Months Of Methotrexate Treatment Research Articles

Unveiling the impact of psoriasis on liver health: does methotrexate play a villainous role?

Psoriasis might bring about an increased risk of liver diseases like nonalcoholic fatty liver disease and fibrosis. The impact of methotrexate on liver function is still a cause for concern, because of the studies suggesting an increased risk of liver damage and others finding no association. The focus of this study was the liver functions in psoriatic patients investigating the impact of long-term use of methotrexate on liver in psoriasis. A retrospective investigation including 140 patients with psoriasis receiving methotrexate treatment for at least 6 months and a control group consisted of 105 healthy ones was conducted. Liver function tests (AST, ALT, PLT) were assessed, and the association of baseline PASI with FIB-4 and APRI values was investigated. Additionally, FIB-4 and APRI values at baseline, 3rd, and 6th months of methotrexate treatment for psoriasis were compared. Compared with the controls, psoriatic patients exhibited significantly higher FIB-4 scores (p = 0.004). A moderate and significant correlation was observed between baseline PASI score and baseline FIB-4 score in psoriatic patients (p < 0.001, rho = 0.626). Long-term methotrexate use had no effect on APRI or FIB-4 (p = 0.104 and p = 0.475, respectively). Psoriatic patients face an elevated risk of liver fibrosis. Long-term methotrexate use does not adversely affect liver function in psoriatic patients. Noninvasive tools like APRI and FIB-4 scores can be employed to evaluate the risk of liver disease in these patients.

The impact of low-dose methotrexate on erectile dysfunction, sex hormone profile and spermiogram in male patients with psoriasis: a prospective study

Purpose Psoriasis, affecting approximately 2% of the world’s population, often necessitates systemic treatments, with methotrexate (MTX) as a cornerstone therapy. Despite documented systemic side effects of MTX, concerns about its impact on male reproductive health persist. We aim to investigate low-dose MTX effect on hormonal, cellular and functional ability of male reproductive system. Materials and methods Our prospective study on 40 male psoriasis patients receiving low-dose MTX (<15mg/week) comprehensively investigates its effects on erectile function, sex hormones, and spermiogram parameters. Results After six months of MTX treatment, a significant decline in erectile function (p < 0.001) decreased total testosterone levels (p = 0.03) were observed. No significant reduction in sperm count was noted after six months of MTX treatment. Conclusions Our study highlights a significant decline in erectile function following low-dose MTX therapy, warranting further investigation into this potential side effect. While reassuring for sperm quantity and quality, the findings emphasise the necessity for larger cohorts and longer follow-up times to validate results and comprehend the complex interactions between MTX and male sexual health.

Dynamics of inflammation-associated plasma proteins following faecal microbiota transplantation in patients with psoriatic arthritis and healthy controls: exploratory findings from the FLORA trial

ObjectivesThe gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on...

Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial.

We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n=15) or sham (n=16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n=31) and at week 26 (n=26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance. Trial failures (n=7) had significantly higher LMR compared with responders (n=19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n=19) versus failures (n=12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient=0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient=27, P = 0.02). Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

Data dynamics of angiogenesis visualization instrumental methods in patients with psoriasis during methotrexate therapy: Clinical and prognostic value of dermatoscopy and ultrasound dopplerography

BACKGROUND: Pathological angiogenesis is one of the important pathogenetic links of psoriasis. At the same time, the prognostic significance of instrumental methods for studying the severity of angiogenesis in psoriatic plaques remains poorly understood.&#x0D; AIM: Clinical assessment of the correlation between the dynamics of angiogenesis parameters (morphometric parameters of vascular glomeruli and Doppler blood flow in the skin and nail bed) and indicators of the methotrexate clinical efficacy during 12 months of therapy.&#x0D; MATERIALS AND METHODS: The work is based on the clinical data analysis of 82 patients with moderate and severe psoriasis vulgaris in the acute stage, who were prescribed methotrexate after initial examination. Patients underwent Doppler ultrasound examination of the skin in psoriatic plaques area and digital dermatoscopy to study the characteristics of vascular angiogenesis loci before treatment and at 1, 3 and 12 months of methotrexate therapy.&#x0D; RESULTS: As a result of comparative correlation analysis of dermatoscopy and ultrasonographic Dopplerography indicators dynamics and psoriasis clinical index values during the treatment of patients with methotrexate, moderate and strong correlations were established between the values of the average diameter of the vascular glomerulus and the degree of increased blood flow in psoriatic plaque area after 1 month of methotrexate treatment and the values of PASI at 3, 6 and 12 months from the start of treatment (r=0.540.76, p=0.0020.005), as well as between the mean vascular glomerulus diameter values and the degree of skin blood flow increase after 3 months and PASI and BSI indices after 6 and 12 months (r=0.360.74, p=0.0010.036). Disappearance of Doppler signals in psoriatic plaques skin and decrease in vascular glomeruli average diameter after 1 month from the start of therapy in 1.76 [1.38; 2.30] and 1.30 [1.38; 2.30] times increase the probability of achieving clinical improvement after three months of methotrexate treatment. The correlation coefficient between the degree of NAPSI reduction after 6 and 12 months of treatment and the dynamics of Doppler blood flow in the nail bed and resistance index of arterial vessels in the nail bed after three months from the start of treatment varied from 0.53 to 0.73.&#x0D; CONCLUSIONS: The dynamics of instrumental methods indicators for studying pathological angiogenesis correlates with the probability of achieving clinical improvement in psoriasis symptoms during systemic methotrexate therapy.

Small extracellular vesicles have distinct CD81 and CD9 tetraspanin expression profiles in plasma from rheumatoid arthritis patients.

Extracellular vesicles (EVs) are implicated in the pathogenesis of rheumatoid arthritis (RA) but little is known about the composition of specific small EV (sEV) subpopulations. This study aimed to characterize the CD63, CD81 and CD9 tetraspanin profile in the membrane of single EVs in plasma from treatment naïve RA patients and assess potential discrepancies between methotrexate (MTX) responder groups. EVs isolated from plasma were characterized using transmission electron microscopy, and detection of surface markers (CD63, CD81 and CD9) on single EVs was performed on the ExoView platform. All RA patients (N = 8) were newly diagnosed, treatment naïve, females, ACPA positive and former smokers. The controls (N = 5) were matched for age and gender. After three months of MTX treatment, responders (N = 4) were defined as those with ΔDAS28 > 1.2 and DAS28 ≤ 3.2 post-treatment. The isolated EVs were 50-200nm in size. The RA patients had a higher proportion of both CD9 and CD81 single positive sEVs compared to healthy controls, while there was a decrease in CD81/CD9 double positive sEVs in patients. Stratification of RA patients into MTXresponders and non-responders revealed a distinctly higher proportion of CD81 single positive sEVs in the responder group. The proportion of CD81/CD9 double positive sEVs (anti-CD9 captured) was lower in the non-responders, but increased upon 3months of MTXtreatment. Our exploratory study revealed distinct tetraspanin profiles in RA patients suggesting their implication in RA pathophysiology and MTX treatment response.

Genome-wide association studyof liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate.

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performedto identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: AGWAS was performedon 346 RA patients. Two outcomes within the first 6months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p=2.58×10-8) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5×ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified.

Adenosine Deaminase Gene Polymorphism and Baseline Serum Level of Adenosine Deaminase as a Biomarker of Response to Methotrexate in Rheumatoid Arthritis.

Methotrexate (MTX) is the first-line therapy for rheumatoid arthritis (RA), but nearly 30% of RA patients do not respond to it. Methotrexate acts by enhancing the level of adenosine, which gets converted to inosine by the enzyme adenosine deaminase (ADA). We studied whether ADA gene polymorphism and serum levels of total ADA are associated with responsiveness to MTX. Two hundred seven disease-modifying antirheumatic drug-naive active RA patients (DAS28-ESR [Disease Activity Score-28 for rheumatoid arthritis with erythrocyte sedimentation rate] ≥3.2) satisfying the European League Against Rheumatism (EULAR)/American College of Rheumatology 2010 criteria were enrolled. Genotyping was done in all patients, and in a subset (n = 59), blood was collected at baseline and at 2 months of MTX treatment for serum total ADA estimation by ELISA. Response at 4 months was assessed by EULAR criteria, and patients were classified as responders or nonresponders. The correlation of baseline clinical parameters, ADA gene polymorphism, and serum total ADA levels with EULAR response was sought. After 4 months of MTX monotherapy, 172 patients (83.1%) were classified as responders and 35 (16.9%) as nonresponders. Except DAS28-ESR (6.1 [5.43-6.84] in responders vs 5.6 [4.77-6.21] in nonresponders, p = 0.02), other baseline parameters (age, disease duration, ESR, and C-reactive protein level) were similar between responders and nonresponders. Single nucleotide polymorphisms in ADA gene, baseline serum ADA levels (10.52 ± 5.37 ng/mL in responders vs 12.28 ± 5.14 ng/mL in nonresponders), or change in ADA levels after 2 months of MTX therapy did not show any association with MTX response (p = 0.73, p = 0.34, p = 0.55, respectively). Adenosine deaminase genotype did not affect the blood ADA level. No association was seen between ADA single nucleotide polymorphism rs244076 as well as serum ADA level and response to MTX therapy.

The impact of single nucleotide polymorphisms in ADORA2A and ADORA3 genes on the early response to methotrexate and presence of therapy side effects in children with juvenile idiopathic arthritis: Results of a preliminary study

Methotrexate (MTX) administered at the dose 10-15mg/m2 is recommended as the first-line therapy in most juvenile idiopathic arthritis (JIA) subtypes. The disease-modifying effect of methotrexate is associated with release of adenosine and mediated via binding to adenosine receptor A2A (ADORA2A) and 3 (ADORA3). The aim of our study was to determine the association between single nucleotide polymorphisms in ADORA2A (rs2236624, rs2298383) and ADORA3 (rs3393) receptor genes on the disease activity and presence of MTX therapy side effects in patients with JIA. One hundred children with JIA of all subtypes treated with MTX were recruited to the study. Demographic and clinical parameters were collected at the baseline of MTX therapy and on a control visit 4-6months after starting MTX. Single nucleotide polymorphism genotyping was performed using genomic DNA isolated from peripheral blood samples. The polymorphic variant of ADORA2A rs2236624 was associated with ~3.5 times higher odds of gastrointestinal side effects occurrence (odds ratio: 3.59, 95% CI: 1.15-11.22, P=0.0282). Children with the ADORA3 rs3393 polymorphic variants (CT/CC) after 6months of MTX treatment had significantly lower number of joints with active arthritis (median: 0.00 vs 1.00, P=0.0400) and value of C-reactive protein (0.60 vs 2.40, P=0.0242) in comparison to TT variant. Although future studies are needed to verify our findings, polymorphisms in ADORA2A and ADORA3 genes may become the determinants of MTX treatment efficacy and gastrointestinal toxicity in children with JIA.

Methrotexate Treatment Inmunomodulates Abnormal Cytokine Expression by T CD4 Lymphocytes Present in DMARD-Naïve Rheumatoid Arthritis Patients.

CD4+T-lymphocytes are relevant in the pathogenesis of rheumatoid arthritis (RA), however, their potential involvement in early RA remains elusive. Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug (DMARD), but its mechanism has not been fully established. In 47 new-onset DMARD-naïve RA patients, we investigated the pattern of IFNγ, IL-4 and IL-17A expression by naïve (TN), central (TCM), effector memory (TEM) and effector (TE) CD4+ subsets; their STAT-1, STAT-6 and STAT-3 transcription factors phosphorylation, and the circulating levels of IFNγ, IL-4 and IL-17. We also studied the RA patients after 3 and 6 months of MTX treatment and according their clinical response. CD4+T-lymphocyte subsets and cytokine expression were measured using flow cytometry. New-onset DMARD-naïve RA patients showed a significant expansion of IL-17A+, IFNγ+ and IL-17A+IFNγ+ CD4+T-lymphocyte subsets and increased intracellular STAT-1 and STAT-3 phosphorylation. Under basal conditions, nonresponder patients showed increased numbers of circulating IL-17A producing TN and TMC CD4+T-lymphocytes and IFNγ producing TN, TCM, TEM CD4+T-lymphocytes with respect to responders. After 6 months, the numbers of CD4+IL-17A+TN remained significantly increased in nonresponders. In conclusion, CD4+T-lymphocytes in new-onset DMARD-naïve RA patients show IL-17A and IFNγ abnormalities in TN, indicating their relevant role in early disease pathogenesis. Different patterns of CD4+ modulation are identified in MTX responders and nonresponders.

Association of MTHFR and RFC1 gene polymorphisms with methotrexate efficacy and toxicity in Chinese Han patients with rheumatoid arthritis.

ObjectiveThe objective was to explore the association of methylene tetrahydrofolate reductase (MTHFR) C667T and A1298C and reduced folate carrier 1 (RFC-1) A80G single nucleotide polymorphisms (SNP) with rheumatoid arthritis (RA) and efficacy and toxicity of methotrexate (MTX) treatment in Chinese Han patients in Henan, China.MethodsTwo hundred ninety-six patients with RA were enrolled (cases) and 120 healthy individuals served as controls. The genotypes of MTHFR C667T and A1298C SNP and RFC-1 A80G SNP were detected by restriction fragment length polymorphism-PCR and compared between cases and controls. We analyzed correlations of clinical effect, toxicity, and SNPs after 6 months of MTX treatment.ResultsWe detected no significant differences in MTHFR C677T and A1298C and RFC-1 A80G SNPs between cases and controls. The RFC-1 A80G SNP differed between RA patients with good and poor efficacy after 6 months of MTX, and was an independent factor of MTX efficacy. The MTHFR C677T SNP was differently distributed in the adverse drug reaction (ADR) and non-ADR groups and was an independent factor of MTX toxicity.ConclusionsIn Chinese Han patients with RA, the MTHFR C667T SNP may correlate with MTX toxicity, whereas the RFC-1 A80G SNP may correlate with MTX efficacy rather than toxicity.

The Abnormal CD4+T Lymphocyte Subset Distribution and Vbeta Repertoire in New-onset Rheumatoid Arthritis Can Be Modulated by Methotrexate Treament.

Patients with long-term, treated, rheumatoid arthritis (RA) show abnormalities in their circulating CD4+ T-lymphocytes, but whether this occurs in recently diagnosed naïve patients to disease-modifying drugs (DMARDs) is under discussion. These patients show heterogeneous clinical response to methotrexate (MTX) treatment. We have examined the count of circulating CD4+ T-lymphocytes, and their naïve (TN), central memory (TCM), effector memory (TEM) and effector (TE) subsets, CD28 expression and Vβ TCR repertoire distribution by polychromatic flow cytometry in a population of 68 DMARD-naïve recently diagnosed RA patients, before and after 3 and 6 months of MTX treatment. At pre-treatment baseline, patients showed an expansion of the counts of CD4+ TN, TEM, TE and TCM lymphocyte subsets, and of total CD4+CD28− cells and of the TE subset with a different pattern of numbers in MTX responder and non-responders. The expansion of CD4+TEM lymphocytes showed a predictive value of MTX non-response. MTX treatment was associated to different modifications in the counts of the CD4+ subsets and of the Vβ TCR repertoire family distribution and in the level of CD28 expression in responders and non-responders. In conclusion, the disturbance of CD4+ lymphocytes is already found in DMARD-naïve RA patients with different patterns of alterations in MTX responders and non-responders.

Dietary Intake of Polyunsaturated Fatty Acids and Pain in Spite of Inflammatory Control Among Methotrexate-Treated Early Rheumatoid Arthritis Patients.

ObjectiveTo investigate potential associations between dietary intake of polyunsaturated fatty acids (FAs) and pain patterns in early rheumatoid arthritis (RA) patients after 3 months of methotrexate (MTX) treatment.MethodsWe included 591 early RA patients with MTX monotherapy from a population‐based prospective case–control study, the Epidemiological Investigation of Rheumatoid Arthritis. Dietary data on polyunsaturated FAs (food frequency questionnaires) were linked with data on unacceptable pain (visual analog scale [VAS] >40 mm), noninflammatory/refractory pain (VAS >40 mm and C‐reactive protein [CRP] level <10 mg/liter), and inflammatory pain (VAS >40 mm and CRP level >10 mg/liter) after 3 months. Statistical analysis included logistic regression.ResultsAfter 3 months of MTX treatment, 125 patients (21.2%) had unacceptable pain, of which 92 patients had refractory pain, and 33 patients had inflammatory pain. Omega‐3 FA intake was inversely associated with unacceptable pain and refractory pain (odds ratio [OR] 0.57 [95% confidence interval (95% CI) 0.35–0.95] and OR 0.47 [95% CI 0.26–0.84], respectively). The omega‐6:omega‐3 FA ratio, but not omega‐6 FA alone, was directly associated with unacceptable pain and refractory pain (OR 1.70 [95% CI 1.03–2.82] and OR 2.33 [95% CI 1.28–4.24], respectively). Furthermore, polyunsaturated FAs were not associated with either inflammatory pain or CRP level and erythrocyte sedimentation rate at followup. Omega‐3 FA supplementation was not associated with any pain patterns.ConclusionOmega‐3 FA was inversely associated with, and the omega‐6:omega‐3 FA ratio was directly associated with, unacceptable and refractory pain, but not with inflammatory pain or systemic inflammation. The inverse association between omega‐3 FA and refractory pain may have a role in pain suppression in RA.

NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis.

SummaryBackgroundThe activation of NLRP3-inflammasome may contribute to inflammatory processes in rheumatoid arthritis (RA). Functional polymorphisms in the genes coding for its components NLRP3 and CARD8 were associated with a proinflammatory phenotype. Our aim was to investigate the influence of these polymorphisms on RA susceptibility and disease activity at the time of diagnosis and after six months of treatment.MethodsA group of 128 RA patients treated with methotrexate and 122 healthy controls were genotyped for NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) polymorphisms.ResultsRA susceptibility was not influenced by the investigated polymorphisms or their interaction. The investigated polymorphisms explained 8% of variability in DAS28 at the time of diagnosis. Carriers of NLRP3 rs35829419 or CARD8 rs2043211 polymorphisms had significantly higher DAS28 at the time of diagnosis (p=0.003; p=0.022; respectively). Polymorphic CARD8 rs2043211 TT genotype was also associated with higher DAS28 after six months of treatment (p=0.033).ConclusionsGenetic variability of inflammasome components may contribute to higher disease activity at the time of diagnosis and after 6 months of methotrexate treatment in RA patients. Better understanding of the immunological mechanisms behind a more active course of RA may suggest novel treatment approaches in a subset of patients with a proinflammatory phenotype.

Mutations in the MTHFR gene are not associated with Methotrexate intolerance in patients with juvenile idiopathic arthritis.

BackgroundMethotrexate (MTX) intolerance is a frequent problem of long-term treatment in juvenile idiopathic arthritis (JIA). Mutations in the methylentetrahydrofolate reductase (MTHFR) gene may increase toxicity of MTX, potentially constituting an initial stimulus for this conditioned response. The objective of this study was to investigate the relationship of common MTHFR gene mutations and occurrence of MTX intolerance in pediatric patients with JIA treated with MTX.MethodsConsecutive JIA patients on at least 3 months of MTX treatment were included in this study. Intolerance to MTX was determined using the Methotrexate Intolerance Severity Score (MISS) questionnaire, and MTX intolerance was defined as MISS values of ≥ 6. Presence of the two most common mutations in the MTHFR gene (C677T and A1298C) was tested using a PCR assay. Results were analyzed using descriptive and non-parametric statistics.Results196 patients were included (73 % female). Of those, 93 (46 %) showed MTX intolerance. 168 patients were genotyped for C677T and A1298C. MTX intolerance was not found to be significantly more frequent among patients with hetero- and homozygous or homozygous mutations C677T or A1298C compared to wild type or heterozygous mutations. Analysis of the correlation between numbers of mutations in these two loci to the MISS score did not yield a statistically significant correlation.ConclusionMutations in the MTHFR gene were not found to be significantly more frequent in JIA patients intolerant to MTX. Toxicity associated with the MTHFR gene seems to result from mechanisms different to those involved in clinical MTX intolerance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12969-016-0071-y) contains supplementary material, which is available to authorized users.

Survivin polymorphism is associated with disease activity in rheumatoid arthritis patients.

Survivin expression was associated with unfavorable and erosive course of rheumatoid arthritis (RA). This is the first study investigating association between BIRC5 polymorphisms, survivin plasma levels and disease activity in RA. A testing group of 123 and validation group of 150 RA patients initially treated with methotrexate monotherapy were genotyped for three BIRC5 promoter polymorphisms. Survivin plasma levels were determined in testing group. BIRC5 c.-31G>C was marginally associated with treatment response after 6 months of methotrexate treatment (p = 0.046) and with DAS28 at the time of inclusion in testing (p = 0.052) and in validation group (p = 0.057). Survivin plasma levels were not associated with BIRC5 polymorphisms or DAS28. BIRC5 -31C>G polymorphism could be useful pharmacogenetic marker for methotrexate treatment response in RA.

Serum RANKL levels associate with anti- citrullinated protein antibodies in early untreated rheumatoid arthritis and are modulated following methotrexate.

IntroductionReceptor activator of nuclear factor kappa B ligand (RANKL) is a key regulator of bone metabolism. Anti-citrullinated protein antibodies (ACPA) have been suggested to cause bone destruction by osteoclast activation. We investigated the relationship between RANKL and ACPA in patients with early untreated rheumatoid arthritis (RA).MethodsPatients with newly diagnosed untreated RA (n = 183) were analyzed at baseline and 3 months after initiating methotrexate (MTX) treatment. Serum RANKL (total RANKL), ACPA (anti-CCP2) and ACPA specificities (anti-citrullinated (cit)-vimentin, anti-cit-enolase and anti-cit-fibrinogen) were determined by enzyme-linked immunosorbent assay (ELISA). Synovial RANKL expression was evaluated by immunohistochemistry in a small group of patients (n = 15). The relationship between anti-cit-vim antibodies and bone destruction was further validated in 1116 RA patients included in the EIRA cohort. Pearson’s chi-square test, Wilcoxon rank sum test, Wilcoxon signed rank test and linear regression models were used.ResultsSerum RANKL concentration was significantly higher (p <0.05) in ACPA-positive (median: 689 pmol/L, IQR 342–1253) compared with ACPA-negative (median: 159 pmol/L, IQR 96–243) patients and this difference was also seen for synovial RANKL expression. Serum RANKL associated with ACPA (p <0.05) and bone erosions in rheumatoid factor (RF)-negative patients (n = 59). Among ACPA specificites, anti-cit-vimentin (amino acids 60–75) was associated with higher RANKL concentration and higher prevalence of bone erosion (p <0.05). Significant reductions in both serum RANKL and ACPA levels were observed after 3 months of MTX treatment (p <0.05).ConclusionsRANKL was elevated in ACPA-positive and in anti-cit-vimentin-positive patients with early untreated RA and associated with bone erosions. These findings give further support for an early direct pathogenic link between ACPA and bone destruction in RA.

MTHFR Functional Genetic Variation and Methotrexate Treatment Response in Rheumatoid Arthritis: A Meta-Analysis

To date, functional MTHFR SNPs have been tested for their impact on low-dose methotrexate (MTX) response in small rheumatoid arthritis (RA) cohorts. We sought to test their effect in the single largest cohort studied to date, and undertook a meta-analysis utilizing stringent study inclusion criteria. RA patients treated with MTX monotherapy from the Yorkshire Early Arthritis Register (YEAR) were genotyped using RFLP assays, and tested for association with treatment efficacy. Studies for meta-analysis were screened by a set of stringent inclusion criteria. rs1801131 and rs1801133 were not associated with response to MTX in the YEAR cohort, nor did they affect the probability of achieving a low disease activity state. A meta-analysis of comparable studies found no association with these SNPs. MTHFR SNPs rs1801131 and rs1801133 are unlikely to have a clinically meaningful effect on the first 6 months of MTX treatment in early RA.

SAT0450 Treatment with Leflunomide Results in a Higher Flare Rate of Chronic Uveitis Compared to Methotrexate in Patients with Juvenile Idiopathic Arthritis Treated with Both Drugs

BackgroundChronic anterior uveitis is a common complication of juvenile idiopathic arthritis (JIA). Leflunomide is a frequently used alternative to methotrexate in the treatment of joint manifestations of JIA. However, very...

Pharmacogenetic Polymorphisms Contributing to Toxicity Induced by Methotrexate in the Southern Spanish Population with Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a common illness of global significance for public health. Methotrexate (MTX) is the most broadly used disease-modifying antirheumatic drug for the treatment of RA, but it displays marked person-to-person variation in its propensity for toxicity. Several studies have suggested that polymorphisms in methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, reduced folate carrier (RFC1) G80A, and ABCB1 C3435T, could be related to methotrexate toxicity. This prospective study examined the different frequencies of MTHFR, RFC1, and ABCB1 pharmacogenetic variations between patients who have RA and those without RA. We also sought to assess the association between these polymorphisms and MTX toxicity. Four single-nucleotide polymorphisms (SNPs) were genotyped: C677T and A1298C from MTHFR, G80A from RFC1, and C3435T from ABCB1. The efficacy and toxicity of MTX were evaluated through clinical follow-up during 1 year of treatment. RA patients showed a higher frequency of the T allele at MTHFR C677T than patients without RA (p=0.049). There was a significant association between the presence of both the T allele at MTHFR C677T (p=0.006), and the C allele at ABCB1 C3435T (p=0.046), with toxicity development after 12 months of MTX treatment. However, there was no correlation between MTX toxicity and either the A allele at MTHFR A1298C or the G allele at RFC1 A80G. These data suggest that the presence of the MTHFR C677T and ABCB1 C3435T SNPs contribute to MTX toxicity in patients with RA. These observations contribute to a rapidly-growing knowledge base on the pharmacogenetics of RA and personalized medicine.