Erythema Nodosum Leprosum Reaction Research Articles

Leprosy Reactions Show Increased Th17 Cell Activity and Reduced FOXP3+ Tregs with Concomitant Decrease in TGF-β and Increase in IL-6.

Background50% of leprosy patients suffer from episodes of Type 1/ reversal reactions (RR) and Type 2/ Erythema Nodosum Leprosum (ENL) reactions which lead to morbidity and nerve damage. CD4+ subsets of Th17 cells and CD25+FOXP3+ regulatory T cells (Tregs) have been shown to play a major role in disease associated immunopathology and in stable leprosy as reported by us and others. The aim of our study was to analyze their role in leprosy reactions.Methodology and Principle FindingsQuantitative reverse transcribed PCR (qPCR), flowcytometry and ELISA were used to respectively investigate gene expression, cell phenotypes and supernatant levels of cytokines in antigen stimulated PBMC cultures in patients with stable disease and those undergoing leprosy reactions. Both types of reactions are associated with significant increase of Th17 cells and associated cytokines IL-17A, IL-17F, IL-21, IL-23 and chemokines CCL20, CCL22 as compared to matching stable forms of leprosy. Concurrently patients in reactions show reduction in FOXP3+ Treg cells as well as reduction in TGF-β and increase in IL-6. Moreover, expression of many T cell markers, cytokines, chemokines and signaling factors were observed to be increased in RR as compared to ENL reaction patients.ConclusionsPatients with leprosy reactions show an imbalance in Th17 and Treg populations. The reduction in Treg suppressor activity is associated withhigherTh17cell activity. The combined effect of reduced TGF-β and enhanced IL-6, IL-21 cytokines influence the balance between Th17 or Treg cells in leprosy reactions as reported in the murine models and autoimmune diseases. The increase in Th17 cell associated cytokines may contribute to lesional inflammation.

The − 308 bp TNF gene polymorphism influences tumor necrosis factor expression in leprosy patients in Bahia State, Brazil

Leprosy or Hansen's disease is a debilitating chronic granulomatous disease caused by Mycobacterium leprae, with high incidence and prevalence in Brazil. The −308bp G/A single nucleotide polymorphism (SNP rs1800629) in the tumor necrosis factor (TNF) gene promoter is a proposed risk factor for leprosy. In Brazil, Northern India, Egypt and Nepal, the common G allele was associated with leprosy. In Eastern India, Thailand and Malawi the minor A allele was the risk factor. Allele A was previously associated with high TNF. We genotyped rs1800629 in 326 leprosy cases from Bahia State, Brazil, including 72 paucibacillary (PB) and 47 multibacillary (MB) without reactions, and 69 reversal reaction (RR) and 78 erythema nodosum leprosum (ENL) with reactions. Logistic regression was used to compare patient groups with 331 healthy controls. Relative TNF mRNA was determined in peripheral blood leukocytes by QRTPCR, and serum TNF levels measured by ELISA. We found that TNF mRNA expression was higher (P=0.03) in leprosy patients compared to endemic controls, but did not differ significantly between clinical subgroups. Carriage of the minor A allele was associated (P=0.003) with low TNF mRNA across leprosy patients. Nevertheless, we found no evidence for either allele at this SNP as a risk factor for leprosy per se (OR=1.12, 95% CI 0.79–1.60, P=0.52), PB (OR=0.99, 95% CI 0.54–1.81, P=0.97), MB (OR=0.86, 95% CI 0.40–1.83, P=0.70), RR (OR=1.37, 95% CI 0.79–2.38, P=0.27) or ENL (OR=0.76, 95% CI 0.40–1.45, P=0.42) when compared to endemic controls. Further studies are required to determine whether the influence of the minor A allele on TNF mRNA levels determines response to treatment, particularly in the context of ENL reaction treatment with anti-TNF therapies and RR reactions where treatment with prednisolone is known to reduce TNF levels. Our findings contribute to understanding TNF as an important determinant of leprosy immunopathology in Brazil.

Erythema necroticans: a rare reaction pattern in leprosy

Leprosy reactions are rare expression of immunological perturbations that interrupt the usual chronic course and the clinical stability of patients with leprosy. They generally occur during anti-mycobacterial treatment and are characterized by the appearance of crops of brightly erythematous tender nodules or plaques. Erythema Necroticans (ENe) is an uncommon manifestation of Type 2 Erythema Nodosum Leprosum (ENL) reaction, encountered in lepromatous and borderline lepromatous cases of leprosy. Severe ENL can become vesicular or bullous and break-down and is termed Erythema Necroticans.

Examining ERBB2 as a candidate gene for susceptibility to leprosy (Hansen’s disease) in Brazil

Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear.

Diabetic Ketoacidosis with Two Life Threatening Infections: Mucormycosis, and Bilateral Emphysematous Pyelonepritis, Preciptating Erythema Nodosum Leprosum as the Initial Presentation of Diabetes

Emphysematous pyelonephritis is an acute necrotizing renal and perirenal infection, caused by gas forming organism. Mucormycosis is an opportunistic aggressive fungal infection causing tissue thrombosis and necrosis. Erythema nodosum leprosum reaction is an inflammatory reaction occurring in borderline and lepromatous leprosy before, during or after multidrug treatment, where immune complexes deposit in various organs resulting in considerable damage to the organs that were site of deposition. Both emphysematous pyelonephritis and mucormycosis are infections that occur principally in diabetics, especially with poor control of blood sugar. Herein we report a 27 year old woman presenting to the emergency department with diabetic ketoacidosis as a first presentation of diabetes, where array of investigations revealed emphysematous pyelonephritis, palatal mucormycosis, and erythema nodosum leprosum. The early aggressive management with the correction of blood glucose and ketoacidosis help to give a successful outcome to the patient. To the best of our knowledge, this case is the first in English literature to report coexisting bilateral emphysematous pyelonephritis and palatal mucormycosis in a diabetic patient, precipitating erythema nodosum leprosum, and highlights the possibility of occurrence of more than one serious condition in a diabetic at a time.

Circulating levels of insulin-like growth factor-I (IGF-I) correlate with disease status in leprosy.

BackgroundCaused by Mycobacterium leprae (ML), leprosy presents a strong immune-inflammatory component, whose status dictates both the clinical form of the disease and the occurrence of reactional episodes. Evidence has shown that, during the immune-inflammatory response to infection, the growth hormone/insulin-like growth factor-I (GH/IGF-I) plays a prominent regulatory role. However, in leprosy, little, if anything, is known about the interaction between the immune and neuroendocrine systems.MethodsIn the present retrospective study, we measured the serum levels of IGF-I and IGBP-3, its major binding protein. These measurements were taken at diagnosis in nonreactional borderline tuberculoid (NR BT), borderline lepromatous (NR BL), and lepromatous (NR LL) leprosy patients in addition to healthy controls (HC). LL and BL patients who developed reaction during the course of the disease were also included in the study. The serum levels of IGF-I, IGFBP-3 and tumor necrosis factor-alpha (TNF-α) were evaluated at diagnosis and during development of reversal (RR) or erythema nodosum leprosum (ENL) reaction by the solid phase, enzyme-labeled, chemiluminescent-immunometric method.ResultsThe circulating IGF-I/IGFBP-3 levels showed significant differences according to disease status and occurrence of reactional episodes. At the time of leprosy diagnosis, significantly lower levels of circulating IGF-I/IGFBP-3 were found in NR BL and NR LL patients in contrast to NR BT patients and HCs. However, after treatment, serum IGF-I levels in BL/LL patients returned to normal. Notably, the levels of circulating IGF-I at diagnosis were low in 75% of patients who did not undergo ENL during treatment (NR LL patients) in opposition to the normal levels observed in those who suffered ENL during treatment (R LL patients). Nonetheless, during ENL episodes, the levels observed in RLL sera tended to decrease, attaining similar levels to those found in NR LL patients. Interestingly, IGF-I behaved contrary to what was observed during RR episodes in R BL patients.ConclusionsOur data revealed important alterations in the IGF system in relation to the status of the host immune-inflammatory response to ML while at the same time pointing to the circulating IGF-I/IGFBP-3 levels as possible predictive biomarkers for ENL in LL patients at diagnosis.

An unexpected case of venous and pulmonary thrombo-embolism in a patient treated with thalidomide for refractory erythema nodosum leprosum: a case report

Recent literature reports an increased incidence of venous thrombosis following thalidomide use in the treatment of diseases with disease-related thrombotic risks such as malignancy, as well as concomitant use with chemotherapy and/or systemic corticosteroids. We report a case of deep vein thrombosis (DVT) and pulmonary embolism (PE) following thalidomide use in a patient with erythema nodosum leprosum (ENL) reaction who was concurrently treated with prednisolone, as well as a review of relevant literature.

Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes

Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes, these findings have not been extensively validated. We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of seven polymorphisms, including a promoter region variant in TNF (G −308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR ( FokI, BsmI, and TaqI). We observed an association between TNF −308A and protection from leprosy with an odds ratio of 0.52 (95% confidence interval = 0.29–0.95, p = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (odds ratio = 0.33, 95% confidence interval = 0.12–0.85, p = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. These results confirm previous findings of an association of TNF −308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation.

A case of erythema nodosum leprosum reaction with diffuse alveolar haemorrhage, successfully treated by pulsed methylprednisolone

ary We present a case of erythema nodosum leprosum (ENL) reaction with dse alveolar haemorrhage (DAH) in a patient who completely recovered with pulsed methylprednisolone. Our case illustrates that ENL could be a predisposing factor for DAH and a high dose of corticosteroid plays an important role in successfully treating such a patient.

Treatment of leprosy/Hansen's disease in the early 21st century

Leprosy, or Hansen's disease (HD), is caused by Mycobacterium leprae, a slowly dividing mycobacterium that has evolved to be an intracellular parasite, causing skin lesions and nerve damage. Less than 5% of people exposed to M. leprae develop clinical disease. Host cell-mediated resistance determines whether an individual will develop paucibacillary or multibacillary disease. Hansen's disease is a worldwide disease with about 150 new cases reported annually in the United States. Effective anti-mycobacterial treatments are available, and many patients experience severe reversal and erythema nodosum leprosum reactions that also require treatment. Leprosy has been the target of a World Health Organization multiple drug therapy campaign to eliminate it as a national public health problem in member countries, but endemic regions persist. In the United States, the National Hansen's Disease Program has primary responsibility for medical care, research, and information.

Polymorphism N248S in the Human Toll‐Like Receptor 1 Gene Is Related to Leprosy and Leprosy Reactions

We investigated the association between a polymorphism of a key innate immunity receptor, Toll-like receptor 1 (TLR1) N248S, and susceptibility to leprosy and its clinical presentation. TLR1 N248S has been shown elsewhere to diminish TLR1 signaling and subsequent leprosy disease. The homozygous genotype SS was more frequent (P=.012) and the heterozygous SN genotype was less frequent (P=.015) in patients with leprosy than in control subjects. Additional observed differences in allelic frequency in patients who experienced reversal reactions and/or erythema nodosum leprosum reactions indicates that altered TLR1 function, or at least a TLR1 N248S-linked trait, may affect the progression from infection to disease as well as the disease course and the risk of debilitating reactional episodes in this population.

Autoantibodies to cerebroside sulphate (sulphatide) in leprosy.

Sera from 40 leprosy patients were screened for autoantibodies to cerebroside sulphate (sulphatide). Anti-sulphatide IgM in groups of patients with lepromatous (LL) and borderline (BL + BB + BT), but not with tuberculoid (TT) disease, were significantly elevated above the levels found in endemic control subjects. Eight-six percent (18 out of 21; mean 1.59 OD units) of LL, 33% (four out of 12; mean 1.08 OD units) of borderline and 13% (one out of eight; mean 0.69 OD units) of tuberculoid patients had anti-sulphatide IgM in their sera above a cut-off value of 2 s.d. above the mean value (0.66 OD units) for control sera. Elevated anti-sulphatide IgG was detected in only one patient's serum, an individual with LL disease. The level of anti-sulphatide IgM was strongly correlated to expression of the TH3 idiotype, an idiotype previously defined by a human MoAb that bound Mycobacterium leprae phenolic glycolipid, Klebsiella capsular polysaccharide, polynucleotides and human tissues. The purified, TH3 MoAb was found in this study to bind sulphatide, but not cholesterol-3-sulphate or cerebroside. It is suggested that anti-sulphatide IgM is elevated in leprosy, in relation to the bacterial load. Anti-sulphatide IgM fell at the onset of erythema nodosum leprosum (ENL) reaction, consistent with the deposition of serum antibodies, and thus may play a part in pathology during periods of inflammation, particularly in multibacillary patients.

Specificity of IgG subclass antibodies in different clinical manifestations of leprosy.

We analysed specific IgG subclasses levels to Mycobacterium leprae sonicate extract (MSE), lipoarabinomannan B (LAM) and phenolic glycolipid I (PGL-I) in the sera of leprosy patients with different clinical manifestations. IgG2 was found to be the predominant antibody to MSE regardless of clinical manifestations, and IgG1 response was mostly seen in lepromatous patients. IgG3 reacted only rarely but IgG4 reacted relatively more in certain clinical groups such as borderline lepromatous and lepromatous with erythema nodosum leprosum (ENL) reaction. Most of the IgG subclass responses to MSE could be accounted for reactivity with LAM, suggesting that LAM is the major immunogen involved in the pathogenesis of leprosy. In contrast to LAM, PGL-I antigen showed considerably lower reactivities for IgG subclasses. An association between IgG subclass responses and clinical manifestations of leprosy was also seen. Whereas borderline lepromatous patients were found to have significantly higher levels of IgG2 and IgG4 to MSE, lepromatous patients had elevated levels of IgG1 and lower levels of IgG2. An interesting observation, however, was the significantly higher levels of IgG2 to LAM in the pure neuritic leprosy patients.

Histopathological study of ocular erythema nodosum leprosum and post-therapeutic scleral perforation: A case report

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae , clinically present either as tuberculoid, borderline or lepromatous type. Erythema nodosum leprosum (ENL) is an acute humoral response in the chronic course of lepromatous leprosy. Although very severe ENL reactions are known in systemic leprosy, such severity is rare in ocular tissues. A leprosy uveitis patient suffered from a severe form of post-therapeutic ENL reaction which resulted in perforation of the globe at the site of preexisting subconjunctival leproma. Painful blind eye was enucleated. Histopathological study revealed infiltration of numerous polymorphs and macrophages packed with acid-fast bacilli in the conjunctiva, cornea, ciliary body, ora serrata and sclera. A profuse influx of neutrophils on a background of macrophages packed with M. leprae confirmed the ocular ENL reaction. This case is reported to alert the ophthalmologists to a rare ocular complication of ENL.

Localized and persistent erythema nodosum leprosum - a rare variant?

Erythema nodosum leprosum (ENL) or Type-2 Lepra reaction is a manifestation of type III hypersensitivity response and usually occurs in certain cases of lepromatous and borderline lepromatous leprosy. It is usually generalized and evanescent, and responds well to oral corticosteroid therapy. Here we report an unusual case of persistent and localized ENL in a 19-year-old girl, which could be diagnosed with the aid of skin biopsy and histopathological examination.

Management of erythema nodosum leprosum by mycophenolate mofetil

Mycophenolate mofetil has been tried in 20 cases of chronic relapsing erythema nodosum leprosum reaction where long use of systemic steroid produce complications or are contraindicated. Excellent results have been observed in all the cases to arrest the reaction followed for a period of six to eight months duration.

Serum Proteome of Leprosy Patients Undergoing Erythema Nodosum Leprosum Reaction: Regulation of Expression of the Isoforms of Haptoglobin

Validated proteome profile allows better understanding of disease progression, subtype classification, susceptibility patterns, and disease prognosis. Leprosy is a spectral disease, with clinically, histologically, immunologically, and bacteriologically distinguishable subtypes. In addition, a significant fraction of patients undergo immune mediated reactions even after multidrug therapy (MDT). Erythema nodosum leprosum (ENL) is an immune complex mediated reactional condition in leprosy, characterized by a systemic inflammatory condition afflicting borderline lepromatous (BL) and lepromatous leprosy patients (LL). In this study, we have analyzed serum proteome of leprosy patients undergoing ENL reactions and compared it with that of healthy noncontact controls. Depletion of albumin and immunoglobulin G (IgG) was optimized using Aurum serum protein mini kit (Bio-Rad), and then two-dimensional gel electrophoresis (2-DE) of these serum samples was performed. Differentially expressed proteins were identified by MALDI-TOF and MALDI-TOF MS/MS mass spectrometry. Significant increase in one of the isoforms of alpha2 chain of haptoglobin was observed in ENL condition. In addition, haptoglobin phenotype was determined for healthy controls and leprosy patients. Hp 0-0 phenotype was detected in 21.4% of the ENL patients undergoing treatment, which on follow up examination showed typable phenotype, thus showing a condition of acquired anhaptoglobinemia. Since ENL still remains a threat to leprosy disease management, the above findings may provide new insights in understanding the development and progression of this inflammatory condition.

Ocular Lesions in the Inmates of Leprosy Rehabilitation Centre

A detailed eye examination of 145 inmates of a leprosy rehabilitation centre was done to determine the prevalence of ocular involvement. Age, gender of patients, type and duration of leprosy, systemic disabilities were noted. The mean age of patients was 45.8 years (range 19-70 years); 72.4% were males; 55.2% were suffering from paucibacillary leprosy. The mean duration of leprosy was 18.2 years in multibacillary type and 13.1 years in paucibacillary type. Ocular lesions related to leprosy were seen in 85.5% of patients; more often in multibacillary leprosy (92.3%). Corneal changes (80.7%) were the most frequently observed lesions followed by eye lid lesions (48.2%). Potentially sight threatening lesions such as lagophthalmos (23.4%), cornealanaesthesia (43.4%), and iridocyclitis (8.9%) were seen in both types of leprosy. Nine out of 26 (34.6%) patients with history of erythema nodosum leprosum reaction showed eye changes related to this reaction. Blindness in one eye due to lesions related to leprosy was seen in 2.7% of eyes. Age related cataract was the most common cause of blindness in patients of leprosy. The prevalence of ocular lesions was found to be high in the inmates of leprosy rehabilitation centre, and they were seen more frequently in patients with longer duration of the disease. Potentially sight threatening lesions were more often associated with systemic disabilities in these patients.

Epidemiological characteristics of leprosy reactions: 15 years experience from north India.

A retrospective analysis of patient's leprosy clinic records at PGIMER, Chandigarh, India for the period 1983 to 1998 was undertaken to study the frequency, time of onset, and risk factors for leprosy reactions. Of the 2600 cases analyzed, 1494 were multibacillary and 1106 had paucibacillary disease. Presentation with reaction was common with 30.9% of our patients having reactions at the time of first visit. The incidence of reversal reaction (RR) was highest during 6 to 12 months after starting multi-drug therapy (MDT), thereafter declining gradually. Late RR occurred in 9.5% of all cases and was noted up to 7 years after treatment. Female gender, widespread disease, and multibacillary disease were identified as risk factors for RR. Erythema nodosum leprosum (ENL) reactions were noted to occur mostly during second or third year after starting MDT. Of the total number of patients who experienced ENL, 64.3% had recurrent episodes which continued for up to 8 years after the start of treatment. Lepromatous leprosy, female gender, and high Bacterial Index (>/=3) were recognized as risk factors for developing ENL. Occurrence of recurrent and late reactions, even though of mild severity, highlights the importance of recognizing and treating them promptly to prevent or reduce morbidity, complications, and further deterioration in the disability status. Although it is hoped that leprosy will have been eliminated at all levels by 2005, the recognition and management of these reactions will continue to be the most essential/significant task in the post elimination era.

Erythema nodosum leprosum is associated with up-regulation of polyclonal IgG1 antibody synthesis.

Erythema nodosum leprosum (ENL) is a serious complication of lepromatous (L) disease in leprosy. We have previously shown that of the four IgG subclasses, IgG1 and IgG3 Mycobacterium leprae-specific antibodies are significantly lower in leprosy patients during ENL reaction compared with untreated L patients. To see if this decrease results from a down-regulation of antibody synthesis during ENL, the frequency of antibody-secreting B cells (ABSC) in the blood compartment was determined by ELISPOT and related to serum immunoglobulin concentrations (microgram/ABSC). Control groups consisted of 16 patients with stable L disease and 32 healthy endemic controls (EC). Paired samples were analysed during acute ENLS (n = 13) and after the reaction had subsided to identify changes associated with ENL. Polyclonal (PC) IgG1 was elevated in L patients compared with EC (325 micrograms versus 180 micrograms). Interestingly, patients during acute ENL showed concentrations higher than L patients (419 micrograms), which decreased after the reaction had subsided (260 micrograms), indicating the transient nature of the antibody response. IgG2 antibodies showed the reverse trend and were lower during ENL and increased after the reaction had subsided. The mean concentrations for PC IgG3 and IgG4 antibodies were similar during ENL and after the reaction had subsided. Thus, decrease in M. leprae-specific IgG1 and IgG3 antibodies is not related to down-regulation of B cell responses. Identification of factors which regulate PC IgG1 antibody synthesis may provide additional insights into determinants of ENL reactions.