Profiling of Serum Oxylipins During the Earliest Stages of Rheumatoid Arthritis.

OBJECTIVE: Eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting that metabolization is enhanced, the role of oxylipins in disease stratification remains unexplored. This study was undertaken to characterize oxylipin networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcomes. METHODS: In total, 60 patients with early RA (according to the American College of Rheumatology/European League Against Rheumatism 2010 criteria), 11 individuals with clinically suspect arthralgia (CSA), and 28 healthy control subjects were recruited. Serum samples were collected at the time of onset. In the early RA group, 50 patients who had not been exposed to disease-modifying antirheumatic drug (DMARD) or glucocorticoid treatment at the time of recruitment were prospectively followed up at 6 and 12 months after having received conventional synthetic DMARDs. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic, and linoleic acids, were identified in the serum by liquid chromatography tandem mass spectrometry. RESULTS: Univariate analyses demonstrated differences in expression patterns of 14 oxylipins across the RA, CSA, and healthy control groups, with each exhibiting a different trajectory. Network analyses revealed a strong grouping pattern of oxylipins in RA patients, whereas in individuals with CSA, a fuzzy network of oxylipins with higher degree and closeness was found. Partial least-squares discriminant analyses yielded variable important projection scores of >1 for 22 oxylipins, which allowed the identification of 2 clusters. Cluster usage differed among the groups (P = 0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in RA patients who were initially treatment-naive. Pathway enrichment analyses revealed different precursors and pathways between the groups, highlighting the relevance of the arachidonic acid pathway in individuals with CSA and the lipooxygenase pathway in patients with early RA. In applying distinct oxylipin signatures, subsets of seropositive and seronegative RA could be identified. CONCLUSION: Oxylipin networks differ across stages during the earliest phases of RA. These distinct oxylipin networks could potentially elucidate pathways with clinical relevance for disease progression, clinical heterogeneity, and treatment response.

Biological dose tapering in daily clinical practice: a 10 year follow-up study / Optimización de la dosis de biológicos en práctica clínica: experiencia de 10 años

OBJECTIVE: To describe practice patterns, long-term outcome, and related factors, in relation to biological therapies tapering in rheumatoid arthritis (RA) patients in a well-controlled real-world setting. METHODS: An observational longitudinal retrospective 10-year study was conducted in all RA patients receiving biological agents in an RA clinic from May 2003 to October 2013. Biological treatment of patients with sustained DAS28<3.2 or SDAI<11 was tapered (dose down-titrated or interval widen) or discontinued as per practice protocol. Primary outcome of tapering was relapse, defined as an increase in DAS28≥1.2. Descriptive, survival analysis, and logistic regression analysis with first relapse as dependent variable were carried out. RESULTS: Of 193 RA patients on biological treatment (mean age 54±14 years, 81% women), tapering was applied in 106 (55%) and discontinuation in 34 (17.6%). During follow-up 38 patients relapsed (62%). Rate of relapse was 10% at 6 months, 19% at 12 months, 33.2% at 2 years and 50% after 5 years. Mean time in dose reduction was 4.5 years [95% confidence interval (95% CI): 3.7-5.3]. Six patients (15.7%) did not respond after reinstatement of full dose of biologic. In the multivariate analysis, pain [OR=1.26 (95% CI: 1.11-1.43); P<.001] and erythrocyte sedimentation rate (ESR) [OR=1.01 (95% CI: 1.00-1.03); P=.011] at baseline were associated with relapse after tapering. CONCLUSIONS: Tapering may be considered a long-term option in RA patients on biologics and low disease activity, especially if low ESR and pain scores are present at baseline; treatment reinstatement could be considered a safe option in case of relapse

OBJETIVO: Describir los patrones de práctica clínica, los resultados a largo plazo y los factores relacionados en relación a la optimización de las terapias biológicas en pacientes con artritis reumatoide (AR) en un entorno de vida real bien controlado. MÉTODOS: Se realizó un estudio retrospectivo observacional longitudinal de 10 años que incluyó a todos los pacientes con AR que recibieron agentes biológicos en una consulta monográfica de AR entre mayo de 2003 y octubre de 2013. Se optimizó el tratamiento biológico (ajuste de dosis o ampliación de intervalo) en los pacientes con DAS28<3,2 o SDAI<11 de forma mantenida según un protocolo de práctica clínica. La variable principal fue la recaída, definida como un aumento en el DAS28≥1,2. Se realizó un análisis descriptivo, de supervivencia y modelos de regresión logística con la primera recaída como variable dependiente. RESULTADOS: De 193 pacientes con AR en tratamiento biológico (edad media 54±14 años, 81% mujeres), se optimizó la dosis en 106 (55%) y se interrumpió el tratamiento en 34 (17,6%). Durante el seguimiento 38 pacientes recayeron (62%). La tasa de recaída fue del 10% a los 6 meses, del 19% a los 12 meses, del 33,2% a los 2 años y del 50% a los 5 años. El tiempo medio con dosis reducida fue de 4 años y medio (intervalo de confianza del 95% [IC 95%]: 3,7 a 5,3). Seis pacientes (15,7%) no respondieron después de restablecer la dosis completa de biológico. En el análisis multivariado, el dolor (OR=1,26 [IC 95%: 1,11 a 1,43]; p < 0,001) y la velocidad de sedimentación globular (VSG) (OR por mm/h=1,01 [IC 95%: 1,00 a 1,03]; p = 0,011) al inicio del estudio se asociaron a recaída tras la optimización. CONCLUSIONES: La optimización de la dosis se puede considerar una opción a largo plazo en pacientes con AR en tratamiento con agentes biológicos y baja actividad de la enfermedad, especialmente si la VSG y el dolor están en niveles bajos; la reinstauración del tratamiento podría considerarse una opción segura en caso de recaída en la mayoría de los pacientes

Biological Dose Tapering in Daily Clinical Practice: A 10 Year Follow-up Study.

OBJECTIVE: To describe practice patterns, long-term outcome, and related factors, in relation to biological therapies tapering in rheumatoid arthritis (RA) patients in a well-controlled real-world setting. METHODS: An observational longitudinal retrospective 10-year study was conducted in all RA patients receiving biological agents in an RA clinic from May 2003 to October 2013. Biological treatment of patients with sustained DAS28<3.2 or SDAI<11 was tapered (dose down-titrated or interval widen) or discontinued as per practice protocol. Primary outcome of tapering was relapse, defined as an increase in DAS28≥1.2. Descriptive, survival analysis, and logistic regression analysis with first relapse as dependent variable were carried out. RESULTS: Of 193 RA patients on biological treatment (mean age 54±14 years, 81% women), tapering was applied in 106 (55%) and discontinuation in 34 (17.6%). During follow-up 38 patients relapsed (62%). Rate of relapse was 10% at 6 months, 19% at 12 months, 33.2% at 2 years and 50% after 5 years. Mean time in dose reduction was 4.5 years [95% confidence interval (95% CI): 3.7-5.3]. Six patients (15.7%) did not respond after reinstatement of full dose of biologic. In the multivariate analysis, pain [OR=1.26 (95% CI: 1.11-1.43); P<.001] and erythrocyte sedimentation rate (ESR) [OR=1.01 (95% CI: 1.00-1.03); P=.011] at baseline were associated with relapse after tapering. CONCLUSIONS: Tapering may be considered a long-term option in RA patients on biologics and low disease activity, especially if low ESR and pain scores are present at baseline; treatment reinstatement could be considered a safe option in case of relapse.

Vitamin D Receptor Polymorphism and DHCR7 Contribute to the Abnormal Interplay Between Vitamin D and Lipid Profile in Rheumatoid Arthritis.

Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNFα-blockade. Vitamin D was decreased in RA (p < 0.001), correlated to HDL-cholesterol (r = 0.217, p < 0.001) and total-/HDL-cholesterol ratio (r = -0.227, p = 0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p = 0.028), higher tender (p = 0.005) and swollen (p = 0.002) joint counts, higher DAS28 (p = 0.018) and HAQ (p = 0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p = 0.008) and vitamin D (p < 0.001) and increased total-cholesterol (p = 0.025) being found in winter/spring. Increasing vitamin D upon TNFα-blockade paralleled RA clinical improvement (r = -0.610, p = 0.027) and DHCR7 elevation (r = 0.766, p = 0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.

Anti-MDA5 dermatomyositis mimicking psoriatic arthritis / Dermatomiositis con anticuerpos anti-MDA5 simulando una artritis psoriásica

Dermatomyositis causes inflammation and damage of muscle and skin, and sometimes involves internal organs, especially lung parenchyma. Patients with dermatomyositis still represent a diagnostic challenge because of the rarity of this disease and the lack of specificity of some of its cutaneous manifestations. Herein, we describe the case of a patient with dermatomyositis, initially diagnosed as psoriatic arthritis, in which the performance of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was decisive to establish a definitive diagnosis

La dermatomiositis causa inflamación y daño del músculo y la piel, y en ocasiones afecta a órganos internos, especialmente el parénquima pulmonar. Los pacientes con dermatomiositis representan todavía un reto diagnóstico debido a la rareza de esta enfermedad y la falta de especificidad de algunas de sus manifestaciones cutáneas. Describimos el caso de una paciente con dermatomiositis, inicialmente diagnosticada de artritis psoriásica, en la que la determinación de anticuerpos anti-MDA5 fue decisiva para establecer un diagnóstico definitivo

Anti-MDA5 dermatomyositis mimicking psoriatic arthritis.

Dermatomyositis causes inflammation and damage of muscle and skin, and sometimes involves internal organs, especially lung parenchyma. Patients with dermatomyositis still represent a diagnostic challenge because of the rarity of this disease and the lack of specificity of some of its cutaneous manifestations. Herein, we describe the case of a patient with dermatomyositis, initially diagnosed as psoriatic arthritis, in which the performance of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was decisive to establish a definitive diagnosis.

Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.

OBJECTIVES: Since lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis. METHODS: Serum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro. RESULTS: Lower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade. CONCLUSION: An altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

Recomendaciones para el uso del metotrexato en artritis reumatoide: incremento y reducción de dosis y vías de administración / Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling of the dose and administration routes

Objetivos. Describir la estrategia terapéutica óptima de uso de metotrexato en AR sobre dosis inicial, vía de administración, incremento y disminución de dosis, seguimiento del paciente y uso de ácido fólico/folínico. Material y método. Once expertos plantearon los interrogantes clínicos a resolver. Se realizó una búsqueda bibliográfica sistemática. Los contenidos fueron seleccionados en una sesión de trabajo y el nivel de acuerdo se estableció posteriormente en una ronda de consenso vía correo. Resultados. La dosis de inicio de metotrexato no debe ser < 10 mg/semana, preferentemente por vía oral, considerando la vía parenteral como alternativa según el cumplimento, ineficacia o efectos secundarios gastrointestinales, polimedicación, obesidad (si requiere dosis > 20 mg/semana), preferencias del paciente, enfermedad muy activa o para evitar errores de medicación. Se cambiará a la vía parenteral cuando haya ineficacia, toxicidad gastrointestinal, incumplimiento o por coste-efectividad antes de pasar a fármacos más caros; y a la inversa, según preferencias del paciente, intolerancia a inyectables, reducción de dosis < 7,5 mg/semana, ineficacia, bajo cumplimiento o efectos adversos gastrointestinales. Se realizará escalada rápida de dosis si la respuesta es inadecuada hasta los 15-20 o, incluso, 25 mg/semana en unas 8 semanas, con incrementos de 2,5-5 mg. La reducción se realizará según la dosis a la que estuviera el paciente, con disminuciones de 2,5-5 mg cada 3-6 meses. El seguimiento del paciente deberá realizarse cada 1-1,5 meses hasta la estabilidad y luego cada 1-3 meses. Conclusiones. Este documento pretende resolver algunos interrogantes clínicos habituales y facilitar la toma de decisiones en la AR tratada con metotrexato (AU)

Objectives, To describe the optimal therapeutic strategy for use of methotrexate in RA patients over the initial dose, route of administration, dose increase and decrease, patient monitoring, and use of folic/folinic acid. Materials and methods. Eleven clinical experts proposed some questions to be solved. A systematic literature search was conducted. The contents were selected in a work session and subsequently validated via email to establish the level of agreement. Results. The initial dose of methotrexate should not be <10 mg/week, preferably orally, but the parenteral route is considered as an alternative due to compliance, non-effectiveness of treatment or gastrointestinal side effects, polypharmacy, obesity (if required doses are >20 mg/week), patient preference, very active disease or to avoid administration errors. Changing to a parenteral administration is proposed when the oral route is not effective enough, gastrointestinal toxicity appears, there is non-compliance or due to cost-effectiveness reasons before using more expensive drugs. On the contrary, due to patient preferences, intolerance to injections, dose reduction <7.5 mg/week, non-effectiveness of the route, poor compliance or gastrointestinal side effects. There should be a rapid dose escalation if inadequate responses occur up to 15–20 or even 25 mg/week in about 8 weeks, with increments of 2.5–5 mg. The reduction will be carried out according to the dose the patient had, with decreases of 2.5–5 mg every 3–6 months. Patient monitoring should be performed every 1–1.5 months until stability is reached and then for every 1–3 months. Conclusions. This document pretends to solve some common clinical questions and facilitate decision-making in RA patients treated with methotrexate (AU)

Recommendations for the use of methotrexate in rheumatoid arthritis: up and down scaling of the dose and administration routes.

OBJECTIVES: To describe the optimal therapeutic strategy for use of methotrexate in RA patients over the initial dose, route of administration, dose increase and decrease, patient monitoring, and use of folic/folinic acid. MATERIAL AND METHOD: Eleven clinical experts proposed some questions to be solved. A systematic literature search was conducted. The contents were selected in a work session and subsequently validated via email to establish the level of agreement. RESULTS: The initial dose of methotrexate should not be <10mg/week, preferably orally, but considering the parenteral route as an alternative due to compliance, non effectiveness of treatment or gastrointestinal side effects, polypharmacy, obesity (if required doses are >20mg/week), patient preference, very active disease or to avoid administration errors. Changing to a parenteral administration is proposed when the oral route is not effective enough, gastrointestinal toxicity appears, there is non-compliance or due to cost-effectiveness reasons before using more expensive drugs. On the contrary, due to patient preferences, intolerance to injections, dose reduction <7.5mg/week, non effectiveness of the route, poor compliance or gastrointestinal side effects. There should be a rapid dose escalation if inadequate responses occurr up to 15-20 or even 25mg/week in about 8 weeks, with increments of 2.5-5mg. The reduction will be carried out according to the dose the patient had, with decreases of 2.5-5mg every 3-6 months. Patient monitoring should be performed every 1-1.5 months until stability and then every 1-3 months. CONCLUSIONS: This document pretends to solve some common clinical questions and facilitate decision-making in RA patients treated with methotrexate.

IFNα serum levels are associated with endothelial progenitor cells imbalance and disease features in rheumatoid arthritis patients.

INTRODUCTION: IFNα has been largely implicated in the ethiopathogenesis of autoimmune diseases but only recently it has been linked to endothelial damage and accelerated atherosclerosis in autoimmunity. In addition, proinflammatory conditions are supposed to be implicated in the cardiovascular status of these patients. Since a role for IFNα in endothelial damage and impaired Endothelial Progenitor Cell (EPC) number and function has been reported in other diseases, we aimed to evaluate the potential associations of IFNα serum levels on EPC populations and cytokine profiles in Rheumatoid Arthritis (RA) patients. METHODS: pre-EPC, EPC and mature EPC (mEPC) populations were quantified by flow cytometry analyzing their differential CD34, CD133 and VEGFR2 expression in blood samples from 120 RA patients, 52 healthy controls (HC), and 83 systemic lupus erythematosus (SLE) patients as disease control. Cytokine serum levels were measured by immunoassays and clinical and immunological data, including cardiovascular (CV) events and CV risk factors, were retrospectively obtained by reviewing clinical records. RESULTS: Long-standing, but not recent onset RA patients displayed a significant depletion of all endothelial progenitor populations, unless high IFNα levels were present. In fact, the IFN(high) RA patient group (n = 40, 33%), showed increased EPC levels, comparable to SLE patients. In addition, high IFNα serum levels were associated with higher disease activity (DAS28), presence of autoantibodies, higher levels of IL-1ß, IL-6, IL-10 and MIP-1α, lower amounts of TGF-ß, and increased mEPC/EPC ratio, thus suggesting higher rates of endothelial damage and an endothelial repair failure. Finally, the relationship between high IFNα levels and occurrence of CV events observed in RA patients seems to support this hypothesis. CONCLUSIONS: IFNα serum marker could be used to identify a group of RA patients with increased disease activity, EPC imbalance, enhanced proinflammatory profile and higher cardiovascular risk, probably due, at least in part, to an impaired endothelial repair.

Estándares de calidad asistencial para las consultas de enfermería en reumatología / Quality of care standards for nursing clinics in rheumatology

Introducción. Las consultas de enfermería en reumatología (CER) son modelos organizativos asistenciales en el ámbito de competencias de enfermería. Hay diversos modelos de CER, pero no existe una definición operacional. El objetivo del proyecto es elaborar estándares de calidad para definir y caracterizar una CER. Método. Estudio Delphi a 2 rondas. El panel estuvo constituido por 67 expertos: reumatólogos y enfermeras del Grupo de Trabajo de Enfermería de la Sociedad Española de Reumatología (SER). El cuestionario se elaboró tras revisión bibliográfica y experiencias de proyectos previos de la SER. El cuestionario consta de 7 apartados: consideraciones generales, estándares de estructura, de proceso, de tratamiento y seguimiento, educación sanitaria, formación e investigación y calidad asistencial. Cada ítem se puntuó de 1 (menos importante) a 9 (más importante) o mediante una cifra. El grado de acuerdo de los expertos se categorizó según el coeficiente de variación (CV) entre muy alto (CV ≤ 25%) y muy bajo (CV > 100%). Resultados. El cuestionario de la segunda ronda (182 ítems) fue respondido por 46 panelistas (34 reumatólogos y 12 enfermeras). Se obtuvo un grado de acuerdo muy importante en los estándares generales, de estructura, de proceso, de tratamiento y seguimiento, educación sanitaria y calidad asistencial. Se encontró menor acuerdo en los estándares relacionados con el tiempo para formación, el número de proyectos de investigación propios de enfermería y de publicaciones recomendables. Conclusión. Los estándares desarrollados en este estudio permitirían establecer mínimos deseables de calidad de estructura, proceso, labor asistencial, investigadora y docente que se pueden utilizar para desarrollar y evaluar las CER (AU)

Background. Nursing clinics in rheumatology (NCR) are organizational models in the field of nursing care. There are various NCR models, but there is no consensus on its operational definition. Our objective is to develop quality standards to define and characterize a NCR. Method. Two-round Delphi method. The panel consisted of 67 experts: rheumatologists and nurses of the nursing working group of the Spanish Society of Rheumatology (SSR). The Delphi questionnaire was developed after a literature and experience review from previous SSR projects. The questionnaire consists of 7 sections: general considerations, standards of structure, process, treatment and monitoring, health education, training and research and quality of care. Each item was scored from 1 (least important) to 9 (most important) or by assigning a number (e.g. waiting days). The degree of agreement among the experts was categorized according to the coefficient of variation (CoV) between very high (CoV≤25%) and very low (CoV>100%). Results. The second round questionnaire (182 items) was answered by 46 panelists (34 rheumatologists and 12 nurses). A very important agreement was reached on the general standards of structure, process, treatment and monitoring, health education and quality of care. Less agreement was observed on standards related to training time, number of recommended nurses’ research projects and publications. Conclusion. The standards developed in this study would be useful for establishing desirable quality standards of structure and process, and criteria for clinical work, research and teaching that can be used to develop and evaluate the NCRs (AU)

Quality of care standards for nursing clinics in rheumatology.

BACKGROUND: Nursing clinics in rheumatology (NCR) are organizational models in the field of nursing care. There are various NCR models, but there is no consensus on its operational definition. Our objective is to develop quality standards to define and characterize a NCR. METHOD: Two-round Delphi method. The panel consisted of 67 experts: Rheumatologists and nurses of the nursing working group of the Spanish Society of Rheumatology (SSR). The Delphi questionnaire was developed after a literature and experience review from previous SSR projects. The questionnaire consists of 7 sections: general considerations, standards of structure, process, treatment and monitoring, health education, training and research and quality of care. Each item was scored from 1 (least important) to 9 (most important) or by assigning a number (e.g., waiting days). The degree of agreement among the experts was categorized according to the coefficient of variation (CoV) between very high (CoV≤25%) and very low (CoV>100%). RESULTS: The second round questionnaire (182 items) was answered by 46 panelists (34 rheumatologists and 12 nurses). A very important agreement was reached on the general standards of structure, process, treatment and monitoring, health education and quality of care. Less agreement was observed on standards related to training time, number of recommended nurses' research projects and publications. CONCLUSION: The standards developed in this study would be useful for establishing desirable quality standards of structure and process, and criteria for clinical work, research and teaching that can be used to develop and evaluate the NCRs.

BAT1 promoter polymorphism is associated with rheumatoid arthritis susceptibility.

OBJECTIVE: To analyze whether the polymorphisms -22 (G/C) and -348 (C/T) of the BAT1 gene are associated with susceptibility to rheumatoid arthritis (RA). METHODS: One hundred fifty-six patients with RA and 154 controls were genotyped for HLA-DRB1 and the polymorphisms -22 and -348 of the BAT1 gene. RESULTS: HLA-DRB1*04 alleles were associated with RA susceptibility (33.9% vs 20.1%; pc = 0.04). Among these, HLA-DRB1*0401 (13.4% vs 5.1%; pc = 0.04) and HLA-DRB1*0404 (5.7% vs 1.2%; pc = 0.2) were increased in patients with RA. Additionally, carriage of BAT1 -348T polymorphism was strongly associated with RA (23.7% vs 12.1%; pc = 0.0002). Significantly, BAT1 -348T was in linkage disequilibrium with HLA-DRB1*0404 and HLA-DRB1*0405. However, BAT1 -348 T was associated independently with HLA-DRB1 shared-epitope alleles (42.6% vs 18.9%; p = 0.001). CONCLUSION: The BAT1 -348T polymorphism is associated with RA susceptibility independently of HLA-DRB1. The role of BAT1 in the regulation of tumor necrosis factor-a suggests that BAT1 may regulate the inflammatory response observed in patients with RA.