Chronic recalcitrant erythema nodosum leprosum: therapeutic dilemma and role of mycobacterium indicus pranii vaccine

Abstract Erythema nodosum leprosum is a severe immune reaction that complicates the usual course of multibacillary leprosy. There is increased activation of T-cells in erythema nodosum leprosum. Treatment modalities available to date for the management are systemic steroids, thalidomide, methotrexate, cyclophosphamide, azathioprine, minocycline, and apremilast but none of them is promising and safe. Mycobacterium indicus pranii is an atypical mycobacterium possessing strong immunomodulatory properties. The vaccine for this mycobacterium has been shown to have both immunotherapeutic and immunoprophylactic effects in multibacillary leprosy patients. We report a case of chronic recalcitrant erythema nodosum Leprosum which responded to Mycobacterium indicus pranii vaccine without any adverse effects, thereby suggesting its role as a novel therapeutic option in this reaction.

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.

Effectiveness of the retreatment of patients with multibacillary leprosy and episodes of erythema nodosum leprosum and/or persistent neuritis: a single-center experience

Abstract: Background: Erythema nodosum leprosum may appear before, during or after treatment of leprosy and is one of the main factors for nerve damage in patients. When it occurs or continues to occur after treatment, it may indicate disease recurrence and a new treatment may be instituted again. Objective: To evaluate the retreatment of patients with multibacillary leprosy who underwent standard treatment with multidrug therapy, but developed or continued to present reactions of erythema nodosum leprosum and/or neuritis 3-5 years after its end. Method: For this objective, a new treatment was performed in 29 patients with multibacillary leprosy who maintained episodes of erythema nodosum and/or neuritis 3-5 years after conventional treatment. Results: In general, we observed that 27 (93.10%) had no more new episodes after a follow up period of eight months to five years. In five of these patients the reason for the retreatment was the occurrence of difficult-to-control neuritis, and that has ceased to occur in all of them. Study limitations: Small number of patients.. Conclusion: In the cases observed, retreatment was an effective measure to prevent the occurrence of erythema nodosum leprosum and/or persistent neuritis.

Etanercept in erythema nodosum leprosum

Abstract: One of the biggest challenges in treating leprosy is the control of reaction events. Patients with lepromatous leprosy may present reaction type II, or erythema nodosum leprosum, during treatment, and this reaction can remain in a recurrent form after being released from the hospital, requiring the use of thalidomide and/or prednisone for long periods of time, in turn increasing the risk of side effects. Two reports of the use of antiTNF to treat erythema nodosum leprosum were found in the literature. A good response was found after an assay with infliximab and etanercept. This study reports on a patient with lepromatous leprosy and recurrent reaction, controlled by using etanercept and a 10-month follow-up, with the interruption of thalidomide and the maintenance of prednisone at 10 mg/day.

Reacciones lepromatosas en pacientes adultos y pediátricos en un centro de referencia. Programa Nacional de Lepra, Paraguay / Lepromatous reactions in adults and pediatric outpatients in a reference center. National Lepra Program, Paraguay

Introducción la lepra, llamada también enfermedad de Hansen, es una afección de la piel y de los nervios periféricos, infectocontagiosa, causada por Mycobacterium leprae. Las reacciones lepromatosas se presentan aún con tratamiento y son expresiones de respuesta inmunitaria. Conocerlas es importante a fin de facilitar el abordaje. Objetivo determinar la frecuencia y tipo de reacciones lepromatosas en pacientes con diagnóstico de lepra que acuden al centro de referencia de Enfermedad de Hansen en el Hospital Distrital de San Lorenzo, de enero 2013 a diciembre 2015. Metodología observacional, descriptivo, retrospectivo de corte transverso. Resultados se incluyeron 217 pacientes, 72% presentaban lepra MB y 63% era de sexo masculino. La prevalencia de reacción lepromatosa fue 44%, siendo más frecuentes las de tipo 2 (65%). Se presentó reacción lepromatosa como debut de la enfermedad en 27 %. Treinta y tres pacientes presentaron de tres a doce episodios de reacción lepromatosa. El tratamiento fue talidomida y corticoides. Conclusiones la prevalencia de leprorreacciones fue cercana al 50%, predominando las de tipo 2. El tratamiento utilizado fue talidomida y/o corticoides dependiendo del tipo de reacción lepromatosa.

Introduction leprosy, wich is cause by Mycobacterium leprae, also known as Hansen's Disease, affects skin and peripheral nerves. Lepromatous reactions (LRs) are expressions of an immune reaction and remain as a major persistent problem. LRs are present even with appropriated treatment. Emphasis must be made in early diagnosis and prevention of the catastrophic consequences of LRs. Objective to determine the frequency and type of lepromatous reactions in leprosy patients with leprosy attending to reference center of Hansen´s Disease in the District Center Hospital in San Lorenzo, from January 2013 to December 2015. Methodology observational, retrospective cross sectional study. Results 217 patients were included, 72% with multibacillary leprosy. 63% were male. Lepromatous reactions were found in 44%, been more frequent Type II reaction, in 65% of cases. LRs as oset disease occurred in 27%. 33 patients presented from 3 to 12 episodes of lepromatous reaction. The number of LRs episodes per patient were 3 to 12. Thalidomide was used as treatment in Erithema Nodosum Leprosum (ENL) and corticosteroids for the other types de LRs. Conclusions prevalence of PRs were 50%, been more frecuent the type II. Reaction the treatment used was Thalidomide and/or corticosteroids depending on the type of lepromatosus reaction.

Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day

BACKGROUND: Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES: These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS: We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS: Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION: A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL. .

Talidomida usada por pacientes com eritema nodoso hansênico / Thalidomide used by patients with erythema nodosum leprosum

INTRODUÇÃO: A talidomida é um fármaco utilizado atualmente no tratamento do eritema nodoso hansênico no Brasil. MÉTODOS: Estudo prospectivo para acompanhar a evolução clínica, registrar os eventos adversos e determinar as concentrações plasmáticas de talidomida em dose diária de 100mg/dia, em 20 pacientes com manifestações clínicas de eritema nodoso hansênico, divididos em dois grupos: após ou em curso da poliquimioterapia para hanseníase. RESULTADOS: Não foram observadas diferenças significativas nos grupos no decorrer do estudo, tanto na evolução clínica favorável dos pacientes, de 70 por cento e 90 por cento, quanto nos eventos adversos registrados que foram tontura e sonolência. Os teores plasmáticos de talidomida em D7 e D14 foram de 0,82±0,4μg/mL e 0,79±0,3μg/mL no grupo 1 e de 0,82±0,4 e 1,55±1,0 no grupo 2, respectivamente. CONCLUSÕES: Na amostra estudada, a poliquimioterapia não interferiu na evolução clínica, na incidência dos efeitos adversos e nos níveis plasmáticos de talidomida.

INTRODUCTION: Thalidomide is a drug currently used in Brazil for treating erythema nodosum leprosum. METHODS: This was a prospective study to follow up clinical evolution, record adverse events and determine plasma thalidomide levels from a dose of 100 mg/day, among 20 patients with clinical manifestations of erythema nodosum leprosum, divided into two groups: during or after leprosy multidrug therapy. RESULTS: No significant differences between the groups were seen during the study, either in relation to favorable clinical evolution among the patients (70 percent and 90 percent), or in relation to the adverse events recorded, which were dizziness and somnolence. The plasma thalidomide levels on D7 and D14 were 0.82 ± 0.4μg/ml and 0.79 ± 0.3 μg/ml in group 1 and 0.82 ± 0.4 and 1.55 ± 1.0 in group 2, respectively. CONCLUSIONS: In this sample, the multidrug therapy had no effect on the clinical evolution, incidence of adverse events and plasma thalidomide levels.

Vasculonecrotic reactions in leprosy

Multibacillary, lepromatous or borderline leprosy patients may present two types of vasculonecrotic reactions: Lucio phenomenon and that associated with erythema nodosum leprosum. Despite they can be distinguished through clinical and histological characteristics; both are often used as synonyms. It is said that leprosy reaction should be properly classified for therapeutic reasons, since it is well known that in Lucio phenomenon there is not a good response to thalidomide. The authors reported two cases of vasculonecrotic phenomena in lepromatous leprosy sharing clinical and histopathological characteristics of both reaction subtypes. The findings may indicate the spectral nature of the reaction phenomena in leprosy and emphasize the importance of the clinic-pathological correlation for proper classification. Our findings may contribute to the understanding of leprosy reactions pathogenesis, broaden the knowledge about their outcome with standard treatment, and provide the scientific background to design better therapeutic strategies for these complications.

Advances in the treatment of reactions in leprosy.

Morbidity in leprosy is almost always due to reactions. Similarly, to a great extent, deformities in leprosy are the consequence of reactions occurring both in borderline patients (type 1 or reversal reactions) and in lepromatous patients (type 2 or ENL reactions). Over the last three decades, work has centred around finding who are prone to getting the reactions, identifying the risk factors and improving the management of reactions in order to alleviate quickly the suffering and prevent and reverse nerve damage consequent to reactions. Though several new drugs have been tried and found somewhat useful, corticosteroids and thalidomide continue to be the mainstay in the management of leprosy reactions. A brief review of the current understanding is presented.

Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type II reaction in leprosy

Type II reaction in leprosy, or erythema nodosum leprosum (ENL), is often characterized by severe clinical symptoms together with nerve function impairment leading to permanent disabilities. Thalidomide has been shown to be a highly effective drug for the treatment of ENL. It is, however, contraindicated for women of childbearing age due to its teratogenicity. On the other hand, pentoxifylline, used to treat hypercoagulable states, is not teratogenic and, like thalidomide, can inhibit the synthesis of tumor necrosis factor-a and other cytokines. In the present randomized double-blind clinical study we compared the effectiveness of orally administered pentoxifylline vs thalidomide in treating type II reaction in 44 patients. Daily doses of 300 mg thalidomide or 1.2 g pentoxifylline were administered for 30 days to multibacillary leprosy patients undergoing type II reaction. Randomly chosen patients were included in the study before, during, and after specific multidrug therapy. Clinical evaluations were performed on the 1st, 7th, 14th, 21st, and 30th days of treatment and laboratory tests were carried out on the 1st and 30th days. As expected, overall, thalidomide proved to be more effective in the treatment of type II leprosy reaction. Nevertheless, continuous treatment with pentoxifylline was effective in relieving the clinical signs of ENL, especially limb edema and systemic symptoms, in 62.5 percent of the patients.

Eritema nodoso como forma de reativação da doença de Chagas em transplantado cardíaco / Erythema nodoso in reactivation of Chagas' disease after cardiac transplantation

O presente caso ilustra uma forma de eritema nodoso, cujo agente foi o Trypanosoma cruzi em paciente chagásica submetida a transplante cardíaco. O diagnóstico foi firmado através do exame histopatológico de biópsia da lesão cutânea e estudo imunohistoquímico. O tratamento com nifurtimox promoveu regressão total das lesões.

Reaction cases treated at the Regional Leprosy Training and Research Institute, Aska, Orissa: a retrospective analysis.

This study is a retrospective analysis of 147 cases of leprosy reaction selected out of 942 cases of leprosy registered between 1992 and 2002 at the RLTRI, Aska (Orissa). The occurrence of reaction was about 16% with a slight increase over the years. There was a preponderance of males, with about 80% cases among males, and the peak occurrence of reaction was found in the age-group of 21-49 years. Reversal reaction (RR) was seen in 68.7% and ENL in 31.3% of cases. Single episode of RR and ENL reactions was seen in 61.2% and 43.5% respectively. In either type the last episode was seen even after about 32 months after RFT. There was a dissociation between nerve and skin manifestation, with both skin and nerve manifestation in 78.96%, skin lesions only in 21.1% and nerve lesions only in 50.9% of cases. About 88% of reaction was seen in MB patients, with a higher proportion of RR, because of inclusion of more borderline cases. Prednisolone was the drug of choice in both types of reaction, though in 17 cases of steroid dependency, thalidomide was proved to have an edge over steroids. Both types taken together, in half of the cases the first episode of reaction developed within 6 months of starting treatment. Multiple episodes were more common with ENL.

Avaliação de série de casos de eritema nodoso hansênico: perfil clínico, base imunológica e tratamento instituído nos serviços de saúde / Erythema nodosum leprosum case series report: clinical profile, immunological basis and treatment implemented in health services

O eritema nodoso hansênico é evento inflamatório agudo no curso crônico da hanseníase. É considerado evento de base imunológica e importante causa de morbidade e incapacidade física. Avaliou-se o perfil clínico, sorológico e histopatológico de 58 pacientes com eritema nodoso hansênico recrutados sequencialmente entre julho-dezembro de 2000, em área urbana hiperendêmica do Brasil Central (Estado de Goiás). A metade dos pacientes apresentava quadro reacional grave, e em 66 por cento dos casos o primeiro episódio reacional ocorreu durante tratamento específico. A maioria dos casos com eritema nodoso hansênico e dos controles apresentaram reatividade para IgM anti-PGL I. Os achados histopatológicos mais freqüentes no eritema nodoso hansênico foram infiltrado neutrofílico, paniculite, vasculite e agressão neural. Dos pacientes com eritema nodoso hansênico, 96 por cento usaram corticosteróide sistêmico no primeiro episódio. Os casos de eritema nodoso hansênico estavam associados à neurite e raramente usaram talidomida como medicação isolada nos serviços de saúde.

Long-term follow-up of erythema nodosum.

One hundred and fifty-four patients with erythema nodosum who attended the skin clinic at Ramathibodi Hospital from January 1990 to December 2000 were evaluated retrospectively with regard to the etiology of erythema nodosum. Of 49 patients who attended the skin clinic during that time 26 returned for reevaluation. Of the 154 patients, their ages ranged from 10-72 years old; 138 were females, 16 were males. The most common cause of erythema nodosum was tuberculosis (12.3%). Upper respiratory tract infection was found in 3.9 per cent. Other causes included Behcet's disease, sytemic lupus erythematous, drugs, pregnancy, chronic myeloid leukemia, leprosy, Reiter's syndrome and inflammatory bowel disease. Of the 26 patients who returned for reevaluation, pulmonary tuberculosis was identified in only one patient who had developed erythema nodosum 16 months earlier. In conclusion, it was found that tuberculosis is still a predominant cause of erythema nodosum among Thai patients.

Pulsed corticosteroid therapy in patients with chronic recurrent ENL: a pilot study.

A pilot study has been undertaken to compare the efficacy of small dose pulsed betamethasone therapy with need based oral steroids in chronic recurrent erythema nodosum leprosum (ENL) patients. Though this mode of therapy was well tolerated, no advantage with intermittent steroid administration was observed. This could have been on account of small dose of steroid given monthly. Treatment of chronic recurrent erythema nodosum leprosum (ENL) patients continues to be unsatisfactory, particularly, because of nonavailability of thalidomide. Though corticosteroids are effective in suppressing all the manifestations and even restoring partially or fully the functional impairment, their side effects and dependence are equally troublesome. Based on (a) the reported efficacy and safety of intermittent use of corticosteroids in several immune complex mediated disorders (Cathcart et al 1976, Kimberly et al 1979), Liebling et al 1981 and Pasricha & Gupta 1984) and (b) ENL (type II) reactions having similar pathology, a pilot study has been undertaken to see the efficacy and the tolerance of pulsed steroids in chronic ENL patients.

A fatal case of erythema necroticans.

Erythema nodosum leprosum (ENL) classically presents as tender, erythematous nodules over the face, arms and legs. Severe ENL can become vesicular or bullous and break-down and is termed erythema necroticans (Jopling & McDougall, 1996) and is treated with corticosteroids. The causes of death in a majority of leprosy patients are the same as in the general population, with the exception of renal damage in lepromatous leprosy. There is possible increased mortality from side-effects of antileprosy drugs, steroids, or other drugs used in reactions, from toxaemia in severe reactions, and from asphyxia due to glottic oedema (Jopling & McDougall, 1996). We report here a case of erythema necroticans, the cause of death being septicaemia, secondary to skin ulcers and urinary tract infection, precipitated by corticosteroids.

The use of pentoxifylline in the treatment of type 2 reactional episodes in leprosy.

It has been suggested that erythma nodosum leprosum (ENL) is associated with enhanced production of TNF-alpha resulting in increased inflammation of the skin and nerve function impairment. Thalidomide and steroids are the major drugs used in the treatment of ENL, but due to the serious problems associated with their use, alternative therapeutic interventions are being considered. In the present retrospective study, the authors report their clinical observations on the effect of pentoxifylline (PTX) in the treatment of ENL. Parameters, such as the clinical involution of reactional lesions, the regression of the inflammatory symptoms associated with the lesions, and the impact on the systemic symptoms common to ENL were assessed at regular intervals during PTX therapy. It was found that PTX therapy led to total elimination of systemic symptoms within the first week of treatment. This improvement was maintained until the end of the study (60 days of treatment). Moreover, the evolution of nodular lesions showed a 100% improvement within the first 14 days of treatment. However, by the 60th day, worsening of the lesions was noted in 20% of the cases. The impression is that PTX is well tolerated, and it may be used for improving patient's clinical condition during ENL reaction. Nevertheless, a randomized, double blind, controlled trial to compare the effects of the widely-accepted thalidomide and the yet untested pentoxifylline for treatment of type 2 reaction is still necessary.

Talidomida: indicaçöes e legislaçäo vigente / Thalidomide: indications and actual legislation

A talidomida, droga que tem ampla aplicaçäo clínica e potentes efeitos antiinflamatórios, qualifica-se como primeira escolha para tratamento de várias doenças. Seu efeito teratogênico, entretanto, limita seu uso clínico. Baseando-se neses conhecimentos, após estudo detalhado de cada um de seus efeitos, e avaliando-se cuidadosamente o risco/benefício de seu emprego, pretende-se indicar a talidomida para algumas situaçöes clínicas já bem estabelecidas. Säo elas: eritema nodoso hansênico, lúpus eritematoso discóide, estomatite aftosa recorrente, doença enxerto-verus-hospedeiro em sua fase crônica, úlceras dolorosas de mucosas em pacientes com HIV/Aids, prurigo nodular, síndrome de Behçet e prurigo actínico. A essas somam-se outras, em que seu uso só deve se indicado se outras drogas resultarem ineficazes. Complementando a avaliaçäo, foram consideradas as situaçöes nas quais a talidomida poderia ser eficaz, necessitando de estudo prévio das características da doença e do paciente para que se efetive sua utilizaçäo. O uso da talidomida deve sempre obedecer às portarias do Ministério da Saúde que regulamentam sua fabricaçäo, indicaçöes e dispensäo. Os principais pontos dessa legislaçäo seräo destacados, em especial a proibiçäo para uso em mulheres em idade fértil.