[Hansen's Disease: An Unusual Manifestation of an Ancient Disease]. / Doença de Hansen: Apresentação Incomum de uma Doença Antiga.

Hansen's disease, commonly known as leprosy, is an infectious disease caused by Mycobacterium leprae. Being rare in developed countries, it is an increasingly common imported disease due to the migratory flow from countries where it is endemic. We present the case of a 21-year-old man who went to the emergency department with complaints of additive polyarthralgia involving large joints, papules, and erythematous plaques on the limbs with bullae and central necrosis and fever with chills for one week. Skin biopsy was performed revealing neutrophilic infiltrate with perineural granulomas. The bacilloscopy detected acid-alcohol resistant bacilli. The diagnosis of multibacillary HD with type 2 lepromatous reaction (erythema nodosum leprosum - ENL) was established, showing clinical improvement under corticosteroid therapy. ENL usually presents with painful lesions, being an atypical presentation of leprosy, especially in the presence of bullae and necrosis, making diagnosis difficult and challenging. Social stigma is often present making it difficult to accept the disease as well as adherence to treatment.

A doença de Hansen, vulgarmente conhecida como lepra, é uma doença infecciosa causada por Mycobacterium leprae. Sendo rara nos países desenvolvidos, configura uma doença de importação cada vez mais frequente considerando o fluxo migratório de países onde é endémica. Apresentamos o caso de um homem de 21 anos que recorreu ao serviço de urgência por poliartralgias de caráter aditivo envolvendo grandes articulações, pápulas e placas eritematosas nos membros com bolhas e necrose central e febre com calafrio com uma semana de evolução. Foi realizada biópsia cutânea que revelou infiltrado neutrofílico com granulomas de distribuição perineural e baciloscopia com deteção de bacilos ácido-álcool resistentes. Foi estabelecido o diagnóstico de DH multibacilar com reação lepromatosa tipo 2 (eritema nodoso leproso), apresentando melhoria clínica sob corticoterapia. O eritema nodoso leproso cursa habitualmente com lesões dolorosas, configurando uma apresentação atípica de lepra, sobretudo na presença de bolhas e necrose, tornando este diagnóstico altamente desafiante. O estigma social é frequentemente limitativo na aceitação da doença e adesão ao tratamento.

MicroRNAs correlate with bacillary index and genes associated to cell death processes in leprosy.

Mycobacterium leprae infects skin and peripheral nerves causing a broad of clinical forms. MicroRNAs (miRNAs) control immune mechanisms such as apoptosis, autophagy as well as to target genes leading to abnormal proliferation, metastasis, and invasion of cells. Herein we evaluated miRNAs expression for leprosy phenotypes in biopsies obtained from patients with and without reactions. We also correlated those miRNAs with both, bacillary index (BI) and genes involved in the micobacteria elimination process. Our results show a significant increase in the miR-125a-3p expression in paucibacillary (PB) patients vs multibacillary (MB) subjects (p = 0.007) and vs reversal reactions (RR) (p = 0.005), respectively. Likewise, there was a higher expression of miR-125a-3p in patients with erythema nodosum leprosum (ENL) vs MB without reactions (p = 0.002). Furthermore, there was a positive correlation between miR-125a-3p, miR-146b-5p and miR-132-5p expression and BI in patients with RR and ENL. These miRNAS were also correlated with genes such as ATG12 (miR-125a-3p), TNFRSF10A (miR-146b-5p), PARK2, CFLAR and STX7 (miR-132-5p). All together we underpin a role for these miRNAs in leprosy pathogenesis, implicating mechanisms such as apoptosis and autophagy in skin. The miR-125a-3p might have a distinct role associated with PB phenotype and ENL in MB patients.

Necrotic erythema nodosum reaction associated with histological alterations of Lucio's phenomenon.

Patients with lepromatous or borderline leprosy may present two types of vasculonecrotic reactions: Lucio's phenomenon (LP) and necrotic erythema nodosum leprosum (nENL). These are serious conditions, which mostly lead to life-threatening infectious and thrombotic complications. The authors report the case of a patient with leprosy recurrence associated with an atypical type II reaction with LP characteristics on histopathology.

Case Report: Rapid Response to Low-Dose Thalidomide in a Case of Severe Steroid Recalcitrant Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, presents with crops of evanescent, tender erythematous nodules accompanied by fever, arthralgia, malaise and organ-specific manifestations and is seen in borderline and lepromatous leprosy. The drugs approved for ENL include nonsteroidal anti-inflammatory drugs, systemic steroids, thalidomide and clofazimine. The management of ENL is challenging because long-term steroid use leads to steroid dependence. The present patient had severe steroid recalcitrant ENL with vesicular and pustular lesions mimicking Sweet's syndrome and was treated effectively with a low-dose thalidomide regimen (100 mg/d) as opposed to high dose (400 mg/d) recommended in literature. We discuss the patho-mechanics and clinical utility of a low-dose thalidomide regimen as an effective treatment option for ENL.

Lepra lepromatosa nodular de diagnóstico tardío procedente de la Amazonía peruana, con el desarrollo de una reacción tipo 2 / Late diagnosis nodular lepromatous leprosy from the Peruvian Amazon, with development of a type 2 reaction

Resumen La lepra o enfermedad de Hansen es una de las clásicas enfermedades olvidadas que aún persiste en Perú. La infección es ocasionada por Mycobacterium leprae. La enfermedad varía en un amplio rango de manifestaciones desde la lepra tuberculoide (paucibacilar) hasta la lepromatosa (multibacilar). Se presenta el caso de un varón de 55 años, agricultor y extractor de madera, procedente de la Amazonia peruana, con lesiones cutáneas antiguas infiltrantes en la cara, cuello, tórax, abdomen y extremidades. La baciloscopia y estudio histológico de una biopsia de piel confirmaron la presencia de bacilos ácido-alcohol resistentes. Se concluyó, en forma tardía, que fue un caso de lepra lepromatosa nodular. Recibió terapia con rifampicina, dapsona y clofamizina por dos años con una lenta mejoría; no obstante, cursó con un eritema nodoso leproso (reacción tipo 2) con buena respuesta a corticoesteroides y talidomida.

Abstract Leprosy or Hansen's disease is one of the classic neglected diseases that still persists in Peru. The infection is caused by Mycobacterium leprae. The disease varies in a wide range of manifestations from tuberculoid (paucibacillary) to lepromatous (multibacillary) leprosy. We present the case of a 55-year-old man, farmer and wood extractor, from the Peruvian Amazon with old infiltrating cutaneous lesions on the face, neck, thorax, abdomen and extremities. The smear and biopsy examinations confirm the presence of acid-alcohol-resistant bacilli compatible with leprosy. It is concluded, with a long delay, it was a case of nodular lepromatous leprosy. He received therapy with rifampicin, dapsone and clofamizine for two years with slow progressive improvement; however, he presented an erythema nodosum leprosum (type 2 reaction) with response to corticosteroids and thalidomide.

[Late diagnosis nodular lepromatous leprosy from the Peruvian Amazon, with development of a type 2 reaction]. / Lepra lepromatosa nodular de diagnóstico tardío procedente de la Amazonía peruana, con el desarrollo de una reacción tipo 2.

Leprosy or Hansen's disease is one of the classic neglected diseases that still persists in Peru. The infection is caused by Mycobacterium leprae. The disease varies in a wide range of manifestations from tuberculoid (paucibacillary) to lepromatous (multibacillary) leprosy. We present the case of a 55-year-old man, farmer and wood extractor, from the Peruvian Amazon with old infiltrating cutaneous lesions on the face, neck, thorax, abdomen and extremities. The smear and biopsy examinations confirm the presence of acid-alcohol-resistant bacilli compatible with leprosy. It is concluded, with a long delay, it was a case of nodular lepromatous leprosy. He received therapy with rifampicin, dapsone and clofamizine for two years with slow progressive improvement; however, he presented an erythema nodosum leprosum (type 2 reaction) with response to corticosteroids and thalidomide.

Image Morphometric Analysis of B Cells and Plasma Cells in Erythema Nodosum Leprosum With Clinicopathological Correlation.

ABSTRACT: Erythema nodosum leprosum (ENL) occurs as an immunological complication of multibacillary leprosy (MBL). The pathogenesis of ENL is long considered to be a T-cell-mediated process. The role of B cells and plasma cells in ENL is not well described in the literature. Therefore, we investigated the B-cell and plasma cell infiltrates in the skin biopsies of biopsy-proven cases of ENL by immunohistochemistry and image morphometry and compared the result with paucibacillary leprosy and MBL. Moreover, we sought a correlation of the B-cell and plasma cell infiltrates with different clinical, hematological, histopathological, and bacteriological parameters as well as the T-cell subsets in the skin biopsies. Our study highlighted a significant reduction in the number of B cells from paucibacillary leprosy to MBL to ENL, although there was no significant variation in the plasma cell infiltrate. The plasma cell infiltrate correlated with absolute neutrophilia in the blood and the presence of eosinophils in the ENL lesions. Both B cells and plasma cells positively correlated with CD4-positive T-helper cells and the CD8-positive cytotoxic T cells. Besides, the B cells also correlated positively with the CD3-positive pan T cells in the biopsy and negatively correlated with the T-regulatory:T-cell ratio. Our results suggested the role of B cells and plasma cells even at the tissue level in the pathobiogenesis of ENL.

Lepromatous leprosy presenting with type II reaction before and type I reaction after treatment.

Lepromatous leprosy is associated with a high bacillary load and poor cellular immune response. Early dermatologic manifestations include erythematous macules, papules, nodules, and plaques with a symmetrical distribution. Leprosy also shows two major reaction states including type I (reversal reaction) and type II (vasculitis). These reactions are usually seen in some patients who are undergoing treatment. Herein, we report an interesting patient with lepromatous leprosy who presented with skin lesions of type II reaction without receiving any anti-leprosy treatment and surprisingly showed a type I reaction eight months after the beginning of the treatment.

Late leprosy reaction presenting as erythema multiforme-like erythema nodosum leprosum with underlying rifampicin resistance and its potential implications.

Erythema multiforme (EM)-like erythema nodosum leprosum (ENL) is a rare atypical presentation, and its late appearance after the completion of multidrug therapy (MDT) is unusual. We describe the case of a lepromatous leprosy patient who after the completion of MDT presented to us with late EM-like ENL and was found to be resistant to rifampicin. We discuss the implications of this finding and the potential role of resistant bacilli in causing reactions with atypical presentations.

Persistent Infection Versus Type 2 Immunological Reaction in Lepromatous Leprosy.

The distinction between persistent infection and immunologic reactions in leprosy is often difficult but critically important since their management is different. We present the case of a 51-year-old Vietnamese female who presented in 2015 with areas of erythema and skin infiltration on face and chest, as well as edema on her hands and feet. Skin biopsy was consistent with lepromatous leprosy. She was treated with rifampin, clarithromycin, and levofloxacin for 2 years. Her lower extremity edema was attributed to type 2 immunological reaction for which she was started on prednisone and methotrexate, but she was lost to follow-up for 19 months. She presented with new skin lesions and pain on her extremities. New biopsies revealed an intense neutrophilic infiltrate in the dermis and acid-fast bacilli focally within cutaneous nerve twigs. As compared with the initial biopsy, the inflammatory infiltrates were diminished and the bacilli had a degenerating appearance. These findings were consistent with type 2 immunological reaction. The patient was treated with thalidomide with improvement in the appearance of the skin lesions. A follow-up biopsy showed lack of neutrophilic infiltrates and decreased number of bacilli. This case illustrates the importance of differentiating between persistent infection and immunologic reactions in leprosy. Clinicians should be aware of these complications. A high index of suspicion and accurate interpretation of skin biopsy results are essential for appropriate diagnosis.

Epidemiological profile and severity of erythema nodosum leprosum in Brazil: a cross-sectional study.

BACKGROUND: Leprosy can cause acute reactions, which may be type 1 (reverse reaction) or type 2 (erythema nodosum leprosum - ENL). ENL has been classified as mild, moderate, or severe. In order to standardize the classification, the Erythema Nodosum Leprosum International Study (ENLIST) Group has developed an objective scale, the ENLIST ENL Severity Scale (EESS), which was the first validated severity scale of ENL in the world. The goal of the study was to describe the sociodemographic and clinical characteristics of patients with ENL attending a tertiary hospital in Piauí, Brazil, classifying them according to the EESS. METHODS: A descriptive cross-sectional observational study was conducted on 26 patients recruited sequentially from May 2017 to February 2018. Their data were statistically analyzed and compared against each other through a structured questionnaire. RESULTS: According to the score obtained in the scale, the patients were divided into two groups: mild ENL and moderate/severe ENL. The extent and number of nodules were related to the severity of the cases, and these data were statistically significant. The majority of the patients were male, between the ages of 31 and 49 years old, with low educational level, and residents in the urban area. CONCLUSIONS: This was the first study to use EESS in Brazil. This scale is easy to apply and allows for the enhancement of treatment protocols. The study also showed a correlation between the number and extension of nodules and the severity of the condition.

NR3C1, ABCB1, TNF and CYP2C19 polymorphisms association with the response to the treatment of erythema nodosum leprosum.

Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.

A retrospective study of the severe and uncommon variants of erythema nodosum leprosum at a tertiary health center in central India.

BACKGROUND: Erythema nodosum leprosum (ENL) classically presents with tender, coppery, evanescent nodules along with constitutional features and visceral involvement. However, uncommon morphological variants of ENL-like erythema nodosum necroticans, erythema multiforme (EM)-like ENL, Sweet's syndrome (SS)-like ENL, Lucio phenomenon, and reactive perforating type of ENL have also been described in the literature. The primary objective of this study was to describe the clinical features of the severe and uncommon morphological variants of ENL. METHODS: This was an observational case series with retrospective review of records of all ENL patients with ulceronecrotic lesions admitted in the Department of Dermato-venereo-leprology of a tertiary health center of central India over a period of 2 years. RESULTS: Eighteen patients were included, all of whom had ulceronecrotic lesions. Four out of them had EM like ENL, two had SS-like presentation, and one of them had annular bullous lesions over old infiltrated plaques of leprosy. CONCLUSIONS: Uncommon variants of ENL can be very commonly misdiagnosed in patients, especially in those who have not been previously diagnosed with leprosy. Hence, a high index of suspicion is required in such cases to avoid delay in the diagnosis and resulting morbidity.

Does histoid leprosy represent a locally hyperimmune variant of lepromatous leprosy?

BACKGROUND: Histoid leprosy is a subtype of leprosy with distinct clinical presentation and histologic features. It accounts for <4% of leprosy cases. The exact location of histoid leprosy along the immune spectrum and its relation to other subtypes is unclear. AIM: To evaluate the local immune phenomenon which define histoid leprosy. DESIGN: Parallel skin biopsies from histoid lesions and from unremarkable skin in patients with histoid leprosy were evaluated and the histologic findings compared. METHODS: Formalin fixed, paraffin embedded tissue sections from lesional and non-lesional biopsies were assessed for changes in epidermis and dermis; type and extent of infiltrate, presence or absence of pseudocapsule and associated reactions. Bacillary index was evaluated using Wade Fite stain for lepra bacilli. RESULTS: Amongst 208 leprosy cases, six cases of histoid leprosy were identified (2.88%). The cases showed presence of nodules, patches and plaques overlying clinically unremarkable skin. Fourteen skin biopsies were evaluated of which the lesional biopsies showed equal proportion of fusocellular, fusocellular epithelioid and fusocellular-vacuolated histology. A greater circumscription was noted in lesional biopsies; however the cellular content of the infiltrate was similar in lesional and non-lesional biopsies. A case of erythema nodosum leprosum in histoid leprosy was also seen. CONCLUSIONS: Ours is the first study comparing normal and lesional skin in histoid leprosy. Though the histoid lesions appear to have a derivation from lepromatous leprosy, the local histologic and clinical alterations may be a result of heightened local immunity or reactive local modifying factors.

Involvement of TNF-Producing CD8+ Effector Memory T Cells with Immunopathogenesis of Erythema Nodosum Leprosum in Leprosy Patients.

Type 2 reaction (T2R) or erythema nodosum leprosum (ENL), a sudden episode of acute inflammation predominantly affecting lepromatous leprosy patients (LL), characterized by a reduced cellular immune response. This possibly indicates a close relationship between the onset of T2R and the altered frequency, and functional activity of T lymphocytes, particularly of memory subsets. This study performed ex vivo and in vitro characterizations of T cell blood subpopulations from LL patients with or without T2R. In addition, the evaluation of activity of these subpopulations was performed by analyzing the frequency of these cells producing IFN-γ, TNF, and IL-10 by flow cytometry. Furthermore, the expression of transcription factors, for the differentiation of T cells, were analyzed by quantitative real-time polymerase chain reaction. Our results showed an increased frequency of CD8+/TNF+ effector memory T cells (TEM) among T2Rs. Moreover, there was evidence of a reduced frequency of CD4 and CD8+ IFN-γ-producing cells in T2R, and a reduced expression of STAT4 and TBX21. Finally, a significant and positive correlation between bacteriological index (BI) of T2R patients and CD4+/TNF+ and CD4+/IFN-γ+ T cells was observed. Thus, negative correlation between BI and the frequency of CD4+/IL-10+ T cells was noted. These results suggest that CD8+/TNF+ TEM are primarily responsible for the transient alteration in the immune response to Mycobacterium leprae in ENL patients. Thus, our study improves our understanding of pathogenic mechanisms and might suggest new therapeutic approaches for leprosy.

Erythema nodosum leprosum presenting as sweet's syndrome-like reaction in a borderline lepromatous leprosy patient.

Erythema nodosum leprosum (ENL) is characterized by tender erythematous nodules, accompanied by fever, malaise, arthralgia, and systemic complications. Atypical clinical manifestations have been reported such as pustular, bullous, ulceration; livedo reticularis; erythema multiforme-like reaction; and Sweet's syndrome (SS)-like presentation. We reported a case of ENL reaction presenting as SS-like reaction in a borderline lepromatous leprosy patient.

Reactive perforating leprosy, erythema multiforme-like reactions, sweet's syndrome-like reactions as atypical clinical manifestations of Type 2 leprosy reaction.

Type 2 leprosy reactions commonly known as erythema nodosum leprosum, but various clinical manifestations of type 2 leprosy reaction were exist. The highlight of this case series was to report various atypical clinical manifestations of type 2 leprosy reaction such as reactive perforating leprosy, erythema multiforme-like reaction, and sweet's syndrome (SS)-like reaction.