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

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

3. 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.

4. 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 대한의학.
J Clin Gastroenterol 2010;44:e242-e248.

5. Methotrexate (MTX) Folic acid antagonist, PO / SC Pharmacodynamics
High dose
Low dose
Dosage
~ 1 g/m2 ( g/m2)
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):
Curr Treat Options Gastroenterol. 2017;15(1):

6. 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):CD

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

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

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

11. 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):

12. 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):

13. 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 Feb;150(2):380-8.e4

14. 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 Feb;150(2):380-8.e4

15. 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 Feb;150(2):380-8.e4

16. 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 Oct;155(4): e9

17. 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 Oct;155(4): e9

18. 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 Oct;155(4): e9

19. 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.