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. 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. 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.
Leprosy is a chronic granulomatous infection principally affecting the skin and peripheral nerves caused by Mycobacterium leprae [1]. Clinical features include skin lesions and neuropathy manifesting as loss of sensation, weakness or nerve pain. Delayed diagnosis or treatment may result in deformities and disability. In 2012,232 857 new cases globally were reported by the WHO [2]. The infection is curable with a combination of antibiotics known as multi-drug therapy (MDT) taken for either 6 or 12 months, but the immunological reactions continue to cause morbidity after the end of treatment. Patients with Type 2 reactions in leprosy develop tender, sub-cutaneous nodules, called erythema nodosum leprosum (ENL), which usually affects multiple organs causing uveitis, neuritis, arthritis, dactylitis, lymphadenitis and orchitis. Systemic illness is frequently associated with symptoms like fever and malaise [3]. Severe ENL can be life-threatening. The recurrent inflammation of eyes and testes can lead to blindness and sterility. In field studies, the rate of ENL in LL patients ranged between 11. 1% and 26%, and in BL patients between 2. 7% and 5. 1%, with higher proportions found in hospital based studies [4]. Although patients may present with ENL, it often occurs during MDT or after completion of MDT. Three patterns of ENL were identified in a cohort of 82 Indian patients: single acute episodes, recurrent acute episodes and chronic ENL [5]. Acute episodes were defined as single episodes responding to steroid treatment and accounted for only 6% of ENL cases, acute multiple ENL (32%) comprised of recurrent episodes with periods off treatment, and chronic when patients needed steroid treatment for more than six months (62%). In Ethiopia, almost one third of patients developed a chronic condition lasting more than two years [6] whereas a hospital based retrospective study in Ethiopia showed that 50% of patients with ENL had chronic ENL [7]. Episodes of active ENL have been reported to last from 14 days [8] to 26. 1 weeks [9]. And episodes occurring over seven or more years have been reported [5,10]. ENL is a result of a combination of cellular activation and humoral immunological response to M. leprae, characterised by the deposition of extra-vascular immune complexes leading to neutrophil infiltration and activation of complement in many organs [11]. It is associated with high levels of circulating tumour necrosis factor-α [12], interleukins IL-2, IL-6, IL-10, IL-8, IL-12 [13] and IFNγ [14], causing systemic toxicity. Circulating immune complexes are formed and deposited throughout the body. This mechanism may account for the eruption of nodules in the skin at sites apparently previously unaffected and for the occurrence of nephritis, arthralgia and neuritis [15]. Immuno-suppression is required to control the symptoms and signs of ENL. In Ethiopia, patients with severe ENL are started on 60 to 80mg of oral prednisolone daily. The effectiveness is variable, and some patients with chronic or recurrent ENL may need to take prednisolone for several years [5]. These prolonged, high doses of steroids are associated with steroid adverse effects [16], and increased mortality of patients with ENL [7]. There is some evidence that clofazimine in MDT may have a protective effect against ENL [17]. The protective effect of clofazimine in preventing ENL is lost after 1 year when MB MDT is stopped. High dose clofazimine is used in the treatment of ENL in certain settings, although trials to show benefit are lacking. Studies are underway in the Philippines [18]. Thalidomide, not available in Ethiopia, has a dramatic effect in controlling ENL and preventing recurrences, although its use is limited by teratogenicity and possible neurotoxicity [19,20]. Thalidomide is known to be ineffective in neuritis or iritis. There is therefore a need to assess other potentially useful drugs in the management of ENL. Ciclosporin is a potent immuno-suppressant used in the treatment for psoriasis, Behcet’s disease, rheumatoid arthritis, inflammatory bowel disease and in solid organ transplantation. Ciclosporin inhibits the development of cell mediated immunity, the production of T cell dependent antibodies and the production and release of lymphokines such as IL-2, which are all a feature of ENL [21]. In-vitro experiments on serum from 25 patients with ENL supported the role of Cyclosprine A (ciclosporin) in restoring the activity of “T suppressor cells” and inhibited IL-2 production [22]. A case series of three patients with uncontrolled ENL on steroids and thalidomide responded well to ciclosporin 10mg/kg/day for a period of 8 months [23]. Their clinical response was reported as being good with decreased need for steroids and decreased recurrence of ENL. As ciclosporin has a slow onset of action and requires about two to four weeks to build up to a therapeutic level [24], prednisolone is usually started at the same time and gradually decreased. In view of the above results, and the need for a non-teratogenic alternative for the management of ENL, ciclosporin was compared to prednisolone only treatment in patients with either acute or chronic ENL. Two pilot studies for phase III clinical trials were designed with the aim to assess the efficacy, safety and tolerability of ciclosporin. Detailed clinical outcomes were selected for these two double-blind randomized trials.
Two separate double-blind controlled trials, with similar methods were conducted randomizing patients with either new acute ENL or chronic ENL to treatment with either ciclosporin or prednisolone. A full history was taken and clinical examination performed. Nerve function was assessed at each visit. Sensory testing was performed with five Semmes-Weinstein monofilaments at designated test sites on hands and feet. Voluntary muscle power was graded using the modified Medical Research Council scale. The severity of ENL symptoms was graded as mild, moderate or severe by consensus of two physicians blinded to each other’s assessment. Laboratory investigations consisted of the following: slit skin smears for bacterial index, full blood count, HIV test, renal function, liver function tests, glucose, erythrocyte sedimentation rate (ESR), urinalysis and a stool specimen examined for ova, cysts and parasites. A skin biopsy was performed for Ridley-Jopling classification. Symptomatic screening for TB was carried out followed by chest x-ray and sputum samples for acid fast bacilli if necessary. All individuals received three days of albendazole 400mg daily to reduce the risk of hyper-infection with Strongyloides stercoralis. Women of reproductive age were tested for pregnancy and contraception was prescribed. Assessments were carried out at weeks 2,4, 6,8, 12,16,20,24,28, and 32 from baseline. Assessment consisted of focussed questions about specific symptoms and adverse effects. The clinical examination including weight and blood pressure was repeated. Blood tests (full blood count, renal function and liver function), and urinalysis were carried out at each visit. Quality of life was assessed with a validated Amharic translation of the SF-36 health-related quality of life assessment tool at recruitment and at week 28. The primary outcome measure was the number of ENL recurrence episodes per patient for each treatment arm, both during treatment period (week 1–16) and the follow-up period (week 17–32). An episode of ENL was defined as the occurrence of ENL requiring the institution or change of treatment (such as an increase in dosage or frequency of treatment or the addition of or switching to another drug). Secondary outcomes were: mean time to ENL recurrence after initial control; severity of ENL at recurrence; amount of additional prednisolone required by patients; frequency of adverse events for patients in each treatment arm; and the difference in score in Quality of Life assessment between start and end for patients in each treatment arm. Severity of ENL was rated in by two physicians’ opinion on the severity, with the options of grading the ENL episode as none, mild, moderate or severe. Additional prednisone prescribed for flare up of ENL (defined as the appearance of 6 or more new ENL nodules) and for deterioration of nerve function (sustained for at least 2 weeks). The dose of additional prednisolone was determined by the examining physician depending on the severity of the symptoms. Adverse events were enquired about at each visit using a standardized form with anticipated adverse events attributable to prednisolone and ciclosporin. Any other adverse events reported by the participant or identified by the physicians were also recorded. Major adverse events were defined as any event leading to admission or prolonged admission, study un-blinding or death. Amongst these were included psychosis, severe infection including tuberculosis, peptic ulcer, glaucoma, cataract, diabetes mellitus major, severe hypertension and haematological abnormalities. Minor adverse events were defined as moon face, acne, hirsutism, gum hyperplasia, fungal infections, gastric pain requiring antacids or any other minor adverse event not requiring admission to hospital or un-blinding. Two study physicians (blinded to each other’s decision) reviewed each adverse event and decided whether it was linked to prednisolone or ciclosporin. Adverse events were also graded by severity, using the Common Terminology Criteria for Adverse Events [25] grading system. Eligible individuals were recruited consecutively and randomly assigned in 1: 1 ratio (block size of two and four), with a computer-generated randomisation list, to one of the two treatment arms. A standard envelope system was used for allocation concealment. The envelopes were prepared by Dr Rea Tschopp (Swiss Tropical and Public Health Institute) who had no other involvement in the study. The allocation procedure was done by the pharmacist who had no clinic contact and was the only individual aware of the treatment allocation. All study participants, physicians, nurses, ward staff, laboratory staff and the physiotherapists were blinded to the allocation. The allocation code was revealed to the researchers once the study was completed, except in the case of a serious adverse event necessitating un-blinding. The sample size was limited by the number of patients presenting with ENL at the leprosy clinic at ALERT. ENL is an infrequent condition and for these pilot studies, it was planned to recruit at least 12 patients with new ENL and 18 patients with recurrent or chronic ENL. Sample size calculations are not generally required for pilot studies, especially for uncommon conditions. The data was entered on Access database and analysed using the Statistical Package for the Social Sciences (SPSS version 20. SPSS Inc. , Chicago, Illinois). An intention to treat analysis was used for calculating the effects of treatment on individuals in each group. As the data in these small studies was not normally distributed, non-parametric tests were used to assess statistical significance (Mann-Whitney U Test). The studies were performed according to the Helsinki Declaration (2008 revision) and approved by the Ethics Committee of the London School of Hygiene and Tropical Medicine (5377–8), the ALERT and AHRI Ethical Review Committee (AA/ht/248/09), the National Ethics Review Committee of Ethiopia (RDHE/34-90/2009), and the Drug Administration and Control Authority of Ethiopia (02/12/70/926). All staff involved underwent Good Clinical Practice training and an independent Data and Safety Monitoring Board reviewed the study design and the safety and efficacy data. The studies are registered with ClinicalTrials. gov: NCT00919776 and NCT00919542. Written informed consent was obtained in Amharic or if the patient spoke a different Ethiopian language, then the information and consent forms were translated verbally into the appropriate language before signing the consent form.
Ten patients with new ENL experienced one or more episodes of ENL recurrence. The mean number of ENL recurrence for the two treatment arm was 1. 29 recurrences per patient in the ciclosporin arm and 2. 4 recurrences per patient for the prednisolone arm. The difference in the total numbers of ENL flare-up is due to fewer flare-ups occurring in ciclosporin group during the intervention period. The number of ENL recurrences per patient were not significantly different between the two treatment arms. Seventeen patients with chronic ENL experienced one or more episodes of ENL recurrence. The mean number of ENL recurrence for the two treatment arm was 2. 3 recurrences per patient in the ciclosporin arm and 2. 0 recurrence per patient for the prednisolone arm. The mean number of ENL recurrences per patient were not significantly different between the two groups of patients (Mann-Whitney U Test, p = 0. 684). The difference in number of ENL recurrences between the two study arms, is largest during the treatment period with more episodes occurring in the ciclosporin arm.
ENL is a complicated phenomenon and we are unable to predict which patients will develop ENL, how severely and how long they will require treatment. ENL is often chronic and recurrent in nature. Although most available immunosuppressant medications may work similarly for controlling the acute symptoms of ENL, prevention of recurrences is far more difficult. Ciclosporin showed promising results in the management of acute ENL in this small pilot study. It 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. Future studies on ENL should have a more tailored prednisolone regimen for patients with chronic or recurrent ENL who are steroid dependant. An alternative regimen of prednisolone is needed, possibly individualized at 1mg/kg then gradually decreasing more slowly over a period of at least 8 weeks allowing for ciclosporin to take over the immunosuppressive action. A valuable feature of these studies is that they demonstrate the importance of separating patients with the first ENL episode from those with chronic ENL. In future studies, patients with acute ENL, may benefit from a faster reduction of prednisolone, whereas patients with chronic ENL would require a slower reduction of prednisolone and a more sustained immune-suppression. An internationally agreed on definition of ENL is essential in order to design adequately powered, high quality multi-centred trials.
Leprosy is caused by a mycobacterium, and is curable with multi-drug therapy, a combination of antibiotics taken for 6 or 12 months. However, some leprosy patients develop an inflammatory condition known as erythema nodosum leprosum (ENL), or Type 2 reaction. ENL affects multiple organs and causes systemic illness as well as nerve damage that leads to disability and deformity. ENL is often chronic and patients have multiple flare-ups requiring prolonged steroid treatment. Patients are at risk of developing adverse events related to long term steroids. There are no effective, non-teratogenic alternative treatments for patients who no longer respond to steroids or have contra-indications to steroids. We conducted two studies to see if ciclosporin, an immunosuppressant used in many inflammatory conditions, could safely be used either as an alternative or in conjunction with prednisolone to treat ENL. Patients with acute ENL showed promising results with ciclosporin treatment, with a 16 week median delay in recurrence of ENL. It did not however appear to have a significant steroid–sparing effects in patients with chronic ENL. This suggests that further ENL studies should look at carefully tailored regimens of medication in order to assess the effect of ciclosporin or other immunosuppressant drugs.
dermatology
somatosensory system
medicine and health sciences
chemical compounds
clinical research design
pathology and laboratory medicine
tropical diseases
limbs (anatomy)
neuroscience
organic compounds
health care
research design
bacterial diseases
steroids
signs and symptoms
neglected tropical diseases
research and analysis methods
infectious diseases
musculoskeletal system
sensory physiology
erythema
chemistry
adverse events
pilot studies
arms
pain sensation
quality of life
organic chemistry
anatomy
physiology
leprosy
biology and life sciences
sensory systems
physical sciences
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