Methotrexate In Treatment Of Rheumatoid Arthritis Research Articles

Red blood cell metabolomics identify ergothioneine as a key metabolite in DMARD-naïve rheumatoid arthritis and response to methotrexate

Using a new red blood cell (RBC) metabolite extraction protocol, we performed a metabolomic analysis on RBCs in rheumatoid arthritis (RA) patients treated or not with methotrexate (MTX), with the two following objectives: to compare the RBC metabolic profiles of MTX-naïve RA patients and healthy controls (HC), and to investigate whether RBC profiles before and after MTX treatment in RA differed between responders and non-responders. Plasma analysis was performed in parallel. Metabolites were extracted and identified in RBCs and plasma by liquid chromatography-mass spectrometry. We compared the metabolomic fingerprints of 31 DMARD-naïve RA patients and 39 HCs. We also compared the RBC and plasma metabolomes of 25 RA patients who responded or not to MTX therapy before (M0) and after a 3-month treatment period (M3). Significance was determined by Storey’s false discovery rate (FDR) q-values to correct for multiple testing. RA patients and HCs differed in the metabolomic signature of RBCs. The signature mainly contained amino acids (AA). Eleven metabolites, including 4 metabolites belonging to the carbohydrate subclass and 2 amino acids (creatine and valine) showed accumulation in RBCs from RA patients. Conversely, citrulline (fold change = 0.83; q = 0.025), histidine (fold change = 0.86; q = 0.014) and ergothioneine (EGT) (fold change = 0.66; q = 0.024), were lower in RBC of RA patients. Five plasma metabolites, including succinic acid and hydroxyproline, were higher in RA patients, and 7 metabolites, including DHEA sulfate, alanine, threonine and ornithine, were lower. Among RA patients undergoing MTX treatment pre-treatment (M0), EGT values were significantly lower in non-responders. In conclusion, low RBC levels of EGT, a food-derived AA barely detectable in plasma, characterize DMARD naïve RA patients and lack of response to MTX treatment.

Differences in IDO1+ dendritic cells and soluble CTLA-4 are associated with differential clinical responses to methotrexate treatment in rheumatoid arthritis.

Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-naïve RA patients to determine their role to inflammatory arthritis management. Thirty-six treatment-naïve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured. DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141+ cDC1s were the major IDO1-expressing cells. IDO1+cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1+cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c+ cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1+cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1+cDC1 cells, low sCTLA-4 and non-response to MTX. Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1+cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1+cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases.

Hepatic and lung methotrexate-associated polymorphic lymphoproliferative disorders arising during postoperative follow-up of renal cell carcinoma: a case report

IntroductionMethotrexate induces lymphoproliferative disorders on rare occasions; however, its pathogenesis remains unknown. A clinical diagnosis based on imaging studies alone is often difficult.Case presentationA 57-year-old Japanese woman was referred to our department for the evaluation of multiple lung and hepatic nodules that developed during methotrexate treatment for rheumatoid arthritis. Since she had a history of nephrectomy for localized renal cell carcinoma, multiple lung and hepatic metastases were initially considered. However, pathological diagnosis of the lung nodules (needle biopsy) revealed methotrexate-associated polymorphic-type lymphoproliferative disorders. After methotrexate discontinuation, continuous smooth shrinkage of the lung and liver lymphoproliferative disorders was observed.ConclusionMethotrexate-associated lymphoproliferative disorders should be considered in the event of newly appearing neoplastic lesions, even during follow-up for renal cell carcinoma, if methotrexate is being administered.

Patterns of Cytopenias Associated with Methotrexate Treated Rheumatoid Arthritis Patients

Objective: To determine the frequency of various patterns of cytopenias with Methotrexate-treated rheumatoid arthritis patients and the correlation of pancytopenia with various factors.
 Study Design: Cross-sectional study.
 Place and Duration of Study: Rheumatology/General Medicine Department, Pak Emirates Military Hospital Rawalpindi from May 2019 to Mar 2020.
 Methodology: Patients with rheumatoid arthritis who were managed with Methotrexate for more than six months were included in the study. Full blood counts were performed for all the patients from the laboratory of the hospital. The frequency of monocytopenia, bi-cytopenia and pancytopenia were calculated.
 Results: Mean age of the study participants was 37.41±5.72 years. One hundred and sixty-eight 168(84%) patients had the presence of any cytopenia, while 32 (16%) did not show the presence of any cytopenia on full blood count. The advancing age and use of polypharmacy had a statistically significant association with cytopenias among patients with rheumatoid arthritis managed with Methotrexate (p-value <0.05).
 Conclusion: The presence of cytopenia emerged as a relatively common finding among rheumatoid arthritis patients managed with Methotrexate. Advanced age of the patient and patients who required more than one medication to control the symptoms of RA were found at a higher risk for developing pancytopenia while being managed with Methotrexate for rheumatoid arthritis.

EBV-positive mucocutaneous ulcer arising in methotrexate-treated rheumatoid arthritis patients: a clinicopathological study of 12 cases with analysis of PD-L1 expression.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized disease entity characterized by EBV-positive atypical B-cell proliferation. EBVMCU is a localized self-limited disease that affects mucosa and skin, especially the oral cavity. EBVMCU develops in immunosuppressive patients, such as those with methotrexate (MTX)-administrated rheumatoid arthritis (RA). Here we clinicopathologically analyzed 12 EBVMCU patients in a single institution. All cases were administrated MTX for RA, and five cases occurred in the oral cavity. All cases except one had demonstrated spontaneous regression after withdrawal of the immunosuppressive agent. We found 4 of 5 cases in the oral cavity had preceding traumatic events in the same site within a week before the onset of EBVMCU. Although there is no detailed and large study that has analyzed the trigger of EBVMCU, a traumatic event would indeed be a significant trigger for EBVMCU in the oral cavity. The cases were histologically classified; six cases were diffuse large B-cell lymphoma-type, five were polymorphous-type, and one was Hodgkin-like lesion type due to morphological appearance and immunophenotype. The PD-L1 expression was also examined by two antibodies for PD-L1 (E1J2J and SP142). Both antibodies revealed identical results for PD-L1 expression, and three cases were positive for PD-L1. The application of SP142 for evaluating the immune status of lymphomagenesis has also been proposed. Nine of 12 cases were negative for PD-L1, which implies that most EBVMCU cases may be caused by an immunodeficiency, rather than an immune-evasion, mechanism. However, as three cases were positive for PD-L1, immune escape may underly the pathogenesis in a subset of EBVMCU cases.

Development of leukocytoclastic vasculitis during long-term methotrexate therapy in patients with rheumatoid arthritis: description of two clinical cases

Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis characterized by immune complex depositions involving dermal post-capillary venules. Cutaneous small vessel vasculitis is most often idiopathic but may be aggravated by secondary causes, such as inflammatory conditions, infections, neoplasms, and drugs exposure.Herein, we describe two patients with a long history of rheumatoid arthritis (RA) treated with methotrexate (MTX) for more than ten years, who later developed generalized LCV with pancytopenia after a viral infection, one with herpes simplex virus, and the other with SARS-CoV-2 virus. Because of the worldwide use of MTX in treatment of RA, strict follow-up and preventive measures are needed nowadays, especially during COVID-19 pandemic, in order to avoid any infection which may provoke LCV with or without systemic manifestations. So, using MTX for treating RA or other similar disorders may be considered a double-edged sword, especially during COVID-19 pandemic.

Short-term glucocorticoids reduce risk of chronic NSAID and analgesic use in early methotrexate-treated rheumatoid arthritis patients with favourable prognosis: subanalysis of the CareRA randomised controlled trial

ObjectiveTo explore non-steroidal anti-inflammatory drug (NSAID) and analgesic use in early rheumatoid arthritis (eRA) patients with a favourable risk profile initiating methotrexate (MTX) with or without glucocorticoid (GC) bridging.MethodsPatients with...

Traditional Chinese medicine Biqi capsule compared with leflunomide in combination with methotrexate in patients with rheumatoid arthritis: a randomized controlled trial

BackgroundBiqi capsule is a traditional Chinese medicine widely used as a complementary and alternative treatment for rheumatoid arthritis (RA). The objective is to understand the efficacy, safety and mechanism of Biqi combined with methotrexate (MTX) in RA.MethodsWe present a randomized, controlled pilot trial on Biqi combined with MTX against patients with active RA. Seventy patients were randomized 1:1 to receive Biqi + MTX or Leflunomide (LEF) + MTX for 24 weeks, and were assessed at baseline, 4, 12 and 24 weeks. Serum and urine samples were collected for metabolomics.ResultsOverall, 81.2% patients in Biqi group achieved ACR20 at 24 weeks. No statistically significant differences were observed in primary or secondary outcomes between the two groups. A better safety profile was observed for Biqi with significantly fewer adverse effects reported (11.4%) compared to LEF group (40%, P < 0.05). Comparison between treatment responders and non-responders indicated a unique urine metabolic profile of enriched fatty acids and decreased acylcarnitines associated with Biqi responders, indicating a restored energy homeostasis in response to Biqi. The gene targets of these metabolites were significantly enriched in interleukin-4 and interleukin-13 pathways, implying that Biqi could ameliorate Th2-derived inflammatory response. Multivariate network analysis indicated that patient morning stiffness and SJC were key factors associated with metabolomics in Biqi-treated patients, whereas CRP was the main factor in LEF group. Therefore, Biqi and LEF likely work by influencing different patient clinical parameters.ConclusionsOur study suggests that Biqi capsule can be a promising alternative option in combination with MTX for RA treatment, and demonstrates the capability of using metabolomics to interrogate mechanism of action for traditional Chinese medicine.Trial registration This trial is registered with ChiCTR, No. ChiCTR-IPR-16009029. Registered August 15, 2016. http://www.chictr.org.cn/showprojen.aspx?proj=15034

Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice.

AimTo assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.MethodsAll RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis.ResultsThe study comprised 213 RA patients starting MTX. During a mean follow‐up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre‐treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2‐20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non‐alcoholic fatty liver disease. No patient developed hepatic failure.ConclusionOnly a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre‐treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

Highly aggressive plasmablastic neoplasms in patients with rheumatoid arthritis treated with methotrexate

Patients with rheumatoid arthritis occasionally develop lymphoproliferative disorders. Methotrexate-associated lymphoproliferative disorders is a lymphoproliferative disease or lymphoma in patients treated with methotrexate for autoimmune diseases, such as rheumatoid arthritis. Here we report two rare cases of highly aggressive plasmablastic lymphoproliferative disorders in rheumatoid arthritis treated with methotrexate.Case 1 is a 68-year-old female patient with leukemic transformation of malignant lymphoma. She received methotrexate therapy for rheumatoid arthritis for >6 years. The patient showed rapid progressive course and died on the 2nd hospital day. After the death, we diagnosed the patient as plasmablastic lymphoma. Case 2 is an 80-year-old female patient with plasmablastic plasma cell myeloma, with a history of methotrexate treatment for rheumatoid arthritis for >5 years. Although M-protein was decreased by chemotherapy, bone marrow examination revealed the further increase of plasmablastic cells and she died 2 months later.The present cases were difficult to diagnose because proliferation of malignant plasmablasts was hardly predicted because neither lymph node enlargement nor an evident M-protein was observed. Both cases showed aggressive features and extremely poor prognosis. Clinicians should be aware of the underlying malignant plasmablastic proliferation when inexplicable inflammatory findings are observed in inactive rheumatoid arthritis patients.

Methotrexate-Induced Oral Erythema Multiforme: a Case Report

Erythema multiforme (EM) is an inflammatory mucocutaneous disorder. It can be triggered by herpes simplex virus infection or adverse drug reaction. Oral EM is characterized by oral mucosal ulcerations and lip lesions without any skin lesions. A 65-year-old man was referred for painful ulcerations covered with necrotic tissue on the vermillion of the upper and lower lips, lateral border of the tongue, and buccal mucosa. Medical history revealed methotrexate treatment for rheumatoid arthritis. Histopathologic analysis showed ulceration areas and moderate to dense perivascular, mainly lymphocytic inflammatory infiltrate. The sudden onset of extensive ulcerations in the oral cavity, a positive drug history, and histopathologic analysis led to the diagnosis of oral EM. Although oral EM is confined to the oral cavity, subsequent attacks can produce more severe forms of EM. Hence, it is important to identify oral EM for early diagnosis, adequate treatment, and follow-up.

Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment.

ObjectiveThe mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA).MethodsBetween October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined.ResultsWe followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity.ConclusionRisk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.

Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis

Regulatory T cells as a biomarker for response to adalimumab in rheumatoid arthritis

Endogenous inspired biomineral-installed hyaluronan nanoparticles as pH-responsive carrier of methotrexate for rheumatoid arthritis

Methotrexate (MTX), an anchor drug for rheumatoid arthritis (RA), has been suffered from refractoriness and high toxicity limiting effective dosage. To mitigate these challenges, the ability to selectively deliver MTX to arthritis tissue is a much sought-after modality for the treatment of RA. In this study, we prepared mineralized nanoparticles (MP-HANPs), composed of PEGylated hyaluronic acid (P-HA) as the hydrophilic shell, 5β-cholanic acid as the hydrophobic core, and calcium phosphate (CaP) as the pH-responsive mineral. Owing to the presence of CaP as the diffusion barrier, mineralized HANPs revealed the pH-responsiveness of release kinetics of MTX across neutral to acidic conditions. HANPs were internalized via receptor-mediated endocytosis in macrophages which involved molecular redundancy among major hyaladherins, including CD44, stabilin-2, and RHAMM. Following endocytosis, MP-HANPs loaded with doxorubicin revealed pH-dependent demineralization followed by dramatic acceleration of drug release into the cytosol compared to other HANPs. Furthermore, an in vivo study showed a significantly high paw-to-liver ratio of fluorescent intensity after systemic administration of MP-HANP-Cy5.5, indicating improved biodistribution of nanoparticles into arthritic paws in collagen-induced arthritis mice. Treatment with MTX-loaded MP-HANPs ameliorated inflammatory arthritis with remarkable safety at high dose of MTX. We highlight the distinct advantages of combining key benefits of biomineralization and PEGylation with HA-based nanoparticles for arthritis-selective targeting, thus suggesting MP-HANPs as a promising carrier of MTX for treatment of RA.

Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis

BackgroundThe aim of the Dose Reduction or Discontinuation of Etanercept in Methotrexate-Treated Rheumatoid Arthritis Patients Who Have Achieved a Stable Low Disease Activity-State study was to investigate the effect of...

Leflunomide combined with methotrexate in treatment of Rheumatoid Arthritis

Objective To explore the efficacy and safety of leflunomide combined with methotrexate in the treatment of rheumatoid arthritis.Methods 120 patients with active rheumatoid arthritis were randomly divided into a treatment group(n=60) and a control group(n=60).The treatment group was treated with leflunomide and methotrexate,while the control group with only methotrexate.The efficacies and adverse reactions compared between two groups.Results The total effective rate was 88.3％ in the treating group and was 71.7％ in the control group,with a statistical difference(P＜0.05).The incidence of adverse reactions was 25％ in the treating group and was 20％ in the control group,with no statistical difference (P＞0.05).Conclusion Leflunomide combined with methotrexate in the treatment of rheumatoid arthritis is effective and worth being clinically generalized. Key words: Rheumatoid arthritis; Leflunomide; Methotrexate

AB0459 Audit of Methotrexate and Pulmonary Function Tests

BackgroundMethotrexate pneumonitis (MTX-P) is most frequently seen within the first year of treatment1 and is best avoided in established cases of Interstitial Lung disease (ILD). BSR recommends that if pre-treatment...

Improving treatment with methotrexate in rheumatoid arthritis—Development of a multimedia patient education program and the MiRAK, a new instrument to evaluate methotrexate-related knowledge

ObjectivesTo develop and test an evidence-based, multimedia patient education program (MPEP) about methotrexate (MTX) treatment for rheumatoid arthritis (RA) and a new measure of patient knowledge [Methotrexate in Rheumatoid Arthritis Knowledge test (MiRAK)]. MethodsThe content of the MPEP and MiRAK was guided by concept-mapping workshops with patients (N = 24), literature review, health professional, and expert linguistic input. The MPEP and MiRAK underwent multiple stages of testing and revision with patients and health professionals. The MiRAK was administered to RA patients (N = 169) and its properties examined using the Rasch analyses. A subset of respondents (N = 131) repeated the MiRAK to determine test–retest reliability. A before–after pilot study with patients who had recently started MTX (N = 31) tested responsiveness of the MiRAK and feasibility and acceptability of the MPEP. ResultsA DVD of 24-minutes duration was produced that presents detailed, evidence-based information about MTX. The Rasch analyses of the 60 MiRAK items revealed that these could be summated into a single score. The MiRAK had good model fit, supporting internal construct validity, good internal consistency (person separation index; 0.84), test–retest reliability (ICC; 0.89), and ability to detect change (ES; 2.38). The before–after study suggested that patients could self-administer the MPEP, with the majority finding it informative and easy to use. ConclusionsWe developed a MPEP about MTX treatment for RA, which was found to be user-friendly and easily implementable. The MiRAK is a new scale, testing a broad spectrum of MTX knowledge. Analyses revealed strong evidence for its validity and reliability.

THU0253 Synoviocyte Apoptosis May Differentiate Responder and Non-Responder Patients to Methotrexate Treatment in Rheumatoid Arthritis

Backgroundthere is no study reporting whether MTX inhibits rheumatoid synovitis by inducing apoptosis of synoviocytes, depending on the clinical sensitivity of MTX.ObjectivesWe aimed to evaluate whether MTX in vitro induces...

The time course of gastric methotrexate intolerance in patients with rheumatoid arthritis and psoriatic arthritis

Objectives This study aimed to evaluate the incidence and the time course of methotrexate (MTX)-associated gastric intolerance in patients with rheumatoid arthritis and psoriatic arthritis.Methods Four hundred twenty subjects undergoing MTX treatment for rheumatoid arthritis (n = 346) and psoriatic arthritis (n = 74) were retrospectively assessed. The incidence and time course of gastric MTX intolerance resulting in treatment discontinuation were investigated. In addition, the relations between gastric intolerance and patient characteristics, including gender, age, diagnosis, and rheumatoid factor (RF) positivity, were examined.Results Overall, oral MTX discontinuation rate due to gastric intolerance was 28.6 %. The time to discontinuation for oral MTX was 8.1 ± 11.5 months on average, with more than half of the discontinuations occurring within the first three months of treatment. Discontinuation was not associated with gender, age, diagnosis, or RF positivity. More than half of the patients that switched to a parenteral treatment regimen (52.6 %, 20/38) could tolerate the agent.Conclusions Gastric MTX intolerance usually develops within the first year of treatment and presents a major obstacle to long-term treatment retention in patients with rheumatologic disease. However, parenteral MTX appears to be a good alternative for patients intolerant of oral MTX.