Effectiveness and Adverse Events of Use of Natalizumab in a Brazilian Cohort of Patients With Multiple Sclerosis.

PURPOSE: Natalizumab (NTZ) is a monoclonal antibody with confirmed efficacy in white populations with recurrent-remitting multiple sclerosis (RRMS); there are few studies, however, in mixed-race populations. Real-world studies of NTZ are needed to better understand the drug's effectiveness. This study evaluated the effectiveness and adverse events of NTZ in a cohort of Brazilian patients with MS, as well as the impact of clinical and demographic factors on patient response to treatment. METHODS: This multicenter, Brazilian observational study was conducted from January 2011 until December 2016 and included patients with RRMS (McDonald criteria 2005 and 2010) aged ≥18 years treated with NTZ for at least 3 months. Demographic, clinical, and radiologic data were obtained from medical records and during follow-up visits. The primary outcomes investigated were the absolute number of relapses and annualized rate of relapses, change in Expanded Disability Status Scale value, and presence of new lesions on magnetic resonance imaging after starting NTZ treatment; the occurrence and type of adverse events were also analyzed. In addition, the impact of demographic and clinical prognostic factors and radiologic activity on the effectiveness of NTZ was measured. Descriptive and univariate statistical analyses used a significance level of P < 0.05. RESULTS: The study enrolled 56 patients; 64% were women, and 36% were of African descent. There was a significant reduction in the mean absolute number (P = 0.001) and in the annualized rate (P = 0.001) of relapses and in the radiologic activity of the disease (P = 0.001). Furthermore, 71% of patients showed no increase in Expanded Disability Status Scale score after 1 year of treatment. The effectiveness of NTZ was not associated with the presence of clinical and demographic prognostic factors, and the most frequent adverse events during the use of NTZ were gastrointestinal symptoms; there were no cases of progressive multifocal leukoencephalopathy. IMPLICATIONS: According to patients' reports and clinicians' observations regarding clinical and radiologic benefits and tolerability to adverse events, the use of NTZ was favorable in this Brazilian MS cohort, regardless of the presence of unfavorable prognostic factors.

Epidemiology of neuromyelitis optica in Latin America.

A major development over the past two decades was the recognition of recurrent neuromyelitis optica (NMO) as a particular central nervous system disorder different from multiple sclerosis (MS). Here we reviewed the epidemiology of NMO in Latin America (LATAM). A predominance of a mixed population is found in this region. Recurrent NMO in black women was described in the Caribbean Islands and in Rio de Janeiro. The prevalence of NMO in LATAM varied from 0.37/100,000 (Volta Redonda city) to 4.2/100,000 inhabitants (Caribbean Islands). NMO differs significantly from MS with respect to gender, ethnicity, morbidity and genetic susceptibility. An association of the HLA DRB1*03 alleles with NMO was described in the French Antilles, Ribeirão Preto, Rio de Janeiro and Mexico. It is not common to find familial forms of NMO. NMO represents 11.8% of all inflammatory idiopathic diseases in South America (SA). In SA, the highest frequency of NMO occurs in African Brazilian young women. The overall relative frequency of NMO among MS cases in this region was 14%, decreasing following a north-south gradient, which parallels the percentage of nonwhite people.

The HLA DRB1*03:01 allele is associated with NMO regardless of the NMO-IgG status in Brazilian patients from Rio de Janeiro.

The aim of this study was to analyze the HLA class II alleles in neuromyelitis optica (NMO) and MS patients from Rio de Janeiro to clarify whether the pattern of genetic predisposition in NMO is different from the one seen in MS or whether it is possible to determine specific alleles of susceptibility or resistance. The DR3 haplotype was over represented in NMO while the DR15 was over represented in MS. The HLA-DRB1*03:01 allele was associated with NMO regardless the NMO-IgG status but did not influence the long term disability. The comparison of the allele and haplotype frequencies significantly discriminated patients with NMO vs. MS.

Influence of UDP-glucuronosyltransferase polymorphisms on mycophenolate mofetil-induced side effects in kidney transplant patients.

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug approved for use in transplantation. Its active metabolite, mycophenolic acid, is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes. In this study, we retrospectively analyzed 74 kidney transplant patients who had been prescribed MMF as part of their immunosuppression regimen. Polymorphisms in UGT1A8 (-999C > T, codon 255A > G, codon 277G > A) were correlated with the occurrence of side effects, such as diarrhea, blood disorders, and infections. The infectious episodes were more frequently observed among individuals receiving MMF (2 g/d) who carryied the variant UGT1A8 codon 277A (P = .031), the haplotype UGT1A8H5 (-999C/codon 55A/codon 277A; P = .02), and the diplotype UGT1A8H2/H5 (-999CC/codon 255AA/codon 277GA; P = .015). The molecular data from this study suggest that UGT polymorphisms may be a factor influencing clinical outcomes among patients receiving MMF for transplant therapy; however, larger studies are warranted.

Role of glutathione s-transferase polymorphisms and chronic allograft dysfunction.

Polymorphisms within genes encoding glutathione S-transferases (GSTs) may affect responses against damage induced by oxidative stress and therefore play a role to prevent chronic allograft dysfunction (CAD). In the present study, we estimated the frequencies of GSTM1- and GSTT1-null genotypes among 227 renal transplant recipients seeking to establish an association with CAD. Patients persistently displaying serum creatinine (sCr) values < or = 1.5 mg/dL, measured creatinine clearances (CLcr) > or = 50 mL/min/1.73 m(2), and 24-hour proteinuria < or = 500 mg were classified as normal graft function (NF; n = 107). In contrast, the CAD group (n = 120) presented sCr > 1.5 mg/dL, CLcr < 50 mL/min/1.73 m(2), and proteinuria > 500 mg. The GSTM1 and GSTT1 polymorphisms were evaluated by the multiplex polymerase chain reaction. The frequencies of GSTT1-null genotypes in NF and CAD cohorts were 15% and 24.2%, respectively (P = .057), while GSTM1-null genotypes in the same groups of patients were 44% and 46.7% (P = .389). A combination of null genotypes for GSTT1 and GSTM1 was observed in 9.2% of patients with CAD and in 5.6% of those with NF (P = .449). This study did not show an association of either GSTT1- and GSTM1-null genotypes with CAD. It is likely that development and progression of CAD are determined by a combination of complex genetic traits resulting from the interplay of several genes rather than a single gene.

Effect of folate, vitamin B6, and vitamin B12 intake and MTHFR C677T polymorphism on homocysteine concentrations of renal transplant recipients.

Plasma hyperhomocysteinemia (HHcy) is considered a risk factor for chronic allograft dysfunction (CAD), the main cause of functional loss in transplant recipients. Genetic polymorphisms that alter enzymes involved in homocysteine (Hcy) metabolism, such as methylenetetrahydrofolate reductase (MTHFR), and vitamin deficiency can result in HHcy. The objectives of this study were to investigate the relationship between HHcy and CAD development, and to evaluate the effect of intake of folate and vitamins B6 and B12 as well as MTHFR C677T polymorphism on Hcy concentrations. Ninety-eight renal transplant recipients including 48 showing CAD and 50 with normal renal function (NRF), were included in this cross-sectional study. Peripheral blood samples were collected for plasma Hcy quantification by liquid chromatography/sequential mass spectrometry (LC-MS/MS), and for MTHFR polymorphism analysis using polymerase chain reaction-restriction fragment length polymorphism. Dietary intake was evaluated using a nutritional questionnaire. HHcy (P=.002) and higher mean concentrations of Hcy (P=.029) were associated with CAD. An association was observed between HHcy and 677T variant allele in the CAD group (P=.0005). There was no correlation between Hcy concentration and folate, vitamin B6 or vitamin B12 intake in the CAD group. However, a negative correlation was observed between Hcy concentration and folate intake (P=.043), and also between Hcy concentration and vitamin B6 intake (P=.030) in the NRF group. According to our study, HHcy is associated with CAD development. In patients with CAD, MTHFR polymorphism seems to have a greater effect on the Hcy concentration than the vitamin intake. Increased folate and vitamin B6 intakes seem to reduce Hcy concentrations among transplant recipients with NRF, and could contribute to reducing the risk of CAD development.

Combination of angiotensin-converting enzyme and methylenetetrahydrofolate reductase gene polymorphisms as determinant risk factors for chronic allograft dysfunction.

OBJECTIVE: The aim of this study was to investigate the frequency of gene angiotensin-converting enzyme insertion/deletion (ACE I/D) and methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) variants, as well as to evaluate the plasma homocysteine concentrations in 217 patients who underwent renal transplantation at least 12 months prior to define risk factors for chronic allograft dysfunction. METHODS: The presence of the polymorphism ACE deletion was assessed by polymerase chain reaction (PCR) analysis. MTHFR polymorphisms were determined by PCR and restriction fragment length polymorphism (RFPL) techniques. The restriction enzymes were Hinf I and Mbo II for MTHFR variants C677T and A1298C, respectively. Plasma homocysteine concentrations were measured by liquid chromatography-tandem mass spectrometry (LS-MS/MS). RESULTS: Hyperhomocysteinemias were more common in patients with chronic allograft dysfunction (P = .004). No statistically significant differences were observed between the allelic and genotypic distributions of MTHFR and ACE polymorphisms. An effective risk factor was found when the polymorphisms of the ACE and MTHFR genes and hyperhomocysteinemia were associated (odds ratio 2.51; 95% confidence interval 1.19-5.28). In conclusion, our study identified that the presence of hyperhomocysteinemia in combination with unfavorable genotypes contributes to an increased risk for development of chronic allograft dysfunction.

Angiotensin-converting enzyme gene polymorphism in chronic allograft nephropathy.

Angiotensin causes an increased activity of hypertrophic and fibrotic processes, which similarly develop in the walls of small vessels of a renal graft during chronic rejection. In this context, the angiotensin-converting enzyme (ACE) gene, associated with increased angiotensin production, has been the subject of studies on renal diseases. The present study evaluated the influence of the ACE gene deletion polymorphism in chronic allograft nephropathy. We evaluated 240 renal transplant recipients including, 119 with normal renal function and 121 with chronic allograft nephropathy. The polymorphism was determined by polymerase chain reaction and genotyping performed after electrophoresis in 1.5% agarose gels stained with ethidium bromide. The frequency of the polymorphic allele was similar in both groups of patients. Furthermore, no significant effect of genotype was observed in chronic allograft nephropathy. Therefore, in this study, we observed no influence of the ACE gene polymorphism in chronic allograft nephropathy.

Hyperhomocysteinemia and MTHFR C677T and A1298C polymorphisms are associated with chronic allograft nephropathy in renal transplant recipients.

Hyperhomocysteine has been reported to be an important risk factor for the development of atherosclerosis. Identification of risk factors, such as hyperhomocysteinemia, is crucial for a better understanding of the events that lead to degenerative processes in the vascular system and for a correct understanding of the potential role of methylene-tetrahydrofolate reductase enzymes (MTHFR) to help in the treatment of vascular disease observed in chronic allograft nephropathy (CAN). In this study we analyzed the plasma homocysteine concentrations and MTHFR C677T and A1298C polymorphism frequencies among 110 renal transplant recipients (53 with CAN and 57 with normal renal function). All recipients had undergone renal transplantation at least 12 months prior to this investigation to establish a possible correlation with the posttransplant outcome. Plasma homocysteine concentrations were measured by liquid chromatography-tandem mass spectrometry and MTHFR polymorphisms were investigated by the PCR-RFLP technique. The results demonstrated that in renal transplant recipients, hyperhomocysteinemia in addition to the presence of the allelic variants for both MTHFR polymorphisms (677T/1298C) might play a role as an additional risk factor for CAN. We understand that analysis of these polymorphisms might have a role in the CAN process. Therefore, studies to evaluate their presence in renal transplant patients may be extremely useful to individualize immunosuppressive protocols to inhibit or retard the progression of CAN.