Cyclophosphamide

Cyclophosphamide versus methylprednisolone for treating
neuropsychiatric involvement in systemic lupus

erythematosus (Review)
Trevisani VFM, Castro AA, Ferreira Neves Neto JJFNN, Atallah ÁN
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2009, Issue 1
http://www.thecochranelibrary.com
Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus (Review)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Analysis 1.1. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 1 Response to treatment. . . 14
Analysis 1.2. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 2 Adverse events. . . . . . 15
Analysis 1.3. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 3 Completion of the protocol after 2
years. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus (Review) i
[Intervention Review]
Cyclophosphamide versus methylprednisolone for treating

neuropsychiatric involvement in systemic lupus
erythematosus
Virginia Fernandes Moça Trevisani1 , Aldemar A Castro2 , João JFNN Ferreira Neves Neto3 , Álvaro N Atallah4
1 Rheumatology/Internal Medicine and Therapeutics, UNISA (Santo Amaro University)/UNIFESP (Paulista Medicine School), Jardim
Marajoara, Brazil. 2 Department of Public Health, State University of Heath Science, Maceió, Brazil. 3 Surgery, Federal University of
São Paulo, São Paulo, Brazil. 4 Brazilian Cochrane Centre, Universidade Federal de São Paulo / Escola Paulista de Medicina, São Paulo,
Brazil
Contact address: Virginia Fernandes Moça Trevisani, Rheumatology/Internal Medicine and Therapeutics, UNISA (Santo Amaro
University)/UNIFESP (Paulista Medicine School), Rua Marie Satzke 119, Jardim Marajoara, Sao Paulo, 04664-150, Brazil.
vmoca@uol.com.br. cochrane.dmed@epm.br.
Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 20 February 2006.
Citation: Trevisani VFM, Castro AA, Ferreira Neves Neto JJFNN, Atallah ÁN. Cyclophosphamide versus methylprednisolone for
treating neuropsychiatric involvement in systemic lupus erythematosus. Cochrane Database of Systematic Reviews 2006, Issue 2. Art.
No.: CD002265. DOI: 10.1002/14651858.CD002265.pub2.
ABSTRACT
Background
Neuropsychiatric involvement in systemic lupus erythematosus is complex and several clinical presentations are related to this disease
such as: convulsions, chronic headache, transverse myelitis, vascular brain disease, psychosis and neural cognitive dysfunction. This
systematic review is an update of a review performed in 2000.
Objectives
To assess the efficacy and safety of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of
systemic lupus erythematosus.
Search strategy
We searched EMBASE, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE up to and including
May 2005. Additional articles were sought through handsearching in relevant journals. There were no language restrictions.
Selection criteria
All randomised controlled trials that compared cyclophosphamide to methylprednisolone were included. Patients of any age and gender
were included as long as they fulfilled the criterion of the American College of Rheumatology for the diagnosis of systemic lupus
erythematosus and presented with any one of the following neuropsychiatric events: convulsions, organic brain syndrome and cranial
neuropathy. Outcome measures included the following: a) overall mortality (primary event); b) motor and psychiatric deficit (primary
event); c) clinical improvement (secondary event).
Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus (Review) 1
Data collection and analysis
Data was independently extracted by two reviewers and cross-checked. The methodological quality of each trial was assessed by the
same two reviewers. Details of the randomisation (generation and concealment), blinding, and the number of patients lost to follow-up
were recorded. Dichotomous data was presented as relative risks with corresponding 95% confidence intervals and a clinical relevance
table was produced.
Main results
We found one randomised controlled trial of 32 patients comparing cyclophosphamide versus methylprednisolone for the treatment
of neuropsychiatric involvement in the systemic lupus erythematosus. A significantly greater number of people responded to treatment
in the cyclophosphamide group. Treatment response was found in 94.7% (18/19) of patients using cyclophosphamide compared with
46.2% (6/13) in the methylprednisolone group at 24 months (RR 2.05, 95% CI 1.13, 3.73) The NNT for response to treatment is
2. Cyclophosphamide use was associated with a reduction in prednisone requirements. A significant decrease in the number seizures
per month was observed in the cyclophosphamide group. All the patients in the cyclophosphamide group had electroencephalographic
improvement. No significant differences in adverse effects between the groups were found. It was not possible to extract more data
from the study because there was a small number of patients in the others clinical subgroups of neurological manifestations and the
authors did not provide sufficient information for data extraction.
Authors’ conclusions
This systematic review found one randomised controlled trial with a small number of patients in the different clinical subgroups
of neurological manifestation. It seems that cyclophosphamide is more effective in the treatment of neuropsychiatric involvement
in systemic erythematosus lupus compared with methylprednisolone. However, properly designed randomised controlled trials that
involve large, representative numbers of individuals, with explicit clinical and laboratory diagnosis criteria, sufficient duration of follow-
up and description of all relevant outcome measures are necessary to guide practice.
PLAIN LANGUAGE SUMMARY
Cyclophosphamide versus methylprednisolone for lupus
Does cyclophosphamide work to treat central nervous system lupus (neuropsychiatric lupus)?
One study of moderate quality provides the best evidence we have to answer this question. The study tested 32 people who had central
nervous system lupus. The study compared people who took cyclosphosphamide by IV (intravenous or through a vein) to people who
took steroids (methylprednisolone by IV). All people took steroid pills (prednisone) at the beginning of the study and the amount was
decreased over the study. The study lasted 2 years.
What is central nervous system lupus and how could cyclophosphamide help?
Systemic lupus erythematosus (SLE) or simply ’lupus’ is a group of diseases in which the body’s immune system attacks the body. In
CNS lupus (central nervous system lupus) the body may have attacked and damaged the cells in the brain and spine. This damage may
cause a person to have convulsions/seizures, chronic headaches, confusion and psychosis. Drugs such as corticosteroids (prednisone or
methylprednisolone) are usually used for lupus to decrease inflammation and control the immune system. Immunosuppressive agents
or cytotoxics such as cyclophosphamide (CTX or Cytoxan) may also be used. These drugs can be given by IV (intravenous or through
your veins) or as pills. Unfortunately, it has not been clear whether these drugs improve the symptoms of CNS lupus and what the side
effects are.
What did the studies show?
More people who took cyclophosphamide improved than people who took methylprednisolone.
- 95 out of 100 people had at least a 20% improvement in symptoms with cyclophosphamide
- 46 out of 100 people had at least a 20% improvement in symptoms with methylprednisolone
Disease activity, seizures, CNS damage also decreased more with cyclophosphamide.
After 6 months of treatment, people who took cyclophosphamide took less prednisone pills than people who took methylprednisolone.
And at the end of two years, it seemed that more people who took cyclophosphamide stayed on their treatment than the people who
took methylprednisolone.
Were there any side effects?
Side effects, such as infections, high blood sugar and high blood pressure, pancreatitis and death occurred about the same amount in
people who took cyclophosphamide or methylprednisolone.
What is the bottom line?
There is “silver” level evidence (www.cochranemsk.org) that cyclophosphamide may improve symptoms of central nervous system
(neuropsychiatric) lupus more than methylprednisolone. It also does not appear to increase side effects. The study in this review was
small and more studies are needed.
BACKGROUND
mide is established in lupus nephritis but it is not established for
The neuropsychiatric involvement in systemic lupus erythemato- neuropsychiatric involvement in SLE (Austin 1986; Felson 1984;
sus (SLE) is complex and several clinical presentations are related Steinberg 1991).
to this disease, such as: convulsions, chronic headache, transverse
myelitis, vascular brain disease, psychosis and neural cogitative The objective of this systematic review was to summarize the evi-
dysfunction. The incidence varies according to patient selection dence from controlled trials for the effectiveness and safety of cy-
and neuropsychiatric events included in the search ranging from clophosphamide in the treatment of lupus neuropsychiatric man-
13% to 60% for the incidence of events and from 7% to 13% in ifestations. This systematic review is an update of a review per-
mortality related to the neuropsychiatric involvement (Gladman formed in 2000.
1994; Sibley 1992).
Factors related to the neuropsychiatric involvement are: self anti-

bodies such as lymphotoxins, antineural and cytoplasmic mem- OBJECTIVES
brane as the anti-ribosomal P, antineurofilament and high lev-
els of cytokinesis as alpha interferon and interleukin 6 (IL-6) ( To assess the efficacy and safety of cyclophosphamide compared to
Bonfa 1987; Boumpas 1995; Denburg 1994; Gladman 1994; methylprednisolone in the treatment of neuropsychiatric involve-
Sibley 1992; Urowitz 1980). As there are no laboratory tests or im- ment in systemic lupus erythematosus.
age exams specific to neuropsychiatric lupus activity, elucidation
of the pathogenesis is difficult (Boumpas 1995; Denburg 1995;
Gladman 1994; Sibley 1992; Urowitz 1980). There are also dif-
ficulties attributing clinical manifestations, as frequently there are METHODS
doubts related to the presence of infection or adverse effect of
medicines.
The treatment depends on establishing the diagnosis and the seri-
Criteria for considering studies for this review
ousness of clinical manifestations. Corticosteroids are widely used
for the treatment of almost all types of manifestation of lupus ac-
tivity. Several reviews have demonstrated the effectiveness of cor-
ticosteroids, although the neuropsychiatric involvement has not
Types of studies
been the main focus. There is controversy on whether the use of
corticoids cause or exacerbate psychotic manifestations (Denburg All randomised controlled trials addressing the therapeutic clinical
1994, Eyanson 1980; Wolkowitz 1990). The use of cyclophospha- question.
Types of participants 4. or/1-3
Patients of any age and gender who fulfil the criterion of the Amer- 5. exp CYCLOPHOSPHAMIDE/
ican Rheumatology Association for the diagnosis of systemic lupus 6. cyclophosphamide.sh,tw,rn.
erythematosus (Tan 1982) and that present the following: neu- 7. cytoxan.tw.
ropsychiatric events (psychosis, visual or auditive hallucination, 8. neosar.tw.
delirium, illogical thoughts and disturbance of behaviour and de- 9. endoxan.tw.
pression); convulsions, organic brain syndrome (delirium, stupor 10. cfx.tw.
and coma); cranial neuropathy (blindness, palpebral ptosis, facial 11. phosphoramide mustard$.tw.
paralysis, ischaemic and haemorrhagic cerebral vascular disease, 12. exp Phosphoramide Mustards/
transverse myelitis, mononeuritis multiplexous). 13. exp immunosuppressive agents/
14. exp IMMUNOSUPPRESSION/
15. immunosuppress$.tw.
Types of interventions 16. or/5-15
Patients who received cyclophosphamide for the treatment of neu- 17. exp Methylprednisolone/
ropsychiatric manifestations compared with patients that received 18. methylprednis$.sh,tw,rn.
methylprednisolone. 19. exp GLUCOCORTICOIDS/
20. glucocorticoid$.tw.
21. adv?ntan.tw.
Types of outcome measures 22. medrol.tw.
The following clinical outcome measures were included for po- 23. medrone.tw.
tential analysis: 24. or/17-23
a) Overall mortality (primary event): patients who died during the 25. and/4,16,24
entire period of treatment; EMBASE
b) Motor and psychiatric deficit (primary event): through clini- 1. exp Systemic Lupus Erythematosus/
cal evaluation of muscular strength, motor disabilities, neuromus- 2. systemic lupus erythematosus.tw.
cular reflexes, and usage of adequate scales of evaluation of neu- 3. sle.tw.
rocognitive dysfunction (mini mental state examination-MMSE), 4. or/1-3
depression (Hamilton-HDRS), and appraisal of psychotic symp- 5. exp Cyclophosphamide/
toms (BPRS, PANSS) or equivalent. 6. cyclophosphamide.sh,tw,rn.
c) Clinical improvement (secondary event): through clinical ap- 7. cytoxan.tw.
praisal, specific neurological measures (evoked potentials, cere- 8. neosar.tw.
brospinal fluid analysis, electromyography, magnetic resonance 9. endoxan.tw.
imaging) and use of evaluation scales of neuropsychiatrics dys- 10. cfx.tw.
function as described above in the item b and global activity by 11. exp Phosphoramide Mustard/
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 12. phosphoramide mustard$.tw.
and damage assessment by Systemic Lupus International Collab- 13. exp Immunosuppressive Treatment/
orating Clinics (SLICC) scores. 14. immunosuppress$.tw.
15. or/5-14
16. exp METHYLPREDNISOLONE/
Search methods for identification of studies 17. methylprednis$.sh,tw,rn.
18. exp GLUCOCORTICOID/
The trial search coordinator of the Cochrane Musculoskeletal
19. glucocorticoid$.tw.
Group searched for any trial or reference to a relevant trial (pub-
20. adv?ntan.tw.
lished, in-press, or in progress). All publications were sought
21. medrol.tw.
through computerized searches of EMBASE (1982-May 2005),
22. medrone.tw.
LILACS (1982-May 2005), MEDLINE (1966-May 2005), the
23. or/16-22
Cochrane Central Register of Controlled Clinical Trials (CEN-
24. and/4,15,23
TRAL) (2005, Issue 4), and by checking reference lists. There were
25. limit 24 to yr=2000 - 2005
no limits on language, date, or other restrictions.
26. random$.ti,ab.
MEDLINE
27. factorial$.ti,ab.
1. exp Lupus Erythematosus, Systemic/
28. (crossover$ or cross over$ or cross-over$).ti,ab.
2. systemic lupus erythematosus.tw.
29. placebo$.ti,ab.
3. sle.tw.
30. (doubl$ adj blind$).ti,ab. effects models) with the corresponding 95% confidence interval.
31. (singl$ adj blind$).ti,ab. When overall results were significant the number needed-to-treat
32. assign$.ti,ab. (NNT) to produce (or prevent) one outcome was calculated. For
33. allocat$.ti,ab. dichotomous outcomes, the number needed-to-treat was calcu-
34. volunteer$.ti,ab. lated as 1/risk difference (RD). Tthe RD is obtained from the
35. crossover procedure.sh. RevMan Analyses graphs.
36. double blind procedure.sh. A clinical relevance table was compiled under Additional Tables
37. randomized controlled trial.sh. to improve the readability of the review.
38. single blind procedure.sh. It was planned that statistical heterogeneity in the results of the
39. or/26-38 trials would be assessed both by inspection of graphical presen-
40. exp animal/ or nonhuman/ or exp animal experiment/ tations (“funnel plot”: plotting the study weight or sample size
41. exp human/ [on the “y” axis] against the odds ratios [on the “x” axis]) and by
42. 40 and 41 performing a test of heterogeneity (standard chi-squared test on N
43. 40 not 42 degrees of freedom where N equals the number of trials contribut-
44. 39 not 43 ing data minus one). Three possible reasons for heterogeneity were
45. 25 and 44 pre-specified: (I) that response differs according to the difference
in the quality of the trial; (II) that response differs according to
the sample size; (III) that response differs according to the clini-
Data collection and analysis cal heterogeneity. These would be assessed by looking at separate
subgroups of trials. Clinical heterogeneity would be assessed by
Two reviewers independently assessed the titles and abstracts of
clinical experts. However, since only one trial was found to meet
all reports. Full text hard copies were obtained for studies that
the inclusion criteria, heterogeneity was not an issue in this review.
appeared in the selection criteria. Two reviewers (VFMT, AAC)
GRADING OF EVIDENCE
selected trials to be included in the review. Disagreements were
We will use the grading system described in the 2004 book Evi-
resolved by consensus.
dence-based Rheumatology (Tugwell 2004) and recommended by
CRITICAL APPRAISAL OF STUDIES
the Musculoskeletal Group:
The methodological quality of each trial was assessed indepen-
Platinum: A published systematic review that has at least two in-
dently by the same reviewers. Details of the randomisation (se-
dividual controlled trials each satisfying the following :
quence number, allocation concealment), blinding and the num-
Sample sizes of at least 50 per group - if these do not find a sta-
ber of patients lost to follow-up were recorded. Each reviewer gave
tistically significant difference, they are adequately powered for a
the trial a score for each item: A - low risk of bias, B - moderate
20% relative difference in the relevant outcome.
risk of bias, or C - high risk of bias (Higgins 2005). Also Jadad´ s
Blinding of patients and assessors for outcomes.
quality checklist (Jadad 1996) which measures the internal validity
Handling of withdrawals >80% follow up (imputations based on
of a trial was applied. The scale measures three items: whether the
methods such as Last Observation Carried Forward (LOCF) are
study is described as randomised, whether the study is described
acceptable).
as double-blind, and whether there is a description of withdrawals
Concealment of treatment allocation.
and dropouts.
Gold: At least one randomised clinical trial meeting all of the
DATA EXTRACTION
following criteria for the major outcome(s) as reported:
Data was independently extracted by the reviewers and cross-
Sample sizes of at least 50 per group - if these do not find a sta-
checked. The results of each trial were summarized in an inten-
tistically significant difference, they are adequately powered for a
tion-to-treat basis in 2 x 2 tables for each outcome. The trials’
20% relative difference in the relevant outcome.
external validity was assessed by analysis of: (a) PARTICIPANTS:
Blinding of patients and assessors for outcomes.
Inclusion, exclusion and diagnostic criteria, male and female, age,
Handling of withdrawals > 80% follow up (imputations based on
number of participants. The calculation of the sample size and
methods such as LOCF are acceptable).
power was also analysed; (b) INTERVENTIONS: besides the
Concealment of treatment allocation.
types of interventions described above, route of administration,
Silver: A randomised trial that does not meet the above criteria.
dosage, and duration was also assessed; (c) OUTCOME (also de-
Silver ranking would also include evidence from at least one study
scribed above). Information from the studies published twice was
of non-randomised cohorts that did and did not receive the ther-
extracted from the publication with the most complete data.
apy, or evidence from at least one high quality case-control study.
ANALYSING AND PRESENTING RESULTS
A randomised trial with a ’head-to-head’ comparison of agents
If appropriate, the studies would be sub-grouped for meta-anal-
would be considered silver level ranking unless a reference were
ysis according to the analysis of the items above and clinical ho-
provided to a comparison of one of the agents to placebo showing
mogeneity. The analysis was performed using relative risk (fixed
at least a 20% relative difference. Randomisation- in blocks by a random number computer gener-
Bronze: The bronze ranking is given to evidence if at least one ated program
high quality case series without controls (including simple before/ Allocation concealment- unclear
after studies in which patients act as their own control) or if the Blinding- not described
conclusion is derived from expert opinion based on clinical ex- Intention-to treat analysis- This trial was analysed by intention-
perience without reference to any of the foregoing (for example, to-treat
argument from physiology, bench research or first principles). Withdrawals and dropouts: the authors described exclusion for
six patients because of thrombotic neuropsychiatric events. The
number of withdrawals and drop-outs in each group was provided.
RESULTS
Effects of interventions
Effectiveness:
Overall, a response rate, defined as according to Neuwelt et al
Description of studies as at least 20% improvement from basal conditions in clinical,
See: Characteristics of included studies; Characteristics of excluded serological, and specific neurological measures, was 75% (Barile-
studies. Fabris 2005). A significantly greater number of people responded
Twenty-five RCTs were found that used different intervention for to treatment in the cyclophosphamide group. Treatment response
SLE manifestations: 14 out of the 25 referred only to the renal was found in 94.7% (18/19) of patients using cyclophosphamide
complications, not mentioning other clinical manifestations, or compared with 46.2% (6/13) in the methylprednisolone group at
not giving data on them, making impossible the data collection on 24 months (RR 2.05, 95% CI 1.13, 3.73) (Figure: comparison 1,
other clinical manifestations. Of the 11 remaining studies, one was outcome 1). The NNT for response to treatment is 2.
a protocol (Euler 1991), one did not provide data on neuropsychi- The median SLEDAI rating favoured the cyclophosphamide
atric involvement, four included only patients taking cyclophos- group after 12 months of follow-up (cyclophosphamide 1 (range 0
phamide, in different regimens, and only laboratory findings were to 5) versus methylprednisolone 4 (range 0 to 30), (p = 0.007). No
analysed; and three studies included patients with systemic mani- significant differences between the groups were found in SLICC
festations, but were excluded because data of neuropsychiatric in- measurements.
volvement was not available in suitable form for analyses. A significant decrease in the number seizures per month was ob-
One study met the included criteria (Barile-Fabris 2005). This served in the cyclophosphamide group. All the patients in the
study included 32 patients aged >18 years old with active neuro- cyclophosphamide group had electroencephalographic improve-
logical involvement in systemic erythematosus (NPSLE) manifes- ment.
tations. Each patient was allocated to receive methylprednisolone Steroid-sparing effect:
1g daily for 3 days as induction treatment. This was then followed Cyclophosphamide use was associated with reduction of pred-
by one of the following two treatments: methylprednisolone 1g nisone requirements by the sixth month of treatment (cyclophos-
for three days monthly for four months, then bimonthly for six phamide 15mg/day (range 10-35); methylprednisolone 27mg/day
months and then every three months for one year or cyclophos- (5-45), p=0.001)
phamide 0.75g/m2 body surface monthly for one year and then Adherence to treatment:
every three months for another year. Oral prednisone was started There was a trend in favour of the cyclophosphamide group to
on the fourth day of treatment, at 1mg/kg/day, for no more than complete the protocol for up 2 years of treatment, though this was
three months and tapered according to disease activity/remission. not statistically significant (RR 2.74 (95% CI 0.96, 7.82).
Adverse events
There were no significant differences in adverse effects, such as in-
fections rate, systemic hypertension, hyperglycaemia, pancreatitis
Risk of bias in included studies and death between the groups (Figure: comparison 1, outcome 2).
Using Jadad´ s quality checklist, the study scored 3 points because It was not possible to extract more data from the study because
the authors described the study as randomised and mentioned there was a small number of patients in the others clinical sub-
the generation of randomisation procedure. In addition, they de- groups of neurological manifestations and the authors did not pro-
scribed the number of patients excluded and exclusion reasons. vide sufficient information to allow data extraction.
They did not described the double-blind procedure. A clinical relevance table summarises these results (see Table 1).
Table 1. Clinical relevance table
Outcome Event rate -CY Event rate -MP Relative Risk Risk Diff (95% CI) NNT
group group (95%CI
Response to treat- 18/19 (94.7%) 6/13 (46.2%) 2.05 (1.13, 3.73) 49% (20, 77) 2
ment at 2yrs
Adherence to treat- 12/19 (63.2%) 3/13 (23.1%) 2.74 (0.96, 7.82) 40% (9, 72) n/a
ment at 2 yrs
legend:
CY=cyclophosphamide;
MP-methyl-
prednisolone; n/a-
not applicable
pathogenic mechanisms involved in central nervous system lupus

and develop a clinically rational approach to propose clinical trials
and assess the efficacy of various therapeutic interventions.
DISCUSSION
This review has highlighted the difficulty and inadequacy of re- AUTHORS’ CONCLUSIONS
search in the area of neuropsychiatric involvement in systemic lu- Implications for practice
pus erythematosus. A number of randomised controlled trials in We found one randomised controlled trial with small number of
systemic lupus erythematosus are restricted to renal involvement. patients in the different clinical subgroup of neurological man-
Neuropsychiatric involvement has been neglected in these trials. ifestation. It seems that cyclophosphamide is more effective in
In the few that included systemic manifestations, lack of clarity the treatment of neuropsychiatric involvement in systemic erythe-
in the definitions of outcomes become the available data sparse matosus lupus compared with methylprednisolone.
and difficult interpretation. As these trials are also of insufficient
quality and small sample size do not enable any valid conclusions Implications for research
about neuropsychiatric involvement.
Properly designed randomised controlled trials that involve large
Neuropsychiatric involvement in systemic lupus erythematosus representative numbers of individuals, with explicit clinical and
increases the disease severity and is associated with poor progno- laboratory diagnosis criteria, sufficient duration of follow-up and
sis. In this update, only one randomised controlled clinical trial description of all relevant outcome measures are necessary to guide
about these specific therapeutic interventions was found. Interest- practice.
ing findings in this study are the higher response rate in the cyclo-
phosphamide group, no differences in adverse effects and deaths
between the groups and difference in the number of patients who
complete the protocol up 2 years of treatment favouring the cyclo-
ACKNOWLEDGEMENTS
phosphamide group. However, this study has some limitations like
the small number of patients in the different clinical subgroup of We thank Louise Falzon for helping develop and implement the
neurological manifestation. Multicenter methodologically rigor- electronic search for this review. Many thanks to Lara Maxwell for
ous trials are needed, but it is necessary to understand the different her valuable editorial review of this manuscript.
REFERENCES
References to studies included in this review Harisdangkul 1989 {published data only}
Hariisdangkul V, Rockhold L, Myers A. Lupus nephritis: Efficacy
Barile-Fabris 2005 {published data only}
of monthly pulse therapy with intravenous methylprednisolone.
Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, Jara LJ, Fraga- Southern Medical Journal 1989;82(3):321–7.
Mouret A, Miranda-Limón JM, et al.Controlled clinical trial of IV
cyclophosphamide versus IV methylprenisolone in severe Hernández 2003 {published data only}
neurological manifestations in systemic lupus erythematous. Annals Cortés-Hernandez J, Ordi- Ros J, Labrador M, Segarra A, Tovar JL,
Rheumatic Diseases 2005;64:620–5. Balalada E, et al.Predictors of poor renal outcome in patients with
lupus nephritis treated with combined pulses of cyclophosphamide
References to studies excluded from this review and methylprednisolone. Lupus 2003;12:287–96.
Austin 1986 {published data only} Kopelman 2003 {published data only}
Austin HA, Klippel JH, Balow JE. [Therapy of lupus nephritis]. Kopelman B. A psychiatric perspective on the therapy of psychosis
New England Journal of Medicine 1986;314:614–9. in systemic lupus erythematosus. Lupus 2003;12(12):947–9.
Boumpas 1992 {published data only} Lavalle- Graef 2004 {published data only}
Boumpas DT, Austin III HA, Vaughn EM, Klippel JH, Steinberg
Alicia Lavalle-Graef, Liudmila Villegas-Acosta, Carlos Lavalle.
ASD, Yarboro CH, Balow JE. [Controlled trial of pulse Trens of Anticardilipin Antibodies after Low-Dose
methylprednisolone versus two regimens of pulse
Methyprednisolone and Cyclophosphamide Treatment of Systemic
cyclophosphamide in severe lupus nephritis]. Lancet 1992;340: Lupus Erythematosus. Archieves of Medical Research 2004;35:
741–5.
421–7.
Chi Chiu Mok 2003 {published data only}
Lehman 2004 {published data only}
Chi Chiu Mok, Chak Sing Lau, Raymond W. S. Wong. Treatment
of Lupus Psychosis with oral cycophosphamide followed by Lehman TJ, Edelheit BS, Onel KB. Combined intravenous
methotrexate and cyclophosphamide for refractory childhood lupus
azathioprine maintenance; an open- label study. The American
Journal of Medicine 2003;115:59–62. nephritis. Annals of rheumatic diseases 2004;63(3):321–3.
Dinat 1982 {published data only} Levey 1992 {published data only}
Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg Levey AS, Lan S-P, Corwin HL, Kasinath BS, Lachin J, Neilson
AD. [Alternative modes of cyclophosphamide and azathioprine EG, Hunsicker LG, Lewis EJ. Progression and remission of renal
therapy in lupus nephritis]. Annals of Internal Medicine 1982;96( disease in the lupus nephritis collaborative study. Annals of Internal
(part 1)):728–35. Medicine 1992;116(2):114–23.
Donatio 1977 {published data only} Liebling 1982 {published data only}
Donatio JV, Holley KE, Ferguson RH, Istrup DM. [Treatment of Liebling MR, McLaughlin K, Boonsue S, Kasdin J, Barnett EV.
diffuse proliferative lupus nephritis with prednisone and combined Monthly pulses of methylprednisolone in SLE nephritis. Journal of
prednisone and cyclophosphamide]. New England Journal of Rheumatology 1982;9:543–8.
Medicine 1978;23:1151–5.
Mackworth 1988 {published data only}
Edwards 1987 {published data only} Mackworth-Young CG, David J, Morgan SH. [A double blind,
Edwards JCW, Snaith ML, Isenberg DA. [A double blind placebo controlled trial of intravenous methilprednisolone in
controlled trial of methylprednisolone infusions in systemic lupus systemic lupus erythematosus]. Annals of Rheumatic Diseases 1988;
erythematosus using individualised outcome assement]. Annals 47:496–502.
Rheumatic Diseases 1987;46:773–6.
Neuwelt 1995 {published data only}
Euler 1991 {published data only}
Neuwelt CM, Lacks S, Kaye BR, Ellamn JB, Borestein DG. Role of
∗
Euler HH, Schroeder JO, Zeuner RA, Teske E. [A randomized
Intravenous Cyclophosphamide in the Treatment of Severe
trials of plasmapheresis and subsequent pulse cyclophosphamide in
Neuropsychiatric Systemic Lupus Erythematosus. The American
severe lupus: design of the LPSG trial]. The International Journal of
Journal of Medicine 1995;98:32–41.
Artificial Organs 1991;14(10):639–46.
Fries 1973 {published data only} Ramos 1996 {published data only}
Fries JF, Sharp GC, McDevitt HO, Holman HR. Ramos PC, Mendez PRJ, Ames MA, Khamashta, Hughes GRV.
[Ciclophosphamide therapy in sistemic lupus erythematosus and Pulse cyclophosphamide in the treatment of neuropsychiatric
polimyositis]. Arthritis & Rheumatism 1973;16(2):154–62. systemic lupus erythematosus. Clinical and Experimental
Rheumatology 1996;14:295–9.
Gorley 1996 {published data only}
Gourley MF, Austin III HA, Scott D, Yarboro CH, Vaughan EM, Sesso 1994 {published data only}
Muir J, Boumppas DT, Klippel JH, Balow JE, Steinberg AD. Sesso R, Monteiro M, Sato E, Kiirsztajn G, Silva L, Ajzen H. A
[Methylprednisolone and cyclophosphamide, alone or in controlled trial of pulse cyclophosphamide versus pulse
combination, in patients with lupus nephritis]. Annals of Internal methilprednisolone in severe lupus nephritis. Lupus 1994;3:
Medicine 1996;125(7):549–57. 107–12.
Steinberg 1971 {published data only} Eyanson 1980
Steinber AD, Kaltreider HB, PJ Staples, Goetzl EJ, Talal N, Decker Eyanson S, Passo MH, Aldo-Benson MA, Benson MD.
JL. [Cyclophosphamide in lupus nephritis: a controlled trial]. [Methylprednisolone pulse therapy for nonrenal lupus
Annals of Internal Medicine 1971;75:165–71. erythematosus]. Annals of Rheumatic Diseases 1980;39:377–80.
Steinberg 1991 {published data only} Felson 1984
Steinberg AD, Steinberg SC. Long-term preservation of renal Felson DT, Anderson J. [Evidence for the superiority of
function in patients with lupus nephritis receiving treatment that immunosuppressive drugs and prednisone over prednisone alone in
includes cyclophosphamide versus those treated with prednisone lupus nephritis]. New England Journal of Medicine 1984;311:
only. Arthritis & Rheumatism 1991;34(8):945–9. 1528–33.
Stojanovich 2003 {published data only} Gladman 1994
Stojanovich L. Stojanovich R, Kostich V, Dzjolich E. Gladman DD, Urowitz MB. [Clinical features of systemic lupus
Neuropsychiatric lupus favourable response to low dose i.v. erythematosus]. In: Klippel JH, Dieppe PA editor(s).
cyclophosphamide and prednisolone. Lupus 2003;12:3–7. Rheumatology. Vol. 6, Baltimore: Mosby, 1994:2.1–20.
Stratta 1992 {published data only} Higgins 2005

Stratta P, Canavese C, Dogliani M, Thea A, Ferrero S, Tognarelli G, Higgins JPT, Green S, editors. Cochrane Database of Systematic
Vercellone A. Intravenous cyclophosphamide pulse therapy in the Reviews 2005.
treatment of systemic lupus erythematosus. Systemic Lupus Jadad 1996
Erythematosus: Renal Vasculitis. Contrib Nephrol 1992;99:126–8. Jadad AR, Moore A, Carroll D, Jenkinson C, Reynolds JM,
Gavaghan DJ, McQuay HJ. [Assessing the quality of reports of
Yee 2003 {published data only}
randomized clinicalt trials: is blinding necessary?]. Controlled
∗
C-S Yee, C Gordon, C Dostal, P Petera, J Dadoniene, B Griffiths.
Clinical Trials 1996;17:1–12.
EULAR randomised controlled trial of pulse cyclophosphamide
and methilpredinisolone versus continuos cyclophosphamide and Sibley 1992
prednisolone followed by azathioprine and prednisolone in lupus Sibley JT, Olszynski PW, Decoteau WE, Sundaram MB. The
nephritis. Annals of Rheumatic Diseases 2003;63:525–9. incidence and prognosis of central nervous system disease in
systemic lupus erythematosus is independent of active disease.
Additional references Journal of Rheumatology 1992;19:47–52.
Tan 1982
Bonfa 1987 Tan EM, Conhen AS, Fries JF, Masi AT, McShane DJ, Rothfield
Bonfa E, Golombek SJ, Kaufman LD. [Association between lupus NF, Schaller JG, Talal N, Winchester RJ. [The 1982 revised criteria
psychosis and anti–ribossomal P protein antibodies]. New England for the classification of sytemic lupus erythematosus]. Arthritis &
Journal of Medicine 1987;317:265–71. Rheumatism 1982;25:1271–7.
Boumpas 1995 Tugwell 2004
Boumpas DT, Austin HA, Fessler BJ, James E, Ballow JE, Klippel Tugwell P, Shea B, Boers M, Brooks P, Simon L, Strand V, Wells G.
JH, Lockshin MD. [Systemic lupus erythematosus; emerging Evidence-Based Rheumatology. BMJ Books, 2004.
concepts]. Annals of Internal Medicine 1995;122:940–50.
Urowitz 1980
Denburg 1994 Urowitz M, Gladman DD, Abel T. [Neuropsychiatric Lupus].
Denburg SD, Carbotte RM, Denburg JA. [Corticosteroids and Journal of Rheumatoly 1980;7:326–33.
neuropsychological functioning in patients with systemic lupus Wolkowitz 1990
erythematosus]. Arthritis & Rheumatism 1994;37:1311–9. Wolkowitz OM, Reus VI, Weingartter H, Thompson K, Breir A,
Denburg 1995 Doran A, Rubinow D, Pickar D. [Cognitive effects of
Denburg JA, Denburg SD, Carbotte RM, Sakic B, Szechtman H. corticosteroids]. American Journal of Psychiatry 1990;147:
[Nervous system lupus: pathogenesis and rationale for therapy]. 1297–1303.
Scandinavian Journal of Rheumatoly 1995;12:263–73. ∗
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Barile-Fabris 2005
Methods 1-Generation of Allocation Sequence:

Computer-generated program
2-Allocation Concealment: Not reported
3- Blinding: Not reported
4 Characteristics of placebo: Not used
5- Sample size calculation: Not reported
6 -Number of patients randomized:32
7-Loss to follow-up: 16 patients.
8-Intention to treat analysis: yes
9 Similarity between groups: Yes
Participants 1- Inclusion criteria: diagnosis of SLE according to the American College of Rheumatology Criteria,
age>18 years, and one of the following active neurological involvement in systemic erythematosus (NPSLE)
manifestations: peripheral/cranial neuropathy, optic neuritis, transverse myelitis, brainstem disease, or
coma. All patients had no more than 15 days of onset, patients with refractory seizures also were included
2-Exclusion criteria were 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 .
3- Characteristics:
Group treated with cyclophosphamide:
Age: 33 (17-48)
Disease evolution in years: 4.2 (.11-16)
Number of ACR criteria: 6
Basal prednisone dose (mg/day):
45(15-60)
Group treated with methylprednisolone:
Age 26 (19-44)
Disease evolution in years:2.5 (.0-12)
Number of ACR criteria: 6
Basal prednisone dose (mg/day): 45 (15-60)
Interventions After randomisation each patient was allocated to receive methylprednisolone 1g daily for 3 days as
induction treatment. This was followed by one of the following two 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 0.75g/m2 body surface monthly for 1 year and then every 3 months for another
year. Oral prednisone 1mg/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 fourth month of treatment; (b) worsening: disease progression of 20 % or more
despite continued treatment for at least 4 months.
Barile-Fabris 2005 (Continued)
Notes 1-Setting: Mexico
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Characteristics of excluded studies [ordered by study ID]
Austin 1986 Randomised controlled trial, but its research question is not relevant.
Boumpas 1992 Randomised controlled trial, but its research question is not relevant.
Chi Chiu Mok 2003 Not randomised.
Dinat 1982 Randomisation method not stated and research question is not relevant.
Donatio 1977 Randomised controlled trial, but its research question is not relevant.
Edwards 1987 Randomisation method not stated, data of neuropsychiatric involvement are not available in suitable form
for analyses.
Euler 1991 Only a protocol.
Fries 1973 Randomisation method not stated. High loss to follow-up. Data available are in an unsuitable form for
analysis.
Gorley 1996 Randomised, high loss to follow-up and research question is not relevant.
Harisdangkul 1989 Not randomised, research question is not relevant.
Hernández 2003 Not randomised trial.
Kopelman 2003 Not randomised controlled trial.
Lavalle- Graef 2004 Not randomized, research question is not relevant
Lehman 2004 Not randomised, research question is not relevant
Levey 1992 Randomised, but the RCT using plasmaphoresis.
Liebling 1982 Randomisation method not stated, research question is not relevant.
Mackworth 1988 Randomisation method not stated,data of neuropsychiatric involvement are not available in suitable form for
analyses.
Neuwelt 1995 Not Randomized.
Ramos 1996 Not Randomised.
Sesso 1994 Randomisation method not stated, research question is not relevant.
Steinberg 1971 Randomised controlled trial, but its research question is not relevant.
Steinberg 1991 Randomised controlled trial, but its research question is not relevant.
(Continued)
Stojanovich 2003 Randomisation method not stated,data of neuropsychiatric involvement are not available in suitable form for
analyses.
Stratta 1992 Not randomised, data of neuropsychiatric involvement are not available in suitable form for analyses.
Yee 2003 Randomized, but data of neuropsychiatric involvement are not available.
DATA AND ANALYSES
Comparison 1. Cyclophosphamide versus Methylprednisolone
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Response to treatment 1 32 Risk Ratio (M-H, Fixed, 95% CI) 2.05 [1.13, 3.73]
2 Adverse events 1 256 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.49, 1.28]
2.1 Urinary tract infections 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.47, 1.57]
2.2 Respiratory 1 32 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.36, 2.93]
2.3 Oropharyngeal candidiasis 1 32 Risk Ratio (M-H, Fixed, 95% CI) 3.50 [0.18, 67.45]
2.4 Herpes Zoster 1 32 Risk Ratio (M-H, Fixed, 95% CI) 3.50 [0.18, 67.45]
2.5 Systemic hypertension 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 5.32]
2.6 Hyperglycemia 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 5.32]
2.7 Pancreatitis 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.01, 5.32]
2.8 Death 1 32 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.03, 1.96]
3 Completion of the protocol after 1 32 Risk Ratio (M-H, Fixed, 95% CI) 2.74 [0.96, 7.82]
2 years
Analysis 1.1. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 1 Response to

treatment.
Review: Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythematosus
Comparison: 1 Cyclophosphamide versus Methylprednisolone
Outcome: 1 Response to treatment
Study or subgroup Cyclophosphamide Methylprednisolone Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Barile-Fabris 2005 18/19 6/13 100.0 % 2.05 [ 1.13, 3.73 ]
Total (95% CI) 19 13 100.0 % 2.05 [ 1.13, 3.73 ]

Total events: 18 (Cyclophosphamide), 6 (Methylprednisolone)
Heterogeneity: not applicable
Test for overall effect: Z = 2.36 (P = 0.018)
0.1 0.2 0.5 1 2 5 10

Methylprednisolone Cyclophosphamide
Analysis 1.2. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 2 Adverse events.
Outcome: 2 Adverse events

1 Urinary tract infections
Barile-Fabris 2005 10/19 8/13 39.1 % 0.86 [ 0.47, 1.57 ]
Subtotal (95% CI) 19 13 39.1 % 0.86 [ 0.47, 1.57 ]

2 Respiratory
Barile-Fabris 2005 6/19 4/13 19.6 % 1.03 [ 0.36, 2.93 ]
Subtotal (95% CI) 19 13 19.6 % 1.03 [ 0.36, 2.93 ]

3 Oropharyngeal candidiasis
Barile-Fabris 2005 2/19 0/13 2.4 % 3.50 [ 0.18, 67.45 ]
Subtotal (95% CI) 19 13 2.4 % 3.50 [ 0.18, 67.45 ]

4 Herpes Zoster
Barile-Fabris 2005 2/19 0/13 2.4 % 3.50 [ 0.18, 67.45 ]
Subtotal (95% CI) 19 13 2.4 % 3.50 [ 0.18, 67.45 ]

5 Systemic hypertension
Barile-Fabris 2005 0/19 1/13 7.3 % 0.23 [ 0.01, 5.32 ]
Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

6 Hyperglycemia
Barile-Fabris 2005 0/19 1/13 7.3 % 0.23 [ 0.01, 5.32 ]
Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

0.01 0.1 1 10 100

Cyclophosphamide Methylprednisolone
(Continued . . . )
(. . . Continued)
7 Pancreatitis
Barile-Fabris 2005 0/19 1/13 7.3 % 0.23 [ 0.01, 5.32 ]
Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

8 Death
Barile-Fabris 2005 1/19 3/13 14.7 % 0.23 [ 0.03, 1.96 ]
Subtotal (95% CI) 19 13 14.7 % 0.23 [ 0.03, 1.96 ]

Total (95% CI) 152 104 100.0 % 0.79 [ 0.49, 1.28 ]
Heterogeneity: Chi2 = 5.29, df = 7 (P = 0.63); I2 =0.0%
0.01 0.1 1 10 100

Cyclophosphamide Methylprednisolone
Analysis 1.3. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 3 Completion of the

protocol after 2 years.
Outcome: 3 Completion of the protocol after 2 years

Barile-Fabris 2005 12/19 3/13 100.0 % 2.74 [ 0.96, 7.82 ]
Total (95% CI) 19 13 100.0 % 2.74 [ 0.96, 7.82 ]

0.1 0.2 0.5 1 2 5 10

Methylprednisolone Cyclophosphamide
WHAT’S NEW
Last assessed as up-to-date: 20 February 2006.
15 September 2008 Amended Converted to new review format. CMSG ID C024-R
HISTORY
Protocol first published: Issue 1, 1999
Review first published: Issue 3, 2000
21 February 2006 New citation required and conclusions have changed Substantive amendment. See published notes
CONTRIBUTIONS OF AUTHORS
Conceiving the review: VFMT, AAC
Designing the review: VFMT, AAC, ANA
Coordinating the review: VFMT, AAC, ANA
Data collection for the review
Developing search strategy: AAC
Undertaking searches: VFMT, AAC, JFNN
Screening search results: VFMT, AAC
Organising retrieval of papers: VFMT
Screening retrieved papers against inclusion criteria: VFMT, AAC
Appraising quality of papers: VFMT, AAC
Abstracting data from papers: VFMT, AAC
Data management for the review
Entering data into RevMan: VFMT
Analysis of data: VFMT, AAC
Interpretation of data
Providing a methodological perspective: VFMT, AAC
Providing a clinical perspective: VFMT, AAC
Providing a policy perspective: VFMT, AAC
Writing the review: VFMT, AAC
DECLARATIONS OF INTEREST
None known
SOURCES OF SUPPORT
Internal sources
• Clinical Trials and Meta-analysis Unit, Federal University of São Paulo, Brazil.
• Universidade Santo Amaro, Brazil.
External sources
• No sources of support supplied
NOTES
This updated version contains one new RCT. The original version of this review did not have any included trials.
INDEX TERMS
Medical Subject Headings (MeSH)

Cyclophosphamide [∗ therapeutic use]; Delirium, Dementia, Amnestic, Cognitive Disorders [∗ drug therapy; etiology]; Immunosup-
pressive Agents [∗ therapeutic use]; Lupus Erythematosus, Systemic [∗ complications; drug therapy]; Methylprednisolone [∗ therapeutic
use]; Neuroprotective Agents [∗ therapeutic use]; Seizures [drug therapy; etiology]
MeSH check words

Humans

Cyclophosphamide

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Cyclophosphamide versus methylprednisolone for treating

neuropsychiatric involvement in systemic lupus

Trevisani VFM, Castro AA, Ferreira Neves Neto JJFNN, Atallah ÁN

Cyclophosphamide versus methylprednisolone for treating

Editorial group: Cochrane Musculoskeletal Group.

PLAIN LANGUAGE SUMMARY

Cyclophosphamide versus methylprednisolone for lupus

What did the studies show?

Were there any side effects?

What is the bottom line?

Factors related to the neuropsychiatric involvement are: self anti-

pathogenic mechanisms involved in central nervous system lupus

Stratta 1992 {published data only} Higgins 2005

Characteristics of included studies [ordered by study ID]

Methods 1-Generation of Allocation Sequence:

Notes 1-Setting: Mexico

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Chi Chiu Mok 2003 Not randomised.

Euler 1991 Only a protocol.

Harisdangkul 1989 Not randomised, research question is not relevant.

Hernández 2003 Not randomised trial.

Kopelman 2003 Not randomised controlled trial.

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

Lehman 2004 Not randomised, research question is not relevant

Levey 1992 Randomised, but the RCT using plasmaphoresis.

Neuwelt 1995 Not Randomized.

Ramos 1996 Not Randomised.

Comparison 1. Cyclophosphamide versus Methylprednisolone

Analysis 1.1. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 1 Response to

Comparison: 1 Cyclophosphamide versus Methylprednisolone

Outcome: 1 Response to treatment

Study or subgroup Cyclophosphamide Methylprednisolone Risk Ratio Weight Risk Ratio

Total (95% CI) 19 13 100.0 % 2.05 [ 1.13, 3.73 ]

0.1 0.2 0.5 1 2 5 10

Comparison: 1 Cyclophosphamide versus Methylprednisolone

Outcome: 2 Adverse events

Study or subgroup Cyclophosphamide Methylprednisolone Risk Ratio Weight Risk Ratio

Subtotal (95% CI) 19 13 39.1 % 0.86 [ 0.47, 1.57 ]

Subtotal (95% CI) 19 13 19.6 % 1.03 [ 0.36, 2.93 ]

Subtotal (95% CI) 19 13 2.4 % 3.50 [ 0.18, 67.45 ]

Subtotal (95% CI) 19 13 2.4 % 3.50 [ 0.18, 67.45 ]

Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

0.01 0.1 1 10 100

Subtotal (95% CI) 19 13 7.3 % 0.23 [ 0.01, 5.32 ]

Subtotal (95% CI) 19 13 14.7 % 0.23 [ 0.03, 1.96 ]

0.01 0.1 1 10 100

Analysis 1.3. Comparison 1 Cyclophosphamide versus Methylprednisolone, Outcome 3 Completion of the

Comparison: 1 Cyclophosphamide versus Methylprednisolone

Outcome: 3 Completion of the protocol after 2 years

Study or subgroup Cyclophosphamide Methylprednisolone Risk Ratio Weight Risk Ratio

Total (95% CI) 19 13 100.0 % 2.74 [ 0.96, 7.82 ]

0.1 0.2 0.5 1 2 5 10

15 September 2008 Amended Converted to new review format. CMSG ID C024-R

• No sources of support supplied

Medical Subject Headings (MeSH)

MeSH check words

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