Rheumatol Int (2005) 25: 169–178
DOI 10.1007/s00296-004-0537-y
R EV IE W A RT I C L E
Tim Niehues Æ Gerd Horneff Æ Hartmut Michels
Michaela Sailer Höck Æ Lothar Schuchmann
Evidence-based use of methotrexate in children with rheumatic diseases:
a consensus statement of the Working Groups Pediatric Rheumatology
Germany (AGKJR) and Pediatric Rheumatology Austria
Received: 22 July 2004 / Accepted: 5 September 2004 / Published online: 2 February 2005

Springer-Verlag 2005
Abstract Juvenile idiopathic arthritis (JIA) is the most
common diagnosis in children and adolescents with rheu-
matic disorders. In many children and adolescents, JIA is
successfully treated with non-steroidal anti-inflammatory
drugs (NSAID) and physiotherapy. However, in a signif-
icant number of cases the disease is resistant to this ther-
apy, and treatment with ‘‘second line’’ disease-modifying
antirheumatic drugs (DMARDs) is required. Methotrex-
ate (MTX) is frequently referred to as ‘‘first-choice second-
line agent’’ for the treatment of JIA. To increase drug
safety, the Working Groups for Children and Adoles-
cents with Rheumatic Diseases in Germany (AGKJR)
Section Pharmacotherapy of the Working Group Pediatric
Rheumatology Germany and Austria: I. Foeldvari; J.P. Haas,
A. Haeffner, D. Hobusch,G. Horneff, A. Hospach, R. Keitzer, G.
Klaus, M. Metzler, H. Michels, T. Niehues, I. Pilz, M. Sailer Höck,
M. Schöntube, L. Schuchmann, K. Schumacher, H.W. Seyberth, E.
Siemers, A. Urban, E. Weißbarth-Riedl. Working Group Pediatric
Rheumatology North-Rhine-Westfalia: S. Benseler, G. Bürk,
S. Fahl, I. Foeldvari, D. Föll, M. Frosch, G. Ganser, S. Kastner,
I. Kleine, E. Lainka, K. Mönkemöller, J. Neubert, U. Neudorf,
T. Niehues, J. Roth, S. Seeliger, N. Wagner, R. Wieland,
H. Winowski.
T. Niehues (&)
Pediatric Immunology and Rheumatology,
Department of Pediatric Oncology, Hematology and Immunology,
Centre for Child Health,
Heinrich-Heine-University,
Dusseldorf, Germany
E-mail: niehues@rz.uni-duesseldorf.de
G. Horneff
University Children’s Hospital of the Martin-Luther-Universität,
Halle-Wittenberg, Germany
H. Michels
Children’s Hospital for Rheumatic Diseases,
Garmisch-Partenkirchen, Germany
M. S. Höck
University Children’s Hospital,
Innsbruck, Austria
L. Schuchmann
Working group Pediatric Rheumatology,
Freiburg, Germany
and Pediatric Rheumatology Austria have initiated the
formulation of evidence-based recommendations. Evi-
dence is based on consensus expert meetings, a MEDLINE
search with the key words ‘‘Methotrexate’’ and ‘‘juvenile
arthritis’’ limited to age 0–18 years, standard textbooks
and review articles, data from the central registry of the
German Research Center for Rheumatic Diseases (De-
utsches Rheumaforschungszentrum Berlin DRFZ), expe-
rience with MTX in adults with rheumatoid arthritis (RA),
and recommendations of the German Society of Rheu-
matology (DGRh). Based on these data, evidence and
recommendations are graded, and evidence-based recom-
mendations for the use of MTX in children and adolescents
with rheumatic disease are presented.
Keywords Methotrexate Æ Children Æ Evidence-based
recommendations Æ Juvenile idiopathic arthritis
Introduction
The German Research Center For Rheumatic Diseases
(Deutsches Rheumaforschungszentrum DRFZ) docu-
mented the treatment of 3,369 children and adolescents
with rheumatic diseases in the year 2000. Juvenile idio-
pathic arthritis (JIA) is the most common group of
diagnoses, with 1,933 documented cases. JIA can be
effectively treated with non-steroidal anti-inflammatory
drugs (NSAID) and physiotherapy in most cases.
However, in a substantial number of cases JIA is resis-
tant to this treatment, and second-line disease-modifying
antirheumatic drugs (DMARD) are used. Methotrexate
(MTX) is described as the first-choice second-line agent
for JIA [1, 2]. The DRFZ is the national German
Pediatric Rheumatology database in which the vast
majority of children with rheumatic disease is registered
[3]. In the DRFZ documentation, 32% of the children
received MTX as their current treatment for JIA.
Methotrexate inhibits the dihydrofolatreductase
(DHFR) and other folic acid-dependent enzymes, and
170
thereby interferes with DNA synthesis, resulting in an
antiproliferative effect on inflammatory cells [4, 5].
Moreover, MTX leads to a release of adenosine from
monocytes, which exerts anti-inflammatory effects [6].
Among pediatric rheumatologists there are consid-
erable differences in the use of MTX, and therefore
standardization is necessary. Even in large facilities, the
prescription of MTX varies considerably—between 48
and 91% per center for polyarthritis, and between 28
and 100% in children with extended oligoarthritis
(DRFZ 2000). At the time this evaluation was done,
MTX was not licensed for use in children with rheumatic
disease in Germany; since 2003, there is now a license for
using MTX subcutaneously in children. Interestingly,
before MTX was licensed in children there was a license
for Etanercept, which is much less commonly used in
children with rheumatic disease and is considered to be a
third-line drug, if treatment with MTX is unsuccessful
[7]. The pharmacotherapy sections of the Working
Groups for Pediatric Rheumatology in Germany and
Austria have put an emphasis on improving the quality
of MTX therapy in childhood, and on standardising the
treatment with MTX with this consensus. We think that
the consensus may also be useful as guidance and ref-
erence for international readers. We are aware that some
of the recommendations may not be applicable in other
countries.
Methods
This consensus is trying to establish evidence-based
recommendations for the use for MTX in childhood
rheumatic disease in order to improve the safety of
treatment with this drug. The recommendations are
based on the following elements:
1. Consensus meetings of caregivers within the Working
Group Pediatric Rheumatology North-Rhine-Westfalia
in Düsseldorf (1 March 2000, 25 September 2000) and
Mülheim an der Ruhr (12 December 2001), as well as
meetings of the Pharmacotherapy section of the
Working Group Pediatric Rheumatology Germany and
Austria in Bad Bramstedt (9 November 2001) and
Garmisch-Partenkirchen (15 November 2002). The
caregivers have a longstanding experience in Pediatric
Rheumatology as documented in the DRFZ database
(see below). Formal consensus techniques (e.g. Delphi
or Nominal group techniques) were not used. Consen-
sus was reached by mailing versions of the manuscript to
all conference attendees and including their criticism.
There was no formal voting process.
2. An extensive literature search using PubMed MED-
LINE with the keywords ‘‘Methotrexate’’, ‘‘Juvenile
Arthritis’’ and ‘‘age 0–18 years’’ (August 2002) was
conducted, which produced 183 hits. Randomised
controlled double-blind studies received the highest
ranking (Table 1). In addition, cited references were
sometimes used.
Table 1 Quality of evidence
Quality Evidence
I ‡1 Properly-randomized controlled trial
II Well-designed controlled trial without randomization
Well-designed cohort or case–control analytic
study, preferably from more than one center
or research group
Comparisons between times or places with or
without the intervention
Dramatic results in uncontrolled experiments
III Opinions of respected authorities, based on
clinical experience, descriptive studies or
reports of expert committees
3. Standard textbooks and reviews [1, 2, 8, 9], which
receive a lower ranking than original papers.
4. Data from the central documentation of the national
DRFZ database in Berlin.
5. Published results from MTX treatment trials in adult
patients with RA, as well as recommendations of the
German Society for Rheumatology (DGRH). These
data were mainly used with regard to side effects,
mode of application, etc. While there are convincing
data for the use of MTX in adults with rheumatic
disease [10–13], it has to be emphasized that the dis-
eases JIA in children and RA in adults show pro-
found differences with regard to clinical presentation
and prognosis. For this reason, the terminology was
recently changed from JRA to JIA [14]. The influence
of growth and development in children and adoles-
cents with regard to pharmacokinetics, compliance,
short- and long-term side effects of MTX is to be
considered.
Evidence was collected from points 1–5 and recom-
mendations were graded as presented in Tables 1 and 2
(adapted from [15, 16]). It is emphasized that in pediatric
rheumatology in particular there are few data regarding
treatment with MTX, especially when it comes to
randomised controlled or controlled trials. To a large
degree the following recommendations only reach evi-
dence grade III.
Table 2 Classification of recommendations
Grade Recommendation
A Good evidence to support the recommendation
that the intervention be performed
B Fair evidence to support the recommendation
that the intervention be performed
C Poor evidence regarding the value or harm of
the intervention; recommendations may be made
on other grounds
D Fair evidence to support the recommendation
that the intervention not be performed
E Good evidence to support the recommendation
that the intervention not be performed
 171

Table 3 Indications for therapy with methotrexate

Results and discussion
Disease Recommendation Grade
When to give MTX (indication)
JIA Indicated IB
Persistent and extended
In children and adolescents, retrospective data on oligoarthritis
treatment with MTX were first published in 1986 [17]. In Seronegative polyarthritis
two placebo-controlled double-blind studies, the efficacy Polyarthritis with systemic onset
of MTX therapy in children with JIA is now confirmed Enthesitis-associated arthritis
Psoriasis arthritis
[18, 19]. However, the observation periods of these Infection-associated arthritis, Possible, no IIIC
studies were rather short (below 1 year), and long-term collagen vascular disease, general
data on the efficacy of MTX in JIA are lacking. There- vasculitis, spondylarthropathies, recommendation
fore the evidence for the efficacy of MTX in JIA is sarcoidosis, uveitis
judged critically by some authors, especially with regard
to the effect on patient-centered disability measures, e.g. the use of MTX in other rheumatic diseases cannot be
joint function and range of motion, quality of life given (grade IIIC).
and pain [8, 20]. Moreover there may be differences in
efficacy between the subtypes of JIA. In the study by
Giannini et al. [18] it is not precisely delineated
which JIA subtypes were studied. Ravelli et al. [21] How much MTX to give (dosage)
conclude in another study that children with extended
oligoarthritis are more likely to profit from treatment The dosage of 5 mg/m2 is not more efficient than placebo
with MTX than children with polyarticular disease [18] (evidence grade I). In a recent European multicenter
forms. In the randomized placebo-controlled study by PRINTO trial 455 of 633 (72%) patients with JIA and
Woo et al. [19] only patients with extended oligoarthritis polyarticular disease forms responded to MTX within
and systemic-onset JIA were enrolled. No significant 9 months of treatment using a standard dosage of 8–
differences in the efficacy of orally-prescribed MTX 12.5 mg/m2 (orally, subcutaneously and intramuscularly)
between patients with oligoarthritis and Still’s disease are (evidence grade II). In the subsequent randomisation of 80
observed. In Still’s disease, only two of five core response children in whom standard dosage did not show efficacy,
variables improve. MTX was either given parenterally as 15–max. 20 mg/m2
Even though there is little evidence for the efficacy of or as 30 mg/m2 over the period of 6 months [26]. Increas-
MTX in other rheumatic diseases of children and ado- ing the dosage to 15–20 mg/m2 resulted in a response rate
lescents (collagen vascular diseases, vasculitis, spond- of 62.5%. However, increasing the dosage to 30 mg/m2 did
ylarthropathies, etc.) positive effects of MTX have been not result in an increase of efficacy (evidence grade I).
observed in single cases (evidence grade III). It is In the oncological setting, determination of MTX
emphasized that evidence for efficacy in children and serum concentrations is an important part of high-dose
adolescents can only be collected if data are gathered by MTX therapy. Serum half-life of MTX is 6–7 h, and
multicenter international trials. Presently there are no MTX and its metabolite 7-hydroxymethotrexate can be
studies on the question at which time point of the JIA measured in similar concentrations over 1 week intra-
disease course MTX therapy should be started. Rec- cellularly. This explains why MTX is efficacious despite
ommendations from text books and some original pa- the fact that it is only given once-weekly [27]. Routine
pers say that MTX therapy is indicated if the use of a measurements of intracellular MTX concentrations are
NSAID has been unsuccessful for the duration of 6– presently not available in Germany. MTX serum levels
8 weeks or if local intraarticular therapy with corticos- appear not to correlate with JIA response to therapy
teroids has not led to a clinical remission [22, 23] (evi- [28]. There is renal elimination of more than 80% MTX;
dence grade III). It is emphasized that intraarticular therefore there is a high risk of accumulation and organ
instillation of corticosteroids is a highly-efficient treat- toxicity in the case of renal insufficiency. Children show
ment option with relatively few complications [24, 25]
(evidence grade II).
Table 4 Dosage and plasma level determination
Consensus Independent of JIA subtype there is an
indication for MTX therapy in children and adolescents Dosage Recommendation Grade
with JIA (grade IB, Table 3). A consensus on the exact 2
Starting dosage 10–15 mg/m IA
time point of treatment initiation does not exist at Maximal dosage 20 mg/m2 IA
present. It is a common practice to start with the treat- Determination of No recommendation IIID
ment of MTX, if treatment with adequately-dosed plasma levels
NSAID over a period of at least 6–8 weeks and/or local Adaptation according No MTX in children IIA
to renal function with renal insufficiency
therapy with corticosteroids has not led to clinical (GFR2)
remission (grade IIIC). A general recommendation for
172
a better clearance of MTX than adults [29–31]. Sys-
tematic studies concerning age-related dosage recom-
mendations for MTX are lacking (evidence grade III).
Consensus A starting dose of 10–15 mg/m2 is recom-
mended (grade IA, Table 4). The dose of parenteral
MTX can be increased to 15–20 mg/m2 (grade IA). In
single cases an increase to 20–25 mg/m2 is possible
(grade IIIC). The adaptation of the dose should follow
clinical efficacy and tolerability, and is currently not
guided by determination of serum concentration (grade
IIID). Before initiation of therapy renal function should
be checked; in the event of renal insufficiency, the use of
MTX is contraindicated (grade IIA).
How to give MTX (mode of MTX application)
At a dose range of 10 mg/m2/week and subcutaneous
application in a dosage of 15 mg/m2/week, the bio-
availability of oral vs intramuscular application is the
same [32, 33]. In higher dose ranges (‡15 mg/m2/week),
parenteral application is recommended because of better
bioavailability and tolerability [34, 35] (evidence grade
III). Subcutaneous injection of MTX is widely used in
children with JIA in Germany and Austria. Subcutane-
ous and intramuscular application appear to be similar
with regard to pharmacokinetics [36]. Meals do not
appear to affect bioavailability of MTX given orally [32,
36–38] (evidence grade III). It has not yet been deter-
mined whether oral or parenteral application leads to a
different efficacy of MTX.
Consensus A recommendation for the optimum mode
of application is not possible at present. In children, it
seems more appropriate to start with oral application
(grade IIIC).
Whether to give folic acid
Because of MTX’s mode of action, it does not appear
useful to give MTX and folic acid simultaneously.
However, there is increasing evidence that the mode of
action is significantly mediated by the anti-inflammatory
adenosine, and is independent of folic acid. Moreover, in
adults with RA, folic acid supplementation lowers
homocystein, which is increased during low-dose MTX
therapy [39, 40].
A European study in children assessing the influence
of folic acid supplementation on levels of homocystein is
presently planned (Hümer, see Addendum). In a meta-
analysis and double-blind placebo-controlled study, 1–
5 mg of folic acid leads to a significant reduction of side
effects whilst preserving efficacy of MTX therapy in
adults [41, 42]. In order to preserve the anti-inflamma-
tory effect, a slightly higher dosage of MTX was neces-
sary (evidence grade I).
Folic acid application in children (1 mg/day) has even
been studied in a double-blind placebo-controlled
crossover study and did not affect anti-inflammatory
efficacy [43]. However, in this study there are no sys-
tematic data on the toxicity, and it is a rather small
cohort of 19 children with JIA, with a very short
observation period of 13 weeks. Therefore it is difficult
to deduce a recommendation based on this study (evi-
dence grade III).
Consensus A consensus regarding the use of folic acid
in MTX therapy of JIA is not reached. In the event of
slight side effects, the use of folic acid at a dosage of
1 mg/day or a single dose of 25% of the MTX dosage
given 24–48 h after MTX application is recommended
(Table 5) (grade of recommendation IIIC).
How to combine MTX with other anti-rheumatic drugs
NSAID are a central part of pharmacotherapy in JIA.
In most studies MTX is used in combination with
NSAID, and this combination is generally well tolerated
(evidence grade I). Children with compromised renal
function present an exception, because the combination
of NSAID and MTX may have severe side effects [44–
46]. It is emphasized that MTX should not be used in
children with reduced renal function. There are no sys-
tematic studies on the combination of MTX with Cox-2
inhibitors (Celecoxib, Rofecoxib) in children and ado-
lescents (evidence grade III). Cox-2 inhibitors are pres-
ently not licensed for treatment of JIA in Germany and
Austria. In adults, combination with corticosteroids
does not appear to result in significant drug–drug inter-
actions [47]. Similarly, the authors have not observed any
significant interactions, and corticosteroids are commonly
used in advanced cases of JIA as a bridging agent before
MTX shows its effect (evidence grade III). In RA patients,
DMARD are increasingly combined with each other [48].
In children and adolescents there is also an experience
in combining DMARD with each other. In the DRFZ
database for the year 2000, 20% of children with JIA
treated with MTX also received DMARD. It is empha-
sized that there are no randomised or prospective studies
on the combination with DMARD and/or cytokine
antagonists (evidence grade III).
The combination of MTX and Etanercept appears
advantageous because methotrexate’s mode of action
appears to be independent of TNFa [49, 50]. Studies on
Table 5 Folic acid supplementation
Situation Folic acid Grade
Methotrexate is No consensus
tolerated without
side effects
Slight side effects dosage: 1·1 mg/day or 48 h IIIC
(aphthous oral ulcers, after MTX 1 · £ 25% of
aversion, nausea, etc.) MTX dosage
Severe side effects See text section
on side effects

RA patients revealed a superiority of combining MTX
and Etanercept vs MTX only [51] (evidence grade I). In
children and adolescents this combination has also
successfully been used [52] (evidence grade II).
Consensus A combination of MTX with NSAID is
recommended (grade IA, Table 6). If indicated (e.g.
acute flare of JIA), MTX can be combined with corti-
costeroids (grade IIIA). Evidence on the combination of
MTX with DMARD or cytokine antagonists from
prospective controlled trials is lacking (grade IIIC, IIB).
Practical aspects: how to monitor MTX therapy
In day-to-day clinical practice, parents and their primary
care physicians raise many questions regarding the
treatment of rheumatic diseases with MTX. The most
common questions relate to laboratory investigations,
vaccinations, infections and operations.
Consensus Methotrexate therapy in children and ado-
lescents with rheumatic diseases is to be conducted by an
experienced pediatric rheumatologist. Regular clinical
and laboratory investigations are taken care of by the
primary-care pediatrician. If problems with MTX ther-
apy arise, a pediatric rheumatologist is consulted.
Which laboratory and other investigations to order
Laboratory investigations before initiation of therapy
are performed to exclude contraindications and pre-
existing organ dysfunction independent of MTX (e.g.
liver or kidney disease). Investigations during therapy
are performed to monitor treatment efficacy and to
permit early recognition of potential side effects. Risks
of MTX therapy are listed in the section ‘‘How to
Table 6 Combination with other anti-rheumatic drugs
Anti-rheumatic drugs
NSAID
Steroids
DMARD (e.g. azathioprine, cyclosporine Aa,
sulfasalazine, (OH)-chloroquine)
Cytokine antagonists (e.g. Etanercept)
a
A combination of cyclosporine A and MTX is possible [60]. Caution is necessary because of renal side effects when combining MTX and
cyclosporine A
Table 7 Laboratory and other investigations
Methotrexate Recommendation
Before therapy Blood count, differential blood count, C-reactive protein, ESR, liver enzymes and function tests
(AST, ALT, alkaline phosphatase, gamma-glutamyl-transferase, LDH, bilirubin, protein), hepatitis
serology (HBV, HCV), VZV serology, renal function tests (urea, uric acid, creatinine), urine analysis.
tuberculin testing.
On therapy Blood count, differential blood count, C-reactive protein, ESR, liver enzymes and function tests and
renal function tests, urine analysis after 4 weeks, then every 8–12 weeks.
173
monitor and manage MTX side effects, contraindica-
tions and interactions’’. Because side effects appear to
occur less frequently in children than in adults, it may be
feasible to choose longer intervals between laboratory
investigations for hematologic, renal or hepatologic side
effects than in adults (evidence grade III).
Consensus Before initiation of MTX therapy in child-
hood it is recommended that the investigations that are
listed in Table 7 be performed. A full blood count and
differential blood count, CRP, ESR, liver and kidney
function tests are performed every 4 weeks, and there-
after every 8–12 weeks. Liver enzymes are controlled
more often if the dose of MTX is increased, or if there
are elevations of liver enzymes. In individual cases it
may be useful to perform an abdominal ultrasound, an
ECG or pulmonary function test (all recommendations
grade IIIC).
How to deal with infection
It has been postulated that there is an increased sus-
ceptibility to infections in children who are treated with
MTX. In the author’s experience, severe infections in
children on low-dose MTX are very uncommon. In 62
children who were treated for longer than 3 years with
MTX, there were four bacterial and eight viral infections
(including six Varicella primary infections) [53]. There
are no systematic studies on the question whether MTX
therapy can be continued during acute infections; the
consensus reflects mainly the experience of the authors
(grade of evidence III).
Consensus In each infectious episode a pediatrician
should be consulted. In case of varicella infection,
treatment with Aciclovir is recommended (grade IIB). If
Combination with MTX Grade
Recommended IA
Recommended, if indication is given (e.g. acute flare) IIIA
Possible, no general recommendation IIIC
Possible, no general recommendation IIB
Grade
IIIC
IIIC
174
exposure to varicella is documented and there is no
immunity against varicella prophylaxis with varicella
hyperimmunoglobulin within 72 h or treatment with
Aciclovir in the second week after incubation (e.g. day
7–9 after exposure) is recommended (grade IIB). It is
recommended that MTX therapy be interrupted during
anti-infective therapy (grade IIIC).
Whether to continue MTX during operations
In a prospective randomised trial in 388 patients with
RA, treatment with MTX was either continued despite
an orthopaedic operation, or interrupted 2 weeks before
and reinstituted 2 weeks after the operation. Interest-
ingly, infections or surgical complications within 1 year
after the operation were less common in patients with
continuous MTX therapy, whilst in the group with
interrupted MTX therapy there were more acute disease
flares [54] (evidence grade I). There is no systematic
study whether the same holds for children before and
after operations. Therefore the consensus again reflects
mostly the opinions of the authors (evidence grade III).
Consensus An interruption of MTX before and after
elective operations appears not to be necessary. A 48-h
interval between administration of MTX and narcosis
appears to be useful,because of potential interactions
with other drugs (grade IIIC).
How to monitor and manage MTX side effects,
contraindications and interactions
Skin, mucosa and gastrointestinal tract
The most common side effects are aversion to the drug
and nausea [1]. Some pediatric rheumatologists use
relaxation techniques and anti-emetic drugs to treat
nausea (dimenhydrinat, ondansetron, tropisetron, meto-
clopramide). Systematic studies regarding the treatment of
these side effects with folic acid have not been performed in
children and adolescents. However, studies in adults show
that folic acid can have a positive effect on gastrointestinal
side effects (evidence grade III).
Consensus Folic acid supplementation can be used for
minor side effects (grade IIIC).
Liver
Mild acute toxicity of low-dose MTX therapy is observed
in 9% of children and results in an elevation of trans-
aminases [45]. In an analysis of the liver biopsies of 56
children treated with MTX (medium treatment duration
of 3.5 years), only two children showed a slight liver
fibrosis (Roenigk stage II–IIIa) [55]. In another study,
there were no long-term side effects seen in 33 liver
biopsies of 25 children with JIA, despite a mean treatment
duration of approximately 5 years (evidence grade III).
Two adipose 13- and 16-year-old patients had recurrent
elevation of transaminases and showed a slight liver
fibrosis (Roenigk IIIa) after treatment duration of 17 or
21 months [56].
The American College of Rheumatology (ACR) has
suggested guidelines for the control of liver toxicity in
RA [57, 58]. The ACR guidelines cannot be automatically
transferred to children and adolescents because liver
function may be different in adults (alcohol, hepatitis), and
there are different consequences of treatment interruption
in adults with RA or children with JIA.
Consensus Before initiation of therapy, liver biopsies
are only indicated if there is a suspicion of liver disease
or if liver disease is already diagnosed. If transaminases
rise during MTX therapy threefold, MTX should be
interrupted until values are normalised. If there is mild
hepatotoxicity, MTX therapy is continued and folic acid
is given. In the event of recurrent hepatotoxicity, MTX
therapy is stopped. Routine liver biopsies during therapy
are not necessary and only indicated if there are excep-
tional situations (pre-existing liver disease, recently-ac-
quired liver disease, exceptionally high liver function
tests). In these cases a pediatric hepatologist is to consult
(all recommendations: grade IIIC).
Hematopoietic system
Methotrexate hematotoxicity is rare, and consists of
macrocytosis, leucocytopenia and thrombocytopenia. In
adults, a frequency of 1–3% is quoted; in children there
are no data (evidence grade III). Severe bone marrow
aplasia has been successfully treated with folic acid and
G-CSF in adults [59].
Consensus Methotrexate therapy is interrupted if leu-
cocytes are below 3,000/ll, neutrophil counts are below
1,500/ll, or platelets are below 100,000/ll. If there is per-
sistent hematotoxicity, a lower dose of MTX therapy
(minimal dose 10 mg/m2) with supplementation of folic acid
should be tried. If hematopoietic toxicity reoccurs, MTX
therapy is stopped (all recommendations: grade IIIC).
Lung
In adults the incidence of pulmonary side effects is a
matter of controversy. Some authors estimate the inci-
dence as <0.5% [60, 61]. There is only one case of a
child with pneumonitis. The diagnosis in this case is
questionable because of the atypical disease course and
the lack of a biopsy [62] (evidence grade III). In pro-
spective studies, MTX therapy in children with rheu-
matic disease did not influence pulmonary function tests
[63–65] (evidence grade II).
Consensus Routine pulmonary function tests before
and after MTX therapy are usually not required (grade
IIE). A general recommendation for the treatment of
MTX-induced pneumonitis is not available.

Malignant disease
Clearly, it is currently impossible to differentiate be-
tween the natural occurrence of lymphomas and the
effects of MTX on lymphomagenesis. The association of
low-dose MTX therapy and neoplasia in adults with RA
is a matter of controversy [66, 67]. In children with
JIA, four Hodgkin lymphomas (two JIA with systemic
onset, one with seronegative and one with seropositive
polyarthritis) and one non-Hodgkin lymphoma
(10-year-old boy with polyarticular JIA) have been re-
ported [68–72] (evidence grade III). In one case there
was additional immunosuppressive therapy with cyclo-
sporine A [69].
Consensus Children who present with unusual symp-
toms, fever of unknown origin, lymph node swellings
and/or hepatosplenomegaly need a diagnostic work-up
for malignant disease using laboratory and other inves-
tigations. A pediatric oncologist is to be consulted (all
recommendations: grade IIIC).
Teratogenicity
Exposure to MTX during the sixth to eighth week of
gestation can lead to a MTX malformation syndrome. It
is thought that there is a threshold dosage of 10 mg
MTX/week [73]. Eight pregnant women who suffered
from rheumatic disease and were exposed to MTX
within the first trimester had newborns without mal-
formations [74]. However, there is one case treated with
low-dose MTX therapy receiving a cumulative dosage of
100 mg in whom the foetus showed severe malforma-
tions [75]. In adults there are single reports on oligo-
spermia and impotence [76, 77].
Consensus Girls of childbearing age should utilise safe
measures of contraception (grade IIIA). The simulta-
neous use of oral contraceptives and MTX needs close
monitoring because of increased bioavailability of
MTX. A gynaecologist is to be consulted.
Contraindications
Contraindications can be deduced from the side effects
described above.
Consensus In children and adolescents with renal
insufficiency, in adolescents who regularly drink alcohol,
and during pregnancy or insufficient contraception,
MTX is not to be given (grade IIIE). In the event of lung
or liver disease, costs and benefits of low-dose MTX
therapy are to be balanced.
Interactions
Phenytoin, barbiturates, tranquillizers, oral contracep-
tives and tetracycline increase the bioavailability of
MTX. The combination of MTX and trimethoprim/
sulfamethoxazole can lead to skin alterations and severe
175
bone-marrow suppression [78]. Probenecid may lower
MTX clearance by 400% [79]. Moreover, penicillins and
cyclosporine A lower renal clearance of MTX.
Consensus The combination of trimethoprim/sulfa-
methoxazole and/or probenecid is contraindicated. The
combination with phenytoin, barbiturates, tranquilliz-
ers, oral contraceptives, tetracycline, penicillins and
cyclosporine A requires special caution (grade IIIA).
How long to treat with MTX and when to terminate
treatment
There are no systematic data concerning which cumu-
lative dosage leads to severe side effects, and how long
children can be treated with MTX. To evaluate treat-
ment efficacy it is recommended internationally that
treatment be for a period of 9–15 months [22, 80, 81]
(evidence grade III). There are no controlled data on the
optimal time point at which to stop MTX therapy. In
retrospective analyses, MTX was discontinued after a
complete remission. Two smaller studies showed that in
13 of 25 (52%) and 5 of 17 (29%) children a relapse
occurred within the first year [82, 83]. A relapse was
more common in younger children below 4.5 years
(evidence grade III).
Consensus There currently is no general recommenda-
tion on the treatment duration in children with JIA due
to a lack of systematic studies.
Addendum
In the meantime Huemer et al. [84] have published their
results of a pilot study on the effect of folic acid sup-
plementation and MTX treatment on homocysteine
levels. They show that patients with JIA requiring
MTX have significantly-elevated baseline plasma hom-
ocysteine concentrations compared to age- and sex-
matched healthy controls, but there is no significant
impact of folate supplementation on homocysteine
concentration.
In a recent analysis in 25 patients with oligo- or
polyarticular JIA, MTX was stopped when remission
was achieved after 3.8 months (group 1) or 12.6 months
(group 2). In this analysis there was no increased num-
ber of relapses in group 1. In addition, MRP8/MRP14
levels were used to indicate residual disease activity [85].
Acknowledgements We thank Prof. Dr. H. I. Huppertz (Professor-
Hess-Kinderklinik Bremen) for critical reading of the manuscript
and Mrs. Petra Knops for the help in preparation of the manu-
script.
References
1. Cassidy JT, Petty R (2001) Textbook of pediatric rheumatol-
ogy, 4th edn. WB Saunders Company, Philadelphia
176
2. Wahn V, Oppermann J, Huppertz HI, Zepp F (2001) Rheu-
matische Erkrankungen im Kindes- und Jugendalter. Hans
Marseille Verlag, Munich
3. Minden K, Niewerth M, Listing J, Zink A, German Study
Group of Pediatric Rheumatologists (2002) Health care pro-
vision in pediatric rheumatology in Germany–national rheu-
matologic database. J Rheumatol 29(3):622–628
4. Olsen NJ, Murray LM (1989) Antiproliferative effects of
methotrexate on peripheral blood mononuclear cells. Arthritis
Rheum 32:378–385
5. Rosenblatt DS, Whitehead VM, Vera N, Pottier A, Dupont M,
Vuchich MJ (1978) Prolonged inhibition of DNA synthesis
associated with the accumulation of methotrexate polygluta-
mates by cultured human cells. Mol Pharmacol 14:1143–
1147
6. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH (2001)
Anti-inflammatory mechanisms of methotrexate in rheumatoid
arthritis. Ann Rheum Dis 60:729–735
7. Horneff G, Forster J, Seyberth HW, Michels H (2000) Rec-
ommendations by the Pediatric and Adolescent Rheumatology
Study Committee on therapy with Etanercept (p75 TNF-alpha
receptor immunoglobulin fusion protein, Pharmacotherapy
Committee). Z Rheumatol 59:365–369
8. Onel KB (2000) Advances in the medical treatment of juvenile
rheumatoid arthritis. Curr Opin Pediatr 12:72–75
9. Seeliger S, Niehues T, Harms E, Frosch M, Roth J (2002)
Methotrexat in der Behandlung der juvenilen idiopathischen
Arthritis. Monatsschr Kinderheilkd 150:452–459
10. Andersen PA, West SG, O’Dell JR, Via CS, Claypool RG,
Kotzin BL (1985) Weekly pulse methotrexate in rheumatoid
arthritis. Clinical and immunologic effects in a randomized,
double-blind study. Ann Intern Med 103:489–496
11. Thompson RN, Watts C, Edelman J, Esdaile J, Russell AS (1984)
A controlled two-centre trial of parenteral methotrexate therapy
for refractory rheumatoid arthritis. J Rheumatol 11:760–763
12. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth
DE, Glass DN, Trentham DE (1985) Efficacy of low-dose
methotrexate in rheumatoid arthritis. N Engl J Med 312:818–822
13. Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS,
Guttadauria M, Yarboro C, Polisson RP, Weiner SR, Luggen
ME, Billingsley LM et al (1985) Comparison of low-dose oral
pulse methotrexate and placebo in the treatment of rheumatoid
arthritis. A controlled clinical trial. Arthritis Rheum 28:721–
730
14. Petty RE, Southwood TR, Baum J, Bhettay E, Glass DN,
Manners P, Maldonado-Cocco J, Suarez-Almazor M, Orozco-
Alcala J, Prieur AM (1998) Revision of the proposed classifi-
cation criteria for juvenile idiopathic arthritis: Durban, 1997. J
Rheumatol 25:1991–1994
15. Feldmann W (2000) Evidence-based pediatrics, 1st edn. BC
Decker, Hamilton
16. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richard-
son WS (1996) Evidence based medicine: what it is and what it
isn’t. BMJ 13:71–72
17. Truckenbrodt H, Hafner R (1986) Methotrexate therapy in
juvenile rheumatoid arthritis: a retrospective study. Arthritis
Rheum 29:801–807
18. Giannini EH, Brewer EJ, Kuzmina N, Shaikov A, Maximov A,
Vorontsov I, Fink CW, Newman AJ, Cassidy JT, Zemel LS
(1992) Methotrexate in resistant juvenile rheumatoid arthritis.
Results of the U.S.A.–U.S.S.R. double-blind, placebo-con-
trolled trial. The Pediatric Rheumatology Collaborative Study
Group and The Cooperative Children’s Study Group. N Engl J
Med 326:1043–1049
19. Woo P, Southwood TR, Prieur AM, Dore CJ, Grainger J,
David J, Ryder C, Hasson N, Hall A, Lemelle I (2000) Ran-
domized, placebo-controlled, crossover trial of low-dose oral
methotrexate in children with extended oligoarticular or sys-
temic arthritis. Arthritis Rheum 43:1849–1857
20. Takken T, Van Der Net J, Helders PJ (2001) Methotrexate for
treating juvenile idiopathic arthritis. Cochrane Database Syst
Rev 4:CD003129
21. Ravelli A, Viola S, Migliavacca D, Ruperto N, Pistorio A,
Martini A (1999) The extended oligoarticular subtype is the
best predictor of methotrexate efficacy in juvenile idiopathic
arthritis. J Pediatr 135:316–320
22. Cassidy JT (1999) Medical management of children with
juvenile rheumatoid arthritis. Drugs 58:831–850
23. Ravelli A, Martini A (2000) Methotrexate in juvenile idiopathic
arthritis: answers and questions. J Rheumatol 27:1830–
1833
24. Breit W, Frosch M, Meyer U, Heinecke A, Ganser G (2000) A
subgroup-specific evaluation of the efficacy of intraarticular
triamcinolone hexacetonide in juvenile chronic arthritis. J
Rheumatol 27:2696–2702
25. Padeh S, Passwell JH (1998) Intraarticular corticosteroid
injection in the management of children with chronic arthritis.
Arthritis Rheum 41:1210–1214
26. Ruperto N, Murray KJ, Gerloni V, Wulffraat N, De Oliveira S,
Falcinin F, Alessio M, Burgos-Vargas R, Corona F, Vesely R,
Foster H, Davidson J, Zulian F, Asplin L, Baildam E, Dole-
zalova P, Walsh J, Buoncompagni A, Garcia-Consuegra J,
Ozdogan H, Saurenmann R, Joos R, Calvo I, Alpigiani LP,
Machado C, Lahdenne P, Cortis E, Lepore L, Hall A, Kimura
Y, Wouters C, Woo P, Martini A (2002) A randomized trial of
Methotrexate in medium versus higher doses in children with
juvenile idiopathic arthritis who failed on standard dose. In:
EULAR Meeting Stockholm, Abstract Nr. 1384
27. Kremer JM, Galivan J, Streckfuss A, Kamen B (1986) Meth-
otrexate metabolism analysis in blood and liver of rheumatoid
arthritis patients. Association with hepatic folate deficiency
and formation of polyglutamates. Arthritis Rheum 29:832–
835
28. Ravelli A, Di Fuccia G, Molinaro M, Ramenghi B, Zonta L,
Regazzi MB, Martini A (1993) Plasma levels after oral meth-
otrexate in children with juvenile rheumatoid arthritis.
J Rheumatol 20:1573–1577
29. Albertioni F, Flato B, Seideman P, Beck O, Vinje O, Peterson
C, Eksborg S (1995) Methotrexate in juvenile rheumatoid
arthritis. Evidence of age-dependent pharmacokinetics. Eur
J Clin Pharmacol 47:507–511
30. Reiff A, Shaham B, Wood BP, Bernstein BH, Stanly P, Szer IS
(1995) High dose methotrexate in the treatment of refractory
juvenile rheumatoid arthritis. Clin Exp Rheumatol 13:113–
118
31. Wallace CA, Bleyer WA, Sherry DD, Salmonson KL, Wedg-
wood RJ (1989) Toxicity and serum levels of methotrexate in
children with juvenile rheumatoid arthritis. Arthritis Rheum
32:677–681
32. Oguey D, Kolliker F, Gerber NJ, Reichen J (1992) Effect of
food on the bioavailability of low-dose methotrexate in patients
with rheumatoid arthritis. Arthritis Rheum 35:611–614
33. Wallace CA (1998) The use of methotrexate in childhood
rheumatic diseases. Arthritis Rheum 41:381–391
34. Balis FM, Mirro J Jr, Reaman GH, Evans WE, McCully C,
Doherty KM, Murphy RF, Jeffries S, Poplack DG (1988)
Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol
6:1882–1886
35. Balis FM, Savitch JL, Bleyer WA (1983) Pharmacokinetics of
oral methotrexate in children. Cancer Res 43:2342–2345
36. Jundt JW, Browne BA, Fiocco GP, Steele AD, Mock D (1993)
A comparison of low dose methotrexate bioavailability: oral
solution, oral tablet, subcutaneous and intramuscular dosing.
J Rheumatol 20:1845–1849
37. Furst DE, Kremer JM (1988) Methotrexate in rheumatoid
arthritis. Arthritis Rheum 31:305–314
38. Dupuis LL, Koren G, Silverman ED, Laxer RM (1995) Influ-
ence of food on the bioavailability of oral methotrexate in
children. J Rheumatol 22:1570–1573
39. Morgan SL, Baggott JE, Lee JY, Alarcon GS (1998) Folic acid
supplementation prevents deficient blood folate levels and
hyperhomocysteinemia during longterm, low dose methotrex-
ate therapy for rheumatoid arthritis: implications for cardio-
vascular disease prevention. J Rheumatol 25:441–446

40. van Ede AE, Laan RF, Blom HJ, Boers GH, Haagsma CJ,
Thomas CM, De Boo TM, van de Putte LB (2002) Homocy-
steine and folate status in methotrexate-treated patients with
rheumatoid arthritis (Oxford). Rheumatology 41:658–665
41. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA,
Tugwell P (1998) The efficacy of folic acid and folinic acid in
reducing methotrexate gastrointestinal toxicity in rheumatoid
arthritis. A metaanalysis of randomized controlled trials. J
Rheumatol 25:36–43
42. van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar
MA, van Denderen CJ, Westgeest TA, Romme TC, de Rooij
DJ, Jacobs MJ, de Boo TM, van der Wilt GJ, Severens JL,
Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de
Putte LB (2001) Effect of folic or folinic acid supplementation
on the toxicity and efficacy of methotrexate in rheumatoid
arthritis: a forty-eight week, multicenter, randomized, double-
blind, placebo-controlled study. Arthritis Rheum 44:1515–1524
43. Hunt PG, Rose CD, McIlvain-Simpson G, Tejani S (1997) The
effects of daily intake of folic acid on the efficacy of metho-
trexate therapy in children with juvenile rheumatoid arthritis. A
controlled study. J Rheumatol 24:2230–2232
44. Dupuis LL, Koren G, Shore A, Silverman ED, Laxer RM
(1990) Methotrexate-nonsteroidal antiinflammatory drug inter-
action in children with arthritis. J Rheumatol 17:1469–1473
45. Singsen BH, Goldbach-Mansky R (1997) Methotrexate in the
treatment of juvenile rheumatoid arthritis and other pediatric
rheumatoid and nonrheumatic disorders. Rheum Dis Clin
North Am 23:811–840
46. Wallace CA, Smith AL, Sherry DD (1993) Pilot investigation
of naproxen/methotrexate interaction in patients with juvenile
rheumatoid arthritis. J Rheumatol 20:1764–1768
47. Lafforgue P, Monjanel-Mouterde S, Durand A, Catalin J,
Acquaviva PC (1993) Is there an interaction between low doses
of corticosteroids and methotrexate in patients with rheuma-
toid arthritis? A pharmacokinetic study in 33 patients. J
Rheumatol 20:263–267
48. O’Dell JR (2001) Combinations of conventional disease-modifying
antirheumatic drugs. Rheum Dis Clin North Am 27:415–426
49. Barrera P, Haagsma CJ, Boerbooms AM, Van Riel PL, Borm
GF, Van de Putte LB, Van der Meer JW (1995) Effect of
methotrexate alone or in combination with sulphasalazine on
the production and circulating concentrations of cytokines and
their antagonists. Longitudinal evaluation in patients with
rheumatoid arthritis. Br J Rheumatol 34:747–755
50. Seitz M, Loetscher P, Dewald B, Towbin H, Rordorf C, Gallati
H, Baggiolini M, Gerber NJ (1995) Methotrexate action in
rheumatoid arthritis: stimulation of cytokine inhibitor and
inhibition of chemokine production by peripheral blood
mononuclear cells. Br J Rheumatol 34:602–609
51. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fle-
ischmann RM, Fox RI, Jackson CG, Lange M, Burge DJ
(1999) A trial of etanercept, a recombinant tumor necrosis
factor receptor:Fc fusion protein, in patients with rheumatoid
arthritis receiving methotrexate. N Engl J Med 340:253–259
52. Schmeling H, Mathony K, John V, Keysser G, Burdach S,
Horneff G (2001) A combination of etanercept and metho-
trexate for the treatment of refractory juvenile idiopathic
arthritis: a pilot study. Ann Rheum Dis 60:410–412
53. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM
(1992) Morbidity associated with long-term methotrexate
therapy in juvenile rheumatoid arthritis. J Pediatr 120:468–473
54. Grennan DM, Gray J, Loudon J, Fear S (2001) Methotrexate
and early postoperative complications in patients with rheu-
matoid arthritis undergoing elective orthopaedic surgery. Ann
Rheum Dis 60:214–217
55. Franke J, Hafner R, Lohrs U, Truckenbrodt H (1996) Methotrexate
and liver fibrosis in juvenile chronic arthritis retrospective study of
73 liver biopsies. Monatsschrift Kinderheilkunde 144:147–151
56. Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH
(1997) The long-term effect of methotrexate therapy on the liver
in patients with juvenile rheumatoid arthritis. Arthritis Rheum
40:2226–2234
177
57. Erickson AR, Reddy V, Vogelgesang SA, West SG (1995)
Usefulness of the American College of Rheumatology recom-
mendations for liver biopsy in methotrexate-treated rheuma-
toid arthritis patients. Arthritis Rheum 38:1115–1119
58. Kremer JM, Alarcon GS, Lightfoot RW Jr, Willkens RF, Furst
DE, Williams HJ, Dent PB, Weinblatt ME (1994) Methotrex-
ate for rheumatoid arthritis. Suggested guidelines for moni-
toring liver toxicity. American College of Rheumatology.
Arthritis Rheum 37:316–328
59. McKendry RJ (1997) The remarkable spectrum of methotrex-
ate toxicities. Rheum Dis Clin North Am 23:939–954
60. Kremer JM, Alarcon GS, Weinblatt ME, Kaymakcian MV,
Macaluso M, Cannon GW, Palmer WR, Sundy JS, St Clair
EW, Alexander RW, Smith GJ, Axiotis CA (1997) Clinical,
laboratory, radiographic, and histopathologic features of
methotrexate-associated lung injury in patients with rheuma-
toid arthritis: a multicenter study with literature review.
Arthritis Rheum 40:1829–1837
61. Salaffi F, Manganelli P, Carotti M, Subiaco S, Lamanna G,
Cervini C (1997) Methotrexate-induced pneumonitis in patients
with rheumatoid arthritis and psoriatic arthritis: report of five
cases and review of the literature. Clin Rheumatol 16:296–304
62. Cron RQ, Sherry DD, Wallace CA (1998) Methotrexate-in-
duced hypersensitivity pneumonitis in a child with juvenile
rheumatoid arthritis. J Pediatr 132:901–902
63. Camiciottoli G, Trapani S, Castellani W, Ginanni R, Ermini
M, Falcini F (1998) Effect on lung function of methotrexate
and non-steroid anti-inflammatory drugs in children with
juvenile rheumatoid arthritis. Rheumatol Int 18:11–16
64. Pelucchi A, Lomater C, Gerloni V, Foresi A, Fantini F, Ma-
razzini L (1994) Lung function and diffusing capacity for car-
bon monoxide in patients with juvenile chronic arthritis: effect
of disease activity and low dose methotrexate therapy. Clin Exp
Rheumatol 12:675–679
65. Schmeling H, Stephan V, Burdach S, Horneff G (2002) Pul-
monary function in children with juvenile idiopathic arthritis
and effects of methotrexate therapy. Z Rheumatol 61:168–172
66. Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Baland-
raud N, Sibilia J (2002) Lymphomas in rheumatoid arthritis
patients treated with methotrexate: a 3-year prospective study
in France. Blood 1(99):3909–3915
67. Rau R (1994) Treatment of chronic polyarthritis with metho-
trexate 1994–a review. Z Rheumatol 53:199–229
68. Cleary AG, McDowell H, Sills JA (2002) Polyarticular juvenile
idiopathic arthritis treated with methotrexate complicated by
the development of non-Hodgkin’s lymphoma. Arch Dis Child
86:47–49
69. Krugmann J, Sailer-Hock M, Muller T, Gruber J, Allerberger
F, Offner FA (2000) Epstein–Barr virus-associated Hodgkin’s
lymphoma and Legionella pneumophila infection complicating
treatment of juvenile rheumatoid arthritis with methotrexate
and cyclosporine A. Hum Pathol 31:253–255
70. Londino AV Jr, Blatt J, Knisely AS (1998) Hodgkin’s disease in
a patient with juvenile rheumatoid arthritis taking weekly low
dose methotrexate. J Rheumatol 25:1245–1246
71. Munro R, Porter DR, Sturrock RD (1998) Lymphadenopathy
in a patient with systemic onset juvenile chronic arthritis. Ann
Rheum Dis 57:513–517
72. Padeh S, Sharon N, Schiby G, Rechavi G, Passwell JH (1997)
Hodgkin’s lymphoma in systemic onset juvenile rheumatoid
arthritis after treatment with low dose methotrexate. J Rheu-
matol 24:2035–2037
73. Bawle EV, Conard JV, Weiss L (1998) Adult and two children
with fetal methotrexate syndrome. Teratology 57:51–55
74. Kozlowski RD, Steinbrunner JV, MacKenzie AH, Clough JD,
Wilke WS, Segal AM (1990) Outcome of first-trimester expo-
sure to low-dose methotrexate in eight patients with rheumatic
disease. Am J Med 88:589–592
75. Buckley LM, Bullaboy CA, Leichtman L, Marquez M (1997)
Multiple congenital anomalies associated with weekly low-dose
methotrexate treatment of the mother. Arthritis Rheum
40:971–973
178
76. Blackburn WD Jr, Alarcon GS (1989) Impotence in three
rheumatoid arthritis patients treated with methotrexate.
Arthritis Rheum 32:1341–1342
77. Sussman A, Leonard JM (1980) Psoriasis, methotrexate, and
oligospermia. Arch Dermatol 116:215–217
78. O’Dell JR (1997) Methotrexate use in rheumatoid arthritis.
Rheum Dis Cl N Am 23:779–796
79. Aherne GW, Piall E, Marks V, Mould G, White WF (1978)
Prolongation and enhancement of serum methotrexate con-
centrations by probenecid. Br Med J 29:1097–1099
80. Brik R, Berkowitz D, Berant M (1998) Duration of metho-
trexate treatment until partial and total remission of refractory
juvenile rheumatoid arthritis. Ann Rheum Dis 57:174–175
81. Huang JL (1996) Methotrexate in the treatment of children
with chronic arthritis–long-term observations of efficacy and
safety. Br J Clin Pract 50:311–314
82. Gottlieb BS, Keenan GF, Lu T, Ilowite NT (1997) Discontin-
uation of methotrexate treatment in juvenile rheumatoid
arthritis. Pediatrics 100:994–997
83. Ravelli A, Viola S, Ramenghi B, Aramini L, Ruperto N,
Martini A (1995) Frequency of relapse after discontinuation of
methotrexate therapy for clinical remission in juvenile rheu-
matoid arthritis. J Rheumatol 22:1574–1576
84. Huemer M, Fodinger M, Huemer C, Sailer-Hock M, Falger J,
Rettenbacher A, Bernecker M, Artacker G, Kenzian H, Lang
T, Stockler-Ipsiroglu S (2003) Hyperhomocysteinemia in chil-
dren with juvenile idiopathic arthritis is not influenced by
methotrexate treatment and folic acid supplementation: a pilot
study. Clin Exp Rheumatol 21:249–255
85. Foell D, Frosch M, Schulze zur Wiesch A, Vogl T, Sorg C, Roth
J (2004) Methotrexate treatment in juvenile idiopathic arthritis:
when is the right time to stop? Ann Rheum Dis 63:206–208