Presentation on theme: "Methotrexate Indications and Approaches"— Presentation transcript:
1 Methotrexate Indications and Approaches Hans Herfarth, MD, PhDUniversity of North Carolina at Chapel HillChapel 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 ColitisDignass et al. 2010; Chande et al. 2014
3 Prescriptions for IBD Medications in the U.S. IMS Health cohort of 108,518 IBD patientsAZA6-MPRx per 100,000 person-months by yearanti-TNFCyclosporineTacrolimusMTXYearHerfarth et al. 2012
4 Therapeutic Use for Methotrexate Compared to Azathioprine/ 6-MP in USA “Nonexistent” What are the reasons?EfficacyToxicityPatient preferenceMissing Data
5 Outline Data for Use of Methotrexate in Crohn’s Disease Sneak Preview: Data for Use of Methotrexate in Ulcerative ColitisSafety and Toxicity of MethotrexatePractical Approach
6 Cochrane-Analyses of Therapeutic Efficacy of Methotrexate or Azathioprine In Crohn’s Disease Number of trialsPatients(drug or placebo)NNTAZA / 6-MPInduction131211No difference to placebo, but significant steroid sparingMTX1(6 low quality or very small)1415Maintenance7/15506 / 4(4 low quality)764McDonald 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 months54 patients steroid-dependent active CDAzathioprine 2mg/kg/day 6 monthsArdizzone 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 IFXDetectable IFXp-valueIFX Trough-levelmg/mlAntibody +IFX+MTX20%<0.086.44%<0.01IFX14%3.8Feagan et al. 2014
9 Prednisone taper week 0-14 COMMIT (Methotrexate+ Infliximab or Infliximab): Proportion of Patients in RemissionPrednisone taper week 0-14IFX + MTXIFX + PlaceboPatients in remission [%]Treatment failure week 14: 24% IFX/MTX, 22% IFXTreatment failure week 50: 44% IFX/MTX, 43% IFXWeeksn= 63/groupFeagan et al. 2014
10 Differences SONIC and COMMIT Disease durationSONIC vs COMMIT (2.2 years vs 9 years).ImmunosuppressionSONIC no previous immunosuppression vs COMMIT 25% previous exposure and failure of azathioprineInclusion criterionSONIC: CDAI > 220 and need for steroids, COMMIT patient in need for steroids (15-40mg) in the previous 4 weeksSONIC >70% prednisone naive at inclusion vs. COMMIT mean dose of prednisone 22 mgTrial DesignSONIC: 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 taperInduction Period Week 1-16Randomization ifclinical response or remission and off steroids week 16MTX 25 mg/weekly*+ folic acid+ 5-ASA**Placebo /weekly +folic acid+ 5-ASA**Maintenance Period Week 17-48Primary EndpointRemission (relapse free survival) and off steroids week 48Dosis 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 + azathioprineRemission: 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
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 trialp<0.02p<0.03Patients (%)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 scorePanaccione et al 2014
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. 1994StudyNumber of patientsMean cumulative dose MTX (mg)Early changes (Roenigk I, II)Advanced changes Roenigk III,IV)Te202,633191Fraser3>1,500Leman111,22592Kozarek61,7335Fournier172,65316I Normal; mild fatty infiltration/nuclear variability/portal inflammationII Moderate-to-severe fatty infiltration/nuclear variability/portalIIIa Tract expansion or inflammation mild fibrosisIIIb Moderate-to-severe fibrosisIV CirrhosisNo cases of Liver cirrhosisAdapted 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
21 Recommended Tests Before Start of Methotrexate Assess for clinical risk factorsLaboratory work upRadiologyConsideration of following tests:ObesityDiabetes mellitusAlcohol intakeAST, ALTAlbuminCBCCreatinineChest X-ray to rule out interstitial lung diseaseSerology testing for: Hepatitis B, CHIVPregnancy Test Lipid profileBlood fasting glucoseVisser et al. 2009
22 Once Weekly Subcutaneous Methotrexate Mono Therapy 25 mg MTX sc + 1mg folic acidSteroid Taper (8 weeks) + 1mg folic acid dailyInduction25 mg MTX sc + 1 mg folic acid + 1 mg folic acid dailyMaintenanceIn case of nausea: Ondansentron 4-8 mg before and on day after injection.
23 Monitoring Methotrexate Therapy CBC, LFTs, creatinine, albuminInductionweek 2, 4, 8Maintenanceq 8-12 weeksIn case of normal LFTs and no risk factors for cirrhosis (NASH, alcohol) long term no need for liver biopsy.
24 ConclusionMethotrexate 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 2015/2016The other bunchNew:MTX in UC (?)