Efficacy Of Methotrexate In Rheumatoid Arthritis Research Articles

Plasma metabolomic profiling as a tool to identify predictive biomarkers of methotrexate efficacy in rheumatoid arthritis

ObjectiveMethotrexate (MTX) remains the first-choice disease-modifying therapy in rheumatoid arthritis (RA). However, clinical response is variable, and no reliable predictive biomarkers of efficacy currently exist. In this study, plasma metabolomic profiling is evaluated as a tool to identify pretreatment biomarkers of MTX response in RA. MethodsPlasma collected from RA patients initiating MTX therapy (n = 20) were analyzed by metabolomic profiling totaling 648 identified metabolites. Pretreatment metabolomic profiles were compared based on clinical response after 16-weeks of MTX therapy. Clinical response to MTX was defined by a clinically meaningful reduction in disease activity score in 28 joints (DAS28-ESR) of greater than 1.2. ResultsPretreatment plasma levels of 19 metabolites were found to differ (p < 0.05) between RA patients based on response to MTX at 16-weeks. Spearman's correlation of pretreatment plasma metabolite levels with change in DAS28-ESR over the treatment period further supported three of the identified metabolites as associated with MTX response (p < 0.05). The identified metabolite levels were all found to be lower in RA patients responsive to MTX but were not found to be intercorrelated. Receiver operating characteristic analysis of each of the identified metabolites, alone or in combination, demonstrated an excellent discrimination between responders and non-responders based on pretreatment plasma levels of nornicotine (AUC = 0.84), N-methylisoleucine (AUC = 0.82), 2,3-dihydroxybutanoic acid (AUC = 0.82), and a combination biomarker panel score (AUC = 0.98). ConclusionPretreatment plasma metabolomic profiling identified multiple metabolites associated with early response to MTX therapy in RA and represents a promising approach for the identification of clinical biomarkers of MTX response in RA.

Application and pharmacological mechanism of methotrexate in rheumatoid arthritis.

Methotrexate (MTX) has been used for the treatment of rheumatoid arthritis (RA) for about forty years and to date MTX remains the part of global standard of treatment for RA. The efficacy of MTX in RA is the result of multiple mechanisms of action. In order to summarize the possible pharmacological mechanisms of MTX in the treatment of RA, this review will elaborate on folate antagonism, promotion of adenosine accumulation, regulation of inflammatory signaling pathways, bone protection and maintenance of immune system function.

Plasma Metabolomic Profiling as a Tool to Identify Predictive Biomarkers of Methotrexate Efficacy in Rheumatoid Arthritis

Plasma Metabolomic Profiling as a Tool to Identify Predictive Biomarkers of Methotrexate Efficacy in Rheumatoid Arthritis

Methotrexate mechanism in treatment of rheumatoid arthritis.

Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.

Coffee and autoimmunity: More than a mere hot beverage!

Coffee is one of the world's most consumed beverage. In the last decades, coffee consumption has attracted a huge body of research due to its impact on health. Recent scientific evidences showed that coffee intake could be associated with decreased mortality from cardiovascular and neurological diseases, diabetes type II, as well as from endometrial and liver cancer, among others. In this review, on the basis of available data in the literature, we aimed to investigate the association between coffee intake and its influence on the immune system and the insurgence of the most relevant autoimmune diseases. While some studies reported conflicting results, general trends have been identified. Coffee consumption seems to increase the risk of developing rheumatoid arthritis (RA) and type 1 diabetes mellitus (T1DM). By contrast, coffee consumption may exert a protective role against multiple sclerosis, primary sclerosing cholangitis, and ulcerative colitis. Concerning other autoimmune diseases such as systemic lupus erythematosus, psoriasis, primary biliary cholangitis and Crohn's disease, no significant association was found. In other studies, coffee consumption was shown to influence disease course and management options. Coffee intake led to a decrease in insulin sensitivity in T1DM, in methotrexate efficacy in RA, and in levothyroxine absorption in Hashimoto's disease. Further, coffee consumption was associated with cross reactivity with gliadin antibodies in celiac patients. Data on certain autoimmune diseases like systemic sclerosis, Sjögren's syndrome, and Behçet's disease, among others, are lacking in the existent literature. As such, further research is warranted.

Patterns of interaction between genetic and nongenetic attributes and methotrexate efficacy in rheumatoid arthritis

The contribution of low-penetrance single nucleotide polymorphisms to methotrexate efficacy in rheumatoid arthritis (RA) is inconsistent between studies. We sought to elucidate architecture of methotrexate response in three cohorts of patients with RA treated with methotrexate. Single nucleotide polymorphism frequencies in genes from folate, purine, and pyrimidine pathways were measured to develop a model of gene-gene interactions using multifactor dimensionality reduction in 439 patients who received methotrexate in the USA and The Netherlands. A third cohort of 530 patients with RA from Sweden was used to replicate the findings. Methotrexate efficacy was assessed using the European League Against Rheumatism criteria in the majority of patients. Nonlinear patterns of gene-gene interactions between variants in aminoimidazole carboxamide ribonucleotide transformylase (C347G), reduced-folate carrier (G80A) and inosine-triphosphate pyrophosphatase (C94A) revealed a predisposing genetic attribute significantly associated with methotrexate response in the USA and Dutch cohorts [odds ratio (OR)=2.9, 95% confidence interval (CI): 1.9-4.2; P<0.001]. Although the finding was not replicated in the Swedish cohort (OR=0.9; 95% CI: 0.64-1.37; P=0.74) a multifactor dimensionality reduction analysis superimposing the predisposing genetic attribute with patient's age, sex, and anticitrullinated peptide antibodies positivity (ACPA) revealed a pattern of interaction significant in all three cohorts (OR=2.2, 95% CI: 1.6-2.9; P<0.01). The selective advantage toward response in the presence of the predisposing genetic attribute was lost in females and ACPA-positive patients, whereas older and male ACPA-negative patients tended to exhibit a greater likelihood of response in the absence of the predisposing genetic attribute. Gene-gene interactions together with nongenetic attributes may contribute to methotrexate efficacy in RA.

Associations between the C677T and A1298C Polymorphisms of MTHFR and the Efficacy and Toxicity of Methotrexate in Rheumatoid Arthritis

The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be associated with the toxicity and efficacy of methotrexate in rheumatoid arthritis (RA), although the results of previous studies have been inconsistent. The aim of this study was to explore whether the C677T and A1298C polymorphisms of MTHFR play a role in the toxicity and efficacy of methotrexate in RA. The authors identified and evaluated studies conducted on the association between the C677T and A1298C polymorphisms of MTHFR and on the toxicity and efficacy of methotrexate in RA. A meta-analysis was then conducted to compare the toxicity and efficacy of methotrexate with respect to the 677CC and 677CT/TT genotypes and the 1298AA and 1298AC/CC genotypes. Eight studies, which included a total of 1514 patients with RA, were included in this meta-analysis. Meta-analysis did not show any association between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in RA in all patients or in Asian patients. The odds ratios (ORs) for adverse effects with 677CC versus 677CT/TT in all patients and in Asian patients were 0.633 (95% CI 0.325, 1.234; p = 0.180) and 0.621 (95% CI 0.233, 1.655; p = 0.341), respectively. The ORs for adverse effects with 1298AA versus 1298AC/CC in all patients and in Asian patients were 0.942 (95% CI 0.479, 1.851; p = 0.861) and 0.978 (95% CI 0.569, 1.681; p = 0.936), respectively. Heterogeneities were evident among the included studies. In addition, no association was found between the C677T and A1298C polymorphisms and the efficacy of methotrexate in RA in all patients. Our meta-analysis including 1514 patients with RA found no association between the C677T and A1298C polymorphisms of MTHFR and the toxicity and efficacy of methotrexate in RA. Because of the paucity of pharmacogenetic data, further studies are needed to determine the role of MTHFR polymorphisms in the toxicity and efficacy of methotrexate.

Reduction of the efficacy of methotrexate by the use of folic acid: Post hoc analysis from two randomized controlled studies

To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study.

A total of 453 rheumatoid arthritis (RA) patients were followed up for 35.2 +/- 27.9 months (range 3-106). The clinical parameters decreased significantly after 6 months. Twenty-eight patients were in remission (6.4%). Rheumatoid factor (RF) positivity was less common in the group of patients in remission, with a higher frequency of visits and methotrexate (MTX) onset after 65 yr. There was a significant degradation of radiographic lesions (n = 60). A total of 101 patients (23.1%) stopped MTX, for toxicity (n = 61) and failure (n = 20). The onset of MTX after 65 yr, a low number of visits and the occurrence of side-effects were predictive of MTX withdrawal. A total of 259 patients (59.3%) had side-effects. A Ritchie's index < or = 10, a lower polymorphonuclear cell count and the absence of RF were predictive of side-effects. The probability of being on MTX at 5 yr was 73%. This study confirms the high efficacy of MTX in RA.

Long‐Term Prospective Study of Methotrexate in the Treatment of Rheumatoid Arthritis

AbstractObjective. To determine the long‐term efficacy and safety of low‐dose methotrexate (MTX) in rheumatoid arthritis (RA).Methods. Eighty‐four—month open prospective trial at a single academic rheumatology center.Results. Twenty‐six patients were enrolled in a prospective study of the long‐term efficacy of MTX in RA; a significant improvement had been demonstrated after 36 months of therapy. Twelve patients remained in the study at the 84‐month visit; the mean weekly dosage of MTX was 10.2 mg. A significant improvement was still noted at 84 months in the number of painful joints, number of swollen joints, joint pain index, joint swelling index, and physician and patient global assessments. A 50% improvement in the joint pain index and joint swelling index was observed in more than 80% of the 12 patients still enrolled. A significant reduction in prednisone dosage was achieved; of 14 patients taking prednisone at entry, 7 had discontinued prednisone completely. Fourteen patients withdrew from the study: 10 between 0 and 36 months, and 4 between 36 and 84 months. Toxicity in 3 patients and visit noncompliance in 1 patient were the reasons for withdrawal between 36 and 84 months. At 84 months, 46% of the patients remained in the study; 11.5% had discontinued due to MTX toxicity.Conclusion. The effectiveness of MTX in the treatment of RA continues to be demonstrated in this prospective study, after 84 months of treatment.