Serum Levels of IFABP2 and Differences in Lactobacillus and Porphyromonas gingivalis Abundance on Gut Microbiota Are Associated with Poor Therapeutic Response in Rheumatoid Arthritis: A Pilot Study.

Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of gut microbiota's bacteria; (2) to evaluate the relationship between the differences in microbial abundance with the serum levels of intestinal fatty-acid binding protein 2 (IFABP2), cytokines, and the response phenotype to csDMARDs therapy in RA. A cross-sectional study was conducted on 23 women diagnosed with RA. The abundance of bacteria in gut microbiota was determined with qPCR. The ELISA technique determined serum levels of IFABP2, TNF-α, IL-10, and IL-17A. We found that the accumulated dose of methotrexate or prednisone is negatively associated with the abundance of Lactobacillus but positively associated with the abundance of Bacteroides fragilis. The Lactobacillus/Porphyromonas gingivalis ratio was associated with the Disease Activity Score-28 for RA with Erythrocyte Sedimentation Rate (DAS28-ESR) (r = 0.778, p = 0.030) and with the levels of IL-17A (r = 0.785, p = 0.027) in the group treated with csDMARD. Moreover, a relation between the serum levels of IFABP2 and TNF-α (r = 0.593, p = 0.035) was observed in the group treated with csDMARD. The serum levels of IFABP2 were higher in patients with secondary non-response to csDMARDs therapy. In conclusion, our results suggest that the ratios of gut microbiota's bacteria and intestinal permeability seems to establish the preamble for therapeutic secondary non-response in RA.

Expression of macrophage migration inhibitory factor and its receptor CD74 in systemic sclerosis.

Macrophage migration inhibitory factor (MIF) has been associated with the pathogenesis of several rheumatic diseases. In systemic sclerosis (SSc) it has been shown that MIF expression is dysregulated in serum and skin. However, the MIF receptor, CD74, has been poorly investigated and its potential role in the pathogenesis of SSc remains unknown. This study aimed to analyze mRNA, tissue, and serum expression of MIF and CD74 in patients with limited (lcSSc) and diffuse (dcSSc) systemic sclerosis. A case-control study in 20 SSc patients and 20 control subjects (CS) from southern México was conducted. MIF and CD74 mRNA expression levels were quantified by real-time PCR, MIF serum levels were measured by an ELISA kit, and MIF and its receptor CD74 were evaluated by immunohistochemistry of skin biopsies. MIF mRNA expression was significantly higher in CS than in SSc patients (p = 0.02), while CD74 showed no differences between patients and CS. MIF serum levels were similar between SSc patients and CS: dcSSc = 3.82 ng/ml, lcSSc = 3.57 ng/ml, and CS = 3.28 ng/ml. In skin biopsies of SSc, MIF and CD74 were enhanced in keratinocytes, while they showed decreased expression in endothelial cells. On the other hand, the staining of CD74 was high in fibroblasts of dcSSc patients. Our findings show MIF and CD74 deregulation at the transcriptional and translational levels in SSc, which might be associated with the proinflammatory process leading to tissue remodeling and excessive fibrosis in SSc.

Autoantibodies to Mi-2 alpha and Mi-2 beta in patients with idiopathic inflammatory myopathy.

OBJECTIVES: The objective of this study was to compare the results obtained from different assays for the detection of anti-Mi-2 antibodies, which are important markers in the diagnosis of DM. METHODS: The study included 82 patients (68 females/14 males), most of whom had DM (n = 57), followed by PM (n = 16) and juvenile DM (n = 9). All samples were tested using a novel particle-based multi-analyte technology (PMAT) (Inova Diagnostics, research use only) in parallel with a line immunoassay (LIA: Euroimmun). To assess clinical specificity for the PMAT assay, a total of 775 disease and healthy controls were tested. RESULTS: 29 samples were positive by at least one test for anti-Mi-2 antibodies. Of those, 24 were Mi-2ß LIA+, five were Mi-2α LIA+ and 23 Mi-2 PMAT+. The comparison shows varying agreement between the different methods (kappa 0.27-0.77). When LIA results were used as reference for receiver operating characteristics analysis, high area under the curve values were found for both PMAT vs LIA Mi-2α and LIA Mi-2ß. When analysing the results in the context of the myositis phenotype, PMAT associated closest with the DM phenotype. In the control group, 3/775 controls (all low levels) were anti-Mi-2+ resulting in a sensitivity and specificity of 28.1% and 99.6%, respectively. CONCLUSION: Overall, good agreement was found between LIA and PMAT for anti-Mi-2 antibodies, which is important for the standardization of autoantibodies. Anti-Mi-2ß antibodies measured by PMAT tend be more highly associated with the clinical phenotype of DM.

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.

Levels of sCD163 in women rheumatoid arthritis: Relationship with cardiovascular risk markers.

AIM: The soluble scavenger receptor differentiation antigen 163 (sCD163), a monocyte/macrophage activation marker, is related to cardiovascular mortality in the general population. This study aimed to evaluate their relationship between serum levels of sCD163 with cardiovascular risk indicators in rheumatoid arthritis (RA). METHODS: A cross-sectional study was performed on 80 women diagnosed with RA. The cardiovascular risks were determined using the lipid profile, metabolic syndrome, and QRISK3 calculator. For the assessment of RA activity, we evaluated the DAS28 with erythrocyte sedimentation rate (DAS28-ESR). The serum levels of sCD163 were determined by the ELISA method. Logistic regression models and receiver operating characteristics (ROC) curve were used to assess the association and predictive value of sCD163 with cardiovascular risk in RA patients. RESULTS: Levels of sCD163 were significantly higher in RA patients with high sensitivity protein C-reactive to HDL-c ratio (CHR)≥0.121 (p=0.003), total cholesterol/HDL-c ratio>7% (p=0.004), LDL-c/HDL-c ratio>3% (p=0.035), atherogenic index of plasma>0.21 (p=0.004), cardiometabolic index (CMI)≥1.70 (p=0.005), and high DAS28-ESR (p=0.004). In multivariate analysis, levels of sCD163≥1107.3ng/mL were associated with CHR≥0.121 (OR=3.43, p=0.020), CMI≥1.70 (OR=4.25, p=0.005), total cholesterol/HDL-c ratio>7% (OR=6.63, p=0.044), as well as with DAS28-ESR>3.2 (OR=8.10, p=0.008). Moreover, levels of sCD163 predicted CHR≥0.121 (AUC=0.701), cholesterol total/HDL ratio>7% (AUC=0.764), and DAS28-ESR>3.2 (AUC=0.720). CONCLUSION: Serum levels of sCD163 could be considered a surrogate of cardiovascular risk and clinical activity in RA.

A community-based study on the prevalence of spondyloarthritis and inflammatory back pain in Mexicans.

BACKGROUND: The prevalence of spondyloarthritis (SpA) varies across populations. In Mexicans, the prevalence of SpA is still unknown. OBJECTIVE: The objective of this study was to determine the prevalence of SpA in the community as well as that of inflammatory back pain (IBP) and ankylosing spondylitis (AS). METHODS: We identified individuals older than 18 years with nontraumatic back pain (BP) in a door-to-door nurse survey using the Community Oriented Program for the Control of Rheumatic Diseases. Then, general physicians and rheumatology fellows selected those likely to have IBP (Berlin criteria). Finally, 2 expert rheumatologists assessed IBP individuals according to clinical data and classification criteria and requested HLA-B27 and radiographic studies to determine the clinical condition of the individual and SpA (European SpA Study Group) classification. RESULTS: The prevalence of BP among 4059 individuals was 14.6% (95% confidence interval [CI], 13.6-15.8). The prevalence of IBP and SpA was 1.3% (95% CI, 1.0-1.7) and 0.6% (95% CI, 0.4-0.9), respectively. Ankylosing spondylitis prevalence was 0.1% (95% CI, 0.02-0.2). Inflammatory back pain and SpA percentage of males and females was similar. The percentage of individuals with IBP according to the 2 experts was lower than that determined by general physicians and rheumatology fellows, but all cases with HLA-B27, radiographic sacroiliitis, SpA, and AS had previous IBP confirmation by the expert. CONCLUSIONS: The prevalence and sex distribution of patients classified with SpA in this community study--as well as that of patients diagnosed with AS--are consistent with those found in recent studies. Expert assessment of individuals with positive responses to questionnaires is relevant for the classification of IBP and SpA.

[Pregnancy and Fallot tetralogy without surgical correction: report of a case]. / Embarazo y tetralogía de Fallot sin corrección quirúrgica Reporte de un caso.

Tetralogy of Fallot is the most common cyanotic congenital heart disease. Women with this condition may become pregnant, and it is important to detect the disease to prevent cardiovascular complications and to reduce maternal and fetal death. The purpose of this paper is to report the case of a pregnant patient with no previous diagnosis of uncorrected tetralogy of Fallot, who reached the end of pregnancy with added diagnoses of severe preeclampsia and HELLP syndrome. For accurate information about the natural history of tetralogy of Fallot it is necessary to review the literature of the past 30 years because there is no recently published series. It is common for patients with tetralogy of Fallot and pregnancy to suffer a gradual increase in the severity of pulmonary stenosis, with exacerbation of symptoms and increased cyanosis. The long-term prognosis is extremely poor in the absence of correction, with a mortality of 10%.

Transforming growth factor beta isoforms and TGF-ßR1 and TGF-ßR2 expression in systemic sclerosis patients.

Systemic sclerosis (SSc) is characterized by chronic inflammation and fibrosis, two processes associated with transforming growth factor ß (TGF-ß) functions. In the present study, we investigated the expression of TGF-ß isoforms in serum and the skin distribution of TGF-ß and two receptors (TGF-ßR1 and TGF-ßR2) and their relationship with some clinical, inflammatory, autoimmune (autoantibodies), and vascular (platelets) biomarkers in SSc patients. A total of 56 SSc patients and 120 control subjects (CS) were included. The serum levels of TGF-ß isoforms were quantified by immunoassay with magnetic microspheres, and the skin biopsies were processed by immunohistochemistry. The soluble levels of the three active TGF-ß isoforms were lower in SSc patients than in CS (p < 0.0001). However, sTGF-ß1 and sTGF-ß3 levels were positively correlated with C-reactive protein levels in SSc patients. Additionally, sTGF-ß2 and sTGF-ß3 levels were positively correlated with the number of platelets in SSc patients. In skin biopsies, TGF-ß1, TGF-ßR1, and TGF-ßR2 expression levels were higher in SSc patients than CS. In conclusion, this is the first study showing a joint decrease of the 3 active TGF-ß isoforms in SSc patients. However, TGF-ß1, TGF-ßR1, and TGF-ßR2 are possibly increased in clinically involved skin. Therefore, it is likely that a distinct role is played by TGF-ß at the local (skin lesions) and systemic levels in SSc patients.

Palpation and Ultrasonography Reveal an Ignored Function of the Inferior Belly of Omohyoid: A Case Series and a Proof-of-Concept Study.

BACKGROUND: Palpation, a traditional haptic ability, is used daily by practitioners of all medical and surgical specialties to assess patients. In the current study, one of the authors, in a routine clinical setting, was able to deduce the dynamic features of the putative inferior belly of omohyoid. This led to a proof-of-concept study that yielded results consistent with the clinical findings. METHODS: The first part of the study involved a survey of 300 rheumatic disease patients in whom the greater supraclavicular fossa was explored by palpation. While the patient kept the head straight, the clinician placed his middle three fingers 2.5-3 cm dorsal to the clavicle in the window between the sternocleidomastoid and trapezius clavicular insertions, explored the supraclavicular fossa, and palpated the paired contractile inferior belly of the assumed omohyoid during flexion in the three orthogonal planes. In the second part of the study, five normal subjects were examined in a similar manner by the same clinician and had independent ultrasonography performed on the dominant side. Descriptive statistics were used, and Yates' corrected chi-squared test was applied to certain nominal variables. Additionally, a comparative anterolateral bilateral neck dissection was performed in a cadaveric specimen. RESULTS: Both studies showed that the contractile structure was the inferior belly of omohyoid and that its contraction occurred during anterior neck flexion and was opposite to the side of neck rotation, resembling the sternocleidomastoid. CONCLUSIONS: Palpation uncovered a previously unknown function of the inferior belly of omohyoid, suggesting that physical examination of the musculoskeletal system based on palpation may lead to hypotheses worthy of exploration.

IFABP2 as a new prognostic biomarker for secondary non-response in rheumatoid arthritis.

BACKGROUND: Increased intestinal permeability promotes the translocation of bacterial products from the local microbiome to the circulation, inducing inflammation and increasing clinical activity in rheumatoid arthritis (RA). This study evaluates whether intestinal fatty acid binding protein 2 (IFABP2) serum levels are prognostic biomarkers of non-response to conventional synthetic disease-modifying antirheumatic drug therapy (csDMARDs) in RA. METHODS: The therapeutic schemes administered to 60 women with RA for at least 18 months were assessed retrospectively, and the treatment response was classified according to the change in DAS28-ESR over time. Serum levels of IFABP2 and TNF-α were determined by ELISA. Receiver operating characteristics (ROC) curve analysis and logistic regression models were used to assess the predictive value and the association of IFABP2 with the non-responder phenotype in RA patients. RESULTS: Eleven women had a responder phenotype, 23 had a primary non-responder phenotype, and 26 had a secondary non-responder phenotype. Secondary non-responders showed higher DAS28-ESR (P = 0.009) and higher IFABP2 serum levels compared to the responder group (P = 0.023) and the primary non-responder group (P = 0.018). IFABP2 serum levels were positively correlated with chloroquine dose (r = 0.581, P = 0.007) and negatively correlated with total cholesterol (r = -0.456, P = 0.019) in secondary non-responders. The area under the curve (AUC) value of IFABP2 for predicting secondary non-response was 0.736, and IFABP2 serum levels > 9.311 ng/mL were associated with secondary non-response to csDMARDs (OR = 6.00, P = 0.003). CONCLUSION: IFABP2 serum levels are potentially a new biomarker predictive of secondary non-response to csDMARDs in RA, although our findings should be validated externally and in a larger cohort.

TGFB1 mRNA expression and frequency of the + 869T>C and + 915G>C genetic variants: impact on risk for systemic sclerosis.

Systemic Sclerosis (SSc) is a chronic autoimmune disease characterized by immune disorder, microvascular damage, and fibrosis. TGFB1 gene encodes for the transforming growth factor isoform 1 (TGF-ß1), one of the most important pro-fibrotic cytokines. Therefore, variants in TGFB1 and changes in its expression could be associated with the pathogenesis of SSc. We aimed to evaluate the association of TGFB1 variants (+ 869T>C [rs1982073] and + 915G > C [rs1800471]) with the TGFB1 mRNA expression and SSc risk in the Southern Mexican population. We included 56 SSc patients and 112 control subjects (CS). The genetic variants were determined by the PCR-RFLP method. The TGFB1 mRNA expression was determined by qPCR. For the + 869T>C variant, the C allele was associated with SSc risk (OR = 1.733; CI = 1.087-2.762; p = 0.020). The C allele for the + 915G>C variant was also associated with SSc risk (OR = 11.168; CI = 1.289-96.754; p = 0.023). The relative expression of TGFB1 mRNA was 1.77-fold lower in SSc patients than in CS. Carriers of polymorphic alleles (TC or CC genotypes) for the + 869T>C variant showed 3.7-fold lower mRNA expression than the TT genotype in patients and 4.81-fold lower in CS. For the + 915G>C variant, patients with GA genotype had 1.78-fold lower mRNA expression than GG genotype carriers. In conclusion, the present study showed that + 869T>C and + 915G>C variants could be SSc risk factors for patients from Southern Mexico, and these genetic variants could induce lower mRNA expression of TGFB1.

The Infection, Coinfection, and Abundance of Intestinal Protozoa Increase the Serum Levels of IFABP2 and TNF-α in Patients With Rheumatoid Arthritis.

Protozoa, nematodes, and platyhelminths are of clinical interest due to their role on the modulation of the immune responses. To determine the frequency of infection by intestinal parasites as well as the status of single or mixed infection (coinfection) and its relation with inflammation and intestinal permeability markers in patients with rheumatoid arthritis (RA), a cross-sectional study was conducted in 18 women diagnosed with RA. A fecal sample of each participant was analyzed for parasitic identification. The DAS28-erythrocyte sedimentation rate score, as well as the serum levels of TNF-α, IL-10, IL-17A, and the intestinal fatty-acid binding protein 2 (IFABP2), was determined through the ELISA technique. The T CD4+ and CD8+ lymphocytes' proportions were determined by flow cytometry. In this study, 50% (n = 9) of the total sample tested were positive to the presence of intestinal protozoa (27% by single infection and 22.2% by coinfection). Blastocystis sp. and Endolimax nana were the most frequently identified protozoa. The serum levels of IFABP2 were increased in patients with infection by protozoa, mainly in those individuals with coinfection and a larger abundance of Blastocystis sp. We found that coinfection by protozoa was related to higher levels of TNF-α and higher frequency of T CD4+ lymphocytes, mainly in patients under antirheumatic treatment. Infection by intestinal protozoa is associated with increased intestinal permeability in patients with RA; thus, infection, coinfection, and abundance of intestinal protozoa should be clinically screened because they could be an associated factor to the clinical variability of the disease.

PON-1 haplotype (-108C>T, L55M, and Q192R) modulates the serum levels and activity PONase promoting an atherogenic lipid profile in rheumatoid arthritis patients.

INTRODUCTION/OBJECTIVE: Paraoxonase 1 (PON1) promotes antioxidant and antiatherogenic activity related to the hydrolysis of oxidized lipids of low-density lipoproteins. In rheumatoid arthritis (RA) patients, it has been reported that low PON1 activity is related to an impaired lipid profile, increasing cardiovascular risk (CVR). The goal of this study was to analyze the effect of common PON1 polymorphisms and haplotypes on enzymatic activity, PON1 serum levels (PON1s), and lipid parameters related to atherogenic profile in RA patients. METHODS: A cross-sectional study was carried out on 250 Mexican patients with RA. The lipid profile was determined by colorimetric tests. The PON1 activity (CMPAase) was measured by spectrophotometry. The levels of PON1s were determined by ELISA, and the polymorphisms in the PON-1 gene (-108C>T, L55M, and Q192R) were genotyped by the PCR-RFLP method. The haplotypes were estimated and statistical analysis was performed. RESULTS: The median of the CMPAase activity and PON1 levels was 13.91 U/mL and 24.75 ng/mL, respectively. The CMPAase activity was significantly lower in carriers of -108TT and 192QQ genotypes (ß = - 4.09, P = 0.001 and ß = - 3.73, P = 0.002, respectively); moreover, the PON1 levels were lower in 192Q allele carriers (P < 0.01). The TLQ haplotype was associated with CMPAase activity < 13.91 U/mL (OR = 2.29, P < 0.001), as well as with levels of PON1s < 24.75 ng/mL (OR = 1.65, P = 0.017). In this study, the CMPAase activity (< 13.91 U/mL) showed a positive association with lower levels of high-density lipoprotein cholesterol (HDL-c; < 40/50 mg/dL), and with a triglycerides/HDL-c ratio > 3%, and a total cholesterol/HDL-c ratio > 4.5/5%, all representatives of an atherogenic risk lipid profile. CONCLUSIONS: PON1 polymorphisms modulate the CMPAase activity and PON1 levels in Mexican patients with RA. The CMPAase activity < 13.91 U/mL is associated with an atherogenic lipid profile, independently of inflammation markers and treatment with anti-rheumatic drugs. Key Points •The haplotype TLQ is a marker for low PONase activity in rheumatoid arthritis. •The haplotype TLQ is a marker for low PON1 serum levels in rheumatoid arthritis. •The enzymatic PON1 activity represents the best marker for an atherogenic lipid profile in rheumatoid arthritis, in comparison with PON1 levels. •The haplotype TLQ is a marker of low PON1 activity, levels of PON1s, and atherogenic lipid profile, independent of treatment therapy in rheumatoid arthritis.

PADI2 Polymorphisms Are Significantly Associated With Rheumatoid Arthritis, Autoantibodies Serologic Status and Joint Damage in Women from Southern Mexico.

The enzymes of the family peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) due to their association with the anti-citrullinated protein antibodies (ACPA) production. To evaluate the association between single-nucleotide polymorphisms (SNPs) in the PADI2 gene and RA susceptibility, related clinical parameters, and the serologic status of autoantibodies in a women population with RA from southern Mexico, a case-control study was conducted (case n=229; control n=333). Sociodemographic characteristics were evaluated, along with clinical parameters, inflammation markers, the levels of ACPAs as anti-cyclic citrullinated peptides (anti-CCPs), anti-modified citrullinated vimentin (anti-MCV), and rheumatoid factor (RF). Genomic DNA was extracted from peripheral blood, and three SNPs of the PADI2 gene (rs1005753, rs2057094, and rs2235926) were performed by qPCR using TaqMan probes. The data analysis reveals that the carriers of the T allele for rs2057094 and rs2235926 presented an earlier onset of the disease (ß= -3.26; p = 0.03 and ß = -4.13; p = 0.015, respectively) while the carriers of the T allele for rs1005753 presented higher levels of anti-CCPs (ß= 68.3; p = 0.015). Additionally, the T allele of rs2235926 was associated with a positive RF (OR = 2.90; p = 0.04), anti-MCV (OR = 2.92; p = 0.05), and with the serologic status anti-CCP+/anti-MCV+ (OR = 3.02; p = 0.03), and anti-CCP+/anti-MCV+/RF+ (OR = 3.79; p = 0.004). The haplotypes GTT (OR =1.52; p = 0.027) and TTT (OR = 1.32; p = 0.025) were associated with the presence of RA. In addition, in this study the haplotype TTT is linked to the presence of radiographic joint damage defined by a Sharp-van der Heijde score (SHS) ≥2 (OR = 1.97; p = 0.0021) and SHS ≥3 (OR = 1.94; p = 0.011). The haplotype TTT of SNPs rs1005753, rs2057094, and rs2235926 of the PADI2 gene confers genetic susceptibility to RA and radiographic joint damage in women from southern Mexico. The evidence reveals that SNPs of the PADI2 gene favors the presence of a positive serologic status in multiple autoantibodies and the clinical manifestations of RA at an early onset age.

The rheumatology physical examination: making clinical anatomy relevant.

To review the importance of physical examination in the diagnostic process of musculoskeletal conditions vis-a-vis the development of sensitive and powerful technologies such as MRI and high-resolution ultrasound. Because the physical examination of the musculoskeletal system is an exercise of applied clinical anatomy, the authors tested, in one-to-one practical examinations, the basal knowledge of musculoskeletal anatomy of rheumatology trainees, rheumatologists, and other professionals of musculoskeletal medicine. The results of the authors' surveys were disappointing, with a correct response rate of 50 to 60% depending on the locales. To correct this deficit, the authors gave many active-learning, case-centered seminars throughout the Americas and some overseas that may have fostered an interest in the study of clinical anatomy. There was an increased interaction between anatomy departments and clinicians, and that daily use of clinical anatomy would make anatomy relevant, improve clinical skills, and probably reduce the overall costs of the health care system.Key Points• Knowledge of musculoskeletal anatomy is the basic diagnostic tool in the regional pain syndromes• Knowledge of musculoskeletal anatomy helps understand the musculoskeletal involvement in the regional and systemic rheumatic disorders• An active-learning methodology was used since 2006 to review the anatomy that is relevant for rheumatology trainees and practitioners of musculoskeletal medicine• A skilled, anatomy-based physical examination and a well-thought diagnostic hypothesis could reduce the use of expensive technologies that, being too sensitive, may lead the unaware clinician astray.

Macrophage migration inhibitory factor promoter polymorphisms are associated with disease activity in rheumatoid arthritis patients from Southern Mexico.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine capable of stimulating inflammatory cytokine and matrix metalloproteinase production from macrophages and synovial fibroblasts, which leads to persistent inflammation and bone degradation, two of the major pathological processes in rheumatoid arthritis (RA). The aim of this study was to evaluate the association of MIF promoter polymorphisms (-794CATT5-8 rs5844572 and -173G > C, rs755622), circulating MIF levels, and mRNA expression with RA susceptibility and disease activity. METHODS: A case-control study was conducted in 200 RA patients and 200 control subjects (CS) from Southern Mexico. Genotyping was performed by conventional PCR and PCR-RFLP methods. MIF mRNA expression was quantified by real-time PCR and MIF serum levels were determined by an ELISA kit. RESULTS: The 7,7 (-794CATT5-8 ) and -173CC (-173G > C) genotypes were associated with higher disease activity in RA patients. MIF serum levels were increased, and MIF mRNA expression was reduced in RA patients as compared to CS. In addition, RA patients with moderate disease activity had higher MIF levels than those with low disease activity. The -794CATT5-8 and -173G > C MIF polymorphisms were not associated with RA susceptibility. CONCLUSION: These results suggest an important role of MIF polymorphisms and MIF serum levels with disease activity in RA.

Hypertriglyceridaemic waist is associated with hyperuricaemia and metabolic syndrome in rheumatoid arthritis patients.

BACKGROUND: /Aim: The hypertriglyceridaemic waist (HTGW) phenotype has been described and suggested in general population as a cardiovascular risk marker. The aim of the present study was to evaluate the HTGW phenotype as a marker related to HUC and MetS in rheumatoid arthritis (RA). MATERIALS AND METHODS: This was a cross-sectional study was designed in 250 RA Mexicans patients. The HTGW phenotype was defined as elevated waist circumference and elevated triglyceride concentration. Logistic regression analysis was used to evaluate the association between the HTGW phenotype, HUC and MetS in its traditional NCEP/ATPIII versions and modified (HTGWm and MetSm). RESULTS: The prevalence of HTGW and HTGWm it was 20.4% and 32%, respectively. All patients with HTGW presented MetS (P < 0.001), and in a multivariate model, the HTGW phenotype was the marker most closely related to HUC in comparison to components of MetS. CONCLUSION: The HTGW may represent a marker for screening of cardiometabolic risk in RA patients, so in clinical practice can be implemented as a low-cost marker in the evaluation of the patient regardless of clinical characteristics of disease.

TNFA -308G>A and -238G>A polymorphisms and risk to systemic sclerosis: impact on TNF-α serum levels, TNFA mRNA expression, and autoantibodies.

Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, characterized by chronic inflammation and fibrosis, which are processes associated with higher serum tumor necrosis factor-α (sTNF-α) levels. TNFA -308G>A and -238G>A polymorphisms have been associated with higher sTNF-α levels. In this study, we genotyped the TNFA -308G>A and -238G>A polymorphisms in 53 SSc patients and 115 unrelated control subjects (CS) from southern Mexico. The TNFA mRNA expression and sTNF-α levels were also quantified by qPCR and enzyme-linked immunosorbent assays, respectively. TNFA -308GA genotype was associated with disease susceptibility according to a codominant genetic model (OR = 3.2, 95% CI 1.05-9.75, p = 0.03), and with higher anti-fibrillarin antibodies (p = 0.01), and higher skin thickening (p = 0.006). TNFA -238GA was not associated with SSc risk. TNFA mRNA expression and sTNF-α levels were similar between SSc patients and CS and were not statistically associated with the TNFA polymorphisms; however, a correlation (rho = 0.362, p = 0.009) between sTNF-α levels with anti-RNA polymerase III antibodies was observed in the SSc patients. In conclusion, the -308G>A polymorphism is a genetic marker of SSc susceptibility in population from southern Mexico, and it is associated with skin thickening and anti-fibrillarin antibodies. In addition, sTNF-α levels correlate positively with the anti-RNA pol III antibodies levels.

KIR/HLA Gene Profile Implication in Systemic Sclerosis Patients from Mexico.

INTRODUCTION: Systemic Sclerosis (SSc) is an autoimmune, inflammatory, and multisystemic disease characterized by the presence of autoantibodies and fibrosis. The pathogenesis involves the interaction between immune system cells such as macrophages, NK cells, T cells, and B cells. Killer-cell Immunoglobulin-like Receptors (KIR) are expressed in NK cells and some T cell subsets that recognize HLA class I molecules as ligands and are involved in regulating the activation and inhibition of these cells. The KIR family consists of 14 genes and two pseudogenes; according to the gene content, the genotype could be AA and Bx. The aim of this study was to evaluate the association between KIR/HLA genes and genotypes with SSc and the clinical characteristics. METHODS: We included 50 SSc patients and 90 Control Subjects (CS). Genotyping of KIR, HLA-C, -Bw4, and -A ∗ 03/ ∗ 11 was made by SSP-PCR. RESULTS: In SSc patients, a higher frequency of KIR2DL2 (p = 0.0007, p' = 0.011), KIR2DS4del (p = 0.001, p' = 0.021), and HLA-C2 (p = 0.02, p' = 0.09) was found. This is the first study to evaluate the frequency of HLA-A ∗ 03/ ∗ 11 in SSc patients, of which a low frequency was found in both groups. Compound genotypes KIR2DL2+/HLA-C1+ or KIR2DL2+/HLA-C2+ have a higher frequency in SSc patients. The Bx genotype was the most frequent and was associated with risk to SSc (p = 0.007, OR = 3.1, 95% CI = 1.4-7.9, p' = 0.014). The genotypes with a higher iKIR number than aKIR (iKIR > aKIR) were found in all individuals; genotypes with 7-8 iKIR genes were increased in SSc patients. We do not find an association between the KIR genes with the clinical characteristics. CONCLUSION: The results suggest that KIR2DL2 and 2DS4del could have a risk role in the development of SSc, but not with clinical manifestations.

Macrophage migration inhibitory factor polymorphisms are a potential susceptibility marker in systemic sclerosis from southern Mexican population: association with MIF mRNA expression and cytokine profile.

INTRODUCTION: Systemic sclerosis (SSc) is a complex autoimmune disease, characterized by microvascular lesions, autoimmunity, and fibrosis. It is suggested that MIF participates in the amplification of the proinflammatory process in SSc; moreover, the promoter polymorphisms - 794 CATT5-8 (rs5844572) and - 173G>C (rs755622) in the MIF gene have been associated with an increase in MIF serum levels in several autoimmune diseases. The aim of this study was to analyze the relationship of the - 794 CATT5-8 and - 173G>C MIF polymorphisms with mRNA expression, MIF serum levels, and the Th1/Th2/Th17 cytokine profile in SSc. MATERIALS AND METHODS: A case-control study was carried out that included 50 patients with SSc and 100 control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP. MIF levels were measured by ELISA kit. The cytokine profile and the MIF mRNA expression were quantified by BioPlex MagPix system and real-time PCR, respectively. RESULTS: An association between the - 794 CATT7 and - 173*C MIF alleles and the 7C haplotype with SSc susceptibility was found (p < 0.05). Also, the 7C haplotype was associated with increased MIF mRNA expression (p = 0.03) in SSc. In addition, an increase of IL-1ß and IL-6 serum levels in SSc patients was found as well as a positive correlation between MIF serum levels and Th1 and Th17 cytokine profiles. CONCLUSION: The MIF 7C haplotype is a susceptibility marker for SSc in the southern Mexican population and is associated with MIF mRNA expression. Moreover, there is a positive correlation between MIF serum levels and Th1 and Th17 inflammatory response in SSc.