Comparison of effectiveness of interventions in reducing mortality in patients of toxic epidermal necrolysis: A network meta-analysis.

BACKGROUND: Limited evidence is available about effectiveness and choice of immunomodulating treatment modalities for toxic epidermal necrolysis (TEN). AIMS: To compare the effectiveness of interventions to reduce mortality in patients of toxic epidermal necrolysis through network meta-analysis. METHODS: Studies were retrieved using PubMed, Google Scholar and Cochrane Database of Systematic Reviews from inception to September 18, 2018. Only English language articles were considered. Observational and randomized controlled studies having ≥ 5 TEN patients in each intervention arm were included. Two investigators independently extracted study characteristics, intervention details and mortality data. Bayesian network meta-analysis was performed using the Markov chain Monte Carlo (MCMC) approach through the random effect model. The ranking analysis was done to provide a hierarchy of interventions. The consistency between direct and indirect evidence was assessed through node spit analysis. The primary outcome was to compare the mortality [Odds ratio OR (95% credibility interval CrI)] among all treatment modalities of TEN. RESULTS: Twenty-four studies satisfying the selection criteria were included. The network analysis showed improved survival with cyclosporine as compared to supportive care [OR- 0.19 (95% CrI: 0.05, 0.59)] and intravenous immunoglobulin [OR- 0.21 (95% CrI: 0.05, 0.76)]. The hierarchy of treatments based on "surface under the cumulative ranking curves" (SUCRA) value were cyclosporine (0.93), steroid+intravenous immunoglobulin (0.76), etanercept (0.59), steroids (0.46), intravenous immunoglobulin (0.40), supportive care (0.34) and thalidomide (0.02). No inconsistencies between direct and indirect estimates were observed for any of the treatment pairs. LIMITATIONS: Evidence is mainly based on retrospective studies. CONCLUSION: The use of cyclosporine can reduce mortality in TEN patients. Other promising immunomodulators could be steroid+intravenous immunoglobulin combination and etanercept.

Management of Darier disease: A review of the literature and update.

Darier disease (DD) is a rare type of inherited keratinizing disorder with no definitive therapeutic approach. The objective of this study is to provide a detailed literature review of all the available treatment modalities of Darier disease, including those that are both surgical and non surgical, to compare their efficacies and to propose a novel therapeutic approach. A complete search of the literature for all articles describing the different treatments of Darier disease, with no restrictions on patients' ages, gender or nationalities, was performed with the use of PubMed. A total of 68 articles were included in the study: 3 prospective studies, 44 case reports/case series and 21 letters/correspondences/clinical images. The treatments described were topical, oral or physical. Retinoids (isotretinoin, tazarotene and adapalene) and fluorouracil were the two most effective topical treatments. Oral retinoids were the most effective oral therapy and were prescribed in the cases of generalized Darier disease. For localized and resistant skin lesions, physical therapies including surgical excision, dermabrasion and CO2 laser ablation were the first line choices. Limitations of this article include the inability to verify the accuracy of the published data, the relatively small sample size, the absence of randomized controlled clinical trials and possible unidentified confounding factors in various studies. In every therapeutic approach to Darier disease, consideration of patient comorbidities, disease distribution, severity and treatment accessibility is essential. Large and randomized clinical trials are necessary for the comparison of the efficacy and the safety of all the treatments of Darier disease and settling a consensus for management.

Effectiveness, safety and tolerability of cyclosporine versus supportive treatment in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A record-based study.

BACKGROUND: Toxic epidermal necrolysis and Stevens-Johnson syndrome comprise life-threatening, drug-induced mucocutaneous disease spectrum. Interest in cyclosporine, a calcineurin inhibitor that can block the function of T-cells, has increased with the discovery of the importance of granulysin in apoptosis in toxic epidermal necrolysis. In our hospital, cyclosporine is given to Stevens-Johnson syndrome/toxic epidermal necrolysis patients as an adjunctive therapy. AIMS: This study is an observational, record-based study comparing the effectiveness and safety of patients receiving cyclosporine versus only supportive therapy. METHODOLOGY: Medical records as bed-head tickets and laboratory investigation reports of Stevens-Johnson syndrome/toxic epidermal necrolysis patients admitted in the hospital over a period of 1 year were collected. Data regarding clinico-demographic profile, suspected drug causing Stevens-Johnson's syndrome/toxic epidermal necrolysis, SCORTEN, body surface area involved, treatment received and outcome were obtained. RESULTS: Twenty-eight patients were analyzed. Nineteen belonged to the cyclosporine group (supportive treatment + cyclosporine), nine to supportive treatment only group. Among the suspected drugs, antiepileptics formed the major group (28.6%). Five patients in the supportive only group and one in the cyclosporine group died. Time for stabilization and reepithelialization and duration of recovery were significantly lower in the cyclosporine group (P < 0.001, P= 0.007, P= 0.01, respectively). The standardized mortality ratio was 0.32 in cyclosporine group which is nearly 3.3 times lower than the only supportive treatment. LIMITATIONS: As it was a record-based study, certain confounding factors (serum blood urea nitrogen) could not be adjusted. CONCLUSION: Cyclosporine (5 mg/kg/day) for 10 days from onset of Stevens-Johnson syndrome/toxic epidermal necrolysis may decrease the risk of dying, may provide faster healing of lesions and might lead to early discharge from hospital.

Guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis: An Indian perspective.

BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening mucocutaneous adverse drug reactions with a high morbidity and mortality that require immediate medical care. The various immunomodulatory treatments include systemic corticosteroids, cyclosporine, intravenous immunoglobulin, cyclophosphamide, plasmapheresis and tumor necrosis factor-α inhibitors. AIM: The ideal therapy of Stevens-Johnson syndrome/toxic epidermal necrolysis still remains a matter of debate as there are only a limited number of studies of good quality comparing the usefulness of different specific treatments. The aim of this article is to comprehensively review the published medical literature and frame management guidelines suitable in the Indian perspective. METHODS: The Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) assigned the task of preparing these guidelines to its special interest group on cutaneous adverse drug reactions. The group performed a comprehensive English language literature search for management options in Stevens-Johnson syndrome/toxic epidermal necrolysis across multiple databases (PubMed, EMBASE, MEDLINE and Cochrane) for keywords (alone and in combination) and MeSH items such as "guidelines," "Stevens-Johnson syndrome," "toxic epidermal necrolysis," "corticosteroids," "intravenous immunoglobulin," "cyclosporine" and "management." The available evidence was evaluated using the strength of recommendation taxonomy and graded using a three-point scale. A draft of clinical recommendations was developed on the best available evidence which was also scrutinized and critically evaluated by the IADVL Academy of Dermatology. Based on the inputs received, this final consensus statement was prepared. RESULTS: A total of 104 articles (meta-analyses, prospective and retrospective studies, reviews [including chapters in books], previous guidelines [including Indian guidelines of 2006] and case series) were critically evaluated and the evidence thus gathered was used in the preparation of these guidelines. RECOMMENDATIONS: This expert group recommends prompt withdrawal of the culprit drug, meticulous supportive care, and judicious and early (preferably within 72 h) initiation of moderate to high doses of oral or parenteral corticosteroids (prednisolone 1-2 mg/kg/day or equivalent), tapered rapidly within 7-10 days. Cyclosporine (3-5 mg/kg/day) for 10-14 days may also be used either alone, or in combination with corticosteroids. Owing to the systemic nature of the disease, a multidisciplinary approach in the management of these patients is helpful.

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.

Cyclosporine in Stevens Johnson syndrome and toxic epidermal necrolysis and retrospective comparison with systemic corticosteroid.

BACKGROUND: Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening dermatological emergencies. Many immunosuppressive modalities have been tried with variable results. AIMS: To determine the efficacy of cyclosporine in cases of SJS and TEN and compare the efficacy with systemic corticosteroid in the same condition. METHODS: Study was conducted at a tertiary hospital during 01 July 2011 to 30 June 2012. SCORTEN was assessed at the time of admission. Total body surface area (TBSA) assessment was like any burn patients. Cyclosporine was administered in the dose of 3 mg/kg body weight in three divided dosage for 07 days and then tapered over another 07 days. Data were compared to a historical series of SJS/TEN patients, managed by systemic steroids a year ago. RESULTS: A total of 11 consecutive patients with a mean age of 32.09 and standard deviation (SD 16.17) were enrolled in to cyclosporine group, which were retrospectively compared to 6 patients with a mean age of 27.87 (SD 13.97) years in the corticosteroid group. The mean duration of re-epithelialization was 14.54 (SD 4.08) and 23 days (SD 6.68) in cyclosporine and corticosteroid group respectively (P = 0.009956). Mean hospital stay was 18.09 (SD 5.02) and 26 (SD 6.48) days in cyclosporine and corticosteroid group respectively (P = 0.02597). A total of 1.11 and 0.51 patients were expected to die against no death and two deaths in cyclosporine and corticosteroid group respectively (Standardized mortality ratio = 3.92) (P = 0.04321). CONCLUSION: This study definitely suggests that cyclosporine has encouraging role in the management of uncomplicated cases of SJS, SJS-TEN overlap or TEN.

Deep venous thrombosis and pulmonary embolism secondary to co-administration of thalidomide and oral corticosteroid in a patient with leprosy.

A 58-year-old Japanese man with a 2-year history of multidrug therapy for borderline lepromatous leprosy presented with skin lesions suggestive of erythema nodosum leprosum (ENL) and was treated with an oral corticosteroid. As attempts to taper the oral corticosteroid resulted in the appearance of new lesions, thalidomide was added along with cyclosporin. Two months after the introduction of thalidomide, deep venous thrombosis (DVT) occurred in both legs and anticoagulant therapy was started without cessation of thalidomide. Pulmonary embolism developed 1 month after the appearance of DVT, and these thromboembolic events were believed to be due to thalidomide. This case highlights the need for vigilance against venous thromboembolism when corticosteroid and thalidomide are co-administrated for the treatment of ENL.

Generalized pustular psoriasis of pregnancy successfully treated with cyclosporine.

Two multigravidae aged 27 and 29 years, with previous uneventful pregnancies, second being psoriatic, reported at 24 and 28 weeks of pregnancies, with generalized pustular lesions. Laboratory findings, including serum calcium were normal. Ultrasonography showed normal fetal growth. Histopathology confirmed pustular psoriasis. Patients were put on cyclosporine 3 mg/ kg weight/ day after failure of an initial systemic steroid. Blood pressure, pulse, and fetal heart sounds were recorded every 12 hours, and ultrasonography and blood parameters, biweekly. Cyclosporine was tapered and stopped after delivery of two healthy babies at 38 weeks. We conclude that cyclosporine can be an option in the management of pustular psoriasis of pregnancy or psoriasis with pustulation in pregnancy.

Response to ciclosporin treatment in Ethiopian and Nepali patients with severe leprosy Type 1 reactions.

Leprosy type 1 reactions (T1R) are immune-mediated events with inflammation of peripheral nerves and skin. We report the clinical outcomes of a closely monitored open prospective trial in which eight Nepali and 33 Ethiopian patients with T1Rs were treated with an Indian generic formulation of ciclosporin (Cn; 5-7.5 mg/kg/day) for 12 weeks and followed up for 24 weeks after starting treatment. Outcomes were measured using a clinical severity score. Among the Nepalis, 75-100% improved in all acute clinical parameters; 67-100% patients maintained improvement, except for those with acute sensory nerve impairment among whom 67% relapsed after stopping treatment. The skin lesions of all Ethiopians on 5 mg/kg/day of Cn improved and 50-60% had peripheral nerve function improvement. Most Ethiopians needed a higher dose of Cn to improve nerve impairment and neuritis, and 50-78% of them developed worse clinical severity scores when Cn was stopped. Four Ethiopians and two Nepalis developed elevated serum creatinine levels on 7.5 mg/kg/day Cn, and three (9%) Ethiopians developed treatable hypertension. This suggests that Cn monotherapy is an effective treatment for severe T1R with few adverse effects. A dose of 5 mg/kg/day seems efficacious in Nepalis, but a higher dose may be required in Ethiopian patients.

Ciclosporina, un tratamiento para pacientes de lepra con neuritis crónica que se asocia con un control del dolor y la reducción de anticuerpos frente al factor de crecimeitno neural / No disponible

Objetivos: La neuritis crónica (NC) es un grave problema en la lepra y resulta difícil de controlar en pacientes que no responden a la prednisona. En este estudio se evalúa (i) la eficacia de la ciclosporina A (CyA) en el control de pacientes NC y (ii) se analiza la presencia de anticuerpos anti-NGF en el suero de pacientes de lepra y su comportamiento durante el tratamiento con CyA. Método: El esquema del estudio es abierto, prospectivo y no-comparativo. Se estudiaron sesenta y siete pacientes de lepra en tres instituciones diferentes de Pará, Brasil, entre enero 2001 a enero 2004. De entre ellos, 47 no presentaron NC y 20 eran pacientes con NC y en tratamiento con al menos 40 mg/día de prednisona para controlar el dolor y afectación neural. A los pacientes se les administró 12 meses de tratamiento en disminución progresiva, empezando con 5 mg/día. La medición fue la afectación sensorial, mediante examen con el sistema del monofilamento Semmes-Weinstein (SWME), fuerza muscular y dolor espontáneo o relacionado con la palpación. Resultados: Se detectaron anticuerpos frente al NGF en el suero de pacientes de lepra, que posiblemente pueda explicar la depleción de NGF en lepra que contribuye a la neuritis, inflamación y pérdida de nociceptión cutánea. Los niveles humorales de estos anticuerpos en pacientes CN eran algo menores que en los pacientes sin CN. Sin embargo, los niveles anti-NGF en pacientes NC tratados con CyA disminuyeron hasta niveles similares a los de los individuos normales. También experimentaban mejoría la afectación sensitiva, fuerza muscular y dolor. Conclusiones: Estos datos parecen indicar que los anticuerpos anti-NGF están presentes en el suero de pacientes de lepra y pueden influenciar el resultado final de la neuritis y que CyA puede ser útil para controlar la afectación neural y el dolor en los pacientes de lepra (AU)

Objetives: Chronic neuritis (CN) is still a major problem in leprosy and is difficult to manage in patients who do not respond well to prednisone. In this study we (i) evaluate the efficacy of cyclosporine A (CyA) in controlling CN patients, and (ii) analyse the presence of anti-NGF antibodies in the sera of leprosy patients, and their behavior during CyA treatment. Design: This was an open, prospective, non-comparative study. Sixty –seven leprosy patients in three different institutions in Pará, Brazil were studied form January, 2001 to January, 2004. Of these, 47 had no CN and 20 were leprosy patients suffering from CN and taking at least 40mg/dya prednisone to control nerve impairment and pain. Patients received 12 months reducing course CyA starting at 5 mg/kg per day. The outcome measure was sensory impairment, assessed using Semmes-Weinstein monofilament examination (SWME), muscular force and spontaneous or palpation-related pain. Results: Antibodies against NGF were detected in the sera of leprosy patients, which may explain the depletion of NGF in leprosy contributing to neuritis, inflammation and loss of cutaneous nociception. The levels of these antibodies in CN patients were slightly lower than in patients with no CN. However, anti-NGF titres in CN patients treated with CyA were lowered to levels similar to those in the normal subjects. There was also improvement in sensory impairment, muscular force and pain. Conclusions: These data suggest that anti-NGF antibodies are present in the sera of leprosy patients and may influence the outcome of neuritis, and that CyA might be a useful drug in controlling nerve impairment and pain in leprosy patients (AU)

Ciclosporina, un tratamiento para pacientes de lepra con neuritis crónica que se asocia con un control del dolor y la reducción de anticuerpos frente al factor de crecimeitno neural / No disponible

Objetivos: La neuritis crónica (NC) es un grave problema en la lepra y resulta difícil de controlar en pacientes que no responden a la prednisona. En este estudio se evalúa (i) la eficacia de la ciclosporina A (CyA) en el control de pacientes NC y (ii) se analiza la presencia de anticuerpos anti-NGF en el suero de pacientes de lepra y su comportamiento durante el tratamiento con CyA. Método: El esquema del estudio es abierto, prospectivo y no-comparativo. Se estudiaron sesenta y siete pacientes de lepra en tres instituciones diferentes de Pará, Brasil, entre enero 2001 a enero 2004. De entre ellos, 47 no presentaron NC y 20 eran pacientes con NC y en tratamiento con al menos 40 mg/día de prednisona para controlar el dolor y afectación neural. A los pacientes se les administró 12 meses de tratamiento en disminución progresiva, empezando con 5 mg/día. La medición fue la afectación sensorial, mediante examen con el sistema del monofilamento Semmes-Weinstein (SWME), fuerza muscular y dolor espontáneo o relacionado con la palpación. Resultados: Se detectaron anticuerpos frente al NGF en el suero de pacientes de lepra, que posiblemente pueda explicar la depleción de NGF en lepra que contribuye a la neuritis, inflamación y pérdida de nociceptión cutánea. Los niveles humorales de estos anticuerpos en pacientes CN eran algo menores que en los pacientes sin CN. Sin embargo, los niveles anti-NGF en pacientes NC tratados con CyA disminuyeron hasta niveles similares a los de los individuos normales. También experimentaban mejoría la afectación sensitiva, fuerza muscular y dolor. Conclusiones: Estos datos parecen indicar que los anticuerpos anti-NGF están presentes en el suero de pacientes de lepra y pueden influenciar el resultado final de la neuritis y que CyA puede ser útil para controlar la afectación neural y el dolor en los pacientes de lepra

Objetives: Chronic neuritis (CN) is still a major problem in leprosy and is difficult to manage in patients who do not respond well to prednisone. In this study we (i) evaluate the efficacy of cyclosporine A (CyA) in controlling CN patients, and (ii) analyse the presence of anti-NGF antibodies in the sera of leprosy patients, and their behavior during CyA treatment. Design: This was an open, prospective, non-comparative study. Sixty –seven leprosy patients in three different institutions in Pará, Brazil were studied form January, 2001 to January, 2004. Of these, 47 had no CN and 20 were leprosy patients suffering from CN and taking at least 40mg/dya prednisone to control nerve impairment and pain. Patients received 12 months reducing course CyA starting at 5 mg/kg per day. The outcome measure was sensory impairment, assessed using Semmes-Weinstein monofilament examination (SWME), muscular force and spontaneous or palpation-related pain. Results: Antibodies against NGF were detected in the sera of leprosy patients, which may explain the depletion of NGF in leprosy contributing to neuritis, inflammation and loss of cutaneous nociception. The levels of these antibodies in CN patients were slightly lower than in patients with no CN. However, anti-NGF titres in CN patients treated with CyA were lowered to levels similar to those in the normal subjects. There was also improvement in sensory impairment, muscular force and pain. Conclusions: These data suggest that anti-NGF antibodies are present in the sera of leprosy patients and may influence the outcome of neuritis, and that CyA might be a useful drug in controlling nerve impairment and pain in leprosy patients

Cyclosporine A treatment of leprosy patients with chronic neuritis is associated with pain control and reduction in antibodies against nerve growth factor.

OBJECTIVES: Chronic neuritis (CN) is still a major problem in leprosy and is difficult to manage in patients who do not respond well to prednisone. In this study we (i) evaluate the efficacy of cyclosporine A (CyA) in controlling CN patients, and (ii) analyse the presence of anti-NGF antibodies in the sera of leprosy patients, and their behaviour during CyA treatment. DESIGN: This was an open, prospective, non-comparative study. Sixty-seven leprosy patients in three different institutions in Pará, Brazil were studied from January, 2001 to January, 2004. Of these, 47 had no CN and 20 were leprosy patients suffering from CN and taking at least 40 mg/day prednisone to control nerve impairment and pain. Patients received 12 months reducing course CyA starting at 5 mg/kg per day. The outcome measure was sensory impairment, assessed using Semmes-Weinstein monofilament examination (SWME), muscular force and spontaneous or palpation-related pain. RESULTS: Antibodies against NGF were detected in the sera of leprosy patients, which may explain the depletion of NGF in leprosy contributing to neuritis, inflammation and loss of cutaneous nociception. The levels of these antibodies in CN patients were slightly lower than in patients with no CN. However, anti-NGF titres in CN patients treated with CyA were lowered to levels similar to those in the normal subjects. There was also improvement in sensory impairment, muscular force and pain. CONCLUSIONS: These data suggest that anti-NGF antibodies are present in the sera of leprosy patients and may influence the outcome of neuritis, and that CyA might be a useful drug in controlling nerve impairment and pain in leprosy patients.