Methotrexate hepatotoxicity in Rheumatoid
Arthritis - An analysis of the physicians´ policy
by Dr Bita Anvari, MD
Assistant professor of Internal Medicine
School of medicine, Kermanshah University of Medical Sciences
Kermanshah - Iran
• When a physician find an elevation in liver enzyme in comparison
with previous enzyme before MTX prescription, he may decide to
decrease or discontinue the drug or change it to another DMARD if
the disease is still active.
• Also other policies in approach to this condition is present, like no
change or even increasing dose especially in patients with high
disease activity index (DAI).
any elevated
enzyme
the physician´s
decision
the result of
next enzyme
Different physician’s decisions:
Discontinuing
Decreasing
Increasing
No change in dose of
methotrexate
• The result of these multiple policies on the next enzyme is unclear
and the physicians need to know what would be happened
after each decision. (for evidence based practice)
Patients and Methods
- Rheumatoid Arthritis patients in academic rheumatology clinic who
received ≥ 7.5 mg methotrexate weekly for at least one month during
their follow up period from 1991-2006.
- They had serial follow up in The Rheumatology clinic of Shariati
Hospital.
- In this presentation I present a part of study on the patients who had
at least one elevated liver enzyme during the MTX therapy.
any elevated
enzyme
the physician´s
decision
the result of
next enzyme
2 patients were
excluded from the
result of policy
Table 1: Change in MTX dose after first enzyme elevation
MTX dose after
enzyme elevation
Frequency
Percent
fixed
rised
start
Discontinue
Decreased
Total
55
9
6
5
27
102
53.9
8.8
5.9
4.9
26.5
100.0
Table 2 – The results of 2nd enzyme after changing MTX dose
MTX dose after enzyme
elevation
next enzyme is normal or high
Total
Normal (%)
High (%)
Fixed
Rised
Start
Discontinue
Decreased
35(63.6)
6(66.7)
2(33.3)
5(100.0)
23(88.5)
20(36.4)
3(33.3)
4(66.7)
0(0)
3(11.5)
55
9
6
5
26
Total
71(70.3)
30(29.7)
101
p=0.01
• Decreased dose or discontinuation were happened among 32
patients (31.4%) and fixed dose or rising dose in 53.9% and 8.8%
respectively.
• The result of next enzyme (in each group) was normal in 90.3%,
63.6% and 66.7% respectively.
• At the 2nd step, if the enzyme was elevated again
(consecutively), the physicians´ policies and the results
were included.
Elevated 2nd
enzyme
consecutively
the physician´
decision
the result of 3rd
enzyme
Second elevated enzyme
(2nd step)
2nd elevated
enzyme
the physician´s
decision
the result of
next enzyme
After 2nd consecutive
liver enzyme elevation
Table 3: The changes in MTX Dose after 2nd consecutive
enzyme elevations
MTX dose after 2 enzyme
elevation
Frequency
Percent
fixed
rised
decreased
discontinue
Total
16
4
7
3
30
53.3
13.3
23.3
10.0
100.0
Table 4 - Third enzyme according to change of MTX dose
(after 2nd consecutive enzyme elevation)
MTX dose after 2
consecutive enzyme
elevation
Fixed
rised
Decreased
discontinue
Total
P=0.1
next enzyme after 2
consecutive elevation
Total
Normal (%)
High (%)
9(64.3)
5(35.7)
14
3(75.0)
7(100.0)
1(25.0)
0(0)
4
7
3(100.0)
0(0)
3
22(78.6)
6(21.4)
28
Results (cont.)
• At the 2nd step, among 30 patients who had two consecutive elevated
liver enzyme, one third (33.3%) discontinued or decreased MTX dose.
• The next enzyme became normal in all of them however it was seen
in 66.7% of the others with fixed or rising dose.
Follow-up after third elevated enzyme
After third enzyme elevation among six patients:
One patient with NASH discontinued MTX by herself
The other (with autoimmune hepatitis) had normal enzyme without
decreasing dose and she receives 15 mg MTX weekly now.
Among three other patients, the enzymes became normal after
decreasing dose
One patient was not referred until the follow-up period in this study
Discussion and Conclusion:
• The most of the patients did not decrease or discontinue MTX but
continued to take it with the same dose and about 64% of them had
normal 2nd enzyme.
• Obvious improvement in liver enzymes after decreased dose or
discontinuation of methotrexate could be seen that makes this
policy the best action in approach to MTX transaminitis.
• However trend to improvement despite of physicians’ decision was
observed. If this natural course may be due to adjustment of
hepatocyte activity or renal clearance need to be further
investigated.