Methotrexate treatment in rheumatoid arthritis: management in clinical remission, common infection and tuberculosis. Results from a systematic literature review

Abstract

This work was performed as part of the Portuguese participation in the 3E Initiative 2007–2008, dedicated to the use of methotrexate (MTX) in rheumatic conditions. Three questions raised by Portuguese rheumatologists and considered relevant to clinical practice remained out of the selection of a set of ten key questions formulated to further establish multinational recommendations on the use of MTX in rheumatic diseases. The authors collected and analyzed all the evidence available by using a systematic literature search methodology and selection criteria concerning the following issues in rheumatoid arthritis (RA): (1) the management of MTX after clinical remission; (2) the management of MTX during infections and (3) the screening and treatment of tuberculosis in patients on MTX treatment. A total of 1,862 references were identified, of which 163 were selected for detailed analysis and 12 included in the final review. The evidence was appraised according to the Oxford Centre for Evidence-based Medicine (EBM) levels of evidence. Although with limited evidence, the authors concluded that: (1) extending the interval for MTX therapy may be a valid alternative regimen in a subset of RA patients in clinical remission (EBM level 2b); (2) MTX may be safe during some common infections in RA patients (EBM level 3b/4); (3) screening and treatment of TB in patients on MTX should be similar to the general population (EBM level 4). The evidence available to support clinical decisions in this area is very limited in number and quality. There is a need for further research and while that is unavailable, practical decisions have to rely on experience and expert opinion.

Appendix I. Full search string carried out in PubMed

Question 1

• I. “Arthritis, Rheumatoid”[Mesh] OR “rheumatoid arthritis”[tw] OR “arthritis”[MeSH]

• II. “Methotrexate”[Mesh] OR “Methotrexate”[tw] OR “mtx”[tw] OR amethopterin [tiab] OR mexate [tiab] OR Emtrexate [tiab] OR Ledertrexat* [tiab] OR Methylaminopterin [tiab] OR Metotrexat* [tiab] OR Rheumatrex [tiab]

• III. Remission[All Fields] OR Stable[All Fields] OR ((“maintenance”[MeSH Terms] OR Maintenance[Text Word]) AND (“therapy”[Subheading] OR “therapeutics”[TIAB] OR “therapeutics”[MeSH Terms] OR therapy [Text Word])) OR (maintenance dosage [All Fields] OR maintenance dosages [All Fields] OR maintenance dose [All Fields] OR maintenance doses [All Fields] OR maintenance dosing [All Fields] OR maintenance dosis[All Fields]) OR (Maintaining [All Fields] AND remission [All Fields])

• IV. #1 AND #2 AND #3

• V. Flare [All Fields] OR “recurrence”[MeSH Terms] OR Recurrence [Text Word] OR “recurrence”[Text Word] OR “recurrence”[MeSH Terms] OR Relapse [Text Word]

• VI. Severity of Illness Index OR Treatment Outcome OR Pain Measurement OR outcome OR outcomes OR efficacy OR acr20 OR acr50 OR acr70 OR acr20 OR acr50 OR acr70 OR “disease activity score” OR “disease activity scores” OR DAS [tw] OR das28 OR das44 OR das28 OR das44 OR sdai OR cdai OR haq [tw] OR “health assessment questionnaire” OR “health assessment questionnaires” OR ((tender OR swollen) AND count) OR “therapy response”

• VII. Radiological damage OR radiographic damage OR radiological response OR radiographic response OR “joint damage” OR “radiological progression” OR “radiographic progression” OR disease progression OR larsen[tw] OR sharp[tw] OR “sharp/van der heijde” OR erosion*

• VIII. Toxicity OR side effects OR adverse effects OR adverse events OR safety OR drug safety OR “abdominal upset” OR (upset AND (abdominal OR stomach OR gastrointestinal)) OR nausea OR anorexia OR stomatitis OR diarrhea OR liver enzymes OR liver enzyme OR alopecia OR mucositis OR leukopenia OR thrombocytopenia OR pancytopenia OR leukopaenia OR thrombocytopaenia OR pancytopaenia OR pneumonitis OR infection OR infections OR lymphoma OR lymphomas OR cirrhosis OR fibrosis OR rash OR headache OR fatigue OR malaise

• IX. #5 OR #6 OR #7 OR #8

• X. Randomized controlled trial OR controlled clinical trial OR randomized controlled trials OR random allocation OR double-blind method OR single-blind method OR clinical trial OR clinical trials OR “clinical trial” OR ((singl* OR doubl* OR trebl* OR tripl* ) AND (mask* OR blind* )) OR “latin square” OR placebos OR placebo* OR random* OR research design [mh:noexp] OR comparative study OR evaluation studies OR cross-over studies OR randomized controlled trial OR randomized controlled trials OR groups[tiab] OR follow up studies OR follow up study OR followup OR prospective study OR prospective studies

• XI. #4 AND #9 AND #11

Question 2

• I. Items I and II, same as Question 1.

• II. “infection”[MeSH] OR “communicable diseases”[Mesh] OR “Infection”[tw] OR “Cross Infection”[Mesh] OR “Wounds and Injuries”[Mesh] OR “tuberculosis”[MeSH] OR Tuberculosis [tiab] OR “herpesvirus 3, human”[MeSH] OR human herpesvirus 3 [tiab] OR “herpes zoster”[MeSH] OR “hepatitis”[MeSH] OR Hepatitis [tiab] OR “bacterial infections and mycoses”[MeSH] OR Opportunistic Infections [Mesh] OR Opportunistic Infections [tiab] OR “Surgical Wound Infection”[Mesh] OR Surgical Wound Infection [tiab] OR “Intraoperative Complications”[Mesh] OR Intraoperative Complications [tiab] OR “Postoperative Complications”[Mesh] OR Postoperative Complications [tiab] OR “mortality”[Mesh]

• III. Clinical Trial[ptyp] OR Meta-Analysis[ptyp] OR Practice Guideline[ptyp] Randomized Controlled Trial[ptyp] OR Review[ptyp] OR Clinical Trial, Phase IV[ptyp] Consensus Development Conference[ptyp] OR Comparative Study[ptyp] OR Controlled Clinical Trial[ptyp] Guideline[ptyp] OR Multicenter Study[ptyp] “epidemiologic studies”[Mesh] OR “trial”[tw]

• IV. #1 AND #2 AND #3

Question 3

• I. Items I and II, same as Question 1.

• II. “Tuberculosis"[MeSH] OR "pulmonary infection"[MeSH OR ]"tuberculin skin test"[MeSH] OR "Mantoux test"[MeSH]

• III. #1 AND #2