YKL-40 serum levels are predicted by inflammatory state, age and diagnosis of idiopathic inflammatory myopathies.

YKL-40 increase according to the aging process, and its functions have been associated with tissue remodeling and systemic inflammation. In Rheumatoid Arthritis (RA) it has been proposed as a possible biomarker of activity and severity, however; in the field of idiopathic inflammatory myopathies (IIM) the role of YKL-40 in IIM is not clear. Thus, we aimed to evaluate if there is an association between the serum levels and muscle tissue expression of YKL-40 with age, IIM phenotype, muscle strength and myositis disease activity. The main finding was that age is the most important variable that affects the YKL-40 serum levels. In muscle biopsy, we observed that YKL-40 is mainly expressed in infiltrating lymphoid cells than in muscle tissue. Using ANCOVA according to the b-coefficients, YKL-40 serum levels are predicted by inflammatory state, age, and IIM diagnosis.

Anti-Drug Antibodies in the Biological Therapy of Autoimmune Rheumatic Diseases.

Autoimmune rheumatic diseases are a cluster of heterogeneous disorders that share some clinical symptoms such as pain, tissue damage, immune deregulation, and the presence of inflammatory mediators. Biologic disease-modifying antirheumatic drugs are some of the most effective treatments for rheumatic diseases. However, their molecular and pharmacological complexity makes them potentially immunogenic and capable of inducing the development of anti-drug antibodies. TNF inhibitors appear to be the main contributors to immunogenicity because they are widely used, especially in rheumatoid arthritis. Immunogenicity response on these treatments is crucial since the appearance of ADAs has consequences in terms of safety and efficacy. Therefore, this review proposes an overview of the immunogenicity of biological agents used in autoimmune rheumatic diseases highlighting the prevalence of anti-drug antibodies.

IL-21 (rs2055979 and rs2221903)/IL-21R (rs3093301) Polymorphism and High Levels of IL-21 Are Associated with Rheumatoid Arthritis in Mexican Patients.

Rheumatoid Arthritis (RA) is characterized by joint destruction, chronic inflammation, and autoantibody production. IL-21/IL-21R plays an essential role in the immunopathology of RA. Elevated IL-21 serum levels have been associated with RA and disease activity. Here, we evaluated the association of IL-21/IL-21R polymorphisms and IL-21 serum levels with RA. The study included 275 RA patients and 280 Control subjects (CSs). Single nucleotide polymorphisms IL-21 (rs2055979 and rs2221903) and IL-21R (rs3093301) were genotyped using PCR-RFLP. Clinical activity was evaluated by DAS28-ESR; IL-21 and anti-CCP serum levels were quantified by ELISA. The IL-21 rs2055979 AA genotype was higher in RA patients than in the CS group (p = 0.0216, OR = 1.761, 95% CI = 1.085-2.859); furthermore, RA patients showed anti-CCP elevated levels compared to the CA genotype (p = 0.0296). The IL21R rs3093301 AA genotype was also higher in RA patients than in the CS group (p = 0.0122, OR = 1.965, 95% CI = 1.153-3.348). The AT haplotypes of IL-21 rs2055979 and rs2221903 were more frequent (49%) in the RA group (p = 0.006). IL-21 serum levels were significantly elevated in the RA group, but without an association with IL-21 polymorphisms. In conclusion, IL-21 rs2255979 and IL-21R rs3093301 are associated with a higher risk of RA, and could be a genetic marker. Moreover, the elevated IL-21 levels in RA suggest that IL-21/IL-21R could be a therapeutic target in RA.

Osteopontin: A Bone-Derived Protein Involved in Rheumatoid Arthritis and Osteoarthritis Immunopathology.

Osteopontin (OPN) is a bone-derived phosphoglycoprotein related to physiological and pathological mechanisms that nowadays has gained relevance due to its role in the immune system response to chronic degenerative diseases, including rheumatoid arthritis (RA) and osteoarthritis (OA). OPN is an extracellular matrix (ECM) glycoprotein that plays a critical role in bone remodeling. Therefore, it is an effector molecule that promotes joint and cartilage destruction observed in clinical studies, in vitro assays, and animal models of RA and OA. Since OPN undergoes multiple modifications, including posttranslational changes, proteolytic cleavage, and binding to a wide range of receptors, the mechanisms by which it produces its effects, in some cases, remain unclear. Although there is strong evidence that OPN contributes significantly to the immunopathology of RA and OA when considering it as a common denominator molecule, some experimental trial results argue for its protective role in rheumatic diseases. Elucidating in detail OPN involvement in bone and cartilage degeneration is of interest to the field of rheumatology. This review aims to provide evidence of the OPN's multifaceted role in promoting joint and cartilage destruction and propose it as a common denominator of AR and OA immunopathology.

Autoantibodies in the pathogenesis of idiopathic inflammatory myopathies: Does the endoplasmic reticulum stress response have a role?

Idiopathic inflammatory myopathies (IIMs) are a group of rare, acquired autoimmune diseases characterized by profound muscle weakness and immune cell invasion into non-necrotic muscle. They are related to the presence of antibodies known as myositis-specific antibodies and myositis-associated antibodies, which are associated with various IIM phenotypes and the clinical prognosis. The possibility of the participation of other pathological mechanisms involved in the inflammatory response in IIM has been proposed. Such mechanisms include the overexpression of major histocompatibility complex class I in myofibers, which correlates with the activation of stress responses of the endoplasmic reticulum (ER). Taking into account the importance of the ER for the maintenance of homeostasis of the musculoskeletal system in the regulation of proteins, there is probably a relationship between immunological and non-immunological processes and autoimmunity, and an example of this might be IIM. We propose that ER stress and its relief mechanisms could be related to inflammatory mechanisms triggering a humoral response in IIM, suggesting that ER stress might be related to the triggering of IIMs and their auto-antibodies' production.

Impaired muscle strength is associated with ultrastructure damage in myositis.

The muscle fiber ultrastructure in Idiopathic Inflammatory Myopathies (IIM) has been scarcely explored, especially in Inclusion Body Myositis. The aim of this study was to implement the Scanning Electron Microscopy (SEM) in a small cohort of IIM patients, together with the characterization of immunological profile for a better understanding of the pathophysiology. For immunological profile characterization, we identified the presence of autoantibodies (Ro-52, OJ, EJ, PL7, PL12, SRP, Jo-1, PMScl75, PMScl100, Ku, SAE1, NXP2, MDA5, TIF1γ, Mi-2α, Mi-2ß) and quantified cytokines (IL-1ß, IFN-α2, IFN-γ, TNF-α, IL-6, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33) and chemokines (CCL2, CXCL8). The histological analysis was made by hematoxylin-eosin staining while the muscle fiber ultrastructure was characterized by SEM. We observed changes in the morphology and structure of the muscle fiber according to muscle strength and muscle enzymes. We were able to find and describe muscle fiber ultrastructure with marked irregularities, porosities, disruption in the linearity and integrity of the fascicle, more evident in patients with increased serum levels of muscle enzymes and diminished muscle strength. Despite the scarce reports about the use of SEM as a tool in all clinical phenotypes of IIM, our work provides an excellent opportunity to discuss and reframe the clinical usefulness of SEM in the diagnostic approach of IIM.

Suicide Risk in Rheumatoid Arthritis Patients is Associated With Suboptimal Vitamin D Levels.

BACKGROUND/OBJECTIVE: Rheumatoid arthritis (RA) patients might experience anxiety and depressive symptoms. Deficient vitamin D levels may be a trigger for these conditions. The aim of this study was to determine the frequency of depression, anxiety symptoms, and suicidal risk or ideation in patients with RA associated with vitamin D serum levels. METHODS: In this cross-sectional study, we recruited RA patients older than 18 years, classified into 3 groups according to serum vitamin D levels: sufficient, ≥30 ng/mL; insufficient, 20-29 ng/mL; and deficient, <20 ng/mL. Based on the self-reported Plutchik and the Hospital Anxiety and Depression Scale, we evaluated the association of suicidal risk, depression, and anxiety with the vitamin D levels in RA and the Rheumatoid Arthritis Quality-of-Life Questionnaire. RESULTS: We studied 72 patients with RA between January and October 2019. We found an inverse correlation between Plutchik score and suicidal risk with inadequate vitamin D levels, but not with the Hospital Anxiety and Depression Scale. Suicidal ideation was associated with a higher score on the Rheumatoid Arthritis Quality-of-Life Questionnaire. CONCLUSIONS: Despite the high prevalence of depressive and anxiety symptoms in RA patients, a Plutchik low correlation coefficient with inadequate serum levels of vitamin D was found. However, in the analysis of covariance, we were able to find that vitamin D levels remain associated with a reduction of suicide ideation. Further studies are needed to identify a risk profile for early psychological interventions to improve the quality of life in RA patients.

The DNA co-vaccination using Sm antigen and IL-10 as prophylactic experimental therapy ameliorates nephritis in a model of lupus induced by pristane.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies such as anti-Sm. Studies in patients with SLE and murine models of lupus reveal that the most critical anti-Sm autoantibodies are predominantly direct against D1(83-119), D2, and B´/B epitopes. OBJECTIVES: The present study aimed to analyze the induction of antigen-specific tolerance after prophylactic immunization with a DNA vaccine encoding the epitopes: D183-119, D2, B´/B, and B´/BCOOH in co-vaccination with IFN-γ or IL-10 in a murine model of lupus induced by pristane. MATERIAL AND METHODS: To obtain endotoxin-free DNA vaccines, direct cloning techniques using pcDNA were performed: D183-119, D2, B´/B, B´/BCOOH, IFN-γ, or IL-10. Lupus was induced by 0.5 mL of pristane via intraperitoneal in BALB/c female mice. Immunoprecipitation with K562 cells was metabolically labeled with 35S and ELISA to detect serum antibodies or mice IgG1, IgG2a isotypes. ELISA determined IL-10 and IFN-γ from splenocytes supernatants. Proteinuria was assessed monthly, and lupus nephritis was evaluated by immunofluorescence, and electron microscopy. RESULTS: The prophylactic co-vaccination with D2/IL-10 reduced the expression of kidney damage observed by electron microscopy, direct immunofluorescence, and H & E, along with reduced level of anti-nRNP/Sm antibodies (P = 0.048). CONCLUSION: The prophylactic co-vaccination of IL-10 with D2 in pristane-induced lupus ameliorates the renal damage maybe by acting as prophylactic DNA tolerizing therapy.

Contribution of rs3211938 polymorphism at CD36 to glucose levels, oxidized low-density lipoproteins, insulin resistance, and body mass index in Mexican mestizos with type-2 diabetes from western Mexico / Contribución del polimorfismo rs3211938 de CD36 a los niveles de glucosa, las lipoproteínas de baja densidad oxidadas, la resistencia a la insulina y el índice de masa corporal en mestizos mexicanos con diabetes de tipo 2 del occidente de México

Background: type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, insulin resistance (IR), and abnormal fatty acid metabolism in which the CD36 receptor has been implicated in glucose and lipid dysregulation. Objective: to evaluate the contribution of polymorphism CD36 rs3211938 to metabolic profile in T2DM Mexican mestizos from western Mexico. Methods: we included 115 individuals classified as non-T2DM (NT2DM) adults and T2DM patients. Polymorphism CD36 rs3211938 was assessed by PCR-RFLP. Anthropometric and metabolic markers were measured by routine methods, and insulin and oxidized LDL (ox-LDL) were measured by ELISA. Results: the distribution of genotypes between NT2DM and T2DM patients was different (p < 0.001), as was the allele frequency (p = 0.002). NT2DM TG carriers showed the lowest levels of basal insulin and HOMA-IR index in comparison with TT carriers (p < 0.05 and p < 0.05, respectively). In the T2DM group TG carriers showed high BMI, WHR, and weight values (p = 0.001; p ≤ 0.05 and p < 0.05, respectively), and the highest levels of basal glucose, HDL-cholesterol, ox-LDL, and HOMA-IR (p < 0.001; p < 0.001; p < 0.001, and p = 0.001, respectively) in comparison with diabetic TT carriers. Conclusion: the CD36 rs3211938 TG genotype is associated with high levels of glucose, ox-LDL, HDL-cholesterol, and IR, and with increased BMI in Mexican mestizo T2DM patients from western Mexico. (AU)

Antecedentes: la diabetes mellitus de tipo 2 (DMT2) es un trastorno metabólico crónico caracterizado por hiperglucemia, resistencia a la insulina (RI) y metabolismo anormal de ácidos grasos en el que se ha implicado el receptor CD36 en la disregulación de la glucosa y los lípidos. Objetivo: evaluar la contribución del polimorfismo CD36 rs3211938 al perfil metabólico en individuos mestizos mexicanos con DMT2 del occidente de México. Métodos: se incluyeron 115 individuos clasificados en adultos sin DMT2 (NDMT2) y pacientes con DMT2. El polimorfismo CD36 rs3211938 se identificó mediante PCR-RFLP. Las mediciones antropométricas y metabólicas se realizaron mediante métodos de rutina y la insulina y las LDL-oxidadas (LDL-ox) se midieron por ELISA. Resultados: las distribuciones de los genotipos entre los pacientes NDMT2 y DMT2 fueron diferentes (p < 0,001), así como la frecuencia alélica (p = 0,002). Los individuos NDMT2 portadores del genotipo TG mostraron niveles más bajos de insulina basal e índice HOMA-IR en comparación con los portadores del genotipo TT (p < 0,05 y p < 0,05, respectivamente). En el grupo DMT2, los portadores del genotipo TG presentaron valores elevados de índice de masa corporal (IMC), índice cintura-cadera (ICC) y peso (p = 0,001; p < 0,05 y p < 0,05, respectivamente) y niveles más altos de glucosa basal, HDL-colesterol, LDL-ox y HOMA-IR (p < 0,001; p < 0,001; p < 0,001 y p = 0,001, respectivamente) en comparación con los portadores del genotipo TT. Conclusión: el genotipo TG del polimorfismo CD36 rs3211938 se asocia a altos niveles de glucosa, ox-LDL, HDL-colesterol y RI, y a aumentos del IMC en los pacientes mestizos mexicanos con DMT2 del occidente de México. (AU)

Contribution of rs3211938 polymorphism at CD36 to glucose levels, oxidized low-density lipoproteins, insulin resistance, and body mass index in Mexican mestizos with type-2 diabetes from western Mexico.

INTRODUCTION: Background: type-2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, insulin resistance (IR), and abnormal fatty acid metabolism in which the CD36 receptor has been implicated in glucose and lipid dysregulation. Objective: to evaluate the contribution of polymorphism CD36 rs3211938 to metabolic profile in T2DM Mexican mestizos from western Mexico. Methods: we included 115 individuals classified as non-T2DM (NT2DM) adults and T2DM patients. Polymorphism CD36 rs3211938 was assessed by PCR-RFLP. Anthropometric and metabolic markers were measured by routine methods, and insulin and oxidized LDL (ox-LDL) were measured by ELISA. Results: the distribution of genotypes between NT2DM and T2DM patients was different (p < 0.001), as was the allele frequency (p = 0.002). NT2DM TG carriers showed the lowest levels of basal insulin and HOMA-IR index in comparison with TT carriers (p < 0.05 and p < 0.05, respectively). In the T2DM group TG carriers showed high BMI, WHR, and weight values (p = 0.001; p ≤ 0.05 and p < 0.05, respectively), and the highest levels of basal glucose, HDL-cholesterol, ox-LDL, and HOMA-IR (p < 0.001; p < 0.001; p < 0.001, and p = 0.001, respectively) in comparison with diabetic TT carriers. Conclusion: the CD36 rs3211938 TG genotype is associated with high levels of glucose, ox-LDL, HDL-cholesterol, and IR, and with increased BMI in Mexican mestizo T2DM patients from western Mexico.

INTRODUCCIÓN: Antecedentes: la diabetes mellitus de tipo 2 (DMT2) es un trastorno metabólico crónico caracterizado por hiperglucemia, resistencia a la insulina (RI) y metabolismo anormal de ácidos grasos en el que se ha implicado el receptor CD36 en la disregulación de la glucosa y los lípidos. Objetivo: evaluar la contribución del polimorfismo CD36 rs3211938 al perfil metabólico en individuos mestizos mexicanos con DMT2 del occidente de México. Métodos: se incluyeron 115 individuos clasificados en adultos sin DMT2 (NDMT2) y pacientes con DMT2. El polimorfismo CD36 rs3211938 se identificó mediante PCR-RFLP. Las mediciones antropométricas y metabólicas se realizaron mediante métodos de rutina y la insulina y las LDL-oxidadas (LDL-ox) se midieron por ELISA. Resultados: las distribuciones de los genotipos entre los pacientes NDMT2 y DMT2 fueron diferentes (p < 0,001), así como la frecuencia alélica (p = 0,002). Los individuos NDMT2 portadores del genotipo TG mostraron niveles más bajos de insulina basal e índice HOMA-IR en comparación con los portadores del genotipo TT (p < 0,05 y p < 0,05, respectivamente). En el grupo DMT2, los portadores del genotipo TG presentaron valores elevados de índice de masa corporal (IMC), índice cintura-cadera (ICC) y peso (p = 0,001; p < 0,05 y p < 0,05, respectivamente) y niveles más altos de glucosa basal, HDL-colesterol, LDL-ox y HOMA-IR (p < 0,001; p < 0,001; p < 0,001 y p = 0,001, respectivamente) en comparación con los portadores del genotipo TT. Conclusión: el genotipo TG del polimorfismo CD36 rs3211938 se asocia a altos niveles de glucosa, ox-LDL, HDL-colesterol y RI, y a aumentos del IMC en los pacientes mestizos mexicanos con DMT2 del occidente de México.

Presence of anti-TIF-1γ, anti-Ro52, anti-SSA/Ro60 and anti-Su/Ago2 antibodies in breast cancer: a cross-sectional study.

OBJECTIVES: The presence of myositis-specific antibodies (MSA), was recently reported in healthy individuals, cancer patients without myopathy and paraneoplastic rheumatic syndromes. We sought to analyze the frequency of MSA, myositis-associated antibodies (MAA) and autoantibodies related to systemic autoimmune rheumatic diseases (SARD) in breast cancer patients. METHODS: One hundred fifty-two breast cancer patients were enrolled in a cross-sectional study. Clinical information was collected, and autoantibodies tested by immunoprecipitation of an 35S-methionine-labeled K562 cell extract, enzyme-linked immunosorbent assay (ELISA) and Western blot when indicated. All statistical tests were performed using the software statistical package for the social science (SPSS) ver. 19.0 (IBM Inc., NYSE, USA). RESULTS: Autoantibodies associated with SARD: anti-52 kD ribonucleoprotein/tripartite motif-containing 21 (anti-Ro52/TRIM21) was found in 5.9% (9/152), anti-Sjögren syndrome-related antigen A/60 kD ribonucleoprotein antibody (anti-SSA/Ro60) in 3.9% (6/152) and anti-Su antigen/Argonaute 2 antibody (anti-Su/Ago2) in 2.6% (4/152). Meanwhile, anti-transcription intermediary factor-1γ (anti-TIF-1γ, p155/140) antibody was positive in 2 cases and anti-polymyositis/scleroderma antibody was detected in one case. As a whole, 14.47% (22/152) of breast cancer patients showed autoantibodies associated with SARD. These specific autoantibodies were not associated with the presence of rheumatic diseases except one rheumatoid arthritis patient positive for anti-Ro52/TRIM21. CONCLUSIONS: Autoantibodies to TIF-1γ were found in two patients with breast cancer without dermatomyositis (DM). More common specificities were autoantibodies anti-SSA/Ro60, anti-Ro52/TRIM21 and anti-Su/Ago2. More studies are needed in order to establish the biological meaning of the presence of SARD-associated autoantibodies in breast cancer.

Downregulation of hippocampal NR2A/2B subunits related to cognitive impairment in a pristane-induced lupus BALB/c mice.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is associated with learning and memory deficit. Murine model of lupus induced by pristane in BALB/c mice is an experimental model that resembles some clinical and immunological SLE pathogenesis. Nevertheless, there is no experimental evidence that relates this model to cognitive dysfunction associated with NR2A/2B relative expression. To evaluate cognitive impairment related to memory deficits in a murine model of lupus induced by pristane in BALB/c mice related to mRNA relative expression levels of NR2A/2B hippocampal subunits in short and long-term memory task at 7 and 12 weeks after LPS exposition in a behavioral test with the use of Barnes maze. A total of 54 female BALB/c mice 8-12 weeks old were included into 3 groups: 7 and 12 weeks using pristane alone (0.5 mL of pristane) by a single intraperitoneal (i.p.) injection. A control group (single i.p. injection of 0.5 mL NaCl 0.9%) and pristane plus LPS exposure using single i.p. pristane injection and LPS of E. coli O55:B5, in a dose of 3mg/kg diluted in NaCl 0.9% 16 weeks post-pristane administration. To determine cognitive dysfunction, mice were tested in a Barnes maze. Serum anti-Sm antibodies and relative expression of hippocampal NR2A/2B subunits (GAPDH as housekeeping gene) with SYBR green quantitative reverse transcription polymerase chain reaction and 2-ΔΔCT method were determined in the groups. Downregulation of hippocampal NR2A subunit was more evident than NR2B in pristane and pristane+LPS at 7 and 12 weeks of treatment and it is related to learning and memory disturbance assayed by Barnes maze. This is the first report using the murine model of lupus induced by pristane that analyzes the NMDA subunit receptors, finding a downregulation of NR2A subunit related to learning and memory disturbance being more evident when they were exposed to LPS.

Evaluación clínica y ultrasonográfica de la glándula tiroides en pacientes con artritis reumatoide.

Introducción: Los pacientes con artritis reumatoide pueden desarrollar enfermedad tiroidea autoinmune (ETA), cuyo diagnóstico clínico puede ser difícil debido a que ambas comparten síntomas como artralgias, mialgias, rigidez matutina o fatiga. Objetivo: Determinar la prevalencia de ETA en pacientes con artritis reumatoide. Método: Estudio transversal que incluyó 78 pacientes con artritis reumatoide y 81 controles clínicamente sanos pareados por edad y sexo. A ambos grupos se realizó cuantificación de anticuerpos antitiroideos, pruebas de función tiroidea, ultrasonido y biopsia de glándula tiroides cuando la puntuación de Thyroid Imaging Reporting and Data System (TIRADS) fue ≥ 4. Resultados: 24.4 % de los pacientes con artritis reumatoide presentó hipotiroidismo (p = 0.003) y altos títulos de anticuerpos antitiroideos versus controles clínicamente sanos; 53 % de los ultrasonidos tiroideos resultó normal en pacientes hipotiroideos; en pacientes con artritis reumatoide positivos para anticuerpos antitiroideos se encontró perfusión incrementada en 40 %. Los casos clasificados como TIRADS 4 fueron enviados a aspiración, con resultado histopatológico benigno. Conclusiones: Se demostró el valor clínico agregado de la evaluación tiroidea en pacientes con artritis reumatoide, conforme a la prevalencia de hipotiroidismo subclínico, positividad de anticuerpos antitiroideos y anomalías en el ultrasonido independientes de la función tiroidea normal o alterada. Introduction: Patients with rheumatoid arthritis can develop autoimmune thyroid disease (ATD), the clinical diagnosis of which can be difficult because both entities share symptoms such as arthralgia, myalgia, morning stiffness or fatigue. Objective: To determine the prevalence of ATD in patients with rheumatoid arthritis. Method: Cross-sectional study that included 78 patients with rheumatoid arthritis and 81 clinically healthy controls matched by age and gender. Both groups underwent anti-thyroid antibodies quantification, thyroid function tests, thyroid ultrasound and thyroid gland biopsy when the Thyroid Imaging Reporting and Data System (TIRADS) score was ≥ 4. Results: Hypothyroidism was found in 24.4% of patients with rheumatoid arthritis (p = 0.003), as well as high titers of anti-thyroid antibodies versus clinically healthy controls; 53% of thyroid ultrasounds were normal in hypothyroid patients, and increased perfusion was found in 40% of rheumatoid arthritis patients who tested positive for anti-thyroid antibodies. Cases classified as TIRADS 4 underwent aspiration with benign histopathological results. Conclusions: Thyroid assessment added clinical value was demonstrated in patients with rheumatoid arthritis, according to the prevalence of subclinical hypothyroidism, anti-thyroid antibodies positivity and ultrasound abnormalities, regardless of normal or altered thyroid function.

Potential Chronotherapeutic Optimization of Antimalarials in Systemic Lupus Erythematosus: Is Toll-Like Receptor 9 Expression Dependent on the Circadian Cycle in Humans?

Toll-like receptor 9 (TLR9) belongs to the group of endosomal receptors of the innate immune system with the ability to recognize hypomethylated CpG sequences from DNA. There is scarce information about TLR9 expression and its association with the circadian cycle (CC). Different patterns of TLR9 expression are regulated by the CC in mice, with an elevated expression at Zeitgeber time 19 (1:00 a.m.); nevertheless, we still need to corroborate this in humans. In systemic lupus erythematosus (SLE), the inhibitory effect of chloroquine (CQ) on TLR9 is limited. TLR9 activation has been associated with the presence of some autoantibodies: anti-Sm/RNP, anti-histone, anti-Ro, anti-La, and anti-double-stranded DNA. Treatment with CQ for SLE has been proven to be useful, in part by interfering with HLA-antigen coupling and with TLR9 ligand recognition. Studies have shown that TLR9 inhibitors such as antimalarial drugs are able to mask TLR9-binding sites on nucleic acids. The data presented here provide the basic information that could be useful for other clinical researchers to design studies that will have an impact in achieving a chronotherapeutic effect by defining the ideal time for CQ administration in SLE patients, consequently reducing the pathological effects that follow the activation of TLR9.

Anti-Cyclic Citrullinated Peptide Antibodies and Severity of Interstitial Lung Disease in Women with Rheumatoid Arthritis.

OBJECTIVE: To evaluate whether serum titers of second-generation anticyclic citrullinated peptide antibodies (anti-CCP2) are associated with the severity and extent of interstitial lung disease in rheumatoid arthritis (RA-ILD). METHODS: In across-sectional study, 39 RA-ILD patients confirmed by high-resolution computed tomography (HRCT) were compared with 42 RA without lung involvement (RA only). Characteristics related to RA-ILD were assessed in all of the patients and serum anti-CCP2 titers quantified. RESULTS: Higher anti-CCP2 titers were found in RA-ILD compared with RA only (medians 77.9 versus 30.2 U/mL, P < 0.001). In the logistic regression analysis after adjustment for age, disease duration (DD), smoke exposure, disease activity, functioning, erythrocyte sedimentation rate, and methotrexate (MTX) treatment duration, the characteristics associated with RA-ILD were higher anti-CCP2 titers (P = 0.003) and + RF (P = 0.002). In multivariate linear regression, the variables associated with severity of ground-glass score were anti-CCP2 titers (P = 0.02) and with fibrosis score DD (P = 0.01), anti-CCP2 titers (P < 0.001), and MTX treatment duration (P < 0.001). CONCLUSIONS: Anti-CCP2 antibodies are markers of severity and extent of RA-ILD in HRCT. Further longitudinal studies are required to identify if higher anti-CCP2 titers are associated with worst prognosis in RA-ILD.

Serum levels of anticyclic citrullinated peptide antibodies, interleukin-6, tumor necrosis factor-α, and C-reactive protein are associated with increased carotid intima-media thickness: a cross-sectional analysis of a cohort of rheumatoid arthritis patients without cardiovascular risk factors.

UNLABELLED: The main cause of death in rheumatoid arthritis (RA) is cardiovascular events. We evaluated the relationship of anticyclic citrullinated peptide (anti-CCP) antibody levels with increased carotid intima-media thickness (cIMT) in RA patients. METHODS: Forty-five anti-CCP positive and 37 anti-CCP negative RA patients, and 62 healthy controls (HC) were studied. All groups were assessed for atherogenic index of plasma (AIP) and cIMT. Anti-CCP, C-reactive protein (CRP), and levels of tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The anti-CCP positive RA patients showed increased cIMT compared to HC and anti-CCP negative (P < 0.001). Anti-CCP positive versus anti-CCP negative RA patients, had increased AIP, TNFα and IL-6 (P < 0.01), and lower levels of high density lipoprotein cholesterol (HDL-c) (P = 0.02). The cIMT correlated with levels of anti-CCP (r = 0.513, P = 0.001), CRP (r = 0.799, P < 0.001), TNFα (r = 0.642, P = 0.001), and IL-6 (r = 0.751, P < 0.001). In multiple regression analysis, cIMT was associated with CRP (P < 0.001) and anti-CCP levels (P = 0.03). CONCLUSIONS: Levels of anti-CCP and CRP are associated with increased cIMT and cardiovascular risk supporting a clinical role of the measurement of cIMT in RA in predicting and preventing cardiovascular events.

Low levels of CD36 in peripheral blood monocytes in subclinical atherosclerosis in rheumatoid arthritis: a cross-sectional study in a Mexican population.

UNLABELLED: Patients with rheumatoid arthritis (RA) have a higher risk for atherosclerosis. There is no clinical information about scavenger receptor CD36 and the development of subclinical atherosclerosis in patients with RA. The aim of this study was to evaluate the association between membrane expression of CD36 in peripheral blood mononuclear cells (PBMC) and carotid intima-media thickness (cIMT) in patients with RA. METHODS: We included 67 patients with RA from the Rheumatology Department of Hospital Civil "Dr. Juan I. Menchaca," Guadalajara, Jalisco, Mexico. We evaluated the cIMT, considering subclinical atherosclerosis when >0.6 mm. Since our main objective was to associate the membrane expression of CD36 with subclinical atherosclerosis, other molecules related with cardiovascular risk such as ox-LDL, IL-6, and TNFα were tested. RESULTS: We found low CD36 membrane expression in PBMC from RA patients with subclinical atherosclerosis (P < 0.001). CD36 mean fluorescence intensity had negative correlations with cIMT (r = -0.578, P < 0.001), ox-LDL (r = -0.427, P = 0.05), TNFα (r = -0.729, P < 0.001), and IL-6 (r = -0.822, P < 0.001). CONCLUSION: RA patients with subclinical atherosclerosis showed low membrane expression of CD36 in PBMC and increased serum proinflammatory cytokines. Further studies are needed to clarify the regulation of CD36 in RA.