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.

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.

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.

A demanda de um centro de referência nacional para hanseníase no nordeste brasileiro: por que o excesso de pacientes? / The need for a national reference center in Brazil's northeastern region: why the excess of patients?

Até 2000, o controle da hanseníase no Brasil foi verticalizado. Depois desta data, o processo de descentralização desta doença deu início a ações que priorizaram o nível primário de atenção à saúde. Entretanto, a assistência ainda permane centralizada em algumas unidades, como o Centro Nacional de Referência em Dermatologia Sanitária D. Libânia (CDERM), em Fortaleza, Ceará. Este centro responde por 84 por cento da detecção do município. O objetivo deste estudo foi investigar os fatores associados à demanda excessiva de casos em nível secundário de atenção representado por este centro de referência. Um estudo transversal foi realizado com 600 usuários selecionados aleatoriamente nos ambulatórios do CDERM. Foram coletados dados: sócio econômico e demográficos, sobre conhecimento da doença e percepção dos serviços. Oitenta e dois por cento dos participantes tinham baixa situação sócio econômica, 90 por cento vieram encaminhados por outras unidades de saúde e 87 por cento tinham a forma multibacilar. Sessenta e nove por cento receberam atendimento prévio em outras Unidades de Saúde, 49 por cento jamais ouviram falar de hanseníase, 24 por cento referiram sentir medo da doença ou terem sofrido discriminação, 39 por cento dos usuários referiram que o atendimento ininterrupto no horário do almoço favorece a permanência no CDERM, 57 por cento e 27 por cento, respectivamente, referiram que a medicação complementar nunca faltou no CDERM e nas Unidades Básicas de Saúde (UBS). Sessenta e um por cento considerou que o compromisso dos profissionais no CDERM foi ótimo contra 14 por cento nas UBS. Os fatores relatados pelos usuários, especialmente logísticos e de qualidade de atendimento e dos profissionais, poderiam explicar a concentração de usuários neste centro de referência.

A demenda de um Centro de Referência Nacional para Hanseníase no Nordeste Brasileiro: por que o excesso de pacientes? / The need for a national reference center in Brazil's northeastern region: why the excess of patients?

Até 2000, o controle de hanseníase no Brasil foi verticalizado. Depois desta data, o processo de descentralização desta doença deu ínicio a ações que priorizaram o nível primário de atenção à saúde. Entretanto, a assistência ainda permanece centralizada em algumas unidades, como o Centro Nacional de Referência em Dermatologia Sanitária D. Libânia (CDERM), em Fortaleza, Ceará. Este centro responde por 84% da detecção do município. O objetivo deste estudo foi investigar os fatores associados à demanda excessiva de casos em nível secundário de atenção representado por este centro de referência. Um estudo transversal foi realizado com 600 usuários selecionados aleatoriamente nos ambulatórios do CDERM. Foram coletados dados: sócio-econômico e demográficos, sobre conhecimento da doença e percepção dos serviços. Oitenta e dois por cento dos participantes tinham baixa situação socio-econômica, 90% vieram encaminhados por outras unidades de saúde e 87% tinham a forma multibacilar. Sessenta e nove por cento receberam atendimento prévio em outras Unidades de Saúde, 49% jamais ouviram falar de hanseníase, 24% referiram sentir medo da doença ou terem sofrido discriminação, 39% dos usuários referiram que o atendimento ininterrupto no horário do almoço favorece a permanência no CDERM, 57% e 27%, respectivamente, referiram que a medicação complementar nunca faltou no CDERM e nas Unidades Básicas de Saúde (UBS). Sessenta e um por cento considerou que o compromisso dos profissionais no CDERM foi ótimo contra 14% nas UBS. Os fatores relatados pelos usuários, especialmente logísticos e de qualidade de atendimento e dos profissionais, poderiam explicar a concentração de usuários neste centro de referência.