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Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus

  1. Virginia Fernandes Moça Trevisani1,*,
  2. Aldemar A Castro2,
  3. João Ferreira Neves Neto3,
  4. Álvaro N Atallah4

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 16 NOV 2012

DOI: 10.1002/14651858.CD002265.pub3


How to Cite

Fernandes Moça Trevisani V, Castro AA, Ferreira Neves Neto J, Atallah ÁN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD002265. DOI: 10.1002/14651858.CD002265.pub3.

Author Information

  1. 1

    Universidade Federal de São Paulo, Rheumatology/Internal Medicine and Therapeutics, São Paulo, São Paulo, Brazil

  2. 2

    State University of Heath Science, Department of Public Health, Maceió, Alagoas, Brazil

  3. 3

    Universidade Federal de São Paulo, Surgery, São Paulo, São Paulo, Brazil

  4. 4

    Escola Paulista de Medicina, Universidade Federal de São Paulo, Brazilian Cochrane Centre, São Paulo, São Paulo, Brazil

*Virginia Fernandes Moça Trevisani, Rheumatology/Internal Medicine and Therapeutics, Universidade Federal de São Paulo, Rua Marie Satzke 119, São Paulo, São Paulo, 04664-150, Brazil. vmoca@uol.com.br. cochrane.dmed@epm.br.

Publication History

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

SEARCH

 
Characteristics of included studies [ordered by study ID]
Barile-Fabris 2005

MethodsGeneration of allocation sequence: computer-generated program
Allocation concealment: not reported
Blinding: not reported
Characteristics of placebo: not used
Sample size calculation: not reported
Number of patients randomised: 32
Loss to follow-up: 16 patients
Intention-to-treat analysis: yes
Similarity between groups: yes


ParticipantsInclusion criteria:
Diagnosis of SLE according to the American College of Rheumatology Criteria, age > 18 years and one of the following active neurological manifestations of systemic erythematosus (NPSLE): peripheral/cranial neuropathy, optic neuritis, transverse myelitis, brainstem disease or coma. All patients were at no more than 15 days since onset. Patients with refractory seizures were also included.

Exclusion criteria:
Central nervous system (CNS) or systemic infections, known hypersensitivity to study drugs or metabolic encephalopathy. Patients who had received pulse methylprednisolone or cyclophosphamide at any time during the 3 months before the start of the study were also excluded. Any patients with neurological manifestations directly related to antiphospholipid syndrome were excluded, as were patients with pure psychiatric involvement.

Characteristics:
Group treated with cyclophosphamide:
Age: 33 (17 to 48)
Disease evolution in years (range): 4.2 (.11 to 16)
Number of ACR criteria: 6
Basal prednisone dose (mg/day): 45 (15 to 60)
Group treated with methylprednisolone:
Age 26 (19 to 44)
Disease evolution in years (range): 2.5 (.0 to 12)
Number of ACR criteria: 6
Basal prednisone dose (mg/day): 45 (15 to 60)


InterventionsAfter randomisation each patient was allocated to receive methylprednisolone 1 g daily for 3 days as induction treatment. This was followed by 1 of the following 2 treatments: methylprednisolone 1 g for 3 days monthly for 4 months, then bimonthly for 6 months and then every 3 months for 1 year; or cyclophosphamide 0.75 g/m2 body surface monthly for 1 year and then every 3 months for another year. Oral prednisone 1 mg/kg/day for no more than 3 months and tapered according to disease activity/remission.


Outcomes(a) Improvement: 20% change from basal condition in clinical, serological and specific neurological measures (evoked potentials, cerebrospinal fluid analysis, electromyography, magnetic resonance imaging etc.) achieved by the 4th month of treatment; (b) worsening: disease progression of 20% or more despite continued treatment for at least 4 months


NotesSetting: Mexico


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: “Patients were prestratified by centre and by NP manifestation and then randomised in blocks of 10 patients by a random number computer generated program.”

Comment: the sequence was adequately generated

Allocation concealment (selection bias)High riskQuote: “These lists, together with operative manuals, were distributed to both centres.”

Comment: the allocation appears not to have been concealed

Blinding (performance bias and detection bias)
Objective outcomes
High riskQuote: “This was followed by one of the following two treatments: MP 1 g daily for 3 days, monthly for 4 months, then bimonthly for 6 months and subsequently every 3 months for 1 year or Cy 0.75 g/m2 body surface monthly for 1 year and then every 3 months for another year. Oral prednisone was started on the fourth day of treatment, at 1 mg/kg/day, for no more than 3 months and tapered according to disease activity/remission.”

Comment: the paper provided no information on blinding participants, study personnel or outcome assessors; however, the study personnel cannot have been blinded to treatment as the dosing schedule was different between groups

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: “Failure to improve after 4 months was considered grounds for stopping treatment early. In which case these patients were only considered in the intention to treat analysis and were subsequently treated according to the recommendations of their attending physician.”...“Fifteen patients were able to complete the protocol up to 2 years of treatment: 12 receiving Cy and only three in the MP group.”

Information provided in flow diagram 1: of the 19 people randomised to receive cyclophosphamide, 13 (68%) completed 12 months of treatment, 12 (63%) completed 24 months of treatment, 2 (11%) terminated treatment early and 2 (11%) died

Of the 13 people randomised to received methylprednisolone, 3 (23%) completed 12 months of treatment, 3 (23%) completed 24 months of treatment, 6 (46%) terminated treatment early and 1 (8%) died

Comment: from flow diagram 1, the number of people who died plus the number of people who terminated treatment early plus the number of people who completed treatment at 12 months does not equal the number of people randomised, in either group. The number of people who completed treatment at 12 and 24 months is not equal across the 2 groups.

Selective reporting (reporting bias)Unclear riskComment: there is insufficient information to permit judgement of ‘yes’ or ‘no’; however, all the outcomes listed in the methods section of the paper are reported in the results section

Other biasHigh riskQuote: “Between July 1998 and July 1999 a total of 32 patients with SLE were enrolled in the trial at two tertiary care centres in Mexico City.... Patients were prestratified by centre and by NP manifestation and then randomised in blocks of 10 patients by a random number computer generated program. ”

Comment: randomising in blocks of 10 for 32 participants at 2 centres could have led to bias (e.g. the tertiary care centre at which the patient was treated could have affected the outcome, and not just the study intervention)

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Austin 1986Randomised controlled trial, but its research question is not relevant

Boumpas 1992Randomised controlled trial, but its research question is not relevant

Cortés-Hernández 2003Not a randomised trial

Dinant 1982Randomisation method not stated and research question is not relevant

Donatio 1977Randomised controlled trial, but its research question is not relevant

Edwards 1987Randomisation method not stated; data for neuropsychiatric involvement are not available in a suitable form for analysis

Euler 1991Only a protocol

Fries 1973Randomisation method not stated; high loss to follow-up; data available are in an unsuitable form for analysis

Gourley 1996Randomised, high loss to follow-up and research question is not relevant

Harisdangkul 1989Not randomised, research question is not relevant

Kopelman 2003Not a randomised controlled trial

Lavalle-Graef 2004Not randomised, research question is not relevant

Lehman 2004Not randomised, research question is not relevant

Levey 1992Randomised, but the uses plasmaphoresis

Liebling 1982Randomisation method not stated; research question is not relevant

Mackworth-Young 1988Randomisation method not stated; data for neuropsychiatric involvement are not available in suitable form for analysis

Mok 2003Not randomised

Neuwelt 1995Not randomised

Ramos 1996Not randomised

Sesso 1994Randomisation method not stated; research question is not relevant

Steinberg 1971Randomised controlled trial, but its research question is not relevant

Steinberg 1991Randomised controlled trial, but its research question is not relevant

Stojanovich 2003Randomisation method not stated; data for neuropsychiatric involvement are not available in a suitable form for analysis

Stratta 1992Not randomised, data for neuropsychiatric involvement are not available in a suitable form for analysis

Yee 2003Randomised, but data for neuropsychiatric involvement are not available

 
Comparison 1. Cyclophosphamide versus methylprednisolone

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

 1 Response to treatment132Risk Ratio (M-H, Fixed, 95% CI)2.05 [1.13, 3.73]

 2 SLICCOther dataNo numeric data

 3 SLEDAIOther dataNo numeric data

 4 Prednisone sparingOther dataNo numeric data

 5 Seizures111Risk Ratio (M-H, Fixed, 95% CI)2.57 [0.92, 7.14]

 6 Adverse events1256Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.49, 1.28]

    6.1 Urinary tract infections
132Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.47, 1.57]

    6.2 Respiratory
132Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.36, 2.93]

    6.3 Oropharyngeal candidiasis
132Risk Ratio (M-H, Fixed, 95% CI)3.50 [0.18, 67.45]

    6.4 Herpes zoster
132Risk Ratio (M-H, Fixed, 95% CI)3.50 [0.18, 67.45]

    6.5 Systemic hypertension
132Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.32]

    6.6 Hyperglycaemia
132Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.32]

    6.7 Pancreatitis
132Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.01, 5.32]

    6.8 Death
132Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.03, 1.96]

 7 Completion of the protocol after 2 years132Risk Ratio (M-H, Fixed, 95% CI)2.74 [0.96, 7.82]

 
Analysis 1.2 Comparison 1 Cyclophosphamide versus methylprednisolone, Outcome 2 SLICC.
SLICC

StudyCyclophosphamide (range)Methylprednisolone (range)Statistical testP value

Barile-Fabris 20050.72 (0.1)0.80 (0.1)Mann Whitney0.071

 
Analysis 1.3 Comparison 1 Cyclophosphamide versus methylprednisolone, Outcome 3 SLEDAI.
SLEDAI

StudyCyclophosphamide (range)Methylprednisolone (range)statistical testP value

Barile-Fabris 20051 (0 to 5)4 (0 to 30)Mann-Whitney0,007

 
Analysis 1.4 Comparison 1 Cyclophosphamide versus methylprednisolone, Outcome 4 Prednisone sparing.
Prednisone sparing

StudyCyclophosphamide (range)Methylprednisolone (range)Statistical testP value

Barile-Fabris 200511.2 (5.20)15.6 (5.30)Mann Whitney0.04*

 
Summary of findings for the main comparison. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus

Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus

Patient or population: patients with neuropsychiatric involvement in systemic lupus erythematosus
Settings: two tertiary care centres in Mexico City
Intervention: cyclophosphamide

Comparison: methylprednisolone

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

Assumed riskCorresponding risk

Control (Methylprednisolone)Cyclophosphamide

Response to treatment (20% improvement)*
Follow-up: mean 24 months
462 per 1000947 per 1000
(522 to 1000)
RR 2.05
(1.13 to 3.73)
32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Absolute risk difference 49% (95% CI 20% to 77%)

Relative per cent change 105% (95% CI 13% to 273%)

NNTB 3 (95% CI 2 to 6)

Adverse events - Urinary tract infections
Follow-up: mean 24 months
615 per 1000529 per 1000
(289 to 966)
RR 0.86
(0.47 to 1.57)
32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Absolute risk difference -90% (95% CI -44% to 26%)

Relative per cent change -14% (95% CI -53% to 57%)

Not statistically significant

Adverse events - Death
Follow-up: mean 24 months
231 per 1000531 per 1000
(7 to 453)
RR 0.23
(0.03 to 1.96)
32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Absolute risk difference -18% (95% CI -43% to 7%)

Relative per cent change -77% (95% CI -97% to 96%)

Not statistically significant

SLICC scores (damage index)

Scale: from 0 to 48

(lower is better)
Follow-up: mean 12 months
See commentSee commentNot estimable32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Available data (medians and ranges) could not be transformed to permit analysis. No significant differences between the groups were found in SLICC measurements.

SLEDAI scores (disease activity index)

Scale: from 0 to 106 (lower is better)
Follow-up: mean 12 months
See commentSee commentNot estimable32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Available data (medians and ranges) could not be transformed to permit analysis. The median SLEDAI rating favoured the cyclophosphamide group.

Prednisone sparing
Follow-up: mean 15 months
See commentSee commentNot estimable32
(1 study)
⊕⊝⊝⊝
very low1,2,3
Available data (medians and ranges) could not be transformed to permit analysis. Cyclophosphamide use was associated with reduction of prednisone requirements by the 6th month of treatment.

Seizures
Follow-up: mean 24 months
333 per 1000856 per 1000

(306 to 1000)
RR 2.57 (0.92 to 7.14)11
(1 study)4
⊕⊝⊝⊝
very low1,2,3
Absolute risk difference 67 % (95% CI 2 5 % to 1 08 %)

Relative percent change 157 % (95% CI -8% to 614 %)

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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; NNTB: number needed to treat for an additional beneficial outcome; RR: risk ratio; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics

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.

 *Response to treatment = 20% improvement from basal conditions on clinical, laboratory or specific neurological testing variables.
1The study had adequate sequence generation, but the allocation concealment was not considered to be adequate. Blinding was not reported. Incomplete data were not addressed adequately. The study was not considered to be free from other bias as only 32 patients were randomised in blocks of 10 and the trial stopped recruiting early due to apparent benefit.
2The 95% confidence interval around the effect estimate is wide and includes both the possibility of significant benefit and harm of intervention.
3Only one study was included.
4Only a subgroup of 11 participants in the study had seizures.