Work productivity and activity impairment in patients with primary Sjögren's syndrome.

OBJECTIVES: In this observational, analytical, cross-sectional study we aimed to describe the impact of primary Sjögren's syndrome (pSS) on work productivity and activities of daily living (ADL) to assess the association between ADL impairment and clinical manifestations and to compare ADL impairment according to patients' socioeconomic condition. METHODS: Patients diagnosed with pSS attending 11 centres from Argentina were included. To evaluate work productivity and ADL impairment, a work productivity and activity impairment questionnaire (WPAI) was used. A multiple linear regression model was performed, considering deterioration on ADL due to health as a dependent variable, adjusted for potential confounders. RESULTS: 252 patients were included, 98.4% were women, with a mean age of 52.6 years (±14.8). The average percentage of time lost due to health was 15.7 hours (±30.1 95% CI: 9.6-21.9); the decrease in work productivity was 27.2 (±30.2 95% CI: 21.3-33.1), the total disability was 33.7 (±35.8 95% CI: 26.4-4) and ADL deterioration was 34.2 (±30.9. 95% CI: 30.4-38). In the multivariate analysis, xerostomia, arthritis and depression showed significant and independent association. The mean of ADL impairment was 38.2 (±30.7) in patients attending public centres versus 28 (± 30.6) in private centres, which was a statistically significant difference. CONCLUSIONS: We found a compromise in all WPAI domains. Arthritis, xerostomia and depression were associated significantly and independently with ADL impairment. Deterioration in ADL was greater in patients treated in public centres. Considering these aspects will allow a better understanding of patients who suffer from this disease.

Effects of Amerindian Genetic Ancestry on Clinical Variables and Therapy in Patients with Rheumatoid Arthritis.

OBJECTIVE: To define whether Amerindian genetic ancestry correlates with clinical and therapeutic variables in admixed individuals with rheumatoid arthritis (RA) from Latin America. METHODS: Patients with RA (n = 1347) and healthy controls (n = 1012) from Argentina, Mexico, Chile, and Peru were included. Samples were genotyped for the Immunochip v1 using the Illumina platform. Clinical data were obtained through interviews or the clinical history. RESULTS: Percentage of Amerindian ancestry was comparable between cases and controls. Morning stiffness (p < 0.0001, OR 0.05), rheumatoid factor (RF; p < 0.0001, OR 0.22), radiographic changes (p < 0.0001, OR 0.05), and higher number of criteria were associated with lower Amerindian ancestry after Bonferroni correction. Higher Amerindian ancestry correlated only with weight loss (pBonferroni < 0.0001, OR 2.85). Increased Amerindian ancestry correlated with higher doses of azathioprine (p < 0.0001, OR 163.6) and sulfasalazine (p < 0.0001, OR 48.6), and inversely with methotrexate (p = 0.001, OR 0.35), leflunomide (p = 0.001, OR 0.16), and nonsteroidal antiinflammatory drugs (pBonferroni = 0.001, OR 0.37). Only the presence of RF and weight loss were modified after confounders adjustment. CONCLUSION: Amerindian ancestry protects against most major clinical criteria of RA, but regarding the association of RF with increased European ancestry, age, sex, and smoking are modifiers. Ancestry also correlates with the therapeutic profiles.

Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial.

OBJECTIVES: This phase II trial evaluated the efficacy and safety of an interleukin (IL) 6 monoclonal antibody for systemic lupus erythematosus (SLE). METHODS: Patients with active disease were randomised to placebo or PF-04236921 10 mg, 50 mg or 200 mg, subcutaneously, every 8 weeks with stable background therapy. SLE Responder Index (SRI-4; primary end point) and British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) were assessed at week 24. Post hoc analysis identified an enriched population based upon planned univariate analyses. RESULTS: 183 patients received treatment (placebo, n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46). The 200 mg dose was discontinued due to safety findings and not included in the primary efficacy analysis. The SRI-4 response rates were not significant for any dose compared with placebo; however, the BICLA response rate was significant for 10 mg (p=0.026). The incidence of severe flares was significantly reduced with 10 mg (n=0) and 50 mg (n=2) combined versus placebo (n=8; p<0.01). In patients with greater baseline disease activity (enriched population), the SRI-4 (p=0.004) and BICLA (p=0.012) response rates were significantly different with 10 mg versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1) occurred. The most frequently reported adverse events included headache, nausea and diarrhoea. CONCLUSIONS: PF-04236921 was not significantly different from placebo for the primary efficacy end point in patients with SLE. Evidence of an effect with 10 mg was seen in a post hoc analysis. Safety was acceptable for doses up to 50 mg as the 200 mg dose was discontinued due to safety findings. TRIAL REGISTRATION NUMBER: NCT01405196; Pre-results.

Elevated IL-1ß levels in anti-Ro/SSA connective tissue diseases patients with prolonged corrected QTc interval.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) have increased IL-1ß levels. IL-1ß and other pro-inflammatory cytokines have a modulating activity on cardiac ion channels and have been associated with increased arrhythmic risk in rheumatoid arthritis patients. Likewise, adult patients with connective tissue diseases (CTDs) may have prolonged QTc intervals associated with the presence of anti-Ro/SSA antibodies. Our objective was to evaluate the presence of serum IL-1ß in subjects with CTDs, in relation to the presence of anti-Ro/SSA antibodies and QTc interval duration. METHODS: 12-lead electrocardiograms (ECG) were performed and blood was withdrawn, measuring electrolytes, IL-1ß anti-Ro/SSA antibodies by ELISA in 73 patients with CTDs. RESULTS: 55 patients were anti-Ro/SSA positive and 18 were anti-Ro/SSA negative. Patients with anti-Ro/SSA positive antibodies had a significantly greater median IL-1ß serum level: 7.29 (range: 0.17-17.3 pg/ml) compared to patients with anti-Ro/SSA negative antibodies whose median was: 1.67 (range 0.55-4.12 pg/ml) p<0.001. The mean QTc interval values obtained in both groups were not significantly different (417.7±23.1 vs. 414.7±21.2, p=0.63). The QTc interval was prolonged in 11 (20%) patients, who were all anti-Ro/SSA positive versus 0 (0 %) in anti-Ro/SSA negative patients p=0.05. Median IL-1ß levels were: 8.7 (range: 2.69-15.1 pg/ml) in patients with prolonged QTc interval versus median: 5.0 (range: 0.17-17.3 pg/ml) in those with normal QTc interval values (<440ms) p=0.006. CONCLUSIONS: IL-1ß is elevated in patients with CTDs that have both anti-Ro/SSA antibodies and prolonged QTc intervals.

Estudio multicéntrico de prevalencia de anticuerpos antirribosomal P en lupus eritematoso sistémico de comienzo juvenil comparado con lupus eritematoso sistémico del adulto / Multicentric prevalence study of anti P ribosomal autoantibodies in juvenile onset systemic lupus erythematosus compared with adult onset systemic lupus erythematosus

Objetivo. Determinar la prevalencia y correlación clínica de los anticuerpos antirribosomal P en lupus eritematoso sistémico (LES) juvenil y compararlos con LES del adulto. Métodos. Se incluyeron en el estudio 30 pacientes con LES juvenil y 92 pacientes con LES del adulto. Consideramos LES de comienzo juvenil a todos aquellos pacientes que comenzaron su enfermedad antes de los 16 años. Se consideraron las manifestaciones clínicas y serológicas que presentaron los pacientes desde el diagnóstico hasta el momento de inclusión en el estudio (manifestaciones acumuladas). El anticuerpo antirribosomal P fue evaluado mediante la técnica de enzimo-inmunoensayo (ELISA). Resultados. La presencia de antirribosomal P fue significativamente mayor en el grupo de pacientes con LES juvenil comparado con LES del adulto (26,7% vs. 6,5%; OR = 5,21 [IC95% = 1,6-16,5], p = 0,003). La alopecía (OR = 10,11; IC95% = 1,25-97) y rash cutáneo (no discoide) (OR = 4,1; IC95% = 1,25-13,89) fueron las únicas manifestaciones clínicas que se asociaron en forma estadísticamente significativa con la presencia del anticuerpo antirribosomal P. Conclusión. Este estudio confirma una mayor prevalencia de anticuerpos antirribosomal P en pacientes con LES juvenil. La alopecia y el rash cutáneo fueros las únicas manifestaciones clínicas asociadas a la presencia de antirribosomal P (AU)

Objective. To investigate the prevalence and associations with clinical manifestations of anti- P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). Methods. Clinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years old) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti- P ribosomal antibodies were tested by ELISA. Results. Anti- P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs. 6.5%; OR = 5.21 [CI95% = 1.6-16.5], p = 0.003). Alopecia (OR = 10.11, CI 95% = 1.25-97) and skin rash (non discoid) (OR = 4.1, CI 95% = 1.25-13.89) were significantly associated with anti- P ribosomal antibodies. Conclusion. Anti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies (AU)

Multicentric prevalence study of anti P ribosomal autoantibodies in juvenile onset systemic lupus erythematosus compared with adult onset systemic lupus erythematosus.

OBJECTIVE: To investigate the prevalence and associations with clinical manifestations of anti- P ribosomal antibodies in patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). METHODS: Clinical and serological data of 30 patients with juvenile-onset SLE (age at onset younger than 16 years old) were compared with data of 92 patients with adult-onset SLE. Symptoms occurring during the entire disease course were considered. Anti- P ribosomal antibodies were tested by ELISA. RESULTS: Anti- P ribosomal antibodies were found significantly more often in pediatric-onset SLE patients (26.7% vs. 6.5%; OR=5.21 [CI95%=1.6-16.5], p=0.003). Alopecia (OR=10.11, CI 95%=1.25-97) and skin rash (non discoid) (OR=4.1, CI 95%=1.25-13.89) were significantly associated with anti- P ribosomal antibodies. CONCLUSION: Anti-ribosomal P antibodies are more often found in patients with juvenile SLE. Alopecia and skin rash were the only clinical manifestations associated to anti-ribosomal P antibodies.

4G/5G plasminogen activator inhibitor-1 and -308 A/G tumor necrosis factor-α promoter gene polymorphisms in Argentinean lupus patients: focus on lupus nephritis.

We investigated the relationship between the 4G/5G plasminogen activator inhibitor (PAI-1) and -308 A/G tumor necrosis factor-α (TNF-α) polymorphisms and the clinical and biochemical features of systemic lupus erythematosus (SLE) in an Argentinean patient cohort. A total of 402 patients were studied, including 179 SLE patients and 223 healthy individuals. PCR-RLFP was used to determine the genotypes of the 4G/5G PAI-1 and -308 A/G TNF-α polymorphisms. SLE patients with lupus nephritis (LN) (n = 86) were compared with patients without LN (n = 93). Additionally, LN patients were divided into proliferative LN and non-proliferative LN groups according to the results of the renal biopsies. No significant differences were noted in the genotype distributions or allele frequencies of these TNF-α and PAI-1 polymorphisms between SLE patients and controls. There were higher numbers of criteria for SLE, more lupus flares and higher damage scores in LN patients, but there were similar frequencies of anti-phospholipid antibody (APA) positivity and anti-phospholipid syndrome. No significant difference was noted for any studied variable between the proliferative LN and non-proliferative LN groups except for the presence of APA. We found no significant differences in the TNF-α and PAI-1 genotype distributions or allele frequencies between groups. We found that the -308 A/G TNF-α and 4G/5G PAI-1 polymorphisms are not associated with susceptibility to SLE in an Argentinean population. We also did not find any association between the presence of any specific allele or genotype and the development of LN in SLE patients. Finally, no association was noted between either of the two polymorphisms and the severity of renal disease.

Rheumatoid arthritis in Latin Americans enriched for Amerindian ancestry is associated with loci in chromosomes 1, 12, and 13, and the HLA class II region.

OBJECTIVE: To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry. METHODS: Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software. RESULTS: A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 × 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 × 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 × 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 × 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies. CONCLUSION: Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13.

The -2518 A/G polymorphism in the monocyte chemoattractant protein 1 gene is associated with the risk of developing systemic lupus erythematosus in Argentinean patients: a multicenter study.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disorder. Monocyte chemoattractant protein 1 (MCP-1), a chemokine involved in the recruitment and migration of monocytes/macrophages, has been shown to be increased in the plasma of SLE patients. The aim of our study was to evaluate the possible association of the polymorphism -2518 of the MCP-1 gene with the risk of developing SLE, manifesting lupus nephritis (LN) and with other clinical features of SLE in an Argentinean population. A group of 171 SLE patients and 120 control subjects were examined. Genotypic and allelic frequencies of the MCP-1 -2518 A/G polymorphism showed significant differences between the SLE and the control groups (p=0.001 and p=0.01, respectively). However, the polymorphism showed no association with LN or with the other clinical variables studied. Our results suggest that the presence of the MCP-1 -2518 A/G polymorphism might be a risk factor for developing SLE in genetically predisposed individuals, but it does not seem to have a role in the evolution of the disease in the Argentinean population.

Study of functional variants of the BANK1 gene in rheumatoid arthritis.

OBJECTIVE: To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA). METHODS: Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a TaqMan 5'-allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi-square test. RESULTS: We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03-1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00-1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04-1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07-1.29]) with RA in the pooled analysis. In a 3-SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04-1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74-0.92]). CONCLUSION: These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

Analysis of IRF5 gene functional polymorphisms in rheumatoid arthritis.

OBJECTIVE: Recent findings suggest that interferon regulatory factor 5 (IRF-5) may play a crucial role in several cellular processes, including the transcription of genes for inflammatory cytokines. Two genetic variants of the IRF5 gene (rs2004640 in exon 1 and rs2280714 in the 3'-untranslated region) have been shown to exert functional modifications affecting IRF5 messenger RNA splicing and expression, and have been associated with genetic predisposition to systemic lupus erythematosus (SLE). The aim of this study was to analyze the possible contribution of the IRF5 gene to the predisposition to rheumatoid arthritis (RA). METHODS: Three case-control cohorts from Spain (724 RA patients and 542 healthy controls), Sweden (281 RA patients 474 healthy controls), and Argentina (284 RA patients and 286 healthy controls) were independently analyzed. Genotyping for IRF5 rs2004640 and rs2280714 was performed using a TaqMan 5' allele-discrimination assay. RESULTS: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls. Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA. CONCLUSION: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA.

Anticuerpos anti-citoplasma de polimorfonuclear neutrófilo en granulomatosis de Wegener, en otras enfermedades autoinmunes y en pacientes hemodializados / Anticytoplasm antibodies of polymorphonuclear neutrophils in Wegeners granulomatosis, other autoimmune diseases and in patients under hemodialysis

Las vasculitis sistémicas son un grupo heterogénio de enfermedades caracterizadas por infiltración inflamatoria y necrosis de la pared vascular. Anticuerpos contra citoplasma de polimorfonuclear neutrófilo (ANCA-C y ANCA-P) fueron descriptos como marcadores serológicos de algunas de estas afecciones y de ciertos tipos de glomerulonefritis. La presencia de ANCA se investigó en el suero de 182 pacientes. En 16/17 con Granulomatosis de Wegener (G.W.) (critérios ACR) se encontró ANCA, 14 de ellos con imagen C (en 10 asociada a imagem P) y en los dos restantes, imagem P solamente (p < 0,001, comparando con los otros grupos estudiados). La presencia de estos anticorpos se asoció con la atividad clínica de la enfermedad (p, 0,01). El único paciente ANCA-C positivo fuera de este grupo tenía estonosis subglótica como única manifestación clínica con histología inespecífica, ANCA-P se encontró, además, en 6 por ciento de los casos con Enfermedades del Tejido Conectivo estudiados, y en 6/66 de la Unidad de Diálisis, lo cual sugiere que un mecanismo relacionado al ANCA puede ser el responsable de la nefropatía en aproximadamente el 10//de los pacientes en hemodiálisis crónica. Los resultados obtenidos indican que la investigación de ANCA puede ser un elemento de ayuda útil para el diagnóstico y monitoreo de la actividad clínica en la G.W (AU)

Anticuerpos anti-citoplasma de polimorfonuclear neutrófilo en granulomatosis de Wegener, en otras enfermedades autoinmunes y en pacientes hemodializados / Anticytoplasm antibodies of polymorphonuclear neutrophils in Wegener's granulomatosis, other autoimmune diseases and in patients under hemodialysis

Las vasculitis sistémicas son un grupo heterogénio de enfermedades caracterizadas por infiltración inflamatoria y necrosis de la pared vascular. Anticuerpos contra citoplasma de polimorfonuclear neutrófilo (ANCA-C y ANCA-P) fueron descriptos como marcadores serológicos de algunas de estas afecciones y de ciertos tipos de glomerulonefritis. La presencia de ANCA se investigó en el suero de 182 pacientes. En 16/17 con Granulomatosis de Wegener (G.W.) (critérios ACR) se encontró ANCA, 14 de ellos con imagen C (en 10 asociada a imagem P) y en los dos restantes, imagem P solamente (p < 0,001, comparando con los otros grupos estudiados). La presencia de estos anticorpos se asoció con la atividad clínica de la enfermedad (p, 0,01). El único paciente ANCA-C positivo fuera de este grupo tenía estonosis subglótica como única manifestación clínica con histología inespecífica, ANCA-P se encontró, además, en 6 por ciento de los casos con Enfermedades del Tejido Conectivo estudiados, y en 6/66 de la Unidad de Diálisis, lo cual sugiere que un mecanismo relacionado al ANCA puede ser el responsable de la nefropatía en aproximadamente el 10//de los pacientes en hemodiálisis crónica. Los resultados obtenidos indican que la investigación de ANCA puede ser un elemento de ayuda útil para el diagnóstico y monitoreo de la actividad clínica en la G.W