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Methotrexate Indications and Approaches

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1 Methotrexate Indications and Approaches
Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina

2 Use of Methotrexate in IBD Recommendations
…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) … 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 Dignass et al. 2010; Chande et al. 2014

3 Prescriptions for IBD Medications in the U.S.
IMS Health cohort of 108,518 IBD patients AZA 6-MP Rx per 100,000 person-months by year anti-TNF Cyclosporine Tacrolimus MTX Year Herfarth et al. 2012

4 Therapeutic Use for Methotrexate Compared to Azathioprine/ 6-MP in USA “Nonexistent”
What are the reasons? Efficacy Toxicity Patient preference Missing Data

5 Outline 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

6 Cochrane-Analyses of Therapeutic Efficacy of Methotrexate or Azathioprine In Crohn’s Disease
Number of trials Patients (drug or placebo) NNT AZA / 6-MP Induction 13 1211 No difference to placebo, but significant steroid sparing MTX 1 (6 low quality or very small) 141 5 Maintenance 7/1 550 6 / 4 (4 low quality) 76 4 McDonald et al. 2014, Patel et al. 2014, Chande et al. 2013, Prefontaine et al. 2010

7 Head-to-Head Comparison Methotrexate and Azathioprine In Crohn’s Disease – Single Blinded Study
MTX 25mg/week iv 3months, then oral 3 months 54 patients steroid-dependent active CD Azathioprine 2mg/kg/day 6 months Ardizzone et al 2003

8 COMMIT (Methotrexate+ Infliximab (IFX) or IFX) IFX-Trough Levels and Presence of IFX antibody
n=126 patients, 63 IFX+MTX, 63 IFX Detectable IFX p-value IFX Trough-level mg/ml Antibody + IFX+MTX 20% <0.08 6.4 4% <0.01 IFX 14% 3.8 Feagan et al. 2014

9 Prednisone taper week 0-14
COMMIT (Methotrexate+ Infliximab or Infliximab): Proportion of Patients in Remission Prednisone taper week 0-14 IFX + MTX IFX + Placebo Patients in remission [%] Treatment failure week 14: 24% IFX/MTX, 22% IFX Treatment failure week 50: 44% IFX/MTX, 43% IFX Weeks n= 63/group Feagan et al. 2014

10 Differences SONIC and COMMIT
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

11 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 Methotrexate Ulcerative Colitis

12 Clinical Studies MTX in UC
Comparison of Methotrexate vs Placebo in Steroid-Refractory Ulcerative Colitis (METEOR) 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)

13 Methotrexate Response in Treatment of Ulcerative Colitis – MERIT-UC
MTX 25 mg sq /weekly* + folic acid+ steroid taper Induction Period Week 1-16 Randomization if clinical response or remission and off steroids week 16 MTX 25 mg/weekly*+ folic acid+ 5-ASA** Placebo /weekly +folic acid+ 5-ASA** Maintenance Period Week 17-48 Primary Endpoint Remission (relapse free survival) and off steroids week 48 Dosis reduction to 15 mg sq/weekly in case of MTX side effects ** no 5-ASA in case of intolerance

14 MERIT-UC Trial – Response and Remission after Open Label MTX Induction Therapy for 16 Weeks
> 50% previous failure of anti-TNF + azathioprine Remission: Steroid-free for 4 weeks + Clinical Mayo ≤ 2 Response: Steroid-free for 4 weeks + decrease in the Clinical Mayo score of ≥ 2 points and at least a 25% decrease from baseline Mayo score

15 Figure 2: Infliximab, Azathioprine or Combination – UC SUCCESS Trial: Week 16 Results
Patients naïve to anti-TNF and AZA or >3 months stop of AZA before trial p<0.02 p<0.03 Patients (%) Remission: Steroid-free (no time defined) + Mayo ≤ 2 including endoscopy Response: Decrease in the total Mayo score of ≥ 3 points and at least a 30% decrease from baseline Mayo score Panaccione et al 2014

16 Safety and Toxicity of Methotrexate

17 Methotrexate (MTX) - Contraindications
Condition Risk Known liver disease Liver cirrhosis Alcoholism Renal insufficiency Systemic toxicity Immunodeficiency Infections Blood dyscrasias (e.g. leukopenia, thrombopenia) Aggravation of blood dyscrasia Pregnancy + planned pregnancy (female and male) Birth Defects

18 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 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 Leman 11 1,225 9 2 Kozarek 6 1,733 5 Fournier 17 2,653 16 I Normal; mild fatty infiltration/nuclear variability/portal inflammation II Moderate-to-severe fatty infiltration/nuclear variability/portal IIIa Tract expansion or inflammation mild fibrosis IIIb Moderate-to-severe fibrosis IV Cirrhosis No cases of Liver cirrhosis Adapted Fournier et al. 2010

19 Methotrexate and Planned Pregnancy
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. 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. Weber-Schoendorfer et al. 2013

20 Approach How to start therapy with Methotrexate

21 Recommended Tests Before Start of Methotrexate
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 Visser et al. 2009

22 Once Weekly Subcutaneous Methotrexate Mono Therapy
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 In case of nausea: Ondansentron 4-8 mg before and on day after injection.

23 Monitoring Methotrexate Therapy
CBC, LFTs, creatinine, albumin Induction week 2, 4, 8 Maintenance q 8-12 weeks In case of normal LFTs and no risk factors for cirrhosis (NASH, alcohol) long term no need for liver biopsy.

24 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.

25 Methotrexate in 2015/2016 The other bunch New: MTX in UC (?)

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