancer and accounts for 20% of all cutaneous neoplasms. The present paper reports a clinical case of cutaneous SCC, rapidly progressive and with regional metastases, which, even after complete resection of the tumor and regional lymph nodes, showed little therapeutic response and evolved to death.

Ocular manifestations of psoriasis.

PURPOSE: We aimed to report the ocular manifestations observed in patients with psoriasis. METHODS: Patients were included and referred to our ophthalmology clinic from dermatology clinics of Universidade do Estado do Pará between October 2013 and August 2014. Clinical interviews were conducted to identify relevant epidemiological data, clinical features, and treatment details, and data were recorded using the same protocol. Subsequent dermatological examinations were performed and disease severity was rated using the Psoriasis Area and Severity Index and the Dermatological Life Quality Index. Complete eye examination was conducted, including visual acuity, biomicroscopy, tonometry, fundoscopy, Schirmer I test, tear breakup time, rose bengal staining, ocular surface disease index, and glaucoma tests. RESULTS: In total, we included 43 patients with psoriasis and 86 controls. Patients with psoriasis had statistically higher incidences of dry eye (16.28%), likely dry eye (32.56%), and blepharitis (16.28%). Furthermore, the rose bengal and ocular surface disease tests were more abnormal in patients with psoriasis (p<0.05). CONCLUSIONS: Patients with psoriasis should undergo regular eye exams, regardless of risk factors, to monitor for the progression of symptomatic or asymptomatic ocular manifestations.

Ocular manifestations of psoriasis / Manifestações oculares observadas em pacientes com psoríase

ABSTRACT Purpose: We aimed to report the ocular manifestations observed in patients with psoriasis. Methods: Patients were included and referred to our ophthalmology clinic from dermatology clinics of Universidade do Estado do Pará between October 2013 and August 2014. Clinical interviews were conducted to identify relevant epidemiological data, clinical features, and treatment details, and data were recorded using the same protocol. Subsequent dermatological examinations were performed and disease severity was rated using the Psoriasis Area and Severity Index and the Dermatological Life Quality Index. Complete eye examination was conducted, including visual acuity, biomicroscopy, tonometry, fundoscopy, Schirmer I test, tear breakup time, rose bengal staining, ocular surface disease index, and glaucoma tests. Results: In total, we included 43 patients with psoriasis and 86 controls. Patients with psoriasis had statistically higher incidences of dry eye (16.28%), likely dry eye (32.56%), and blepharitis (16.28%). Furthermore, the rose bengal and ocular surface disease tests were more abnormal in patients with psoriasis (p<0.05). Conclusions: Patients with psoriasis should undergo regular eye exams, regardless of risk factors, to monitor for the progression of symptomatic or asymptomatic ocular manifestations.

RESUMO Objetivos: Relatar as manifestações oculares observadas em pacientes com psoríase atendidos no Ambulatório de Dermatologia da X e encaminhados ao Y, no período de outubro de 2013 a agosto de 2014. Métodos: A amostra foi constituída por um grupo composto por 43 pacientes com psoríase e um grupo controle com 86 pacientes sem psoríase. Foi realizada uma entrevista clínica com dados epidemiológicos, aspectos clínicos da doença e terapia empregada, sendo todas as informações registradas em protocolo próprio. Posteriormente, realizou-se o exame dermatológico, no qual foi avaliado o índice de gravidade da Psoríase por área (PASI) e índice dermatológico de qualidade de vida (DLQI), e o exame oftalmológico completo, incluindo: Acuidade Visual, Biomicroscopia, Tonometria, Fundoscopia, Teste de Schirmer I, Tempo de Ruptura do Filme Lacrimal (TBUT), rosa bengala, índice de doença da superfície ocular (OSDI) e exames para glaucoma. Resultados: Observou-se que nos pacientes com psoríase houve frequência estatisticamente maior de envolvimento ocular, como olho seco (16,28%), provável olho seco (32,56%) e blefarite (16,28%). Além disso, os valores do rosa bengala e do OSDI apresentaram-se mais alterados nos pacientes com psoríase (p<0,05). Conclusão: Dessa forma, sugere-se que esses pacientes realizem exames oftalmológicos periódicos, já que as manifestações oculares podem progredir sem sintomatologia e ocorrer independentemente de fatores de risco.

Assessment of psoriasis severity in Brazilian patients with chronic plaque psoriasis attending outpatient clinics: a multicenter, population-based cross-sectional study (APPISOT).

PURPOSE: Data on chronic plaque psoriasis severity and its potential clinical and lifestyle implications in the Brazilian population are limited. The primary aim of this study was to assess the clinical severity of plaque psoriasis in Brazil. Further objectives included evaluating potential associations between disease severity and demographic, lifestyle, and clinical characteristics, health-related quality of life (HRQOL), and work productivity. MATERIALS AND METHODS: This observational (non-interventional) cross-sectional study was conducted in 26 dermatologic clinics across 11 Brazilian states. Psoriasis severity was assessed using investigator judgment and Finlay's Rule of Tens: a Psoriasis Area and Severity Index (PASI) score >10, a Body Surface Area (BSA) > 10%, or a Dermatology Life Quality Index (DLQI) score >10. RESULTS: Among 1125 patients, 205 (18.2%) had moderate-to-severe disease. On multiple regression analyses, psoriasis severity was significantly (directly) associated with the presence of physical inactivity and comorbid pain, anxiety, and depression; and significantly (inversely) associated with HRQOL and work productivity. LIMITATIONS: Cross-sectional studies cannot assess temporal trends, and observational studies cannot conclusively determine causality or exclude biases and confounding due to unmeasured variables. CONCLUSIONS: Among Brazilian patients with moderate-to-severe psoriasis, disease severity had far-reaching adverse impacts on lifestyle, comorbidities, HRQOL, and work productivity.

Endoplasmic Reticulum Stress Markers and Their Possible Implications in Leprosy's Pathogenesis.

Mycobacterium leprae causes leprosy, a dermatoneurological disease which affects the skin and peripheral nerves. One of several cellular structures affected during M. leprae infection is the endoplasmic reticulum (ER). Infection by microorganisms can result in ER stress and lead to the accumulation of unfolded or poorly folded proteins. To restore homeostasis in the cell, the cell induces a series of signaling cascades known as the unfolded protein response called UPR (unfolded protein response). The present work is aimed at investigating the in situ expression of these markers in cutaneous lesions of clinical forms of leprosy and establish possible correlation expression patterns and types of lesion. A total of 43 samples from leprosy patients were analyzed by immunohistochemistry with monoclonal antibodies against GRP78/BiP, PERK, IRE1α, and ATF6. A statistically significant difference between the indeterminate, tuberculoid, and lepromatous clinical forms was detected, with high expression of GRP78/BiP, PERK, IRE1α, and ATF6 in tuberculoid forms (TT) when compared to lepromatous leprosy (LL) and indeterminate (I) leprosy. These results represent the first evidence of ER stress in samples of skin lesions from leprosy patients. We believe that they will provide better understanding of the complex pathogenesis of the disease and facilitate further characterization of the cascade of molecular events elicited during infection.

NFκB transcription factor (p65) immunohistochemistry in leprosy dermal microvasculature.

Leprosy caused by Mycobacterium leprae is characterized by a spectrum of clinical manifestations that are determined by the predominant immunological profile of the host. The recruitment of leukocytes to the sites of injury can influence the development of these profiles. Cell adhesion molecules such as ICAM-1, VCAM-1 and CD62E participate in this process and their expression is regulated by transcriptions factors such as NFκB. To correlate the expression of cell adhesion molecules and NFκB (p65) in leprosy lesions, 30 skin biopsies of patients with leprosy [16 with the tuberculoid (TT) or borderline tuberculoid (BT) forms and 14 with the lepromatous (LL) or borderline lepromatous (BL) forms] were analyzed by immunohistochemistry. A larger mean number of cells expressing VCAM-1 (BT/TT: 18.28 ± 1.4; BL/LL: 10.67 ± 1.2; p = 0.0002), ICAM-1 (BT/TT: 9.92 ± 1.1; BL/LL: 5.87 ± 1.0; p = 0.0084) and CD62E (BT/TT: 13.0 ± 1.5; BL/LL: 2.58 ± 0.3; p = 0.0001) were observed in BT and TT lesions. The mean number of cells expressing NFκB was similar in the two clinical forms (BT/TT: 2.21 ± 2.7; BL/LL: 2.35 ± 3.1;p = 0.9285). No significant correlation was observed between expression of the transcription factor and adhesion molecules analyzed. The synthesis of ICAM-1, VCAM-1 and CD62E depends on the activation of NFκB, which acts synergistically with other transcription factors. Adequate activation of intracellular signaling pathways results in the production of endothelial adhesion molecules, contributing to the recruitment of cells to the site of injury and thus eliciting an effective inflammatory response in the elimination of the bacillus.

Efeito do óleo de copaíba associado ao microagulhamento na pele de ratos: um estudo comparativo / Effect of copaiba oil associated with microneedling on the skin of rats: a comparative study

Introdução: O microagulhamento é técnica cuja finalidade é o estímulo do colágeno, bem como de drug delivery. O óleo de copaíba apresenta efeitos cicatrizantes e anti-inflamatórios que já foram demonstrados em vários modelos animais. Objetivo: Avaliar o efeito do óleo de copaíba associado ao microagulhamento na pele de ratos. Métodos: Foram utilizados 30 ratos distribuídos em seis grupos com cinco animais cada, submetidos a: microagulhamento isolado, microagulhamento associado a óleo mineral e microagulhamento associado a óleo de copaíba. Foram realizadas biópsias em todos os animais 14 dias e 30 dias após. Os parâmetros avaliados foram presença de colágeno, fibroblastos e vasos, classificada em ausente (0), leve (1), moderada (2) ou intensa (3). Resultados: Houve diferença estatisticamente significante entre os grupos em relação ao colágeno com 14 (p = 0,0091) e 30 dias (p = 0,0357) e fibroblastos com 30 dias (p = 0,0357). O grupo que utilizou microagulhamento e óleo de copaíba, apresentou, após 30 dias, maior produção de colágeno e de fibroblastos. Conclusões: o óleo de copaíba associado ao microagulhamento foi capaz de estimular maior produção de colágeno e de fibroblastos na pele de ratos.

Introduction: Microneedling is a technique aiming at stimulating the production of collagen as well as serving as drug delivery. Copaiba oil has healing and anti-inflammatory effects that have already been demonstrated in several animal models. Objective: To evaluate the effect of copaiba oil associated with microneedle removal on the skin of rats. Methods: Thirty rats were distributed in six groups of five animals each, subsequently undergoing: isolated microneedling, microneedling associated to mineral oil, and microneedling associated with copaiba oil. Biopsies were carried out in all animals at 14 and 30 days after the procedure. The parameters evaluated were: presence of collagen, fibroblasts and vessels, according to the following ratings: absence (0), mild (1), moderated (2) or intense (3). Results: There was a statistically significant difference between the groups regarding the production of collagen at 14 days (p = 0.0091) and 30 days (p = 0.0357); and fibroblasts at 30 days (p = 0.0357). the group that used microneedling and copaiba oil, presented, after 30 days, a greater production of collagen and fibroblasts. Conclusions: Copaiba oil associated with microneedling was capable of stimulating a greater production of collagen and fibroblasts in the skin of rats.

Th9 cytokines response and its possible implications in the immunopathogenesis of leprosy.

AIMS: Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated. METHODS: To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL. RESULTS: Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-ß and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-ß was observed in LL compared with TT. IL-4, IL-10 and TGF-ß tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue. CONCLUSIONS: The results suggest that Th9 lymphocytes may be involved in the response to Mycobacterium leprae, positively or negatively regulating microbicidal activity of the local immune system in the disease.

In situ expression of M2 macrophage subpopulation in leprosy skin lesions.

The clinical manifestations of the leprosy depend on host immune response and the macrophages are the primary cells involved in this process. M1 and M2 cells exhibited distinct morphology, distinct surface marker profiles, as well as different cytokine and chemokine secretion. Macrophages express receptors such as CD163, CD68, CD206, and costimulatory molecules such as CD80 and CD86, and cytokines that trigger a suppressive or inflammatory response. Thirty-three untreated patients were selected, 17 patients had the tuberculoid leprosy (TT) and 16 had the lepromatous leprosy (LL). We performed immunohistochemistry to detect IL-13, IL-10, TGF-ß, FGF-ß, CD163, CD68, arginase 1. M2 macrophages showed significant differences between the groups studied with increase in the expression of costimulatory molecules (CD68 and CD163), arginase 1 and cytokines (IL-10, IL-13, TGF-ß and FGF-b) in the LL form. Response of M2 macrophages emerge as an alternative for a better understanding of the innate immunity in the polar forms of leprosy, highlighting the role of cytokines, arginase 1 and costimulatory molecules in the repair and suppressive responses in the lepromatous form of the disease.