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Part II. high-dose methotrexate with leucovorin rescue for severe COVID-19: An immune stabilization strategy for SARS-CoV-2 induced 'PANIC' attack.
Frohman, EM, Villemarette-Pittman, NR, Cruz, RA, Longmuir, R, Rowe, V, Rowe, ES, Varkey, TC, Steinman, L, Zamvil, SS, Frohman, TC
Journal of the neurological sciences. 2020;:116935
Abstract
Here, in Part II of a duology on the characterization and potential treatment for COVID-19, we characterize the application of an innovative treatment regimen for the prevention of the transition from mild to severe COVID-19, as well as detail an intensive immunotherapy intervention hypothesis. We propose as a putative randomized controlled trial that high-dose methotrexate with leucovorin (HDMTX-LR) rescue can abolish 'PANIC', thereby 'left-shifting' severe COVID-19 patients to the group majority of those infected with SARS-CoV-2, who are designated as having mild, even asymptomatic, disease. HDMTX-LR is endowed with broadly pleiotropic properties and is a repurposed, generic, inexpensive, and widely available agent which can be administered early in the course of severe COVID-19 thus rescuing the critical and irreplaceable gas-exchange alveoli. Further, we describe a preventative treatment intervention regimen for those designated as having mild to moderate COVID-19 disease, but who exhibit features which herald the transition to the severe variant of this disease. Both of our proposed hypothesis-driven questions should be urgently subjected to rigorous assessment in the context of randomized controlled trials, in order to confirm or refute the contention that the approaches characterized herein, are in fact capable of exerting mitigating, if not abolishing, effects upon SARS-CoV-2 triggered 'PANIC Attack'. Confirmation of our immunotherapy hypothesis would have far-reaching ramifications for the current pandemic, along with yielding invaluable lessons which could be leveraged to more effectively prepare for the next challenge to global health.
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Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of randomized controlled clinical trials.
Vanni, KMM, Lyu, H, Solomon, DH
Rheumatology (Oxford, England). 2020;(4):709-717
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OBJECTIVE To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases. METHODS We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models. RESULTS Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported. CONCLUSION Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.
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Brief Update on Dermatologic Uses of Methotrexate.
Shah, RA, Nwannunu, CE, Limmer, AL, Patel, RR, Mui, UN, Tyring, SK
Skin therapy letter. 2019;(6):5-8
Abstract
Methotrexate (MTX), an agent originally intended for anti-neoplastic use, has been successfully employed in the treatment of a variety of dermatologic conditions. In addition to its multiple clinical indications, variable dosing and modes of administration make it a viable option for patients of all ages and most comorbidities. MTX is a folate analog that antagonizes dihydrofolate reductase, thus inhibiting thymidylate synthesis and, ultimately, the production of pyrimidine. Depending on dosage, MTX can function as an anti-inflammatory agent, immunomodulator, or antimetabolite. Patients suffering from psoriasis have benefited from MTX in addition to those with atopic dermatitis, chronic urticaria, pemphigus vulgaris, bullous pemphigoid, cutaneous lupus erythematosus, cutaneous sarcoidosis, and mycosis fungoides. Although patients with these conditions can benefit from MTX treatment, the drug can cause adverse sequelae, including hematologic, pulmonary, gastrointestinal, and hepatic side effects. Therefore, the drug should be administered under careful physician supervision.
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A systemic review and meta-analysis of the clinical efficacy and safety of total glucosides of peony combined with methotrexate in rheumatoid arthritis.
Feng, ZT, Xu, J, He, GC, Cai, SJ, Li, J, Mei, ZG
Clinical rheumatology. 2018;(1):35-42
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To assess the efficacy and safety of the combination of total glucoside of peony (TGP) and methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). Randomized controlled trial (RCT) data on the traditional Chinese active component TGP combined with MTX vs. MTX alone for the treatment of RA was collected by searching the Pubmed, Embase, Cochrane Library, CNKI, VIP Journals database, and Wanfang database up to February 2017. Study selection, data extraction, data synthesis, and data analyses were performed according to the Cochrane standards. A total of eight RCTs involving 522 participants were included in this meta-analysis. Compared with MTX alone, the use of TGP combined with MTX exhibited better therapeutic effects for the treatment of RA (P = 0.004). In addition, TGP combined with MTX caused a more significant decrease in erythrocyte sedimentation rate (ESR) (P < 0.0001) and swollen joint count (SJC) (P < 0.00001). However, no significant differences were found in C-reactive protein (CRP) (P = 0.19), duration of morning stiffness (DMS) (P = 0.32), or tender joint count (TJC) (P = 0.23) between the two groups. In addition, adverse events were more frequently reported in the MTX monotherapy group than in the TGP and MTX combination group (P = 0.0007). Our study demonstrates that TGP combined with MTX is more effective than MTX alone for the treatment of RA. Nevertheless, the adverse effects of the combination of TGP and MTX need to be further assessed. Due to the poor methodological quality of included trials, well-designed, multi-center, and large-scale RCTs are necessary to draw a more definitive conclusion.
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Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting.
Ferrara, G, Mastrangelo, G, Barone, P, La Torre, F, Martino, S, Pappagallo, G, Ravelli, A, Taddio, A, Zulian, F, Cimaz, R, et al
Pediatric rheumatology online journal. 2018;(1):46
Abstract
BACKGROUND Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly prescribed. However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of MTX in the management of patients with JIA. Therefore, the Methotrexate Advice and RecommendAtions on Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations for the use of MTX in the treatment of JIA. METHODS The preliminary executive committee identified a total of 9 key clinical issues according to the population, intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review. During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations were made. RESULTS Recommendations relating to the efficacy, optimal dosing and route of administration and duration of treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations in patients with JIA were developed. The selected topics were considered to represent clinically important issues facing clinicians caring for patients with JIA. Evidence was insufficient to formulate recommendations for the use of biomarkers predictive of treatment response. CONCLUSIONS These consensus recommendations provide balanced and evidence-based recommendations designed to have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA.
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Morphea and Eosinophilic Fasciitis: An Update.
Mertens, JS, Seyger, MMB, Thurlings, RM, Radstake, TRDJ, de Jong, EMGJ
American journal of clinical dermatology. 2017;(4):491-512
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Morphea, also known as localized scleroderma, encompasses a group of idiopathic sclerotic skin diseases. The spectrum ranges from relatively mild phenotypes, which generally cause few problems besides local discomfort and visible disfigurement, to subtypes with severe complications such as joint contractures and limb length discrepancies. Eosinophilic fasciitis (EF, Shulman syndrome) is often regarded as belonging to the severe end of the morphea spectrum. The exact driving mechanisms behind morphea and EF pathogenesis remain to be elucidated. However, extensive extracellular matrix formation and autoimmune dysfunction are thought to be key pathogenic processes. Likewise, these processes are considered essential in systemic sclerosis (SSc) pathogenesis. In addition, similarities in clinical presentation between morphea and SSc have led to many theories about their relatedness. Importantly, morphea may be differentiated from SSc based on absence of sclerodactyly, Raynaud's phenomenon, and nailfold capillary changes. The diagnosis of morphea is often based on characteristic clinical findings. Histopathological evaluation of skin biopsies and laboratory tests are not necessary in the majority of morphea cases. However, full-thickness skin biopsies, containing fascia and muscle tissue, are required for the diagnosis of EF. Monitoring of disease activity and damage, especially of subcutaneous involvement, is one of the most challenging aspects of morphea care. Therefore, data harmonization is crucial for optimizing standard care and for comparability of study results. Recently, the localized scleroderma cutaneous assessment tool (LoSCAT) has been developed and validated for morphea. The LoSCAT is currently the most widely reported outcome measure for morphea. Care providers should take disease subtype, degree of activity, depth of involvement, and quality-of-life impairments into account when initiating treatment. In most patients with circumscribed superficial subtypes, treatment with topical therapies suffices. In more widespread disease, UVA1 phototherapy or systemic treatment with methotrexate (MTX), with or without a systemic corticosteroid combination, should be initiated. Disappointingly, few alternatives for MTX have been described and additional research is still needed to optimize treatment for these debilitating conditions. In this review, we present a state-of-the-art flow chart that guides care providers in the treatment of morphea and EF.
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Methotrexate for maintenance of remission in ulcerative colitis.
Wang, Y, MacDonald, JK, Vandermeer, B, Griffiths, AM, El-Matary, W
The Cochrane database of systematic reviews. 2015;(8):CD007560
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BACKGROUND Methotrexate, a folate antagonist, is an immunosuppressant drug that is effective for treating several inflammatory disorders including Crohn's disease. Ulcerative colitis, a related chronic inflammatory bowel disease, can be challenging to treat. T his updated systematic review summarizes the current evidence on the use of methotrexate for induction maintenance of remission in ulcerative colitis. OBJECTIVES The objectives of this review were to assess the efficacy and safety of methotrexate for maintenance of remission in patients with ulcerative colitis. SEARCH METHODS We searched MEDLINE, EMBASE, CENTRAL and the Cochrane IBD/FBD group specialized trials register from inception to June 26, 2014. Study references and review papers were also searched for additional trials. Abstracts from major gastroenterological meetings were searched to identify research published in abstract form only. SELECTION CRITERIA Randomized controlled trials in which methotrexate was compared to placebo or an active comparator in patients with quiescent ulcerative were considered for inclusion. DATA COLLECTION AND ANALYSIS Two authors independently extracted data and assessed the risk of bias for each study. The primary outcome was the occurrence of clinical or endoscopic relapse as defined by the primary studies. Secondary outcomes included frequency and nature of adverse events, change of disease activity score and steroid-sparing effect. We calculated the risk ratio and corresponding 95% confidence interval for dichotomous outcomes. Data were analyzed on an intention-to-treat basis. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. MAIN RESULTS Three trials (165 patients) fulfilled the inclusion criteria. One study compared oral methotrexate (12.5 mg/week) to placebo, another compared oral methotrexate (15 mg/week) to 6-mercaptopurine (6-MP, 1.5 mg/kg/day) or 5-aminosalicylic acid (5-ASA, 3 g/day) and the other compared methotrexate (15 mg/week) in combination sulfasalazine (3 g/day) to sulfasalazine. The placebo-controlled study was rated as low risk of bias. The study comparing methotrexate to 6-MP and 5-ASA was rated as high risk of bias and the study assessing methotrexate and sulfasalazine was rated as unclear risk of bias for sequence generation, allocation concealment and blinding. The placebo-controlled study found no statistically significant differences in the proportion of patients who maintained remission. At nine months, 36% (5/14) of methotrexate patients maintained remission compared to 54% (10/18) of placebo patients (RR 0.64, 95% CI 0.28 to 1.45). A GRADE analysis indicated that the overall quality of the evidence for this outcome was low due to very sparse data (15 events). The study comparing combination therapy to sulfasalazine found no statistically significant difference in the proportion of patients who maintained remission. At 12 months, 100% (14/14) of patients in the combination group maintained remission compared to 75% (9/12) of sulfasalazine patients (RR 1.32, 95% CI 0.94 to 0.86), A GRADE analysis indicated that the overall quality of the evidence for this outcome was very low due to unknown risk of bias and very sparse data (23 events). There were no statistically significant differences in maintenance of remission rates between methotrexate and 6-MP or between methotrexate and 5-ASA. At 76 weeks, 14% (1/7) of methotrexate patients maintained remission compared to 64% (7/11) of 6-MP patients (RR 0.22, 95% CI 0.03 to 1.45) and 0% (0/2) of 5-ASA patients (RR 1.13, 95% CI 0.06 to 20.71). A GRADE analysis indicated that the overall quality of the evidence from this study was very low due to high risk of bias and very sparse data. Adverse events reported in these studies included transient leucopenia, migraine, nausea and dyspepsia, mild alopecia, mild increase in aspartate aminotransferase levels, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia AUTHORS' CONCLUSIONS The results for efficacy and safety outcomes between methotrexate and placebo, methotrexate and sulfasalazine, methotrexate and 6-mercaptopurine and methotrexate and 5-aminosalicylic acid were uncertain. Whether a higher dose or parenteral administration of methotrexate would be effective in quiescent ulcerative colitis is unknown. At present there is no evidence supporting the use of methotrexate for maintenance of remission in ulcerative colitis. More studies are needed to determine the efficacy and safety of methotrexate maintenance therapy in patients with quiescent ulcerative colitis. Large scale methodologically rigorous randomized controlled trials are needed. These studies should investigate higher doses of methotrexate (e.g. 15 to 25 mg/week) and parenteral administration.
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Prolonged response of meningeal carcinomatosis from non-small cell lung cancer to salvage intrathecal etoposide subsequent to failure of first-line methotrexate: a case report and literature review.
Park, MJ
The American journal of case reports. 2015;:224-7
Abstract
BACKGROUND As the incidence of meningeal carcinomatosis (MC) in non-small cell lung cancer (NSCLC) patients has been increasing, MC has recently become an important clinical problem in the management of NSCLC. However, development of new treatments is lacking and a standard treatment guideline is not yet available. Research on salvage intrathecal chemotherapy after failure of first-line treatment for NSCLC patients with MC has rarely been reported in the literature. Here, we report the case of an NSCLC patient with MC who showed durable response to salvage intrathecal etoposide subsequent to failure of first-line methotrexate. CASE REPORT A 58-year-old Asian man with lung adenocarcinoma with bone metastasis presented gait disturbance, diplopia, and progressively increasing headache. The diagnosis of MC was made by brain magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology. After MC progression was suspected during the first-line treatment of intrathecal MTx, intrathecal etoposide was used as a salvage treatment. Brain MRI performed after 2 months of the treatment demonstrated disappearance of enhancing lesions along the ependymal lining of the lateral ventricles. His clinical status markedly improved from Eastern Cooperative Oncology Group performance status of 4 to 2. Stable neurologic status was maintained and CSF cytology remained negative while weekly injection of etoposide was continued for 19 weeks. However, hepatic metastatic lesions persistently progressed despite systemic palliative chemotherapy and the patient died of the disease. CONCLUSIONS To our knowledge, this is the first case report in which intrathecal etoposide was successfully used to treat MC from NSCLC after failure of MTx. This case report might provide preliminary evidence of the feasibility of intrathecal etoposide as salvage intrathecal chemotherapy (ITC). Further clinical trials including larger numbers of patients are necessary to evaluate the role of this ITC regimen for NSCLC patients with MC.
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The influence of genetic RFC1, MS and MTHFR polymorphisms on the risk of acute lymphoblastic leukemia relapse in children and the adverse effects of methotrexate.
Niedzielska, E, Węcławek-Tompol, J, Matkowska-Kocjan, A, Chybicka, A
Advances in clinical and experimental medicine : official organ Wroclaw Medical University. 2013;(4):579-84
Abstract
Polymorphism in genes coding drug-metabolizing enzymes may cause individual differences in the effectiveness and toxicity of many medications, including cytostatics. Although in recent years intensive treatment has positively influenced the prognosis in leukemias, many adverse effects resulting from nonspecific actions and the narrow therapeutic index of anti-cancer drugs are still observed during therapy. Determining selected gene polymorphisms may increase both the safety and the efficacy of treatment, and might help in developing individual therapies.
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Review article: remission rates achievable by current therapies for inflammatory bowel disease.
Peyrin-Biroulet, L, Lémann, M
Alimentary pharmacology & therapeutics. 2011;(8):870-9
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BACKGROUND New medical therapies have improved outlook in inflammatory bowel disease but published impact on surgical rates has been modest suggesting that many patients are still not attaining remission. AIM: To review remission rates with current medical treatments for inflammatory bowel disease. METHODS We searched MEDLINE (source PUBMED, 1966 to January, 2011). RESULTS Induction and maintenance of remission was observed in 20% (range, 9-29.5%) and 53% (range, 36.8-59.6%) of ulcerative colitis (UC) patients treated with oral 5-ASA derivatives. Induction of remission was noted in 52% (range, 48-58%) of Crohn's disease (CD) patients and 54% of UC patients treated with steroids in population-based cohorts. Maintenance of remission was reported in 71% (range, 56-95%) of CD patients on azathioprine over a 6-month to 2-year period and in 60% (range, 41.7-82.4%) in UC at 1 year or longer. Induction and maintenance of remission was noted in 39% (range, 19.3-66.7%) and 70% (range, 39-90%) of CD patients on methotrexate over a 40-week period. Induction of remission was reported in 32% (range, 25-48%), 26% (range, 18-36%) and 20% (range, 19-23%) of CD patients on infliximab, adalimumab or certolizumab pegol, respectively. The corresponding figures were 45% (range, 39-59%), 43% (range, 40-47%) and 47.9% at weeks 20-30 among initial responders. Induction of remission was observed in 33% (range, 27.5-38.8%) and 18.5% of UC patients on infliximab or adalimumab, respectively. Maintenance of remission was noted in 33% (range, 25.6-36.9%) of UC patients on infliximab at week 30. Approximately one-fifth of CD and UC patients treated with biologicals require intestinal resection after 2-5 years in referral-centre studies. CONCLUSION In the era of biologics, the proportion of patients with inflammatory bowel disease not entering remission remains high.