Infections in the era of immunobiologicals.

Immunobiologicals represent an innovative therapeutic option in dermatology. They are indicated in severe and refractory cases of different diseases when there is contraindication, intolerance, or failure of conventional systemic therapy and in cases with significant impairment of patient quality of life. The main immunobiologicals used in dermatology basically include inhibitors of tumor necrosis factor-alpha (anti-TNF), inhibitors of interleukin-12 and -23 (anti-IL12/23), inhibitors of interleukin-17 and its receptor (anti-IL17), inhibitors of interleukin-23 (anti-IL23), rituximab (anti-CD20 antibody), dupilumab (anti-IL4/IL13) and intravenous immunoglobulin. Their immunomodulatory action may be associated with an increase in the risk of infections in the short and long term, and each case must be assessed individually, according to the risk inherent to the drug, the patient general condition, and the need for precautions. This article will discuss the main risks of infection associated with the use of immunobiologicals, addressing the risk in immunocompetent and immunosuppressed patients, vaccination, fungal infections, tuberculosis, leprosy, and viral hepatitis, and how to manage the patient in the most diverse scenarios.

Consensus on the therapeutic management of atopic dermatitis ‒ Brazilian Society of Dermatology: an update on phototherapy and systemic therapy using e-Delphi technique.

This publication is an update of the "Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology" published in 2019, considering the novel, targeted-oriented systemic therapies for atopic dermatitis. The initial recommendations of the current consensus for systemic treatment of patients with atopic dermatitis were based on a recent review of scientific published data and a consensus was reached after voting. The Brazilian Society of Dermatology invited 31 experts from all regions of Brazil and 2 international experts on atopic dermatitis who fully contributed to the process. The methods included an e-Delphi study to avoid bias, a literature search and a final consensus meeting. The authors added novel approved drugs in Brazil and the indication for phototherapy and systemic therapy for AD. The therapeutical response to systemic treatment is hereby reported in a suitable form for clinical practice and is also part of this updated manuscript.

Consensus on the therapeutic management of atopic dermatitis ‒ Brazilian Society of Dermatology: an update on phototherapy and systemic therapy using e-Delphi technique

Abstract This publication is an update of the "Consensus on the therapeutic management of atopic dermatitis - Brazilian Society of Dermatology" published in 2019, considering the novel, targeted-oriented systemic therapies for atopic dermatitis. The initial recommendations of the current consensus for systemic treatment of patients with atopic dermatitis were based on a recent review of scientific published data and a consensus was reached after voting. The Brazilian Society of Dermatology invited 31 experts from all regions of Brazil and 2 international experts on atopic dermatitis who fully contributed to the process. The methods included an e-Delphi study to avoid bias, a literature search and a final consensus meeting. The authors added novel approved drugs in Brazil and the indication for phototherapy and systemic therapy for AD. The therapeutical response to systemic treatment is hereby reported in a suitable form for clinical practice and is also part of this updated manuscript.

Lucius phenomenon: the importance of a primary dermatological care

Abstract Leprosy presents a varied clinical spectrum. Lucius phenomenon is a rare leprosy reaction characterized by erythematous, painful, slightly infiltrated macules and hemorrhagic bullae that progress to ulceration. This case report describes a patient whose diagnosis of leprosy occurred in the presence of Lucius phenomenon. Late diagnosis and delay in the implementation of specific therapy contributed to an unfavorable outcome, highlighting the importance of early identification and treatment of this disease, as well as its complications.

Lucius phenomenon: the importance of a primary dermatological care.

Leprosy presents a varied clinical spectrum. Lucius phenomenon is a rare leprosy reaction characterized by erythematous, painful, slightly infiltrated macules and hemorrhagic bullae that progress to ulceration. This case report describes a patient whose diagnosis of leprosy occurred in the presence of Lucius phenomenon. Late diagnosis and delay in the implementation of specific therapy contributed to an unfavorable outcome, highlighting the importance of early identification and treatment of this disease, as well as its complications.

Comparable efficacy of adapalene 0.3% gel and tretinoin 0.05% cream as treatment for cutaneous photoaging.

BACKGROUND: Adapalene has been previously evaluated as a treatment for actinic keratosis (AK) and solar lentigines and shown to improve signs of photoaging. OBJECTIVES: To evaluate whether adapalene 0.3% gel is non-inferior to tretinoin 0.05% cream as treatment for photoaged skin. MATERIALS & METHODS: An investigator-blinded, parallel-group comparison study was conducted in Brazil. Subjects were randomised in a 1:1 ratio to receive, once daily, adapalene 0.3% gel or tretinoin 0.05% cream. Subjects were evaluated at Weeks 1, 4, 8, 12, 16, 20 and 24, based on clinical signs of cutaneous photoaging, histopathological and digital morphometric findings, as well as safety and tolerability. RESULTS: A comparison of clinical efficacy showed that both treatments did not differ significantly regarding clinical evaluation of the following criteria: global cutaneous photoaging, periorbital wrinkles, ephelides/melanosis, forehead wrinkles, and AK. CONCLUSION: Adapalene 0.3% gel showed non-inferior efficacy to tretinoin 0.05% cream as treatment for photoaged skin, with a similar safety profile. Adapalene 0.3% gel may therefore be considered a safe and effective option for the treatment of mild or moderate photoaging.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach.

BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). PATIENTS AND METHODS: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

Abstract: BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Genotyping comparison of Mycobacterium leprae isolates by VNTR analysis from nasal samples in a Brazilian endemic region.

This study analyzed the genetic diversity by MIRU-VNTR of Mycobacterium leprae isolates from nasal cavities and related to epidemiological and clinical data. The sample consisted of 48 newly diagnosed leprosy cases that tested positive for M. leprae PCR in nasal secretion (NS) attending to the National Reference Center of Dermatology Dona Libania (CDERM), Fortaleza, Brazil. Total DNA was extracted from NS of each patient and used for amplification of four M. leprae VNTR loci. Four clusters of M. leprae isolates were formed with identical genotypes. In the spatial analysis, 12 leprosy cases presented similar genotypes organized into 4 clusters. The most common genotypes in the current study was AC8b: 8, AC9: 7, AC8a: 8, GTA9: 10, which may represent a genotype of circulating strains most often in Ceará. A minimum set of four MIRU-VNTR loci was demonstrated to study the genetic diversity of M. leprae isolates from NS.

Evaluation of 16S rRNA qPCR for detection of Mycobacterium leprae DNA in nasal secretion and skin biopsy samples from multibacillary and paucibacillary leprosy cases.

Mycobacterium leprae bacilli are mainly transmitted by the dissemination of nasal aerosols from multibacillary (MB) patients to susceptible individuals through inhalation. The upper respiratory tract represents the main entry and exit routes of M. leprae. Therefore, this study aimed to evaluate the sensitivity and specificity of real-time quantitative polymerase chain reaction (qPCR) in detecting M. leprae in nasal secretion (NS) and skin biopsy (SB) samples from MB and paucibacillary (PB) cases. Fifty-four NS samples were obtained from leprosy patients at the Dona Libânia National Reference Centre for Sanitary Dermatology in Ceará, Brazil. Among them, 19 MB cases provided both NS and SB samples. Bacilloscopy index assays were conducted and qPCR amplification was performed using specific primers for M. leprae 16S rRNA gene, generating a 124-bp fragment. Primer specificity was verified by determining the amplicon melting temperature (Tm = 79.5 °C) and detection limit of qPCR was 20 fg of M. leprae DNA. Results were positive for 89.7 and 73.3% of NS samples from MB and PB cases, respectively. SB samples from MB patients were 100% positive. The number of bacilli detected in NS samples were 1.39 × 103-8.02 × 105, and in SB samples from MB patients were 1.87 × 103-1.50 × 106. Therefore, qPCR assays using SYBR Green targeting M. leprae 16S rRNA region can be employed in detecting M. leprae in nasal swabs from leprosy patients, validating this method for epidemiological studies aiming to identify healthy carriers among household contacts or within populations of an endemic area.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients.

BACKGROUND: Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. METHODOLOGY AND FINDINGS: An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. CONCLUSION: Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00669643.

Daylight photodynamic therapy - Experience and safety in treatment of actinic keratoses of the face and scalp in low latitude and high brightness region.

Daylight photodynamic therapy has been used in countries with high latitudes during the summer for actinic keratoses treatment with reports of similar efficacy to conventional photodynamic therapy. We evaluate its safety in 20 patients in the city of Fortaleza, a local with low latitude and high brightness. Sixteen patients did not report any discomfort due to the procedure. Daylight photodynamic therapy is an easy application method with great tolerability by the patient and has the possibility of being performed throughout the year in these regions. It can mean a promising tool in the control of skin cancer.

Leprosy reactions: The predictive value of Mycobacterium leprae-specific serology evaluated in a Brazilian cohort of leprosy patients (U-MDT/CT-BR).

BACKGROUND: Leprosy reactions, reversal reactions/RR and erythema nodosum leprosum/ENL, can cause irreversible nerve damage, handicaps and deformities. The study of Mycobacterium leprae-specific serologic responses at diagnosis in the cohort of patients enrolled at the Clinical Trial for Uniform Multidrug Therapy Regimen for Leprosy Patients in Brazil/U-MDT/CT-BR is suitable to evaluate its prognostic value for the development of reactions. METHODOLOGY: IgM and IgG antibody responses to PGL-I, LID-1, ND-O-LID were evaluated by ELISA in 452 reaction-free leprosy patients at diagnosis, enrolled and monitored for the development of leprosy reactions during a total person-time of 780,930 person-days, i.e. 2139.5 person-years, with a maximum of 6.66 years follow-up time. PRINCIPAL FINDINGS: Among these patients, 36% (160/452) developed reactions during follow-up: 26% (119/452) RR and 10% (41/452) had ENL. At baseline higher anti-PGL-I, anti-LID-1 and anti-ND-O-LID seropositivity rates were seen in patients who developed ENL and RR compared to reaction-free patients (p<0.0001). Seroreactivity in reactional and reaction-free patients was stratified by bacilloscopic index/BI categories. Among BI negative patients, higher anti-PGL-I levels were seen in RR compared to reaction-free patients (p = 0.014). In patients with 0

Daylight photodynamic therapy - Experience and safety in treatment of actinic keratoses of the face and scalp in low latitude and high brightness region

ABSTRACT Daylight photodynamic therapy has been used in countries with high latitudes during the summer for actinic keratoses treatment with reports of similar efficacy to conventional photodynamic therapy. We evaluate its safety in 20 patients in the city of Fortaleza, a local with low latitude and high brightness. Sixteen patients did not report any discomfort due to the procedure. Daylight photodynamic therapy is an easy application method with great tolerability by the patient and has the possibility of being performed throughout the year in these regions. It can mean a promising tool in the control of skin cancer.

Carcinoma basocelular desenvolvido sobre nevo sebáceo: tratamento com terapia fotodinâmica abordando campo de cancerização / Basal cell carcinoma growth over a nevus sebaceous: treatment of the field cancerization with photodynamic therapy

Nevo sebáceo de Jadassohn é hamartoma congênito que pode apresentar evolução para neoplasia cutânea maligna. A terapia fotodinâmica é utilizada para tratamento de ceratoses actínicas e carcinomas basocelulares superficiais ou nodulares, podendo-se observar o campo de cancerização cutâneo através da lâmpada de Wood, durante a realização da técnica. Relata-se um caso do uso da terapia fotodinâmica para o tratamento de um carcinoma basocelular, que se desenvolveu sobre nevo sebáceo, demonstrando-se o campo cancerizável através do uso da lâmpada de Wood. O procedimento consistiu em alternativa de tratamento não cirúrgico para o carcinoma basocelular, com excelente resultado estético. A paciente encontra-se em seguimento clínico, não apresentando recidiva da neoplasia 18 meses após o tratamento.

The sebaceous nevus of Jadassohn is a congenital hamartoma that may develop into a malignant cutaneous neoplasia. Photodynamic therapy is used to treat actinic keratoses and superficial or nodular basal cell carcinomas, and the cutaneous field cancerization can be observed using the Wood's lamp during the performance of the technique. This article describes a case of photodynamic therapy used in the treatment of a basal cell carcinoma, which developed on a sebaceous nevus, where the field cancerization was demonstrated through the use of Wood's lamp. The procedure is a non-surgical alternative for the treatment of the basal cell carcinoma, with excellent aesthetic outcome. The patient is on clinical follow-up, with absence of recurrence of the neoplasia 18 months after the treatment.

Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): results of an open label, randomized and controlled clinical trial, among multibacillary patients

BACKGROUND: Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. METHODOLOGY AND FINDINGS: An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. CONCLUSION: Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide.

Can baseline ML Flow test results predict leprosy reactions? An investigation in a cohort of patients enrolled in the uniform multidrug therapy clinical trial for leprosy patients in Brazil.

BACKGROUND: The predictive value of the serology to detection of IgM against the Mycobacterium leprae-derived phenolic glycolipid-I/PGL-I to identify leprosy patients who are at higher risk of developing reactions remains controversial. Whether baseline results of the ML Flow test can predict leprosy reactions was investigated among a cohort of patients enrolled in The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR). METHODS: This was a descriptive study focusing on the main clinical manifestations of leprosy patients enrolled in the U-MDT/CT-BR from March 2007 to February 2012 at two Brazilian leprosy reference centers. For research purposes, 753 leprosy patients were categorized according to a modified Ridley-Jopling (R&J) classification and according to the development of leprosy reactions (reversal reaction/RR and erythema nodosum leprosum/ENL), and whether they had a positive or negative bacillary index/BI. RESULTS: More than half of the patients (55.5 %) reported leprosy reaction: 18.3 % (138/753) had a RR and 5.4 % (41/753) had ENL. Leprosy reactions were more frequent in the first year following diagnosis, as seen in 27 % (205/753) of patients, while 19 % (142/753) developed reactions during subsequent follow-up. Similar frequencies of leprosy reactions and other clinical manifestations were observed in paucibacillary (PB) and multibacillary (MB) leprosy patients treated with U-MDT and regular MDT (R-MDT) (P = 0.43 and P = 0.61, respectively). Compared with PB patients, leprosy reactions were significantly more frequent in MB patients with a high BI, and more patients developed RR than ENL. However, RR and neuritis were also reported in patients with a negative BI. At baseline, the highest rate of ML Flow positivity was observed in patients with a positive BI, especially those who developed ENL, followed by patients who had neuritis and RR. Among reaction-free patients, 81.9 % were ML Flow positive, however, the differences were not statistically significant compared to reactional patients (P = 0.45). CONCLUSIONS: MB and PB patients treated with R-MDT and U-MDT showed similar frequencies of RR and other clinical manifestations. Positive ML Flow tests were associated with MB leprosy and BI positivity. However, ML Flow test results at baseline showed limited sensitivity and specificity for predicting the development of leprosy reactions.

Terapia fotodinâmica com luz do dia: farmacoeconomia no uso do creme de metilaminolevulinato para ceratoses actínicas faciais / Daylight photodynamic therapy: pharmacoeconomics of methyl aminolevulinate cream use for facial actinic keratoses

Introdução: As ceratoses actínicas são as lesões pré-malignas de pele mais comuns, apresentando caráter crônico e recorrente. A terapia fotodinâmica com luz do dia tem sido utilizada no tratamento de ceratoses actínicas de face e couro cabeludo. Objetivo: Demonstrar a possibilidade da realização da terapia fotodinâmica com luz do dia em serviço público para o tratamento de ceratoses actínicas em face, utilizando um tubo de creme de metilaminolevulinato em até quatro pacientes. Métodos: Foram selecionados 10 pacientes para a realização de terapia fotodinâmica com luz do dia, realizando-se curetagem das ceratoses actínicas seguidas da aplicação de filtro químico e creme de metilaminolevulinato em toda a face. Resultados: um tubo de creme de metilaminolevulinato, foi suficiente para tratar até quatro pacientes com múltiplas ceratoses actínicas de face, enquanto os estudos sugerem o uso de pelo menos 1g para tratar uma face completa. Conclusões: O resultado nos leva a afirmar que na terapia fotodinâmica com luz do dia, a utilização de quantidade inferior a 1 grama de creme de metilaminolevulinato no tratamento de ceratoses actínicas de face é posologia factível para obtenção de efetiva resposta clínica.

Introduction: Actinic keratoses are the most common premalignant skin lesions, with a chronic and recurrent nature. Daylight photodynamic therapy has been used in the treatment of actinic keratoses of the face and scalp. Objective: To demonstrate the possibility of implementing daylight photodynamic therapy at a public service, for the treatment of facial actinic keratosis, using one tube of methyl aminolevulinate cream for up to four patients. Methods: Ten patients were selected to undergo daylight photodynamic therapy at the Centro de Dermatologia Dona Libânia, located in the city of Fortaleza (CE), Brazil. Curettage was performed on the actinic keratosis and a methyl aminolevulinate cream based chemical filter was applied across the face. Results: One tube of methyl aminolevulinate cream was enough for treating up to four patients with multiple facial actinic keratoses, whereas studies suggest the use of at least one gram to treat one face completely. Conclusion: It was possible to conclude when administering daylight photodynamic therapy, an amount of less than one gram of methyl aminolevulinate cream in the treatment of facial actinic keratoses is a dosage sufficient to obtain an effective clinical response.