Multinational Evidence-Based Recommendations For

Multinational evidence-based recommendations
for
the use of methotrexate in rheumatic disorders
with a focus on rheumatoid arthritis: integrating
systematic literature research and expert
opinion of a broad international panel of
rheumatologists in the 3E Initiative
ELVIS P CRISPINO MD
OBJECTIVE
 To develop evidence-based
recommendations for the use of
methotrexate in daily clinical practice
in rheumatic disorders
 Methotrexate is the disease-modifying
antirheumatic drug (DMARD) of first
choice
 treatment of rheumatoid arthritis (RA)
 used in other systemic rheumatic disorders
 Variations
 Dosage
 Folicacid supplementation
 Safety monitoring
 specific clinical situations such as the

perioperative period and before/during pregnancy
 Existing guidelines often lack this level of detail

3E Initiative (Evidence, Expertise,
Exchange)
 is a multinational effort
 promoting evidence-based medicine
 detailed recommendations addressing clinical
problem
 Promotes epidemiology
 teaching and conducting systematic
 literature research following a strict methodology
METHODS
 total of 751 rheumatologists from 17 countries
 participated in the 3E Initiative of 2007–8
 Each country
 scientific committee (one principal investigator
and five to 16 members )
 bibliographic team consisted of 6 international
fellows,3 mentors,1 organizer
 10clinically relevant questions on the use
of methotrexate in rheumatic disorders
were formulated and selected by a Delphi
vote
 1.preadministration work-up
 2.optimal dosage and route
 3.use of folic acid
 4.safety monitoring
 5.hepatotoxicity
 6 Longterm safety (>2 years)
 7. mono versus combination therapy
 8. management in the perioperative period
 9.before/during pregnancy, and
 10.methotrexate as a steroid-sparing agent in
other rheumatic disorders
 bibliographic team conducted a systematic
literature review
 Medline
 Embase
 Cochrane Library and European League
against Rheumatism (EULAR) 2005–7
 American College of Rheumatology (ACR)
2005–6 abstracts were systematically
searched for articles published up to
September 2007
 relevantdata were extracted and
appropriate statistics were calculated,
including effect sizes, hazard ratios (HR),
and standardized mortality ratios with 95%
CI
2nd round
l discuss the generated
evidence and propose a set of
recommendations
3rd round
scientific committees (n = 94 participants)
 merged all propositions to 10 final recommendations
by
 discussion and Delphi vote
 grade of recommendation according to the
Oxford Levels of Evidence was assessed
and the
 level of agreement was measured on a
10-point visual analogue scale
 (1, no agreement; 10, full agreement).
total of 16 979 references was identified, of which
304 articles
were systematically reviewed (table 1)
 Meanlevel of agreement among the
rheumatologists was 8.1 (range 7.4–8.8)
 percentage of rheumatologists who

indicated that they would change their
clinical practice according to each
recommendation is shown in table 3.
RECOMMENDATION 1
work-up for patients starting methotrexate
 Alcohol intake  Albumin

 SGPT/SGOT  Creatinine
 Complete blood count
(CBC)
 Serology for HIV
 Chest x ray (obtained
within the previous
year); consider  Bloodfasting glucose,
 Hepatitis B/C,  Pregnancy test
 Lipid profile and
 estimated creatinine clearance of less than 79
ml/minute
 increases severe methotrexate (pulmonary)
toxicity
 hypoalbuminaemia is associated with
methotrexate-induced
 thrombocytopenia, liver and pulmonary toxicity
 lung abnormalities on radiographs - PNEUMONITIS
observational evidence was combined
with expert opinion, following from contraindications to
methotrexate use frequently listed in randomised controlled
trials (RCT) in RA from the past 15 years
 significant renal disease, hepatic disorders,

leucopenia less than 3.0 X10 9 /l,
 thrombocytopenia less than 100 X10 9 /l,
age greater than

 70 years, malignancy, pregnancy or inadequate
contraception,
 history of alcohol/drug abuse, acute or chronic
infection and
 pulmonary disease
RECOMMENDATION 2
 Oral methotrexate should be started at 10–15

mg/week, with
 escalation of 5 mg every 2–4 weeks up to 20–30
mg/week,
 depending on clinical response and tolerability;
parenteral administration should be considered
in the case of inadequate response or
intolerance
Recommendation 3
 Prescriptionof at least 5 mg folic acid per week
with methotrexate therapy is strongly
recommended
 meta-analysis of nine studies including 788 RA
patients
 suggested that folic acid supplementation
reduces gastrointestinal and liver toxicity of
methotrexate
 without reducing efficacy
Recommendation 4
 When starting methotrexate or increasing the dose, ALT

(SGPT) with or without AST, creatinine and CBC should
be performed every 1– 1.5 months until a stable dose is
reached and every 1–3 months
 clinical assessment for side effects and risk factors
should be performed at each visit
 One study suggests that ALT alone might detect
 90% of the elevated AST or paired tests
for monitoring hepatotoxicity
 fournational recommendations and the
1996 ACR guidelines
 suggest monitoring every 1–3 months
Recommendation 5
 Methotrexate should be stopped if

 Increase in ALT/AST greater than three times the
upper limit of normal (ULN)
 reinstituted at a lower dose following normalisation
 persistently
elevated up to three times the ULN, the
dose of methotrexate should be adjusted;
 Pooled data of 2062 RA patients after a
mean of 3.3 years on
 methotrexate showed that the cumulative
incidence of abnormal
 ALT/AST was 48.9% above the ULN and
16.8% above two to three times the ULN
 ACR guidelines for monitoring
hepatotoxicity showed 80% sensitivity and
82% specificity for
 detecting fibrosis/cirrhosis of serial
abnormal AST tests
 evidence suggests that liver enzyme elevation is
frequent but often transient, that
 multiple rather than single findings associate
with an abnormal biopsy (as noted earlier) and
that methotrexate-induced fibrosis/cirrhosis is
rare.
 non-steroidal anti-inflammatory
 drugs, obesity and alcohol and other
diagnostic procedures than
 liver biopsy in the case of persistently
elevated liver enzymes after the
discontinuation of methotrexate
Recommendation 6
 Based on its acceptable safety profile,
methotrexate is appropriate for long-term
use.
 methotrexate compared with patients
without methotrexate had a lower mortality
 incidence rate (23/1000 versus 26.7/1000
patient-years) and
 reduced cardiovascular mortality (HR 0.3;
95% CI 0.2 to 0.7
 in two case–control studies, methotrexate was
not a risk factor and even reduced the risk of
cardiovascular disease
 methotrexate was less often discontinued
because of toxicity than other DMARD, except
for hydroxychloroquine
 Long-term methotrexate use
 was not associated with an increased risk of
serious infections
Recommendation 7
 the balance of efficacy/toxicity favours
methotrexate monotherapy over combination
with other conventional DMARD; methotrexate
should be considered as the anchor for
combination therapy
 combination therapy showed a trend for more
 EULAR moderate response and remission, but
only ACR70 responses were significantly more
often achieved (RR 2.41; 95%
 CI 1.07 to 5.44).81
 Methotrexate combination therapy was
superior to methotrexate monotherapy
mainly in patients with a previous
inadequate response to methotrexate
 toxicity,methotrexate combined
 with sulfasalazine and methotrexate
combined with leflunomide
 each significantly increased the risk of
gastrointestinal side effects and
hepatotoxicity
Recommendation 8
 Methotrexate,
as a steroid-sparing agent, is
recommended in
 giant-cellarteritis and polymyalgia rheumatica and can be
considered in patients with
 systemic lupus erythematosus or (juvenile) dermatomyositis.
 higher prednisone discontinuation rate

 significantly lower cumulative steroid dose
 fewer relapses with methotrexate therapy after
 No studies were found comparing the
steroid-sparing effect of methotrexate with
other DMARD.
Recommendation 9
 Methotrexate can be safely continued in
the perioperative period in RA patients
undergoing elective orthopaedic surgery.
 who continued methotrexate - fewer RA
flares than patients who stopped
methotrexate.
 perioperative use of methotrexate was not
associated with wound morbidity (p=0.84) and
 significantly reduced RA flares.
 methotrexate can be safely continued in the
 perioperative period of elective orthopaedic surgery,
no studies
 were found regarding (non-)elective non-
orthopaedic surgery.
 Methotrexate should not be used for at least 3
months
Recommendation 10
 Methotrexate should not be used for at least 3
months before planned pregnancy for men and
women and should not be used
 during pregnancy or breast feeding.
 Sixstudies assessed the outcome of

continued methotrexate therapy before/during
pregnancy in (mostly) RA patients
 Eighteen induced abortions were reported,
but the reasons were not stated.
 A total of 20 (24%) miscarriages, five (6%)
congenital malformations and 62 (75%)
 live births was reported

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Multinational evidence-based recommendations

 specific clinical situations such as the

 Existing guidelines often lack this level of detail

 percentage of rheumatologists who

 Alcohol intake  Albumin

 significant renal disease, hepatic disorders,

age greater than

 Oral methotrexate should be started at 10–15

 When starting methotrexate or increasing the dose, ALT

 Methotrexate should be stopped if

 higher prednisone discontinuation rate

 during pregnancy or breast feeding.

 Sixstudies assessed the outcome of

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