Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

Investigation of TLR5 and TLR7 as candidate genes for susceptibility to systemic lupus erythematosus.

OBJECTIVES: The aim of this study was to evaluate the relevance of genetic variants of TLR5 (rs5744168) and TLR7 (rs179008) gene in systemic lupus erythematosus (SLE) in a Spanish population. MATERIAL AND METHODS: Our study population consisted of 752 SLE patients and 1107 healthy controls. All individual were of Spanish Caucasian origin. The TLR5 and TLR7 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. RESULTS: No statistically significant differences were observed when the allele and genotype distribution of TLR5 rs5744168 and TLR7 rs179008 polymorphisms was compared between SLE patients and healthy controls. A significant increase frequency in the CC genotype of the TLR5 rs5744168 polymorphism among SLE patients without nephritis was found (93% vs. 87% in SLE patients with nephritis, p=0.03, OR=2.11 95%CI 0.93-3.51). However, this difference did not reach statistical significance in the allele frequencies (p=0.08). CONCLUSION: These results suggest that the tested variations of TLR5 and TLR7 genes do not confer a relevant role in the susceptibility or severity to SLE in the Spanish population.

The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.

The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.

No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus.

The aim of this study was to determine the potential role of three IRF3 gene polymorphisms (rs2304204, rs7251 and rs2304207) with systemic lupus erythematosus (SLE). Our study population consisted of 610 patients with SLE and 730 healthy controls. All individual were of Spanish Caucasian origin. The IRF3 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. No statistically significant differences were found when allele and genotype distribution of rs2304204, rs7251 and rs2304207 polymorphisms were compared between patients with SLE and controls [overall P values: rs7251, P = 0.06; rs2304204, P = 0.26 and rs2304207, P = 0.36, by chi-squared test on a 3 x 2 contingency table. Overall allelic P values: rs7251, P = 0.8, OR (95%CI) = 1.03 (0.87-1.22); rs2304204, P = 0.2, OR (95%CI) = 1.12 (0.93-1.34) and rs2304207, P = 0.8, OR (95%CI) = 1.02 (0.82-1.26)]. In addition, no evidence of association with haplotypes and clinical features of SLE was found. Our data suggest that the IRF3 polymorphisms do not appear to play a major role in the susceptibility or severity of SLE in a Spanish population.

The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype.

OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. RESULTS: Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. CONCLUSIONS: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.

A large multicentre analysis of CTGF -945 promoter polymorphism does not confirm association with systemic sclerosis susceptibility or phenotype.

OBJECTIVE: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype. METHODS: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay. RESULTS: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing. CONCLUSION: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype.

Aspergilosis pulmonar invasiva en un paciente afectado de espondilitis anquilosante en tratamiento con infliximab / Invasive pulmonary aspergillosis in a man with ankylosing spondylitis receiving infliximab

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Asociación de los antígenos HLA-DR10,DR4 y DR1 con artritis reumatoidea / The association of the HLA-DR10,DR4 and DR1 antigens with rheumatoid arthritis

Objetivo:Establecer la relación entre los antígenos HLA de clase I y II y artritis reumatoidea. Material y métodos: Mediante un diseño de casos y controles se ha evaluado una muestra de conveniencia de 39 pacientes con artritis reumatoidea,que cumplían al menos cuatro criterios del American College of Rheumatology (ACR).Como grupo de comparación se utilizaron 264 controles sanos de la población.La tipificación de HLA se determinó serológicamente.Resultados:En el análisis se determinó por regresión logística,se detectó asociación de la enfermedad con DR10 (RR:7,7;IC 95 por ciento ,28,9-2,1),DR4 (RR:5,3;IC 95 por ciento,11,7-2,4)y DR1 (RR:3,6;IC 95 por ciento,8,0-1,6).La presencia de más de uno de estos antígenos no significaba mayor riesgo de padecer la enfermedad.No hemos observado asociación entre la presencia de estos antígenos y la gravedad de la enfermedad,manifestada por la seropositividad o afectación sistémica del proceso.Conclusiones:Nuestros resultados confirman que los antígenos HLA de clase II,DR10,DR4 y DR1, que comparten secuencias de aminoácidos en la región que contacta con el receptor del antígeno de los linfocitos T, son un factor de riesgo para el desarrollo de la artritis reumatoidea.

Asociación de los antígenos HLA-DR10,DR4 y DR1 con artritis reumatoidea / The association of the HLA-DR10,DR4 and DR1 antigens with rheumatoid arthritis

Objetivo:Establecer la relación entre los antígenos HLA de clase I y II y artritis reumatoidea. Material y métodos: Mediante un diseño de casos y controles se ha evaluado una muestra de conveniencia de 39 pacientes con artritis reumatoidea,que cumplían al menos cuatro criterios del American College of Rheumatology (ACR).Como grupo de comparación se utilizaron 264 controles sanos de la población.La tipificación de HLA se determinó serológicamente.Resultados:En el análisis se determinó por regresión logística,se detectó asociación de la enfermedad con DR10 (RR:7,7;IC 95 por ciento ,28,9-2,1),DR4 (RR:5,3;IC 95 por ciento,11,7-2,4)y DR1 (RR:3,6;IC 95 por ciento,8,0-1,6).La presencia de más de uno de estos antígenos no significaba mayor riesgo de padecer la enfermedad.No hemos observado asociación entre la presencia de estos antígenos y la gravedad de la enfermedad,manifestada por la seropositividad o afectación sistémica del proceso.Conclusiones:Nuestros resultados confirman que los antígenos HLA de clase II,DR10,DR4 y DR1, que comparten secuencias de aminoácidos en la región que contacta con el receptor del antígeno de los linfocitos T, son un factor de riesgo para el desarrollo de la artritis reumatoidea.

[Class I and II HLA antigens in patients with systemic lupus erythematosus in the south of Spain]. / Antígenos HLA de clase I y II en pacientes con lupus eritematoso sistémico en el sur de España.

BACKGROUND: To establish the relation between class I and II HLA antigens, systemic lupus erythematosus (SLE), autoantibodies production, and clinical manifestations in the south of Spain (Málaga). METHODS: In a regional hospital we undertook a case-control study with a consecutive sample of 104 patients with SLE who fulfilled at least 4 criteria of ARA. Three hundred and twenty-eight local controls with no apparent pathology were included for comparison. We evaluated clinical and analytical aspects about multisystem autoimmune disease. HLA typing was serologically determined. RESULTS: Univariate analysis showed a relation between SLE and the specificities B8 (21% of patients vs 10% of controls, p = 0.005; RR = 2.3), DR3 (36% vs 20%, p = 0.0006; RR = 2.5), DRw52 (69% vs 49%, p = 0.001; RR = 2.3), and DQ2 (49% vs 36%, p = 0.0150; RR = 1.7). However, in logistic regression multivariate analysis, there was a confounding effect between DR3 and DRw52, and it could be that only this specificity, HLA-DRw52 (RR = 2.0; 95% CI: 1.1-4.0), and of lesser degree B8 (RR = 1.9; 95% CI: 0.9-4.4), are really associated with SLE. Also, in multivariate analysis, DR6 showed a negative association (5% vs 25%, p = 0.011; RR = 4.2; 95% CI: 1.5-17.2) with anti-U1RNP, while DRw52 showed a negative association with IgG-aCL (50% vs 85%, p = 0.019; RR = 0.21; 95% CI: 0.06-0.76). Furthermore, DQ2/DQ6 showed positive association with anti-SSA/Ro antibodies (50% vs 24%; p = 0.046; RR = 3.0; 95% CI: 1.0-9.0). There were also several associations between clinical manifestations and HLA. The specificities DR and DRw53 were almost always risk factors, but only DR5 was a protector for renal lesion. DRw52 and DQ specificities were always protectors when they were associated with some clinical manifestations. Isolated DR3 antigen, is not associated with any of the above-mentioned manifestations. CONCLUSIONS: The previously described relation between SLE and the antigen DR3 is confirmed, but this association could be a result of the presence of DRw52 specificity in patients, that is in linkage disequilibrium with DR3.

[Immunogenetics of the Sjogren's syndrome in southern Spain]. / Inmunogenética del síndrome de Sjögren en el sur de España.

To establish the relation between HLA antigens, Primary Sjögren Syndrome (PSS) and autoantibodies production, in our geographical area, we undertook a case-control study with a consecutive sample of 30 patients with PSS (Fox's criteria) attending in a reference hospital. Two hundred and sixty-four local controls with no apparent pathology were included for comparison. In patients we evaluated clinical and analytical aspects about multisystem autoimmune disease. Anti-SSA/Ro and -SSB/La autoantibodies were determined by double immunodiffusion. HLA typing was serologically determined. In logistic regression multivariate analysis, there were significant association between PSS and specificities HLA-Cw7 (73% in cases, versus 35% in controls; RR = 8.0; 95% CI: 23.2-2.7), HLA-DR3 (63% vs 20%; RR = 3.4; 95% CI: 9.5-1.4) and HL-DR11 (43% vs 13%; RR = 4.1; 95% CI: 12.0-1.4). In patients, the anti-SSA/Ro autoantibodies production were associated with HLA-DR3 antigen (83% vs 25%; RR = 6./; 95% CI: 1.3-34.2). All HLA-DQ2/DQ6 heterozygotes patients (8 cases) had anti-SSA/Ro autoantibodies, versus only one half of the remainder (p = 0.029; RR = 6.3). In anti-SSA/Ro negative patients there weren't association with HLA-DR3 antigen (33% vs 20%). HLA-DR3 were associated with the presence of anti-SSB/La autoantibodies, but there wasn't signification (p = 0.081). We conclude that our patients with PSS present association with HLA-DR11 specificity, that it's a risk factor for the disease development. HLA-DR3 would determined the anti-SSA/Ro autoantibodies, and maybe also anti-SSB/La autoantibodies, production. Furthermore, HLA-DQ2/DQ6 heterozygosity would determined immune response to SSA/Ro autoantigen.

[Clinical and analytical manifestations of primary antiphospholipid antibody syndrome]. / Manifestaciones clínicas y analíticas del síndrome de anticuerpos antifosfolípido primario.

STUDY OBJECTIVE: Description of the clinical and analytical manifestations of 8 patients with Primary Antiphospholipid Syndrome (PAPS). DESIGN: Series of cases. SETTING: Patients seen in the Internal Medicine Department of a third level Medical Center in Malaga Province. PATIENTS AND INTERVENTIONS: We describe the symptoms and signs, as well as the analytical determinations that may be related with autoimmunity in 8 patients diagnosed of PAPS (Harris' Criteria). The antiphospholipid antibodies were determined by a) Biologic false-positive Venereal Disease Research Laboratory (BFP-VDRL), b) Lupus Anticoagulant (LAC): Enlargement of the activated thromboplastin partial time > 6" and Exner test, c) Anticardiolipin antibodies (aCL), IgG (UGPL/ml), IgM (UMPL/ml) by enzyme-linked immunosorbent assay (ELISA). RESULTS: Four patients were females and four males. The mean age was 35.1 +/- 13.6. None of the patients had criteria of systemic lupus erythematous. The principal clinical manifestations of the PAPS were the venous and arterial thrombotic events in different areas (7 patients); The female patient that didn't have thrombotic event presented thrombocytopenia. Only one patient had 1 abortion. The four females had livedo reticularis (LVR), associated in two of them with arterial hypertension and stroke (Sneddon syndrome). Others manifestations seen, have been, Raynaud's phenomenon, acrocyanosis, migraine, arthritis and myositis. All the patients had IgG aCL, 3 IgM aCL, 7 enlargement of the activated thromboplastin partial time and none presented VRL. Five patient had positive antinuclear antibodies (ANA), but none of them had anti- DNA, hypocomplementemia nor lymphopenia. As far as treatment goes three of the patients are anticoagulated with continuous dicoumarins . The remaining patients keep treatment with platelet antiaggregant, had a satisfactory evolution. CONCLUSIONS: This group of patients presented venous and arterial thrombotic events such as principal manifestation of the PAPS. The most sensitive test to detect antiphospholipid antibodies were the enlargement of the activated thromboplastin partial time and the aCL. It could be interest the determination of aCL in young people the present thrombotic events without another apparent cause.

[Effectiveness of the treatment of systemic lupus erythematosus with methotrexate]. / Eficacia del tratamiento con metotrexato en el lupus eritematoso sistémico.

BACKGROUND: To evaluate the efficacy of methotrexate in patients with systemic lupus erythematosus (SLE) without major organ involvement resistant to medium-high doses of prednisone. METHODS: Crossover, open clinical trial with two treatment periods, the first of 3 months and the second of 6 months, an intermediate control period of 3 months and another at the end of 6 months. A sample of 15 consecutive patients with SLE who, with no major organ damage, had active disease in spite of receiving more than 10 mg/day of prednisone or who relapsed on reduction of this doses during a period of at least 3 months. 7.5 mg/week of methotrexate were administered orally, divided into three doses of 2.5 mg/12 hours. Statistical significance was evaluated by Student's paired t test and chi 2; the strength of association by the Mantel-Haenzel odds ratio (OR) method and the precision, by Miettinen's confidence interval (CI). A p value of less than 0.05 was considered significant. RESULTS: Two patients failed to finish the study; one for worsening of cutaneous lesions of necrotizing vasculitis which she already had previously, and the other for an increase in her transaminase levels. In the remaining 13 there were 10 flares of disease activity during the control phases, 2 severe, versus 2 flares during the periods of methotrexate use (OR 7.69 (95% confidence interval, 1.67 to 33.33; p = 0.021). There were no significant changes in analytical results or prednisone requirements. During treatment six patients had oral aphthae and five had dyspepsia; three had an increase in transaminase levels, which in one caused the treatment to be stopped. There were two urinary infections, one community acquired pneumonia and one upper airway symptoms requiring antibiotic treatment; one female patient had acute cholecystitis with cholelithiasis necessitating surgical intervention. CONCLUSIONS: Weekly low doses of methotrexate may prevent flares of activity of SLE in this type of patients, but it does not reduce the requirements of prednisone, nor modify analytical data. Toxic effects are rare and reversible upon interrupting medication.

Avascular necrosis of bone in human immunodeficiency virus infection and antiphospholipid antibodies.

We describe 3 cases of human immunodeficiency virus (HIV) infected patients with antiphospholipid antibodies (aPL) in serum who developed avascular necrosis (AVN), an association that to our knowledge, has rarely been described. Given that the 3 patients had stopped their intravenous drug addiction 2 years before the clinical picture appeared, and none had any known risk factors for developing AVN, there may be an association, perhaps fortuitous, between HIV infection, the presence of aPL and the development of AVN.

[Anticardiolipin antibodies in women with habitual abortion. A case-control study]. / Anticuerpos anticardiolipina en mujeres con abortos de repetición. Estudio de casos y controles.

According to case and control studies we determine the prevalence of anticardiolipin antibodies (ACA) and autoimmune phenomena in 23 women with recurrent abortions (two or more) without apparent cause after study, using as pattern a sample of 86 patients belonging to different subgroups: 21 women with only one abortion, 15 with toxemia, 30 healthy pregnants and 20 healthy non-pregnants. We found that 6 (26%) of the cases with recurrent abortions showed high ACA-IgG versus 6 (7%) of the control group (p = 0.009), with an odds ratio (OR) of 4.7 (Confidence Interval [CI] 95%, 1.4-15). We didn't find a relation with ACA-IgM, OR or 2.2 (CI 95%, 0.72-6.50; p = 0.160). Our patients only showed as manifestation of antiphospholipid antibodies syndrome, recurrent abortions, finding neither association with thrombotic phenomena, nor thrombocytopenia. They didn't show either clinical or analytical manifestations of autoimmune disease. We concluded that the ACA-IgG can be associated to the fetal loss in these kind of patients.

Clinical course and prognosis of Brucella spondylitis.

A multicentre prospective study of 593 patients with brucellosis, of whom 58 (9.7%) had spondylitis, was performed in order to evaluate the possible clinical, radiological and evolutionary differences in the different segments of the spinal column. Five of the patients with cervical spondylitis (71%) had compression of the medulla or roots, versus just two (11%) in the dorsal group and nine (21%) in the lumbar group (p less than 0.05). There were no other clinical, haematological or biochemical differences between the three spinal segments, and both the serological response and the percentage of positive blood cultures were also similar in the three groups. The patients with cervical and dorsal spondylitis had a significantly higher number of paravertebral and/or epidural masses than those with lumbar spondylitis (p less than 0.05). Seventy-one percent of the patients with cervical spondylitis made unsatisfactory progress, versus 11% and 5% of those in the dorsal and lumbar groups, respectively (p less than 0.05 and p less than 0.001). In conclusion, given the high incidence of paravertebral and/or epidural masses, the neurological involvement, and the high rate of important functional disabilities, cervical spondylitis should be considered to be a very severe complication of brucellosis, and its treatment and follow-up must therefore be energetic and rigorous in order to detect and correct as early as possible compressions of the neural axis and its roots.