Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

A case-control study suggests that the CCR6 locus is not involved in the susceptibility to giant cell arteritis.

OBJECTIVES: Polymorphisms of the CC chemokine receptor 6 (CCR6) gene have been recently reported to be associated with a number of autoimmune diseases. We aimed to investigate the possible influence of CCR6 rs3093024 gene variant in the susceptibility to and clinical expression of GCA. METHODS: The CCR6 polymorphism rs3093024 was genotyped in a total of 463 Spanish patients diagnosed with biopsy-proven GCA and 920 healthy controls using a TaqMan® allelic discrimination assay. PLINK software was used for the statistical analyses. RESULTS: No significant association between this CCR6 variant and GCA was observed (p=0.42, OR=0.94, CI95% 0.79-1.10). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no statistical significant difference was detected either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. CONCLUSIONS: Our results suggest that the CCR6 rs3093024 polymorphism may not play a relevant role in the GCA pathophysiology.

Evaluación clínica de los pacientes con artritis reumatoide en España / Clinical evaluation of patients with rheumatoid arthritis in Spain

Fundamento: En los últimos años se han desarrollado instrumentos que permiten evaluar la eficacia clínica de las intervenciones en pacientes con artritis reumatoide (AR). Sin embargo, no hay datos sobre su utilización en la evaluación rutinaria de los pacientes con AR en nuestro país. Objetivo: Analizar los instrumentos utilizados en la evaluación clínica de pacientes con AR en España. Material y métodos: Revisión de 1.379 historias clínicas (HC), seleccionadas aleatoriamente, de pacientes con AR atendidos en 48 servicios de atención especializada de 16 comunidades autónomas. Se realizó una estimación semicuantitativa del número de visitas en dos años en las que se habían utilizado diferentes instrumentos de seguimiento clínico. Resultados: La rigidez matutina y la valoración subjetiva del médico en una escala adjetiva fueron los instrumentos más utilizados (habitualmente o siempre en más del 70% de las HC). El 49,5% de los pacientes tenía al menos un recuento formal de articulaciones dolorosas y tumefactas; el recuento articular más utilizado fue el índice completo del American College of Rheumatology (ACR). La utilización de escalas analógicas visuales (EAV) fue muy infrecuente. Ninguno de los instrumentos de valoración del estado funcional y del estado general de salud fue utilizado habitualmente en la práctica clínica diaria. Conclusiones: El uso de instrumentos cuantitativos en la valoración clínica y el seguimiento de los pacientes con AR en nuestro país es muy escaso, prevaleciendo los instrumentos de seguimiento tradicionales

Background: Several instruments to evaluate the efficacy of clinical interventions in patients with rheumatoid arthritis (RA) have been developed in the last few years. However, there are no data on the utilization of these instruments in the routine evaluation of patients with RA in Spain. Objective: To analyze the instruments used in the clinical evaluation of patients with RA in Spain. Material and methods: The medical records of 1,379 patients diagnosed with RA randomly selected and treated in 48 specialized care units in 16 Autonomous Communities were reviewed. The number of consultations in which several clinical follow-up instruments were employed in a 2-year period was estimated semiquantitatively. Results: The most frequently used instruments (usually or always in > 70% of medical records) were morning stiffness and the physician's overall assessment of disease activity using adjective scales. A total of 49.5% of the patients had at least one formal count of tender and swollen joints and the ACR index was the most commonly used. Visual analogue scales (VAS) were used very infrequently. None of the instruments to evaluate functional ability or overall health status were routinely used in daily practice. Conclusions: The use of quantitative instruments in the clinical evaluation and follow-up of patients with RA is low and traditional instruments of follow-up prevail

[Incidence and characteristics of tuberculosis in patients with autoimmune rheumatic diseases]. / Incidencia y características de la tuberculosis en pacientes con enfermedades reumáticas autoinmunes.

OBJECTIVE: To describe the incidence and characteristics of the infection caused by Mycobacterium tuberculosis in patients with autoimmune diseases. PATIENTS AND METHODS: Searching in the database of the department at our institution, all new cases of tuberculosis from 1991 to 2000 were identified in patients with autoimmune diseases; the total follow-up time was calculated as the difference between first and last visits. Time with immunosuppressive drug therapy was obtained for patients with rheumatoid arthritis from a database oriented to the longitudinal follow-up of these patients. The incidence density was calculated as the quotient between the absolute frequency of cases and the sum of individual periods at risk for each subgroup. RESULTS: Fifteen cases of tuberculosis were identified from 3,634 risk patients followed for an accumulated period of 9,795 years (overall incidence 153 per 100,000 patients-year). Fourteen patients were receiving disease-modifying drugs and eleven were receiving corticosteroids at diagnosis. The location of tuberculosis infection was the lung for 33.3% of cases. The incidence by drugs in patients with rheumatoid arthritis was 143 per 100,000 patients-year with methotrexate, 2,703 per 100,000 patients-year with azathioprin, 7,692 per 1,000 patients-year with cyclophosphamide, and 4,878 per 100,000 patients-year for anti-TNFalpha. CONCLUSIONS: Compared with the general population, the incidence density of tuberculosis is increasing in our population, with a higher frequency of extrapulmonary involvement. The incidence density is variable among patients with rheumatoid arthritis depending upon the used drugs.

Incidencia y características de la tuberculosis en pacientes con enfermedades reumáticas autoinmunes / Incidence and characteristics of tuberculosis in patients with autoimmune rheumatic diseases

Objetivo. Describir la incidencia y las características de la infección por Mycobacterium tuberculosis en pacientes con enfermedades autoinmunes.Pacientes y métodos. Se identificaron los casos nuevos de tuberculosis desde 1991 a 2000 en pacientes con enfermedad autoinmune a partir de la base de datos del servicio; se calculó el tiempo total de seguimiento como la diferencia entre la primera y la última visita. El tiempo de tratamiento con fármacos inmunosupresores se obtuvo en pacientes con artritis reumatoide de una base de datos orientada al seguimiento longitudinal de estos pacientes. Se calculó la densidad de incidencia como el cociente entre la frecuencia absoluta de casos y la suma de los períodos individuales de riesgo en cada subgrupo. Resultados. Se identificaron 15 casos de tuberculosis en 3.634 pacientes en riesgo seguidos durante un período acumulado de 9.795 años (incidencia global: 153 por 100.000 pacientes-año).Catorce pacientes estaban recibiendo fármacos modificadores de la enfermedad y once corticosteroides en el momento del diagnóstico. La localización de la infección tuberculosa fue pulmonar en el 33,3 por ciento de los casos. La incidencia por fármacos en pacientes con artritis reumatoide fue de 143 por 100.000 pacientes-año con metotrexato, 2.703 por 100.000 pacientes-año con azatioprina, 7.692 por 1.000 pacientes-año con ciclofosfamida y 4.878 por 100.000 pacientes-año con anti-TNF . Conclusiones. La densidad de incidencia de tuberculosis está aumentada en nuestra población comparado con la de la población general, existiendo una mayor frecuencia de afectación extrapulmonar. La densidad de incidencia es variable en pacientes con artritis reumatoide en función de los fármacos utilizados (AU)

El estudio sobre el manejo de la artritis reumatoide en España (emAR) (II). Características de los pacientes / Study on the treatment of Rheumatoid Arthritis in Spain (emAR) (II). Patients' characteristics

Fundamento: El estudio sobre el manejo de la artritis reumatoide (AR) en España ha supuesto una oportunidad para conocer si las características de los pacientes difieren de una comunidad autónoma a otra dentro del ámbito español. Material y método: Revisión de 1.379 historias clínicas seleccionadas de forma aleatoria entre 9.299 individuos diagnosticados de AR y atendidos en 48 servicios de atención especializada de 16 comunidades autónomas. Se analizaron las características sociodemográficas, de la enfermedad y diferentes variables administrativas. Resultados: La mediana de edad fue de 63 años (53,1-71), el 73 por ciento eran mujeres y el tiempo de evolución 105 meses (57-172), sin diferencias entre comunidades autónomas. El 75 por ciento era factor reumatoide positivo y el 37,4 por ciento tenía alguna manifestación extraarticular. El 51 por ciento había tenido una AR activa a lo largo de 2 años de seguimiento, la mayoría se encontraba en una clase funcional II del ACR y el 25,9 por ciento necesitó de alguna cirugía. El estudio sobre el manejo de la artritis reumatoide en España (emAR) (II). Características de los pacientes articular a lo largo de su evolución. Existió una gran variabilidad en la expresión clínica de la enfermedad de una comunidad autónoma a otra. La mayoría de los pacientes fueron derivados por servicios de atención primaria. Los pacientes derivados desde servicios de urgencia tuvieron un acceso temprano a atención especializada. Conclusiones: Las características clínicas y demográficas de los pacientes con AR en España no difieren globalmente de los estudios ya publicados, pero existe una marcada variabilidad entre comunidades autónomas. (AU)

Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Corticosteroids remain the cornerstone of therapy for giant-cell arteritis, but relapse during dose tapering and corticosteroid-related adverse events often complicate management of this condition. Although several approaches, including combined therapy with cytotoxic agents, have been suggested to overcome these problems, no study has clearly shown benefits of alternate treatments. OBJECTIVE: To analyze the safety and efficacy of combined therapy with corticosteroids and methotrexate in giant-cell arteritis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: University-based clinic. PATIENTS: 42 patients with new-onset giant-cell arteritis according to biopsy. INTERVENTION: High initial doses of corticosteroid were given; the dose was then tapered quickly until therapy was completely withdrawn. Methotrexate or placebo was given weekly from the start of corticosteroid therapy for 24 months. MEASUREMENTS: Number of relapses, cumulative dose of corticosteroid, and number of adverse events were assessed on completion of follow-up. RESULTS: Compared with combined prednisone and placebo therapy, treatment with prednisone and methotrexate reduced the proportion of patients who experienced at least one relapse (45% vs. 84.2%; P = 0.02) and the proportion of patients who experienced multiple relapses (P = 0.004). The mean cumulative dose of prednisone was 4187 +/- 1529 mg in the methotrexate group and 5489.5 +/- 1396 mg in the placebo group (mean difference, 1302 mg [95% CI, 350 to 2253 mg]; P = 0.009). Overall, the rate and severity of adverse events were similar between groups. Treatment was discontinued in 3 patients in the methotrexate group who experienced definite drug-related adverse events. In sensitivity analysis that included patients lost to follow-up, differences between groups in number of relapses and cumulative dose of prednisone were significant. CONCLUSIONS: Treatment with methotrexate plus corticosteroid is a safe alternative to corticosteroid therapy alone in patients with giant-cell arteritis and is more effective in controlling disease.

Lag time between onset of symptoms and access to rheumatology care and DMARD therapy in a cohort of patients with rheumatoid arthritis.

OBJECTIVE: To study demographic and clinical variables associated with a longer delay in disease modifying antirheumatic drug (DMARD) therapy initiation in a cohort of patients with rheumatoid arthritis (RA). METHODS: We studied 527 new RA patients (74.3% female, median age at symptom onset 55 yrs) in a hospital setting who fulfilled the ACR criteria for the diagnosis of RA. Demographic, clinical, laboratory, and treatment variables were collected longitudinally into a computerized research database. Risk factors for delay in use of DMARD therapy and first evaluation by a rheumatologist were analyzed using a Cox regression model. RESULTS: The median lag time between symptom onset and first rheumatologist encounter was 17 months and between onset of symptoms and first DMARD therapy 19 months. Variables associated with longer delay to DMARD therapy were the lag time between symptom onset and first rheumatologist visit (RR 0.73, 95% CI 0.71-0.76) and years of education. Variables associated with longer delay in first visit with rheumatologist were swollen/tender joint count, age at symptom onset, home support, labor force status, marital status, and years of education. CONCLUSION: Awareness of factors associated with a longer delay in access to rheumatology care and DMARD therapy may help break down barriers that prevent their early access, irrespective of patient age, socioeconomic status, initial symptoms, or need for treatment.

The CD69 activation pathway in rheumatoid arthritis synovial fluid T cells.

OBJECTIVE: To study the CD69 activation pathway in synovial fluid (SF) T lymphocytes from patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) or SF mononuclear cells (SFMC) were used in proliferation assays with anti-CD69, anti-CD28, anti-CD3, phorbol myristate acetate (PMA), and/or recombinant interleukin-2 (IL-2). CD69+, CD69-, and resting SF T cells were also proliferated. CD25 expression and production of IL-2 after CD69 activation were assessed by flow cytometry and in a bioassay with the IL-2-dependent cell line CTLL-2. RESULTS: RA SFMC did not proliferate either in the presence of anti-CD69 monoclonal antibodies alone or with concomitant PMA activation, when compared with paired or control PBMC. Similar low proliferative responses via the CD3 or CD28 pathway with PMA were observed. This defective proliferation of RA SFMC after stimulation through the CD69 molecule was explained in part by a failure to express CD25 and to produce IL-2. SF CD69- T cells and resting SF T cells had higher rates of proliferation through the alternative costimulatory pathway CD28 than did SF CD69+ T cells or freshly isolated SF T cells. CONCLUSION: Freshly isolated SF T cells present a profound state of hyporesponsiveness through the CD69 and CD28 costimulatory pathways. This state appears to be dependent on the activation status of SF T cells, since CD69- and resting SF T cells showed recovery of the ability to proliferate through the CD28 activation pathway.