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Selva-O'Callaghan A.,Vall dHebron General Hospital
Clinical nuclear medicine | Year: 2011

Cerebrotendinous xanthomatosis is a rare recessive autosomal disease caused by mutations of the sterol 27-hydroxylase gene (CYP27), which leads to reduced synthesis of bile acids, particularly chenodeoxycholic acid (Cali et al, J Biol Chem. 1991;266:7779-7783; Gallus et al, Neurol Sci. 2006;27:143-149). The disease is characterized by progressive neurologic dysfunction due to accumulation of cholestanol in neurologic tissues (Moghadasian et al, Arch Neurol. 2002;59:527-529; Selva-O'Callaghan et al, Rheumatology. 2007;46:1212-1213). Long-term treatment with chenodeoxycholic acid can arrest or even reverse progression of the disease (Pierre et al, J Inherit Metab Dis. In press).Brain SPECT with 740 MBq of Tc-99m ethyl cysteinate dimmer, using a double-head gamma camera (Siemens E.cam) with high-resolution, low-energy parallel collimators was performed in our patient at onset and 2 years after starting chenodeoxycholic acid treatment. SPECT acquisitions were performed using a 360-degree orbit, 1 image/30 seg/3 degree, and 128 × 128 matrix. Reconstruction was by means of filtered back-projection, Butterworth 5/0.25, without attenuation correction. Pre- and post-SPECT dicom images were reoriented into Talairach space using NeuroGam (Segami Corporation). To visually identify abnormal perfusion regions, volume render brain image was computed, where abnormal perfusion regions were found by comparing with age-matched normal database, and Brodmann areas (BA) were quantified. Pre- versus post-treatment changes were computed by means of relative percentage between counts. Post-treatment SPECT showed better perfusion than pretreatment SPECT with an increase between 5% and 10% in frontal cortex (BA 9, BA 24, BA 32, BA 46, BA 47), parietal cortex (BA 5, BA 31), and temporal cortex (BA 20, BA 22, BA 28, BA 36, BA 37, BA 38), and with an increase of more than 10% in frontal cortex (BA 45) and parietal cortex (BA 23). This case illustrates the benefit of bile acid therapy for halting and even reversing neurologic retardation in this condition.

Labirua-Iturburu A.,Autonomous University of Barcelona | Selva-O'Callaghan A.,Autonomous University of Barcelona | Zock J.-P.,Center for Research in Environmental Epidemiology | Zock J.-P.,Hospital del Mar Medical Research Institute IMIM | And 5 more authors.
Clinical Rheumatology | Year: 2014

Interstitial lung disease (ILD) is common in patients with myositis and is related with the presence of antisynthetase autoantibodies (aSA). Together with other manifestations, the resulting condition is known as the antisynthetase syndrome (ASS). Contact with certain environmental and occupational agents is also associated with the development of ILD. The objective of this study was to analyze occupational exposure and associated clinical manifestations in a cohort of patients with ASS. aSA had been identified by line immunoassay and confirmed by immunoprecipitation. Serial pulmonary function tests had been carried out to assess lung function. Thirty-two ASS patients and a control group of 32 myositis patients without aSA underwent a specific questionnaire interview to evaluate their cumulative exposure to biological dust, mineral dust, and gases/fumes up to disease onset. Comparisons were done with the Fisher exact test and Mann-Whitney test. Out from 32 ASS patients (median age, 42.7 yeras; IQR 32.2-52.5), twenty-six patients had anti-Jo-1, three anti-PL-12, and three anti-PL-7. Nine had polymyositis, 15 dermatomyositis, one amyopathic dermatomyositis, and seven pure ILD without myositis. Sixteen ASS patients (50 %) and seven (22 %) myositis patients without aSA had ever been highly exposed to dust, gases, or fumes (p < 0.05). A more than 10 % improvement in forced vital capacity occurred in 61 % of highly exposed patients and 23 % of those with low/no exposure (p = 0.06) over the observation period. In conclusion, a high percentage of patients with ASS had been exposed to dusts, gases, or fumes. © 2014 Clinical Rheumatology.

Miller F.W.,U.S. National Institutes of Health | Chen W.,University of Texas M. D. Anderson Cancer Center | O'Hanlon T.P.,U.S. National Institutes of Health | Cooper R.G.,University of Liverpool | And 21 more authors.
Genes and Immunity | Year: 2015

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5 × 10-8) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1∗03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B∗08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. © 2015 Macmillan Publishers Limited All rights reserved.

Miller F.W.,U.S. National Institutes of Health | Cooper R.G.,University of Manchester | Vencovsky J.,Institute of Rheumatology | Rider L.G.,U.S. National Institutes of Health | And 29 more authors.
Arthritis and Rheumatism | Year: 2013

Objective: To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 × 10-8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. Conclusion: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches.

Trallero-Araguas E.,Vall dHebron General Hospital | Rodrigo-Pendas J.A.,Autonomous University of Barcelona | Selva-O'Callaghan A.,Autonomous University of Barcelona | Martinez-Gomez X.,Autonomous University of Barcelona | And 4 more authors.
Arthritis and Rheumatism | Year: 2012

Objective Anti-p155 autoantibody, which was recently described in adult patients with dermatomyositis (DM), seems to be associated with cancer in this population. We performed a systematic review and meta-analysis to ascertain the accuracy of anti-p155 testing for the diagnosis of cancer-associated myositis. Methods We searched relevant databases, with no restrictions on study design or language, for original studies that included adult patients with probable/definite DM or amyopathic DM who were evaluated for neoplasm and anti-p155 status. Pooled sensitivity and specificity were calculated using a bivariate model. We computed the diagnostic odds ratio (OR), likelihood ratios (LRs) for positive and negative test results, positive and negative predictive values, and the summary receiver operating characteristic (SROC) curve. Statistical heterogeneity between studies was assessed using the I2 statistic, and 95% confidence intervals (95% CIs) were computed for the parameters studied. Results Six studies including a total of 312 adult patients with DM were selected. The pooled sensitivity of anti-p155 for diagnosing cancer-associated DM was 78% (95% CI 45-94%), and specificity was 89% (95% CI 82-93%). The diagnostic OR was 27.26 (95% CI 6.59-112.82), and LRs for positive and negative test results were 6.79 (95% CI 4.11-11.23) and 0.25 (95% CI 0.08-0.76), respectively. Heterogeneity was substantial except with regard to the LR for a positive test result. The area under the SROC curve was 0.91 (95% CI 0.88-0.93). Taking the pooled prevalence of 17% as pretest probability, anti-p155 had a positive predictive value of 58% and a negative predictive value of 95%. Conclusion Our findings indicate that anti-p155 autoantibody determination is useful for diagnosing cancer-associated myositis and guiding disease management. © 2012 American College of Rheumatology.

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