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

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          Abstract

          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.

          Author summary

          Erythema Nodosum Leprosum (ENL) reaction is a severe multisystem immune-mediated complication of lepromatous and borderline leprosy. It causes high morbidity and mortality and usually requires urgent medical attention. Although thalidomide is an effective drug for ENL treatment, it is not available in many leprosy endemic countries including Ethiopia. Prednisolone is widely used for treatment of ENL reactions but its efficacy is less than 40%. As a result, patients with ENL reactions receive Prednisolone for prolonged periods. 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 hypothesized that perhaps these complications result from changes in lipid concentration due to prednisolone. Therefore, this study was aimed to determine changes in lipid profiles in patients with ENL reactions. We found that prednisolone treatment not only alters lipid concentrations in patients with ENL reactions but also reduced the antibody responses to M. leprae antigens. Our result has shown that prednisolone treatment has increased low and high lipoproteins in patients with ENL reactions. We also found that use of prednisolone for prolonged time in chronic ENL was correlated with increased triglycerides (TG) and low density lipoproteins (LDL) showing the need for monitoring lipid profiles during prednisolone treatment of these patients to avoid the risks associated with increased TG and HDL such as diabetes and hypertension.

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          Most cited references36

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          Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis.

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          To appraise the data on systemic adverse effects of inhaled corticosteroids. A computerized database search from January 1, 1966, through July 31, 1998, using MEDLINE, EMBASE, and BIDS and using appropriate indexed terms. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies. Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1.5 mg/d (0.75 mg/d for fluticasone propionate), although there is a considerable degree of interindividual susceptibility. Meta-analysis showed significantly greater potency for dose-related adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a 10:1-mg basis. Inhaled corticosteroids in doses above 1.5 mg/d (0.75 mg/d for fluticasone propionate) may be associated with a significant reduction in bone density, although the risk for osteoporosis may be obviated by post-menopausal estrogen replacement therapy. Although medium-term growth studies showed suppressive effects with 400-microg/d beclomethasone dipropionate, there was no evidence to support any significant effects on final adult height. Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression. All inhaled corticosteroids exhibit dose-related systemic adverse effects, although these are less than with a comparable dose of oral corticosteroids. Metaanalysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.8 mg/d. The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life.
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            Since the advent of glucocorticoid therapy for autoimmune disease in the 1940s, their widespread application has led to the concurrent therapy-limiting discovery of many adverse metabolic side effects. Unanticipated hyperglycemia associated with the initiation of glucocorticoids often leads to preventable hospital admissions, prolonged hospital stays, increased risks for infection and reduced graft function in solid organ transplant recipients. Challenges in managing steroid-induced diabetes stem from wide fluctuations in post-prandial hyperglycemia and the lack of clearly defined treatment protocols. The mainstay of treatment is insulin therapy coincident with meals. This article aims to review the pathogenesis, risk factors, diagnosis and treatment principles unique to steroid-induced diabetes.
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              Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India.

              Erythema nodosum leprosum (ENL) or type 2 lepra reactions complicate lepromatous leprosy and borderline lepromatous leprosy. We report an 11-year retrospective case record analysis of 481 outpatients with borderline lepromatous and lepromatous leprosy at the Dhoolpet Leprosy Research Center in Hyderabad, India.. The overall prevalence of ENL was 24%, 49.4% among cases of lepromatous leprosy (LL) and 9% among cases of borderline lepromatous (BL) leprosy. Logistic regression analysis identified LL (odds ratio [OR] = 8.4, 95% confidence interval [CI] = 4.6-15.4, P or = 4+ (OR = 5.2, 95% CI = 2.1-12.9, P = 0.001) as major risk factors. The average patient with ENL was male, 34.7 years of age, and had multiple episodes of ENL (mean = 3.1) over an 18.5-month period. Three types of ENL were identified: single acute ENL, multiple acute ENL (repeated discrete episodes), and chronic ENL (continuous episodes). Acute single ENL is rare, accounting for only 8% of cases. Chronic ENL accounted for 62.5% of the cohort. Chronic ENL was of longer duration and more severe. An age > or = 35 years was a risk factor for developing chronic ENL. Patients with chronic ENL were more compliant with multi-drug therapy, especially during the first six doses of multi-drug therapy. Distinguishing these different types of ENL would be useful for patient management and developing improved treatment of these debilitating reactions. Improved strategies for treatment and management of these reactions need to be developed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ValidationRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                28 December 2018
                December 2018
                : 12
                : 12
                : e0007035
                Affiliations
                [1 ] London School of Hygiene and Tropical Medicine (LSHTM), London, United Kingdom
                [2 ] Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia
                [3 ] Department of Microbiology, Immunology & Pathology, Colorado State University, Fort Collins, CO, United States of America
                Swiss Tropical and Public Health Institute, SWITZERLAND
                Author notes

                The authors have declared that no competing interests exist

                Author information
                http://orcid.org/0000-0001-6632-3142
                http://orcid.org/0000-0002-3101-3926
                Article
                PNTD-D-18-01320
                10.1371/journal.pntd.0007035
                6328235
                30592714
                8bbdf558-e706-46c0-a926-e1a567dc1642
                © 2018 Negera et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 August 2018
                : 28 November 2018
                Page count
                Figures: 8, Tables: 0, Pages: 16
                Funding
                The project was funded by Homes and Hospital of St Gilles (UK) and Armauer Hansen Research Institute (Ethiopia). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Bacterial Diseases
                Leprosy
                Medicine and Health Sciences
                Tropical Diseases
                Neglected Tropical Diseases
                Leprosy
                Biology and Life Sciences
                Biochemistry
                Proteins
                Lipoproteins
                Biology and Life Sciences
                Biochemistry
                Lipids
                Lipid Profiles
                Biology and Life Sciences
                Organisms
                Bacteria
                Actinobacteria
                Mycobacterium Leprae
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Biology and Life Sciences
                Immunology
                Immune Response
                Antibody Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Antibody Response
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Serology
                Biology and Life Sciences
                Biochemistry
                Lipids
                Custom metadata
                vor-update-to-uncorrected-proof
                2019-01-10
                All relevant data are within the manuscript.

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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