Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of erythema nodosum leprosum with thalidomide.

BACKGROUND: Erythema nodosum leprosum (ENL) is an acute and systemic inflammatory reaction of leprosy characterised by painful nodules and involvement of various organs. Thalidomide is an immunomodulatory and anti-inflammatory drug currently used to treat this condition. Cereblon (CRBN) protein is the primary target of thalidomide, and it has been pointed out as necessary for the efficacy of this drug in others therapeutics settings. OBJECTIVES: In this study, we aimed to evaluate the influence of CRBN gene variants on the dose of thalidomide as well as its adverse effects during treatment of ENL. METHODS: A total of 103 ENL patients in treatment with thalidomide were included in this study. DNA samples were obtained from saliva and molecular analysis of CRBN gene were performed to investigate the variants rs1620675, rs1672770 and rs4183. Different genotypes of CRBN variants were evaluated in relation to their influence on the dose of thalidomide and on the occurrence of adverse effects. FINDINGS: No association was found between CRBN variants and thalidomide dose variation. However, the genotypes of rs1672770 showed association with gastrointestinal effects (p = 0.040). Moreover, the haplotype DEL/C/T (rs4183/rs1672770/rs1620675) was also associated with gastrointestinal adverse effects (p = 0.015). MAIN CONCLUSIONS: Our results show that CRBN variants affect the treatment of ENH with thalidomide, especially on the adverse effects related to the drug.

Visceral leishmaniasis and HIV coinfection in Brazil: epidemiological profile and spatial patterns.

BACKGROUND: Geographical overlap of human visceral leishmaniasis (HVL) and HIV infection favors occurrences of HVL/HIV coinfection. The increasing numbers of cases of HVL/HIV coinfection are a worldwide concern and knowledge of the factors involved can help in developing preventive measures. METHODS: We aimed to identify spatial patterns and describe the epidemiological profile of HVL/HIV coinfection in Brazil from 2007 to 2015. This was an ecological study, in which thematic maps were created through geoprocessing tools, based on secondary data obtained from open-access platforms, to identify priority areas for interventions for controlling HLV/HIV coinfection, using the TerraView 4.2.2 software. RESULTS: We found spatial autocorrelations between the HVL/HIV rates of neighboring municipalities according to the global Moran index (0.10; p<0.01). The highest HVL/HIV rate was in the central-western region. Among the epidemiological characteristics according to the regions, an increasing trend in the annual variation rate was observed, with positive values over the years and statistical significance (p<0.05) in the North with 1.62 (95% CI 0.57 to 2.69; p=0.02) and Northeast with 6.41 (95% CI 2.60 to 10.37; p=0.006). Similarly, increasing trends were observed in the states of Maranhão with 21.34 (95% CI 13.99 to 9.16; p<0.001) and Sergipe with 5.44 (95% CI 0.61 to 10.50; p=0.04). CONCLUSIONS: Our results showed spatial overlap between occurrences of HVL and HIV with spatial patterns of HVL/HIV coinfection, thus revealing that the numbers of cases reported are increasing. Identifying areas with higher coinfection indices contributes to applying interventions and control measures among targeted populations, to prevent new cases.

Evaluation of Polymorphisms in Toll-Like Receptor Genes as Biomarkers of the Response to Treatment of Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL) is an inflammatory complication caused by a dysregulated immune response to Mycobacterium leprae. Some Toll-like receptors (TLRs) have been identified as capable of recognizing antigens from M. leprae, triggering a wide antimicrobial and inflammatory response. Genetic polymorphisms in these receptors could influence in the appearance of ENL as well as in its treatment. Thus, the objective of this work was to evaluate the association of genetic variants of TLRs genes with the response to treatment of ENL with thalidomide and prednisone. A total of 162 ENL patients were recruited from different regions of Brazil and clinical information was collected from their medical records. Genomic DNA was isolated from blood and saliva samples and genetic variants in TLR1 (rs4833095), TLR2 (rs3804099), TLR4 (rs1927914), and TLR6 (rs5743810) genes were genotyped by TaqMan real-time PCR system. In order to evaluate the variants' association with the dose of the medications used during the treatment, we applied the Generalized Estimating Equations (GEE) analysis. In the present sample, 123 (75.9%) patients were men and 86 (53.1%) were in treatment for leprosy during the ENL episode. We found an association between polymorphisms in TLR1/rs4833095, TLR2/rs3804099, TLR4/rs1927914, and TLR6/rs5783810 with the dose variation of thalidomide in a time-dependent manner, i.e., the association with the genetic variant and the dose of the drug was different depending on the moment of the treatment evaluated. In addition, we identified that the association of polymorphisms in TLR1/rs4833095, TLR2/rs3804099, and TLR6/rs5783810 with the dose variation of prednisone also were time-dependent. Despite these associations, in all the interactions found, the influence of genetic variants on dose variation was not clinically relevant for therapeutic changes. The results obtained in this study show that TLRs polymorphism might play a role in the response to ENL treatment, however, in this context, they could not be considered as useful biomarkers in the clinical setting due small differences in medication doses. A larger sample size with patients with a more genetic profile is fundamental in order to estimate the association of genetic variants with the treatment of ENL and their clinical significance.

Erythema Nodosum Leprosum: Update and challenges on the treatment of a neglected condition.

Erythema Nodosum Leprosum (ENL) occurs due to the immunological complication of multibacillary leprosy and is characterized by painful nodules and systemic compromising. It is usually recurrent and/or chronic and has both physical and economic impact on the patient, being a very important cause of disability. In addition, ENL is a major health problem in countries where leprosy is endemic. Therefore, adequate control of this condition is important. The management of ENL aims to control acute inflammation and neuritis and prevent the onset of new episodes. However, all currently available treatment modalities have one or two drawbacks and are not effective for all patients. Corticosteroid is the anti-inflammatory of choice in ENL but may cause dependence, especially for chronic patients. Thalidomide has a rapid action but its use is limited due the teratogenicity and neurotoxicity. Clofazimine and pentoxifylline have slow action and have important adverse effects. Finally, there is no pattern or guidelines for treating these patients, becoming more difficult to evaluate and to control this condition. This review aims to show the main drugs used in the treatment of ENL and the challenges in the management of the reaction.

Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of erythema nodosum leprosum with thalidomide

BACKGROUND Erythema nodosum leprosum (ENL) is an acute and systemic inflammatory reaction of leprosy characterised by painful nodules and involvement of various organs. Thalidomide is an immunomodulatory and anti-inflammatory drug currently used to treat this condition. Cereblon (CRBN) protein is the primary target of thalidomide, and it has been pointed out as necessary for the efficacy of this drug in others therapeutics settings. OBJECTIVES In this study, we aimed to evaluate the influence of CRBN gene variants on the dose of thalidomide as well as its adverse effects during treatment of ENL. METHODS A total of 103 ENL patients in treatment with thalidomide were included in this study. DNA samples were obtained from saliva and molecular analysis of CRBN gene were performed to investigate the variants rs1620675, rs1672770 and rs4183. Different genotypes of CRBN variants were evaluated in relation to their influence on the dose of thalidomide and on the occurrence of adverse effects. FINDINGS No association was found between CRBN variants and thalidomide dose variation. However, the genotypes of rs1672770 showed association with gastrointestinal effects (p = 0.040). Moreover, the haplotype DEL/C/T (rs4183/rs1672770/rs1620675) was also associated with gastrointestinal adverse effects (p = 0.015). MAIN CONCLUSIONS Our results show that CRBN variants affect the treatment of ENH with thalidomide, especially on the adverse effects related to the drug.

Predisposition to idiopathic thrombocytopenic purpura maps close to the major histocompatibility complex class I chain-related gene A.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune condition with poorly known etiology, characterized by platelet destruction. Genetic association studies of this disease are scarce, discrepant, and restricted to major histocompatibility complex (MHC) polymorphisms. Hence, a case-control study was conducted with an aim to map the MHC to IPT susceptibility using HLA-B and nine microsatellite loci encompassing MHC class I, II, and III regions. We compared the allelic frequencies in samples of unrelated healthy controls and ITP patients. After correction for multiple tests, only allele MICA*183, also known as A5.1, demonstrated an association, resulting in the identification of a major predisposing region close to STR-MICA. This result may highlight the putative functional role of MICA in the immune response to ITP.