methotrexate indications and approaches hans herfarth, md, phd university of north carolina at...
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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