Methotrexate In Rheumatoid Arthritis Patients Research Articles

Changes in metabolic parameters and serum YKL-40 levels in Chinese rheumatoid arthritis patients during tocilizumab therapy.

To investigate the metabolic changes during therapy of tocilizumab (TCZ) and methotrexate (MTX) in non-diabetic rheumatoid arthritis (RA) patients and for the first time explore the associations between metabolic parameters and serum YKL-40 (sYKL-40) levels. We enrolled active non-diabetic RA patients who were refractory to MTX. Patients received intravenous TCZ (8mg/kg) once every 4weeks combined with MTX for 24weeks. Metabolic parameters and sYKL-40 levels were measured before TCZ infusion at baseline, week 4, week 12, and week 24. Correlations were assessed by the Spearman's rank correlation analysis. A total of 91 non-diabetic RA patients were enrolled in this study. At week 24, we observed a significant elevation in body mass index (BMI), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels. In contrast, there was a significant decrease in TC/HDL‑C ratio. No apparent changes in insulin resistance were found. Additionally, we detected a significant reduction in sYKL-40 levels during the study. At week 24, changes in sYKL-40 levels showed a significant negative correlation (r = -0.334, p = 0.002) with changes in TC levels. The combined therapy of TCZ and MTX resulted in a significant increase in BMI and lipid levels, while an evident decrease in the TC/HDL‑C ratio and sYKL-40 levels in RA patients. Additionally, there was a significant correlation between the decrease in sYKL-40 levels and the increase in TC levels during treatment with TCZ and MTX. Key Points • Lipid levels elevated significantly and sYKL-40 levels decreased obviously after therapy of TCZ combined with MTX in Chinese RA patients. • There was a significant correlation between the increase in TC levels and the decrease in sYKL-40 levels during treatment with TCZ and MTX in RA patients.

E034 Drug-induced accelerated nodulosis in a patient with rheumatoid arthritis

Abstract Background/Aims Drug-induced accelerated nodulosis (DIAN) is characterized by the occurrence or progression of multiple subcutaneous nodules in a patient treated for rheumatoid arthritis (RA). It was first and most commonly reported with methotrexate in RA patients. Methods A 37-year-old normotensive, non-diabetic, seropositive rheumatoid arthritis female presented with complaints of nodules over the bilateral hands and feet from the last three months. The treatment history included methotrexate therapy (10 mg/week) for one year. Methotrexate-induced rheumatoid accelerated nodulosis (MIAN) was suspected. Methotrexate was stopped and hydroxychloroquine was added considering the low disease activity. The nodules decreased in number as well as size. On follow-up, she presented with increased multiple joint pain and swelling with ESR 60 mm/hour, CRP 13.6 mg/L, and leflunomide was added. After six months of leflunomide use, she again developed multiple bilateral nodules on the extensor and palmar surface of fingers and feet, ranging from 0.5 to 1 cm. The CRP was 9.2 mg/L, ESR 80 mm/hour, complete blood count showed mild anaemia with normal renal and liver function tests. The nodule biopsy showed palisading granuloma consisting of lymphocytes and histiocytes in mid and deep reticular dermis with large foci of fibrin deposition and collagen degeneration s/o rheumatoid nodule. Leflunomide was stopped. Results The leflunomide was switched to sulfasalazine along with colchicine, and hydroxychloroquine was continued. The patient is doing well on follow-up in terms of disease activity and nodule size. Palmeiro. A.G., et al. 2022 reviewed 39 studies from 1st Jan 1988 to 1st Jan 2022 and found 109 cases of accelerated nodulosis. 99 patients had RA, methotrexate was the culprit drug in 89, followed by etanercept in 7 and leflunomide was in just 3 patients. Although there are no exact treatment guidelines, tumour necrosis factor inhibitors were avoided due to increased nodulosis risk. Recently, Valor-Méndez. L., et al 2020 reported improved nodulosis with Janus Kinase inhibitors like baricitinib, which seems to be a future option. Histologically, rheumatoid nodules and accelerated nodulosis are indistinguishable. The exact pathogenesis is unknown but, polymorphic variants of methionine synthase reductase or haplotype HLA-DRB1*0401, and adenosine A1 receptor promotion in multinucleated giant cells are associated. Conclusion Drug-induced accelerated nodulosis (DIAN) and MIAN are not that rare but diagnosis is challenging. It causes significant morbidity and affects the quality of life because of the predominant involvement of hands and feet. It should be suspected especially when disease activity is low or rapidly progressive nodules with a change in immunotherapy. Partial to total improvement can be achieved by identifying and stopping the culprit drug. We need specific guidelines, more treatment options, and a specific national registry to report such adverse effects with biologics and non-biologic disease-modifying antirheumatic drugs. Disclosure H. Singh: None. R. Kaur: None. G. Mohan: None.

Use of Methotrexate for More Than 4 Years Is Not Associated with Liver Fibrosis in Rheumatoid Arthritis Patients

Background. Methotrexate is an anchor drug in the management of rheumatoid arthritis (RA). However, the association between methotrexate and development of liver fibrosis remains a subject of controversy. Non-invasive methods to assess liver fibrosis, such as the FIB-4 score, have been developed. RA patients on methotrexate therapy should be monitored for any signs of liver fibrosis. This study aims to investigate the correlation between methotrexate cumulative dose and the FIB-4 score in rheumatoid arthritis patients who received methotrexate therapy to assess the hepatotoxic effects of methotrexate.
 Methods. This cross-sectional study involved rheumatoid arthritis patients who received methotrexate therapy at Dr. Hasan Sadikin General Hospital Bandung from September 2022 to November 2022. Clinical data, laboratory tests (including platelet values and liver function test), and cumulative methotrexate doses were extracted from medical records. Data were analyzed using the Spearman correlation test.
 Results. This study involved 100 subjects aged between 22-82 years, comprising 93% women and 7% men. The median FIB-4 score was 0.73 (0.24-6.80), while the median methotrexate cumulative dose was 2477.5 mg, with a range of 1005-10400 mg. The results showed that correlation coefficient between the FIB-4 score and methotrexate cumulative dose in rheumatoid arthritis patients was -0.089 (p=0.378).
 Conclusion. There is no significant correlation between FIB-4 score and cumulative dose of methotrexate in rheumatoid arthritis patients. The use of methotrexate in RA patients over 4 years is relatively safe as it does not increase the risk of liver fibrosis.

Serum Cytokine Profiles in Patients with Rheumatoid Arthritis Before and After Treatment with Methotrexate.

Rheumatoid arthritis (RA) is an inflammatory autoimmune illness affecting around 1% of the population globally. Cytokines have a crucial role in the pathogenesis of RA. The objectives of the present study were to compare the serum cytokine profiles between methotrexate (MTX)-treated and MTX-naive RA patient groups, MTX-treated RA patient group and healthy controls, and MTX-naive RA patient group and healthy controls. Enzyme linked immunosorbent assay (ELISA) kits were used to quantify the serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-17, IL-6, interferon-gamma (IFN-γ), and IL-10 in 80 RA patients (48 MTX treated and 32 MTX naive) and 80 healthy controls. For all cytokine assays, absorbance was measured at 450 nm using a microplate reader (Bio-Rad). Independent sample t-test was used to compare the serum cytokine concentrations between the study groups using SPSS version 25. MTX-treated RA patient group had significantly reduced serum levels of TNF-α (36.13 ± 17.64 versus 45.82 ± 23.07, *P = 0.037), IL-17 (307.85 ± 151.74 versus 435.42 ± 241.19, **P = 0.006), and IFN-γ (414.93 ± 212.13 versus 527.15 ± 269.61, *P = 0.041) compared to MTX-naive RA patients. Both MTX-treated and MTX-naive RA patient groups had significantly high serum levels of TNF-α, IL-1β, IL-17, IL-6, IFN-γ, and IL-10 when compared to healthy controls (***P < 0.001). Downregulation of the serum concentrations of certain key cytokines, viz. TNF-α, IL-17, and IFN-γ, demonstrates the anti-inflammatory effect of MTX in RA patients.

The effect of smoking on response to methotrexate in rheumatoid arthritis patients: A systematic review and meta-analysis.

In the current study, we aimed to investigate the effect of smoking on inadequate response to methotrexate (MTX-IR) in rheumatoid arthritis (RA) patients. We searched PubMed, Embase, and Web of Science until 6 June 2022. Observational or interventional studies investigating MTX-IR in RA patients based on smoking status were included. Two independent reviewers assessed the risk of bias and the certainty of the evidence using the Risk of Bias in Nonrandomized Studies-of Interventions and Grades of Recommendation, Assessment, Development, and Evaluation tools, respectively. We included 23 studies in the systematic review and 13 in the meta-analysis. Of the 13 included studies, 6 had a moderate risk, 3 had a serious risk, and 4 had a critical risk of bias. The overall random-effect meta-analysis suggested that smokers were 58% more likely to be MTX-IR when compared with nonsmokers [odds ratio (OR) 1.58, 95% confidence interval 1.21-2.06; P = .001; I2 = 69.3%]. The common-effect meta-analysis of the adjusted ORs demonstrated an overall OR of 2.69 (1.88-3.83; P < .001; I2 = 27.1%). The current study showed that smoking is a significant predictor of MTX-IR, especially in disease-modifying antirheumatic drug-naïve early RA patients, as most of the included studies in the meta-analysis consisted of this population.

Risk of Hepatotoxicity in Leflunomide Vs Methotrexate in Treatment of Rheumatoid Arthritis

Objective: To compare the hepatotoxicity in Leflunomide vs Methotrexate in rheumatoid arthritis patients. Study design: Cross sectional study. Place and duration of study: Study was conducted from Jun 2021 to Mar 2022 at Department of Rheumatology and immunology Sheikh Zayed Hospital Lahore. Methodology: Inclusion criteria were any patient aged between 18-70 years males and females. Patients who were diagnosed with RA according to ACR criteria 2010. Exclusion criteria were pregnancy, Known case of hepatitis B or C, patients having known hypersensitivity to DMARDS. Group A (MTX) of 150 patients received 20 mg/week of MTX and Group B (LEF) of 150 patients received 20mg/day of LEF. The collected data was analyzed on (SPSS) version 24.0. Results: 40 patients were excluded from study. Mean age of patients in Group A (MTX) was 52.73±9.34 years and in Group B (LEF) it was 51.15 + 9.79 years. 44 patients (33.8%) of group A which were given MTX developed GI symptoms while 22 patients (16.9%) of group B who were given LEF developed GI symptoms. Similarly hepatotoxicity was seen in 15 patients (11.5%) of MTX group while 27 patients (20.8%) of LEF group developed hepatotoxicity which was statistically significant (p = 0.04). 5 patients (3.8%) of LEF developed liver fibrosis. Conclusion: We conclude that most LEF with rapid onset of action is quicker in reducing symptoms of RA patients and is associated with high degree of hepatotoxicity with low liver fibrosis when compared with MTX. Keywords: Hepatotoxicity, LEF, MTX, Rheumatoid arthritis

Neuropsychiatric adverse drug reactions associated with low dose methotrexate in rheumatoid arthritis patients

Background: Neuropsychiatric adverse drug reactions (NPADRs) are not commonly associated with low dose methotrexate (LDMTX) in patients with rheumatoid arthritis (RA). Research design and methods: In this case series assessment, we described the nature and frequency of NPADRs with LDMTX in the Dutch DREAM-RA registry, including causality of NPADRs, the impact on further LDMTX treatment and the impact on patient reported Health Related Quality of Life (HRQoL). Results: A total of 71 NPADRs (frequency 6.8%) associated with LDMTX were captured in the DREAM-RA registry. NPADRs were registered for 62 (5.9%) out of 1048 patients with 10.9 NPADRs per 1000 patient years. Headache, dizziness and depression were most frequently reported. The causality was considered probable for 67 NPADRs (94.4%) and definite for 1 NPADR (1.4%). NPADRs led to LDMTX withdrawal in 34 cases (47.9%) and was not restarted in 16 cases (47.1%). Median mental HRQoL was significantly decreased around the occurrence of the NPADR and remained significantly lower after the event. Median physical HRQoL was not significantly affected. Conclusions: Knowledge on the nature, frequency and impact of the demonstrated NPADRs during LDMTX therapy will enhance attention towards these potential ADRs allowing better risk assessment and communication to patients.

Spontaneous regression of breast lymphoproliferative disorders after withdrawal of methotrexate in rheumatoid arthritis patients with Epstein\u2013Barr virus infection: a case report and review of the\xa0literature

BackgroundLymphoproliferative disorder (LPD) has been shown to occur after treatment with methotrexate (MTX). Currently, MTX-LPD has become widely recognized, but its mechanism and prognostic factors remain unclear.Case presentationWe report the first case of Epstein–Barr virus (EBV)-associated MTX-LPD of the breast. A 63-year-old Asian woman with long-term rheumatoid arthritis presented to our facility with intermittent fever. A physical examination revealed a 3-cm lump in her left breast. She had been taking MTX for the past 15 years. Laboratory studies revealed slightly elevated levels of EBV-viral capsid antigen antibody immunoglobulin G and EBV nuclear antibody. Contrast-enhanced computer tomography revealed a mass in the left breast, a subcutaneous nodule in the abdomen, a mass in the left lung, and a nodule in the left retroperitoneum. The definitive diagnosis was consistent with MTX-LPD merging into an EBV-positive, diffuse large B-cell lymphoma. Six months following the withdrawal of MTX, the breast mass had markedly shrunk and the patient remained in good health for 1 year with no evidence of relapse of LPD.ConclusionMTX-LPD rarely occurs in the breast, and it is difficult to diagnose because there have only been six reported cases of breast MTX-LPD reported in the literature. EBV-positive MTX-LPD tends to regress spontaneously after MTX withdrawal, and our case also had similar results. It is important to make an appropriate diagnosis of MTX-LPD of the breast based on imaging and pathology to determine the appropriate treatment protocol for this rare disorder.

Therapeutic Maintenance Level of Methotrexate in Rheumatoid Arthritis: A RBSMR Study.

Objectives:The aim of this study was to determine the therapeutic maintenance level of methotrexate for rheumatoid arthritis patients enrolled in the Moroccan biotherapy registry and to identify predictive factors for discontinuing MTX treatment.Methods:A cross-sectional study was conducted using the baseline data of the Moroccan biotherapy registry for RBSMR (a multicentric study that aims to evaluate tolerance of biological therapy on patients affected with rheumatic diseases). Demographics and disease features were compared using descriptive statistics. Therapeutic maintenance levels were determined according to a Kaplan-Meier survival curve and a univariate Cox proportional hazards regression model was used to compare the strength of potential factors, followed by a multivariate Cox model to identify significant predictors of MTX discontinuation. Statistically significant results were considered for p values less than 0.05.Results:224 patients with rheumatoid arthritis were included in this study. The mean age of patients was 51.83±11.26 years with a majority of females (87.50%). The median duration of disease was 12 [1.66–41.02] years. The therapeutic maintenance level of MTX was 91.1% at 1 year, 87.1% at 2 years, and 68.3% at 5 years. The median of treatment duration was 2, 02 [0, 46–27,76] years. Causes of treatment interruption were side effects (66/88=75%), inefficiency (12/88=13.63%), and other reasons (10/88=11.36%). Predictive factors for stopping MTX were presence of rheumatoid factor (HR 2.24; 95% CI 1.14–5.15; p=0.02) and the access to education (HR 0.37; 95% CI 0.16–0.88; p=0.02).Conclusion:The therapeutic maintenance level of MTX in our study was satisfactory and comparable to other series, and influenced by many factors such as the occurrence of a side effect. It is necessary to sensitise medical practitioners on symptomatic prevention and management of side effects.

Study on the Regulation of Qinxitong Combined with Methotrexate Tablets on Multiple Inflammatory Indicators and Mechanism Factors in Rheumatoid Arthritis

Objective: To study the changes of several inflammatory index mechanism factors in the clinical efficacy of tablet and methotrexate in rheumatoid arthritis. Methods: 20 patients with rheumatoid arthritis were randomly divided into observation (n =10) and control (n =10), then normal people as normal (n=10), all three groups were given methotrexate and the observation group were treated with Qin interest pain tablets. Expression of inflammatory index mechanism factors in each group. Results: After treatment, inflammatory index mechanism factors were detected; a significant decrease of IFN-g, IL-1b, IL-10, IL-37, TNF-a and other factors was found before and after combination treatment (P &lt;0); IL-8 and IL-13 expression (P &lt;0); the CRP, ESR score of the study group was lower than the control group (P &lt;0.05); and the inflammatory index mechanism factors were affected by drug combination. Conclusion: Tablets combined with methotrexate in rheumatoid arthritis patients is better than methotrexate. It obviously changed the expression of the patient’s inflammatory index mechanistic factors, which has a regulatory effect on the inflammatory mechanistic factors.

Development of PBPK model for intra-articular injection in human: methotrexate solution and rheumatoid arthritis case study

A physiologically based model describing the dissolution, diffusion, and transfer of drug from the intra-articular (IA) space to the plasma, was developed for GastroPlus® v9.8. The model is subdivided into compartments representing the synovial fluid, synovium, and cartilage. The synovium is broken up into two sublayers. The intimal layer acts as a diffusion barrier between the synovial fluid and the subintimal layer. The subintimal layer of the synovium has fenestrated capillaries that allow the free drug to be transported into systemic circulation. The articular cartilage is broken up into 10 diffusion sublayers as it is much thicker than the synovium. The cartilage acts as a depot tissue for the drug to diffuse into from synovial fluid. At later times, the drug will diffuse from the cartilage back into synovial fluid once a portion of the dose enters systemic circulation. In this study, a listing of all relevant details and equations for the model is presented. Methotrexate was chosen as a case study to show the application and utility of the model, based on the availability of intravenous (IV), oral (PO) and IA administration data in patients presenting rheumatoid arthritis (RA) symptoms. Systemic disposition of methotrexate in RA patients was described by compartmental pharmacokinetic (PK) model with PK parameters extracted using the PKPlus™ module in GastroPlus®. The systemic PK parameters were validated by simulating PO administration of methotrexate before being used for simulation of IA administration. For methotrexate, the concentrations of drug in the synovial fluid and plasma were well described after adjustments of physiological parameters to account for RA disease state, and with certain assumptions about binding and diffusion. The results indicate that the model can correctly describe PK profiles resulting from administration in the IA space, however, additional cases studies will be required to evaluate ability of the model to scale between species and/or doses.

Олокизумаб в лечении ревматоидного артрита

Olokizumab is a new humanized monoclonal antibody targeting IL-6 that is approved for treatment of patients with moderately severe or severe active rheumatoid arthritis despite therapy with methotrexate and other conventional diseasemodifying antirheumatic drugs or biologic agents. The efficacy and favorable safety profile of olokizumab in combination with methotrexate in rheumatoid arthritis patients who had previously failed methotrexate or tumour necrosis factor inhibitors were established in the several international 3 phase clinical trials (CREDO). The authors present two cases of successful olokizumab administration and discuss the indications for its use in patients with rheumatoid arthritis to achieve clinical improvement and to prevent progression of AA-amyloidosis.

Current smoking predicts inadequate response to methotrexate monotherapy in rheumatoid arthritis patients naïve to DMARDs: Results from a retrospective cohort study.

Identifying predictors of inadequate response to methotrexate (MTX) in rheumatoid arthritis (RA) is key to move from a “trial and error” to a “personalized medicine” treatment approach where patients less likely to adequately respond to MTX monotherapy could start combination therapy at an earlier stage. This study aimed to identify potential predictors of inadequate response to MTX in RA patients naïve to disease modifying anti-rheumatic drugs.Data from a real-life cohort of newly diagnosed RA patients starting MTX (baseline, T0) as first-line therapy were analyzed. Outcomes, assessed after 6 months (T1), were defined as failure to achieve a disease activity score 28 (DAS28) low disease activity (LDA) or a good/moderate response to MTX, according to the European League Against Rheumatism (EULAR) response criteria. Logistic regression was used to assess the associations between baseline variables and the study outcomes.Overall, 294 patients (60.5% females, median age 54.5 years) with a median disease duration of 7.9 months were recruited. At T1, 47.3% of subjects failed to achieve LDA, and 29.3% did not have any EULAR-response. In multivariate analysis, significant associations were observed between no LDA and current smoking (adjusted odds ratio [adjOR] 1.79, P = .037), female gender (adjOR 1.68, P = .048), and higher DAS28 (adjOR 1.31, P = .013); and between no EULAR-response and current smoking (adjOR: 2.04, P = .019), age (adjOR: 0.72 per 10-years increases, P = .001), and higher erythrocyte sedimentation rate (adjOR: 0.49; P = .020). By contrast, there were no associations between past smoker status and study outcomes.In summary, in our real-life cohort of disease modifying anti-rheumatic drug naïve RA patients, current smoking habit independently predicts inadequate response to MTX. This, together with other independent predictors of response to treatment identified in our study, might assist with personalized monitoring in RA patients. Further studies are required to investigate whether smoking quitting strategies enhance the therapeutic response to MTX.

Effect of Folic Acid Supplementation for Reducing Methotrexate Side Effects in Patients with Rheumatoid Arthritis: an Evidence-based Case Report

Background: Rheumatoid arthritis is a chronic inflammatory joint disease,indicated by a symmetrical erosive synovitis. Disease-modifying anti-rheumaticdrugs (DMARDs) are known to interfere with signs and symptoms of RA, improvephysical function and therefore increase patient productivity. Methotrexate is ananchor drug for rheumatoid arthritis patients, however, its related mechanism ofaction with folate deficiency resulting in some side effects, includinggastrointestinal and liver toxicity. Folic acid supplementation may reduce theseside effects. Method: A search was conducted on Pubmed, Cochrane, EBSCOhost,and ProQuest. After the selection of title and abstract was done using inclusionand exclusion criteria, which led to one relevant article. The selected study wascritically appraised for its validity, importance, and applicability. Result: Inrheumatoid arthritis patient receiving methotrexate, there was a statisticallysignificant reduction in the incidence of abnormal transaminase elevation (RR:0.19, 95% CI: 0.10-0.36), but the reduction in gastrointestinal side effects did notreach statistical significance (RR: 0.76, 95% CI: 0.57-1.01) Conclusion: Folic acidsupplementation has an effect in reducing gastrointestinal and liver toxicity as sideeffects of methotrexate in rheumatoid arthritis patients.

What do we know about the possibility of predicting the potential efficacy and safety of methotrexate, by measuring the concentration of its metabolites in rheumatoid arthritis?

Rheumatoid arthritis (RA) is characterized by a progressive course with the formation of joint deformities and the development of severe functional disorders. The most favorable conditions for changing the course of the disease emerge in the first months after its onset. Methotrexate (MTX) occupies a leading position in the treatment of RA. There is a need to develop tools that will be able to predict the efficacy and tolerability of MTX at the earliest stages of RA treatment. The concentration of active metabolites of MTX is considered as a potential biomarker that enables one to predict what response to therapy with this drug will be.The paper analyzes the most relevant works devoted to the study of the concentration of active MTX metabolites polyglutamates (MTX PGs) in patients with RA. It is shown that the presented studies do not cover all the possibilities of therapeutic drug monitoring, in particular the determination of the levels of MTX PGs in mononuclear cells over time. Further investigation is needed to develop an objective approach to prescribing MTX in RA patients.

Analysis of association of ADORA2A and ADORA3 polymorphisms genotypes/haplotypes with efficacy and toxicity of methotrexate in patients with Rheumatoid arthritis.

Adenosine receptors ADORA2A and ADORA3 are part of the adenosine-mediated antiinflammatory pathway and are overexpressed in patients with Rheumatoid arthritis (RA). Methotrexate (MTX) antiinflammatory effects are partially mediated via increased release of adenosine into extracellular space. Polymorphisms in ADORA2A and ADORA3 genes may have an impact on the efficacy and toxicity of MTX in RA patients. The study included 127 RA patients. Treatment efficacy was estimated using the changes in Disease activity score (DAS28) after 6 months of MTX monotherapy, according to EULAR response criteria. Patients with good and moderate response were classified as "responders", and with a poor response as "nonresponders". Adverse effects were collected during the follow-up period. Genotyping for polymorphisms within ADORA2A gene (rs2298383, rs2236624, rs5751876, rs17004921) and ADORA3 gene (rs2298191, rs1544223, rs3393) was performed using the KASPar assays. Among patients 112 (88.19%) were responders (18.8% good, 81.2% moderate). We observed no association between analyzed genotypes or alleles and MTX response by EULAR criteria but carriers of ADORA2A rs17004921 T allele (CT + TT) had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype (p = 0.013). Adverse effects were reported in 31 patients (24.41%). Bone erosions were present in 82 (64.6%) patients. Haplotype block was observed among all 3 analyzed polymorphisms within ADORA3 gene and TAA haplotype was associated with bone erosions (29% vs 15.6%, p = 0.023) and hepatotoxicity (51.3% vs 21.6%, p = 0.013). According to our study, ADORA3 TAA haplotype may be associated with bone erosions and hepatotoxicity in RA patients treated with MTX.

Membrane-Spanning Protein Genetic Polymorphisms Related to Methotrexate Therapeutic Outcomes in a Chinese Rheumatoid Arthritis Population.

Methotrexate (MTX) is a first-line disease-modifying antirheumatic drug for rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. The differences in drug efficacy and adverse drug reactions may be caused by genetic variations. We investigated the effects of single-nucleotide polymorphisms (SNPs) in 2 genes encoding membrane-spanning proteins, namely, reduced folate carrier-1 RFC-1/SLC19A1 (G>A [rs7499], A>G [rs2838956] and 180G>A [rs1051266]) and adenosine triphosphate-binding cassette B1 (rs1045642). Tagged SNPs were genotyped in 162 patients with RA in China. Then, we analyzed the relationships between these SNPs and therapeutic outcomes related to MTX in Chinese RA patients. No significant associations were found between the RFC-1/SLC19A1 (G>A [rs7499] and A>G [rs2838956]) and adenosine triphosphate-binding cassette B1 (rs1045642) gene polymorphisms and the response to MTX in RA patients. However, MTX-related toxicity was associated with one SNP, RFC-1 rs1051266 AA vs GG (odds ratio, 6.523; 95% confidence interval, 1.596-26.565; P = .009). SLC19A1 A>G rs2838956 showed a trend toward a significant association (odds ratio, 0.377; 95% confidence interval, 0.124-1.143; P = .085) with toxicity. Our results suggest that the RFC-1 80G>A (rs1051266) SNP exerts a potentially protective effect against the risk of adverse drug reactions in Chinese RA patients treated with MTX. Further studies are required to validate these findings.

Association between ABCB1 C3435T polymorphism and methotrexate treatment outcomes in rheumatoid arthritis patients: a meta-analysis.

Aim: This study was conducted to investigate the relationship between ABCB1 gene C3435T polymorphism and methotrexate treatment outcomes in rheumatoid arthritis patients. Methods: Seven electronic databases (PubMed, EMBASE, Web of Science, Cochrane, OVID, Chinese biomedical literature [CBM], China National Knowledge Infrastructure [CNKI] and Wanfang databases) were searched to select eligible publications until 18 July 2018. The references of relevant articles were also manually searched. The quality evaluation of the included studies was carried out according to the guidelines of the Newcastle-Ottawa Scale. Data were analyzed with Review Manager 5.3 and Stata 13.0 software. In total, 12 articles involving 2014 patients were included. Conclusion: Our results demonstrated that the ABCB1 gene C3435T polymorphism might be a reliable predictor of response to methotrexate in rheumatoid arthritis patients. However, well-designed, multicenter and large-scale prospective studies are required to further confirm the validity of our results.

Network meta‐analysis of tofacitinib versus biologic treatments in moderate‐to‐severe rheumatoid arthritis patients

Rheumatoid arthritis (RA) is an autoimmune disease characterized primarily by inflammation and pain in the joints. Tofacitinib is an oral drug recently approved for RA treatment; it inhibits Janus protein kinases (JAK) that reduces RA symptoms when conventional DMARDs do not trigger a response. This study aimed to compare the efficacy of biological DMARDs in monotherapy or combined with methotrexate in RA patients and compare the treatments. We reviewed the literature for articles published up to June 2017, evaluating the efficacy and safety of the biological DMARDs indicated for RA in patients with inadequate responses to conventional DMARDs and naïve to biological DMARDs, in similar populations, considering ACR50 as the efficacy variable. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each drug combination, and these parameters were transformed into differences in responses to assess the effectiveness of the alternative medicines. Equivalence therapeutic alternatives (ETA) were ensured to assess the possibility of considering these medications with equivalent efficacy. A network meta-analysis (NMA) was performed using Bayesian approaches and the fixed-effects model. Twenty-seven randomized clinical trials (RCTs) that met the pre-established criteria were identified. The 95% CI of biological DMARDs was higher than that of placebo without methotrexate, except for certolizumab, golimumab-m, anakinra-m and adalimumab monotherapy. These DMARDs performed significantly better than the placebo, except for etanercept, certolizumab, tofacitinib and golimumab. Certolizumab-m was better than anakinra-m and adalimumab, and tocilizumab alone or combined with methotrexate was superior to adalimumab. Etanercept-m yielded a higher difference in responses compared with the other biological DMARDs, which presented more homogeneous responses, except for adalimumab and anakinra-m, which yielded worse results. None of the biological DMARDs displayed ETA to etanercept-m; however, they displayed ETA with certolizumab-m, except for adalimumab and anakinra-m. All biological DMARDs used in combination with methotrexate, except for etanercept, anakinra, certolizumab and tocilizumab without methotrexate, were displayed ETA on using ACR50 at week 24 in patients naïve to biological DMARDs. Etanercept displayed a greater difference in responses, although the high uncertainty of the comparative results prevented the confirmation of the increased efficacy of this drug.

Validation of a clinical pharmacogenetic model to predict methotrexate nonresponse in rheumatoid arthritis patients.

To study the performance of a clinical pharmacogenetic model for the prediction of nonresponse in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) in combination with other synthetic or biologic disease-modifying anti-rheumatic drugs. This prediction model includes gender, smoking status, rheumatoid factor positivity and four genetic variants in AMPD1 (rs17602729), ATIC (rs2372536), ITPA (rs1127354)and MTHFD1 (rs17850560). A total of314 RA patients from three Dutch studies were retrospectively included. Eligible patients were adults diagnosed with RA and had a treatment duration with MTX and follow-up for at least two study evaluation visits. Prediction model risk scores at the first and second evaluation were calculated and compared with the actual nonresponse (disease activity score>2.4). Regression and receiver operating characteristic curve analyses of the prediction model were performed. Also, the sensitivity, specificity and the positive and negative predictive values (PPV and NPV) were determined. The receiver operating characteristic area under the curve was 75% at first and 70% after second evaluation. At the second evaluation, prediction nonresponse had a sensitivity of 67% (CI: 54-78%), specificity of 69% (CI: 60-77%), PPV of 52% (CI: 45-60%) and NPV of 80% (CI: 73-85%). This study demonstrates that the clinical pharmacogenetic model has an inadequate performance for the prediction of nonresponse to MTX in RA patients treated with combination therapies.