Methotrexate for Ulcerative Colitis: To Use or Not to Use? 2018.10.11. 소화기내과 목요세미나 Methotrexate for Ulcerative Colitis: To Use or Not to Use? 천 재 영 / 김 광 우

Management of IBD Nat Rev Gastroenterol Hepatol. 2014;11(2):99-108.

AZA/6-MP for Maintenance of UC AZA/6-MP is effective as maintenance therapy for patients with UC who are Unresponsive or intolerant to 5-ASA Steroid-dependent KASID guideline AZA/6-MP is recommended to patients with UC with early or frequent relapses who are taking adequate dosage of 5-ASA. (evidence : very low, recommendation : weak) In patients with UC who showed clinical remission with corticosteroid, thiopurine can be used to maintain remission without corticosteroids. (evidence : low, recommendation : weak) Intest Res 2017;15(1):7-37.

Darkside of Thiopurine: Adverse Events Dose-dependent Idiosyncratic (Intolerance) (<30%) BM suppression* Flu-like symptom Liver injury (sinusoidal dilatation, fibrosis, veno-occlusive disease, etc.) GI symptom (nausea, vomiting, diarrhea) Malignancy (lymphoma, skin cancer) Pancreatitis Hepatitis Stepwide dose up & monitoring Switch to 6-MP (50-70% effective) *40% under a mean dosage of 1.8 mg/kg/day in Korean 대한장연구학회. 염증성 장질환. 2016. 대한의학. J Clin Gastroenterol 2010;44:e242-e248.

Methotrexate (MTX) Folic acid antagonist, PO / SC Pharmacodynamics High dose Low dose Dosage ~ 1 g/m2 (0.5-33.6 g/m2) 7.5-30 mg once weekly Mechanism Inhibits dihydrofolate reductase (DHFR)  Deprives rapidly proliferating cancer cells Inhibits lymphocyte proliferation, proinflammatory cytokine production, and neutrophil chemotaxis Action Anti-cancer Regulation of inflammation Indication ALL, NHL, breast ca, head & neck cancer, osteogenic sarcoma, bladder cancer, etc. RA, PsA, CD Mortality 6% Not reported Toxicity Grade IV neutropenia (20-70%) GI (80%, serious) Liver (80%, mild to moderate) Lung (~10%) Cardiac (3%, serious) Infection (2~35%) GI (21%, minor, controllable, less with folate supplementation) Liver (13%, mild transient elevated enzymes, no cirrhosis) Lung (1%, mostly in underlying lung ds) Infection (low) No risk for malignancy Int J Rheum Dis. 2010;13(4):288-93. Curr Treat Options Gastroenterol. 2017;15(1):84-104.

MTX for Induction & Maintenance of CD Clinical remission at W16 in steroid-refractory CD 25mg IM weekly Proportion of patients maintaining clinical remission 15mg IM weekly N Engl J Med. 1995;332(5):292-7. Cochrane Database Syst Rev. 2014;(8):CD006884.

Previous Studies on the Efficacy of MTX in UC Inflamm Bowel Dis. 2010;16(8):1421-30.

Gastroenterology. 2016 Feb;150(2):380-8.e4 Gastroenterology. 2018 Oct;155(4):1098-1108.e9

Therapeutic Goals in UC 관해 유지 입원 감소 삶의 질 향상 수술 예방

Treat-to-target in UC Remission = resolution of symptoms (clinical remission) + inflammation (mucosal healing) Clinical remission = rectal bleeding (-) + normalization of bowel movement Mucosal healing = a Mayo endoscopic subscore of 0-1 Quality of Life Disease Prognosis Am J Gastroenterol. 2015;110(9):1324-38

UC Mayo Score Variables Categories Score Stool frequency normal 1-2 stools more than normal 1 3-4 stools more than normal 2 > 4 stools more than normal 3 Rectal bleeding none visible blood with stool less than half visible blood with stool more than half bleeding > 50% of BM and at least 1BM with blood alone Physician’s global assessment mild moderate severe Mucosal appearance normal or inactive disease mild (erythema, decreased vascular pattern, mild friability) moderate (marked erythema, absent vascular pattern, friability, erosions) severe (spontaneous bleeding, ulceration) Korean J Gastroenterol. 2009;53(3):145-160

1. Efficacy of MTX for Induction Therapy in UC (METEOR) Europe, multi-center, RCTs Steroid-dependent UC (n = 111) MTX SC 15 mg/w vs. placebo Primary endpoint : steroid-free remission* at W16 *a Mayo score ≤ 2 with no subscore >1, and complete steroid withdrawal Gastroenterology. 2016 Feb;150(2):380-8.e4

MTX, Really Ineffective in UC for Induction Therapy? Overestimated steroid-free remission with MTX (45%  32%) For “treat-to-target” Lower drop-out due to aggravated UC in the MTX group Endpoints (at W16) Placebo MTX p-value Steroid-free rectal bleeding = 0 21.6% 46.7% 0.006 Steroid-free stool frequency = 0 17.7% 36.7% 0.03 Steroid-free mucosal healing (Mayo endoscopic of 0-1) 25% 35% 0.28 CRP <5 mg/L without steroids 33.3% 0.17 Placebo MTX p-value Drop-out related to UC 41.2% 18.3% 0.008 Gastroenterology. 2016 Feb;150(2):380-8.e4

Study Population Steroid-dependent UC inactive  inactive or active: steroid-sparing effect ?  이도 저도 아닌 연구가 된 경향. 이미 mucosal healing 환자가 많아서 endoscopic MH을 평가하기에 적절하지 않은 환자가 많았음. anti-TNF 투여 환자가 20%  poor prognosis 환자가 많았음. Gastroenterology. 2016 Feb;150(2):380-8.e4

2. Efficacy of MTX for Maintenance Therapy in UC (MERIT-UC) US, multi-center, RCTs Moderate-to-severe UC MTX 25 mg/w with steroids for induction of remission  steroid-free responder at W16 (n=84) Primary endpoint : relapse-free survival throughout 32 weeks a Mayo score ≤ 2 with no subscore >1 at W48 no clinical relapse throughout 32 weeks and no rescue therapy Gastroenterology. 2018 Oct;155(4):1098-1108.e9

MTX, Really Ineffective in UC for Maintenance Therapy? Study endpoints for maintenance of response Drop-out due to aggravated UC Placebo MTX p-value Mucosal healing at W48 38% 30% 0.36 Relapse btw W16 and W48 55% 50% 0.67 Anti-TNF-experienced Anti-TNF-naïve Placebo MTX p-value Drop-out related to UC 55% 50% 0.65 Gastroenterology. 2018 Oct;155(4):1098-1108.e9

MTX, Really Ineffective in UC for Induction Therapy? Efficacy of MTX with steroids for induction of steroid-free clinical remission or response Steroid-free remission at W16 based on exposure of medication Not evaluated endoscopic activity at W16 Fecal calprotectin > 50 mg/kg at W16 : 93% Gastroenterology. 2018 Oct;155(4):1098-1108.e9

Take Home Message Efficacy of MTX for steroid-free clinical remission, but not mucosal healing, in steroid-dependent UC (maybe, more effective in thiopurine-refractory or intolerant UC) No efficacy of MTX compared to placebo for maintenance therapy in UC Clinical utility of MTX for the management of UC is limited.