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

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Presentation on theme: "Methotrexate Indications and Approaches Hans Herfarth, MD, PhD University of North Carolina at Chapel Hill Chapel Hill, North Carolina."— Presentation transcript:

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

2 … 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. (2 nd European CD guideline) Dignass et al. 2010; Chande et al 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

3 Rx per 100,000 person-months by year 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 TacrolimusCyclosporine

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

5 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

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 No difference to placebo, but significant steroid sparing MTX Induction 1 (6 low quality or very small) 1415 AZA / 6-MP Maintenance 7/ / 4 MTX Maintenance 1 (4 low quality) 764 McDonald et al. 2014, Patel et al. 2014, Chande et al. 2013, Prefontaine et al. 2010

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

8 Detectable IFX p-value IFX Trough- level mg/ml p-value Antibody + p-value IFX+MTX20% < <0.08 4% <0.01 IFX14% 3.820% Feagan et al COMMIT (Methotrexate+ Infliximab (IFX) or IFX) IFX-Trough Levels and Presence of IFX antibody n=126 patients, 63 IFX+MTX, 63 IFX

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

10 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

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 2014 Methotrexate Ulcerative Colitis

12 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)

13 MTX 25 mg sq /weekly* + folic acid+ steroid taper Randomization if clinical response or remission and off steroids week 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** Primary Endpoint Remission (relapse free survival) and off steroids week 48 Primary Endpoint Remission (relapse free survival) and off steroids week 48 Induction Period Week 1-16 Maintenance Period Week 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

14 MERIT-UC Trial – Response and Remission after Open Label MTX Induction Therapy for 16 Weeks 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 > 50% previous failure of anti-TNF + azathioprine

15 Figure 2: Infliximab, Azathioprine or Combination – UC SUCCESS Trial: Week 16 Results Panaccione et al 2014 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 Patients naïve to anti-TNF and AZA or >3 months stop of AZA before trial p<0.02 p<0.03

16 Safety and Toxicity of Methotrexate

17 Methotrexate (MTX) - Contraindications ConditionRisk Known liver diseaseLiver cirrhosis AlcoholismLiver cirrhosis Renal insufficiencySystemic toxicity ImmunodeficiencyInfections Blood dyscrasias (e.g. leukopenia, thrombopenia) Aggravation of blood dyscrasia Pregnancy + planned pregnancy (female and male) Birth Defects

18 StudyNumber of patients Mean cumulative dose MTX (mg) Early changes (Roenigk I, II) Advanced changes Roenigk III,IV) Te202, Fraser3>1,50030 Leman111,22592 Kozarek61,73351 Fournier172, Adapted Fournier et al 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 No cases of Liver cirrhosis

19 113 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 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.

20 How to start therapy with Methotrexate Approach

21 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

22 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.

23 CBC, LFTs, creatinine, albumin Induction week 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.

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


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