Lupus
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Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy R Sakthiswary and E Suresh Lupus published online 7 January 2014 DOI: 10.1177/0961203313519159 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/01/07/0961203313519159 A more recent version of this article was published on - Feb 14, 2014
Published by: http://www.sagepublications.com
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Lupus (2014) 0,
1–11
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REVIEW
Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy R Sakthiswary1 and E Suresh2 1
Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Malaysia; and 2Department of Medicine, Alexandra Hospital (Jurong Health), Singapore
Objective: The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE). Methods: A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model. Results: Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls (p ¼ 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls (p ¼ 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials. Conclusion: The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE. Lupus (2014) 0, 1–11. Key words: Systemic lupus erythematosus; SLE; lupus; methotrexate; efficacy
Introduction Antimalarials are the usual choice for patients with non-organ-threatening systemic lupus erythematosus (SLE), particularly those with articular, cutaneous and constitutional manifestations.1 According to one recent systematic review,2 they are highly effective in preventing lupus flares, and improving long-term survival as well. However, they are not universally effective in inducing complete remission in all patients with SLE. One lupus database review revealed that 8% of patients discontinued hydroxychloroquine (HCQ) because of inefficacy, and another 29% because of adverse effects such as anorexia, nausea, headache, dizziness, visual disturbance, hearing loss, skin rash and myopathy.3 Correspondence to: Rajalingham Sakthiswary, Universiti Kebangsaan Malaysia, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia. Email: [email protected] Received 9 September 2013; accepted 11 December 2013
Given that non-organ-threatening SLE is associated with considerable morbidity and reduced quality of life,4 it is vital to gain adequate control of the disease, but apart from HCQ, only corticosteroids, belimumab and aspirin have thus far been approved by the Food and Drug Administration (FDA) in the United States for treatment of SLE. Of these, corticosteroids are not appropriate for long-term use because of their side-effect profile, and belimumab is very expensive, and may not be affordable for patients in many parts of the world. Hence, in practice, clinicians often turn to other disease-modifying treatment options, even in the absence of convincing controlled trial data. Methotrexate (MTX), for example, was first tested as early as 1965, and shown to rapidly improve arthralgia, skin rashes and purpura in a small sample of 10 patients,5 but, to date, there has been a paucity of controlled trial data on its efficacy. By contrast, several randomized controlled trials have established the efficacy of MTX in rheumatoid arthritis (RA), and it is indeed the
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10.1177/0961203313519159
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(LUP)
[1–11] [PREPRINTER stage]
Methotrexate in SLE R Sakthiswary and E Suresh
2
most commonly prescribed disease-modifying antirheumatic drug (DMARD) because of its excellent efficacy/toxicity trade-off, and highest long-term retention rate, when compared with other DMARDs.6,7 Whilst MTX may not be necessary in patients with mild SLE, who are well controlled on HCQ, and not be appropriate for those with severe disease, who would need more aggressive therapies, most clinicians would consider this as an option for the remaining large group of patients with non-organ-threatening disease, who (a) either do not respond or respond sub-optimally to HCQ, (b) react adversely to HCQ, or in those who (c) are unable to taper the dose of corticosteroids. In the last three decades, several trials, mostly uncontrolled, have examined the effects of MTX in SLE, with variable results. In this systematic review, we summarize the results of these studies, and evaluate the evidence for efficacy of MTX in SLE.
Methodology
The bibliographies of relevant studies were then used to get additional references. We also sought unpublished trials, relevant conference proceedings, and trial registries from the references of these studies. We only considered articles that were published in English. Data extraction The following data were extracted from each study chosen for inclusion: study design, study population, sample size, dose and duration of MTX therapy, and organ involvement. Additionally, handling of the control arm was recorded for all controlled trials. Outcome measures that were studied included (a) disease activity scores (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)),9 (b) steroid dose reduction, and (c) change in serological and laboratory markers (anti-double-stranded DNA (anti-dsDNA), serum complement 3 and 4, and erythrocyte sedimentation rate (ESR)). Quality assessment
Search strategy and study selection We searched MEDLINE, EMBASE and Cochrane Controlled Trials registry using the search terms ‘systemic lupus erythematosus’, ‘lupus’ and ‘SLE’ (both as medical subject heading (MeSH) and free text). These were combined using the set operator and with studies identified with the term ‘methotrexate’. No date restrictions were applied. Randomized controlled trials and observational studies that examined the effects of weekly MTX in adult SLE patients were eligible for inclusion. Other inclusion criteria included:
Study quality was independently scored by both the authors for all the randomized controlled trials included for the review. This was based on the ‘‘Instrument to measure the likelihood of bias’’, proposed by Jadad et al.10 The Jadad score could range from 0 to 5, and is determined on the basis of a simple three-point questionnaire that addresses randomization, blinding, and withdrawals and drop-outs. The higher the Jadad score, the lesser the likelihood of bias in the results (‘low’ score ¼ 0 to 2, ‘high’ score ¼ 3 to 5). Data synthesis and statistical analysis
a. Diagnosis of SLE based on either American College of Rheumatology (ACR) criteria or the treating physician’s opinion. b. Treatment with MTX for a minimum duration of three months. This duration was chosen on the basis of existing knowledge of the pharmacodynamics of weekly oral MTX treatment.8 c. Administration of placebo or standard therapy for patients randomized to the control arm in case-control studies. Abstracts of the studies identified by initial screening were evaluated by the lead author (RS) for appropriateness. The full text of those studies that met our inclusion criteria were retrieved and independently assessed by both the authors. Any disagreements were resolved by consensus.
Data were pooled using a random-effects model for a more conservative estimate of the effects of MTX therapy on SLEDAI and steroid dose reduction. The advantage of this model is that it allows for heterogeneity across the studies.11 The outcome of MTX therapy versus controls was expressed as odds ratio (OR) with 95% confidence intervals (CI). Changes in serological (anti-dsDNA and serum complement levels) and laboratory markers (ESR) were not statistically analysed owing to the small numbers of studies (only one controlled trial for each of these two outcome measures). Comprehensive Meta-analysis software version 2.0 was used to generate the forest plots for the pooled data.
Lupus Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
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(LUP)
[1–11] [PREPRINTER stage]
Methotrexate in SLE R Sakthiswary and E Suresh
3
Results Of the 53 studies that were identified, 44 were excluded (see Figure 1 for algorithm). The remaining nine studies, with 351 subjects, which met the eligibility criteria, were included in this systematic review.12–20 These included three randomized controlled (see Table 1),12–14 and six observational studies (see Table 2).15–20 Of these, six had a prospective study design.12–16,20 Of the three randomized controlled trials, two were double blinded,12,13 and one had an open-label design14 (see Table 3 for Jadad score of the three controlled trials). Among the observational studies, only two had employed control groups,18,20 but across the studies, the controls used were rather heterogeneous. Patients in the control arm were either on
placebo, corticosteroids or antimalarials as the comparator drug. The geographic distribution of these studies was wide, with three studies from North America,13,15,18 two each from Asia14,20 and Europe,16,19 and one each from Australia17 and South America.12 These studies were all published between 1994 and 2012, and the duration of the individual studies ranged from six to 26 months. The sample sizes of individual studies ranged from 12 to 86 subjects, and the dose of MTX ranged from 2.5 mg to 25 mg/week. All of these studies predominantly involved patients with arthritis or mucocutaneous features. Unlike the observational studies, all the randomized, controlled studies gave specific numbers and reasons for drop-outs.
Figure 1 The algorithm for selection of studies. Lupus Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
Bangladesh
Islam et al.14
2012
2008
1999
Year
Prospective open-label randomized study for 24 weeks
Prospective, doubleblinded, randomized placebo-controlled study for 12 months
Prospective, doubleblinded, randomized placebo-controlled study for six months
Study design
SLE patients with arthralgia or arthritis, and active skin lesions 15 patients on MTX 26 patients on CQ
SLE with moderately active disease (SLAM-R 8) and limited damage (SLICCDI 15) 41 patients on MTX 45 patients on placebo
20 patients on MTX (active arm) 20 patients on placebo (control arm)
Study population
Lupus
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ESR
VAS Number of swollen and tender joints Physician global assessment index Patient global assessment index SLEDAI EMS
Primary outcomes Reduction in log-transformed dose of prednisolone SLAM-R Secondary outcomes SLEDAI SF-36 PCS SF-36 MCS
SLEDAI
Dose of prednisolone
VAS for articular pain
Outcome measures VAS scores for pain were significantly higher in the placebo group than in the MTX group after the first month (p < 0.001) Prednisolone dose reduction was achieved in 13 of the MTX-treated patients, but in only one of the controls (p < 0.001) Mean SLEDAI scores in controls were significantly higher than in MTX-treated patients at months 3,4, 5 and 6 (p < 0.001) Significant reduction in prednisolone dose in the MTX group (p ¼ 0.01) MTX use was associated with significant reduction in the mean SLAM-R (p ¼ 0.039) No significant difference between the two groups in SLEDAI and SF-36 PCS Significant improvement in SF-36 MCS in the MTX group (p ¼ 0.034) No significant difference between the two groups in VAS, number of swollen and tender joints, physician global assessment index, patient global assessment index and SLEDAI (p ¼ non-significant for all of the above) EMS improved significantly only in the MTX group (p < 0.05) ESR changes were in favour of CQ group (p < 0.01)
Findings
Two patients in the MTX group and four in the CQ group were on a stable dose of prednisolone, with a maximum of 10 mg/day Two patients in each arm were excluded because of adverse events and central nervous system involvement.
Only 40% of patients who were screened were randomized Significant numbers of dropouts because of lupus flare or adverse events Corticosteroid dosages were not modified according to protocol.
Two placebo-treated patients dropped out because of severe flare requiring hospitalization, and two patients taking MTX dropped out because of side effects.
Comments
(LUP)
MTX: methotrexate; VAS: visual analogue score; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLAM-R: revised Systemic Lupus Activity Measure; SLICC-DI: Systemic Lupus International Collaborating Clinics (SLICC) Damage Index; PCS: physical component score (of the Short form-36); MCS: mental component score (of the Short form-36); CQ: chloroquine; ESR: erythrocyte sedimentation rate; EMS: early morning stiffness.
Canada
Brazil
Carneiro et al.12
Fortin et al.13
Country
Reference
Table 1 Summary of randomized controlled trials of methotrexate in systemic lupus erythematosus (SLE)
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Methotrexate in SLE R Sakthiswary and E Suresh
4
Country
Canada
Germany
Australia
Canada
Reference
Wilson et al.15
Gansauge et al.16
Kipen et al.17
Rahman et al.18 Retrospective cohort study
Cross-sectional
Open prospective for six months
Open prospective study for up to 26 months
Study design
17 patients receiving MTX for persistently active arthritis despite a previous trial of antimalarial therapy. 17 control patients with active arthritis despite six months of treatment with an antimalarial agent.
24 SLE patients, predominantly with arthritis.
22 SLE patients with one or more of the following: active polyarthritis, dermatitis, cutaneous vasculitis, and pleuritis
12 SLE patients with arthritis (n ¼ 7), refractory cutaneous lupus rashes (n ¼ 2), vasculitis (n ¼ 2), and recurrent pleuropericarditis (n ¼ 1).
Study population
Primary outcome Reduction in actively inflamed joint count of at least 60% over six months Secondary outcomes Reduction in steroid dose SLEDAI
Corticosteroid dose reduction
SLEDAI Corticosteroid dose Anti-dsDNA C3 and C4 ESR
Joint count, serological variables and prednisolone doses were serially evaluated.
Outcome measures Six out of nine patients who were treated for 7–26 months were able to reduce the prednisolone dose by an average of 42%. No apparent effect on antidsDNA, complement levels or ESR was noted. Mean SLEDAI decreased significantly from 12.2 to 4 (p ¼ 0.001). Mean dose of prednisolone was reduced from a mean of 17.4 mg to 8.8 mg/day over the six months (p ¼ 0.001). Mean ESR decreased from 46 to 32 mm/hour (p ¼ 0.02), but there was no significant change in anti-dsDNA or complement levels. The median monthly steroid intake during MTX therapy (279.4 mg) was lower than during the six months prior to MTX therapy (298.1 mg), (p ¼ NS). After six months, 15 patients in the MTX showed at least a 60% improvement in the inflamed joint count compared to two patients in the control group (p < 0.001). The mean daily prednisone dose fell by 35% and 27% in the MTX and control groups, respectively (p ¼ NS). SLEDAI reduced by 0.76 in the MTX group, compared to an increase of 2.05 in the control group (p ¼ 0.03).
Findings
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(continued)
Patients in the MTX group had a higher mean joint count than those in the control group at baseline (p ¼ 0.003).
The cumulative probability of continuing MTX was noted to be 68% at 12 months, and 61% at 24 months.
Patients with renal or central nervous system involvement were excluded. All patients had failed to achieve remission despite six months of treatment with corticosteroids.
Three patients discontinued MTX because of side effects. Patients with renal or central nervous system involvement were excluded.
Comments
(LUP)
1998
1997
1997
1994
Year
Table 2 Summary of observational studies of methotrexate in systemic lupus erythematosus (SLE)
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Methotrexate in SLE R Sakthiswary and E Suresh
5
Lupus
Germany
Japan
Wenzel et al.19
Miyawaki et al.20
2012
2004
Year
Open labelled, prospective, control study for 12–18 months
Retrospective
Study design
SLE patients with low serum complement levels and/or antidsDNA above the normal range. All patients had been on
http://lup.sagepub.com/
Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy R Sakthiswary and E Suresh Lupus published online 7 January 2014 DOI: 10.1177/0961203313519159 The online version of this article can be found at: http://lup.sagepub.com/content/early/2014/01/07/0961203313519159 A more recent version of this article was published on - Feb 14, 2014
Published by: http://www.sagepublications.com
Additional services and information for Lupus can be found at: Email Alerts: http://lup.sagepub.com/cgi/alerts Subscriptions: http://lup.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Feb 14, 2014 >> OnlineFirst Version of Record - Jan 7, 2014 What is This?
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(LUP)
[1–11] [PREPRINTER stage]
Lupus (2014) 0,
1–11
http://lup.sagepub.com
REVIEW
Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy R Sakthiswary1 and E Suresh2 1
Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre (UKMMC), Malaysia; and 2Department of Medicine, Alexandra Hospital (Jurong Health), Singapore
Objective: The objective of this review is to evaluate the evidence for efficacy of methotrexate (MTX) in systemic lupus erythematosus (SLE). Methods: A comprehensive, computerized search was performed in MEDLINE (PubMed), EMBASE and the Cochrane Controlled Trials registry to screen for studies that examined the efficacy of MTX in adult SLE patients. The Jadad scoring system was used to assess study quality, and data were pooled using the random effects model. Results: Of the 53 articles that were identified, 44 were excluded. Nine studies (including three randomized controlled and six observational) were eligible for inclusion. All of the included studies predominantly involved patients with arthritis or mucocutaneous features. There was significant reduction of the SLE Disease Activity Index (SLEDAI) among MTX-treated patients when compared with controls (p ¼ 0.001, odds ratio (OR) 0.444, 95% confidence interval (CI) 0.279 to 0.707). There was also significant reduction in the average dose of corticosteroids among MTX-treated patients when compared with controls (p ¼ 0.001, OR 0.335, 95% CI 0.202 to 0.558). The effect of MTX on laboratory and serological markers, including erythrocyte sedimentation rate, anti-dsDNA and complement levels (C3 and C4), could not be determined because of the limited numbers of controlled trials. Conclusion: The use of MTX is associated with significant reductions in SLEDAI and the average dose of corticosteroids in adult patients with SLE. Lupus (2014) 0, 1–11. Key words: Systemic lupus erythematosus; SLE; lupus; methotrexate; efficacy
Introduction Antimalarials are the usual choice for patients with non-organ-threatening systemic lupus erythematosus (SLE), particularly those with articular, cutaneous and constitutional manifestations.1 According to one recent systematic review,2 they are highly effective in preventing lupus flares, and improving long-term survival as well. However, they are not universally effective in inducing complete remission in all patients with SLE. One lupus database review revealed that 8% of patients discontinued hydroxychloroquine (HCQ) because of inefficacy, and another 29% because of adverse effects such as anorexia, nausea, headache, dizziness, visual disturbance, hearing loss, skin rash and myopathy.3 Correspondence to: Rajalingham Sakthiswary, Universiti Kebangsaan Malaysia, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Malaysia. Email: [email protected] Received 9 September 2013; accepted 11 December 2013
Given that non-organ-threatening SLE is associated with considerable morbidity and reduced quality of life,4 it is vital to gain adequate control of the disease, but apart from HCQ, only corticosteroids, belimumab and aspirin have thus far been approved by the Food and Drug Administration (FDA) in the United States for treatment of SLE. Of these, corticosteroids are not appropriate for long-term use because of their side-effect profile, and belimumab is very expensive, and may not be affordable for patients in many parts of the world. Hence, in practice, clinicians often turn to other disease-modifying treatment options, even in the absence of convincing controlled trial data. Methotrexate (MTX), for example, was first tested as early as 1965, and shown to rapidly improve arthralgia, skin rashes and purpura in a small sample of 10 patients,5 but, to date, there has been a paucity of controlled trial data on its efficacy. By contrast, several randomized controlled trials have established the efficacy of MTX in rheumatoid arthritis (RA), and it is indeed the
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
10.1177/0961203313519159
XML Template (2014) [3.1.2014–3:32pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/130275/APPFile/SG-LUPJ130275.3d
(LUP)
[1–11] [PREPRINTER stage]
Methotrexate in SLE R Sakthiswary and E Suresh
2
most commonly prescribed disease-modifying antirheumatic drug (DMARD) because of its excellent efficacy/toxicity trade-off, and highest long-term retention rate, when compared with other DMARDs.6,7 Whilst MTX may not be necessary in patients with mild SLE, who are well controlled on HCQ, and not be appropriate for those with severe disease, who would need more aggressive therapies, most clinicians would consider this as an option for the remaining large group of patients with non-organ-threatening disease, who (a) either do not respond or respond sub-optimally to HCQ, (b) react adversely to HCQ, or in those who (c) are unable to taper the dose of corticosteroids. In the last three decades, several trials, mostly uncontrolled, have examined the effects of MTX in SLE, with variable results. In this systematic review, we summarize the results of these studies, and evaluate the evidence for efficacy of MTX in SLE.
Methodology
The bibliographies of relevant studies were then used to get additional references. We also sought unpublished trials, relevant conference proceedings, and trial registries from the references of these studies. We only considered articles that were published in English. Data extraction The following data were extracted from each study chosen for inclusion: study design, study population, sample size, dose and duration of MTX therapy, and organ involvement. Additionally, handling of the control arm was recorded for all controlled trials. Outcome measures that were studied included (a) disease activity scores (Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)),9 (b) steroid dose reduction, and (c) change in serological and laboratory markers (anti-double-stranded DNA (anti-dsDNA), serum complement 3 and 4, and erythrocyte sedimentation rate (ESR)). Quality assessment
Search strategy and study selection We searched MEDLINE, EMBASE and Cochrane Controlled Trials registry using the search terms ‘systemic lupus erythematosus’, ‘lupus’ and ‘SLE’ (both as medical subject heading (MeSH) and free text). These were combined using the set operator and with studies identified with the term ‘methotrexate’. No date restrictions were applied. Randomized controlled trials and observational studies that examined the effects of weekly MTX in adult SLE patients were eligible for inclusion. Other inclusion criteria included:
Study quality was independently scored by both the authors for all the randomized controlled trials included for the review. This was based on the ‘‘Instrument to measure the likelihood of bias’’, proposed by Jadad et al.10 The Jadad score could range from 0 to 5, and is determined on the basis of a simple three-point questionnaire that addresses randomization, blinding, and withdrawals and drop-outs. The higher the Jadad score, the lesser the likelihood of bias in the results (‘low’ score ¼ 0 to 2, ‘high’ score ¼ 3 to 5). Data synthesis and statistical analysis
a. Diagnosis of SLE based on either American College of Rheumatology (ACR) criteria or the treating physician’s opinion. b. Treatment with MTX for a minimum duration of three months. This duration was chosen on the basis of existing knowledge of the pharmacodynamics of weekly oral MTX treatment.8 c. Administration of placebo or standard therapy for patients randomized to the control arm in case-control studies. Abstracts of the studies identified by initial screening were evaluated by the lead author (RS) for appropriateness. The full text of those studies that met our inclusion criteria were retrieved and independently assessed by both the authors. Any disagreements were resolved by consensus.
Data were pooled using a random-effects model for a more conservative estimate of the effects of MTX therapy on SLEDAI and steroid dose reduction. The advantage of this model is that it allows for heterogeneity across the studies.11 The outcome of MTX therapy versus controls was expressed as odds ratio (OR) with 95% confidence intervals (CI). Changes in serological (anti-dsDNA and serum complement levels) and laboratory markers (ESR) were not statistically analysed owing to the small numbers of studies (only one controlled trial for each of these two outcome measures). Comprehensive Meta-analysis software version 2.0 was used to generate the forest plots for the pooled data.
Lupus Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
XML Template (2014) [3.1.2014–3:32pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/LUPJ/Vol00000/130275/APPFile/SG-LUPJ130275.3d
(LUP)
[1–11] [PREPRINTER stage]
Methotrexate in SLE R Sakthiswary and E Suresh
3
Results Of the 53 studies that were identified, 44 were excluded (see Figure 1 for algorithm). The remaining nine studies, with 351 subjects, which met the eligibility criteria, were included in this systematic review.12–20 These included three randomized controlled (see Table 1),12–14 and six observational studies (see Table 2).15–20 Of these, six had a prospective study design.12–16,20 Of the three randomized controlled trials, two were double blinded,12,13 and one had an open-label design14 (see Table 3 for Jadad score of the three controlled trials). Among the observational studies, only two had employed control groups,18,20 but across the studies, the controls used were rather heterogeneous. Patients in the control arm were either on
placebo, corticosteroids or antimalarials as the comparator drug. The geographic distribution of these studies was wide, with three studies from North America,13,15,18 two each from Asia14,20 and Europe,16,19 and one each from Australia17 and South America.12 These studies were all published between 1994 and 2012, and the duration of the individual studies ranged from six to 26 months. The sample sizes of individual studies ranged from 12 to 86 subjects, and the dose of MTX ranged from 2.5 mg to 25 mg/week. All of these studies predominantly involved patients with arthritis or mucocutaneous features. Unlike the observational studies, all the randomized, controlled studies gave specific numbers and reasons for drop-outs.
Figure 1 The algorithm for selection of studies. Lupus Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
Bangladesh
Islam et al.14
2012
2008
1999
Year
Prospective open-label randomized study for 24 weeks
Prospective, doubleblinded, randomized placebo-controlled study for 12 months
Prospective, doubleblinded, randomized placebo-controlled study for six months
Study design
SLE patients with arthralgia or arthritis, and active skin lesions 15 patients on MTX 26 patients on CQ
SLE with moderately active disease (SLAM-R 8) and limited damage (SLICCDI 15) 41 patients on MTX 45 patients on placebo
20 patients on MTX (active arm) 20 patients on placebo (control arm)
Study population
Lupus
Downloaded from lup.sagepub.com at b-on: 01100 Universidade do Porto on April 24, 2014
ESR
VAS Number of swollen and tender joints Physician global assessment index Patient global assessment index SLEDAI EMS
Primary outcomes Reduction in log-transformed dose of prednisolone SLAM-R Secondary outcomes SLEDAI SF-36 PCS SF-36 MCS
SLEDAI
Dose of prednisolone
VAS for articular pain
Outcome measures VAS scores for pain were significantly higher in the placebo group than in the MTX group after the first month (p < 0.001) Prednisolone dose reduction was achieved in 13 of the MTX-treated patients, but in only one of the controls (p < 0.001) Mean SLEDAI scores in controls were significantly higher than in MTX-treated patients at months 3,4, 5 and 6 (p < 0.001) Significant reduction in prednisolone dose in the MTX group (p ¼ 0.01) MTX use was associated with significant reduction in the mean SLAM-R (p ¼ 0.039) No significant difference between the two groups in SLEDAI and SF-36 PCS Significant improvement in SF-36 MCS in the MTX group (p ¼ 0.034) No significant difference between the two groups in VAS, number of swollen and tender joints, physician global assessment index, patient global assessment index and SLEDAI (p ¼ non-significant for all of the above) EMS improved significantly only in the MTX group (p < 0.05) ESR changes were in favour of CQ group (p < 0.01)
Findings
Two patients in the MTX group and four in the CQ group were on a stable dose of prednisolone, with a maximum of 10 mg/day Two patients in each arm were excluded because of adverse events and central nervous system involvement.
Only 40% of patients who were screened were randomized Significant numbers of dropouts because of lupus flare or adverse events Corticosteroid dosages were not modified according to protocol.
Two placebo-treated patients dropped out because of severe flare requiring hospitalization, and two patients taking MTX dropped out because of side effects.
Comments
(LUP)
MTX: methotrexate; VAS: visual analogue score; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLAM-R: revised Systemic Lupus Activity Measure; SLICC-DI: Systemic Lupus International Collaborating Clinics (SLICC) Damage Index; PCS: physical component score (of the Short form-36); MCS: mental component score (of the Short form-36); CQ: chloroquine; ESR: erythrocyte sedimentation rate; EMS: early morning stiffness.
Canada
Brazil
Carneiro et al.12
Fortin et al.13
Country
Reference
Table 1 Summary of randomized controlled trials of methotrexate in systemic lupus erythematosus (SLE)
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Methotrexate in SLE R Sakthiswary and E Suresh
4
Country
Canada
Germany
Australia
Canada
Reference
Wilson et al.15
Gansauge et al.16
Kipen et al.17
Rahman et al.18 Retrospective cohort study
Cross-sectional
Open prospective for six months
Open prospective study for up to 26 months
Study design
17 patients receiving MTX for persistently active arthritis despite a previous trial of antimalarial therapy. 17 control patients with active arthritis despite six months of treatment with an antimalarial agent.
24 SLE patients, predominantly with arthritis.
22 SLE patients with one or more of the following: active polyarthritis, dermatitis, cutaneous vasculitis, and pleuritis
12 SLE patients with arthritis (n ¼ 7), refractory cutaneous lupus rashes (n ¼ 2), vasculitis (n ¼ 2), and recurrent pleuropericarditis (n ¼ 1).
Study population
Primary outcome Reduction in actively inflamed joint count of at least 60% over six months Secondary outcomes Reduction in steroid dose SLEDAI
Corticosteroid dose reduction
SLEDAI Corticosteroid dose Anti-dsDNA C3 and C4 ESR
Joint count, serological variables and prednisolone doses were serially evaluated.
Outcome measures Six out of nine patients who were treated for 7–26 months were able to reduce the prednisolone dose by an average of 42%. No apparent effect on antidsDNA, complement levels or ESR was noted. Mean SLEDAI decreased significantly from 12.2 to 4 (p ¼ 0.001). Mean dose of prednisolone was reduced from a mean of 17.4 mg to 8.8 mg/day over the six months (p ¼ 0.001). Mean ESR decreased from 46 to 32 mm/hour (p ¼ 0.02), but there was no significant change in anti-dsDNA or complement levels. The median monthly steroid intake during MTX therapy (279.4 mg) was lower than during the six months prior to MTX therapy (298.1 mg), (p ¼ NS). After six months, 15 patients in the MTX showed at least a 60% improvement in the inflamed joint count compared to two patients in the control group (p < 0.001). The mean daily prednisone dose fell by 35% and 27% in the MTX and control groups, respectively (p ¼ NS). SLEDAI reduced by 0.76 in the MTX group, compared to an increase of 2.05 in the control group (p ¼ 0.03).
Findings
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(continued)
Patients in the MTX group had a higher mean joint count than those in the control group at baseline (p ¼ 0.003).
The cumulative probability of continuing MTX was noted to be 68% at 12 months, and 61% at 24 months.
Patients with renal or central nervous system involvement were excluded. All patients had failed to achieve remission despite six months of treatment with corticosteroids.
Three patients discontinued MTX because of side effects. Patients with renal or central nervous system involvement were excluded.
Comments
(LUP)
1998
1997
1997
1994
Year
Table 2 Summary of observational studies of methotrexate in systemic lupus erythematosus (SLE)
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Methotrexate in SLE R Sakthiswary and E Suresh
5
Lupus
Germany
Japan
Wenzel et al.19
Miyawaki et al.20
2012
2004
Year
Open labelled, prospective, control study for 12–18 months
Retrospective
Study design
SLE patients with low serum complement levels and/or antidsDNA above the normal range. All patients had been on
