Association of c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic and disease risk in systemic lupus erythematosus patients: A cross-sectional study.

Systemic lupus erythematosus (SLE) patients present a high prevalence of cardiometabolic risk, associated with worse clinical manifestations and mortality. Folate, an essential micronutrient that participates in vital immune cellular functions, could positively affect the cardiometabolic and disease risk in SLE, through the methylenetetrahydrofolate reductase (MTHFR) enzyme, which participates in the folate metabolism, where single nucleotide variants (SNVs) have been described as a potential genetic risk factor for SLE. The aim of this study was to determine the association of the c.+677 C>T (rs1801133) and c.+1298 A>C (rs1801131) MTHFR genetic variants with cardiometabolic risk and clinical disease variables in SLE patients. A case-control study was conducted on 394 unrelated Mexican-mestizo women: 199 with SLE according to the 1997 SLE-ACR criteria and 196 control subjects (CS). Folic acid and homocysteine levels were evaluated by immunoassays. Genotyping of MTHFR genetic variants was carried out by allelic discrimination. No significant differences were found for folic acid (p = .15) and homocysteine serum levels (p = .59) between groups. According to the CC c.+677 MTHFR genotype, this was associated with low cardiovascular disease (CVD) risk by the Castelli index (OR = 0.42; p = .03) in SLE patients. The TC (OR = 1.3; p = .03) and the TA (OR = 1.6; p < .01) haplotypes from c.+677 C>T plus c.+1298 MTHFR were associated with SLE risk, while the CC MTHFR haplotype (OR = 0.5; p = .01) was found as a non-risk factor for the disease. In conclusion, the TC and the TA MTHFR haplotypes are associated with disease risk; meanwhile, the CC c.+677 MTHFR genotype confers lower cardiometabolic risk in Mexican-mestizo SLE patients.

Relationship of serum and dietary vitamin D with high cardiometabolic risk in Mexican systemic lupus erythematosus patients: A cross-sectional study.

Objetive: Serum and dietary vitamin D could influence clinical disease activity and cardiometabolic outcomes in systemic lupus erythematosus (SLE). This study aimed to assess the relationship of serum and dietary vitamin D with cardiometabolic risk in Mexican SLE patients and healthy subjects (HS).Methods: 224 SLE patients and 201 HS were included in this cross-sectional study. Serum calcidiol was measured using a competitive enzyme-linked immunosorbent assay (ELISA). Vitamin D dietary intake was assessed by collecting three 24h food records. Dietary patterns (DPs) were identified using principal component analysis (PCA). Cardiometabolic status was analyzed through biochemical measurements and cardiometabolic indexes.Results: Calcidiol deficiency (<20 ng/mL) was associated with 1.66-fold higher risk of excess weight by body mass index (BMI) (≥25 kg/m2) (p = .02), 2.25-fold higher risk to low high-density lipoprotein-cholesterol (HDL-C) (<40 mg/dL) (p < .001), and 1.74-fold higher risk to high triglycerides (TG) ≥150 mg/dL (p = .02). Inadequate vitamin D dietary intake was associated with 1.92-fold higher risk of presenting non-healthy waist circumference (WC) (>80 cm) (p < .01), 2.05-fold higher risk of android waist to hip ratio (WHR ≥85) (p < .01), and 1.72-fold higher risk to excess weight (p = .02). Non-adherence to a DP rich in vitamin D food sources was associated with higher WC, WHR, triglycerides, and lower high-density lipoprotein-cholesterol (HDL-C); furthermore, in HS, non-adherence to the DP rich in vitamin D food sources provided 2.11-fold higher risk to calcidiol deficiency.In Cconclusion: A pattern of Calcidiol deficiency, inadequate vitamin D dietary intake, and non-adherence to a DP rich in vitamin D food sources was related to high cardiometabolic risk in SLE patients and HS.

Aberrant B-cell activation and B-cell subpopulations in rheumatoid arthritis: analysis by clinical activity, autoantibody seropositivity, and treatment.

Few studies analyze the role of B-cell subpopulations in rheumatoid arthritis (RA) pathophysiology. Therefore, this study aimed to analyze the differences in B-cell subpopulations and B-cell activation according to disease activity, RA subtype, and absence of disease-modifying antirheumatic drugs (DMARDs) therapy. These subgroups were compared with control subjects (CS). One hundred and thirty-nine subjects were included, of which 114 were RA patients, and 25 were controls. Patients were divided into 99 with seropositive RA, 6 with seronegative RA, and 9 without DMARDs. The patients with seropositive RA were subclassified based on the DAS28 index. A seven-color multicolor flow cytometry panel was used to identify B-cell immunophenotypes and cell activation markers. There were no changes in total B-cell frequencies between RA patients and controls. However, a lower frequency of memory B cells and pre-plasmablasts was observed in seropositive RA compared to controls (P < 0.0001; P = 0.0043, respectively). In contrast, a higher frequency of mature B cells was observed in RA than in controls (P = 0.0002). Among patients with RA, those with moderate activity had a higher percentage of B cells (P = 0.0021). The CD69+ marker was increased (P < 0.0001) in RA compared to controls, while the CD40+ frequency was decreased in patients (P < 0.0001). Transitional, naïve, and double-negative B-cell subpopulations were higher in seronegative RA than in seropositive (P < 0.01). In conclusion, in seropositive and seronegative RA patients, there are alterations in B-cell activation and B-cell subpopulations, independently of clinical activity and DMARDs therapy.

BAFFR expression in circulating T follicular helper (CD4+CXCR5+PD-1+) and T peripheral helper (CD4+CXCR5-PD-1+) cells in systemic lupus erythematosus.

BACKGROUND: Circulating T follicular helper (cTfh) and T peripheral helper (Tph) subpopulations are shown to be higher in systemic lupus erythematosus (SLE) patients and have been involved in promoting extrafollicular B cell responses. However, a possible association with the B cell activating factor (BAFF), a cytokine mainly related to B cell responses and disease activity in SLE, has not been investigated. Therefore, this study aimed to evaluate the association of cTfh and Tph subpopulations with the BAFF system expression and clinical activity in SLE patients. METHODS: This study included 43 SLE patients and 12 healthy subjects (HS). The identification of cTfh (CD4+CXCR5+PD-1+), Tph (CD4+CXCR5-PD-1+) cells, expression of membrane-bound BAFF (mBAFF), BAFFR, TACI, BCMA, and intracellular IL-21 was performed by flow cytometry. Serum levels of IL-21, CXCL13, and BAFF were analyzed using ELISA. The SLEDAI-2K score was used to evaluate disease activity in SLE patients. RESULTS: Compared with HS, SLE patients showed a significantly increased percentage of cTfh and Tph cells, higher in patients with clearly active disease. SLE patients had markedly higher IL-21-producing cTfh and Tph cells than HS. Both subpopulations were positively correlated with the disease activity in SLE patients. Tph cells were negatively correlated with CD19+CXCR5+ B cells and positively correlated with CD19+CXCR5- B cells. A low expression of mBAFF and their receptors TACI and BCMA was found on cTfh and Tph cells in SLE patients and HS. However, SLE patients with clearly active disease showed decreased expression of BAFFR on cTfh and Tph subpopulations than patients with mildly active/nonactive disease. Serum IL-21, CXCL13, and BAFF levels were higher in SLE patients than in HS. Levels of CXCL13 were correlated with disease activity. Non-significant correlations were observed among T cell subpopulations and IL-21, CXCL13, and BAFF levels. CONCLUSIONS: This study emphasizes the importance of cTfh and Tph cells in SLE pathogenesis. Besides the importance of IL-21, our results suggest that BAFFR could play a role in cTfh and Tph subpopulations in the autoimmunity context.

Nutritional, biochemical, and clinical determinants of hyperuricemia in systemic lupus erythematosus patients: Relationship with clinical and renal disease activity.

Systemic lupus erythematosus (SLE) is the prototypical autoimmune disease considered as an independent risk factor for mortality by cardiovascular disease. Currently, uric acid is described as a novel biomarker associated with cardiometabolic risk. However, nutritional and serum determinants that influence hyperuricemia development in autoimmune diseases have not been fully elucidated. This study aimed to assess the nutritional, biochemical, and cardiometabolic determinants of hyperuricemia and its relationship with clinical variables in SLE patients. A cross-sectional study was conducted in 167 SLE patients and 195 control subjects (CS). Nutrient intake, anthropometry, biochemical, and cardiometabolic indexes were evaluated. In SLE patients, adequate protein (OR = 0.4; p = 0.04) and carbohydrate (OR = 0.2; p = 0.01) intakes were associated with a lower risk of hyperuricemia. SLE patients with hyperuricemia presented a higher risk of clinical (OR = 2.2; p = 0.03) and renal activity (OR = 3.4; p < 0.01), as well as triglycerides ≥150 mg/dL (OR = 3.6; p < 0.01), hs-CRP ≥1 mg/L (OR = 3.1; p < 0.01), Kannel score ≥3 (OR = 2.5; p = 0.02), and BMI ≥25 kg/m2 (OR = 2.2; p = 0.02). Oppositely, serum levels of HDL-C ≥40 mg/dL (OR = 0.2; p < 0.01) were associated with a lower risk of hyperuricemia. According to the pharmacotherapy administered, prednisone treatment was associated with a high risk of hyperuricemia (OR = 4.7; p < 0.001). In contrast, the hydroxychloroquine treatment was associated with a lower risk of hyperuricemia (OR = 0.4; p = 0.02). In conclusion, SLE patients with hyperuricemia presented a high risk of clinical and renal activity as well as worse cardiometabolic status. Notably, an adequate intake of protein, carbohydrates, healthy HDL-C serum levels, and hydroxychloroquine treatment could be determinants of lower risk of hyperuricemia.

ICOS Gene Polymorphisms (IVS1 + 173 T/C and c. 1624 C/T) in Primary Sjögren's Syndrome Patients: Analysis of ICOS Expression.

Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, which affects exocrine glands. T cell activation is a trigger mechanism in the immune response. Hyperreactivity of T cells and antibody production are features in pSS. ICOS can be critical in the pathogenesis of pSS. Methods: A total of 134 pSS patients and 134 control subjects (CS) were included. Genotyping was performed by PCR-RFLP. ICOS mRNA expression was quantified by real-time PCR, and CD4+ ICOS+ T cells were determined by flow cytometry. Results: The ICOS IVS1 + 173 T>C polymorphisms were not associated with susceptibility to pSS (p = 0.393, CI = 0.503−1.311). However, the c.1624 C>T polymorphism was associated with a reduction in the risk of development of pSS (p = 0.015, CI = 0.294−0.884). An increase in ICOS mRNA expression in patients was observed (3.7-fold). Furthermore, pSS patients showed an increase in membranal-ICOS expression (mICOS). High expression of mICOS (MFI) was associated with lymphocytic infiltration. Conclusions: The IVS1 + 173 polymorphism is not a genetic marker for the development of pSS, while c.1624 T allele was associated with a low risk. However, elevated mICOS expression in pSS patients with high lymphocytic infiltration was found. ICOS may have an important role in the immunopathogenesis of pSS and should be analyzed in T cell subsets in pSS patients as a possible disease marker.

Association of cardiometabolic risk status with clinical activity and damage in systemic lupus erythematosus patients: A cross-sectional study.

Cardiometabolic status is a key factor in mortality by cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). This study evaluated the association of cardiometabolic risk status with clinical activity and damage in SLE patients. A cross-sectional study was conducted in 158 SLE patients and 123 healthy subjects (HS). Anthropometry, glucose, hs-CRP, lipid profile, oxLDL, sCD36, anti-oxLDL antibodies, and cardiometabolic indexes were evaluated. SLE patients had dyslipidemia, higher sCD36, anti-oxLDL antibodies, hs-CRP, and risk (OR > 2) to present Castelli score ≥ 4.5, HDL-C < 40 mg/dL and LDL-C ≥ 100 mg/dL. Disease evolution time was correlated with glucose and BMI, damage with TG, and clinical activity with TG, TG/HDL-C ratio, and Kannel index. Active SLE patients had risk (OR > 2) to present a Castelli score ≥ 4.5, Kannel score ≥ 3, TG/HDL-C ratio ≥ 3 and HDL-C < 40 mg/dL. In conclusion, SLE patients have high cardiometabolic risk to CVD related to disease evolution time, and clinical activity.

Metabolic syndrome in rheumatoid arthritis patients: Relationship among its clinical components.

BACKGROUND: Metabolic syndrome (MetS) prevalence in rheumatoid arthritis (RA) patients is known to vary considerably across the world. This study aimed to determine the prevalence of MetS in RA patients from western Mexico and to analyze the interrelation of the MetS components with the clinical variables of RA. METHODS: This case-control study included 216 RA patients and 260 control subjects (CS). MetS prevalence was determined according to the NCEP/ATP III and the Latin American Consensus of the Latin American Diabetes Association (ALAD) criteria. RESULTS: MetS was observed in 30.6% RA patients and 33.3% of controls (p > 0.05) according to NCEP/ATP III and 28.7% in RA patients and 31.1% for controls using ALAD criteria. Total cholesterol, LDL-C, and Castelli's I-II indexes were lower in RA (p < 0.001) than in CS. The RA patients with MetS had more swollen joints than those without MetS (p = 0.018). In RA patients with MetS, DAS-28 score correlated with smoking index (rho = 0.4601, p = 0.0004) and VLDL-C (rho = 0.3108, p = 0.0056); similarly, rheumatoid factor (RF) correlated with age (rho = 0.2031, p = 0.0027), smoking index (rho = 0.3404, p < 0.0001), triglycerides (rho = 0.1958, p = 0.0039), and VLDL-C (rho = 0.1761, p = 0.0162). CONCLUSIONS: The MetS prevalence in RA patients from western Mexico is not higher than controls; however, in RA patients with MetS, some inflammatory markers are associated with MetS components; thus, the control of MetS in RA could be beneficial to regulate disease activity.

The Novel Role of MIF in the Secretion of IL-25, IL-31, and IL-33 from PBMC of Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune inflammatory joint disease with complex pathogenesis associated with cytokine dysregulation. Macrophage migration inhibitory factor (MIF) plays a role in systemic inflammation and joint destruction in RA and could be associated with the secretion of other immune-modulatory cytokines such as IL-25, IL-31, and IL-33. For the above, our main aim was to evaluate the IL-25, IL-31, and IL-33 secretion from recombinant human MIF (rhMIF)-stimulated peripheral blood mononuclear cells (PBMC) of RA patients. The rhMIF and lipopolysaccharide (LPS) plus rhMIF stimuli promote the secretion of IL-25, IL-31, and IL-33 (p < 0.05) from PBMC of RA patients. The study groups, the different stimuli, and the interaction between both showed a statistically significant effect on the secretion of IL-25 (p < 0.05) and IL-31 (p < 0.01). The study of the effect of the RA patient treatments and their interaction with the effect of stimuli did not show an interaction between them. In conclusion, our study generates new evidence for the role of MIF in the secretion of IL-25, IL-31, and IL-33 and its immunomodulatory effect on RA.

IFN-α kinoid in systemic lupus erythematosus: results from a phase IIb, randomised, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care. METHODS: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering. RESULTS: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable. CONCLUSIONS: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering. TRIAL REGISTRATION NUMBER: NCT02665364.

Functional MIF promoter haplotypes modulate Th17-related cytokine expression in peripheral blood mononuclear cells from control subjects and rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17, and macrophage migration inhibitory factor (MIF). MIF induces IL-17 secretion and MIF promoter polymorphisms influence the expression of selected downstream mediators. The aim of this study was to investigate the relationship between known functional MIF haplotypes and Th17-related cytokine secretion profile in peripheral blood mononuclear cells (PBMC) from control subjects (CS) and RA patients stimulated with lipopolysaccharide (LPS) and recombinant human MIF (rhMIF). The -794 CATT5-8 and -173G > C polymorphisms of the MIF gene were determined by conventional PCR and PCR-RFLP, respectively. The most frequent haplotypes of the MIF polymorphism and PBMC were identified from three subjects homozygous for each haplotype and in both study groups, the PBMC were obtained and stimulated with LPS or rhMIF. The secretion of cytokines related to the Th17 profile was determined by a multiplex immunoassay (MAGPIX). LPS stimulation induced the secretion of cytokines related to the Th17 profile in PBMC from CS and RA patients, whereas, rhMIF only stimulated this response in PBMC from RA patients. PBMC from CS carriers of the MIF 7C haplotype showed more IL-17A, IL-17F, IL-22, and IL-23 secretion than non-7C carriers after LPS stimulation. In the case of rhMIF stimulation, the PBMC from CS carriers of the 7C haplotype secreted more IL-17A and IL-23 than non-7C carriers. In conclusion, genetic variants of the MIF promoter modulate the secretion of cytokines related to the Th17 profile in PBMC from CS inducing a differential response in comparison to PBMC from RA patients.

MIF promotes a differential Th1/Th2/Th17 inflammatory response in human primary cell cultures: Predominance of Th17 cytokine profile in PBMC from healthy subjects and increase of IL-6 and TNF-α in PBMC from active SLE patients.

Macrophage migration Inhibitory Factor (MIF) is a cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive-feedback-loop with proinflammatory cytokines and could perpetuate the inflammatory process in Systemic Lupus Erythematosus (SLE).The aim of this study was to assess the effect of recombinant-human-MIF (rhMIF) on the expression of Th1, Th2 and Th17 cytokines in Peripheral Blood Mononuclear Cells (PBMC) from Healthy Subjects (HS) and SLE patients. The PBMC were isolated from SLE patients classified according to the 1997 SLE ACR criteria and HS donors; all subjects included were women from an unrelated Mexican-Mestizo population. The PBMC isolated were stimulated with rhMIF, LPS and ISO-1 in different combinations; Th1, Th2 and Th17cytokine profiles levels were determined by MAGPIX Bio-plex assay in supernatants from cell cultures. We observed in supernatants of PBMCs from HS treated with rhMIF a predominance of Th17 cytokine profile with an increase of IL-17A, IL-17F and IL-21 versus PBMCs from SLE patients, which showed an inflammatory profile represented by increase of IL-6 cytokine. According to SLE remission/activity presented at enrollment in the study (Mex-SLEDAI index), the PBMC from active SLE patients showed higher levels of TNF-α and IL-6 versus PBMC from remission SLE patients. In conclusion, our results suggest that MIF can induce a differential inflammatory response in physiological and pathological conditions with a predominance of a Th17 cytokine profile in PBMC from HS and an increase in TNF-α and IL-6 expression in PBMC from active SLE patients.

Analysis of Potential Vitamin D Molecule Biomarkers: Association of Calcitriol and Its Hydroxylation Efficiency Ratio with Cardiovascular Disease Risk in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease in which hypovitaminosis D by calcidiol quantification has been associated with disease severity. However, other vitamin D molecules could be implicated in RA pathophysiology and its comorbidities such as cardiovascular disease (CVD), which impacts the severity and mortality of RA patients. This study aimed to assess the relationship between calcidiol, calcitriol, its hydroxylation efficiency ratio, and the soluble vitamin D receptor (sVDR) and clinical and CVD risk variables to propose potential vitamin D molecule biomarkers for RA. A cross-sectional study of females was conducted on 154 RA patients and 201 healthy subjects (HS). Calcidiol, calcitriol, and the sVDR were measured in blood serum, and vitamin D hydroxylation efficiency was estimated using the calcitriol/calcidiol ratio score. CVD risk was calculated by the high-sensitivity C-reactive protein (hs-CRP) cutoff values. Disease activity was evaluated with the Disease Activity Score for 28 standard joints (DAS28-CRP). Results: The hydroxylation efficiency ratio and calcitriol serum levels were higher in RA patients with hypovitaminosis D (p < 0.001). Moreover, RA patients had a higher probability of a high hydroxylation efficiency ratio (OR = 2.02; p = 0.02), calcitriol serum levels (OR = 2.95; p < 0.001), and sVDR serum levels (OR = 5.57; p < 0.001) than HS. This same pattern was also observed in RA patients with high CVD risk using CRP serum levels; they showed a higher hydroxylation efficiency ratio (OR = 4.51; p = 0.04) and higher calcitriol levels (OR = 5.6; p < 0.01). Calcitriol correlates positively with the sVDR (r = 0.21, p = 0.03), CRP (r = 0.28, p < 0.001), and cardiometabolic indexes (p < 0.001) also showed discrimination capacity for CVD risk in RA patients with CRP ≥ 3 mg/L (AUC = 0.72, p < 0.01). In conclusion, hypovitaminosis D in RA patients was characterized by a pattern of a higher hydroxylation efficiency ratio and higher calcitriol and sVDR serum levels. Notably, higher calcitriol serum levels and a higher vitamin D hydroxylation efficiency ratio were associated with higher CVD risk in RA patients.

STAT4 Gene Variant rs7574865 Is Associated with Rheumatoid Arthritis Activity and Anti-CCP Levels in the Western but Not in the Southern Population of Mexico.

Rheumatoid Arthritis (RA) is a multifactorial autoimmune disease. Currently, several genes play an important role in the development of the disease. The objective was to evaluate the association of the STAT4 rs7574865 and rs897200 gene variants with RA susceptibility, DAS28, RF, and anti-CCP in Western and Southern Mexico populations. Genotyping was performed on 476 samples (cases = 240; controls = 236) using the Taqman® system and qPCR probes. Disease activity was assessed using DAS28 and HAQ DI. CRP, ESR, RF, and anti-CCP were determined for clinical assessment. Our study showed there is a statistically significant association with susceptibility to RA for the rs7574865 variant in the Western population for the GT and TT genotypes. The same genotypes also showed a moderate-to-high activity according to DAS28 and positive anti-CCP compared to the control group. This association was not found in the Southern population. This work confirms the association of the rs7574865 variant with RA, as well as a moderate-to-high activity and positive anti-CCP in the Western population but not in the Southern population. No association of the rs897200 variant was found in any of the studied populations.

Association of - 717 A > G (rs2794521) CRP polymorphism with high cardiovascular risk by C-reactive protein in systemic lupus erythematosus patients.

INTRODUCTION: Systemic lupus erythematosus (SLE) is an autoimmune disease where genetic factors have been related to SLE susceptibility and disease severity. CRP polymorphisms have been associated with high C-reactive protein (CRP) serum levels, cardiovascular disease (CVD), and high clinical disease activity in SLE patients; however, the evidence is still inconclusive. OBJECTIVE: This study was aimed to assess the association of the - 717 A > G, - 409 G > A, + 1444 C > T, and + 1846 C > T CRP polymorphisms with genetic susceptibility, clinical disease activity, and CVD risk in Mexican-mestizo SLE patients. METHODS: A comparative cross-sectional study was conducted on 369 unrelated women: 183 with SLE according to the 1997 SLE-ACR criteria and 186 healthy subjects (HS). The clinical disease activity was assessed by the Mex-SLEDAI score; CRP and lipid profile were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. The CRP polymorphisms genotyping was carried out by allelic discrimination. RESULTS: SLE patients with - 717 AA genotype had higher CRP serum levels than SLE carriers of AG and GG genotypes (AA = 5 mg/L vs. AG = 3.2 mg/L vs. GG = 2.4 mg/L; p = 0.01), and the AA genotype was associated with high CVD risk by CRP in SLE patients (OR = 3; CI: 1.2-7.6; p < 0.01). CONCLUSIONS: The - 717 A > G CRP polymorphism is a risk factor for high CRP levels and high CVD risk in Mexican-mestizo SLE patients. Key Points • Cardiovascular disease is one of the major causes of death in SLE patients due to the higher prevalence of traditional and non-traditional cardiovascular risk factors. • C-reactive protein is a liver-derived acute-phase protein suggested as one powerful independent risk predictor factor for cardiovascular disease. • Single nucleotide polymorphisms in CRP have been suggested as genetic susceptibility factors that could modify the SLE pathophysiology outcomes. • Mexican-mestizo SLE patients carrying the -717 A>G CRP AA genotype had 3-fold high cardiovascular disease risk than SLE patients with AG or GG genotypes.

Complementary Therapies and Their Association with Problems in Therapeutic Adherence to Conventional Synthetic DMARDs in Rheumatoid Arthritis: A Cross-Sectional Study.

The use of complementary therapies is highly prevalent among patients with rheumatoid arthritis (RA). Nevertheless, the use of complementary medicine could involve problems in the following of scientifically accepted treatments. To date, there is limited information regarding the association of nonconventional therapies with problems regarding compliance with the treatment. Therefore, the objective of this study was to identify whether the utilization of complementary therapies is associated with a high risk of problems regarding therapeutic adherence to conventional synthetic disease-modifying anti-rheumatic drugs (cs-DMARDs) in RA patients. A survey was performed with RA patients in an outpatient rheumatology clinic in a university hospital; the use of complementary therapies, as well as their type, was identified. To assess problems with therapeutic adherence, we used the four-item Morisky-Green scale. A comprehensive assessment of clinical and therapeutic characteristics was performed. Univariable and multivariable models were performed to identify the risk of problems with therapeutic adherence in users of complementary therapies. In total, 250 RA patients were included; 92% used complementary therapies. Of them, the most frequently used were herbal medicine (65%), homeopathy (64%), and cannabis and its derivatives (51%). In the univariable logistic regression analysis, the factors associated with problems in the therapeutic adherence to cs-DMARDs were age (p = 0.019), the presence of other comorbidities (p = 0.047), and the use of complementary therapies (p = 0.042). After controlling for potential confounders, the use of complementary therapies increased the risk of problems with therapeutic adherence to cs-DMARDs (adjusted OR = 2.84, 95% CI = 1.06-7.63, p = 0.037). We concluded that the use of complementary therapies increases the risk of problems with therapeutic adherence. Therefore, for physicians and healthcare professionals, the early identification of the use of nonconventional therapies in their RA patients is required, followed by a directed discussion with their patients about the risks and benefits to which they could be exposed to complementary therapies.

Vitamin D Receptor (VDR) Genetic Variants: Relationship of FokI Genotypes with VDR Expression and Clinical Disease Activity in Systemic Lupus Erythematosus Patients.

Vitamin D (VD) deficiency is more frequent in systemic lupus erythematosus (SLE) patients than in control subjects (CS); genetic variants in the VD receptor (VDR) could contribute to the clinical disease activity. This study was aimed to determine the association of the VDR variants FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) with susceptibility to the disease, VD status, VDR mRNA expression, and clinical disease activity in SLE patients. A cross-sectional study was conducted in 194 SLE and 196 CS Mexican women. Immunoassays quantified serum calcidiol and calcitriol. Genotyping was performed by allelic discrimination assays and mRNA VDR expression by qPCR. The FokI variant was not in linkage disequilibrium with BsmI, ApaI, and TaqI VDR variants. SLE patient carriers of the TT FokI genotype showed higher clinical disease activity scores. Notably, the mRNA VDR expression was higher in SLE patients vs. CS, in active vs. inactive SLE patients, and in participants of both study groups with vitamin D deficiency, higher calcitriol levels, and TT FokI genotype carriers. In conclusion, the TT FokI VDR genotype was related to high VDR expression and clinical disease activity in systemic lupus erythematosus patients.

Analysis of TNFSF13B polymorphisms and BAFF expression in rheumatoid arthritis and primary Sjögren's syndrome patients.

BACKGROUND: The increased expression of B cell-activating factor (BAFF) has been linked to autoantibody production in autoimmune diseases (ADs). The aim of this study was to investigate the association among TNFSF13B gene (OMIM: 603969) single nucleotide polymorphisms (SNPs), TNFSF13B mRNA, and soluble BAFF (sBAFF) expression in patients with rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS). The diagnostic value of sBAFF also was evaluated by the area under the curve (AUC) of receiver operating characteristic or receptor (ROC) curves. METHODS: Genotypes of the TNFSF13B rs9514827 (-2841 T > C), rs1041569 (-2701 A > T) and rs9514828 (-871 C > T) SNPs were determined by PCR-RFLP assay. TNFSF13B mRNA and sBAFF expression were performed by RT-qPCR and ELISA, respectively. The study included 320 RA patients, 101 pSS patients, and 309 healthy subjects (HS). RESULTS: The rs9514828 T allele and the TAT haplotype were associated with an increased risk to develop RA. In both ADs, the TNFSF13B mRNA levels were increased in comparison with HS. The rs9514828 (-871 C > T) polymorphism was associated with increased gene expression in RA patients. Also, sBAFF levels were higher in both ADs, however pSS patients showed the highest sBAFF levels. sBAFF showed higher diagnostic performance for pSS with an AUC of 0.968, with a similar accuracy of anti-SSA/Ro antibody diagnosis (AUC = 0.974). CONCLUSIONS: Our findings demonstrate that the TNFSF13B rs9514828 (-871 C > T) polymorphism is a risk factor for RA in the western Mexican population. sBAFF levels may be a potential diagnosis biomarker in pSS.

CRP Serum Levels Are Associated with High Cardiometabolic Risk and Clinical Disease Activity in Systemic Lupus Erythematosus Patients.

Systemic lupus erythematosus (SLE) patients have a higher frequency of cardiovascular risk factors such as high C-reactive protein (CRP) levels than the general population. CRP is considered a cardiovascular disease marker that could be related to SLE clinical disease activity. This study aimed to assess the association between CRP with cardiometabolic risk and clinical disease activity in SLE patients. A comparative cross-sectional study was conducted in 176 female SLE patients and 175 control subjects (CS) with median ages of 38 and 33 years, respectively; SLE patients were classified by the 1997 SLE-ACR criteria, and the clinical disease activity by the Mexican-SLEDAI (Mex-SLEDAI). CRP and lipid profile (triglycerides, cholesterol, HDL-C, and LDL-C) were quantified by turbidimetry and colorimetric-enzymatic assays, respectively. SLE patients had higher CRP levels than CS (SLE: 5 mg/L vs. CS = 1.1 mg/L; p < 0.001). In SLE patients, CRP levels ≥ 3 mg/L were associated with a higher risk of cardiometabolic risk status assessed by LAP index (OR = 3.01; IC: 1.04−8.7; p = 0.04), triglycerides/HDL-C index (OR = 5.2; IC: 2.1−12.8; p < 0.001), Kannel index (OR = 3.1; IC: 1.1−8.1; p = 0.03), Castelli index (OR = 6.6; IC: 2.5−17.8; p < 0.001), and high clinical disease activity (OR = 2.5: IC: 1.03−6.2; p = 0.04; and ß coefficient = 5.8; IC: 2.5−9.4; R2 = 0.15; p = 0.001). In conclusion, high CRP levels were associated with high cardiometabolic risk and clinical disease activity in SLE patients.

Therapeutic response to leflunomide in combo therapy and monotherapy is associated to serum teriflunomide (A77 1726) levels.

There is a significant rate of therapeutic failure in rheumatoid arthritis (RA) patients treated with leflunomide (LEF). This study investigates the utility values of teriflunomide levels (A77 1726) in identifying RA patients who remained with moderate or severe disease activity after the treatment with LEF. In this cross-sectional study, we compared: (a) RA patients who achieved a DAS28-ESR ≤ 3.2, and (b) RA patients who maintained a DAS28-ESR > 3.2 after treatment. ROC curves determined the cut-off of A77 1726 with the better performance to identify patients achieving a DAS28-ESR ≤ 3.2. Of the 115 patients treated with LEF, 69 (60%) remained with moderate/severe disease activity and 46 (40%) achieved low disease activity/remission. Higher A77 1726 levels showed a negative correlation with DAS28-ESR (r = - 0.42, p < 0.001) and other parameters of disease activity. We obtained the following utility values with the cut-off of A77 1726 > 10 µg/mL to identify RA patients who achieved a DAS28-ESR ≤ 3.2: sensitivity of 91.31%; specificity of 73.91%; positive predictive value of 70.00%; and negative predictive value of 92.73%. Serum A77 1726 discriminated between RA patients who remained with moderate/severe disease activity despite the treatment with LEF both as monotherapy and LEF as combo therapy.