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.

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.

Polymorphisms CYP2R1 rs10766197 and CYP27B1 rs10877012 in Multiple Sclerosis: A Case-Control Study.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease. Low vitamin D levels have been reported to be a risk factor for MS, and genetic variances could be implicated. The aim of this study was to evaluate the association of MS with rs10766197 polymorphism of CYP2R1 gene and rs10877012 polymorphism of CYP27B1 gene. The second aim was to analyse whether these polymorphisms are associated with the severity of the progression of MS. Material and Methods. In a case-control study, we included 116 MS patients and 226 controls, all of whom were Mexican Mestizo. MS was diagnosed by McDonald criteria (2017). A complete neurological evaluation was performed to evaluate the severity of disease progression. Serum 25-hydroxyvitamin D [25(OH) vitamin D] levels were measured by ELISA. Single nucleotide polymorphisms rs10766197 of CYP2R1 gene and rs10877012 SNP of CYP27B1 gene were genotyped by real-time PCR. RESULTS: Serum 25(OH) vitamin D levels were lower in MS patients than in controls (p = 0.009). No differences were observed between serum 25(OH) vitamin D levels of MS patients with severe progression compared to low progression (p = 0.88). A higher frequency of the A allele of CYP2R1 rs10766197 was observed between MS patients and controls (p = 0.05). No differences were observed in the frequency of T allele of CYP27B1 rs10877012 (p = 0.65). In subanalysis, patients with GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS compared to controls (p = 0.03). No increased risk was observed in GT + TT genotypes of CYP27B1 rs10877012 (p = 0.63). No differences were observed in allele frequencies of either polymorphism between patients with severe vs. low disease progression. CONCLUSION: Lower serum 25(OH) vitamin D levels were observed in MS patients than in controls, although these levels were not associated with disease progression. Carriers of GA + AA genotypes of CYP2R1 rs10766197 had an increased risk of MS. None of these polymorphisms was associated with severe progression of MS.

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.