ARTICLE
Auteur(s) : Catherine Goujon,
Frédéric Bérard, Karima Dahel, Isabelle Guillot, Anca Hennino,
Audrey Nosbaum, Nathalie Saad, Jean-François Nicolas
Allergology and Clinical Immunology Department, URCI-LS 36 768
(Unité Recherche Clinique Immunologie- Lyon Sud, 69495
Pierre-Benite Cedex, France) and INSERM U 503, IFR 128 Biosciences
Lyon-Gerland
accepté le 18 Octobre 2005
A topic dermatitis (AD) is a frequent chronic inflammatory skin
disorder secondary to the activation in the skin of
allergen-specific T cells [1-5]. The available therapies for
moderate to severe AD include topical agents and systemic drug
treatment. Topical agents (corticosteroids, immunomodulators) are
very effective but their use is limited by the body surface
affected by the eczema [6]. Systemic therapies (UV light therapy
and cyclosporine) are associated with immunosuppression and
therefore to an increased risk of carcinoma, and lymphoma and
nephropathy, respectively.Methotrexate (MTX) is a well-known drug
used for more than 40 years at low doses in the treatment of
psoriasis [7-9]. Its side-effects mostly affect the bone-marrow,
the liver and the lung and are easily prevented by regular clinical
and biological follow-up. At the doses used in psoriasis, MTX has
no immunosuppressive activity. Recent studies by Genestier et al.
have shown that MTX selectively depletes activated T cells by an
apoptosis-dependant mechanism without effect on naive and memory T
cells [10]. Since AD lesions are mediated by activated T cells and
since MTX has been shown to improve the clinical symptoms of eczema
in a model of antigen-specific dermatitis in mice [11], we
hypothesized that MTX could be used to treat AD patients eligible
for systemic therapy. We report here on an open retrospective study
of 20 patients with moderate to severe AD who received low dose MTX
for 3 to 30 months.
Patients and methods
Patients
Twenty patients (ten females and ten males), 17 to 68 years old,
received MTX for the treatment of moderate to severe AD from 2002
to 2004. Table 1( Table 1 ) summarizes
the main characteristics of the patients. These patients were
eligible for systemic treament, i.e. presented with AD with low
response to routine treatment or with an affected body surface area
too important for local treatment. 14 patients had had AD since
childhood and 6 as adults. The AD affected the face for 17
patients, the body for 18 patients with flexural folds, the neck,
the V neck and the limbs. Only 2 patients had a localisation only
on the face but the subjective perceptions of symptoms were severe.
The intensity of the disease was classified as mild, moderate and
severe according to the following criteria: the degree of itching,
the intensity of inflammatory signs (erythema,
papulation/infitration with oozing/crusting) and the body surface
area. AD was moderate in 7 patients and severe in 13 patients.
Table 1 Clinical parameters of AD patients enrolled in
the study and response to methotrexate therapy after 3 months of
use
|
Subjects
|
Age
|
Sex
|
Beginning of AD
|
Intensity
|
Lesion site
|
Dosage per week during the first 3 months
|
Treatment Duration
|
Improvement
|
Side Effects during the first 3 months of use
|
|
Time to clinical improvement
|
After 3 months of MTX*
|
|
1
|
25
|
M
|
Adult
|
Moderate
|
Face
|
25 mg IM
|
8 months
|
6 weeks 80%
|
80%
|
No
|
|
2
|
30
|
M
|
Childhood
|
Moderate
|
Face
|
25 mg IM
|
6 weeks
|
6 weeks 80%
|
80% not evaluable
|
Nauseas and increase of liver enzymes
|
|
Hands
|
|
3
|
32
|
F
|
Childhood
|
Severe
|
Body
|
25 mg IM
|
5 weeks
|
No improvement
|
No
|
Nauseas
|
|
4
|
19
|
F
|
Childhood
|
Moderate
|
Face
|
25 mg IM
|
7 months
|
1 month 90%
|
90%
|
No
|
|
Folds
|
|
5
|
40
|
F
|
Childhood
|
Moderate
|
Face
|
25 mg IM
|
2 months
|
2 months 90%
|
90%
|
No
|
|
Body
|
|
6
|
17
|
F
|
Childhood
|
Moderate
|
Face
|
7.5 mg 2 months then 10 mg
|
4 months
|
6 weeks 50%
|
80%
|
No
|
|
Folds
|
|
7
|
32
|
F
|
Childhood
|
Severe
|
Face
|
25 mg IM
|
12 months
|
2 months 90%
|
90%
|
No
|
|
Body
|
|
8
|
33
|
M
|
Childhood
|
Moderate
|
Face
|
25 mg IM
|
18 months
|
2 months 70%
|
70%
|
Transient increase of liver enzymes
|
|
9
|
29
|
M
|
Childhood
|
Severe
|
Face
|
7.5 mg
|
12 months
|
2 months 90%
|
80%
|
No
|
|
Body
|
|
10
|
23
|
M
|
Childhood
|
Severe
|
Face
|
25 mg IM
|
2 months
|
No improvement
|
No
|
No
|
|
Body
|
|
11
|
46
|
M
|
Childhood
|
Severe
|
Face
|
15 mg
|
1 month
|
Worsening
|
No
|
No
|
|
Body
|
|
12
|
58
|
F
|
Adult
|
Severe
|
Face
|
7.5 mg 10 weeks then 25 mg IM
|
13 weeks
|
No improvement
|
No
|
No
|
|
Body
|
|
13
|
35
|
F
|
Childhood Adult
|
Severe
|
Face
|
25 mg IM
|
24 months
|
2 months 90%
|
90%
|
Nausea at the beginning of treatment
|
|
Folds and V neck
|
|
14
|
41
|
M
|
Adult
|
Severe
|
Members
|
25 mg
|
4 months
|
2 months 50%
|
70%
|
No
|
|
15
|
49
|
M
|
Childhood
|
Moderate
|
Face
|
7.5 mg
|
3 months
|
2 weeks 100%
|
100%
|
No
|
|
V nek
|
|
Folds
|
|
16
|
52
|
F
|
Adult
|
Severe
|
Face
|
25 mg IM
|
27 months
|
6 weeks 60%
|
80%
|
Nausea at the beginning of treatment
|
|
Body
|
|
17
|
30
|
M
|
Adult
|
Severe
|
Face
|
25 mg IM
|
30 months
|
5 weeks 40%
|
75%
|
Transient Lymphopenia
|
|
Body
|
|
18
|
22
|
F
|
Childhood
|
Severe
|
Face
|
25 mg IM
|
3 months
|
40%
|
40%
|
No
|
|
Body
|
|
19
|
68
|
F
|
Adult
|
Severe
|
body
|
15 mg
|
3 months
|
6 weeks 40%
|
40%
|
No
|
|
20
|
44
|
M
|
Childhood
|
Severe
|
Face
|
25 mg IM
|
20 months
|
3 weeks 80%
|
90%
|
No
|
|
Body
|
Methotrexate
Because patients were treated in our unit by several
dermatologists, the dose and the form of the medication varied
greatly. However, the initial dose of MTX was inferior or equal to
25 mg weekly dosage. Most of the patients (14/20) started with
a 25 mg IM /week. When the dose was decreased, the oral form
was chosen. The initial dose for the 6 other patients was: 7.5
mg/week for 4 patients and 15 mg/week for 2 patients. Before
beginning of MTX a complete clinical examination was made,
including spirometry, chest X-ray and biological tests.
Concomitant therapies
All patients used emollients daily on the whole body surface. Some
patients used topical treatments (corticosteroids and/or
tacrolimus) before the beginning of MTX treatment. These patients
were asked not to change their treatment habits during the MTX
trial (except for tacrolimus which was stopped before the beginning
of MTX). No other systemic therapy was allowed, including systemic
corticosteroids, anti-histamines, antileucotrienes, hepatotoxic
drugs and systemic immunosuppressants.
Follow-up
Patients were seen every month at consultation. Laboratory tests
were performed before the treatment and every two weeks during the
first three months and monthly thereafter. They included a complete
blood count, serum creatinine, aspartate aminotransferase and
alanine aminotransferase. The physician performed a global
assessment, using a scale from 0 to 100, with a score of 0
indicating the absence of improvement and a score of 100 the
absence of disease activity. The outcome of the study was judged
after 3 months of MTX use or before, if the patient interrupted the
treatment for any reason.
Results
Efficacy
The beginning of improvement occurred between the fourth and the
eighth week of MTX initiation: the erythema and papulation became
lighter, the itching acceptable, the excoriations superficial and
the body surface area decreased dramatically.
Fifteen patients, i.e. 75% of patients, were greatly improved
(> or equal to 70% for 13 patients) by MTX within 3 months of
use (table 1).
Patients n° 2 and 3 stopped the study before 3 months because of
nausea. The AD lesions were unaffected by MTX treatment in 2
patients (n° 10 and 12) and got worse in one patient (n° 11).
Side effects during the first 3 months of MTX use were noted in
6 patients (n° 2, 3, 8, 13, 16, 17) and required discontinuation of
MTX in 2 patients (n° 2, 3). The most frequent adverse events were
nausea (4/20) and mild increase of liver enzymes (2/20).
Follow up after 3 months of MTX use
- • The mean treatment duration was one year for the 15
patients who completed the 3 months initial treatment.
- • No side effects were observed in these 15 patients
even after several months of treatment.
- • Six patients (n° 1, 5, 6, 15, 16 and 20) were able to
stop MTX because of a dramatic improvement of AD lesions (low
disease activity with mild erythema and papulation, and a body
surface area < 10%) allowing a maintenance therapy using
emollients and corticosteroids or tacrolimus.
Discussion
Efficacy
The present study shows that short-term low-dose MTX is an
effective treatment of adult AD. Physician’s global assessment
estimated that an improvement of > 70% occurred in 13 out of 20
patients (65%). These data confirm and extend the results obtained
in the few previous reports suggesting that MTX could be helpful in
the management of eczemas. Egan et al. used MTX to treat 5 patients
with palmo-plantar pompholyx and were able to decrease or stop oral
corticosteroid therapy in all patients. Shaffrali et al. used
low-dose MTX in 5 elderly patients with eczema, with a satisfactory
response in four and a discontinuation for the last one for other
medical problems. Balasubramaniam et al reported an AD patient
intolerant to azathioprine and cyclosporine with a successful
result and good tolerance of MTX [12-14; Hanifin J., personal
communication].
Regimen schedule
Although the dose (7.5 to 25 mg) and the route (IM and oral) of MTX
varied greatly among the patients treated in this study, there was
no apparent better efficacy of the higher IM doses versus the low
oral doses. Therefore, we recommend using MTX as oral tabs. This
oral form does not need to follow the intermittent oral schedule of
3 doses divided over a 24-hour period each week which is used for
the treatment of psoriasis because of the kinetics of proliferation
of psoriatic epidermal cells.
Safety
No serious adverse event occurred in this study. We propose
following the guidelines about MTX use in psoriasis. However, we
insist on the necessity of checking respiratory function in AD
patients using MTX because of the possibility of MTX-induced lung
fibrosis, which could be more frequent in AD patients with
associated asthma.
Proposal for drug dosage schedules in moderate to severe
AD
According to our experience in our clinical unit and the previous
guidelines, we suggest the following regimen schedule in AD in
cases of no contra-indications for its prescription):
- – initial weekly dosage MTX 15 mg in one single
dose;
- – increase of 5 mg weekly in case of inefficiency
after 2 months of treatment;
- – maximum dosage 25 mg;
- – stop treatment after 3 months if no improvement;
- – maintenance dosage between 5 and 7.5 mg.
Conclusion
Recent studies have shown that MTX was as effective as cyclosporine
in the treatment of psoriasis [16]. Because the side-effects of MTX
are easily prevented by a monthly biological follow-up and because
it is devoid of immunosuppressive activity, MTX is considered as
the first line systemic therapy in psoriasis.
Based on our present results suggesting that MTX is an effective
and safe treatment of AD, we propose that it could be used in
patients with moderate to severe AD with low response to
conventional topical treatments and/or to cyclosporine. MTX,
prescribed during episodes of peak disease activity, would be
either tapered off when the disease subsided in response to therapy
or maintained at the lowest efficient dosage or even switched to
another agent.
Placebo-controlled clinical trials are needed to demonstrate the
effectiveness and safety of MX in AD and to define its place as a
first line systemic therapy in moderate to severe AD [15, 17,
18].
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