Interleukin-18 in Brazilian Rheumatoid Arthritis Patients: Can Leflunomide Reduce It?

OBJECTIVES: Rheumatoid arthritis affects about 1% of the world's population. This is a chronic autoimmune disease. It is predominant in females with progressive joint damage. Immune cells are involved, especially Th1/Th17 lymphocytes and their inflammatory cytokines. These proteins have different functions in the immune system, such as IL-16 is a chemotactic factor; IL-18 can activate NFκB transcription producing inflammatory proteins; IL-31 can activate the JAK/STAT pathway which leads to the production of inflammatory factors in chronic diseases; IL-33 promotes IL-16 secretion which causes lymphocyte recruitment, and IL-32 and IL-34 appear to increase TNF secretion by macrophages activation in AR. The aim of this study was to evaluate serum levels of IL-16, IL-18, IL-31, IL-32, IL-33, and IL-34 and compare them with the severity and treatment of RA patients if there are any correlations. METHODS: A total of 140 RA patients and 40 healthy donors were recruited from the Department of Rheumatology at Hospital das Clínicas from the Federal University of Pernambuco. 60 AR patients were naïve for any treatment. Serum cytokine levels were determined using an ELISA kit. RESULTS: Serum IL-16 (p = 0.0491), IL-18 (p < 0.0001), IL-31 (p = 0.0004), and IL-32 (p = 0.0040) levels were significantly increased in RA patients compared with healthy donors. It was observed that patients using leflunomide had the lowest IL-18 levels, close to controls levels (p = 0.0064). CONCLUSION: IL-16, IL-18, IL-31, and IL-32 are increased in the serum of RA patients. IL-18 is at lower levels in those AR who are taking leflunomide as treatment.

Increased levels of the soluble oncostatin M receptor (sOSMR) and glycoprotein 130 (sgp130) in systemic sclerosis patients and associations with clinical parameters.

OBJECTIVE: The objective of the present study was to evaluate the serum levels of soluble oncostatin M (OSM), OSM receptor (sOSMR) and glycoprotein130 (sgp130) in patients with systemic sclerosis (SSc), and the possible associations and correlations with clinical parameters. METHODS: Serum levels of OSM, sOSMR and sgp130 were evaluated by ELISA in eighty-four SSc patients and eighty-four healthy volunteers. RESULTS: SSc patients had significantly elevated levels of sOSMR and sgp130 when compared with healthy individuals (p < 0.0001 and p = 0.025, respectively). Diffuse cutaneous SSc and limited cutaneous SSc patients also presented higher levels of sOSMR when compared with healthy individuals (p = 0.003 and p = 0.0001, respectively). Patients with digital ulcers presented higher levels of sOSMR when compared to those without ulcers (p = 0.034). However, sOSMR levels were lower in patients with esophageal dysfunction than patients without this involvement (p = 0.038). OSM levels were undetectable in serum from SSc patients and healthy volunteers. CONCLUSION: Serum levels of sOSMR and sgp130 are elevated in patients with systemic sclerosis. In addition, associations were observed with important clinical manifestations, suggesting that sOSMR is a candidate biomarker of this disease. More studies are needed to clarify the functions of IL-6 family cytokines in systemic sclerosis.

Increased serum levels of galectin-9 in patients with chikungunya fever.

Chikungunya fever (CHIKF) is an arboviral disease that has caused an epidemic burst of chronic inflammatory joint disease in Latin America in the last few years. Efforts are being spent in understanding the mechanisms by which it may cause such articular damage and in determining possible biomarkers of the disease. Galectins (GAL) are a family of animal lectins with an affinity for beta-galactosides. They have multiple functions including working as receptors in innate immunity and as a control for inflammatory responses in both innate and adaptive immunity. They regulate functions of immune cells, such as lymphocytes and macrophages, which have a main role in the chikungunya inflammatory process. Galectins are also involved in chronification of viral diseases, participate in the immunopathogenesis of chronic joint diseases such as rheumatoid arthritis, and have a role in inflammation in other arboviral diseases, such as dengue. Thus, we intended to determine the serum levels of galectin-1, -3, -4, -7, and -9 in patients with subacute and chronic articular manifestations of CHIKF and to evaluate their associations with clinical manifestations. We evaluated 44 patients with clinical manifestations of CHIKF and serological confirmation with IgM and/or IgG chikungunya virus (CHIKV) antibodies. Forty-nine age- and gender-matched healthy individuals served as controls. Anti-CHIKV IgM and IgG antibodies and galectins serum levels were measured by ELISA. We found higher levels of GAL-9 (patients median 2192 [1500-2631] pg/mL, controls median 46.88 [46.88-46.88] pg/mL, p < 0.0001) and lower levels of GAL-3 (patients median 235.5 [175.5-351.8] pg/mL, controls median 2236.0 [1256.0-2236.0] pg/mL, p < 0.0001) in patients than in controls. There was no statistical difference in levels of GAL-1, -4 and -7 between patients and control groups. There was no difference in GAL-9 serum levels between patients with subacute or chronic symptoms (median 2148 [1500-2722] pg/mL x 2212 [1844-2500] pg/mL, p = 0.3626). A significant association of GAL-9 with joint stiffness, both in its duration and intensity, was found. These results may reflect the participation of GAL-9 in the immunopathogenesis of the inflammatory process in chikungunya fever, as morning stiffness may reflect the systemic inflammatory process.

Arboviruses related with chronic musculoskeletal symptoms.

Arboviruses (ARthropods BOrne VIRUSES) are disease-causing viruses transmitted through the bite of hematophagous arthropods, such as mosquitoes and ticks. Among these, the alphavirus, genus of the Togaviridae family, is considered the most arthritogenic species, responsible for diseases such as chikungunya fever (CHIK), O'nyong-nyong virus fever, Ross River virus disease, Barmah Forest virus disease, Sindbis virus disease, and Mayaro fever. These arboviral diseases, especially CHIK, have impacted public health in recent decades, leading to devastating epidemics, particularly in developing countries, due to their high potential for chronicity, functional impairment, and great impact on the quality of life. In a similar way, chronic musculoskeletal symptoms have been described in all alphavirus infections. However, CHIK is the best studied. The purpose of this article is to review physiopathology, clinical manifestations, diagnosis, and treatment of alphaviruses, focusing on CHIK and chronic evolution of musculoskeletal symptoms.

Atorvastatin inhibits IL-17A, TNF, IL-6, and IL-10 in PBMC cultures from patients with severe rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage, and it may present with comorbidities at the systemic level. The Th1/Th2/Th17 CD4+ lymphocyte imbalance produces inflammatory cytokines, which begin to act, injuring joint tissue. Atorvastatin is a cholesterol- lowering drug with a range of biological effects including anti-inflammatory potential. Patients with rheumatoid arthritis who used statins exhibited clinical improvement. However, the mechanism is not fully understood. Therefore, we aimed to evaluate the RA immunomodulatory activity of atorvastatin. METHODS: Peripheral blood mononuclear cells (PBMCs) of RA patients and healthy donors were exposed to atorvastatin in different concentrations following a cytotoxicity assay. Th1, Th2, and Th17 cytokines profiles were evaluated in the culture supernatant by cytometric bead array (CBA). Data were analyzed using the Wilcoxon test, and differences were considered significant when p < 0.05. RESULTS: Atorvastatin showed no toxicity at the tested doses in RA PBMC cultures, and at 10µM, it showed the most significant results, reducing IL-17A (p = 0.002), TNF (p = 0.002), and IL-6 (p = 0.008) supernatant levels. The outcomes also revealed that only patients with more severe disease activity and those sensitive to corticoid treatments were responders to atorvastatin in vitro. CONCLUSION: These findings suggest the potential immunomodulatory action of atorvastatin as a mechanism in rheumatoid arthritis treatment.

Sensitivity and specificity of Interleukin 29 in patients with rheumatoid arthritis and other rheumatic diseases.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and progressive inflammation that can cause a high degree of disability in affected individuals. Proinflammatory cytokines play central roles in the development of degradative and inflammatory responses in RA. IL-29 has been identified in RA and reported as a biomarker of the disease. OBJECTIVE: To analyze serum levels and accuracy of IL-29 in RA patients compared to healthy subjects and patients with other rheumatic diseases. METHODS: IL-29 serum levels were measured in 121 patients with RA, 53 patients with systemic lupus erythematosus (SLE), 60 patients with systemic sclerosis (SSc), 29 patients with fibromyalgia (FM), 50 patients with osteoarthritis (OA) and 68 healthy individuals as controls. IL-29 levels in serum were investigated by ELISA. Sensitivity, specificity and likelihood ratios (LR) for having RA were calculated. RESULTS: Serum levels of IL-29 were increased in RA patients 113.6 (IQR = 31.25-308.5) pg/ml compared to non-RA patients (SLE, SSc, OA, and FM) (31.25 pg/ml) and healthy controls (31.25 pg/ml, p < 0.001). The IL-29 cut-off values to distinguish patients with RA from non-RA patients were 61.11 pg/ml (sensitivity 57.02, specificity 92.71, LR: 7.82) and for all subjects 32.96 pg/ml (sensitivity 64.46, specificity 87.31, LR: 5.08). Additionally, IL-29 correlated negatively with age (r=-0189, p = 0.038) and disease duration (-0.192, p = 0.037). Interestingly, IL-29 correlated positively with neutrophil count in RA patients positive for rheumatoid factor (r = 0.259, p = 0.022). CONCLUSION: IL-29 is higher in the serum of patients with RA compared to non-RA subjects and may have potential for use as a biological marker.

IL-27 in patients with Chikungunya fever: A possible chronicity biomarker?

BACKGROUND/PURPOSE: Although many patients with chikungunya virus disease (CHIKVD), an arboviral disease characterized by sudden fever and incapacitating poliartralgia, develop chronic articular symptoms, the mechanisms involved in CHIKVD's chronification and its possible biomarkers remain poorly understood. Interleukin (IL)-17A, IL-21, IL-22, IL-29, and transforming growth factor (TGF)-ß have been implicated in the pathogenesis of other inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Since chronic manifestations of CHIKVD share many clinical and immunological characteristics with those diseases, we assessed the serum levels of those cytokines and analyzed their associations with clinical manifestations in patients with CHIKVD. METHODS: We evaluated 45 patients (36 female, mean age: 55.2 ± 13.8 years) with CHIKVD serologically confirmed by enzyme-linked immunosorbent assay (ELISA), articular manifestations upon evaluation, and no previous history of inflammatory rheumatologic diseases, along with 49 healthy age- and sex-matched controls. We tested anti-Chikungunya IgM and IgG antibodies and measured IL-17A, IL-21, IL-22, IL-27, IL-29, and TGF-ß serum levels with specific ELISA kits. RESULTS: IL-27, IL-17A, and IL-29 appeared in most patients but not in controls. IL-27 serum levels were higher in patients with chronic symptoms (median: 523.0 pg/mL [62.5-1,048]) than in ones in the acute or subacute stage (median: 62.5 pg/mL [62.5-483.8], p = .008). In patients with CHIKVD, we found significant correlations between IL-27 levels and tender joint counts (r = .32, p = .006), along with associations between IL-17A levels and swollen joint counts (r = .315, p = .0352). Furthermore, patients with arthritis had higher IL-17A levels (median: 23.14 pg/mL [20.6-25.86]) than ones without (median: 20.29 pg/mL [3.91-22.43], p = .0352). We did not detect IL-22 in either group or IL-21 in patients with CHIKVD. CONCLUSION: Serum levels of IL-17A, IL-27, and IL-29 were high in patients with CHIKVD and had important associations with articular manifestations, which might indicate the inflammatory nature of Chikungunya infection in patients with joint symptoms and the roles of those cytokines in the disease's pathophysiology.