The effects of prednisolone treatment on serological responses and lipid profiles in Ethiopian leprosy patients with Erythema Nodosum Leprosum reactions.

BACKGROUND: Erythema nodosum leprosum (ENL) is a systemic inflammatory complication occurring mainly in patients with lepromatous leprosy (LL) and borderline lepromatous leprosy (BL). Prednisolone is widely used for treatment of ENL reactions. However, it has been reported that prolonged treatment with prednisolone increases the risk for prednisolone-induced complications such as osteoporosis, diabetes, cataract and arteriosclerosis. It has been speculated that perhaps these complications result from lipid profile alterations by prednisolone. The effects of extended prednisolone treatment on lipid profiles in ENL patients have not been studied in leprosy patients with ENL reactions. Therefore, in this study we conducted a case-control study to investigate the changes in lipid profiles and serological responses in Ethiopian patients with ENL reaction after prednisolone treatment. METHODS: A prospective matched case-control study was employed to recruit 30 patients with ENL and 30 non-reactional LL patient controls at ALERT Hospital, Ethiopia. Blood samples were obtained from each patient with ENL reaction before and after prednisolone treatment as well as from LL controls. The serological host responses to PGL-1, LAM and Ag85 M. leprae antigens were measured by ELISA. Total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low density lipoprotein (LDL) were measured by spectrophotometric method. RESULTS: The host antibody response to M. leprae PGL-1, LAM and Ag85 antigens were significantly reduced in patients with ENL reactions compared to LL controls after treatment. Comparison between patients with acute and chronic ENL showed that host-response to PGL-1 was significantly reduced in chronic ENL after prednisolone treatment. Untreated patients with ENL reactions had low lipid concentration compared to LL controls. However, after treatment, both groups had comparable lipid profiles except for LDL, which was significantly higher in patients with ENL reaction. Comparison within the ENL group before and after treatment showed that prednisolone significantly increased LDL and HDL levels in ENL patients and this was more prominent in chronic ENL than in acute patients with ENL. CONCLUSION: The significantly increased prednisolone-induced LDL and TG levels, particularly in patients with chronic ENL reactions, is a concern in the use of prednisolone for extended periods in ENL patients. The findings highlight the importance of monitoring lipid profiles during treatment of patients to minimize the long-term risk of prednisolone-induced complications.

Metformina, un medicamento antidiabético como agente terapéutico en el tratamiento del eritema nodoso leproso crónico de moderado a severo / No disponible

El eritema nodoso leproso (ENL) o leprorreacción tipo 2 es una complicación que afecta a los pacientes de lepra lepromatosa y borderline lepromatosa. El ENL está considerado un episodio mediado por inmunocomplejos o reacción de hipersensibilidad de tipo III. También se asocia a niveles elevados séricos de factor de necrosis tumoral alfa (TNF-α). Los dos principios activos administrados para su control son la talidomida y la prednisolona orales, ya que ambos inhiben el TNF. Por los efectos adversos de estos medicamentos, proponemos el uso de un medicamento antidiabético con un buen perfil de seguridad para controlar la inflamación en el ENL. Los beneficios de la metformina sobre la medicación actual son su perfil de seguridad, disponibilidad en el mercado durante décadas, seguridad en mujeres embarazadas, amplio rango de dosis y no requiere complicados seguimientos de control. Además, la metformina se puede administrar como monoterapia o en combinación con dosis bajas de esteroides o en pacientes ENL diabéticos. Se propone investigar su administración en las ENL

Erythema Nodosum leprosum (ENL) or type 2 Leprae reaction is a known complication affecting lepromatous and borderline lepromatous leprosy patients. ENL has been regarded as an immune complex-mediated disease or type III hypersensitivity reaction. ENL was associated with high serum tumour necrosis factor-alpha (TNF alpha) levels. Capsule Thalidomide (TLD) and systemic oral prednisolone are the two current effective drugs for the management of ENL by inhibiting TNF. Because of major adverse effects by these drugs, it is hypothesized to use an antidiabetic drug with good safety profile for managing the inflammations in ENL. The benefits of using metformin over the currently available drugs are its safety profile, available in market for long decades, can be given safely in pregnant women, wide range of dose selection and no much follow up special investigations. In addition metformin can be used as monotheraphy or in combination with low dose of steroids or in diabetic ENL patients. This hypothesis will encourage the researcher in field of leprosy to try with a safe drug

A Randomized Controlled Double Blind Trial of Ciclosporin versus Prednisolone in the Management of Leprosy Patients with New Type 1 Reaction, in Ethiopia.

BACKGROUND: Leprosy Type 1 (T1R) reactions are immune-mediated events leading to nerve damage and preventable disability affecting hands, feet and eyes. Type 1 Reactions are treated with oral corticosteroids. There is little evidence on alternative treatments for patients who do not respond to steroids or experience steroid adverse effects. We report the results of a randomized controlled trial testing the efficacy and adverse effect profile of ciclosporin and prednisolone (CnP) in comparison to prednisolone only (P) in patients with new T1R in Ethiopia. Ciclosporin is a potent immunosuppressant. Outcomes were measured using a clinical severity score, recurrence rate, adverse events and quality of life. RESULTS: Seventy three patients with new T1R were randomized to receive CnP or P for 20 weeks. Recovery rates in skin signs was similar in both groups (91% vs 88%). Improvements in nerve function both, new and old, sensory (66% vs 49%) and motor (75% vs 74%) loss were higher (but not significantly so) in the patients on CnP. Recurrences rates of T1R (85%) were high in both groups, and recurrences occurred significantly earlier (8 weeks) in patients CnP, who needed 10% more additional prednisolone. Serious major and minor adverse events rates were similar in patients in the two treatment arms of the study. Both groups had a significant improvement in their quality of life after the study, measured by the SF-36. CONCLUSIONS: This is the first double-blind RCT assessing ciclosporin, in the management of T1R in Africa. Ciclosporin could be a safe alternative second-line drug for patients with T1R who are not improving with prednisolone or are experiencing adverse events related to prednisolone. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for leprosy patients with reactions and nerve damage are needed.

Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia.

BACKGROUND: Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL. METHODS AND RESULTS: Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin. CONCLUSIONS: This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients' assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid-sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale.

Ileofemoral Deep Vein Thrombosis (DVT) in Steroid Treated Lepra Type 2 Reaction Patient.

In 1998 a 57-year-old man having skin leisons of 6 months duration reported to Central Leprosy Teaching and Research Institute (CLTRI), Chengalpattu. It was diagnosed as a case of borderline lepromatous leprosy with a type 2 lepra reaction, was treated with multi bacillary-multi drug therapy (MBMDT) for a period of 12 months and the patient was released from treatment (RFT) in September 1999. For reactions the patient was treated with prednisolone for more than 10 months. After 14 years in April 2013 the same patient presented to CLTRI with complaints of weakness of both hands with loss of sensation for 4 months, so making a diagnosis suggestive of MB relapse with neuritis the patient was started with MB-MDT for period of 12 months with initial prednisolone 25 mg OD dose then increased to 40 mg for painful swollen leg and to follow the neuritis associated pain and swelling. Increased dose is not beneficial and the patient was investigated for other pathology. Doppler ultra-sound revealed a left ileofemoral deep vein thrombosis (DVT) in that patient with levels. Prednisolone was withdrawn and the patient was started with anticoagulant heparin followed by warfarin. During this period rifampicin was also withdrawn. After patient was in good condition he was put on MB-MDT regimen. Till the 6th pulse the patient continues to show improvement in functions without steroids and any tenderness, he is taking multivitamins; regular physiotherapy. This DVT appears to be due to prednisolone and such causative relationship though rare should be kept in mind when patient on long term treatment with steroids/and or immobilized or on prolonged bed rest report with such symptomatology.

Using methotrexate to treat patients with ENL unresponsive to steroids and clofazimine: a report on 9 patients.

UNLABELLED: Erythema nodosum leprosum (ENL) is a chronic recurrent systemic complication of multi-bacillary leprosy frequently associated with the development of neuritis, iritis, orchitis, arthritis and dactylitis. It is well managed by thalidomide, but thalidomide is not available in Bangladesh. The World Health Organization recommends high doses of clofazimine and prednisolone. About 19% of patients do not respond completely to this regimen or experience relapse when reducing steroid dosage. OBJECTIVE: We undertook this study to determine whether oral prednisolone combined with methotrexate was an effective and safe treatment regimen for individuals with ENL resistant to clofazimine and prednisolone. METHODOLOGY: Between September, 2006-June, 2011, we treated nine resistant ENL patients with a combination of prednisolone and methotrexate for 24-36 months with a mean duration of 30 months. RESULT: We observed improvement leading to persistent remission of ENL in all our patients. Adverse effects were mild weight gain, weight gain with facial swelling, folliculitis and extensive Pityriasis versicolor infection in one patient and crusted scabies in another. CONCLUSION: A combination of prednisolone and methotrexate was safe and effective in managing ENL not controlled by clofazimine and prednisolone.

Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study.

The present study was undertaken to compare the efficacy and safety of thalidomide to that of oral prednisolone in the treatment of moderate to severe type 2 lepra reaction. Sixty patients with a histologically confirmed diagnosis of erythema nodosum leprosum with a clinical score of 4 or more (i.e. moderate to severe type 2 reaction) were randomly allocated to two groups comprising 30 patients each. Group 1 patients were given thalidomide at a dose of 300 mg/day for 1 week and the dose was gradually reduced, and Group 2 received prednisolone 40 mg daily for 2 weeks, which was tapered by 10 mg every 2 weeks. Thalidomide induced a faster clinical response (cutaneous as well as systemic) compared with prednisolone. Patients taking thalidomide had fewer relapses and a longer period of remission than those receiving prednisolone.

A study of steroid-induced diabetes mellitus in leprosy.

Steroids, while still the most powerful drugs to manage leprosy reactions, predispose some patients to other morbidities such as diabetes, glaucoma, hypertension etc. A prospective cohort study was done in Kolkata, India among leprosy patients in reaction to determine the extent of steroid induced diabetes mellitus (SID). All leprosy patients with type 1 or type 2 reactions or neuritis admitted in 2006 to the Leprosy Mission Hospital in Kolkata, who had no past or current history and whose blood sugars on fasting were <126 mg/dl or postprandial <200 mg/dl were monitored fortnightly while on steroid therapy, estimating blood glucose by a glucometer using standard strips. Of 81 patients, 19 (23.5%) manifested steroid-induced diabetes mellitus. Compared to those who didn't, there were significantly more LL/BL patients with positive BI among SID whose cumulative prednisolone dosage was nearly 9000 mg as compared to half the amount among others. Steroid induced diabetes is a serious complication among leprosy patients treated with prednisolone for reactions requiring careful monitoring for detection and appropriate clinical management.

Sarcoidosis mimics lepromatous leprosy: a case report.

A 34-year-old Thai man presented with a two years history of progressively enlarged lepromatous leprosy like nodules and plaques on his back, chest, and scalp. Skin biopsy showed diffuse nonnecrotizing granulomatous inflammation with numerous multinucleated giant cells, lymphocytes, and plasma cells infiltration. The missed diagnosis of leprosy was made and was treated with antilepromatous drugs for one year. After repeated skin biopsy, the diagnosis was compatible with sarcoidosis. He was treated with prednisolone 40 mg per day for two weeks. The lesions gradually decreased in size and were controlled with prednisolone 10 mg per day.

Guillain-Barré syndrome-like presentation in borderline leprosy with type-2 reaction.

A 46-year-old man with borderline lepromatous leprosy with type-2 reaction being treated with multi-bacilliary-multiple drug therapy and steroids presented with an acute onset of flaccid quadriparesis. A nerve conduction study and CSF analysis were similar to that seen in Guillain Barre syndrome. Muscle weakness improved considerably with an increased dose of corticosteroid; after 6 months the patient recovered completely.

Reactions and their management.

The uneventful response to chemotherapy in leprosy is marked by clinically disturbing episodes encountered in 20-30% of patients and these phenomena are called "reactions". Generally they are classified as reversal reaction (type-1) and erythema nodosum leprosum (type-2). The cutaneous menifestations are: (1) Type-2 reactions in LL, BL types constituting erythema nodosum leprosum, erythema multiforme, erythema necroticans, subcutaneous nodules, lepromatous exacerbation. (2) Type-1 reactions in borderline and tuberculoid leprosy. The other manifestations include: Acute neuritis, lymphadenitis, arthritis, oedema of the hands and feet, ocular lesions, etc. Sequelae of reactions are: Paralytic deformities, non-paralytic deformities, extensive scarring and renal damage. A simple guideline to identify the risk-prone cases has been narrated. Prednisolone in standard dosage schedule as recommended by WHO is now being widely used in control programmes.

Adverse events of standardized regimens of corticosteroids for prophylaxis and treatment of nerve function impairment in leprosy: results from the 'TRIPOD' trials.

Reactions in leprosy causing nerve function impairment (NFI) are increasingly treated with standardized regimens of corticosteroids, often under field conditions. Safety concerns led to an assessment of adverse events of corticosteroids, based on data of three trials studying prevention of NFI (the TRIPOD study). A multicentre, randomized, double-blind placebo-controlled trial was conducted in leprosy control programmes in Nepal and Bangladesh. Treatment was with prednisolone according to fixed schedules for 16 weeks, starting in one trial with 20 mg/day (prophylactic regimen: total dosage 1.96 g) and in the other two trials with 40 mg/day (therapeutic regimen: total dosage 2.52 g). Minor adverse events were defined as moon face, fungal infections, acne, and gastric pain requiring antacid. Major adverse events were defined as psychosis, peptic ulcer, glaucoma, cataract, diabetes and hypertension. Also, the occurrence of infected plantar, palmar, and corneal ulceration was monitored, together with occurrence of TB. Considering all three trials together, minor adverse events were observed in 130/815 patients (16%). Of these, 51/414 (12%) were in the placebo group and 79/401 (20%) in the prednisolone group. The relative risk for minor adverse events in the prednisolone group was 1.6 (P = 0.004). Adverse events with a significantly increased risk were acne, fungal infections and gastric pain. Major adverse events were observed in 15/815 patients (2%); 7/414 (2%) in the placebo group and 8/401 (2%) in the prednisolone group. No major adverse events had a significantly increased risk in the prednisolone arm of the trials. No cases of TB were observed in 300 patients who could be followed-up for 24 months. Standardized regimens of corticosteroids for both prophylaxis and treatment of reactions and NFI in leprosy under field conditions in developing countries are safe when a standard pre-treatment examination is performed, treatment for minor conditions can be carried out by field staff, referral for specialized medical care is possible, and sufficient follow-up is done during and after treatment.

Steroid therapy for paralytic deformities in leprosy.

One-hundred-forty-nine patients with 272 nerve paralyses, with visible deformity and gross disability, were prospectively followed up with steroid therapy. Out of 151 ulnar paralyses, 101 recovered (67%). Out of 52 median nerve paralyses, 45 recovered (86%); out of 69 foot drops, 54 recovered (78%) for an overall improvement of 73%. Serious side effects were few. Hence, steroid therapy should be widely encouraged for the treatment of early nerve damage to prevent permanent deformity/disability, and vigilance in spotting complications of steroid therapy is emphasized.

Response to treatment by multidrug regimens in the THELEP controlled clinical drug trials. Subcommittee on Clinical Trials of the Chemotherapy of Leprosy (THELEP) Scientific Working Group of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

During the period 1977-1983, clinical trials of five multidrug regimens were conducted among 215 patients with previously untreated multibacillary leprosy at the Institut Marchoux, Bamako, Mali, and the Central Leprosy Teaching and Research Institute, Chingleput, South India. The trials were designed primarily to permit measurement of the proportions of persisting Mycobacterium leprae in the patients' skin lesions. In addition, the combination of the large number of patients studied, the large volume of carefully standardized data, and the employment of multidrug regimens provided a unique opportunity to measure the clinical response of patients to treatment by these regimens. Persisting M. leprae were detected in 7.8% of all specimens; the frequency did not vary with centre, regimen, or duration of treatment. The bacterial index (BI) decreased by a mean annual rate of 75%, the logarithmic biopsy index by a mean annual rate of 87%, and the logarithm10 number of acid-fast bacilli per g tissue by a mean annual rate of 69%. The rate of decrease of these measures of the numbers of M. leprae was related to the 'strength' of the regimen. Although no difference of clinical status as a function of regimen was demonstrated, a difference was observed between the two centres, probably the result of different clinical criteria employed by the responsible physicians. A change of histopathological classification in the course of the trials was recorded for 12% of the patients, most representing upgrading from LLs to BL, without relation to regimen or treatment centre. ENL was less severe for the patients treated by the maximal regimen in Chingleput, which included daily clofazimine; as expected, the majority of patients treated by this regimen were found to have maximal pigmentation. Prednisolone was evidently preferred for treatment of ENL in Chingleput, whereas thalidomide was preferred in Bamako. Fourteen cases of jaundice were observed, primarily among the patients treated by the maximal regimens, that included daily administration of rifampicin for the entire two years of the trials. Measurements of weight and blood pressure, and studies of the blood and of hepatic and urinary tract function revealed only negligible differences among regimens and between centres. In many cases, those differences that were observed were associated with ENL.