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Methotrexate for ankylosing spondylitis

  1. Junmin Chen1,*,
  2. Mirella MS Veras2,
  3. Chao Liu3,
  4. Junfang Lin1

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 20 NOV 2012

DOI: 10.1002/14651858.CD004524.pub4


How to Cite

Chen J, Veras MMS, Liu C, Lin J. Methotrexate for ankylosing spondylitis. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004524. DOI: 10.1002/14651858.CD004524.pub4.

Author Information

  1. 1

    The First Affiliated Hospital of Fujian Medical University, Department of Hematology and Rheumatology, Fuzhou, Fujian Province, China

  2. 2

    University of Ottawa, Centre for Global Health, Institute of Population Health, Ottawa, Ontario, Canada

  3. 3

    The First Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China

*Junmin Chen, Department of Hematology and Rheumatology, The First Affiliated Hospital of Fujian Medical University, #20 Chazhong Road, Fuzhou, Fujian Province, 350005, China. drjunminchen@hotmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

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Characteristics of included studies [ordered by year of study]
Altan 2001

MethodsRandomized allocation: randomization method not given.
Outcome assessment blinded.
Treatment allocation possibly open to patients and care providers.
Parallel groups.
Duration: 12 months.
Sample size at entry: 51.
MTX and naproxen group: 26.
Naproxen group: 25.
Personal communication with the trial report author confirmed that all participants completed the trial, and results include all the participants.


ParticipantsPatients with AS fulfilling New York criteria.
Other inclusion criteria:
morning stiffness > 15 min; sleep disturbance caused by pain; limitation of daily functional activity; CRP > 0.5 mg/dl.
Exclusion criteria:
total ankylosis involving the whole spine; failure of hepatic and renal tests; severe anaemia, leucopenia or thrombocytopenia.
Age: 46.78 years ± 11.76 (mean ± SD).
M:F ratio: 76%: 24%.
Mean disease duration: 9.52 (4 to 30) years.
HLA B27 positive: 88.2%.
With peripheral arthritis: 12%.


InterventionsMTX + naproxen group: MTX orally, 7.5 mg/week, plus naproxen 1000 mg/day.
Naproxen group: naproxen 1000 mg/day.


Outcomes1. Morning stiffness (units of scale not specified, we assumed the scale was in minutes).
2. Pain in the day (VAS 0 to 10 cm, where 0 = no pain and 10 = severe pain).
3. Pain in the night (VAS 0 to 10 cm, where 0 = no pain and 10 = severe pain).
4. Patient global assessment (scale of 1 to 5, where 1 = no disease activity and 5 = severe disease activity).
5. Physician global assessment (scale of 1 to 5, where 1 = no disease activity and 5 = severe disease activity).
6. Enthesis index (0 to 90, where the more severe the disease, the higher the score).
7. Function index (score 0 to 40, where 0 = the best and 40 = the worst).
8. Spondylitis index (score 0 to 10, where the more severe the disease, the higher the score).
9. ESR (percent change from baseline, according to information from author).
10. CRP (change from baseline, according to information from author).


NotesOutcomes were poorly presented, for example:
Morning stiffness was -35.09 ± 1.01 (naproxen alone) and -52.60 ± 0.70 (naproxen plus MTX), respectively. The unit was unknown and likely to be minute. We are not sure whether this figure was mean ± SD or mean ± SE. Nor are we sure whether this figure was score or percent change from baseline. According to author's correspondence, data were presented as percent change from baseline. After discussion, we entered end point mean ± SD (we assumed as SD) values.
Some baseline parameters were significantly different between intervention groups (summarised in  Table 1).
Our attempts to contact the authors to clarify the uncertainties have been unsuccessful so far.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgment of low risk or high risk.

Allocation concealment (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgment of low risk or high risk.

Blinding (performance bias and detection bias)
All outcomes
High riskOnly outcome assessment was reported to be blind. Because they did not use placebo, blinding of personnel and participants was impossible.

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data.

Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

Other biasHigh riskSome baseline parameters were significantly different between intervention groups. Furthermore, presentation of outcomes was poor.

Roychowdhury 2002

MethodsRandomized allocation: randomization and concealment methods not specified.
Outcome assessment blinded.
Patients and care providers blinded.
Parallel groups.
Duration: 24 weeks.
Sample size at entry: 30.
MTX group: 12 completed;
Placebo group: 16 completed.
Two participants withdrew, but it was unclear to which intervention group(s) they belonged.
Outcomes of each patient were provided.


ParticipantsPatients with AS fulfilling modified New York criteria and active disease defined as at least two of the following symptoms despite treatment with NSAIDs and/or other DMARDs:
morning stiffness > 30 min; sleep disturbance due to pain and stiffness; peripheral arthritis; ESR > 30 mm/h or CRP > 20 mg/L; spinal pain; pain in both buttocks during the day or night.
Sulphasalazine or other DMARDs discontinued at least four weeks before study entry.
Exclusion criteria:
serious systemic disease, malignancies, impaired organ function or serious infections; pregnancy and breast feeding; mental disorders; alcohol or drug abuse; history of intestinal disease.
Age: 44 ± 10 years (mean ± SD).
M:F ratio: 87%: 13%.
Mean disease duration: 17 (3 to 26) years.
With peripheral arthritis: 30%.


InterventionsMTX group: MTX, orally, 10 mg/week.
Placebo group: placebo orally, 10 mg/week.


Outcomes1. Bath ankylosing spondylitis disease activity index (BASDAI) (change from baseline) (VAS-10cm, where 0 = no disease activity and 10 = severe disease activity).
2. Bath ankylosing spondylitis metrology (BASMI) (change from baseline) (score from 0 to 10, where 0 = severely limited spinal mobility and 10 = overall normal).
3. CRP (change from baseline) (mg/L).


Notes30 patients entered the trial and 28 completed.
It is not known to which intervention group the two drop-outs belonged.
Our attempts to contact the authors have been unsuccessful to date.
Each patient's data were given, from which we calculated the summary values.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgement of low risk or high risk.

Allocation concealment (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgement of low risk or high risk.

Blinding (performance bias and detection bias)
All outcomes
Low riskReported as double blind, placebo-controlled.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

Other biasLow riskThe study appears to be free of other sources of bias.

Gonzalez-Lopez 2004

MethodsRandomized allocation: computer generated randomization numbers.
Patients, care-providers and outcome investigators blinded.
Parallel groups.
Duration: 24 weeks.
Sample size at entry: 35
MTX - 17
Placebo - 18
Withdrawals and drop-outs clearly specified. Outcomes analysis: ITT.


ParticipantsPatients with AS fulfilling New York criteria.
Other inclusion criteria:
minimum duration since diagnosis one year; having active disease at the time of the baseline evaluation, defined by the combination of three conditions: (1) physician assessment VAS at least 30 mm (0 to 100), (2) presence of inflammatory back pain (stiffness and pain worsening with rest and improving with exercise), (3) morning stiffness lasting 45 mins and/or peripheral arthritis; aged 18 years or more; stable dose of anti-inflammatory drugs; DMARDs ceased eight weeks before entry.
Exclusion criteria:
previous MTX treatment; history of hepatitis, pneumonitis; anaemia (Hb lower than 11 g/L); active infection, alcohol or drug abuse, mental or psychiatric disorders; those requiring corticosteroid or immunosuppressive treatment(s).
Age: 32 years ± 10 (MTX group), 38 years ± 10 (placebo group) (mean ± SD).
M:F ratio: 69%: 31%.
Mean disease duration since first symptoms: 9.5 ± 8 years (MTX group), 5.7 ± 5 years (placebo group).
With peripheral arthritis: 60%.


InterventionsMTX group: MTX 7.5 mg/week orally.
Placebo group: placebo orally,


OutcomesPrimary outcomes: response in the composite index (*see Notes section for this trial for details).
Secondary outcomes:
1. Morning stiffness (VAS 100 mm, 0 = no stiffness, 100 = severe).
2. Physical well-being (VAS 100 mm, 0 = feeling very well, 100 = feeling very bad).
3. Bath ankylosing spondylitis disease activity index (BASDAI) (from 0 to 10, 0 = no disease activity and 10 = severe disease activity).
4. Bath ankylosing spondylitis functional index (BASFI) (from 0 to 10, 0 = excellent, 10 = poor function).
5. Physician global assessment (VAS 100 mm, 0 = no disease activity and 100 = severe disease activity).
6. Patient global assessment (VAS 100 mm, 0 = no disease activity and 100 = severe disease activity).
7. Health assessment questionnaire for spondyloarthropathies (HAQ-S) (from 0 to 3, 0 = no difficulty and 3 = unable to do).
8. Spinal pain (VAS 10 cm, 0 = no pain, 10 = severe).
9. Disappearance of peripheral arthritis (event).


Notes* Composite index defined by improvement of 20% in at least 5 of following:
1. Severity of morning stiffness VAS 100 mm;
2. Physical well-being VAS 100 mm;
3. BASDAI;
4. BASFI;
5. HAQ-S;
6. Physician global assessment VAS 100 mm;
7. Patient global assessment VAS 100 mm.
as well as no worsening in any of the scales (defined as >20% worsening compared to baseline).

8. Disappearance of peripheral arthritis

9. Spinal pain (from 0 to 10)
All outcomes reported as mean ± SD of endpoint value except BASFI. Mean change from baseline ± SD reported for BASFI.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer generated random list.

Allocation concealment (selection bias)Low riskSequentially numbered drug containers of identical appearance.

Blinding (performance bias and detection bias)
All outcomes
Low riskThe patients and researchers involved in administration of the interventions, clinical evaluations, and statistical analyses were blinded to the treatment assignment for the duration of the trial.

Incomplete outcome data (attrition bias)
All outcomes
Low riskFor dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.

Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

Other biasHigh riskSome baseline parameters were significantly different between intervention groups.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Breban 2008There is another separate Cochrane review addressing biologics in AS.

Kabasakal 2009Not a RCT.

Li 2008There is another separate Cochrane review addressing biologics in AS.

Mulleman 2011There is another separate Cochrane review addressing biologics in AS.

Pérez-Guijo 2007Not a RCT.

Xie 2003This trial compared the effects of different dosage of MTX and did not include the comparison specified in the inclusion criteria.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Haque 1999

MethodsRCT

ParticipantsPatients with seronegative spondyloarthropathies. Data of AS patients were not available in the article abstract.

InterventionsMethotrexate. Comparison is unknown.

OutcomesTherapeutic response.

NotesThis study could not be reviewed because of lack of full text.

 
Comparison 1. MTX versus No MTX

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Response in the composite index1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 BASDAI (VAS-10 cm, 0=no disease activity, 10=severe disease activity) (end point value)263Mean Difference (IV, Random, 95% CI)0.96 [-1.22, 3.14]

 3 BASFI (score 0-10, 0=excellent, 10=poor function) (change from baseline)135Mean Difference (IV, Random, 95% CI)0.9 [-0.43, 2.23]

 4 Function index (score 0-40, 0=the best, 40=the worst) (end point value)1Mean Difference (IV, Random, 95% CI)Totals not selected

 5 Pain in the night (VAS-10 cm, 0=no pain, 10=severe pain) (end point value)1Mean Difference (IV, Random, 95% CI)Totals not selected

 6 Pain in the day (VAS-10 cm, 0=no pain, 10=severe pain) (end point value)151Mean Difference (IV, Random, 95% CI)0.89 [-0.44, 2.22]

 7 Spinal pain (VAS 10 cm, 0=no pain, 10=severe) (end point value)135Mean Difference (IV, Fixed, 95% CI)-0.90 [-2.64, 0.84]

 8 BASMI (VAS-10 cm, 0=severely limited spinal mobility, 10=overall normal) (end point value)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 9 Spondylitis index (score 0-10, the more severe the disease, the higher the score) (end point value)1Mean Difference (IV, Random, 95% CI)Totals not selected

 10 Enthesis index (score 0-90, the more severe the disease, the higher the score) (end point value)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 11 Disappearance of peripheral arthritis (event)1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 12 Patient global assessment (different scales, the more severe the disease, the higher the score) (end point value)284Std. Mean Difference (IV, Fixed, 95% CI)0.12 [-0.31, 0.55]

 13 Physician global assessment (different scales, the more severe the disease, the higher the score) (end point value)286Std. Mean Difference (IV, Random, 95% CI)-0.14 [-1.03, 0.75]

 14 Physical well-being (VAS 10 cm, 0=feeling very well, 10=very bad)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 15 Morning stiffness duration (units not specified in trial report, we assumed minutes)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 16 Severity of morning stiffness (VAS 10 cm, 0=no stiffness, 10=severe)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 17 Health assessment questionnaire for spondyloarthropathies (HAQ-S) (0-3, 0=no difficulty, 3=unable to do)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 18 CRP (change from baseline) (percentage for Altan, ug/ml for others)279Std. Mean Difference (IV, Fixed, 95% CI)0.04 [-0.40, 0.48]

 19 ESR (percentage change from baseline)151Std. Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.59, 0.51]

 20 Side effect151Risk Ratio (M-H, Random, 95% CI)16.37 [0.99, 269.44]

 21 Withdrawal for any reason135Risk Ratio (M-H, Random, 95% CI)1.06 [0.07, 15.62]

 
Summary of findings for the main comparison. MTX treated compared to no MTX treated for AS

MTX treated compared to no MTX treated for AS

Patient or population: Patients with AS
Settings: Inpatient clinic in Turkey (Altan 2001), outpatient rheumatology clinic in Guadalajara, Mexico (Gonzalez-Lopez 2004), and United Kingdom (Roychowdhury 2002)
Intervention: MTX
Comparison: No MTX

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

No MTXMTX

ASAS 40See commentSee commentNot estimable-See commentNot reported

Partial remissionSee commentSee commentNot estimable-See commentNot reported

BASFI (score from 0 to 10, 0=excellent, 10=poor function)

Follow-up: 24 weeks
The mean change

in BASFI score in the control group was
0.4
The mean change

in BASFI score in the intervention group was
0.9 lower

(0.43 lower to 2.23 higher)
35
(1 study)
⊕⊕⊝⊝

low1,2
MD = 0.9 (-0.43 to 2.23)

Relative improvement 8.57%
(95% CI 29.42 to 46.57)

Absolute improvement

3% (95% CI 10.3% to 16.3%)

Not statistically significant

X-Ray of the spineSee commentSee commentNot estimable-See commentNot reported

MRISee commentSee commentNot estimable-See commentNot reported

Serious adverse eventSee commentSee commentNot estimable-See commentNot reported

Withdrawal for any reason

Follow-up: 24 weeks
56 per 100059 per 1000
(4 to 868)
RR 1.06
(0.07 to 15.62)
35
(1 study)
⊕⊕⊝⊝

low1,2
Relative percent change 6 %
(95% CI 93% to 1462%)

Absolute risk difference 0%
(95% CI 15% to 16%)

Not statistically significant

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Baseline imbalance.
2 Few patients and few events.
 
Table 1. Comparison of baseline parameters between no MTX treatment and MTX treated group in Altan 2001

InterventionFunction indexPain in the dayPain in the nightSpondylitis indexEnthesis indexPatient assessmentPhysician assessmentMorning stiffness

MTX29.12 ± 25.183.93 ± 2.065.28 ± -2.383.31 ± 3.217.21 ± 7.462.65 ± 1.003.09 ± 0.8953.75 ± 32.62

No MTX20.89 ± 18.104.00 ± 2.804.10 ± 3.071.00 ± 1.913.78 ± 5.022.73 ± 0.992.21 ± 0.9721.31 ± 17.88

 
Table 2. Clinical relevance table - dichotomous

Outcome# Patients (# Trials)Control event rateAbsolute RDRelative % changeNNTStatistical significanceQuality of evidence

Response to composite index at 24 weeks35 (1)16.7% (3/18)36%218% (I)3statistically significantlow1,2

Response to composite index: defined by improvement ≥ 20% at

least 5 of following and no worsening in any of the scales (>20% worsening compared to baseline): severity of morning stiffness;

physical well-being; BASDAI; BASFI; HAQ-S; physician global assessment; and patient global assessment.
MTX = methotrexate; RR = relative risk, RD = risk difference, NNT = number needed to treat
I = improvement

 1 Baseline imbalance.
2 Few patients and few events.