Rafael Valle-Oñate

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.

Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis

Objective To establish the predictive validity of the Assessment of SpondyloArthritis international Society (ASAS) spondyloarthritis (SpA) classification criteria. Methods 22 centres (N=909 patients) from the initial 29 ASAS centres (N=975) participated in the ASAS-cohort follow-up study. Patients had either chronic (>3 months) back pain of unknown origin and age of onset below 45 years (N=658) or peripheral arthritis and/or enthesitis and/or dactylitis (N=251). At follow-up, information was obtained at a clinic visit or by telephone. The positive predictive value (PPV) of the baseline classification by the ASAS criteria was calculated using rheumatologists diagnosis at follow-up as external standard. Results In total, 564 patients were assessed at follow-up (345 visits; 219 telephone) with a mean follow-up of 4.4 years (range: 1.9; 6.8) and 70.2% received a SpA diagnosis by the rheumatologist. 335 patients fulfilled the axial SpA (axSpA) or peripheral SpA (pSpA) criteria at baseline and of these, 309 were diagnosed SpA after follow-up (PPV SpA criteria: 92.2%). The PPV of the axSpA and pSpA criteria was 93.3% and 89.5%, respectively. The PPV for the ‘clinical arm only’ was 88.0% and for the ‘clinical arm’±‘imaging arm’ 96.0%, for the ‘imaging arm only’ 86.2% and for the ‘imaging arm’+/-‘clinical arm’ 94.7%. A series of sensitivity analyses yielded similar results (range: 85.1–98.2%). Conclusions The PPV of the axSpA and pSpA criteria to forecast an experts diagnosis of ‘SpA’ after more than 4 years is excellent. The ‘imaging arm’ and ‘clinical arm’ of the axSpA criteria have similar predictive validity and are truly complementary.

Serum monocyte chemotactic protein-1 concentrations distinguish patients with ankylosing spondylitis from patients with mechanical low back pain.

Objectives This study aimed to identify potential blood-derived biomarkers distinguishing patients with ankylosing spondylitis from those with mechanical low back pain. Methods Serum and synovial fluid samples from our cohorts were assayed by using enzyme-linked immunosorbent assay for the following inflammatory biomarkers: interleukin (IL)-1&agr;, IL-6, IL-8, IL-17, IL-23, monocyte chemotactic protein (MCP)-1, macrophage inflammatory proteins (MIP)-1&agr;, MIP-1&bgr;, tumor necrosis factor-&agr; (TNF-&agr;), interferon-&agr; (IFN-&agr;), IFN-&bgr;, metalloproteinase (MMP-3), and bone morphogenetic protein 7 (BMP-7). Results After screening, a panel of serum and synovial fluid samples with a series of potential biomarkers, cytokines including IL-6, IL-8, MMP-3, and MCP-1 were selected for additional testing because they exhibited higher concentrations than paired serum samples in the synovial fluid. Sera obtained from 50 patients with ankylosing spondylitis and 27 patients with mechanical low back pain were measured for these biomarkers. Conclusions The MCP-1 serum was identified as a biomarker candidate, distinguishing ankylosing spondylitis from mechanical low back pain with a sensitivity of 96% and a specificity of 83.3%.

Associação entre os níveis séricos de potenciais biomarcadores com a presença de fatores relacionados à atividade clínica e ao mau prognóstico em espondiloartrites

BACKGROUND Serum biomarkers traditionally associated with inflammatory activity and a poor prognosis in rheumatic diseases do not show the same relationship in spondyloarthritis. OBJECTIVE To establish the association between serum levels of potential biomarkers with the presence of factors related to clinical activity and poor prognosis in spondyloarthritis. METHODS Sixty-two patients were included: 13 with reactive arthritis, 19 with ankylosing spondylitis, and 30 with undifferentiated spondyloarthritis. The results were compared with those from 46 healthy controls. Clinical, radiological, and laboratory characteristics were assessed. The results were analyzed based on the presence of uveitis, enthesitis, inflammatory back pain, arthritis, HLA-B27 and sacroiliac involvement. The analyzed biomarkers included ESR, US-CRP, SAA, LBP, FSC-M, and MMP-3; and cytokine serum levels measured were: IL-17, IL-6, IL-1α , TNF-α , IFN-γ, and IL-23. RESULTS Forty-three (69.4%) patients were male. The average age was 31.9 ± 9.9 years and the age at the onset of symptoms was 26.9 ± 7.3 years. HLA-B27 was positive in 26 (41.9%) patients, inflammatory back pain in 42 (67.7%), arthritis in 44 (71.0%), and enthesitis in 34 (54.8%). IL-17, IL-23, TNF-α , IL-6, IL-1α , and US-CRP levels were significantly higher in patients with SpA when compared to controls. US-CRP (P = 0.04), IL-6 (P = 0.003), IL-1α (P = 0.03), and LBP (P = 0.03) levels were associated with presence of HLA-B27, inflammatory back pain, and arthritis. CONCLUSION An increase in serum levels of US-CRP, IL-6, IL-1α , and LBP was correlated with factors associated with clinical activity and poor prognosis in spondyloarthritis.

Psoriatic Arthritis in South and Central America

Psoriasis and its related manifestations, including psoriatic arthritis, are prevalent disorders in the Western world, particularly among Caucasians. The study of these disorders in Latin America lags way behind the study of other more common rheumatic disorders, such as rheumatoid arthritis and systemic lupus erythematosus. From the scarce evidence available, however, it appears that the prevalence and incidence of psoriasis and psoriatic arthritis are lower than in other parts of the Western world and almost negligible among natives from the Andean region, although confirmatory epidemiologic studies are lacking.

Periodontal Disease in Individuals With a Genetic Risk of Developing Arthritis and Early Rheumatoid Arthritis: A Cross-Sectional Study

BACKGROUND Recent consensus emphasizes the importance of studying individuals at risk for rheumatoid arthritis (pre-RA) and those with early RA (eRA). Periodontal tissues have been recently evaluated, but these studies are limited. To evaluate the periodontal condition, immunoglobulin (Ig)G subclasses against Porphyromonas gingivalis in individuals with pre-RA and eRA were compared with controls to establish an association between periodontal infection markers and rheumatic activity. METHODS Rheumatologic and periodontal condition was evaluated in 119 individuals with pre-RA, 48 patients with eRA, and matched controls. P. gingivalis IgG1 and IgG2 were analyzed. C-reactive protein, erythrocyte sedimentation rate (ESR), rheumatoid factor, anticitrullinated protein antibodies (ACPAs), and RA activity were measured. The groups were compared with McNemar test and paired t-test. Conditional logistic regression was performed for pre-RA confounders, and χ(2) test was used to evaluate periodontal variables and RA activity indices. RESULTS Pre-RA individuals showed significantly higher levels of plaque index (P = 0.01) and bleeding on probing (P = 0.03) and higher severity of periodontal disease (P = 0.02). Periodontitis was associated with pre-RA (odds ratio, 3.39; 95% confidence interval, 1.64 to 7.01) but not with eRA. In pre-RA, P. gingivalis-specific IgG2 was associated with ACPAs (P = 0.049) and disease severity visual analog scale (P = 0.03). In eRA, IgG2 against P. gingivalis was associated with ESR (P = 0.046) and ACPAs (P = 0.04). P. gingivalis was associated with ACPAs (P = 0.04). CONCLUSIONS This study shows that individuals with pre-RA have significant inflammatory periodontal involvement. There was a significant association between IgG against P. gingivalis and ACPAs in pre-RA and markers of RA activity in individuals with eRA.

Global partnering opportunities and challenges of psoriasis and psoriatic arthritis in Latin America: a report from the GRAPPA 2010 annual meeting.

Documenting the disease burden of psoriasis and psoriatic arthritis (PsA) in Central and South America is difficult. The most conclusive data have come from the Iberoamerican Registry of Spondyloarthritis (RESPONDIA), which registered patients with a diagnosis of spondyloarthritis in a multinational, multicenter (Argentina, Brazil, Costa Rica, Chile, Mexico, Peru, Uruguay, Venezuela, Spain, and Portugal) cross-sectional study conducted between 2006 and 2007. Compared with elsewhere in the Western world, patients with PsA from RESPONDIA were older at study visit, at onset of symptoms, and at diagnosis of spondyloarthritis (SpA); had longer mean disease duration from onset of symptoms to diagnosis; and were more likely to have dactylitis, nail involvement, enthesitis, and peripheral arthritis in lower and upper extremities. It is critical to understand the biologic basis, estimate the disease burden, and determine the clinical treatment of PsA in Latin America. The Group for Research and Assessment of Psoriasis and PsA (GRAPPA) has an increasing number of members from this region. In a coordinated effort, GRAPPA, the Latin American Psoriasis and PsA Society (LAPPAS), and the Pan American League of Associations for Rheumatology (PANLAR) are supporting clinician researchers with educational initiatives in Latin America to understand these conditions.

Epidemiology of Spondyloarthritis in Colombia

There are no formal statistics about the incidence, prevalence or demographics of patients with spondyloarthropathies (SpAs) in Colombia. However, information from a few studies provides a preliminary snapshot of SpAs in the country. In this article, the authors review what has been published; document what their group is doing and outline what they still need to do in the future. The analysis suggests that although information on SpA in Colombia is limited, it is known that the diagnostic entities of SpA are different than those reported at other latitudes. Thus, it is important to improve and expand the current database of SpA, particularly undifferentiated SpA, not only in Colombia but in all of Latin America.

Biomarcadores en espondiloartropatías

Among rheumatic diseases and specifically spondyloarthropathies (SpA), the study of biomarkers, defined as molecules that reflect either biologic or specific pathological process, is an important and necessary area in basic and clinical research, being a consequence or the response of an intervention. Other markers provide information about the pathogenesis of this disease. Recently, HLA-B27 has been used as diagnostic criteria to detect SpA. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) are clinical scores used to assess disease activity. A new activity index, Ankylosing Spondylitis Disease Activity Score (ASDAS) considers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as biomarkers. This review describes the state of the art of research on SpA biomarkers. There are promising new candidates as biomarkers such as metallopro-teinase 3, Type II collagen neoepitopes (C2C and C1-2C), C-propeptide of Type II collagen (CPII), aggrecan 846 epitope, macrophage colony stimulating factor, serum amyloid A protein and interleukin-6, among others.

Eficácia terapêutica e segurança de metotrexato + leflunomida em pacientes colombianos com artrite reumatoide ativa refratária ao tratamento convencional

INTRODUCTION: The combination of methotrexate (MTX) + leflunomide (LFN) has been shown to be effective in the treatment of RA. Its safety has been questioned. OBJECTIVE: To evaluate the effectiveness and safety of the combination of MTX + LFN in patients with active RA. METHODS: This was a 24-week multicenter study, which included 88 patients with active disease despite consistent treatment with methotrexate and prednisolone. RESULTS: We included 78 women (88%) and 10 men. The age was 51.3 ± 12.4 years, and the evolution of disease was 8 ± 6.8 years. Patients had active disease, which was indicated by a median of IQR of 10.0 (7.0-13.0) for swollen and of 14.0 (18.0-10.0) for tender joints for the whole group. The ACR responses achieved at week 24 were: ACR20: 76.0%; ACR50: 67.1%; ACR70: 23.9%. There was improvement in the activity of disease: DAS-28 score: 5.8 ± 1.2 at baseline vs. 3.8 ± 1.6 at week 24 (P = 0.000). The most significant adverse event was elevation of transaminases in eight patients (26%). Eight patients were withdrawn due to adverse events: four due to the elevation of transaminases, and one each due to diabetes insipidus, rash, diabetes mellitus and osteomuscular pain. CONCLUSION: The combination of MTX + LFN is effective for treating RA in patients for whom conventional treatment has failed. Strict medical and laboratory control is to be enforced for safety.