Risk Factors Associated with Adverse Events Leading to Methotrexate Withdrawal in Elderly Rheumatoid Arthritis Patients: A Retrospective Cohort Study.

Background: Rheumatoid arthritis (RA) in elderly population represents a challenge for physicians in terms of therapeutic management. Methotrexate (MTX) is the first-line treatment among conventional synthetic-disease-modifying anti-rheumatic drugs (cs-DMARDs); however, it is often associated with adverse events (AEs). Therefore, the objective of this study was to identify the incidence and risk factors of MTX discontinuation due to AEs in elderly patients with RA in a long-term retrospective cohort study. Methods: Clinical sheets from elderly RA patients taking MTX from an outpatient rheumatology consult in a university centre were reviewed. To assess MTX persistence, we used Kaplan-Meir curves and Cox regression models to identify the risk of withdrawing MTX due to adverse events. Results: In total, 198 elderly RA patients who reported using MTX were included. Of them, the rates of definitive suspension of MTX due to AEs were 23.0% at 5 years, 35.6% at 10 years and 51.7% at 15 years. The main organs and system involved were gastrointestinal (15.7%) and mucocutaneous (3.0%). Factors associated with withdrawing MTX due to AEs were MTX dose ≥ 15 mg/wk (adjusted HR: 2.46, 95% CI: 1.22-4.96, p = 0.012); instead, the folic acid supplementation was protective for withdrawal (adjusted HR: 0.28, 95% CI: 0.16-0.49, p < 0.001). Conclusions: Higher doses of MTX increase the risk of withdrawals in elderly RA, while folic acid supplementation reduces the risk. Therefore, physicians working in therapeutic management for elderly patients using MTX must focus on using lower MTX doses together with the concomitant prescription of folic acid.

Intravenous Vitamin C as an Add-on Therapy for the Treatment of Sepsis in an Intensive Care Unit: A Prospective Cohort Study.

Background and Objectives: According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis is defined as "life-threatening organ dysfunction caused by a dysregulated host response to infection". The increased presence of free radicals causes an increase in oxidative stress. Vitamin C is an essential water-soluble vitamin with antioxidant activity and immunoregulatory effects that plays a potential role in the treatment of bacterial infections. Our aim was to evaluate the effectiveness of adding vitamin C to the conventional treatment of sepsis to decrease its mortality rate. Materials and Methods: In a prospective cohort study, we included patients with a diagnosis of sepsis and a SOFA score ≥ 9 who were evaluated in an Intensive Care Unit at a secondary-care hospital. According to the intensive care specialist, they were treated using two different strategies: Group 1-patients with sepsis treated with conventional treatment without vitamin C; Group 2-patients with sepsis with the addition of vitamin C to conventional treatment. Results: We included 34 patients with sepsis. The incidence of mortality was 38%, and 47% of patients used vitamin C as an adjuvant to the basic treatment of sepsis. In the basal analyses, patients treated with use of vitamin C compared to patients treated without vitamin C required less use of glucocorticoids (75% vs. 100%, p = 0.039). At follow-up, patients treated without vitamin C had higher mortality than patients treated with vitamin C as an adjuvant for the treatment of sepsis (55.6% vs. 18.8%, p = 0.03). We observed that the use of vitamin C was a protective factor for mortality in patients with sepsis (RR: 0.54, 95% CI: 0.31-0.96, p = 0.03). Conclusions: The use of vitamin C as an adjuvant to treatment decreases the risk of mortality by 46% in patients with sepsis and SOFA ≥ 9 compared to patients treated without vitamin C as an adjuvant to sepsis.

Genetic Variant HLA-DRB1*0403 and Therapeutic Response to Disease-Modifying Therapies in Multiple Sclerosis: A Case-Control Study.

Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.

Prevalence of Latent Tuberculosis Infection (LTBI) in Mexican Patients With Rheumatoid Arthritis (RA).

INTRODUCTION: Patients with rheumatoid arthritis (RA) are at increased risk of developing tuberculosis, and even more so if they receive biological agents. In Mexico, the prevalence of latent tuberculosis infection (LTBI) in RA diagnosed by interferon-gamma release assay (IGRA) is largely unknown. The objective was to determine LTBI prevalence and the associated risk factors in rheumatoid arthritis patients. METHODS: A cross-sectional study was performed comprising 82 patients with RA who attended the rheumatology service at a second-level hospital. Demographic characteristics, comorbidity, Bacillus Calmette-Guerin (BCG) vaccination and smoking history, type of treatment, disease activity and functional capacity were investigated. The Disease Activity Score 28 and the Health Assessment Questionnaire-Disability Index were applied for the estimate of RA activity and functional capacity. Further information was compiled from the electronic medical records and personal interviews. LTBI was determined by QuantiFERON TB Gold Plus (QIAGEN, Germantown, USA). RESULTS: Prevalence of LTBI was 14% (95% confidence interval (CI): 8.6% to 23.9%). Factors associated with LTBI were history of smoking (odds ratio (OR) = 6.63 95% CI 1.01 to 43.3) and disability score (OR = 7.19 95%CI 1.41 to 36.6). CONCLUSIONS: The prevalence of LTBI in Mexican patients with RA was 14%. Our results suggest prevention of smoking and functional incapacity could reduce the risk of LTBI. Further research could endorse our results.

Association of the STAT4 Gene rs7574865 Polymorphism with IFN-γ Levels in Patients with Systemic Lupus Erythematosus.

STAT4 plays an important role in disease activity in SLE patients. STAT4 particles have the capacity to activate the transcription of genes associated with the production of TH1 and Th17 lymphocytes, with a greater predominance on the production of IFN-γ and IL-17A. The presence of variants in STAT4 genes has a major impact on the generation of autoimmunity. However, there are few studies evaluating the impact of these variants on the production of proinflammatory cytokines such as IFN-γ and IL-17A. Methods-A case-control study was carried out with 206 Mexican mestizo patients residing in Western Mexico with a diagnosis of SLE and a group of 80 patients without autoimmune diseases was captured to determine the cut-off point for high IFN-γ levels. In this study, SLE patients with high IFN-γ levels were considered as cases (cut-off > 15.6 pg/mL), and SLE patients with normal IFN-γ levels were considered as controls (cut-off ≤ 15.6 pg/mL). Disease activity was identified from the systemic lupus erythematosus disease activity index (SLEDAI). For the determination of levels of cytokines IFN-γ, IL-12, and IL17A, commercial ELISA kits were used. Genotyping of STAT4 rs7574865 (G > T) was performed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. Results-The patients with SLE had a median age of 45 years with a range of disease duration from 4 years to 18 years; 45.6% were identified as having disease activity. In this sample, we identified a high IFN-γ prevalence of 35.4%. The levels of IFN-γ were higher in the patients with genotype TT than GG. We found that TT genotype conferred a higher risk of high IFN-γ when compared to the GG and GT genotypes. Conclusions-In this study, we identified that the polymorphic genotype TT of the STAT4 gene rs7574865 polymorphism is associated with increased levels of IFN-γ. However, its strength of association was weak, so complementary studies are needed to evaluate its impact on SLE patients.

Influence of the Osteogenomic Profile in Response to Alendronate Therapy in Postmenopausal Women with Osteoporosis: A Retrospective Cohort Study.

BACKGROUND: Postmenopausal osteoporosis is a multifactorial disease. Genetic factors play an essential role in contributing to bone mineral density (BMD) variability, which ranges from 60 to 85%. Alendronate is used as the first line of pharmacological treatment for osteoporosis; however, some patients do not respond adequately to therapy with alendronate. AIM: The aim of this work was to investigate the influence of combinations of potential risk alleles (genetic profiles) associated with response to anti-osteoporotic treatment in postmenopausal women with primary osteoporosis. METHODS: A total of 82 postmenopausal women with primary osteoporosis receiving alendronate (70 mg administered orally per week) for one year were observed. The bone mineral density (BMD; g/cm2) of the femoral neck and lumbar spine was measured. According to BMD change, patients were divided into two groups: responders and non-responders to alendronate therapy. Polymorphic variants in CYP19, ESR1, IL-6, PTHR1, TGFß, OPG and RANKL genes were determined and profiles were generated from the combination of risk alleles. RESULTS: A total of 56 subjects were responders to alendronate and 26 subjects were non-responders. Carriers of the G-C-G-C profile (constructed from rs700518, rs1800795, rs2073618 and rs3102735) were predisposed to response to alendronate treatment (p = 0.001). CONCLUSIONS: Our findings highlight the importance of the identified profiles for the pharmacogenetics of alendronate therapy in osteoporosis.

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.

Myostatin Levels and the Risk of Myopenia and Rheumatoid Cachexia in Women with Rheumatoid Arthritis.

Background: Myostatin is a regulator of muscle size. To date, there have been no published studies focusing on the relation between myostin levels and myopenia in rheumatoid arthritis (RA). Objective: Evaluate the value of serum myostatin as a biomarker of cachexia and low skeletal muscle mass (LSMM) in RA patients, along with whether high serum myostatin is associated to these conditions after adjusting for potential confounders. Methods: This cross-sectional study included 161 female RA patients and 72 female controls. In the RA group, we assessed several potential risk factors for LSMM and rheumatoid cachexia. Dual-energy X-ray absorptiometry was used to quantify the skeletal muscle mass index (SMMI) (considering LSMM ≤ 5.5 kg/m2) and the presence of rheumatoid cachexia (a fat-free mass index ≤ 10 percentile and fat mass index ≥ 25 percentile of the reference population). Serum myostatin concentrations were determined by ELISA. To identify a cut-off for high serum myostatin levels, we performed ROC curve analysis. Multivariable logistic regression analysis was used to identify the risk factors for LSMM and rheumatoid cachexia. The risk was expressed as odds ratios (ORs) and their 95% confidence intervals (95% CIs). Results: Compared to the controls, the RA group had a higher proportion of LSMM and exhibited high serum myostatin levels (p < 0.001). ROC curve analysis showed that a myostatin level ≥ 17 ng/mL was the most efficient cut-off for identifying rheumatoid cachexia (sensitivity: 53%, specificity: 71%) and LSMM (sensitivity: 43%, specificity: 77%). In the multivariable logistic regression, RA with high myostatin levels (≥17 ng/mL) was found to increase the risk of cachexia (OR = 2.79, 95% CI: 1.24-6.29; p = 0.01) and LSMM (OR = 3.04, 95% CI: 1.17-7.89; p = 0.02). Conclusions: High serum myostatin levels increase the risk of LSMM and rheumatoid cachexia. We propose that high myostatin levels are useful biomarkers for the identification of patients in risk of rheumatoid cachexia and myopenia.

Serum irisin concentrations and osteoporotic vertebral fractures in women with rheumatoid arthritis: A cross-sectional study.

ABSTRACT: Irisin stimulates osteoblast differentiation increasing bone mass a decreasing in irisin levels might contribute to osteoporotic fractures in inflammatory diseases. To date, there is controverted whether irisin levels are associated with osteoporotic fractures in rheumatoid arthritis (RA). Therefore, we evaluate the association of serum irisin with osteoporotic Vertebral Fractures (VFs) in women with RA.A total of 148 women with RA was included in the study.Clinical characteristics and risk factors of VFs was evaluated. For measurement of bone mineral density we included the assessment of lumbar spine (AP L1-L4) and Femoral Neck by dual-energy X-ray absorptiometry (DXA). VFs were evaluated by lateral vertebral assessment (LVA) of the dorsal and lumbar regions using X-ray and digital vertebral morphometry by DXA, using the Genant scale. Serum irisin levels were measured by ELISA. A reference group of 97 women with non-rheumatic diseases were included to compare irisin levels.RA patients had a median age of 59 years and 41% had osteoporosis. Seventy three (49%) had VFs. Lower irisin levels were observed in RA patients compared to controls (94 ±â€Š74 vs 135 ±â€Š103, P < .001). Irisin concentrations were lower in RA + VFs than RA non-VFs (74 ±â€Š42 vs 113 ±â€Š92 ng/mL, P = .001). In the multivariable logistic regression analysis the low 50 percentile irisin levels < 73 ng/mL (OR:3.1, 95% CI:1.55-6.2, P = .001), and disease duration of RA (OR:1.04, 95% CI:1.001-1.08, P = .04) were associated with an increase in the risk of VFs.A decrease of irisin levels is associated to VFs in RA. These results are valuable to consider that RA patients with low levels of irisin are in a potential risk of VFs.

Seizures in systemic lupus erythematosus: A scoping review.

Systemic lupus erythematosus is a systemic autoimmune disease that affects the central nervous system, either by direct neuronal damage, injury to brain vessels, or by pathogenic mechanisms indirectly induced by immune mechanisms related to the production and deposition of immune complexes. The prevalence of explicit episodes of seizures among SLE patients, varies from 2 to 8%. In some cases, patients with positivity for antiphospholipid or anti-ß2 glycoprotein antibodies are found to be more prone to exhibit seizures compared to seronegative patients, other subjects at risk are carries of gene abnormalities codifying for ion channels. The exclusion of vasculitis or thrombosis is required for accurate treatment, imaging studies and alternative sequences are mandatory in patients with known SLE who present with a seizure. Several statements regarding SLE-related seizure remain to be decoded. In this scoping review we analyzed published information about prevalence, pathogenesis, clinical characteristics, diagnostic and therapeutic SLE patients that manifest a seizure, our objective is to provide with useful information for prompt diagnosis and individualized treatment.

Assessment of serum macrophage migration inhibitory factor (MIF), adiponectin, and other adipokines as potential markers of proteinuria and renal dysfunction in lupus nephritis: a cross-sectional study.

BACKGROUND: To date, the association of serum macrophage migration inhibitory factor (MIF) and serum adipokines with lupus nephritis is controversial. OBJECTIVE: To assess the utility of serum MIF, leptin, adiponectin and resistin levels as markers of proteinuria and renal dysfunction in lupus nephritis. METHODS: Cross-sectional study including 196 systemic lupus erythematosus (SLE) patients and 52 healthy controls (HCs). Disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Renal SLE involvement was investigated by renal-SLEDAI. MIF, adiponectin, leptin and resistin levels were quantified by ELISA. We assessed the correlations of quantitative variables by Spearman correlation (rs). Multivariable linear regression adjusted the variables associated with the severity of proteinuria. RESULTS: SLE patients had higher MIF (p = 0.02) and adiponectin (p < 0.001) than HCs. Patients with renal SLE involvement (n = 43) had higher adiponectin (19.0 vs 13.3 µg/mL, p = 0.002) and resistin (10.7 vs 8.9 ng/mL, p = 0.01) than patients with non-renal SLE (n = 153). Proteinuria correlated with high adiponectin (r s  = 0.19, p < 0.009) and resistin (r s  = 0.26, p < 0.001). MIF (r s  = 0.27, p = 0.04). Resistin correlated with increased creatinine (r s  = 0.18, p = 0.02). High renal-SLEDAI correlated with adiponectin (r s  = 0.21, p = 0.004). Multiple linear regression showed that elevated adiponectin (p = 0.02), younger age (p = 0.04) and low MIF (p = 0.02) were associated with the severity of proteinuria. Low MIF and high adiponectin levels interacted to explain the association with the severity of proteinuria (R2 = 0.41). CONCLUSIONS: High adiponectin combined with low MIF concentrations int+eract to explain the severity of proteinuria in renal SLE. These findings highlight the relevance of adiponectin, resistin and MIF as markers of LN.

Anti-nucleosome antibodies increase the risk of renal relapse in a prospective cohort of patients with clinically inactive systemic lupus erythematosus.

An important goal in the management of systemic lupus erythematosus (SLE) is the prediction of relapses. This study assesses whether anti-nucleosome antibodies (anti-NCS) increase the risk of renal relapse in inactive SLE. A prospective cohort of 115 patients with inactive SLE (M-SLEDAI ≤ 2) were followed for 12 months to assess the development of relapse (increase of M-SLEDAI ≥ 4) and specific renal flare (renal SLEDAI ≥ 4). At baseline, we identified potential risk factors for relapse, including anti-NCS. At baseline, 18 (16%) of the 115 patients with inactive SLE were anti-NCS positive. At the 12-month follow-up, anti-NCS-positive patients had a higher incidence of renal relapse compared to anti-NCS-negative patients (38.9% vs 13.4%, respectively). In Cox regression analysis, after adjusting for age, disease duration, anti-dsDNA, and immunosuppressive drugs, the presence of anti-NCS positivity at baseline increased the risk of renal relapse (HR: 5.31, 95% CI 2.03-13.92). Nevertheless, there were no differences in the incidence of other relapses in anti-NCS-positive versus anti-NCS-negative. Our results indicate that in inactive SLE, anti-NCS determination can be useful for identifying patients with a higher risk of developing renal relapse. Interestingly, this study identified that continued use of oral immunosuppressive therapy in patients with inactive SLE can reduce the risk of renal relapse.

The Effect of Visceral Abdominal Fat Volume on Oxidative Stress and Proinflammatory Cytokines in Subjects with Normal Weight, Overweight and Obesity.

PURPOSE: The increase of visceral abdominal fat (VAF) and oxidative stress (OS) are independent predictors for cardiovascular risk. This study aimed to determine the association of VAF with proinflammatory cytokines, oxidants, antioxidants, and oxidative damage to DNA in subjects with normal weight, overweight, and obesity. PATIENTS AND METHODS: A cross-sectional study that included 21 men and 71 women who attended for a medical check-up was conducted. Dual-energy X-ray absorptiometry (DXA) was used to measure the VAF volume. ELISA and colorimetric techniques were used for chemical analysis. RESULTS: Low activity of superoxide dismutase (SOD) was found in overweight and obese subjects compared to the normal weight group (p=0.005). In contrast, the activity of glutathione peroxidase (GPx) was higher in the overweight and obesity groups compared to the normal weight subjects (p=0.017). The total antioxidant capacity (TAC) was also increased in the overweight group compared to the normal weight group (p=0.04). According to the volume of VAF, the levels of tumor necrosis factor alfa and interleukin 6 showed no differences between subjects with normal and high VAF. Subjects with high VAF show higher levels of 8-isoprostans compared to normal VAF group (p=0.039). Less concentration of 8-oxoguanine-DNA-N-glycosylase-1 (hOGG1) was found in the high VAF group (p=0.032) compared to the normal VAF subjects. VAF was positively correlated with lipoperoxides (LPO) (r=0.27, p<0.05) and 8-isoprostanes (r=0.25, p<0.05). We also found correlations between oxidative stress markers and anthropometric ratios for intra-abdominal fat. The waist-hip ratio was positively correlated with LPO (r=0.30, p<0.05) and TAC (r=0.24, p<0.05). CONCLUSION: These findings suggest that the predominantly oxidative damage associated with VAF in overweight or obesity is lipoperoxidation and oxidative DNA damage. Alterations in endogenous antioxidant defenses may not be linked to the amount of VAF.

miRNA-24 Gene Sequence, DHFR -829C-T Genotypes, and Methotrexate Response in Mexican Patients with Rheumatoid Arthritis.

AIM: The present study looked for variation in the miRNA-24 sequence, and evaluated the associations between the dihydrofolate reductase (DHFR) gene-829 C-T polymorphism and plasma DHFR concentrations with response to methotrexate (MTX) treatment in Mexican patients with rheumatoid arthritis (RA). METHODS: A total of 135 women with RA were classified as responders (disease activity score [DAS28] <3.2) or nonresponders to MTX (DAS28 > 3.2). We determined the genotype of the patients using the polymerase chain reaction-restriction fragment length polymorphism method. Plasma DHFR enzyme levels and mi-RNA24 sequences were assessed by enzyme-linked immunosorbent assay (ELISA) and Sanger sequencing, respectively. Allelic frequencies and the genotypic distribution of the polymorphism were analyzed by the chi-square test. RESULTS: The genotype frequencies of the DHFR -829C-T polymorphism among responders were 37.0% CC, 52.1% CT, and 10.9% TT and for nonresponders were 33.9% CC, 56.4% CT, and 9.7% TT. No significant differences in genotype frequencies were found between the groups (p = 0.88). The DHFR levels relative to genotype for responders were 6.8 ± 2.7, 6.1 ± 2.7, and 6.5 ± 1.5 ng/mL for CC, CT, and TT, respectively, and for nonresponders were 6.5 ± 2.0, 6.1 ± 3.1, and 7.4 ± 1.8 ng/mL for CC, CT, and TT, respectively. No significant differences were found between the two groups. Similarly, both groups showed no sequence variations in miRNA-24 gene. CONCLUSION: The -829C-T polymorphism of DHFR gene was not associated with response to MTX by RA patients, and no variations were found in the miRNA-24 sequence that might modify the response to treatment or DHFR enzyme levels in a Mexican population with RA.

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.

Serum levels of P-glycoprotein and persistence of disease activity despite treatment in patients with systemic lupus erythematosus.

Around 25% of patients with systemic lupus erythematosus (SLE) could be refractory to conventional therapies. P-glycoprotein expression on cell surface has been implied on drug resistance, however, to date, it is unknown if P-gp serum levels are associated with SLE disease activity. Evaluate the association of serum P-gp levels and SLE with disease activity despite treatment. A cross-sectional study was conducted on 93 female SLE patients, all receiving glucocorticoids at stable doses for the previous 6 months before to baseline. SLE patients were classified into two groups: (a) patients with active disease [SLE disease activity index (SLEDAI) ≥ 3] despite treatment, and (b) patients with inactive disease (SLEDAI < 3) after treatment. Forty-three healthy females comprised the control group. Serum P-gp, anti-DNA, and both anti-nucleosome antibody levels were measured using ELISA. Active-SLE patients despite treatment had higher P-gp levels compared with inactive-SLE after treatment (78.02 ng/mL ± 114.11 vs. 33.75 ng/mL ± 41.11; p = 0.018) or versus reference group subjects (30.56 ng/mL ± 28.92; p = 0.011). P-gp levels correlated with the scores of SLEDAI (r = 0.26; p = 0.01), Mexican-SLEDAI (MEX-SLEDAI) (r = 0.32; p = 0.002), SLICC/ACR damage index (r = 0.47; p < 0.001), and with prednisone doses (r = 0.33; p = 0.001). In the multivariate model, the high P-gp levels were associated with SLICC/ACR score (p = 0.001), and SLEDAI score (p = 0.014). Our findings support a relationship between serum P-gp levels and SLE with disease activity despite treatment, but it requires further validation in longitudinal studies.

Disease Activity Score on 28 Joints and Polypharmacy Are Independent Predictors for Health-Related Quality of Life Evaluated by INCAVISA in Patients With Rheumatoid Arthritis.

OBJECTIVE: The aim of this study was to investigate the main factors associated to a diminished health-related quality of life (HRQoL) evaluated by INCAVISA (Health-Related Quality of Life Inventory for Latin American Patients) in patients with rheumatoid arthritis (RA). METHODS: Female, 18 years or older, RA (American College of Rheumatology 1987 criteria and American College of Rheumatology/European League against Rheumatism 2010 criteria) patients who attended the outpatient rheumatology department of the Hospital Civil "Dr. Juan I. Menchaca," Guadalajara, Mexico, matched with healthy controls were included. Patients with any known comorbidities or treatment with antidepressive drugs were excluded. Trained physicians performed the RA clinical evaluation and INCAVISA. All data were analyzed using SPSS 21.0 software (SPSS Inc, Chicago, IL); P < 0.05 was considered statistically significant. RESULTS: Patients with polypharmacy (≥3 drugs) had a lower HRQoL by INCAVISA. The number of drugs, total comorbidities, and DAS-28 (Disease Activity Score on 28 Joints) were negatively correlated with total INCAVISA. In multivariate analysis, DAS-28 and polypharmacy were independent predictors for a negative perception of HRQoL evaluated by INCAVISA in RA patients. CONCLUSIONS: Disease activity and disability secondary to RA have a negative impact in the HRQoL. Other factors such as the number of drugs prescribed to these patients have been shown to be important for the negative perception of their HRQoL evaluated by INCAVISA.

Serum leptin and serum leptin/serum leptin receptor ratio imbalance in obese rheumatoid arthritis patients positive for anti-cyclic citrullinated peptide antibodies.

INTRODUCTION: Leptin has a prominent role in the development and maintenance of acute and chronic inflammatory states such as rheumatoid arthritis (RA) and obesity. Nevertheless, the association of serum leptin (sLep) and soluble leptin receptor (sLepR) in RA pathogenesis has not been clarified. The purpose of this study was to evaluate the association of sLep, sLepR and leptin production indexes such as sLep/fat mass ratio with clinical activity and biomarkers and anti-cyclic citrullinated peptide (anti-CCP) antibodies in RA compared with body mass index (BMI) matched control subjects. METHODS: We included 64 RA patients and 66 controls matched for age, gender and BMI. Subjects were evaluated for BMI, fat mass distribution, sLep, sLepR, sLep/fat mass ratio and sLepR/fat mass ratio. Patients were evaluated for clinical activity and anti-CCP antibodies. RESULTS: We found two or three fold increased sLep levels, sLep/sLepR ratio and sLep/fat mass ratio in obese anti-CCP positive RA patients vs. CONTROLS: Partial correlations showed that anti-CCP antibodies were correlated with sLep/fat mass ratio (partial r = 0.347, P = 0.033) after adjustment for age, subcutaneous adipose tissue and fat mass. CONCLUSIONS: In preobese and obese RA patients there is and increased production of sLep according to anti-CCP positivity. This phenomenon suggests there is an additive effect of chronic inflammation resulting from RA and obesity in which leptin favors the humoral response against citrullinated proteins. In summary, the data observed in our study suggests sLep could be a surrogate marker of chronicity and humoral immunity in RA in the presence of obesity.

Osteoprotegerin Polymorphisms in a Mexican Population with Rheumatoid Arthritis and Generalized Osteoporosis: A Preliminary Report.

Bone disease in rheumatoid arthritis (RA) is a complex phenomenon where genetic risk factors have been partially evaluated. The system formed by receptor activator for nuclear factor-κB (RANK), receptor activator for nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG): RANK/RANKL/OPG is a crucial molecular pathway for coupling between osteoblasts and osteoclasts, since OPG is able to inhibit osteoclast differentiation and activation. We aim to evaluate the association between SNPs C950T (rs2073617), C209T (rs3134069), T245G (rs3134070) in the TNFRSF11B (OPG) gene, and osteoporosis in RA. We included 81 women with RA and 52 healthy subjects in a cross-sectional study, genotyped them, and measured bone mineral density (BMD) at the lumbar spine and the femoral neck. Mean age in RA was 50 ± 12 with disease duration of 12 ± 8 years. According to BMD results, 23 (33.3%) were normal and 46 (66.7%) had osteopenia/osteoporosis. We found a higher prevalence of C allele for C950T SNP in RA. Polymorphisms C209T and T245G did not reach statistical significance in allele distribution. Further studies including patients from other regions of Latin America with a multicenter design to increase the sample size are required to confirm our findings and elucidate if C950T SNP could be associated with osteoporosis in RA.

Influence of Anti-TNF and Disease Modifying Antirheumatic Drugs Therapy on Pulmonary Forced Vital Capacity Associated to Ankylosing Spondylitis: A 2-Year Follow-Up Observational Study.

OBJECTIVE: To evaluate the effect of anti-TNF agents plus synthetic disease modifying antirheumatic drugs (DMARDs) versus DMARDs alone for ankylosing spondylitis (AS) with reduced pulmonary function vital capacity (FVC%). METHODS: In an observational study, we included AS who had FVC% <80% at baseline. Twenty patients were taking DMARDs and 16 received anti-TNF + DMARDs. OUTCOME MEASURES: changes in FVC%, BASDAI, BASFI, 6-minute walk test (6MWT), Borg scale after 6MWT, and St. George's Respiratory Questionnaire at 24 months. RESULTS: Both DMARDs and anti-TNF + DMARDs groups had similar baseline values in FVC%. Significant improvement was achieved with anti-TNF + DMARDs in FVC%, at 24 months, when compared to DMARDs alone (P = 0.04). Similarly, patients in anti-TNF + DMARDs group had greater improvement in BASDAI, BASFI, Borg scale, and 6MWT when compared to DMARDs alone. After 2 years of follow-up, 14/16 (87.5%) in the anti-TNF + DMARDs group achieved the primary outcome: FVC% ≥80%, compared with 11/20 (55%) in the DMARDs group (P = 0.04). CONCLUSIONS: Patients with anti-TNF + DMARDs had a greater improvement in FVC% and cardiopulmonary scales at 24 months compared with DMARDs. This preliminary study supports the fact that anti-TNF agents may offer additional benefits compared to DMARDs in patients with AS who have reduced FVC%.