Analysis of interleukin 7 and platelet-derived growth factor-BB mRNA expression as potential markers in erythema nodosum leprosum.

Erythema nodosum leprosum (ENL) is an immunological complication of leprosy characterized by acute inflammation of the skin, nerves, and other organs. Identifying laboratory parameters is important for early diagnosis of leprosy reactions. Various cytokine biomarkers have been examined and only a few studies have reported on angiogenesis in leprosy. This study aims to understand the pathomechanism of ENL by examining IL-7 and platelet-derived growth factor (PDGF)-BB mRNA expression that can be the development and consideration of new effective therapies to prevent reactions, recurrences, and defects in leprosy. The study used a cross-sectional analytic design. Sampling was done by peripheral blood from the patient and measuring mRNA expression with specific primers RT-PCR. The expression of mRNA IL-7 and PDGF-BB was significantly different between multibasilar patients without reaction and with ENL reaction, where there was an increased expression in ENL patients. This could be used as the development of potential biomarkers in ENL and development of new therapeutic intervention pathways in ENL.

Reverse Koebner phenomenon in erythema nodosum leprosum.

BACKGROUND: Erythema nodosum leprosum (ENL) is an immunologically mediated phenomenon complicating the course of leprosy. Reverse Koebner phenomenon is the term used to describe the sparing of previously injured or diseased skin by new skin lesions of the disease. METHODS: A middle-aged woman with a known case of lepromatous leprosy for the past year presented with an eruption of reddish painful nodules over her body. The lesions were found to characteristically spare the sites of previous scars. RESULTS: This sparing phenomenon of previous scar sites has been termed reverse Koebner phenomenon, a site of the body that offers greater resistance than the rest of the body to the onset of the disease, seen in various diseases, but it has never been described in ENL. CONCLUSION: This sparing of scar sites in ENL can be attributed to reverse Koebner phenomenon.

Chronic type 2 reaction in lepromatous leprosy with underlying Plasmodium falciparum infection: A case report.

Tropical diseases prevalent in leprosy-endemic areas may alter the immunological patient response and also complicate the presentation of leprosy reactional episodes. The introduction of anti-malarial drugs in our case produced a subsidence of reaction. With dwindling manpower skilled in leprosy, the reactional episodes are very often treated with non-steroidal anti-inflammatory drugs, steroids and thalidomide, neglecting the possibility of other co-existing infections, tropical or other. Our case emphasises the importance of history, examination and balanced investigation in the context of tropical diseases in endemic areas before injudicious intervention.

Whole blood transcriptomics reveals the enrichment of neutrophil activation pathways during erythema nodosum leprosum reaction

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.

Case report: Cyclophosphamide pulse therapy for chronic recalcitrant erythema nodosum leprosum.

Chronic recalcitrant erythema nodosum leprosum (ENL) or type 2 reaction (T2R) is a severe condition found in approximately 50% of multibacillary leprosy subjects. T2R is associated with important morbidities and may lead to several disabilities, not only due to nerve damage but also due to the prolonged use of corticosteroids, thalidomide, or immunosuppressors. We describe here four leprosy patients with chronic recalcitrant ENL treated with cyclophosphamide pulse therapy. All subjects had been on prednisone and thalidomide therapy for at least 30 months but showed inflammatory activity when doses were reduced. Pulse therapy with 1.0 g of cyclophosphamide was used every 4-6 weeks for a minimum of three applications. After pulse therapy, all cases presented total or partial regression of symptoms, and we were able to taper thalidomide and prednisone doses, with better control of ENL, avoiding further hospital admissions and disabilities. No side effects were observed during or after infusion therapy. Cyclophosphamide pulse therapy may be useful and safe to control chronic recalcitrant ENL.

Leprosy Reactions: Experience in the Puerto Rico Hansen's Disease Population.

OBJECTIVE: Hansen's disease (HD) is a chronic granulomatous infection endemic in the tropics. Its main clinical manifestations involve the cutaneous, nervous, and musculoskeletal systems. Leprosy reactions (LR) are systemic inflammatory and immune-mediated complications of HD. These include reversal reactions (RR), erythema nodosum leprosum (ENL), and Lucio phenomenon. These reactions significantly increase disease-related morbidity and disability. We aimed to determine the number and type of LR, their association to hosts' immune responses (Ridley Jopling classification), timing of development, and treatment of HD patients in Puerto Rico. METHODS: A retrospective medical record review was performed on 291 HD patients containing LR status data available from the Dermatology Service at the Hispanic Alliance for Clinical & Translational Research. RESULTS: Our data revealed that 83 (29%) patients developed LR, of which 31% had RR and 69% had ENL. Most LR were observed in patients in the lepromatous border (97%): Borderline lepromatous leprosy (BL) and Lepromatous Leprosy (LL). Most patients with RR and ENL had a single episode (83% and 62%, respectively), and those that received multi-drug therapy (MDT) had a reaction onset occurring most frequently within the first year of MDT and after the first year of MDT, respectively. Prednisone was the first line treatment used to manage both types of LR. CONCLUSION: Most lepromatous reactions occur within the lepromatous border. ENL was the most common LR. Prompt recognition and management of these immunologic reactions is essential to prevent long term nerve function impairment.

Histoid leprosy complicated by erythema nodosum leprosum mimicking connective tissue disease.

Erythema nodosum leprosum (ENL) is an immunological complication of leprosy seen in 50% of lepromatous and 10% of borderline lepromatous leprosy. It usually presents as a multisystem disease with papulo-nodular skin lesions and fever. Arthralgia or arthritis is a common initial presentation of erythema nodosum leprosum. Pure rheumatologic presentation of lepromatous leprosy complicated by erythema nodosum leprosum is extremely rare, mimics connective tissue disease and is treated with steroids.

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders.

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon's normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions-in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer's and Parkinson's diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen's disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component.

A Case of Lepromatous Leprosy With Erythema Nodosum Leprosum.

Erythema nodosum leprosum is an immunologic reaction that occurs in patients with lepromatous leprosy. We present the case of a 23-year-old female with a one-week history of fever and painful erythematous nodules along her upper and lower extremities. The patient had immigrated to the United States from Micronesia, where she was partially treated for leprosy two years prior. Histological examination from a punch biopsy demonstrated noncaseating granulomatous inflammation with numerous bacilli highlighted by the Fite stain. The acid-fast bacilli smear was positive. Given the patient's clinical, laboratory, and histological findings, a diagnosis of lepromatous leprosy with a type 2 erythema nodosum leprosum reaction was established. Multidrug antibiotic therapy with rifampin, dapsone, minocycline, and prednisone was initiated, following the addition of clofazimine. Early recognition and treatment of leprosy are crucial to preventing chronic and disabling complications, especially in instances of systemic inflammatory responses such as erythema nodosum leprosum.

Systemic manifestation of necrotic erythema nodosum leprosum: A case report of a fatal leprosy.

Necrotic erythema nodosum leprosum (ENL) is an uncommon manifestation of type 2 lepra reaction, encountered in lepromatous and borderline lepromatous cases of leprosy. Necrotic ENL is associated with the involvement of multiple organs, therefore delayed diagnosis and treatment will lead to complications and poor prognosis. The aim of this case report was to report a challenging case of necrotic ENL misdiagnosed with multiple cellulitis since there were no signs of prior leprosy nor had any antimycobacterial treatment. A 45-year-old man was presented to the surgery department of Dr. Zainoel Abidin Hospital, Banda Aceh, Indonesia, with complaints of fever, joint pain, and painful tender skin lesions with ulceration over the trunk, extremities, and ears for one month. The patient was diagnosed clinically with multiple cellulitis and underwent a debridement procedure. Clinical improvement was absent, the patient was then consulted to the dermatology department. Physical examination showed normal vital signs, madarosis, inguinal lymphadenopathy, thickening of nerves, and sensation of numbness in both hands and feet. Laboratory examinations on admission showed leucocytosis, anemia, thrombocytopenia, hypoalbuminemia, hypocalcemia, and elevated creatinine and ureum level. A slit skin smears examination yielded positive acid-fast bacilli (AFB) with a bacteriological index (BI) value of 3+ and morphological index (MI) of 72%. The patient was diagnosed with lepromatous leprosy with necrotic ENL reaction. Intravenous methylprednisolone and cefoperazone-sulbactam were given. Multidrug therapy mulitbacillary (MDT-MB) without dapsone, and ofloxacin 400 mg was initiated. On day 17, the patient had septic shock. The patient became unconscious and experienced death. This case highlights that medical professionals should be aware of the various manifestations of necrotic ENL to correctly diagnose and provide treatment as soon as possible to prevent mortality, especially in leprosy-endemic country, Indonesia.

Hemophagocytic Lymphohistiocytosis in Erythema Nodosum Leprosum: Case Report of an Unusual Conundrum.

Hemophagocytic lymphohistiocytosis (HLH) and erythema nodosum leprosum (ENL) result from a complex agent-host interaction and form a continuum of the same spectrum. A 30-year-old multi-gravida presented at 36 weeks gestation with fever and erythematous raised lesions over the face and upper and lower limbs after defaulting treatment for borderline lepromatous leprosy. Skin biopsy confirmed ENL, hence multi-drug therapy (MDT) and oral steroids were restarted. However, her condition worsened and she developed icterus, periorbital puffiness, pleural effusion, ascites and splenomegaly. Laboratory investigations showed pancytopenia, conjugated hyperbilirubinemia, transaminitis, elevated lactate dehydrogenase, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia. Dapsone was stopped on the suspicion of dapsone hypersensitivity but hyperbilirubinemia progressed. Diagnosis of HLH was clinched after bone marrow aspirate showed florid hemophagocytosis and subsequently, intravenous immunoglobulin (2 g/kg) over 5 days and dexamethasone were administered. The patient improved gradually with normalization of laboratory parameters and restarted MDT. This case depicts a rare and potentially catastrophic complication of ENL and emphasizes a vigil for HLH syndrome in such cases.

Thalidomide and steroid in the management of erythema nodosum leprosum.

OBJECTIVE: The objective of the study was to assess the efficacy and safety profiles of combined treatment of prednisolone with thalidomide (Gr-A) and prednisolone with clofazimine (Gr. B) in patients with erythema nodosum leprosum (ENL) or type 2 lepra reactions. MATERIALS AND METHODS: Efficacy of both regimens was assessed on the basis of clinical recovery of recurrent ENL measured by reaction severity score (RSS), Visual Analog Scale (VAS), and recurrence of type 2 lepra reaction. The causality assessment of adverse drug reactions was done using the WHO UMC causality assessment scale. RESULTS: The average age of patients with recurrent ENL was 42.8 years (male) and 51.8yrs (female) and had mean duration of leprosy and recurrent ENL 2.4 years and 2.09 years, respectively. 80% of nonrecurrence was observed in Gr-A versus 66% in Gr-B. Significant (P < 0.05) lower RSS and VAS was found in both the treatment groups as compared to pretreatment value. The reduction in RSS and VAS was statistically significant (P < 0.05) in Gr-A compared to Gr-B treatment. CONCLUSION: Thalidomide combination with steroid was found to be more efficacious than clofazimine combination with steroid in the treatment of ENL both the treatment regimens showed few tolerable side effects. Improved strategies for the treatment and management of these reactions need to be developed.

The Type I Interferon Pathway Is Upregulated in the Cutaneous Lesions and Blood of Multibacillary Leprosy Patients With Erythema Nodosum Leprosum.

In leprosy patients, acute inflammatory episodes, known as erythema nodosum leprosum (ENL), are responsible for high morbidity and tissue damage that occur during the course of Mycobacterium leprae infection. In a previous study, we showed evidence implicating DNA-sensing via TLR9 as an important inflammatory pathway in ENL. A likely important consequence of TLR9 pathway activation is the production of type I interferons (IFN-I) by plasmacytoid dendritic cells (pDCs), also implicated in the pathogenesis of several chronic inflammatory diseases. In this study, we investigated whether the IFN-I pathway is activated during ENL. Blood samples and skin lesions from multibacillary patients diagnosed with ENL were collected and the expression of genes of the IFN-I pathway and interferon-stimulated genes were compared with samples collected from non-reactional multibacillary (NR) patients. Whole blood RNAseq analysis suggested higher activation of the IFN-I pathway in ENL patients, confirmed by RT-qPCR. Likewise, significantly higher mRNA levels of IFN-I-related genes were detected in ENL skin biopsies when compared to NR patient lesions. During thalidomide administration, the drug of choice for ENL treatment, a decrease in the mRNA and protein levels of some of these genes both in the skin and blood was observed. Indeed, in vitro assays showed that thalidomide was able to block the secretion of IFN-I by peripheral blood mononuclear cells in response to M. leprae sonicate or CpG-A, a TLR9 ligand. Finally, the decreased frequencies of peripheral pDCs in ENL patients, along with the higher TLR9 expression in ENL pDCs and the enrichment of CD123+ cells in ENL skin lesions, suggest the involvement of these cells as IFN-I producers in this type of reaction. Taken together, our data point to the involvement of the pDC/type I IFN pathway in the pathogenesis of ENL, opening new avenues in identifying biomarkers for early diagnosis and new therapeutic targets for the better management of this reactional episode.

Beneficial Effect of Minocycline as Additional Treatment to Prednisone for Pustular Erythema Nodosum Leprosum.

Introduction: Pustular erythema nodosum leprosum (ENL) is an atypical manifestation associated with chronic ENL. The use of corticosteroid alone might not be sufficient for this condition, and addition of another anti-inflammatory drug is often necessary. Minocycline is a tetracycline antibiotic with anti-neutrophilic properties, which may accelerate the treatment of pustular ENL. This case report aimed to elaborate on the beneficial effect of minocycline for pustular ENL. Case: We report a case of pustular ENL in a 23-year-old male who had been released from treatment (RFT) of lepromatous leprosy (LL). The patient had been on prednisone for six months as treatment for ENL. The condition recurred when prednisone was tapered to 10 mg daily. Eventually, pustules developed on the erythematous nodules, and the lesions did not improve despite seven weeks of treatment with 40-60 mg prednisone. Later, 100 mg minocycline once daily was given in addition to 60 mg prednisone once daily and improvement was rapidly observed on the ninth day after minocycline administration. This condition was sustained for four weeks with prednisone tapering, and no side effects were reported during the treatment. Discussion: Minocycline is an antibiotic with anti-inflammatory properties. Only a few studies have been conducted regarding the use of minocycline in chronic ENL, but there was no reported case of minocycline use for pustular ENL in RFT patient. The addition of minocycline to prednisone may accelerate the improvement of pustular ENL. We observed an improvement after the ninth day of minocycline administration compared to seven weeks of prednisone monotherapy. No new ENL lesions occurred during four weeks of minocycline administration therapy. Conclusion: Pustular ENL is an atypical manifestation of chronic ENL, and the addition of minocycline to prednisone may accelerate its therapeutic effect on the patient.

Diagnostic Value of Neutrophil-to-Lymphocyte Ratio, Lymphocyte-to-Monocyte Ratio, and Platelet-to-Lymphocyte Ratio in the Diagnosis of Erythema Nodosum Leprosum: A Retrospective Study.

Erythema nodosum leprosum (ENL) is an acute immune complex-mediated condition of the dermis, subcutaneous tissue, and other tissues seen in patients with multibacillary (MB) leprosy, causing severe impairment to patients' quality of life. To date, there is no standard diagnostic criteria for ENL. We aimed to study the diagnostic value and accuracy of Neutrophil-to-Lymphocyte ratio (NLR), Lymphocyte-to-Monocyte ratio (LMR), and Platelet-to-Lymphocyte ratio (PLR) in diagnosing ENL. This is an analytic retrospective study with a cross-sectional design that describes the distribution and clinical characteristics of all newly diagnosed MB patients of Dr. Soetomo General Hospital Surabaya in the years 2018-2020. NLR, LMR, and PLR were calculated for all patients, and a receiver operating characteristic curve (ROC) was generated to identify the cut-off points. Among a total of 182 patients with MB leprosy, 22 cases (12.09%) were reported with ENL. WBC, neutrophils, monocytes, and thrombocytes showed a positive correlation with the incidence of ENL, but not lymphocytes. The NLR cut-off point for the diagnosis of ENL was 4.99 (sensitivity 86.4%, specificity 82.5%, accuracy 82.97), while that of PLR was 237.46 (sensitivity 63.6%, specificity 73.1%, accuracy 71.98%). LMR had poor sensitivity and specificity levels of 50% and 28.7%, with cut-off point of 2.28 and accuracy of 31.32%. These results suggest that NLR and PLR could be potential biomarkers for the diagnosis of ENL.

Erythema nodosum leprosum with genital ulceration - A rare and interesting case report.

Erythema nodosum leprosum (ENL) is a type III hypersensitivity phenomenon seen in the lepromatous spectrum of leprosy. Involvement of external genitalia is very rare, and genital mucosal involvement is still rare. We report a 39-year-old man with episodic fever, red raised skin lesions predominantly in the lower extremities, and painful genital ulcers for 1-month duration. Genital examination revealed two irregularly shaped, mildly indurated, punched-out tender ulcers with yellowish slough on an erythematous base. Bilateral ulnar and common peroneal nerves were moderately thickened, more on the left side with bilateral stocking type of anesthesia associated with the left side fixed ulnar claw hand and left foot drop. By appropriate investigations and therapeutic elimination, the patient was diagnosed as borderline lepromatous Hansen's disease with type 2 reaction and grade 2 deformity. This case is reported for the rare occurrence of ENL lesions involving the genital mucosa in the form of ulceration.

Lucio's phenomenon: A systematic literature review of definition, clinical features, histopathogenesis and management.

Leprosy is a chronic disease with clinical presentations according to the immunologic spectrum. Lepromatous form is the most advanced, with the highest transmissibility and risk of causing disabilities. Lucio's phenomenon is a rare manifestation among lepromatous patients with a rapid and severe evolution and high mortality. It is difficult to differentiate from ulcerative/necrotic erythema nodosum leprosum and has no consensus on how it should be treated. This article is a qualitative review of the literature after the introduction of multidrug therapy, aiming to bring consensus related to the clinical, laboratory and histopathological diagnostic criteria of the disease and its management.

Methotrexate in erythema nodosum leprosum: Pitfalls to avoid.

We read with interest the short report by Rani et al. entitled "An uncommon variant of erythema nodosum leprosum responding well to methotrexate: Report of two cases." The article describes two cases of erythema nodosum leprosum (ENL) with 'atypical features' and good response to low dose methotrexate. The authors address a few concerns regarding methotrexate in ENL, emphasizing the rational usage of this agent.

Hanseníase virchowiana e eritema nodoso hanseníco em gestante de 34 semanas sem diagnóstico prévio / Virchowian leprosy and erythema nodosum leprosum in a 34-week pregnant woman without any previous diagnosis

Relatamos um caso de uma paciente feminina, gestante de terceiro trimestre, em acompanhamento pré-natal regular na unidade básica de saúde, com boa evolução gestacional, porém apresentando lesões de pele há cerca de um ano, acompanhadas de alteração de sensibilidade, além de fáscies infiltrada e madarose. Sendo o Brasil um país endêmico em Hanseníase, ocupando o 2º lugar no mundo em número de novos casos, chama a atenção o diagnóstico tardio da paciente em questão. Aproveitamos este emblemático relato de caso para discutir aspectos importantes em relação à terapêutica no período gestacional (poliquimioterapia conforme manual do ministério, sem nenhuma alteração por conta da gestação), desfecho obstétrico, orientações quanto à lactação (não contra-indicada com a mãe em tratamento; pelo contrário, devendo ser estimulada) e cuidado ao recém nato. [au]

We report a case of a pregnant female patient in the third trimester undergoing regular prenatal care at a Basic Health Unit, with good gestational evolution, but presenting skin lesions for approximately a year accompanied by changes in sensitivity, in addition to facial infiltration and madarosis. Considering Brazil as an endemic country for leprosy, ranking 2nd in the world concerning the number of new cases, late diagnosis of the patient in question stands out. We use this emblematic case report to discuss important aspects concerning the treatment of leprosy during the gestational period (multidrug therapy according to the Ministry of Health manual, without any changes due to pregnancy), obstetric outcome, guidelines regarding breastfeeding (not contraindicated with the mother in treatment; on the contrary, it should be stimulated) and care for the newborn. [au]