Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P1 receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P1 enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E2 production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-α, IL-6, IL-1β, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-α, IFN-γ, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines

Frecuencia de HLA-B27 en una población colombiana con signos de espondiloartritis

12 páginasBackground: The strong association between HLA-B27 and spondyloarthritis (SpA) has demonstrated that typing the HLA-B27 antigen is a crucial step in diagnosis and aids in defining the progression and severity of disease. Objective: To describe the frequency of HLA-B27 in Colombian individuals with clinical manifestations associated with SpA. Materials and Methodology: We retrospectively analyzed 4109 HLA-B27 typing requests to the Hospital Militar Central and the Instituto de Referencia Andino from Colombian individuals with clinical signs suggestive of SpA between 2009 and 2012. We used basic digital cytometry followed by Polymerase Chain Reaction with sequence specific primers when confirmation was needed. We determined the frequency of HLA-B27 in the population and levels of association of HLA-B27 with SpA. Results: Our population included 1585 men (36.8%) and 2524 women (61.4%). The predominant age range was between 19 and 45 years (49.9%). The majority (95.4%) of the study population came from the Andean region and eastern plains. The most frequent clinical manifestations were peripheral. Only a small fraction (12.1%) of the 4109 subjects was HLA-B27 positive. Of those, 56.9% were male, and 54.7% were between 19 and 45 years old. In contrast, when rheumatologists referred the HLA B27, 64% were found to be positive. Conclusion: The frequency of the HLA-B27 allele in individuals with clinical signs suggestive of SpA was low, in accordance with the lower prevalence found in Colombian patients diagnosed with SpA compared to American and European population.Antecedentes: la fuerte asociación entre HLA-B27 y la espondiloartritis (SpA) ha demostrado que la tipificación del antígeno HLA-B27 es un paso crucial en el diagnóstico y ayuda a definir la progresión y la gravedad de la enfermedad. Objetivo: Describir la frecuencia de HLA-B27 en colombianos con manifestaciones clínicas asociadas a EspA. Materiales y Metodología: Analizamos retrospectivamente 4109 solicitudes de tipificación HLA-B27 al Hospital Militar Central y al Instituto de Referencia Andino de individuos colombianos con signos clínicos sugestivos de SpA entre 2009 y 2012. Utilizamos citometría digital básica seguida de Reacción en Cadena de la Polimerasa con secuencia cebadores específicos cuando se necesitaba confirmación. Determinamos la frecuencia de HLA-B27 en la población y los niveles de asociación de HLA-B27 con SpA. Resultados: Nuestra población estuvo compuesta por 1585 hombres (36,8%) y 2524 mujeres (61,4%). El rango de edad predominante fue entre 19 y 45 años (49,9%). La mayoría (95,4%) de la población de estudio provenía de la región andina y llanos orientales. Las manifestaciones clínicas más frecuentes fueron periféricas. Solo una pequeña fracción (12,1 %) de los 4109 sujetos fue HLA-B27 positivo. De ellos, el 56,9% eran hombres y el 54,7% tenían entre 19 y 45 años. En cambio, cuando los reumatólogos derivaron el HLA B27, el 64% resultó positivo. Conclusión: La frecuencia del alelo HLA-B27 en individuos con signos clínicos sugestivos de SpA fue baja, de acuerdo con la menor prevalencia encontrada en pacientes colombianos con diagnóstico de SpA en comparación con la población americana y europea

Treatment of Early Rheumatoid Arthritis in a Multinational Inception Cohort of Latin American Patients the GLADAR Experience

Background: Treatment of rheumatoid arthritis (RA) has evolved dramatically in the last decade. However, little is known about the way rheumatologists in Latin America treat their patients in clinical practice, outside the scope of clinical trials.Objective: the objective of this study was to describe treatment patterns at disease onset in early RA with data from a large, multicenter, multinational inception cohort of Latin American patients.Methods: Consecutive patients with early RA (<1 year of disease duration as diagnosed by a rheumatologist) from 46 centers in 14 Latin American countries were enrolled in the study. Clinical data, laboratory assessments, and a detailed registry on type of prescriptions were collected at baseline and at 3, 6, 12, 18, and 24 months of follow-up. Hands and feet x-rays were obtained at baseline and at 12 and 24 months. All data were captured in Arthros 6.1 database. Continuous variables were expressed as means and SDs, and categorical variables were expressed as percentages and 95% confidence intervals (95% CIs). Only therapeutic data at baseline are presented, corresponding to the period between disease onset and second visit (3 months).Results: A total of 1093 patients were included. Eighty-five percent were female, and 76% had a positive rheumatoid factor. Mean age at diagnosis was 46.5 (SD, 14.2) years, and mean disease duration at the first visit was 5.8 (SD, 3.8) months. Between baseline and second visit (3 months), 75% of patients (95% CI, 72%-78%) received disease-modifying antirheumatic drugs. Methotrexate (MTX) alone or in combination was the most frequently used (60.5%), followed by antimalarials (chloroquine or hydroxychloroquine, 32.1%), sulfasalazine (7.1%), and leflunomide (LEF, 4%). in 474 patients (43%), initiation of disease-modifying antirheumatic drugs was within the first month after the first visit. in addition, 290 patients (26%; 95% CI, 23%-29%) received combination therapy as initial treatment. the most frequently used combinations were MTX + chloroquine (45%), MTX + hydroxychloroquine (25%), and MTX + sulfasalazine (16%). Eleven patients (1%; 95% CI, 0.5%-1.8%) received biologics. Sixty-four percent (95% CI, 60%-66%) received corticosteroids. of those, 80% (95% CI, 77%-84%) received 10 mg of oral prednisone or less.Conclusions: in this cohort of Latin American patients with early RA, most patients received MTX very early in their disease course. Combination therapy was used approximately in 1 of every 4 patients as initial therapy. Biologics were rarely used at this early stage, and low-dose prednisone was commonly used.Abbott LaboratoriesAbbottHosp Italiano Buenos Aires, Serv Clin Med, Secc Reumatol, Buenos Aires, DF, ArgentinaFdn Dr Pedro M Catoggio Progreso Reumatol, Buenos Aires, DF, ArgentinaHosp Gen Dr Miguel Silva, Unidad Invest Dr Mario Alvizouri Munoz, Morelia, Michoacan, MexicoHosp Prov Rosario, Serv Reumatol, Rosario, Santa Fe, ArgentinaUniv Nacl Rosario, RA-2000 Rosario, ArgentinaHosp Privado, Ctr Med Cordoba, Dept Reumatol, Cordoba, ArgentinaHosp San Martin La Plata, Dept Reumatol, La Plata, Buenos Aires, ArgentinaUniv Fed Minas Gerais, Hosp Clin, Dept Aparelho Locomotor, Serv Reumatol, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo UNIFESP, Dept Med Interna, Serv Reumatol, São Paulo, BrazilPontificia Univ Catolica Rio Grande do Sul, Dept Reumatol, Porto Alegre, RS, BrazilUniv Fed Parana, Hosp Clin, Dept Clin Med, Disciplina Reumatol, BR-80060000 Curitiba, Parana, BrazilHosp Geral Goiania Dr Alberto Rassi, Secao Reumatol, Goiania, Go, BrazilPontificia Univ Catolica Chile, Fac Med, Dept Clin Immunol & Rheumatol, Santiago, ChileHosp Clin San Borja Arriaran, Dept Reumatol & Inmunol, Santiago, ChileClin Univ Bolivariana, Corp Invest Biol, Dept Inmunol Clin & Reumatol, Medellin, Antioquia, ColombiaHosp Mil, Dept Reumatol & Inmunol, Bogota, ColombiaHosp Especialidades Ctr Med La Raza, Ctr Med Nacl Siglo 21, Dept Reumatol, Mexico City, DF, MexicoUniv Autonoma Nuevo Leon, Hosp Univ Dr Jose Eleuterio Gonzalez, Dept Med Interna, Serv Reumatol, Monterrey, Nuevo Leon, MexicoHosp Gen Occidente Secretaria Salud, Dept Inmunol & Reumatol, Zapopan, Jalisco, MexicoHosp Presidente Estrella Urena, Clin Corominas, Clin Union Med, Dept Reumatol, Santiago, Dominican RepHosp Univ Caracas, Minist Salud, Ctr Nacl Enfermedades Reumat, Serv Reumatol, Caracas, VenezuelaUniversidade Federal de São Paulo UNIFESP, Dept Med Interna, Serv Reumatol, São Paulo, BrazilWeb of Scienc