multinational evidence-based recommendations for

8/14/2019 Multinational Evidence-based Recommendations For

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Multinational evidence-basedMultinational evidence-based recommendationsrecommendationsfor for

the use of methotrexate in rheumatic disordersthe use of methotrexate in rheumatic disorderswith a focus on rheumatoid arthritiswith a focus on rheumatoid arthritis : integrating: integrating

systematic literature research and expertsystematic literature research and expertopinion of a broad international panel of opinion of a broad international panel of

rheumatologists in the 3E Initiativerheumatologists in the 3E Initiative

ELVIS P CRISPINO MDELVIS P CRISPINO MD


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OBJECTIVEOBJECTIVE

To develop evidence-basedTo develop evidence-basedrecommendations for the use of recommendations for the use of

methotrexate in daily clinical practicemethotrexate in daily clinical practicein rheumatic disordersin rheumatic disorders


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Methotrexate is the disease-modifyingMethotrexate is the disease-modifyingantirheumatic drug (DMARD) of firstantirheumatic drug (DMARD) of firstchoicechoice

treatment of rheumatoid arthritis (RAtreatment of rheumatoid arthritis (RA ))used in other systemic rheumatic disordersused in other systemic rheumatic disorders


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VariationsVariations

DosageDosageFolic acid supplementationFolic acid supplementationSafety monitoringSafety monitoring

specific clinical situations such as thespecific clinical situations such as theperioperative period and before/during pregnancyperioperative period and before/during pregnancy

Existing guidelines often lack this level of detailExisting guidelines often lack this level of detail


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3E Initiative (Evidence, Expertise,Exchange)

is a multinational effortis a multinational effortpromoting evidence-based medicinepromoting evidence-based medicinedetailed recommendations addressing clinicaldetailed recommendations addressing clinicalproblemproblemPromotes epidemiologyPromotes epidemiologyteaching and conducting systematicteaching and conducting systematic

literature research following a strict methodologyliterature research following a strict methodology


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METHODSMETHODS

total of 751 rheumatologists from 17 countriestotal of 751 rheumatologists from 17 countriesparticipated in the 3E Initiative of 20078participated in the 3E Initiative of 20078Each countryEach country

scientific committee (one principal investigator scientific committee (one principal investigator and five to 16 members )and five to 16 members )bibliographic team consisted of 6 internationalbibliographic team consisted of 6 international

fellows,3 mentors,1 organizer fellows,3 mentors,1 organizer


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10 clinically relevant questions on the10 clinically relevant questions on the useuseof methotrexateof methotrexate in rheumatic disordersin rheumatic disorderswere formulated and selected by a Delphiwere formulated and selected by a Delphivotevote


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1.preadministration work-up1.preadministration work-up2.optimal dosage and route2.optimal dosage and route3.use of folic acid3.use of folic acid4.safety monitoring4.safety monitoring5.hepatotoxicity5.hepatotoxicity

6 Longterm safety (>2 years)6 Longterm safety (>2 years)7. mono versus combination therapy7. mono versus combination therapy8. management in the perioperative period8. management in the perioperative period

9.before/during pregnancy, and9.before/during pregnancy, and10.methotrexate as a steroid-sparing agent in10.methotrexate as a steroid-sparing agent inother rheumatic disordersother rheumatic disorders


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bibliographic team conducted a systematicbibliographic team conducted a systematicliterature reviewliterature review

MedlineMedlineEmbaseEmbaseCochrane Library and European LeagueCochrane Library and European League

against Rheumatism (EULAR) 20057against Rheumatism (EULAR) 20057American College of Rheumatology (ACR)American College of Rheumatology (ACR)20056 abstracts were systematically20056 abstracts were systematically

searched for articles published up tosearched for articles published up toSeptember 2007September 2007


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relevant data were extracted and

appropriate statistics were calculated,including effect sizes, hazard ratios (HR),and standardized mortality ratios with 95%CI


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2nd roundl discuss the generatedevidence and propose a set of recommendations

3 rd roundscientific committees (n = 94 participants)

merged all propositions to 10 final recommendationsbydiscussion and Delphi vote


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grade of recommendation according to theOxford Levels of Evidence was assessedand thelevel of agreement was measured on a10-point visual analogue scale(1, no agreement; 10, full agreement).


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total of 16 979 references was identified, of whichtotal of 16 979 references was identified, of which304 articles304 articles

were systematically reviewed (table 1)were systematically reviewed (table 1)


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Mean level of agreement among therheumatologists was 8.1 (range 7.48.8)

percentage of rheumatologists whoindicated that they would change their clinical practice according to eachrecommendation is shown in table 3.


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RECOMMENDATION 1work-up for patients starting methotrexate

Alcohol intakeSGPT/SGOTComplete blood count

(CBC)Chest x ray (obtainedwithin the previousyear); consider

Hepatitis B/C,Lipid profile and

AlbuminCreatinine

Serology for HIV

Blood fasting glucose,Pregnancy test


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estimated creatinine clearance of less than 79ml/minuteincreases severe methotrexate (pulmonary)

toxicityhypoalbuminaemia is associated withmethotrexate-induced

thrombocytopenia, liver and pulmonary toxicitylung abnormalities on radiographs - PNEUMONITIS


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observational evidence was combinedwith 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 than70 years, malignancy, pregnancy or inadequatecontraception,history of alcohol/drug abuse, acute or chronicinfection andpulmonary disease


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RECOMMENDATION 2RECOMMENDATION 2

Oral methotrexate should be started at 1015mg/week, withescalation of 5 mg every 24 weeks up to 2030

mg/week,depending on clinical response and tolerability;parenteral administration should be consideredin the case of inadequate response or

intolerance


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Recommendation 3

Prescription of at least 5 mg folic acid per week with methotrexate therapy is stronglyrecommendedmeta-analysis of nine studies including 788 RA

patientssuggested that folic acid supplementationreduces gastrointestinal and liver toxicity of methotrexatewithout reducing efficacy


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Recommendation 4

When starting methotrexate or increasing the dose, ALT(SGPT) with or without AST, creatinine and CBC shouldbe performed every 1 1.5 months until a stable dose isreached and every 13 monthsclinical 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 testsfor monitoring hepatotoxicity


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four national recommendations and the1996 ACR guidelinessuggest monitoring every 13 months


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Recommendation 5

Methotrexate should be stopped if Increase in ALT/AST greater than three times theupper limit of normal (ULN)

reinstituted at a lower dose following normalisation

persistently elevated up to three times the ULN, thedose of methotrexate should be adjusted;


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Pooled data of 2062 RA patients after amean of 3.3 years onmethotrexate showed that the cumulativeincidence of abnormalALT/AST was 48.9% above the ULN and16.8% above two to three times the ULN


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ACR guidelines for monitoringhepatotoxicity showed 80% sensitivity and82% specificity for detecting fibrosis/cirrhosis of serialabnormal AST tests


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evidence suggests that liver enzyme elevation isfrequent but often transient, thatmultiple rather than single findings associate

with an abnormal biopsy (as noted earlier) andthat methotrexate-induced fibrosis/cirrhosis israre.


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non-steroidal anti-inflammatorydrugs, obesity and alcohol and other diagnostic procedures thanliver biopsy in the case of persistentlyelevated liver enzymes after thediscontinuation of methotrexate


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Based on its acceptable safety profile,methotrexate is appropriate for long-termuse.

methotrexate compared with patientswithout methotrexate had a lower mortalityincidence rate (23/1000 versus 26.7/1000

patient-years) andreduced cardiovascular mortality (HR 0.3;95% CI 0.2 to 0.7

Recommendation 6


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in two casecontrol studies, methotrexate wasnot a risk factor and even reduced the risk of cardiovascular disease

methotrexate was less often discontinuedbecause of toxicity than other DMARD, exceptfor hydroxychloroquineLong-term methotrexate use

was not associated with an increased risk of serious infections


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Recommendation 7

the balance of efficacy/toxicity favoursmethotrexate monotherapy over combinationwith other conventional DMARD; methotrexateshould be considered as the anchor for combination therapycombination therapy showed a trend for moreEULAR moderate response and remission, but

only ACR70 responses were significantly moreoften achieved (RR 2.41; 95%CI 1.07 to 5.44).81


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Methotrexate combination therapy wassuperior to methotrexate monotherapymainly in patients with a previousinadequate response to methotrexate


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toxicity, methotrexate combinedwith sulfasalazine and methotrexatecombined with leflunomideeach significantly increased the risk of gastrointestinal side effects andhepatotoxicity


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Recommendation 8Methotrexate, as a steroid-sparing agent, isrecommended in

giant-cell arteritis and polymyalgia rheumatica and can beconsidered in patients withsystemic lupus erythematosus or (juvenile) dermatomyositis.

higher prednisone discontinuation ratesignificantly lower cumulative steroid dosefewer relapses with methotrexate therapy after


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No studies were found comparing thesteroid-sparing effect of methotrexate withother DMARD.


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Recommendation 9

Methotrexate can be safely continued inthe perioperative period in RA patientsundergoing elective orthopaedic surgery.who continued methotrexate - fewer RAflares than patients who stoppedmethotrexate.


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perioperative use of methotrexate was notassociated with wound morbidity (p=0.84) andsignificantly reduced RA flares.

methotrexate can be safely continued in theperioperative period of elective orthopaedic surgery,no studies

were found regarding (non-)elective non-

orthopaedic surgery.Methotrexate should not be used for at least 3months


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Recommendation 10

Methotrexate should not be used for at least 3months before planned pregnancy for men andwomen and should not be used

during pregnancy or breast feeding.

Six studies assessed the outcome of

continued methotrexate therapy before/duringpregnancy in (mostly) RA patients


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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

multinational evidence-based recommendations for

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