Margarida Cruz

Contribution for new genetic markers of rheumatoid arthritis activity and severity: sequencing of the tumor necrosis factor-alpha gene promoter

The objective of this study was to assess whether clinical measures of rheumatoid arthritis activity and severity were influenced by tumor necrosis factor-alpha (TNF-α) promoter genotype/haplotype markers. Each patients disease activity was assessed by the disease activity score using 28 joint counts (DAS28) and functional capacity by the Health Assessment Questionnaire (HAQ) score. Systemic manifestations, radiological damage evaluated by the Sharp/van der Heijde (SvdH) score, disease-modifying anti-rheumatic drug use, joint surgeries, and work disability were also assessed. The promoter region of the TNF-α gene, between nucleotides -1,318 and +49, was sequenced using an automated platform. Five hundred fifty-four patients were evaluated and genotyped for 10 single-nucleotide polymorphism (SNP) markers, but 5 of these markers were excluded due to failure to fall within Hardy-Weinberg equilibrium or to monomorphism. Patients with more than 10 years of disease duration (DD) presented significant associations between the -857 SNP and systemic manifestations, as well as joint surgeries. Associations were also found between the -308 SNP and work disability in patients with more than 2 years of DD and radiological damage in patients with less than 10 years of DD. A borderline effect was found between the -238 SNP and HAQ score and radiological damage in patients with 2 to 10 years of DD. An association was also found between haplotypes and the SvdH score for those with more than 10 years of DD. An association was found between some TNF-α promoter SNPs and systemic manifestations, radiological progression, HAQ score, work disability, and joint surgeries, particularly in some classes of DD and between haplotypes and radiological progression for those with more than 10 years of DD.

ANKH and Susceptibility to and Severity of Ankylosing Spondylitis

Objective. Unconfirmed reports describe association of ankylosing spondylitis (AS) with several candidate genes including ANKH. Cellular export of inorganic pyrophosphate is regulated by the ANK protein, and mutant mice (ank/ank), which have a premature stop codon in the 3’ end of the ank gene, develop severe ankylosis. We tested the association between single-nucleotide polymorphisms (SNP) in these genes and susceptibility to AS in a population of patients with AS. We investigated the role of these genes in terms of functional (BASFI) and metrological (BASMI) measures, and the association with radiological severity (mSASSS). Methods. Our study was conducted on 355 patients with AS and 95 ethnically matched healthy controls. AS was defined according to the modified New York criteria. Four SNP in ANKH (rs27356, rs26307, rs25957, and rs28006) were genotyped. Association analysis was performed using Cochrane-Armitage and linear regression tests for dichotomous and quantitative variables. Analyses of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASFI, and mSASSS were controlled for sex and disease duration. Results. None of the 4 markers showed significant single-locus disease associations (p > 0.05), suggesting that ANKH was not a major determinant of AS susceptibility in our population. No association was observed between these SNP and age at symptom onset, BASDAI, BASFI, BASMI, or mSASSS. Conclusion. These results confirm data in white Europeans that ANKH is probably not a major determinant of susceptibility to AS. ANKH polymorphisms do not markedly influence AS disease severity, as measured by BASMI and mSASSS.

DAS28, CDAI and SDAI cut-offs do not translate the same information: results from the Rheumatic Diseases Portuguese Register Reuma.pt

OBJECTIVES . The 28-joint DAS (DAS28), clinical disease activity index (CDAI) and simplified disease activity index (SDAI) are indices frequently used to assess disease activity in RA patients. Cut-off values were defined to classify the states of RA disease activity: remission, low, moderate and high. The aim of this work was to assess disease activity states classified by DAS28, CDAI and SDAI and to analyse their agreement in the Rheumatic Diseases Portuguese Register Reuma.pt. METHODS . A total of 2795 patients and 14 440 visits were selected from Reuma.pt for analysis. Pearsons correlation coefficients (PCCs) were calculated for the three indices. McNemars chi-squared tests, PCCs and kappa statistics were performed to analyse and compare the distribution of visits among all disease activity states and indices. RESULTS A strong correlation was found between the three indices throughout the 14 440 visits: r = 0.874 for DAS28/CDAI, r = 0.877 for DAS28/SDAI and r = 0.984 for CDAI/SDAI (all PCCs with P < 0.0001). However, when categorization in the different disease activity states was analysed, McNemars chi-squared tests and PCCs revealed significant disagreement between the cut-offs of the three indices. CONCLUSION DAS28, CDAI and SDAI cut-offs do not translate into the same clinical information in Reuma.pt. Although this might be expected for the original DAS28 cut-offs, when compared with CDAI and SDAI significant disagreement was also found for the DAS28 modified cut-offs. For visits where patients are in CDAI or SDAI remission, we also find disagreement between these two indices, which may contradict previous conclusions that acute phase reactants add little to composite disease activity indices for RA.

Angiografia como método de diagnóstico da síndrome do desfiladeiro torácico neurovascular: a propósito de um caso

O termo sindrome do desfiladeiro toracico (SDT) e usado para descrever o quadro clinico atribuivel a compressao do plexo braquial, arteria e veia subclavias na regiao designada por desfiladeiro toracico. Ate hoje, nenhum exame foi considerado gold standard para o diagnostico. Os autores descrevem o caso de uma adolescente de 16 anos observada na consulta de Reumatologia por omalgia direita com 3 meses de evolucao, acompanhada de disestesias do antebraco e mao homolaterais, desencadeadas por movimentos de abducao do ombro. Na observacao, a manobra de hiperabducao do membro superior direito desencadeava os sintomas e um enfraquecimento significativo do pulso radial e da pressao arterial, que nao sucediam no membro superior contralateral, tendo sido diagnosticada sindrome do desfiladeiro toracico a direita. Foi realizada tomografia axial computorizada (TAC) da regiao toracica, que nao revelou massas infra-claviculares nem axilares a direita. O ecodoppler do membro superior mostrou uma onda trifasica na arteria subclavia, realizou-se tambem angiografia das arterias subclavia e axilar do membro superior direito. Esta apresentou-se normal em posicao neutra, mas, com o braco em abducao maxima, observou-se uma reducao do contraste no interior da arteria axilar. Os autores propoem que, quando a clinica for sugestiva de SDT e existir uma suspeita de compressao vascular, deve ser realizada angiografia das arterias subclavia e axilar, para localizar e caracterizar a compressao. A SDT dessa paciente foi atribuida a uma hipotonia muscular do ombro, que foi ultrapassada apos fisioterapia com exercicios de reforco dos musculos elevadores do ombro.