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. 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. 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.
Leprosy is a chronic granulomatous infection principally affecting the skin and peripheral nerves caused by the obligate intracellular organism Mycobacterium Leprae [1]. In 2014, the WHO reported 213 899 new cases globally [2]. Multi-drug therapy (MDT) cures the infection by Mycobacterium leprae. Although the bacteria may be eliminated, the damage done to nerves by the bacteria and by consequent immunological reactions leads to very visible and stigmatizing disabilities and deformities. Type 1 reactions (T1R) affect up to 30% of patients with borderline leprosy [3]. Although T1Rs can occur at any time, the frequency is higher in the first six months of MDT treatment [4]. T1R manifest clinically with erythema and oedema of skin lesions and tender peripheral nerves with loss of nerve function. Skin lesions become acutely inflamed and oedematous. Inflammation is usually in pre-existing lesions, but not all the lesions may be involved. Oedema of the hands, feet and face can also be a feature of a reaction but systemic symptoms are unusual. Nerves can become swollen, painful and tender. Acute neuritis may also occur without evidence of skin inflammation. The inflammatory process in leprosy reactions leads to nerve function impairment (NFI) which if not treated rapidly leads to permanent loss of nerve function causing peripheral sensory and motor neuropathy. Recurrent T1Rs can lead to further nerve damage [5]. Progressive NFI can also occur in the absence of a reactional state, so the history of timing of symptoms aids to differentiate from NFI due to a reaction. T1Rs are the result of spontaneous enhancement of cellular immunity and delayed hypersensitivity reactions to M. leprae antigens presented by macrophages and dendritic cells in the skin and by Schwann cells on nerves [6,7]. Immuno-suppression is required to control the symptoms and signs of T1R, but this management remains challenging. Oral prednisolone, the drug of choice, has frequent side effects and approximately 40% of individuals with T1R do not show clinical improvement [8,9]. There is a lack of evidence for efficacious and safe second line treatments for T1R. Ciclosporin is a potent immuno-suppressant that has been widely and successfully used as a treatment for psoriasis, Behcet’s disease, rheumatoid arthritis, inflammatory bowel disease and transplantation. Given that ciclosporin selectively inhibits the activation of CD4 T cells and the expression of cytokines such as IL-2 and TNF-α [10], it was thought to be useful in the treatment of T1R. Three case studies have been published [11,12], showing good response to ciclosporin and delayed recurrence of T1R. An uncontrolled pilot study was carried out assessing the efficacy of ciclosporin in severe T1R in Ethiopian and Nepali patients [13]. In the Ethiopian part of the study, performed in ALERT Hospital, Addis Ababa, ciclosporin was given to 33 patients with T1R for three months in a dose range of 5–7. 5mg/kg/day. This led to improvements in skin lesions in 85% of patients and 45% of patients had improvement in nerve pain and tenderness. Sensory nerve impairment improved in 45% of Ethiopian patients and motor function impairment in 53% of patients. Almost 88% of Ethiopian patients needed the higher dose of ciclosporin to show improvement partly because of the severity of the reaction. The study showed that in those patients treated with high-dose ciclosporin, 53% of patients with sensory impairment and 60% with motor impairment improved. A few Ethiopian patients with NFI of greater than 6 months duration, responded to ciclosporin. This was an encouraging result as in many leprosy endemic countries patients present late with chronic NFI. Almost 70% percent of Ethiopian patients developed new signs of reaction after stopping treatment, suggesting that they would benefit from a treatment period longer than three months. In the Nepali study, ten patients treated with ciclosporin were compared to a similar group of patients treated with prednisolone. Improvement in skin lesion was at 87. 5% in the ciclosporin group compared to 74% in the prednisolone group. Similarly the ciclosporin group showed 83% improvement in sensory testing compared to 22% in the prednisolone group. Few ciclosporin side effects were seen in the two clinical trials conducted in T1R. Of the 33 Ethiopian patients, three developed hypertension; of the ten Nepali patients one developed jaundice (possibly dapsone related), two developed raised serum creatinine levels and two other patients developed mild side effects (loss of appetite and indigestion controlled with antacids). The results of the above studies were encouraging as it appeared that ciclosporin monotherapy may be an effective alternative treatment in prednisolone-resistant or prednisolone-dependent cases of T1R. The study recommended using higher doses of ciclosporin (7. 5mg/kg/day) in future studies, longer periods of treatment, as well as tapering the drug slowly or adding low dose prednisolone to prevent relapse. We tested our hypothesis that ciclosporin would be as effective as prednisolone in the treatment of patients with leprosy reactions and nerve function impairment and that patients treated with ciclosporin would have fewer side effects than patients treated with prednisolone. A randomized controlled trial comparing ciclosporin and prednisolone in the treatment of leprosy T1R was designed and conducted.
A double-blind controlled trial was conducted randomizing patients with new and recent onset T1R to treatment with either ciclosporin and prednisolone or prednisolone alone. Patients were recruited at the ALERT hospital leprosy clinic, in Addis Ababa, Ethiopia. Type 1 Reaction (T1R) was diagnosed when a patient with leprosy had erythema and oedema in skin lesions and/or neuritis. A patient could have skin reaction only, a nerve reaction only or a skin and nerve reaction. Neuritis was diagnosed when a leprosy patient had any of the following on history or examination: Nerve function impairment (NFI) was defined as clinically detectable impairment of sensory or motor nerve function using the definitions below [14]. New NFI was defined as less than six months duration of reduction in sensory or motor function on history or examination. Motor loss was defined by a decrease in voluntary muscle testing (VMT) score, by 1 point or more from the normal score of 5, using the modified MRC scale. Sensory loss was defined by a decrease in sensation as measured by Semmes Weinstein monofilament testing. In the hands, this was defined as not being able to perceive the 0. 2gm monofilament at 2 points out of 3 in each nerve of the hand. In the feet, this was defined as not being able to perceive the 2gm monofilament at 3 out of 4 sites of the foot. Silent neuropathy (SN): A patient had silent neuropathy when he/she had sensory and/or motor impairment of recent onset (less than six months duration) in an area innervated by one or more nerve without signs of a reaction (RR or ENL) or nerve pain with or without tenderness. T1R recurrence or flare-up was defined as an increase in skin severity score to 4 or more out of 9 AND/OR an increase in NFI defined as worsening of VMT by one point in two or more muscles, or by 2 points in one muscle and/or worsening of ST: decreased sensation in at least two out of 3 points per nerve on the hand and/or 3 or more points on the feet. NB: nerve tenderness was not part of the definition for T1R recurrence. NFI outcomes were defined clinically as (based on Marlowe study [13]: Clinical Severity Score: used to assess T1R severity (21 items; range of 0–63). The maximum score possible for skin (A), sensation (B) and motor function (C) are 9,24 and 30 respectively. Mild T1R is characterised by a score of 4 or less; moderate T1R by a score between 4. 5 and 8. 5 and severe T1R is a score of 9 or more. This Severity Scale for T1R based, on the INFIR clinical severity scoring system, was developed and prospectively validated in Bangladesh and Brazil [15]. It has so far been used in clinical trials on intravenous methylprednisolone [16], on azathioprine [17] and in the on-going TENLEP studies [18]. Participants (aged between 18 and 65 years and weighing more than 30 kg) were recruited from the leprosy clinic in ALERT Hospital, Addis Ababa, Ethiopia. Individuals with newly diagnosed T1R or neuritis were eligible for entry in the trial. The following individuals were excluded: those unwilling to give consent or return for follow up; those with severe active infections such as tuberculosis or severe inter-current disease; HIV positive individuals; pregnant or breastfeeding women. Women of reproductive age not willing to use contraception for the duration of the study were also excluded. The participants were randomly allocated to receive the standard ALERT hospital prednisolone regimen for T1R or the ciclosporin (Cn) arm (Table 1). We theorized that given the slow onset of action of ciclosporin compared to prednisolone and high relapse rate of T1R, the most effective regimen in leprosy reaction would be an initial ciclosporin dose of 7. 5mg/kg/day, divided in two doses, gradually tapered down over a total period of 20 weeks and adding prednisolone cover for the first four weeks of treatment. The TIR patients on the prednisolone arm (P) would get 20 weeks of a gradually reducing course of prednisolone only. Weight adjusted medication cards for each treatment arm were designed for the pharmacist, using a 10 kilogram range in patient weight. A double placebo system was used because of the different formulation of prednisolone (pink tablets) and ciclosporin (brown capsules). Each placebo was identical to its active counterpart and each participant took a combination of brown capsules and pink tablets as an essential way of blinding both patients and study physicians. Prednisolone tablets and prednisolone placebo (PP) tablets were produced by Ethiopian Pharmaceuticals Manufacturing Factory (EPHARM), in Addis Ababa, Ethiopia. Both were analysed for active ingredient by Dr Harparkash Kaur at LSHTM. Ciclosporin capsules (Panimune Bioral) and ciclosporin placebo (PC) capsules were produced by Panacea-Biotec Ltd, Solan, India and were provided with a certificate of analysis. A full history was taken and clinical examination performed. Nerve function was assessed at each visit, by one of three trained physiotherapists. 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 results of the examination findings were recorded and a Clinical Severity Score calculated using the severity scale. Severity of reaction was also recorded as mild, moderate or severe by a second physician’s opinion blinded to the Clinical Severity Score. 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 by chest x-ray and sputum samples for acid fast bacilli as necessary. All individuals received three days of albendazole 400mg daily to reduce the risk of hyper-infection with Strongyloides stercoralis at enrolment. Women of reproductive age were tested for pregnancy and contraception was prescribed, usually the oral contraceptive pill and condoms. Assessments were carried out at weeks 2,4, 6,8, 12,16,20,24,28, and 32 from enrolment. 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 [19] at recruitment and at week 28. Each patient’s quality of life is graded with two scores: a physical score (PCS) and a mental score (MCS), which in turn are composed of four subscales each. The primary outcome measure was the change in Clinical Severity Score and in clinical nerve function impairment and at week 4,20, and 28 for patients in each treatment arm. Secondary outcomes were: Criteria for using additional prednisolone were defined as sustained deterioration in nerve function nerve pain unresponsive to analgesics for a period of at least two weeks; new erythematous and raised skin patches; deterioration in nerve function which the study doctors believe requires immediate additional prednisolone and ENL flare-up with the appearance of new subcutaneous nodules. As the study was double-blinded, regimen for additional prednisolone depended on the time at which the reaction flare-up occurred. If the reaction recurrence was within the first ten weeks of treatment or there was facial involvement, extra prednisolone was added to make up a total of 40mg (with the pharmacist deciding on the exact additional dose of prednisolone required) and then tapered according to the original regimen. If T1R recurrence was after the first ten weeks of treatment, then prednisolone 20mg was added and tapered down according to the original regimen. The physician could prescribe more additional prednisolone if the reaction was severe. 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, 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. Patients who experienced blurred vision were referred to the ophthalmologist for ophthalmic review and had their serum glucose checked. Three 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 [20] grading system. Eligible individuals were recruited consecutively and randomly assigned in 1: 1 ratio (block size of 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 an individual 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, based on the Hypothesis of Non-Inferiority, was calculated with the study statistician, in consultation with ALERT hospital physicians. Prednisolone is known to show an improvement of 60% in nerve function in new T1R. Given that the true mean cure rates of the treatment agents and the active control are θ1 = θ2 = 60%, the non-inferiority margin was selected to be δ = 0. 25. The sample size was calculated using a power of β = 80% and significance of α = 0. 05, giving us a sample of n = 48 in each arm respectively. The data was entered in Access database and analysed using the Statistical Package for the Social Sciences (SPSS version 20. SPSS Inc. , Chicago, Illinois). An intention to treat analysis (ITT) was used for calculating the effects of treatment on individuals in each group and t tests and ANOVA (analysis of variance) were used as appropriate. The Mann-Whitney U test was used for all statistical tests of continuous variables and Fisher’s exact test was used to compare dichotomous variables. 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 (5376), 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 study is registered with ClinicalTrials. gov: NCT00919815. 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.
The two groups did not differ significantly in respect of reaction type, or mean number of enlarged and tender nerves per patient (Table 3). There was a significant difference in the duration of NFI between patients recruited to the two groups (Chi Square, p = 0. 039). Twice as many patients in the ciclosporin arm reported isolated new NFI but in the prednisolone arm, there were more patients reporting combination of old and new NFI. Patients in the two treatment arms had similar duration of reported T1R symptoms prior to presenting at the clinic (p = 0. 2). Severity of T1R, assessed both by specialist opinion and by the Clinical Severity Score, was not significantly different between the two groups (Table 4). The 73 patients recruited had a total of 876 peripheral nerves examined. Nerve function impairment of less than 6 months duration (new NFI) was reported for 308 nerves (35%). A further 24% of nerves were reported to have been impaired for longer than 6 months (old NFI). In both old and new NFI, sensory loss was more frequent than motor loss or mixed loss. Of the nerves examined, 72% were enlarged, and 34% of nerves were tender on palpation. A larger proportion of nerves were impaired in the ciclosporin group patients (68% vs. 52%) and this group had significantly higher proportion of purely sensory and mixed sensory/motor types of new NFI (p = 0. 0387) The ulnar nerves were found to be both the most frequently enlarged and tender nerves, followed by the lateral popliteal, radial cutaneous and posterior tibial nerves. Nerve tenderness was present in 300 nerves and was more common in the ciclosporin group (40% vs. 29%). Apart from a higher number of affected sensory nerves in the ciclosporin group, there was no major significant difference between the two groups of patients with newly diagnosed T1R, recruited to the study. The change in group mean Clinical Severity Score over time for patients in each arm of the trial is shown in Fig 2. Changes in the three sub-scores are also shown. Variation in group mean T1R severity scores during the 32 weeks and between the two treatment arms, was assessed by ANOVA. Patients in both treatment arms had large and statistically significant improvement with time in all four scores (p<0. 000). This is consistent with a good clinical response with both treatments. There was no significant difference in all four severity scores between the two treatment arms over the 32 weeks (Score A, p = 0. 241; Score B, p = 0. 664, Score C, p = 0. 749 and Clinical Severity Score, p = 0. 531). In the ANOVA week by week breakdown, patients on the ciclosporin arm showed significantly higher skin score (A), at weeks 6 and 8 (p<0. 000). This was probably due to a greater number of patients in the ciclosporin arm experiencing a flare-up in skin reaction at this time. The difference between the two treatment groups in median improvement of Clinical Severity Scores were compared at week 0,4, 6,20, and 28 as shown in Fig 3. These time periods were deemed important, as at week 4, the prednisolone in the ciclosporin arm is stopped; at week 6 is the steroid free period for those on the ciclosporin arm; at week 20 the intervention period ends, and week 28 represents the end of the study. All four components of the severity scores show a downward trend, suggesting improvement in both groups of patients. The largest and sustained decrease in score occurs in the skin (A). At week 6, the difference in skin score between the two treatment arms is evident with the patients in the ciclosporin arm having a wider range in score despite a similar median score. Throughout the 32 weeks in the study, the median sensory score (B) does not reach the score of 0, which represents intact sensation. Analysis by patient and by nerves were also done to assess the improvement in T1R in patients treated with either ciclosporin or prednisolone. The general outcome for patients (Table 5) was decided by study physician assessment on review of patient notes and taking into account the changes in skin as well as nerves between week 0 and week 20, the end of the intervention period. There is no significant difference in all six clinical outcomes listed in Table 5 between the patients in the two treatment arms. Clinical outcomes in the follow-up period were recorded as those that maintained improvement and those that relapsed at the end of treatment. A larger proportion of patients appears to be maintaining improvement after the end of the intervention period in the ciclosporin arm (67% vs. 39%, p = 0. 044). The change in motor function, between baseline and the end of intervention, in nerves with reported weakness of less than six months duration is not significantly different between the two study arms (p = 0. 085). Fig 4 illustrates that motor function in both treatment arms recovered or improved in a large proportion of nerves (74% in the ciclosporin arm and 68% in the prednisolone arm (one tailed t test: p = 0. 043). 70% of nerves with sensory loss reported as being of less than six months duration in the ciclosporin arm and 56% in the prednisolone arm improved or recovered (Fig 5). Patients who received ciclosporin and prednisolone had better improvement in nerve function impairment than those who received prednisolone only (one tailed t test: p = 0. 038). Patients in both treatment arms had their nerves assessed three months after the end of the intervention and improvement in nerve function was maintained in the majority of patients. Motor function remained stable in 88% (Cn arm) and 76% (P arm), and sensory function in 78% (Cn arm) and 79% (P arm). Nerves reported to have been impaired for longer than six months also showed improvement. Of the nerves with old motor function 37% in the Cn arm and 39% in the P arm recovered or improved. Of the nerves with old loss of sensation, 46% in the Cn arm and 36% in the P arm recovered or improved.
This study is the first double-blind RCT assessing ciclosporin, a potent immunosuppressant in the management of T1R. All the patients with T1R treated with ciclosporin and prednisolone or with prednisolone alone improved in all three Clinical Severity Score components. There was no statistically significant differences between the two study arms, suggesting that treatment of T1R with ciclosporin and prednisolone in non-inferior to prednisolone alone. Recurrences of T1R were equally frequent in both treatment arms. These recurrences were treated with additional prednisolone. The patients on the ciclosporin arm of the study received 10% less steroids than those on the prednisolone only arm during the 32 weeks of study. This study has shown that the steroid-sparing effect of ciclosporin is limited. The pilot study done by Marlowe in 2007 suggested that ciclosporin may be as efficient as prednisolone in the treatment of T1R. The study designs are different and no additional prednisolone was given in the Marlowe study for T1R or NFI flare-up; the dose of ciclosporin was increased in such cases. In view of the fewer side effects of ciclosporin compared to prednisolone, ciclosporin could be a useful safe alternative second-line drug for patients with T1R in whom prednisolone is not effective, or is causing adverse events. We would recommend that ciclosporin be prescribed in conjunction with oral prednisolone (unless the latter is contraindicated) for the initial eight weeks. Presently a 20 week course of ciclosporin for a patient in the weight range of 40–49kg, would cost USD 820, compared to a course of prednisolone costing USD 10. This study has highlighted that corticosteroid treatment for T1R and NFI is sub-optimal even when given in a standard reducing course over 20 weeks. The TENLEP multi-centre RCTs are comparing a 32-week vs 20-week course of prednisolone for NFI [18]. This would mean a cumulative dose of prednisolone greater than 5grams compared to 3. 5grams over 20 weeks recommended by Rao [24]. The development of more prolonged treatment protocols would require careful monitoring of adverse events and in particular the long term sequelae of corticosteroid therapy. This study illustrates the difficulty in switching off leprosy inflammation. Better treatment agents for reactions and nerve damage are needed. Clinical studies in T1R should be accompanied by laboratory based research to investigate the mechanisms of inflammation in T1R, identify patients at risk of recurrences and possibly identify a better agent for the treatment of T1R.
Leprosy infection is cured with multi-drug therapy (MDT), but patients may develop immune mediated skin and nerve lesions. These immunological reactions lead to disability and deformity secondary to neuropathy. Prednisolone is the main drug used to treat reactions but is only partially effective and patients have a high rate of side effects. Identifying better agents for treating leprosy reactions is an important clinical goal. We tested the safety and efficacy of ciclosporin, an immunosuppressant used in many inflammatory conditions, in Type 1 reactions (T1R) in leprosy patients in Ethiopia. A double-blind randomized controlled clinical trial comparing the efficacy and adverse event profiles of ciclosporin and prednisolone was conducted in patients presenting with acute T1R. Patients on ciclosporin and prednisolone had similar improvements in clinical outcomes which were measured as skin and nerve function improvement. Both groups had a high rate of T1R recurrence (85%) and the patients on ciclosporin required more additional prednisolone to treat recurrences. We assessed patient quality of life and this was significantly improved with both treatments. This is the first assessment of patient quality of life in a leprosy patients trial. Ciclosporin may be a useful alternative in the treatment of T1R, but that the need for additional steroids decreases its value.
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A Randomized Controlled Double Blind Trial of Ciclosporin versus Prednisolone in the Management of Leprosy Patients with New Type 1 Reaction, in Ethiopia