Low-dose Methotrexate Therapy Research Articles

Clinicopathological characteristics of low-dose methotrexate-induced epidermal dysmaturation: A study of 22 patients.

Erosions of the skin and mucous membranes with epidermal dysmaturation are a known side effect of cytostatic chemotherapy regimens and can also be observed during low-dose methotrexate (MTX) therapy. The study aimed to delineate the clinical and histopathological alterations. A database search of the archive for dermatopathology was conducted, identifying 22 patients who developed epidermal dysmaturation on low-dose MTX. Clinical and laboratory changes, along with an array of histologic parameters were analyzed and statistically evaluated using SPSS. Patients were predominantly female with a mean age of 69.1years. The main indications were psoriasis vulgaris and rheumatoid arthritis. Clinically, patients mostly presented erosive plaques at the injection site, on mucosal surfaces, and disseminated lesions. Most patients showed normal laboratory values. Histopathologically, key findings included enlarged keratinocytes with pale cytoplasm and enlarged nuclei with prominent nucleoli, along with the degeneration of the basal layer. Consistent observations in the dermal compartment included infiltration of neutrophilic granulocytes, lymphocytes, and histiocytes. This study proposes clinicopathological criteria for the diagnosis of MTX-associated skin toxicity, aiming to increase awareness among clinicians and pathologists for early diagnosis. Early recognition can prevent potentially life-threatening progression.

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.

Platelet Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Mitigate Methotrexate-Induced Nephrotoxicity in Rat via Nrf2/Pparγ/HO-1 and NF-Κb/Keap1/Caspase-3 Signaling Pathways: Oxidative Stress and Apoptosis Interplay.

the nephrotoxicity of methotrexate (MTX) is observed in high-dose therapy. Moreover, low-dose MTX therapy for rheumatic diseases is debatable and claimed to cause renal impairment. This study aimed at studying the effect of methotrexate in repeated low doses on rat kidneys and assessing the efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and platelet rich plasma (PRP) for attenuating this effect. Forty-two male Wistar rats were used, 10 rats were donors of AD-MSCs and PRP, 8 rats served as control, and the remaining rats were subjected to induction of nephrotoxicity by MTX intraperitoneal injection once weekly for successive 8 weeks and then assigned into 3 groups of 8 animals each: Group II: received MTX only. Group III: received MTX + PRP. Group IV: received MTX + AD-MSCs. After one month, rats were anaesthetized, serum-sampled, and renal tissue removed for biochemical, histological, and ultrastructural evaluation. there was significant tubular degeneration, glomerulosclerosis, fibrosis, decreased renal index, along with increased levels of urea and creatinine in the MTX group compared to the control group. Immunohistochemical expression of caspase-3 and iNOS in the renal tissue was significantly increased in group II compared to groups III and IV. Biochemical results revealed higher tissue malondialdehyde (MDA) concentration in the MTX-injected group which decreased significantly in co-treatment with either AD-MSC or PRP + MTX. MSC promoted the activation of the Nrf2/PPARγ/HO-1 and NF-κB/Keap1/caspase-3 pathways, increased antioxidant enzyme activities, reduced lipid peroxidation levels, and alleviated oxidative damage and apoptosis. PRP showed therapeutic effects and molecular mechanisms similar to MSC. Furthermore, MSC and PRP treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NF-κB, interleukin-1ß, and TNF-α), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (iNOS) markers in the kidney. repeated administration of low-dose MTX resulted in massive renal tissue toxicity and deterioration of renal function in rats which proved to be attenuated by PRP and AD-MSCs through their anti-inflammatory, anti-apoptotic and anti-fibrotic properties.

Adverse effect profile with low-dose methotrexate therapy in patients suffering with rheumatic diseases

Background: Methotrexate (MTX) is the anchor drug for the management of many systemic inflammatory diseases. High-dose MTX is associated with various toxicities which may lead to drug discontinuation or interruption of therapy. Low-dose MTX is widely used for treating various systemic autoimmune diseases and is considered relatively safe. Aims and Objectives: In this study, we describe the clinical features and factors affecting adverse effects of low-dose MTX in a large cohort of patients with autoimmune rheumatic diseases (AIRDs) from a tertiary health center in South India. Materials and Methods: This was a retrospective analysis wherein we aimed to characterize the clinical features seen in and factors associated with adverse effects due to low-dose MTX. We reviewed the medical records of patients who were receiving MTX for their underlying AIRD from the Department of Clinical Immunology and Rheumatology and General Medicine. Inclusion: Patients with AIRDs being treated with MTX, who suffered from adverse events. Excluded: Patients on other csDMARDs and bDMARDs. Clinical profile, indications of therapy, dose of MTX, adverse effects, and deranged laboratory parameters were noted. Results: A total of 815 subjects using MTX were identified over a period of 6 months duration (n = 713 (87%) females). Underlying autoimmune conditions included rheumatoid arthritis (n = 675, 82.8%). The most common adverse event noted was hair loss (7.7%), followed by nausea (3.9%). Cytopenia and transaminitis were noted in 1.6% and 2.2%, respectively. Higher incidence of adverse events was seen in those without folic acid intake (81.2%; P = 0.0001). Conclusion: Low-dose MTX, although causes mild adverse effects and has the potential to cause life-threatening adverse events like cytopenia, is usually well tolerated. Identification of toxicities early improves the outcomes of patient care. Folate supplementation ameliorates side effects.

Gynecomastia associated with methotrexate therapy for psoriatic arthritis

Methotrexate is widely used for treatment rheumatic diseases, including psoriatic arthritis. Adverse reactions could develop during methotrexate therapy, the most common of which are skin lesions, liver dysfunction, diarrhea, nausea, etc. Gynecomastia is a rare complication of low-dose methotrexate therapy. The mechanism of its development is not fully understood. We present a case report of the development of gynecomastia in a patient with psoriatic arthritis during treatment with methotrexate.

Hepatic safety of low dose methotrexate therapy in patients with Rheumatoid Arthritis.

Objective: To determine the Hepatic safety of low dose methotrexate therapy in patients with Rheumatoid Arthritis. Study Design: Prospective and Descriptive study. Settings: Department of Medicine, Peshawar Institute of Medical Sciences. Period: May 2020 to May 2021. Material &amp; Methods: A total of 151 patients with rheumatoid Arthritis were included in this study. All diagnosed patients were advised baseline liver function tests and routine blood investigations. Patients were started on methotrexate 7.5 mg weekly. On each monthly follow-up visit, liver function tests were done to detect hepatotoxicity. Results: A total of 151 patients of rheumatoid arthritis were included in this study with a female to male ratio of 1.4:1. Average age of the patients was 43.76 years -+ 12.7 SD with range 17-72 years. Only in 17 (11.26%) of patients on 7.5 mg /weekly dose of methotrexate, mild hepato-toxicity was observed based on the elevation of aminotransferases more than two times upper limit of Reference(ULR). Conclusion: Although Hepato-toxicity can occur in a minority of patients on low dose methotrexate therefore in low dose it is a safe drug for the treatment of 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.

Pharmacomicrobiology of Methotrexate in Rheumatoid Arthritis: Gut Microbiome as Predictor of Therapeutic Response.

Rheumatoid arthritis (RA) is a disabling autoimmune disease with invasive arthritis as the main manifestation and synovitis as the basic pathological change, which can cause progressive destruction of articular cartilage and bone, ultimately leading to joint deformity and loss of function. Since its introduction in the 1980s and its widespread use in the treatment of RA, low-dose methotrexate (MTX) therapy has dramatically changed the course and outcome of RA treatment. The clinical use of this drug will be more rational with a better understanding of the pharmacology, anti-inflammatory mechanisms of action and adverse reaction about it. At present, the current clinical status of newly diagnosed RA is that MTX is initiated first regardless of the patients’ suitability. But up to 50% of patients could not reach adequate clinical efficacy or have severe adverse events. Prior to drug initiation, a prognostic tool for treatment response is lacking, which is thought to be the most important cause of the situation. A growing body of studies have shown that differences in microbial metagenomes (including bacterial strains, genes, enzymes, proteins and/or metabolites) in the gastrointestinal tract of RA patients may at least partially determine their bioavailability and/or subsequent response to MTX. Based on this, some researchers established a random forest model to predict whether different RA patients (with different gut microbiome) would respond to MTX. Of course, MTX, in turn, alters the gut microbiome in a dose-dependent manner. The interaction between drugs and microorganisms is called pharmacomicrobiology. Then, the concept of precision medicine has been raised. In this view, we summarize the characteristics and anti-inflammatory mechanisms of MTX and highlight the interaction between gut microbiome and MTX aiming to find the optimal treatment for patients according to individual differences and discuss the application and prospect of precision medicine.

Safety and immunogenicity of a primary yellow fever vaccination under low-dose methotrexate therapy-a prospective multi-centre pilot study1.

More people on immunosuppression live in or wish to travel to yellow fever virus (YFV)-endemic areas. Data on the safety and immunogenicity of yellow fever vaccination (YFVV) during immunosuppression are scarce. The aim of this study was to compare the safety and immunogenicity of a primary YFVV between travellers on methotrexate and controls. We conducted a prospective multi-centre controlled observational study from 2015 to 2017 in six Swiss travel clinics. 15 adults (nine with rheumatic diseases, five with dermatologic conditions and one with a gastroenterological disease) on low-dose methotrexate (≤20mg/week) requiring a primary YFVV and 15 age and sex-matched controls received a YFVV. Solicited/unsolicited adverse reactions were recorded, YFV-RNA was measured in serum samples on Days 3, 7, 10, 14, 28 and neutralizing antibodies on Days 0, 7, 10, 14, 28. Patients´ and controls' median ages were 53 and 52years; 9 patients and 10 controls were female. 43% of patients and 33% of controls showed local side effects (P = 0.71); 86% of patients and 66% of controls reported systemic reactions (P = 0.39). YFV-RNA was detected in patients and controls on Day 3-10 post-vaccination and was never of clinical significance. Slightly more patients developed YFV-RNAaemia (Day 3: n = 5 vs n = 2, Day 7: n = 9 vs n = 7, Day 10: n = 3 vs n = 2, all P > 0.39). No serious reactions occurred. On Day 10, a minority of vaccinees was seroprotected (patients: n = 2, controls: n = 6). On Day 28, all vaccinees were seroprotected. First-time YFVV was safe and immunogenic in travellers on low-dose methotrexate. Larger studies are needed to confirm these promising results.

Development of pancytopenia after single low-dose methotrexate therapy in patients with chronic kidney disease: a review of the literature

Methotrexate (MTX) is widely used in the treatment of both rheumatoid arthritis (RA) and psoriatic arthritis (PA) with a side effect of pancytopenia. However, very few cases of severe pancytopenia caused by low-dose MTX therapy have been described in chronic kidney disease. Pancytopenia occurred after using a single dose of MTX in three patients with chronic kidney dysfunction. While one patient died due to sepsis and multiple organ failure, the others recovered. The severity of MTX-inducedpancytopenia in our cases was likely related to the underlyingkidney disease. These cases suggest that uremic patients may develop severe fatal bone marrow toxicity even with a single dose of MTX. Therefore, close blood count monitoring after MTX treatment in this population would be beneficial.

Nephrotoxicity Associated with Low-dose Methotrexate and Outpatient Parenteral Microbial Therapy: A Case Report, Review of the Literature and Pathophysiologic Insights.

Methotrexate (MTX) toxicity can affect multiple organ systems, manifesting as nephrotoxicity, myelosuppression, hepatotoxicity, mucositis, and gastrointestinal upset. Serious adverse events are rare in patients prescribed low-dose methotrexate. We present a case of an 86-year-old female on a weekly dose of oral MTX 12.5 mg for rheumatoid arthritis presenting with painful gingiva and oral bleeding during outpatient antimicrobial therapy (OPAT) for osteomyelitis with vancomycin and piperacillin-tazobactam. She had acute kidney injury (AKI), elevated serum MTX levels, thrombocytopenia, neutropenia, and a vancomycin level three times therapeutic concentration. MTX toxicity was suspected to have been triggered by vancomycin and piperacillin-tazobactam causing AKI and impaired renal clearance of MTX which itself is nephrotoxic. The patient was managed with leucovorin, alkalinized intravenous fluids, and filgrastim injections over a 2-week period. Her renal function continued to be reduced at 5-week outpatient follow-up, far after other markers of toxicity normalized. This case demonstrates the importance of considering potential drug-drug interactions and the need for robust monitoring for OPAT in select groups.

A Call to Systematically Monitor for Adverse Events in Users of Low-Dose Methotrexate Therapy.

In their article, Solomon and colleagues reported prespecified safety analyses comparing adverse events in users of low-dose methotrexate plus folic acid compared with those randomly assigned to pl...

Methotrexate and its mechanisms of action in inflammatory arthritis.

Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.

Ultrasound liver elastography for the detection of liver fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy: A cross-sectional study.

Long-term low-dose methotrexate therapy is associated with liver fibrosis. Although liver biopsy is the gold standard for detecting fibrosis, it is an invasive procedure associated with morbidity and mortality risks. Hence noninvasive imaging techniques such as transient elastography (TE) and shear wave elastography (SWE) have been studied to measure liver stiffness. To assess the utility of TE and SWE in detecting fibrosis in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. A cross-sectional prospective study was undertaken on 54 patients with psoriasis and reactive arthritis who had received ≥1.5 g of methotrexate. Various clinical and biochemical [fibrosis 4 index (FIB4), aspartate-transaminase-to-platelet ratio index (APRI)] parameters were calculated and liver stiffness measurement (LSM) was done with TE and SWE. The degree of steatosis was measured using controlled attenuation parameter (CAP). Liver biopsy was done when indicated and was interpreted by a pathologist blinded to clinical and imaging results. Fifty four patients with a mean age of 40.3 years and a male-to-female ratio of 5:1 were included. The mean cumulative methotrexate dose was 3.04 g. The median FIB4, APRI, and gamma-glutamyl transpeptidase-to-platelet ratio values were 0.75, 0.23, and 0.15, respectively. The median LSM for TE and SWE was 5.3 and 7.32 kPa, respectively. SWE and TE showed a weak positive correlation (r = 0.26, P = 0.053). The mean CAP was 217 dB/m (area under the receiver operating characteristic = 0.70). In the 19 of 26 cases whose liver biopsies could be assessed, only 4 (21%) showed F1 fibrosis (Ishak staging). The median LSM on SWE was significantly higher in patients with a cumulative methotrexate dose ≥ 4 g when compared with those with a dose <4 g (9.85 vs 7.1, P = 0.02). Other parameters did not correlate with TE and SWE. The small sample size and the low number of cases with significant fibrosis on histopathology were the major limitations of this study. Histologically detectable LF is uncommon in patients with psoriasis and reactive arthritis on long-term methotrexate therapy. Both TE and SWE are good at detecting the absence of fibrosis in these patients. In our study, SWE and TE values did not correlate with clinical, biochemical, or histopathological parameters.

Methotrexate exposure and risk of strongyloidiasis.

Rheumatologic disease patients receiving immunomodulating drugs such as methotrexate (MTX) have increased infection rates. Strongyloides, a global endemic intestinal parasite, can cause significant or fatal disease in immunocompromised patients. The risk of serious Strongyloides infection with MTX dosed for rheumatologic disease is unknown. We performed a systematic literature review searching EMBASE, Medline and Web of Science databases. All studies reporting humans exposed to MTX and tested for Strongyloides were reviewed. Exclusion criteria were bone marrow transplantation, intrathecal route and MTX exposure completed >1year prior to clinically apparent Strongyloides disease. After excluding duplicates, 294 articles were reviewed. Of these, 29 cases were described in 27 papers. Twenty cases (69%) had an underlying rheumatologic or dermatologic disease, the rest had a haematologic disease. Hyperinfection or dissemination was found in 59% of cases (52% low-dose MTX; 75% high-dose MTX). Death occurred in 34% of cases (19% low-dose MTX; 75% high-dose MTX, P<0.01). All eight patients on high-dose MTX received other immunosuppressants. Corticosteroids were taken in 18/21 patients on low-dose MTX. One of the three patients on MTX monotherapy had hyperinfection syndrome. None had disseminated Strongyloides. Serious Strongyloides infection can occur with low-dose MTX particularly when given with other immunosuppression. Global travel and greater awareness of rheumatologic conditions in low- to middle-income countries will increase the exposure of individuals prescribed MTX (with or without corticosteroids) to Strongyloides. Strongyloides screening and treatment should be considered for individuals receiving low-dose MTX therapy, particularly if combined with additional immunosuppression.

Reactivation of latent tuberculosis associated with methotrexate therapy

Tuberculosis is highly prevalent in developing world. Post primary tuberculosis occurs in the setting of depressed immunity commonly affecting the lungs. Reactivation of tuberculosis concomitantly at different non-pulmonary sites is very uncommon. Here we report an immunocompetent male with rheumatoid arthritis presented with reactivation of cutaneous and meningeal tuberculosis while on low dose methotrexate therapy. The case report highlights the fact that the treating clinician should be vigilant enough to suspect reactivation of latent tuberculosis even with non biological disease modifying anti rheumatoid drugs therapy in tropical world.

High Vs. Low-Intensity Bridging Chemotherapy in Children with Acute Lymphoblastic Leukemia Awaiting Chimeric Antigen Receptor T-Cell Therapy: A Population-Based Study from Ontario, Canada

Background: Chimeric antigen receptor T-cells (CAR-T) have emerged as a promising treatment for children with relapsed/refractory acute lymphoblastic leukemia (ALL). While CAR-T outcomes have been published, little data exist on how to manage these patients for the weeks to months between T-cell collection and CAR-T infusion. Unlike stem cell transplant (SCT), where higher burden of disease is associated with poor outcomes and is often a contraindication, successful outcomes for children with high disease burden pre-CAR-T have been demonstrated. Thus, traditional high-intensity chemotherapy for relapsed ALL that aims to minimize disease burden but carries significant morbidity may not be the best option for pre-CAR-T populations. We thus compared our population-based experience in using high vs. low-intensity chemotherapy regimens to bridge patients in terms of toxicity, inpatient days, and success in reaching CAR-T infusion.Methods: The Hospital for Sick Children (Sickkids) is the provincial referral centre for cellular therapy for children in Ontario, Canada. All Ontario children referred to Sickkids between 2014-2018 for first T-cell collection with intent to proceed to CAR-T therapy were included and followed until CAR-T infusion, decision to pursue alternative therapy, or death. Bridging regimen details were collected and classified as low vs. high intensity based on whether such therapy was likely associated with >7 days of neutropenia. Disease and outcome variables were compared between high vs. low intensity regimens using Chi squared, Fisher's exact, or Wilcoxon tests.Results: The cohort included 32 patients with a median age of 9.7 years at the time of first T-cell collection [interquartile range (IQR) 6.0-12.3]. The median number of previous relapses was 2 (IQR 1-2), 14 (44.0%) had undergone prior SCT, and 4 (12.5%) had Down syndrome. The vast majority of patients (28, 87.5%) were successfully bridged to receive CAR-T therapy with a median time to infusion of 81 days (IQR 60-105). Two patients experienced manufacturing failure and pursued SCT instead, 1 died of toxicity, and 1 was still awaiting infusion at the end of the study period. Low-intensity bridging regimens were used following collection for 19 (59.4%) patients, most often based on low-dose intravenous methotrexate, 3-drug induction (vincristine/steroids/asparaginase), or maintenance therapy. The most common high-intensity regimens included cyclophosphamide/etoposide, high dose cytarabine, or 4-drug induction (vincristine/steroids/asparaginase/anthracycline). Patients receiving high-intensity therapy did not seem to have more aggressive disease prior to starting bridging treatment (as indicated by peripheral blasts, number of previous relapses, prior SCT) that would have justified choosing high-intensity treatments. Patients receiving initial high-intensity regimens were however more likely to have been collected in first half of the study period (Table 1). Patients receiving initial high-intensity regimens also developed more microbiologically documented infections and experienced a greater number of inpatient days (Table 1). Excluding patients experiencing manufacturing failure or still awaiting CAR-T at the end of the study period, the likelihood of receiving CAR-T also did not vary [high-intensity regimen - 11/12 (91.7%) vs. low-intensity regimen - 17/17 (100%); p=0.41].Conclusions: We demonstrate in our population-based cohort of heavily pre-treated and high-risk patients that initial low-intensity chemotherapy had a very high likelihood of successfully bridging children to CAR-T infusion. Low-intensity bridging regimens were associated with lower rates of toxicity and higher quality of life as indicated by fewer inpatient days. Low-intensity regimens should be considered the first line option in this population. [Display omitted] DisclosuresGrupp:Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Can etanercept treatment failure in moderate-to-severe psoriasis be overcome by addition of low-dose methotrexate? A single-center experience

Background: Loss of efficacy is a major anticipated shortcoming of utilizing etanercept and other biologic agents for treating moderate-to-severe psoriasis.Purpose: To investigate the addition of low-dose methotrexate as a means to increase etanercept drug survival.Methods: Eleven patients with severe psoriasis were switched to a combination of etanercept with low-dose methotrexate therapy, after a primary or secondary failure with etanercept treatment as a monotherapy. Time period for cessation of combined treatment and side effects were documented. The effect of previous methotrexate treatment was investigated.Results: Six men and five women were included in the study. The patients had moderate-to-severe psoriasis with a mean baseline Psoriasis Area and Severity Index (PASI) of 29 (median 25). Median duration of etanercept monotherapy was 12 months. Median duration of combined treatment was 13 months. Combined treatment was discontinued in three patients due to side effects. Previous failure of methotrexate monotherapy did not alter the duration of the combined treatment.Conclusion: Addition of low-dose methotrexate may rescue etanercept therapy after failure of etanercept monotherapy in patients with moderate-to-severe psoriasis.

Clinical Outcomes of Low-Dose Methotrexate Therapy as a Second-Line Drug for Intravenous Immunoglobulin-Resistant Kawasaki Disease.

PurposeIntravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease (KD). However, there is still no standard treatment for IVIG-resistant KD. This study aimed to evaluate the efficacy of low-dose methotrexate (MTX) as a treatment for IVIG-resistant KD.Materials and MethodsWe retrospectively analyzed 10-year data for patients with IVIG-resistant KD who were administered MTX at Severance Children's Hospital.ResultsThe subjects included 75 patients with KD aged 5 months to 9.2 years who had been administered MTX. Their maximum body temperatures decreased significantly within 24 h of therapy. The patients' C-reactive protein levels were significantly lower 1 week after administering the first dose of MTX than those before treatment. No adverse effect for MTX was observed.ConclusionMTX treatment of IVIG-resistant KD resulted in rapid defervescence, improvement of clinical symptoms, and normalization of acute-phase reactants in all patients. Thus, MTX could be a candidate treatment for IVIG-resistant KD.

Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low-dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report

The t(3;21)(q26.2;q22) translocation is a rare chromosomal abnormality exhibited almost exclusively in therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) or in the blastic crisis phase of chronic myelogenous leukemia, which results in the fusion of the runt related transcription factor 1 (RUNX1, also called AML1) gene at 21q22 to the myelodysplasia syndrome 1 (MDS1)-ecotropic virus integration site 1 (EVI1) complex locus (MECOM) at 3q26.2, generating various fusion transcripts, including AML1/MDS1/EVI1 (AME). The present study examined the case of an 84-year-old Japanese woman who developed t-MDS/AML with t(3;21)(q26.2;q22) subsequent to receiving low-dose methotrexate (MTX) treatment for rheumatoid arthritis. Following treatment with MTX for 6 years, the patient developed anemia and neutropenia, and MTX was discontinued. A total of 3 years later, the patient was diagnosed with MDS with t(3;21)(q26.2;q22) and del (5q), which progressed rapidly to AML within 3 months. The patients was subsequently treated with azacitidine and cytarabine chemotherapy, but succumbed to the disease 6 months after diagnosis. Sequencing analysis of the nested reverse transcription-PCR products from the leukemic cells revealed the expression of two types of alternatively-spliced AME transcripts with or without RUNX1 exon 6 sequences. Western blot analysis of the leukemic cells of the patient additionally revealed that the corresponding AME fusion protein products were expressed at high levels, and that these cells also prominently expressed CCAAT/enhancer-binding protein α, the repression of which has been reported to be involved in leukemogenesis mediated by AME. To the best of our knowledge, the case discussed in the present study represents the first report of MDS/AML with t(3;21)(q26.2;q22) developing following low-dose MTX therapy for rheumatoid arthritis. Nonetheless, the clinical and molecular features of the patient in the present study were representative of those patients who typically develop this disease following exposure to chemotherapy or radiotherapy for primary malignancy, which implicates MTX in the pathogenesis of t-MDS/AML. Moreover, we confirmed the expression of two AME fusion proteins for the first time in primary leukemic cells and analyzed several cellular factors implicated in AME-mediated leukemogenesis to gain some insight into its molecular mechanisms.