MethotrexateIndications and Approaches

Hans Herfarth, MD, PhDUniversity of North Carolina at Chapel Hill

Chapel Hill, North Carolina

…but at present, methotrexate is generally reserved for

treatment of active or relapsing Crohn's disease in those

refractory to or intolerant of thiopurines or anti-TNF agents.

(2nd European CD guideline)

Dignass et al. 2010; Chande et al. 2014

Use of Methotrexate in IBD Recommendations

… at present there is no evidence supporting the use of

methotrexate for induction or maintenance of remission in

active ulcerative colitis.

Cochrane review Methotrexate Ulcerative Colitis

Rx p

er

10

0,0

00

pers

on

-mon

ths

by y

ear

Year

IMS Health cohort of 108,518 IBD patients

anti-TNF

AZA

6-MP

MTX

Prescriptions for IBD Medications in the U.S.

Herfarth et al. 2012

TacrolimusCyclosporine

What are the reasons?

• Efficacy

• Toxicity

• Patient preference

• Missing Data

Therapeutic Use for Methotrexate Compared to Azathioprine/ 6-MP in USA “Nonexistent”

• Data for Use of Methotrexate in Crohn’s Disease

• Sneak Preview: Data for Use of Methotrexate in Ulcerative Colitis

• Safety and Toxicity of Methotrexate

• Practical Approach

Outline

Cochrane-Analyses of Therapeutic Efficacy of Methotrexate or Azathioprine In Crohn’s

DiseaseNumber of

trialsPatients

(drug or placebo)NNT

AZA / 6-MPInduction 13 1211

No difference to placebo, but

significant steroid sparing

MTXInduction

1(6 low quality or

very small)141 5

AZA / 6-MPMaintenance

7/1 550 6 / 4

MTXMaintenance

1 (4 low quality)

76 4

McDonald et al. 2014, Patel et al. 2014, Chande et al. 2013, Prefontaine et al. 2010

54 patients steroid-dependent active CD

MTX 25mg/week iv 3months, then oral 3 months

Azathioprine 2mg/kg/day 6 months

3 months 6 months0%

10%

20%

30%

40%

50%

60%

70%

33%

63%

44%

56%

Azathioprine Methotrexate

Rem

issi

on (

%

pati

ents

)

Ardizzone et al 2003

Head-to-Head Comparison Methotrexate and Azathioprine In Crohn’s Disease – Single Blinded

Study

Detectable IFX

p-value IFX Trough-level

mg/ml

p-value Antibody +

p-value

IFX+MTX 20%<0.08

6.4<0.08

4%<0.01

IFX 14% 3.8 20%

Feagan et al. 2014

COMMIT (Methotrexate+ Infliximab (IFX) or IFX) IFX-Trough Levels and Presence of IFX antibody

n=126 patients, 63 IFX+MTX, 63 IFX

0 4 8 12 16 20 24 28 32 36 40 44 48 520

20

40

60

80

100

MTX

Placebo

COMMIT (Methotrexate+ Infliximab or Infliximab): Proportion of Patients in Remission

Feagan et al. 2014

Weeksn= 63/group

Pa

tient

s in

rem

issi

on [

%]

Prednisone taper week 0-14

Treatment failure week 14: 24% IFX/MTX, 22% IFXTreatment failure week 50: 44% IFX/MTX, 43% IFX

IFX + MTX

IFX + Placebo

• Disease duration SONIC vs COMMIT (2.2 years vs 9 years).

• Immunosuppression SONIC no previous immunosuppression vs COMMIT 25%

previous exposure and failure of azathioprine

• Inclusion criterion SONIC: CDAI > 220 and need for steroids, COMMIT patient

in need for steroids (15-40mg) in the previous 4 weeks SONIC >70% prednisone naive at inclusion vs. COMMIT

mean dose of prednisone 22 mg

• Trial Design SONIC: Dual therapy (IFX + AZA) vs COMMIT initial Steroid

taper which might have masked the effects of MTX

Differences SONIC and COMMIT

Methotrexate in Ulcerative Colitis

… at present there is no evidence supporting the use of

methotrexate for induction and maintenance of remission in

active ulcerative colitis.

Cochrane review 2014 Methotrexate Ulcerative Colitis

Clinical Studies MTX in UC

Randomized, double blind, prospective trial investigating the efficacy of Methotrexate in induction and maintenance of steroid free remission in ulcerative colitis (MEthotrexate Response In Treatment of UC - MERIT-UC)

Comparison of Methotrexate vs Placebo in Steroid-Refractory Ulcerative Colitis (METEOR)

MTX 25 mg sq /weekly* + folic acid+ steroid taper

Randomization ifclinical response or remission and off steroids week 16

MTX 25 mg/weekly*+ folic acid+ 5-ASA**

Placebo /weekly +folic acid+ 5-ASA**

Primary EndpointRemission (relapse free survival) and off steroids week 48

Ind

uct

ion

Peri

od W

eek

1-

16

Main

tenan

ce

Peri

od W

eek

17-4

8

• Dosis reduction to 15 mg sq/weekly in case of MTX side effects• ** no 5-ASA in case of intolerance

Methotrexate Response in Treatment of Ulcerative Colitis – MERIT-UC

Week 160%

20%

40%

60%

80%

100%

50%

30%

Patients with clinical response week 16 and off steroids since week 12 (n=96)Patients in clinical remission and off steroids since week 12 (n=96)

Steroid free Response and Remission

MERIT-UC Trial – Response and Remission after Open Label MTX Induction Therapy for 16

Weeks

Remission: Steroid-free for 4 weeks + Clinical Mayo ≤ 2Response: Steroid-free for 4 weeks + decrease in the Clinical Mayo score of ≥ 2 points and at least a 25% decrease from baseline Mayo score

> 50% previous failure of anti-TNF + azathioprine

Steroid-free Remission0%

20%

40%

60%

80%

100%

24% 22%

40%

AZA (n=76)IFX (n=77)AZA+IFX (n=78)

Figure 2: Infliximab, Azathioprine or Combination – UC SUCCESS Trial: Week 16

Results

Panaccione et al 2014

Pati

en

ts (

%)

Remission: Steroid-free (no time defined) + Mayo ≤ 2 including endoscopyResponse: Decrease in the total Mayo score of ≥ 3 points and at least a 30% decrease from baseline Mayo score

Patients naïve to anti-TNF and AZA or >3 months stop of AZA before trial

p<0.02

p<0.03

Safety and Toxicity of Methotrexate

Methotrexate (MTX) - Contraindications

Condition Risk

Known liver disease Liver cirrhosis

Alcoholism Liver cirrhosis

Renal insufficiency Systemic toxicity

Immunodeficiency Infections

Blood dyscrasias (e.g. leukopenia, thrombopenia)

Aggravation of blood dyscrasia

Pregnancy + planned pregnancy (female and male)

Birth Defects

Study Number of patients

Mean cumulative dose MTX (mg)

Early changes (Roenigk I, II)

Advanced changes

Roenigk III,IV)

Te 20 2,633 19 1

Fraser 3 >1,500 3 0

Leman 11 1,225 9 2

Kozarek 6 1,733 5 1

Fournier 17 2,653 16 1

Adapted Fournier et al. 2010

Liver Biopsy Results in Patients Treated with Methotrexate

RA: In 719 patients , who underwent liver biopsy, only two reported cases of liver cirrhosis.Kremer et al. 1994

No cases of Liver cirrhosis

113 low dose MTX exposed men/pregnancies vs 412 non-MTX exposed men/pregnancies.

No differences in major birth defects, spontaneous abortion, gestational age at delivery or birth weight.

Methotrexate and Planned Pregnancy

Weber-Schoendorfer et al. 2013

Stop methotrexate at least 3 months before planned pregnancy: High risk for Birth defects, not advised during lactation. FDA category x.

Stop methotrexate at least 3 months before planned pregnancy.“Expert opinion” in 2008.

How to start therapy with Methotrexate

Approach

Assess for

clinical risk

factors

Laboratory

work up

Radiology Consideration of

following tests:

Obesity

Diabetes

mellitus

Alcohol intake

AST, ALT

Albumin

CBC

Creatinine

Chest X-ray

to rule out

interstitial

lung disease

Serology testing

for:

Hepatitis B, C

HIV

Pregnancy Test

Lipid profile

Blood fasting

glucose

Recommended Tests Before Start of Methotrexate

Visser et al. 2009

• 25 mg MTX sc + 1mg folic acid

• Steroid Taper(8 weeks) + 1mg folic acid daily

Induction

• 25 mg MTX sc + 1 mg folic acid + 1 mg folic acid daily

Maintenance

Once Weekly Subcutaneous Methotrexate Mono Therapy

In case of nausea: Ondansentron 4-8 mg before and on day after injection.

• CBC, LFTs, creatinine, albumin

Inductionweek 2, 4,

8

• CBC, LFTs, creatinine, albumin

Maintenance

q 8-12 weeks

Monitoring Methotrexate Therapy

In case of normal LFTs and no risk factors for cirrhosis (NASH, alcohol) long term no need for liver biopsy.

Conclusion

• Methotrexate is underused (“ignored”), but is a viable therapeutic alternative in Crohn’s disease with similar efficacy as azathioprine/6-MP.

• METEOR and MERIT-UC will clarify if MTX is effective in ulcerative colitis.

• Methotrexate seems to be not “unsafer” compared to azathioprine or anti-TNF agents.

New: MTX in UC (?)

The other bunchMethotrexate in 2015/2016