Serum P-glycoprotein level: a potential biomarker of DMARD failure in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the utility of elevated serum P-glycoprotein (P-gp) as a risk marker of therapeutic response failure in rheumatoid arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: A cross-sectional study was conducted in 151 RA patients. Patients were classified into two groups according to the response achieved in terms of the disease activity score (DAS)28 after ≥ 6 months: (1) patients with a therapeutic response to DMARDs, with DAS28 < 3.2; and (2) patients without a response to DMARDs, with persistent DAS28 ≥ 3.2. We explored a wide group of clinical factors associated with therapeutic resistance. Serum P-gp levels were measured by ELISA. The risk of P-gp elevation as a marker of failure to achieve a therapeutic response to DMARDs was computed using multivariate logistic regression. RESULTS: Serum P-gp levels were significantly higher in RA patients (n = 151) than in the controls (n = 30) (158.70 ± 182.71 ng/mL vs. 14.12 ± 8.97 ng/mL, p < 0.001). The P-gp level was correlated with the DAS28 score (r = 0.39, p < 0.001). RA patients with DMARD failure had higher serum P-gp levels than patients with a therapeutic response (206 ± 21.47 ng/mL vs 120.60 ± 15.70 ng/mL; p = 0.001). High P-gp levels increased the risk of DMARD failure (OR 3.36, 95% CI 1.54-7.27, p = 0.001). After adjusting for confounding variables, elevated P-gp remained associated with DMARD failure (OR 2.64, 95% CI 1.29-5.40, p = 0.01). CONCLUSION: Elevated serum P-gp is associated with DMARD failure. The P-gp level can be considered a clinical tool for evaluating the risk of DMARD failure in patients; however, future prospective studies should be performed to evaluate the utility of this marker in predicting long-term responses.

Association between bone turnover markers, clinical variables, spinal syndesmophytes and bone mineral density in Mexican patients with ankylosing spondylitis.

OBJECTIVES: To compare bone turnover marker (BTM) levels and bone mineral density (BMD) between patients with ankylosing spondylitis (AS) and healthy controls (HC) and to evaluate, in AS, the association between BTM levels and clinical variables, spinal syndesmophytes, and BMD using multivariate analysis. METHOD: Seventy-eight AS patients were compared with 58 HC matched by gender. Spinal syndesmophytes in AS and other characteristics were assessed. C-terminal telopeptide fragments of type I collagen (CTX), bone-specific alkaline phosphatase (BAP), osteocalcin (OC) serum levels, and BMD of the lumbar spine, femoral neck, and forearm were evaluated. RESULTS: AS males and females had lower BAP levels than their respective HC (p < 0.001 and p = 0.001). AS patients with bridging syndesmophytes had higher OC levels than AS patients either with non-bridging syndesmophytes (p = 0.001) or without spinal syndesmophytes (p < 0.001). OC and CTX levels correlated significantly with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). In the multivariate linear regression adjusted by age, gender, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BMD in the lumbar spine, and C-reactive protein (CRP), we observed an association between BAP levels and anti-tumour necrosis factor (anti-TNF) use (p = 0.05) whereas OC levels were associated with mSASSS (p < 0.001) and anti-TNF use (p = 0.05), and CTX levels were exclusively associated with mSASSS (p = 0.03). In the logistic regression analysis, only OC levels were associated with the presence of syndesmophytes in AS [odds ratio (OR) 2.42, 95% confidence interval (CI) 1.19-5.75]. CONCLUSIONS: We observed an increase in OC levels in AS patients with syndesmophytes. BTM levels were associated with the severity of spinal damage. Future longitudinal studies should evaluate whether these BTMs should be included as tools to determine the prognosis and progression of spinal damage.

Prescription for antiresorptive therapy in Mexican patients with rheumatoid arthritis: is it time to reevaluate the strategies for osteoporosis prevention?

Glucocorticoids are frequently used in rheumatoid arthritis (RA) in order to alleviate symptoms of joint inflammation, retard erosions and to treat extra-articular manifestations, although these drugs may increase the risk of bone mineral loss and osteoporotic fractures. To date, in Mexico there are no studies that identify the frequency of patients with RA with corticosteroids, receiving therapy for osteoporosis. Therefore, we evaluated the prevalence and factors related to the prescription of antiresorptives in 520 Mexican patients with RA. We used a multivariate model to identify variables associated with antiresorptives prescription. We identified that although 79% of patients were under treatment with glucocorticoids, only 13% received antiresorptive agents as preventive therapy for osteoporosis. The multivariate analysis identified that higher proportions of antiresorptive drugs prescriptions were associated with female patients (OR 11.40, 95% CI: 1.5-84.3, P = 0.02), an age of 40 years or more (OR 3.22, 95% CI: 1.3-8.3, P = 0.02) and to consume a lower number of cointerventions with other drugs (OR 1.09, 95% CI: 1.0-1.2, P = 0.03). Corticosteroid treatment was not associated with the prescription of antiresorptives (P = 0.31). In conclusion, a low proportion of Mexicans with RA receive antiresorptive therapy independently regardless of whether they consume or not chronically corticosteroids. Additional strategies should be evaluated to encourage the prevention and early treatment for osteoporosis in patients with RA.

Pulmonary function in ankylosing spondylitis: association with clinical variables.

To evaluate the association between pulmonary function and clinical variables in ankylosing spondylitis (AS) and to compare the pulmonary function of patients with AS with that of healthy controls, 61 AS patients and 74 healthy controls were included. In AS, we assessed clinical disease indices (BASDAI, BASFI, BASG), morning stiffness, number of hypersensitive entheses, metrology measures, 6-min walking test, acute phase reactants, radiological presence of "bamboo spine," and severity of radiological involvement in sacroiliac and vertebral joints. AS and healthy controls had similar age and gender. All the parameters of pulmonary function were significantly diminished in AS than in healthy controls (p < 0.001), with a higher proportion of restrictive pattern (57.4 vs. 5.4 %). In AS, pulmonary function correlated negatively with BASDAI, BASFI, BASG, morning stiffness, number of hypersensitive entheses, occiput-wall distance, and ESR, and positively with 6-min walking test. There was no association between pulmonary function with radiological stage of vertebral joints and sacroiliac joints, "bamboo spine," disease duration, or chest expansion. A higher frequency of AS patients had a decreased pulmonary function and results of the 6-min walking test. These abnormalities in AS were more related with disease activity than with mobility limitation.

Comparison of the use of blood pressure telemonitoring versus standard medical care in the achievement of short-term therapeutic goals in blood pressure in patients with uncontrolled hypertension: An open-label clinical trial.

Background: In Mexico less than half of the treated hypertensive patients reach blood pressure (BP) targets. Most hypertensive individuals rely on the standard medical care (SMC) to achieve the BP control goals; however, the efficacy of BP telemonitoring (BPT) to achieve BP targets has been poorly studied. Aim: To compare the efficacy of BPT versus SMC to achieve BP goals in patients with uncontrolled hypertension. Methods: A two-arm, open-label clinical trial was conducted in patients ≥18 years with uncontrolled hypertension. The participants were randomized to 2 arms (BPT vs SMC) and followed for 12 weeks. For the statistical analysis, the chi-squared test and covariance were used. Results: One hundred and seventy-eight participants were included, BPT (n = 94) and SMC (n = 84), after 12 weeks of follow up, we observed a baseline-adjusted reduction in systolic BP with both BPT (-13.5 [1.3] mmHg) and the SMC (-5.9 [1.4] mmHg; p < 0.001) but a greater decrease with BPT (p < 0.001). Likewise, we found a baseline-adjusted reduction of diastolic BP with BPT (-6.9 [0.9] mmHg) and SMC (-2.7 [0.9] mmHg) (p = 0.007) with a more significant percentage change from baseline with BPT (-6.8% [1.0] vs 2.5% [1.1]; p = 0.007). In the BPT arm, a larger proportion of patients achieved the BP target versus SMC (30.5% vs 12.8%; p = 0.005). Conclusion: BPT showed a greater proportion of patients achieving office BP control goals (<140/90 mmHg), compared to standard medical care.

Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. METHODS: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. RESULTS: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). CONCLUSION: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Serum oxidative stress is increased in patients with post cholecystectomy bile duct injury.

BACKGROUND: Post-cholecystectomy bile duct injuries are identified by the onset of jaundice as well as elevated bilirubin and alkaline phosphatase levels during the peri-operative period. It is unknown how serum oxidative stress markers are modified in patients with post-cholecystectomy bile duct injuries. OBJECTIVE: To determine serum oxidative stress marker levels (lipid peroxidation by-products, nitrites/nitrates and total antioxidant capacity) in patients with post-cholecystectomy bile duct injuries. PATIENTS AND METHODS: A prospective, transversal and analytical study was designed with two groups. Group 1: 5 healthy volunteer subjects. Group 2: 52 patients with post-cholecystectomy bile duct injuries (43 female and 9 male). An elective bilio-digestive reconstruction was performed at week 8. The serum oxidative stress marker levels were quantified by colorimetric method. RESULTS: Patients with bile duct injuries had a significant increased serum lipid peroxides (malondialdehyde and 4-hydroxy-alkenals) and nitric oxide metabolites (nitrites/nitrates) levels compared to the control group. In contrast, total antioxidant capacity in patients with bile duct injuries remained similar compared to healthy controls. CONCLUSIONS: The results show that oxidative stress is usually associated to bile duct injury.

The -174G/C Interleukin-6 Gene Promoter Polymorphism as a Genetic Marker of Differences in Therapeutic Response to Methotrexate and Leflunomide in Rheumatoid Arthritis.

Objective. To evaluate the association of -174G/C IL-6 polymorphism with failure in therapeutic response to methotrexate (MTX) or leflunomide (LEF). This prospective, observational cohort included 96 Mexican-Mestizo patients with moderate or severe rheumatoid arthritis (RA), initiating MTX or LEF, genotyped for IL-6 -174G/C polymorphism by PCR-RFLP. Therapeutic response was strictly defined: only if patients achieved remission or low disease activity (DAS-28 < 3.2). Results. Patients with MTX or LEF had significant decrement in DAS-28 (p < 0.001); nevertheless, only 14% and 12.5% achieved DAS-28 < 3.2 at 3 and 6 months. After 6 months with any of these drugs the -174G/G genotype carriers (56%) had higher risk of therapeutic failure compared with GC (RR: 1.19, 95% CI: 1.07-1.56). By analyzing each drug separately, after 6 months with LEF, GG genotype confers higher risk of therapeutic failure than GC (RR = 1.56; 95% CI = 1.05-2.3; p = 0.003), or CC (RR = 1.83; 95% CI = 1.07-3.14; p = 0.001). This risk was also observed in the dominant model (RR = 1.33; 95% CI = 1.03-1.72; p = 0.02). Instead, in patients receiving MTX no genotype was predictor of therapeutic failure. We concluded that IL-6 -174G/G genotype confers higher risk of failure in therapeutic response to LEF in Mexicans and if confirmed in other populations this can be used as promissory genetic marker to differentiate risk of therapeutic failure to LEF.

Metabolic profile and insulin sensitivity in healthy young Mexicans with a strong family history of non-insulin-dependent diabetes mellitus in the paternal branch.

The objective was to identify early metabolic defects and insulin sensitivity in a group of healthy young Mexicans with a family history of NIDDM in first and second degree on the paternal branch. The design was a cross-sectional study, and the setting was a hospital and a school of medicine in Guadalajara, Jalisco, Mexico. The subjects were 20 healthy, non-obese, young (age 19-20 years), born in Mexico, with family history of NIDDM in first and second degree in the paternal branch, and 20 controls. Measurements were serum values of creatinin, uric acid, total cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, and insulin, insulin tolerance test, glucose/insulin ratio, LDL cholesterol, VLDL cholesterol, total cholesterol/HDL cholesterol ratio and LDL cholesterol/HDL cholesterol ratio. In terms of results, only the total cholesterol was slightly, although significantly (p = 0.05) higher in probands (4.3 +/- 0.5 mmol/L) than in control subjects (3.9 +/- 0.5 mmol/L). In conclusion, healthy young Mexicans with a strong family history of NIDDM in the paternal branch were not different in insulin sensitivity from those without family history of NIDDM, and only showed a slight increase in serum total cholesterol.

[Mild preeclampsia and serum insulin values in the third pregnancy trimester]. / Preeclampsia leve y valores de insulina sérica en el tercer trimestre del embarazo.

The purpose of this investigation was to determine the baseline insulin level in sera during fasting and after an oral glucose load in patients with mild preeclampsia and compare these values with those obtained from pregnant women with normal arterial pressure during the third trimester of their pregnancy. A cross-sectional study was realized in 38 patients with mild preeclamsia and 39 patients with normal arterial pressure values, both groups in their third trimester of pregnancy. We determined baseline arterial pressure, serum glucose and insulin, and the insulin/glucose ratio with at least 6 hours of fasting, and one hour after 50 g of glucose PO. The hypertensive group was under treatment with alfametildopa and/or hidralazine, patients with known coexistent conditions that would alter glucose or insulin levels were not included. The glucose was measured with the glucose oxidase method and the insulin levels by radioimmunoanalysis. The insulin/glucose ratio was obtained as the coefficient of insulin/glucose. Both patient groups had similar ages, number of pregnancies, gestational age and pre-pregnancy body mass index. We found no difference in glucose levels during fasting nor glucose post-load between groups. Insulin fasting levels were lower in the preeclampsia group compared with the normotensive one (7.1 +/- 3.8 vs 10.6 +/- 8.7 microU/mL, p = 0.02), however there was no difference in either group after the glucose load was administered (66.8 +/- 46.5 vs 71.0 +/- 51.9, p = N.S.). The insulin/glucose ratio had the same behavior than insulin. The hypertensive group showed a lower fasting insulin levels compared with the normotensive group. We suggest further research be done on this matter with strict selection criteria in order to emit final conclusions.

Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthritis.

BACKGROUND: Hyperhomocysteinaemia is a factor related to the development of atherosclerosis in rheumatoid arthritis (RA). However, Hispanics with RA develop high rates of coronary disease; there are no studies about the frequency and factors related to high levels of homocysteine in Mexican patients. OBJECTIVE: To evaluate the prevalence and characteristics associated with hyperhomocysteinaemia in Mexican patients with RA. METHODS: One hundred and fifty-two patients with RA were compared with 153 controls. The assessment in RA included clinical characteristics, disease activity (RADAR), functioning (HAQ-Di and global functional status), comorbidity, and radiological damage. Laboratory determinations included total serum homocysteine (tHcy), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and lipid profile. RESULTS: Median levels of homocysteine were higher in RA compared with controls (11.3 vs. 9.3, p<0.001). Twenty per cent of the patients with RA had hyperhomocysteinaemia (>15 micromol/L) compared with 6% in controls (p<0.001). There was statistical association between hyperhomocysteinaemia in RA with male gender (p<0.001), impairment in the global functional status (p = 0.004), higher radiological damage (p = 0.001), and CRP (p = 0.04). There was no association with RADAR, HAQ-Di, or RF, methotrexate dose or duration of use. In the adjusted multivariate model, the two variables associated with higher risk for hyperhomocysteinaemia were male gender (OR = 4.2, 95% CI 2 to 12, p = 0.006) and higher radiological damage (III-IV) (OR = 3.4, 95% CI 1.3 to 9, p = 0.01). CONCLUSIONS: Our data show a high prevalence of hyperhomocysteinaemia in Mexican patients with RA. More effort is required to evaluate and treat earlier this coronary risk factor.

Serum concentrations of aminoterminal propeptide of type III procollagen and propeptide of human type I procollagen in systemic lupus erythematosus.

The purpose of this study was to assess the association between the serum levels of aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) with disease activity and damage in systemic lupus erythematosus (SLE). Thirty-three patients with SLE were compared with 31 controls. The assessment in SLE included disease activity indices (SLEDAI, MEX-SLEDAI) and damage index (SLICC/ACR). PIIINP and PICP were measured by radioimmunoassay. Compared with controls, mean levels of PIIINP were higher in SLE (2.9+/-1.8 vs. 1.8+/-1.2, P=0.006). PICP was also increased in SLE versus controls (163+/-94 vs. 102+/-62, P=0.007). PIIINP was correlated with SLICC/ACR (r=0.33, P=0.048). No correlation was observed between PICP and PIIINP with other clinical or therapeutic variables. These preliminary data suggests a role of PIIINP as a marker for chronic damage. Follow-up studies are required to evaluate its utility in predicting future damage.

Autonomic dysfunction in patients with systemic lupus erythematosus.

OBJECTIVE: To assess the prevalence and severity of autonomic dysfunction (AD) in patients with systemic lupus erythematosus (SLE). METHODS: Fifty-nine consecutive patients with SLE and 97 healthy controls were assessed for AD using 4 noninvasive tests: heart rate responses to the Valsalva maneuver (Val), maximum-minimum heart rate (MM) response to deep breathing, heart response to standing up (30:15 ratio), and changes in blood pressure to sustained handgrip (Hand). AD was categorized as incipient, definite, severe, or atypical according to criteria proposed by Ewing. Disease characteristics, comorbid conditions, disease activity index [Mexican Systemic Lupus Erythematosus Disease Activity Index (Mex-SLEDAI)], cardiac complaints, and drug history were also documented. Laboratory analysis included rheumatoid factor, antinuclear antibodies, anti-dsDNA antibodies, and anticardiolipin antibodies (aCL). RESULTS: Forty-eight percent of the patients with SLE had one or more abnormal tests compared with 33% of the controls (p=0.05); differences were greater when the severity of the neuropathy was considered: 12 (21%) patients with SLE had definite or severe AD using Ewing's criteria, compared with only 2 (2%) controls (p < 0.001). No statistical associations were observed between AD and age, disease duration, hypertension, Mex-SLEDAI, anti-dsDNA, aCL antibodies, or other drugs. CONCLUSION: The prevalence of AD in SLE using noninvasive tests is high. One-fifth of our patients had definite or severe AD. No significant associations were observed between AD and clinical or serological variables of disease activity. Prospective studies are needed to determine the potential effect of AD in the morbidity of patients with SLE.

Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus.

The aim of this study was to compare the efficacy of intravenous cyclophosphamide (IVCYC) versus oral enalapril in mild or moderate pulmonary hypertension (PH) in systemic lupus erythematosus (SLE). Thirty-four patients with SLE who had systolic pulmonary artery pressure (SPAP) > 30 mmHg by Doppler echocardiography were randomized to receive IVCYC (0.5 g/mt2 body surface area, monthly), or oral enalapril (10 mg/day) for six months. The primary outcome was the significant decrease in SPAP. An additional outcome measure included the improvement in the heart functional class (NYHA). Sixteen patients received cyclophosphamide and 18 enalapril. IVCYC decreased the median values of SPAP from 41 to 28 mmHg (P < 0.001), and enalapril from 35 to 27 mmHg (P = 0.02). IVCYC reduced more than twice as much SPAP than enalapril (P = 0.04). In those patients with SPAP > or = 35 mmHg, cyclophosphamide decreased from 43 to 27 mmHg (P = 0.003), but enalapril was not effective (P = 0.14). The NYHA functional class improved only in those with cyclophosphamide (P = 0.021). Also IVCYC had a higher frequency of side effects including infections (RR = 1.6; 95% CI, 1.001-2.47), and gastrointestinal side effects (RR = 14.6; 95% CI, 2.15-99.68). We concluded that IVCYC was effective in mild and moderate PH associated with SLE. Further research is needed to evaluate its long-term efficacy.