The multiple sclerosis-associated regulatory variant rs10877013 affects expression of CYP27B1 and VDR under inflammatory or vitamin D stimuli.

BACKGROUND: Vitamin D deficit is considered an important risk factor for many inflammatory and autoimmune diseases. OBJECTIVE: To investigate the influence of the multiple sclerosis (MS)-associated regulatory variant rs10877013 on the expression of genes involved in vitamin D activation (CYP27B1), vitamin D receptor (VDR), and vitamin D degradation (CYP24A1) under inflammatory environment or vitamin D. METHODS: We used lipopolysaccharide and interferon-gamma (LPS+IFNγ) activated monocytes from 119 individuals and vitamin D-stimulated lymphoblastoid cell lines (LCLs, n = 109) of 1000 genomes to quantify the mRNA expression of vitamin D genes by quantitative reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: We found that CYP27B1 mRNA expression level was associated with the rs10877013 genotypes (p = 5.0E-6) in LPS+IFNγ treated monocytes, but not in vitamin D-stimulated LCLs. Inversely, rs10877013 genotypes were associated with VDR expression in LCLs (p = 6.0E-4) but not in monocytes. Finally, CYP24A1 was highly induced by the active form of vitamin D and its expression correlated with the expression of VDR in LCLs but neither the MS-associated variant in the region (rs2248359) nor any other variant located in 1 Mb around CYP24A1 was associated with its expression. CONCLUSIONS: The MS-associated variant rs10877013 is a genetic determinant that affects the functioning of the vitamin D system linking environmental and genetic factors.

A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands.

BACKGROUND: Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS). OBJECTIVES: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters. METHODS: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients. RESULTS: We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06). CONCLUSIONS: Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.

The high producer variant of the Fc-receptor like-3 (FCRL3) gene is involved in protection against multiple sclerosis.

Some polymorphisms in the FCRL3 gene, a member of the Fc-receptor like family, have been associated with several autoimmune diseases and recently with multiple sclerosis (MS). We performed a case-control study of three SNPs in FCRL3 gene in 645 MS patients and 786 controls, all Caucasians from the South of Spain. Genotype and allele frequencies of two SNPs (rs7528684/FCRL3_3 and rs7522061/N28D), which were in high linkage disequilibrium (r(2) = 0.87), differed between MS cases and controls. The C allele of FCRL3_3 was found to be protective for MS (per allele OR = 0.81, 95% C.I. = 0.70-0.94; P-value = 0.007) as was the G variant of N28D, but no association was found for rs11264799/FCRL3_4. Haplotype analysis confirmed these associations with highly consistent effect sizes for haplotypes carrying the C allele of FCRL3_3.

Recommendations for the use of methotrexate in psoriatic arthritis. / Recomendaciones sobre el uso de metotrexato en pacientes con artritis psoriásica.

OBJECTIVES: To develop recommendations for the management of methotrexate (MTX) in psoriatic arthritis (PsA), based on best evidence and experience. METHODS: A group of 12 experts on MTX use was selected. The coordinators formulated 14 questions about the use of MTX in PsA patients (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed 12 preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre for Evidence Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). RESULTS: A total of 12 preliminary recommendations on the use of MTX were proposed, 9 of which were accepted. One was included in a different recommendation and another 2 were not voted on and were thereafter clarified in the main text. CONCLUSIONS: These recommendations aim to answer frequent questions and help in decision making strategies when treating PsA patients with MTX.

Abatacept in patients with rheumatoid arthritis and interstitial lung disease: A national multicenter study of 63 patients.

OBJECTIVE: Interstitial lung disease (ILD) is one of the most serious complications of rheumatoid arthritis (RA). In the present study, we aimed to assess the efficacy of abatacept (ABA) in patients with ILD associated to RA. METHODS: National multicenter, non-controlled, open-label registry study of RA patients with ILD treated with ABA. RESULTS: 63 patients (36 women) with RA-associated ILD undergoing ABA therapy were studied. The mean ± standard deviation age at the time of the study was 63.2 ± 9.8 years. The median duration of RA and ILD from diagnosis were 6.8 and 1 year, respectively. RA was seropositive in 55 patients (87.3%). In 15 (23.8%) of 63 patients the development of ILD was closely related to the administration of synthetic or biologic disease modifying anti-rheumatic drugs. After a follow-up of 9.4 ± 3.2 months, two-thirds of patients remained stable whereas one-quarter experienced improvement in the Modified Medical Research Council scale. At that time forced vital capacity remained stable in almost two-thirds of patents and improved in one out of five patients assessed. Also, diffusing capacity of the lung for carbon monoxide remained stable in almost two-thirds and showed improvement in a quarter of the patients assessed. At 12 months, 50% of the 22 patients in whom chest HRCT scan was performed due persistence of respiratory symptoms showed stabilization, 8 (36.4%) improvement and 3 worsening of the HRCT scan pattern. Eleven of 63 patients had to discontinue ABA, mainly due to adverse events. CONCLUSION: ABA appears to be an effective in RA-associated ILD.

Quality standards for rheumatology outpatient clinic. The EXTRELLA project. / Estándares de calidad asistencial para las consultas externas de reumatología. El proyecto EXTRELLA.

INTRODUCTION: In recent years, outpatient clinics have undergone extensive development. At present, patients with rheumatic diseases are mainly assisted in this area. However, the quality standards of care are poorly documented. OBJECTIVE: To develop specific quality criteria and standards for an outpatient rheumatology clinic. METHOD: The project was based on the two-round Delphi method. The following groups of participants took part: scientific committee (13 rheumatologists), five nominal groups (45 rheumatologists and 12 nurses) and a group of discussion formed by 9 patients. Different drafts were consecutively generated until a final document was obtained that included the standards that received a punctuation equal or over 7 in at least 70% of the participants. RESULTS: 148 standards were developed, grouped into the following 9 dimensions: a) structure (22), b) clinical activity and relationship with the patients (34), c) planning (7), d) levels of priority (5), e) relations with primary care physicians, with Emergency Department and with other clinical departments, f) process (26), g) nursing (13), h) teaching and research (13) and i) activity measures (8). CONCLUSION: This study established specific quality standards for rheumatology outpatient clinic. It can be a useful tool for organising this area in the Rheumatology Department and as a reference when proposing improvement measures to health administrators.

Effects of the multiple sclerosis associated -330 promoter polymorphism in IL2 allelic expression.

The -330 IL2 gene promoter polymorphism has been associated with multiple sclerosis (MS) [J. Neuroimmunol. 119 (2001) 101], but the basis underlying this association remains unknown to date. In the present work, we have found that IL2 promoter-luciferase constructs, transfected in Jurkat cell line, showed twofold higher levels of gene expression in the -330 G allele. However, the transcriptional effect of this polymorphism in lymphocytes showed that the G allele was related to lower expression of IL2. This difference increased in the patient group. Divergence between in vivo and in vitro influence of the -330 IL2 promoter polymorphic site suggests the existence of additional unknown polymorphisms affecting gene regulation. Our data show an increased IL2 expression among GT and TT genotypes previously associated with susceptibility to MS.

Recomendaciones sobre el uso de metotrexato en pacientes con artritis psoriásica / Recommendations for the use of methotrexate in psoriatic arthritis

Objetivos: Desarrollar recomendaciones sobre el uso de metotrexato (MTX) en pacientes con artritis psoriásica (APs) basadas en la mejor evidencia y experiencia. Métodos: Se seleccionó un grupo de 12 expertos reumatólogos en el manejo de MTX. Los coordinadores generaron 14 preguntas sobre el uso de MTX en pacientes con APs (perfiles de indicación, eficacia y seguridad) para ser contestadas mediante una revisión sistemática de la literatura. En función de las preguntas se definieron los criterios de inclusión y exclusión y las estrategias de búsqueda (para interrogar Medline, Embase y la Cochrane Library). Dos revisores seleccionaron los artículos resultantes de la búsqueda. Se generaron tablas de evidencia. Paralelamente se evaluaron abstracts de congresos de EULAR y ACR. Con toda esta evidencia los coordinadores generaron 12 recomendaciones preliminares que se evaluaron, discutieron y votaron en una reunión de grupo nominal con el resto de expertos. Para cada recomendación se estableció el nivel de evidencia, grado de recomendación, y grado de acuerdo mediante un Delphi. Se definió acuerdo si al menos el 80% de los participantes contestan sí a la recomendación (sí o no). Resultados: De las 12 recomendaciones preliminares se aceptaron 9 recomendaciones sobre el uso de MTX en la APs. Una se englobó en otra y otras 2 no se llegaron a votar porque se decidió no incluirlas, pero se comentan en el texto final. Conclusiones: Estas recomendaciones pretenden resolver algunos interrogantes clínicos habituales y facilitar la toma de decisiones con el uso de MTX en la APs

Objectives: To develop recommendations for the management of methotrexate (MTX) in psoriatic arthritis (PsA), based on best evidence and experience. Methods: A group of 12 experts on MTX use was selected. The coordinators formulated 14 questions about the use of MTX in PsA patients (indications, efficacy, safety and cost-effectiveness). A systematic review was conducted to answer the questions. Using this information, inclusion and exclusion criteria were established, as were the search strategies (Medline, EMBASE and the Cochrane Library were searched). Two different reviewers selected the articles. Evidence tables were created. At the same time, European League Against Rheumatism and American College of Rheumatology abstracts were evaluated. Based on this evidence, the coordinators proposed 12 preliminary recommendations that the experts discussed and voted on in a nominal group meeting. The level of evidence and grade of recommendation were established using the Oxford Centre for Evidence Based Medicine and the level of agreement with the Delphi technique (2 rounds). Agreement was established if at least 80% of the experts voted yes (yes/no). Results: A total of 12 preliminary recommendations on the use of MTX were proposed, 9 of which were accepted. One was included in a different recommendation and another 2 were not voted on and were thereafter clarified in the main text. Conclusions: These recommendations aim to answer frequent questions and help in decision making strategies when treating PsA patients with MTX

Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations.

The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone.

Genetic diversity of influenza A(H1N1)2009 virus circulating during the season 2010-2011 in Spain.

BACKGROUND: Genetic diversity of influenza A(H1N1)2009 viruses has been reported since the pandemic virus emerged in April 2009. Different genetic clades have been identified and defined based on amino acid substitutions found in the haemagglutinin (HA) protein sequences. In Spain, circulating influenza viruses are monitored each season by the regional laboratories enrolled in the Spanish Influenza Surveillance System (SISS). The analysis of the HA gene sequence helps to detect the genetic diversity and viral evolution. OBJECTIVES: To perform an analysis of the genetic diversity of influenza A(H1N1)2009 viruses circulating in Spain during the season 2010-2011 based on analysis of the HA sequence gene. STUDY DESIGN: Phylogenetic analysis based on the HA1 subunit of the haemagglutinin gene was carried out on 220 influenza A(H1N1)2009 viruses circulating during the season 2010-2011. RESULTS: Six different genetic groups were identified among circulating A(H1N1)2009 viruses, five of them were previously reported during season 2010-2011. A new group, characterized by E172K and K308E changes and a proline at position 83, was observed in 12.27% of the Spanish viruses. CONCLUSION: Co-circulation of six different genetic groups of influenza A(H1N1)2009 viruses was identified in Spain during the season 2010-2011. Nevertheless, at this stage, none of the groups identified to date have resulted in significant antigenic changes according to data collected by World Health Organization Collaborating Centres for influenza surveillance.

Estándares de calidad asistencial para las consultas externas de reumatología. El proyecto EXTRELLA / Quality standards for rheumatology outpatient clinic. The EXTRELLA project

Introducción. En los últimos años, el peso específico de las consultas externas ha aumentado considerablemente. En la actualidad, la mayor parte de la atención reumatológica se lleva a cabo en esta área del hospital. Sin embargo, apenas existe documentación respecto a estándares de calidad asistencial. Objetivo. Desarrollar, mediante consenso, estándares de calidad asistencial específicos para las consultas externas de reumatología. Método. El proyecto se llevó a cabo mediante metodología Delphi a 2 rondas. Se contó con la participación de un comité científico (13 reumatólogos), 5 grupos nominales (45 reumatólogos y 12 enfermeras especializadas) y un grupo de discusión formado por 9 pacientes. Se generaron de forma sucesiva diversos borradores hasta obtener un documento final que incluyó los estándares que recibieron una puntuación igual o superior a 7 en al menos el 70% de los participantes. Resultados. El documento consta de 148 estándares distribuidos en 9 áreas temáticas: a) estructura (22); b) actividad clínica y relación con los pacientes (34); c) planificación (7); d) niveles de prioridad (5); e) relación con atención primaria, con el servicio de urgencias y con otros servicios del hospital (20); f) proceso (26); g) enfermería (13); h) docencia e investigación (13), e i) cómputo de actividad (8). Conclusión. Se han consensuado unos estándares de calidad asistencial que pueden ser útiles para organizar la actividad en las consultas externas de los servicios de reumatología y servir como marco de referencia a la hora de elevar propuestas de mejora a la gerencia del hospital o a otros estamentos de la administración (AU)

Introduction. In recent years, outpatient clinics have undergone extensive development. At present, patients with rheumatic diseases are mainly assisted in this area. However, the quality standards of care are poorly documented. Objective. To develop specific quality criteria and standards for an outpatient rheumatology clinic. Method. The project was based on the two-round Delphi method. The following groups of participants took part: scientific committee (13 rheumatologists), five nominal groups (45 rheumatologists and 12 nurses) and a group of discussion formed by 9 patients. Different drafts were consecutively generated until a final document was obtained that included the standards that received a punctuation equal or over 7 in at least 70% of the participants. Results. 148 standards were developed, grouped into the following 9 dimensions: a) structure (22), b) clinical activity and relationship with the patients (34), c) planning (7), d) levels of priority (5), e) relations with primary care physicians, with Emergency Department and with other clinical departments, f) process (26), g) nursing (13), h) teaching and research (13) and i) activity measures (8). Conclusion. This study established specific quality standards for rheumatology outpatient clinic. It can be a useful tool for organising this area in the Rheumatology Department and as a reference when proposing improvement measures to health administrators (AU)

Hexose-6-phosphate dehydrogenase: a new risk gene for multiple sclerosis.

A recent genome-wide association study (GWAS) performed by the The Wellcome Trust Case-Control Consortium based on 12 374 nonsynonymous single-nucleotide polymorphisms (SNPs) provided evidence for several genes involved in multiple sclerosis (MS) susceptibility. In this study, we aimed at verifying the association of 19 SNPs with MS, with P-values < or =0.005, in an independent cohort of 732 patients and 974 controls, all Caucasian from the South of Spain. We observed an association of the rs17368528 polymorphism with MS (P=0.04, odds ratio (OR)=0.801, 95% confidence interval (CI)=0.648-0.990). The association of this polymorphism with MS was further validated in an independent set of 1318 patients from the Canadian Collaborative Project (P=0.04, OR=0.838, 95% CI=0.716-0.964). This marker is located on chromosome 1p36.22, which is 1 Mb away from the MS-associated kinesin motor protein KIF1B, although linkage disequilibrium was not observed between these two markers. The rs17368528 SNP results in an amino-acid substitution (proline to leucine) in the fifth exon of the hexose-6-phosphate dehydrogenase (H6PD) gene, in which some variants have been reported to attenuate or abolish H6PD activity, in individuals with cortisone reductase deficiency. This study corroborates the association of one locus determined by GWAS and points to H6PD as a new candidate gene for MS.

Tag-SNP analysis of the GFI1-EVI5-RPL5-FAM69 risk locus for multiple sclerosis.

A recent genome-wide association study conducted by the International Multiple Sclerosis Genetic Consortium (IMSGC) identified, among others, a number of putative multiple sclerosis (MS) susceptibility variants at position 1p22. Twenty-one SNPs positively associated with MS were located at the GFI-EVI5-RPL5-FAM69A locus. In this study, we performed an analysis and fine mapping of this locus, genotyping eight Tag-SNPs in 732 MS patients and 974 controls from Spain. We observed an association with MS in three of eight Tag-SNPs: rs11804321 (P=0.008, OR=1.29; 95% CI=1.08-1.54), rs11808092 (P=0.048, OR=1.19; 95% CI=1.03-1.39) and rs6680578 (P=0.0082, OR=1.23; 95% CI=1.07-1.41). After correcting for multiple comparisons and using logistic regression analysis to test the addition of each SNP to the most associated SNPs, we observed that rs11804321 alone was sufficient to model the association. This Tag-SNP captures two SNPs in complete linkage disequilibrium (r(2)=1), both located within the 17th intron of the EVI5 gene. Our findings agree with the corresponding data of the recent IMSGC study and present new genetic evidence that points to EVI5 as a factor of susceptibility to MS.

IL2RA/CD25 gene polymorphisms: uneven association with multiple sclerosis (MS) and type 1 diabetes (T1D).

BACKGROUND: IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. METHODS AND RESULTS: Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3'- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. CONCLUSIONS: These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.