메토트렉세이트에 대한 숨겨진 질문들

이상원 ( Sang Won Lee ) 대한류마티스학회 2012 대한류마티스학회지 Vol.19 No.1

Since the 1950`s, methotrexatehas been the most widely used for the treatment of rheumatoid arthritis among various disease-modifying anti-rheumatic drugs (DMARDs). In this review, several hidden questions on methotrexate were discussed. First, so far, methotrexate has been considered to improve rheumatoid arthritis by inhibiting cell proliferation through the reduction of synthesis regarding purine and pyrimidine. Recently, a new concept was proposed that methotrexate could increase the release of adenosine, which subsequently decreases the inflammatory function of immune cells, and can finally quench the inflammation in affected joints of rheumatoid arthritis. Second, there were only three clinical trials done to directly compare the efficacy between methotrexate and biologics. With these results, methotrexate showed comparable therapeutic efficacy to biologics, but did not prevent radiological progression. In the future, clinical trials to directly compare the efficacy of methotrexate to biologics will be needed. Third, measuring the serum concentration of methotrexate is not appropriate, since circulating methotrexate is rapidly cleared by cellular uptake or renal excretion. Methotrexate polyglutamate is a more stable compound than methotrexate and it is more likely to relate to efficacy or adverse effects of methotrexate. Recently, the efforts to measure methotrexate polyglutamate in red blood cells have been done to increase therapeutic efficacy and reduce its adverse effects. Fourth, NSAIDs can decrease the excretion of methotrexate though renal tubular cells and it may increase the serum concentration of methotrexate and the risk of its toxicity, suggesting that physicians should pay close attention to dose adjustments concerning methotrexate combined with NSAIDs.

자궁경관 임신에서 Methotrexate의 효능

고현선 ( Hyun Sun Ko ),김연희 ( Yeun Hee Kim ),안현영 ( Hyun Young Ahn ),박인양 ( In Yang Park ),이희중 ( Hee Joong Lee ),이영 ( Young Lee ),김사진 ( Sa Jin Kim ),김수평 ( Soo Pyung Kim ),신종철 ( Jong Chul Shin ) 대한주산의학회 2005 Perinatology Vol.16 No.1

목적 : 본 연구는 자궁경관임신의 보존 치료방법인 methotrexate의 치료 효과를 알아보고자 하였으며, 나아가 자궁경관 임신의 적절한 치료방법을 찾아보고자 하였다. 방법 : 1999년 1월부터 2004년 5월까지 가톨릭의과대학 부속병원에 입원한 환자 44예의 자궁경부 임신 환자 중 methotrexate 치료를 받은 35예의 환자들을 대상으로 하였다. 환자들의 임상적 특징, 치료방법, methotrexate 의 주입경로(전신, 국소, 혹은 복합요법), 소파술유무, 부작용 및 치료 성과를 중심으로 분석하였다. 통계적인 분석으로 unpaired t-test, Wilcoxon 순위 합검정, Fisher`s exact test를 이용하여 유의성을 검증하였으며, p값이 0.05 이하일 때 통계적으로 유의하다고 판정하였다. 결과 : Methotrexate에 의한 치료 성공율은 82.9%였고 태아 생존유무에 따라 유의한 차이는 없었다. 입원당시 혈중 beta-hCG 수치는 태아 심박동이 있는 경우 유의하게 높았다(p=0.0085). Methotrexate의 주입경로는 태아 심박동이 있는 경우와 심박동이 없는 경우 전신요법이 각각 37.5%, 81.5%에서 시행되었고, 복합요법은 각각 50.5%, 14.8%로 태아 심박동이 있는 경우 주로 복합요법이, 태아 심박동이 없는 경우 주로 전신요법이 시행되어 유의한 차이를 보였다(p=0.035). Methotrexate의 복합요법을 시행한 8예 모두 치료에 성공적이었다. Methotrexate의 주된 부작용은 간독성이었으나, 심각하지는 않았다. 결론 : 본 연구결과, methotrexate는 투여 경로에 따른 차이는 증명되지 않았으나, 임신 초기에 진단된 자궁경관 임신의 치료에 있어 효과적인 치료 방법이다. 또한, 전신요법과 양막강내 국소 주입의 복합요법은 자궁경관 임신에서 매우 효과적일 것으로 기대된다. Objectives : This retrospective study was performed to evaluate the overall efficacy of methotrexate chemotherapy and to determine its proper management protocol in cervical pregnancy. Method : From January 1999 to May 2004, 44 patients of cervical pregnancy admitted in hospitals attached to Catholic University Medical Center. Among those, data of 35 cases received methotrexate therapy were analyzed. Clinical characteristics, route of methotrexate administration, concomitant invasive procedures, complications, and outcomes were analyzed. Analysis was performed by unpaired t-test, Fisher`s exact test and Wilcoxon`s rank sum test. Results : The overall success rate of methotrexate was 82.9% and there was no significant difference according to viability, although initial beta hCG was significantly increased in viable pregnancy (p=0.0085). Major route of methotrexate was systemic in nonviable pregnancy and combined in viable pregnancy (p=0.035). In all patients who had a combination of systemic and local injection with methotrexate, treatment outcome was successful. Most common complication of methotrexate was liver toxicity, but not serious. Conclusion : Our results suggest that methotrexate treatment is effective as a therapeutic modality for early cervical pregnancy, but its administration route might be not related with efficacy. Furthermore, the combination of systemic and local intra-amniotic injection seems to be more effective.

류마티스관절염 동물모델에서 메토트렉세이트의 STAT3-TH17/STAT5-Treg Axis 조절을 통한 관절염의 치료효과

박은미 ( Eun Mi Park ),박미경 ( Mi Kyung Park ),이동건 ( Dong Gun Lee ),백승예 ( Seung Ye Baek ),우정원 ( Jung Won Woo ),곽승기 ( Seung Ki Kwok ),조미라 ( Mi La Cho ),박성환 ( Sung Hwan Park ) 대한류마티스학회 2013 대한류마티스학회지 Vol.20 No.2

Objective. Methotrexate is the first-line drug in treatment of rheumatoid arthritis (RA) exhibiting higher efficacy and better tolerability than most other DMARDs. To have a better understanding of the anti-arthritic mechanism of methotrexate, we investigated the effect of methotrexate on suppressing the autoimmune inflammatory and destructive arthritis in collagen-induced arthritis (CIA) mice. Methods. The effects of methotrexate on joint inflammation were assessed by clinical scoring and histologic analysis. Levels of cytokines and autoreactive antibodies were analyzed by immunohistochemistry and ELISA. The population of TH17 and Foxp3+ regulatory T (Treg) cells and phosphorylation of their critical transcription activators, STAT3 and STAT5, were examined by fluorescence microscopy and flow cytometry, respectively. Results. Treatment with methotrexate significantly alleviated joint inflammation and cartilage destruction in CIA. Serum levels of total immunoglobulins G, G1, G2a specific to type II collagen were also reduced considerably in methotrexate- treated mice. The drug inhibited the expression of proinflammatory cytokines such as IL-1β, TNF-α, IL-6 and IL-17 in arthritic joints ex vivo as well as by splenocytes in vitro. Moreover, methotrexate treatment resulted in reciprocal modulation of TH17 cells and Foxp3+ regulatory T (Treg) cells in spleen tissues, in which TH17 cells were decreased and Treg cells in number were increased. Subsequent analysis of CD4+T cells showed that phosphorylation of STAT3 was decreased whereas phosphorylation of STAT5 was increased in methotrexate-treated mice. Conclusion. Methotrexate treatment effectively suppressed autoimmune arthritis and restored homeostasis of the immune system by reciprocal regulation of TH17 and Treg cells in a mouse model of collagen-induced arthritis.

Diclofenac과 methotrexate 병합 경구 투여한 백서에서의 급성 장관손상과 장내세균전위

김정욱 ( Jeong Wook Kim ) 대한내과학회 2007 대한내과학회지 Vol.73 No.3

Background: NSAIDs and methotrexate induce gut damage and bacterial translocation (BT). However, there is no study examining the combined effects of methotrexate and NSAID on gut damage and BT. We examined the combined effects of methotrexate and NSAID-induced enteropathy and bacterial translocation in an experimental animal model. Methods: Rats received either no drug, NSAID alone (diclofenac 80 mg/kg and 120 mg/kg per os), methorexate alone (20 mg/kg per os) or NSAID with methotrexate. Gut barrier dysfunction, the degree of intestinal adhesion, stool pellet number, bacterial number of total aerobes and Gram negatives in the distal ileal and cecal contents and the number of Gram negatives in the mesenteric lymph nodes, liver, spleen, kidney and heart were measured. Results: Administration of diclofenac or methotrexate alone caused an increase in gut barrier dysfunction and intestinal adhesion and a decrease in stool pellet number. Administration of diclonfenac alone induced enteric bacterial overgrowth and increased BT to the mesenteric lymph nodes, liver, spleen, kidney and heart. Administration of methotrexate alone induced enteric bacterial undergrowth and BT to the mesenteric lymph nodes, liver, spleen but not to the kidney and heart. The supplements with methotrexate increased the NSAID-induced gut barrier dysfunction and intestinal adhesion, and decreased the stool pellet number. However, the reduced NSAID-induced enteric Gram negative bacterial overgrowth (with a dose of diclofenac of 80 mg/kg) and BT to the liver, spleen, kidney and heart. Conclusion: Methotrexate increases NSAID-induced intestinal damage, but reduces NSAID-induced BT to the liver, spleen, kidney and heart in experimental animals.(Korean J Med 73:258-266, 2007)

A Rare Case of Methotrexate Induced Pancreatitis in Ectopic Pregnancy

Jiwon Choi,Mina Kang,Young Min Hur,Young Ju Kim,Sunwha Park Ewha Womans University School of Medicine 2023 EMJ (Ewha medical journal) Vol.46 No.2

Ectopic pregnancy (EP) refers to blastocyst implantation outside the uterine endometrium. EP is major cause of maternal morbidity and mortality. Treatment options include surgery, medical therapy with methotrexate, or expectant management. Methotrexate is the primary regimen used in cases of early, unruptured ectopic pregnancies. Most side effects of methotrexate are minor, including nausea, vomiting, abdominal discomfort, and photosensitive skin reaction. Serious side effects, including bone marrow suppression, and pulmonary fibrosis, are invariably observed when methotrexate is administered in high doses with frequent dosing intervals, in chemotherapeutic protocols for malignancy. These side effects are uncommon with the doses used to treat ectopic pregnancies. Since cases of methotrexate-induced pancreatitis are rare, we report a case of pancreatitis in a patient with EP treated with methotrexate and expect to consider pancreatitis as a side effect of methotrexate in a patient with upper abdominal pain undergoing methotrexate chemotherapy.

자궁경관 임신에서 자궁경관 흡입 소파술 및 국소 Methotrexate 주입술과 병합한 전신 Methotrexate의 단회요법과 다회요법의 비교

이일한 ( Il Han Lee ),한승수 ( Seung Su Han ),김동호 ( Dong Ho Kim ),이상훈 ( Sang Hoon Lee ) 대한산부인과학회 2008 Obstetrics & Gynecology Science Vol.51 No.9

Objective: To compare the clinical efficacy of systemic single-dose and multiple-dose methotrexate (MTX) regimens combined with aspiration curettage and local MTX in treatment of cervical pregnancy. Methods: Between January 2000 and December 2006, 40 cases of cervical pregnancies were treated with combined systemic and local methotrexate therapy at the Department of Obstetrics and Gynecology, Chung-Ang University Hospital. The patients were treated with either of the two regimens:a) Single dose regimen (Group 1): 1 mg/kg of intramuscular MTX with leucovorin treatment (18 cases).b) Multiple dose regimen (Group 2): four doses of 1 mg/kg of intramuscular MTX with leucovorin treatment (22 cases). Combination treatment with aspiration curettage and local MTX injection were done in all patients after clinically indicated.Baseline characteristics, regimens used and number of doses administered, treatment outcome, presence and severity of side effects were analyzed. Results: The mean age of the patients was 28±2.8 vs 28.4±2.4 years and gestational age at diagnosis was 49.4±8.3 vs 56.4±7.4 days. Initial level of serum β-hCG ranges was 3,242.2±189.2 vs 2,864.3±172.4 IU/mL. There were no significant differences in initial β-hCG values, gestational age between single-dose group and multiple-dose groups, The overall success rate of MTX management for an ectopic pregnancy was 82.5% (33/40) with 66.7% (12/18) and 95.5% (21/22) for single and multiple dose groups respectively. Multiple dose group had more rapid downward trend of hCG and more rapid stabilization. Side effects occurred in 20% (8/40) of the study group with 16.7% (3/18) and 22.7% (5/22) for single and multiple dose groups respectively but not significant. Conclusion: Systemic single-dose and multiple-dose MTX regimen combined with local MTX injection with aspiration curettage and local MTX injection is an effective and safe treatment modality for cervical pregnancies. In our study, multiple-dose regimen treatment is more effective, mild side effects comparable with single dose regimen. Further comparative studies with long-term follow-up are needed to evaluate reproductive outcome and to reduce side effects.

비파열성 난관 임신에서 Methotrexate 일회 투여요법의 임상적 효과

배종운(Jong Woon Bae),김승룡(Seung Ryong Kim),문영진(Young Jin Moon),박문일(Moon II Park),조삼현(Sam Hyun Cho),정성로(Sung Ro Chung),문형(Hyung Moon),황윤영(Youn Yeung Hwang) 대한산부인과학회 2000 Obstetrics & Gynecology Science Vol.43 No.4

Objectives: The early detection of ectopic tubal pregnancy in unruptured state is increased as the transvaginal sonography and sensitive serum hCG test are available. For this unruptured tubal pregnancy, the medical treatment using methotrexate via various routes and dosage is being tried. Our study was to evaluate the efficacy of single systemic injection of methotrexate in the treatment of unruptured tubal pregnancies. Material and Methods: From the January 1997 to July 1999, of 152 ectopic pregnancy patients, 22 patients who were diagnosed as unruptured tubal pregnancies were treated with single-dose systemic methotrexate injection (50 mg/m2/IM). Exclusion criteria were unstable vital signs with hemoperitoneum, adnexal mass > 5-6 cm. Serum hCG titers were checked before injection and 4, 7 day after injection. If serum hCG titer declined more than 15% on 7 day after injection compared with titer on 4 day, the weekly hCG titer was followed until it was <10 mIU/ml .If the hCG titer did not decline more than 15 %, a second dose was given. If hCG titer was not decreased or vital signs became unstable after 1-2 injections, the treatment was considered failure and surgery was done. Results: 18 cases (82%) of 22 were successfully treated with single-dose methotrexate. The mean size of ectopic mass and initial serum hCG titers were 2.7±1.3 cm (range, 1.5-5.4 cm) and 3,298±1,007 mIU/ml (range, 132-12,239), respectively. Of 22, 6 cases (28%) needed second dose of methotrexate. The mean time to resolution of serum β-hCG titer was 27.5±13.6 days (range, 8-53 days). Elevation of liver enzyme did not occurred in all cases during treatment. Initial hCG titer was more important prognostic factor than ectopic mass size for successful medical treatment. Conclusion : Single-dose methotrexate appears to be an effective medical treatment for the unruptured tubal pregnancy. However, patients selection using strict criteria is needed to increase its success rate.

The Advantage of Cyclosporine A and Methotrexate Rotational Therapy in Long-Term Systemic Treatment for Chronic Plaque Psoriasis in a Real World Practice

( Chong Won Choi ),( Bo Ri Kim ),( Jungyoon Ohn ),( Sang Woong Youn ) 대한피부과학회 2017 Annals of Dermatology Vol.29 No.1

Background: Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. Objective: To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. Methods: From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow- up. The occurrences of any laboratory abnormalities during the treatments were investigated. Results: A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. Conclusion: We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis. (Ann Dermatol 29(1) 55∼60, 2017)

척수강내 Methotrexate과량 투여의 치료

남은미,이현경,이순남 大韓血液學會 1997 大韓血液學會誌 Vol.32 No.1

류마티스 관절염 환자에서 Methotrexate와 관련된 간질성 폐렴

김지연 ( Ji Yeon Kim ),김완욱 ( Wan Uk Kim ),김성일 ( Sung Il Kim ),류완희 ( Wan Hee Yoo ),박성환 ( Sung Hwan Park ),홍연식 ( Yeon Sik Hong ),김석찬 ( Seok Chan Kim ),조철수 ( Chul Soo Cho ),김호연 ( Ho Youn Kim ),이연수 ( Youn So 대한류마티스학회 1998 대한류마티스학회지 Vol.5 No.1

The use of oral methotrexate in a low dose given once weekly has become the mainstay of therapy for active and sustained rheumatoid arthritis. Pneumonitis can be expected to occur in patients taking low doses of methotrexate for rheumatoid arthritis. The pathology suggests that methotrexate pneumonitis is a hypersensitivity reaction although arguments have been put forth that it is idiosyncratic. Treatment of presumed methotrexate pneumonitis, even while waiting for special stains, cultures, or tissue sections from bronchoscopic biopsy, should be glucocorticoids given intravenously or by mouth. Empirical antibiotic treatment can be used until infectious causes are ruled out. In recent years there has been an increase in the number of reports of pulmonary complications associated with low-dose methotrexate therapy for rheumatic diseases. Among these complications interstitial pneumonitis has been most often reported (more than 35 cases since the first report in 1983). We report a case of methotrexate-associated pulmonary complication in rheumatoid arthritis confirmed by trans-bronchoscopic lung biopsy, which resolved by treatment of corticosteroid therapy.