Calcineurin inhibitors revisited: A new paradigm for COVID-19?

Abstract The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause mild, moderate or severe disease (COVID-19). In severe disease, there is hyperinflammation causing severe symptoms. Severe COVID-19 is an immunological phenomenon, rather than a direct viral damage disease. Therapies for COVID-19 are all investigational therapies. In case of severe disease, treatment with a calcineurin inhibitor could be promising. In this article we explain the mechanisms of calcineurin inhibitor treatment for COVID-19, based on experiences seen in solid organ transplant recipients who suffered from COVID-19.

Diagnostic and therapeutic guidelines for plaque psoriasis - Brazilian Society of Dermatology

Abstract: Psoriasis is a chronic inflammatory disease that affects 1.3% of the Brazilian population. The most common clinical manifestations are erythematous, scaling lesions that affect both genders and can occur on any anatomical site, preferentially involving the knees, elbows, scalp and genitals. Besides the impact on the quality of life, the systemic nature of the disease makes psoriasis an independent risk factor for cardiovascular disease, especially in young patients with severe disease. By an initiative of the Brazilian Society of Dermatology, dermatologists with renowned clinical experience in the management of psoriasis were invited to form a work group that, in a partnership with the Brazilian Medical Association, dedicated themselves to create the Plaque Psoriasis Diagnostic and Treatment Guidelines. The relevant issues for the diagnosis (evaluation of severity and comorbidities) and treatment of plaque psoriasis were defined. The issues generated a search strategy in the Medline-PubMed database up to July 2018. Subsequently, the answers to the questions of the recommendations were devised, and each reference selected presented the respective level of recommendation and strength of scientific evidence. The final recommendations for making up the final text were worded by the coordinators.

Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology

Abstract: BACKGROUND: Atopic dermatitis is a highly prevalent inflammatory and pruritic dermatosis with a multifactorial etiology, which includes skin barrier defects, immune dysfunction, and microbiome alterations. Atopic dermatitis is mediated by genetic, environmental, and psychological factors and requires therapeutic management that covers all the aspects of its complex pathogenesis. OBJECTIVES: The aim of this article is to present the experience, opinions, and recommendations of Brazilian dermatology experts regarding the therapeutic management of atopic dermatitis. METHODS: Eighteen experts from 10 university hospitals with experience in atopic dermatitis were appointed by the Brazilian Society of Dermatology to organize a consensus on the therapeutic management of atopic dermatitis. The 18 experts answered an online questionnaire with 14 questions related to the treatment of atopic dermatitis. Afterwards, they analyzed the recent international guidelines on atopic dermatitis of the American Academy of Dermatology, published in 2014, and of the European Academy of Dermatology and Venereology, published in 2018. Consensus was defined as approval by at least 70% of the panel. RESULTS/CONCLUSION: The experts stated that the therapeutic management of atopic dermatitis is based on skin hydration, topical anti-inflammatory agents, avoidance of triggering factors, and educational programs. Systemic therapy, based on immunosuppressive agents, is only indicated for severe refractory disease and after failure of topical therapy. Early detection and treatment of secondary bacterial and viral infections is mandatory, and hospitalization may be needed to control atopic dermatitis flares. Novel target-oriented drugs such as immunobiologicals are invaluable therapeutic agents for atopic dermatitis.

Evaluation of the use of tacrolimus ointment for the prevention of hypertrophic scars in experimental model

Abstract BACKGROUND: Tacrolimus, for its activity on modulation of collagen production and fibroblast activity, may have a role in the prevention of hypertrophic scars. OBJECTIVES: Evaluate macroscopic, microscopic, metabolic, laboratory effects and side effects of the use of topical tacrolimus ointment, in different concentrations, in the prevention of hypertrophic scars. METHODS: Twenty-two rabbits were submitted to the excision of 2 fragments of 1 cm of each ear, 4 cm apart, down to cartilage. The left ear of the animals was standardized as control and Vaseline applied twice a day. The right ear received tacrolimus ointment, at concentrations of 0.1% on the upper wound and 0.03% on the lower wound, also applied twice a day. Macroscopic, microscopic, laboratory criteria and the animals' weight were evaluated after 30 days of the experiment. RESULTS: Wounds treated with tacrolimus, at concentrations of 0.1% and 0.03%, when compared to control, showed a lower average degree of thickening (p = 0.048 and p <0.001, respectively). The average of scar thickness and lymphocyte, neutrophil and eosinophil concentrations are lower in the treated wounds compared to the control (p <0.001, p=0.022, p=0.007, p=0.044, respectively). The mean concentration of lymphocytes is lower in wounds treated with a higher concentration of the drug (p=0.01). STUDY LIMITATIONS: experiment lasted only 30 days. CONCLUSIONS: Tacrolimus at the 2 concentrations evaluated reduced the severity of inflammatory changes and positively altered the macroscopic aspect of the scar in the short term. Its use was shown to be safe, with no evidence of systemic or local adverse effects.

Effect of conversion from calcineurin inhibitors to everolimus on hepatitis C viremia in adult kidney transplant recipients / Efeitos da conversão de inibidores da calcineurina para Everolimo na viremia por hepatite C em receptores adultos de transplantes renais

ABSTRACT Introduction: Currently, there is no specific immunosuppressive protocol for hepatitis C (HCV)-positive renal transplants recipients. Thus, the aim of this study was to evaluate the conversion effect to everolimus (EVR) on HCV in adult kidney recipients. Method: This is an exploratory single-center, prospective, randomized, open label controlled trial with renal allograft recipients with HCV-positive serology. Participants were randomized for conversion to EVR or maintenance of calcineurin inhibitors. Results: Thirty patients were randomized and 28 were followed-up for 12 months (conversion group, Group 1 =15 and control group, Group 2 =13). RT-PCR HCV levels reported in log values were comparable in both groups and among patients in the same group. The statistical analysis showed no interaction effect between time and group (p value G*M= 0.852), overtime intra-groups (p-value M=0.889) and between group (p-value G=0.286). Group 1 showed a higher incidence of dyslipidemia (p=0.03) and proteinuria events (p=0.01), while no difference was observed in the incidence of anemia (p=0.17), new onset of post-transplant diabetes mellitus (p=1.00) or urinary tract infection (p=0.60). The mean eGFR was similar in both groups. Conclusion: Our study did not show viral load decrease after conversion to EVR with maintenance of antiproliferative therapy.

RESUMO Introdução: Atualmente não há um protocolo imunossupressor específico para os receptores de transplantes renais portadores de hepatite C (HCV). Assim, o objetivo deste estudo foi avaliar o efeito da conversão a Everolimo (EVR) na HCV em receptores adultos de transplantes renais. Método: Trata-se de um estudo unicêntrico, prospectivo, randomizado, exploratório, controlado, aberto em receptores de aloenxertos renais com sorologia positiva para HCV. Os participantes foram randomizados para conversão a EVR ou manutenção dos inibidores da calcineurina. Resultados: Trinta pacientes foram randomizados e 28 foram acompanhados por um período de 12 meses (grupo de conversão, Grupo 1 = 15 e grupo controle, Grupo 2 =13). Níveis de RT-PCR HCV descritos em valores logarítmicos foram comparáveis entre os grupos e entre pacientes em um mesmo grupo. A análise estatística não mostrou efeitos de interação entre tempo e grupo (valor p G*M= 0,852), ao longo do tempo em cada grupo (valor p M=0,889) e entre grupos (valor p G=0,286). O Grupo 1 apresentou uma maior incidência de eventos de dislipidemia (p=0,03) e proteinúria (p=0,01); não houve diferença na incidência de anemia (p=0,17), diabetes mellitus de início pós-transplante (p=1,00) ou infecção do trato urinário (p=0,60). A TFGe média foi semelhante nos dois grupos. Conclusão: Nosso estudo não mostrou redução da carga viral após conversão a EVR com manutenção do tratamento antiproliferativo.

Hipertensão arterial no tratamento do câncer / Hypertension in cancer treatment

A hipertensão arterial sistêmica (HAS) é uma condição clínica multifatorial caracterizada por elevação sustentada dos níveis pressóricos. No Brasil, a hipertensão arterial atinge 32,5% (36 milhões) de indivíduos adultos, mais de 60% idosos, contribuindo direta ou indiretamente para 50% das mortes por doença cardiovascular. A HAS é uma das comorbidades mais frequentemente observadas em pacientes com câncer. Algumas drogas são diretamente relacionadas ao desenvolvimento ou piora da HAS como os agentes alquilantes e os inibidores do fator de crescimento endotelial. O controle adequado dos níveis de pressão arterial (PA) em pacientes com câncer visa aumentar a tolerância dos doentes à quimioterapia, reduzir a incidência de lesões em órgãos-alvo e, em última análise, reduzir a mortalidade geral. A PA deve ser aferida semanalmente durante o primeiro ciclo e a cada duas a três semanas após. O diagnóstico e tratamento da HAS devem seguir as recomendações atuais da 7aDiretriz Brasileira de Hipertensão e, quando possível, realizados antes do tratamento oncológico. Os IECA e BRA são anti-hipertensivos usados com maior frequência para o tratamento da HAS associada aos inibidores de fator de crescimento endotelial (iVEGF). Os bloqueadores de canal de cálcio não diidropiridínicos, como o verapamil e o diltiazem, são contraindicados com o uso concomitante de iVEGF. A descontinuação definitiva deve ser o último recurso. Os oncologistas e cardiologistas devem desenvolver abordagens em conjunto para manejar a HAS de forma eficaz e segura, com objetivo de manter o benefício do tratamento oncológico e de diminuir a morbidade e mortalidade cardiovascular

Systemic arterial hypertension (SAH) is a multifactorial condition, characterized by a sustained elevation in blood pressure. In Brazil, arterial hypertension affects 32.5% (36 million) adult individuals, more of 60% of whom are elderly, directly or indirectly contributing to 50% of deaths due to cardiovascular disease. SAH is one of the most commonly observed comorbidities in people with cancer. Some drugs are directly related to the development or worsening of SAH, such as alkylating agents and endothelial growth factor inhibitors. Adequate control of blood pressure (BP) in patients with cancer aims to increase patients' tolerance to chemotherapy, reduce the incidence of target organ damage and, ultimately, reduce overall mortality. BP must be measured every week in the first cycle and every two-three weeks after. The diagnosis and treatment of SAH should follow the current recommendations of the VII Brazilian Guideline on Hypertension, and where possible, should be performed before the oncological treatment. ACE inhibitors and ARBs are the most commonly used antihypertensive drugs for the treatment of SAH associated with vascular endothelial growth factor inhibitors (VEGFI). Non-dihydropyridine calcium channel blockers, such as Verapamil and Diltiazem, are contraindicated with the concomitant use of VEGFI. Definitive suspension should be the final resort. Oncologists and cardiologists must develop joint approaches to manage the SAH effectively and safely, with the objective of maintaining the benefit of the oncological treatment and reducing cardiovascular morbidity and mortality

Hepatitis autoinmune refractaria: ¿cómo escoger el tratamiento de segunda línea o de rescate? / Refractory autoimmune hepatitis: how to choose second-line or rescue therapy?

Autoimmune hepatitis (AIH) is a liver disease of unknown etiology, with a breakdown in peripheral selftolerance against hepatocytes with both genetic and environmental factors involved. It is characterized by an immune mediated liver injury, with detectable autoantibodies, elevated levels of immunoglobulin G and histological criteria including, necroinflammation, lymphoplasmacytic infiltrates and hepatitis interface. It can be asymptomatic or can present as acute hepatitis or liver cirrhosis. Most patients (70-80%) respond to first line therapy (based on steroids ± azathioprine). In those patients not tolerating azatioprine, in steroid resistant, and those with repeated relapses (20-40%), a long-term second line therapy must be considered to avoid progression of liver disease. This last medications include other immunosuppressants like mycophenolate mophetil, calcineurin inhibitors (cyclosporine or tacrolimus), biologic agents (infliximab and rituximab), and other immunosuppressive agents (sirolimus, everolimus), all with good overall clinical results, but not exempt of side effects. Other difficult scenarios include fulminant AIH, end-stage AIH cirrhosis and the management of post-transplant AIH. In this article we will review the literature related to second- line therapy especially of steroid resistant AIH. Future directions in the treatment of HAI should be guided to the individual patient (personalized) and may include cell therapies, such as infusion of autologous, antigen-specific, and liver-homing regulatory T cells to restore hepatic immune tolerance

La hepatitis autoinmune (HAI) es una hepatopatía de etiología desconocida, con pérdida de la tolerancia inmune contra los hepatocitos con factores genéticos y ambientales asociados. Se caracteriza por fenómenos de daño inmunológicos, con autoanticuerpos circulantes, una concentración elevada de gammaglobulina sérica y en la biopsia de hígado actividad necroinflamatoria, infiltrados linfoplasmocitarios y daño de interfase. La HAI es una entidad que se puede presentar en forma asintomática, como hepatitis aguda o como cirrosis hepática. El 70-80% de los pacientes responden adecuadamente al tratamiento inmunosupresor de primera línea (corticoides ± azatioprina). En los pacientes que no toleran azatioprina, en los corticorresistentes o en aquellos con recaídas repetidas a pesar de terapia (20-40%), es necesario recurrir a terapias de segunda línea de largo plazo, para evitar la progresión de la hepatopatía. Estas últimas incluyen micofenolato mofetil, inhibidores calcineurínicos (ciclosporina o tacrolimus), agentes biológicos (infliximab y rituximab), y otros fármacos inmunosupresores (sirolimus, everolimus), con resultados alentadores, pero no exentos de efectos colaterales. Otros escenarios complejos incluyen: la HAI de presentación aguda grave y fulminante, la cirrosis terminal autoinmune y la HAI post-trasplante. En este trabajo se revisa la literatura en relación a terapias de segunda línea especialmente en HAI corticoide resistente. El futuro del tratamiento de la HAI va encaminado a una terapia personalizada y que podría incluir terapias celulares como la infusión de células T regulatorias, antígeno específicas y autólogas, para reestablecer los mecanismos de tolerancia inmune hepática.

Pénfigo familiar benigno (Enfermedad de Hailey-Hailey). A propósito de dos casos / Benign familial pemphigus (Hailey-Hailey disease). A report of two cases

El pénfigo familiar benigno (Enfermedad de Hailey-Hailey) es una rara genodermatosis localizada en pliegues, que cursa en brotes con ardor y prurito localizado predominantemente en verano. Presentamos dos pacientes con Enfermedad de Hailey-Hailey de diagnóstico tardío(AU)

Benign familial pemphigus (Hailey-Hailey disease) is a rare genodermatosis located in folds, which presents in outbreaks with burning and itching predominantly in summer. Two patients with Hailey-Hailey disease of late diagnosis are reported (AU)

Vitiligo - Part 2 - classification, histopathology and treatment

In an unprecedented effort in the field of vitiligo, a global consensus resulted on a suggested new classification protocol for the disease. The main histopathological finding in vitiligo is the total absence of functioning melanocytes in the lesions, while the inflammatory cells most commonly found on the edges of the lesions are CD4+ and CD8+ T lymphocytes. Physical and pharmacological treatment strategies aim to control the autoimmune damage and stimulate melanocyte migration from the unaffected edges of lesions and the outer hair follicle root sheath to the affected skin; moreover, surgical treatments can be combined with topical and physical treatments.