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Methotrexate
Indications and Approaches
Hans Herfarth, MD, PhD
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
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
Prescriptions for IBD Medications in the U.S.
Rx per 100,000 person-months by year
IMS Health cohort of 108,518 IBD patients
4500
AZA
4000
3500
3000
aza
6-MP
2500
cyclosp
m6mp
anti-TNF
2000
mtx
tacro
1500
biol
1000
Cyclosporine
500
Tacrolimus
MTX
0
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Year
Herfarth et al. 2012
Therapeutic Use for Methotrexate Compared to
Azathioprine/ 6-MP in USA “Nonexistent”
What are the reasons?
•
Efficacy
•
Toxicity
•
Patient preference
•
Missing Data
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
Cochrane-Analyses of Therapeutic Efficacy of
Methotrexate or Azathioprine In Crohn’s Disease
Number of
trials
AZA / 6-MP
Induction
MTX
Induction
13
1
(6 low quality or very
small)
AZA / 6-MP
Maintenance
7/1
MTX
Maintenance
1
(4 low quality)
Patients
(drug or placebo)
NNT
1211
No difference to placebo,
but significant steroid
sparing
141
5
550
6/4
76
4
McDonald et al. 2014, Patel et al. 2014, Chande et al. 2013, Prefontaine et al. 2010
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 steroiddependent active CD
Azathioprine 2mg/kg/day 6 months
Remission (% patients)
Azathioprine
70%
63%
60%
50%
40%
Methotrexate
56%
44%
33%
30%
20%
10%
0%
3 months
6 months
Ardizzone et al 2003
COMMIT (Methotrexate+ Infliximab (IFX) or IFX)
IFX-Trough Levels and Presence of IFX antibody
n=126 patients, 63 IFX+MTX, 63 IFX
Detectable
IFX
IFX+MTX
p-value
20%
IFX Troughlevel
mg/ml
6.4
<0.08
IFX
14%
p-value
Antibody
+
4%
<0.08
3.8
p-value
<0.01
20%
Feagan et al. 2014
COMMIT (Methotrexate+ Infliximab or Infliximab):
Proportion of Patients in Remission
Prednisone taper
week 0-14
MTX
IFX + MTX
Patients in remission [%]
100
Placebo
IFX + Placebo
80
60
40
Treatment failure week 14: 24% IFX/MTX, 22% IFX
Treatment failure week 50: 44% IFX/MTX, 43% IFX
20
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Weeks
n= 63/group
Feagan et al. 2014
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
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
Comparison of Methotrexate vs Placebo in SteroidRefractory 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)
Methotrexate Response in Treatment of Ulcerative Colitis –
MERIT-UC
Maintenance Period
Week 17-48
Induction Period
Week 1-16
MTX 25 mg sq /weekly* + folic
acid+ steroid taper
Randomization if
clinical response or remission and off steroids week 16
MTX 25 mg/weekly*+ folic acid+
5-ASA**
Placebo /weekly +folic acid+ 5ASA**
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
MERIT-UC Trial – Response and Remission after Open
Label MTX Induction Therapy for 16 Weeks
100%
> 50% previous failure of anti-TNF + azathioprine
80%
60%
40%
50%
30%
20%
0%
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)
Week 16
Steroid free Response and Remission
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
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
100%
Patients (%)
80%
60%
p<0.02
p<0.03
40%
40%
24%
20%
22%
AZA (n=76)
IFX (n=77)
AZA+IFX (n=78)
0%
Steroid-free Remission
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
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
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
3
0
Leman
11
1,225
9
2
Kozarek
6
1,733
5
1
Fournier
17
2,653
16
1
No cases of Liver cirrhosis
Adapted Fournier et al. 2010
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
Approach
How to start therapy with Methotrexate
Recommended Tests Before Start of Methotrexate
Assess for
Laboratory work Radiology
Consideration of
clinical risk
up
following tests:
factors
Obesity
AST, ALT
Chest X-ray to Serology testing for:
Diabetes mellitus
Albumin
rule out
Alcohol intake
CBC
interstitial lung HIV
Creatinine
disease
Hepatitis B, C
Pregnancy Test
Lipid profile
Blood fasting glucose
Visser et al. 2009
Once Weekly Subcutaneous Methotrexate Mono Therapy
• 25 mg MTX sc +
1mg folic acid
• Steroid Taper
(8 weeks) + 1mg
folic acid daily
Maintenance
• 25 mg MTX sc + 1
mg folic acid + 1
mg folic acid daily
Induction
In case of nausea: Ondansentron 4-8 mg before and on day after
injection.
Monitoring Methotrexate Therapy
• CBC, LFTs,
creatinine,
albumin
Induction
week 2, 4, 8
Maintenance
q 8-12 weeks
• CBC, LFTs,
creatinine,
albumin
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
azathioprine or anti-TNF agents.
“unsafer”
compared
to
The other bunch
Methotrexate in 2015/2016
New:
MTX in UC (?)