Citation: Zhao LQ, Yu DY, Cheng JW. Intravenous glucocorticoids
therapy in the treatment of Graves’ ophthalmopathy: a systematic review and
Meta-analysis. Int J Ophthalmol 2019;12(7):1177-1186
DOI:10.18240/ijo.2019.07.20
·Meta-Analysis·
Intravenous
glucocorticoids therapy in the treatment of Graves’ ophthalmopathy: a
systematic review and Meta-analysis
Li-Quan Zhao1, Dan-Yang
Yu2, Jin-Wei Cheng3
1Department
of Ophthalmology, Shanghai Pudong New Area People’s Hospital, Shanghai 201200,
China
2Department
of Ophthalmology, 920th Hospital of Jiont Logistics Support Force, Kunming
6500032, Yunnan Province, China
3Department
of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University
School of Medicine, Shanghai 200080, China
Correspondence
to: Jin-Wei
Cheng. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai 200080, China.
jinwei_cheng@yeah.net
Received:
2018-10-25 Accepted:
2019-02-24
Abstract
AIM: To evaluate the benefit and harms of high-dose intravenous
glucocorticoids (IVGC) as first-line treatment for Graves’ ophthalmopathy (GO).
METHODS: A systematic review and Meta-analysis of randomized
clinical trials (RCTs) comparing IVGC for the treatment of GO, with placebo or
other treatments, were conducted. Electronic databases were searched, and
standard methodological guidance of Cochrane Handbook for Systematic Reviews of
Interventions was used. The primary outcome was overall response, and secondary
outcomes included the improvement and change in clinical activity score (CAS),
and adverse events.
RESULTS: Ten RCTs were included in the Meta-analysis. Low
quality evidence (one trial) showed that participants receiving IVGC achieved
significantly higher response compared to participants receiving placebo [risk
ratio (RR) 7.50, 95% confidence interval (CI) 1.14 to 49.26]. Moderate quality
evidence (four trials) support appreciable benefit of IVGC in response compared
with oral glucocorticoids (OGC), with of RR being 1.51 (95%CI 1.25 to 1.83).
There was low quality evidence (one trial) compatible with appreciable benefit
for IVGC plus orbital radiotherapy in response (RR 1.38, 95%CI 1.07 to 1.79),
compared with OGC plus orbital radiotherapy. One IVGC versus rituximab trial
provided moderate quality evidence suggesting that participants using IVGC
achieved significantly lower response compared to participants using rituximab
(RR 0.70, 95%CI 0.50 to 0.98). One IVGC versus mycophenolate mofetil (MMF) trial
provided moderate quality evidence suggesting that participants using IVGC
achieved significantly lower response compared to participants using MMF (RR
0.74, 95%CI 0.63 to 0.88). Very low quality evidence (one trial) showed that
participants with dysthyroid optic neuropathy (DON) receiving IVGC were more
likely to achieve response compared to participants receiving orbital
decompression (RR 3.33, 95%CI 0.51 to 21.89).
CONCLUSION: The current evidence is moderate quality, which is
sufficient to support IVGC to be as the first-line treatment for
moderate-to-severe GO, and the use of rituximab or MMF to be the second-line
treatment instead of IVGC. However, the evidence is very low quality, which is
insufficient to support the use of IVGC or orbital decompression as the
first-line treatment of DON.
KEYWORDS: glucocorticoids; Graves’
ophthalmopathy; Meta-analysis
DOI:10.18240/ijo.2019.07.20
Citation: Zhao
LQ, Yu DY, Cheng JW. Intravenous glucocorticoids therapy in the treatment of
Graves’ ophthalmopathy: a systematic review and Meta-analysis. Int J
Ophthalmol 2019;12(7):1177-1186
INTRODUCTION
Graves’
ophthalmopathy (GO) is an autoimmune disorder that has puzzled physicians and
scientists for nearly two centuries, which generally occurs in the patients
with hyperthyroidism, and sometimes occurring in patients with hypothyroidism
or euthyroid[1, 2, 3, 4]. Recently, the European Group on Graves’ Orbitopathy
(EUGOGO) published the first guideline for the management of GO, which
recommend high-dose intravenous glucocorticoids (IVGC) as the first-line
treatment for active and moderate-to-severe GO and the immediate treatment for
dysthyroid optic neuropathy (DON)[5].
Since the
1950s, glucocorticoids have been the most common immunosuppressive agents used
in the treatment of active and moderate-to-severe GO[6],
and more and more randomized trials and Meta-analyses have proven the
beneficial effect of high-dose IVGC in GO[7, 8, 9, 10]. However,
the efficacy and safety of IVGC were not accurately estimated. Moreover, the
rigorous and detailed use of IVGC has not been established. Hence, an
evidence-based approach might need to evaluate the benefit and harms, and the
present study was conducted as a systematic review and Meta-analysis of all
published randomized clinical trials comparing IVGC for the treatment of GO,
with placebo or other treatments.
METHODS
This
Meta-analysis was performed using the standard methodological guidance of
Cochrane Handbook for Systematic Reviews of Interventions, and also conformed
to the PRISMA statement[11, 12, 13].
Outcome
Measures The primary outcome of efficacy was
overall response. “Response” to treatment was defined as an improvement in
composite outcome, single sign such as visual function, or symptoms. The
secondary efficacy outcomes included the improvement in clinical activity score
(CAS), and the change in CAS. Adverse outcomes were also assessed, including
total adverse events and Cushingoid symptoms, weight gain, gastrointestinal
events, hypertension, hyperglycaemia.
Search
Strategy Published randomized clinical trials
were identified through a comprehensive search of PubMed, EMBASE, and CENTRAL
(which contains the Cochrane Eyes and Vision Trials Register). The keywords for
the interventions were methylprednisolone, glucocorticoid, corticosteroid, or
steroid. The keywords for the disease were Graves’ ophthalmopathy, Graves’
orbitopathy, Graves’ eye disease, thyroid associated ophthalmopathy, thyroid
associated orbitopathy, thyroid ophthalmopathy, thyroid eye disease, thyroid
orbitopathy, endocrine ophthalmopathy, endocrine eye disease, or endocrine
orbitopathy. The limit for article types was clinical trial. Language
restriction was not used in the electronic searches. The last search was
performed on 31 December 2017. The reference lists of all identified full
articles were also retrieved for the additional studies.
Study
Selection Published studies were selected,
which were based on pre-determined selection criteria. 1) Study type:
randomized clinical trials, including placebo- or active-controlled. 2)
Population: patients with the diagnosis of GO. 3) Intervention: intravenous
corticosteroid therapy, with or without the combined therapy, versus placebo or
other interventions. 4) Outcome variables: one or more of the outcome variables
be covered, including response, the improvement in CAS, and the change in CAS.
The
electronic searches and trial eligibility were conducted independently by two
reviewers (Cheng JW and Zhao LQ). First, the title and abstract of all obtained
articles from the comprehensive searches were screened to determine their
relevance. Then, if the title and abstract were definite or ambiguous to
identify, full articles were scrutinized.
Data
Extraction Data extraction was performed
according to the customized protocol, independently by two reviewers (Cheng JW
and Zhao LQ) and in duplicate. If there was any disagreement, it was resolved
by discussion. For each included study, a customized form of data was
extracted, as follows, 1) Method: randomization method, allocation concealment,
blinding (participants, investigators, examiners), loss to follow-up,
compliance, intention-to-treat or per protocol analysis, and location. 2)
Participants: inclusion and exclusion criteria, sample size, patient age, sex,
activity and severity of GO. 3) Interventions: dose, route, and duration of
interventions, comparison interventions, and co-interventions. 4) Outcomes:
efficacy outcomes (overall response, the improvement and change in CAS),
adverse outcomes, assessment times, and length of follow-up. 5) Notes: general
information such as article title, authors and source, published year, and
published language.
Quality
Assessment The methodological quality of each
included study was independently assessed by two authors (Cheng JW and Zhao
LQ), using the Cochrane Collaboration’s tool for assessing risk of bias. The
parameters of the Cochrane Collaboration’s tool included random sequence
generation and allocation concealment for assessing selection bias, blinding of
participants and personnel for assessing performance bias, blinding of outcome
assessment for assessing detection bias, incomplete outcome data for assessing
attrition bias, selective reporting for assessing reporting bias, and other
sources of bias, such as stopping early for benefit.
We assessed
each parameter of Cochrane Collaboration’s tool and graded it as low risk of
bias, unclear risk of bias, and high risk of bias. If any parameter of any
trial graded as high risk of bias, a sensitivity analysis was used to assess
the effect of the trials on the results of Meta-analysis.
Statistical
Analysis The statistical analysis was
performed using the Review Manager software version 5.3 from the Cochrane
Collaboration. For efficacy outcomes, risk ratios (RRs) with 95% confidence
intervals (CIs) for dichotomous outcomes, and standardized mean difference
(SMD) with 95%CIs for continuous outcomes were calculated. For safety outcomes,
odds ratios with 95%CIs for adverse events were calculated.
The
statistical heterogeneity was stated using the Cochran’s Q statistic and I2 metrics. If no heterogeneity was identified, when a P value
>0.1 and I2 value <50%, the fixed effects model was
used to Meta-analyses. Otherwise, if heterogeneity was identified, the random
effects model was used, and also heterogeneity was explored by conducting
subgroup analyses[14, 15].
The
sensitivity analyses were performed, as the studies at high risk of bias in one
or more domains were excluded. Subgroup analyses were also conducted, based on
the activity of disease (active, and inactive), the severity of disease (mild,
moderate to severe, and sight threatening), the type of outcome criteria, the
protocols of interventions (daily, weekly, and monthly), and the type of
comparison interventions [placebo, oral glucocorticoids (OGC), surgery,
rituximab, and so on]. Standard funnel plots were also constructed to
investigate the potential of publication bias, by examining visually the
asymmetry[16].
The ‘Summary
of findings’ table of primary outcome (overall response) was created using
GRADEproGDT software. The GRADE approach, were used to assess the quality of
clinical evidence, which might be downgraded depending on five considerations,
including study limitations (high risk of bias), publication bias, imprecision
(wide CIs), unexplained heterogeneity or inconsistency, and indirectness of
evidence[17].
RESULTS
The
selection flow chart is shown in Figure 1. A total of 275 articles were
identified across the electronic searches, and then 90 duplicates were removed.
We reviewed the remaining 185 abstract reports, and 20 full-text articles
potentially met the selection criteria were scrutinized. Finally, 10 eligible
randomized clinical trials included in the systematic review[18, 19, 20, 21, 22, 23, 24, 25, 26, 27].
Figure 1
Flow diagram of study selection.
Trials
Characteristics The characteristics of 10 eligible
randomized controlled trials are shown in Table 1. Overall, 569 participants
were evaluated, with the mean age of 45y, and involving 411 females and 158
males. Eight trials reported participants with the activity categorized as the
active phase, and two reported participants as both active and inactive. One
trial reported participants with the severity rated as sight threatening (DON);
seven reported participants as moderate to severe; and two reported
participants as mild to moderate. The follow-up periods ranged from 12wk to 2y.
One study
compared IVGC with placebo; five compared IVGC with OGC; one compared IVGC plus
orbital radiotherapy (IVGC+OR) with OGC plus orbital radiotherapy (OGC+OR); one
compared IVGC with rituximab; one compared IVGC with mycophenolate mofetil
(MMF); and one compared IVGC with surgical decompression.
Risk of Bias
and Publication Bias All trials had a prospective,
parallel design. One trial had a high risk of bias in four domains; one trial
had a high risk of bias in three domains; two trials had a high risk of bias in
two domains of performance bias and detection bias; and four trials had a high
risk of bias in one domain of performance bias. Two trials were found with low
risk of bias (Figure 2).
Figure 2
Risk of bias of included studies.
Funnel plot
for the response of IVGC (with or without orbital radiotherapy) versus placebo
or other interventions is qualitatively symmetrical, indicating low probability
of publication bias (Figure 3).
Figure 3
Funnel plot for the response of IVGC versus control RR: Risk ratio; IVGC: Intravenous
glucocorticoids; OGC: Oral glucocorticoids; IVGC+OR: Intravenous
glucocorticoids plus orbital radiotherapy; OGC+OR: Oral glucocorticoids plus
orbital radiotherapy; MMF: Mycophenolate mofetil.
Efficacy:
response The forest plot of response compared
IVGC with control is shown in Figure 4, and the ‘summary of findings’ table is
shown in Table 2.
Figure 4
Forest plot of response compared IVGC with control IVGC: Intravenous glucocorticoids;
OGC: Oral glucocorticoids; IVGC+OR: Intravenous glucocorticoids plus orbital
radiotherapy; OGC+OR: Oral glucocorticoids plus orbital radiotherapy; MMF:
Mycophenolate mofetil.
One trial
was included in the comparison of IVGC versus placebo. Participants receiving
IVGC achieved significantly higher response compared to participants receiving
placebo (RR 7.50, 95%CI 1.14 to 49.26, P=0.04). The evidence (one trial,
15 participants, low quality) was double-downgraded because the 95%CI was very
wide because of only one included trial, subgroup analyses was not conducted.
Response was
reported as outcomes in four trials comparing IVGC with OGC. No heterogeneity
across the results of four included studies was identified (Chi2=0.12, df=3, P=0.99; I2=0). The finding was compatible
with significantly increased chance of response for IVGC (RR 1.51, 95%CI 1.25
to 1.83, P<0.0001, four trials, 235 participants, moderate quality
evidence). We did not perform sensitivity analysis as all trials had a high
risk of bias. Table 3 shows the subgroup analyses, which also suggested
that IVGC was associated with significantly higher response.
Table 3
Subgroup analyses of response compared intravenous with OGC
Items |
No. of trials |
RR (95%CI) |
Heterogeneity |
Overall effect |
Activity of disease |
|
|
|
|
Active phase |
3 |
1.53 (1.22, 1.91) |
P=0.97; I²=0 |
Z=3.75; P=0.0002 |
Active and inactive phase |
1 |
1.46 (1.00, 2.11) |
Not applicable |
Z=1.98; P=0.05 |
Severity of disease |
|
|
|
|
Mild to moderate |
1 |
1.46 (1.00, 2.11) |
Not applicable |
Z=1.98; P=0.05 |
Moderate to severe |
3 |
1.53 (1.22, 1.91) |
P=0.97; I2=0 |
Z=3.75; P=0.0002 |
Type of outcome criteria |
|
|
|
|
Composite outcome |
1 |
1.46 (1.00, 2.11) |
Not applicable |
Z=1.98; P=0.05 |
Symptoms |
3 |
1.53 (1.22, 1.91) |
P=0.97; I2=0 |
Z=3.75; P=0.0002 |
Protocols of interventions |
|
|
|
|
Weekly |
3 |
1.48 (1.18, 1.87) |
P=0.99; I2=0 |
Z=3.38; P=0.0007 |
Monthly |
1 |
1.59 (1.12, 2.25) |
Not applicable |
Z=2.61; P=0.009 |
OGC: Oral
glucocorticoids; RR: Risk ratio.
One trial
comparing IVGC+OR with OGC+OR reported response as an outcome. The finding was
compatible with appreciable benefit for the combination of IVGC and orbital
radiotherapy (RR 1.38, 95%CI 1.07 to 1.79, P=0.01). The evidence (one
trial, 82 participants, low quality) was double-downgraded because of serious
imprecision (wide 95%CIs) and study limitations (high risk of bias).
Response was
reported as an outcome in one trial comparing IVGC with rituximab. Participants
receiving IVGC achieved significantly lower response compared to participants
receiving rituximab (RR 0.70, 95%CI 0.50 to 0.98, P=0.04, one trial, 31
participants, moderate quality evidence).
One trial
comparing IVGC with MMF reported composite outcome improvement as response. The
finding was compatible with appreciable benefit for IVGC (RR 0.74, 95%CI 0.63
to 0.88, P=0.0005). The evidence (one trial, 158 participants, moderate
quality) was downgraded depending on study limitations (high risk of bias).
One trial
comparing IVGC with surgery reported visual improvement as response.
Participants receiving IVGC were more likely to achieve visual improvement
compared to participants receiving surgical decompression (RR 3.33, 95%CI 0.51
to 21.89, P=0.21). Although the finding was compatible with increased
chance of response for IVGC (one trial, 15 participants, very low quality
evidence), the effect of IVGC compared to surgery was uncertain because of
serious imprecision (wide 95%CIs) and study limitations (high risk of bias).
Efficacy:
clinical activity score improvement One trial
was included in the comparison of IVGC versus placebo. The finding was
compatible with significantly increased chance of the improvement of CAS for
IVGC (RR 2.65, 95%CI 1.11 to 6.33, P=0.03). The evidence (one trial, 15
participants, low quality) was double-downgraded depending on very serious
imprecision.
The
improvement of CAS was reported as an outcome in one trial comparing IVGC with
OGC. Participants receiving IVGC achieved significantly more improvement of CAS
compared to participants receiving OGC (RR 1.50, 95%CI 1.04 to 2.17, P=0.03).
Because of serious imprecision (wide 95%CIs) and study limitations (high risk
of bias), the evidence (one trial, 70 participants, low quality) was
double-downgraded.
One trial
comparing IVGC+OR with OGC+OR reported the improvement of CAS. Participants
receiving IVGC+OR achieved significantly more improvement of CAS compared to
participants receiving OGC+OR (RR 2.36, 95%CI 1.35 to 4.12, P=0.002).
The evidence (one trial, 82 participants, low quality) was double-downgraded
depending on serious imprecision (wide 95%CIs) and study limitations (high risk
of bias).
One trial
compared IVGC with rituximab. Participants receiving IVGC were less likely to
achieve the improvement of CAS compared to participants receiving rituximab (RR
0.76, 95%CI 0.56 to 1.02, P=0.07). Because of serious imprecision, the
evidence was downgraded (one trial, 31 participants, moderate quality).
The
improvement of CAS was reported as an outcome in one trial comparing IVGC with
MMF. Participants receiving IVGC were significantly less likely to achieve the
improvement of CAS compared to participants receiving MMF (RR 0.76, 95%CI 0.65
to 0.89, P=0.0007). Because of high risk of bias, the evidence was
downgraded (one trial, 158 participants, moderate quality).
Efficacy:
clinical activity score change Four trials comparing IVGC with OGC
reported the change of CAS. Significant heterogeneity across four included
studies was identified (Chi2=14.09, df=3, P=0.003; I2=79%), and the random effects model was used. The decrease
of CAS was significantly higher in the IVGC group compared to the OGC group
(SMD -1.07, 95%CI -1.73 to -0.40, P=0.002). Depending on serious
imprecision (wide 95%CIs) and study limitations (high risk of bias), the
evidence was double-downgraded (four trials, 198 participants, low quality).
One trial
reported the change of CAS between IVGC+OR and OGC+OR. The decrease of CAS was
significantly higher in the IVGC+OR group compared to the OGC+OR group (SMD
-1.09, 95%CI -1.56 to -0.63, P<0.00001). Because of serious
imprecision (wide 95%CIs) and study limitations (high risk of bias), the
evidence was double-downgraded (one trial, 82 participants, low quality).
The change
of CAS was reported in one trial comparing IVGC with rituximab. The finding was
compatible with significantly lower decrease of CAS for IVGC (SMD 0.95, 95%CI
0.20 to 1.69, P=0.01). The evidence was downgraded (one trial, 31
participants, moderate quality) because of imprecision.
One trial
reported the change of CAS between IVGC and MMF. The finding was compatible
with significantly lower decrease of CAS for IVGC (SMD 0.67, 95%CI 0.35 to
1.00, P<0.00001). The evidence was downgraded (one trial, 158 participants,
moderate quality), because of study limitations.
Adverse
Events Participants receiving IVGC were
more likely to achieve Cushingoid symptoms (OR 19.00, 95%CI 0.77 to 469.21, P=0.07),
and hypertension (OR 8.00, 95%CI 0.58 to 110.27, P=0.12) compared to
participants receiving placebo.
Participants
receiving IVGC were significantly less likely to achieve adverse events
compared to participants receiving OGC (OR 0.24, 95%CI 0.08 to 0.67, P=0.006).
The findings were compatible with significantly decreased chance of Cushingoid
symptoms (OR 0.12, 95%CI 0.02 to 0.66, P=0.01) and hypertension (OR
0.24, 95%CI 0.08 to 0.69, P=0.008) for IVGC. Participants receiving IVGC
were less likely to weight gain (OR 0.40, 95%CI 0.07 to 2.20, P=0.29)
and gastrointestinal events (OR 0.60, 95%CI 0.24 to 1.50, P=0.28)
compared to participants receiving OGC. The finding was compatible with little
difference in hyperglycaemia between IVGC and OGC (OR 1.02, 95%CI 0.46 to 2.27, P=0.96). Participants receiving IVGC were less likely to achieve adverse
events compared to participants receiving rituximab (OR 0.26, 95%CI 0.04 to
1.55, P=0.14). Participants receiving IVGC were more likely to achieve
adverse events compared to participants receiving MMF (OR 0.26, 95%CI 0.04 to
1.55, P=0.14).
DISCUSSION
Intravenous
Glucocorticoids Versus Placebo The IVGC versus placebo trial
provided low quality evidence which supported the use of IVGC for the treatment
of active and moderate-to-severe GO.
The finding
was compatible with significantly increased chance of composite outcome
improvement for IVGC, suggesting that for patients using placebo with a
response rate of 11%, the response rate using IVGC would be between 12.5% and
100%. Additionally, participants receiving IVGC achieved significantly more
improvement of CAS compared to participants receiving placebo. Participants
receiving IVGC were more likely to achieve Cushingoid symptoms and hypertension
compared to participants receiving placebo.
Although
good methodological quality of the IVGC versus placebo trial was found, a small
sample size was the main limitation. The evidence of the effect of IVGC on both
response and CAS improvement was low quality.
Intravenous
Versus Oral Glucocorticoids The IVGC versus OGC trials provided
moderate quality evidence which was sufficient to support appreciable benefit
of IVGC for the treatment of active and moderate-to-severe GO.
Participants
receiving IVGC achieved significantly higher response compared to participants
receiving OGC, assuming approximately 53% overall response of participants
receiving OGC, the anticipated overall response of participants receiving IVGC
would be between 66.3% and 97.0%. The findings were compatible with
significantly increased chance of the improvement and decrease of CAS for IVGC.
Additionally, participants receiving IVGC were less likely to achieve adverse
events compared to participants receiving OGC.
All five
included trials had limitations in methodology. Therefore, we downgraded the
evidence of the effect of IVGC on overall response to moderate quality. In
addition, the evidence of the effect of IVGC on CAS improvement and change was
double-downgraded to be of low quality.
Intravenous
Versus Oral Glucocorticoids Combined With Orbital Radiotherapy The IVGC+OR versus OGC+OR trial
provided low quality evidence which supported appreciable benefit of the
combination of IVGC and orbital radiotherapy.
The finding
was compatible with significantly increased chance of response for IVGC+OR,
suggesting that for patients receiving OGC+OR with approximately 63% response
rate, the response rate receiving IVGC+OR would be between 67.4% and 100%.
Participants receiving IVGC+OR achieved significantly more improvement and
higher decrease of CAS compared to participants receiving OGC+OR.
The included
trial had a high risk of bias in performance bias. The evidence of the effect
of between IVGC+OR and OGC+OR was double-downgraded to be of low quality.
Intravenous
Glucocorticoids Versus Rituximab The IVGC versus rituximab trial
provided moderate quality evidence which supported the use of rituximab for
moderate to severe and active GO. Participants using IVGC were significantly
less likely to achieve disease inactivation compared to participants using
rituximab, assuming approximately 100% inactivation rate of rituximab, the
anticipated inactivation rate of IVGC would only be between 50.0% and 98.0%.
Participants receiving IVGC achieved significantly less improvement and lower
decrease of CAS compared to participants receiving rituximab. However, participants
receiving IVGC were less likely to achieve adverse events compared to
participants receiving rituximab.
The included
trial had low risk of bias in the majority of domains, however, small sample
size was still one main limitation. The evidence of the effect of between IVGC
and rituximab was downgraded to be of moderate quality.
Intravenous
Glucocorticoids Versus Mycophenolate Mofetil The IVGC versus MMF trial provided
moderate quality evidence which supported the use of MMF for moderate-to-severe
and active GO.
Participants
using IVGC were significantly less response compared to participants using MMF,
assuming approximately 91% response rate of MMF, the anticipated response rate
of IVGC would only be between 57.3% and 80.1%. Participants receiving IVGC
achieved significantly less improvement and lower decrease of CAS compared to
participants receiving MMF. Otherwise, participants receiving IVGC were more
likely to achieve adverse events compared to participants receiving MMF. The
included trial had a high risk of bias in performance bias, and the evidence of
the effect of between IVGC and MMF was downgraded to be of moderate quality.
Intravenous
Glucocorticoids Versus Surgery The IVGC versus surgery trial
provided the evidence of very low quality which was insufficient to support the
use of either IVGC or orbital decompression as the first-line treatment of DON.
Assuming that approximately 17% of participants receiving surgical
decompression achieve visual improvement, the anticipated rate of visual
improvement using IVGC would be between 8.7% and 100%. Participants receiving
IVGC were more likely to achieve visual improvement compared to participants
receiving surgical decompression, but no significant difference was found.
The included
trial had a high risk of bias in performance bias and detection bias. A small
sample size was also the limitation. Therefore, the applicability of the
available trial data to clinical practice is still relatively limited.
Depending on
very serious imprecision and study limitations, the evidence of the effect of
between IVGC and surgery on visual improvement was downgraded to be of very low
quality.
Potential
Biases in the Review Process No obvious bias could be identified
from the review process. However, there are several limitations should be
discussed. First, the limitation is the potential of publication bias. It was
attempted to avoid the potential of publication bias by searching in multiple
databases. Unfortunately, it is possible that some papers might be missed,
especially those published in languages other than English. A second limitation
is different durations of the examination of the data across included studies.
Third, the criteria of “response” also differed among studies. Fourth, the
cumulative doses and protocols were different among the included studies, which
significantly influenced the efficacy and safety of IVGC[28, 29].
Agreements
and Disagreements with Other Studies or Reviews A previous systematic review
included 33 randomized clinical trials of all treatment modalities for GO[8]. Four trials compared OGC with IVGC, and the findings
suggested that in patients with moderate-to-severe GO, participants receiving
IVGC achieved significantly higher chance in the decrease of CAS compared to
participants receiving OGC (SMD -0.64, 95%CI -1.11 to -0.17, random effects
model), also less likely to achieve adverse events. However, the systematic
review did not assess methodological quality of the included studies.
A recently
systematic review of methylprednisolone pulse therapy for GO included eight
randomized clinical trials[10]. The study quality
was assessed by the Jadad scoring system (range from 1 to 5). A higher response
rate using IVGC was found than using placebo (RR 7.50, 95%CI 1.14 to 49.26) and
OGC (RR 1.48, 95%CI 1.18 to 1.86), and IVGC+OR was markedly more effective than
OGC+OR (RR 1.40, 95%CI 1.11 to 1.77). One trial (15 patients) compared IVGC
with surgery, with an RR of 3.33 (95%CI 0.51 to 21.89). Except for PubMed,
EMBASE, and CENTRAL, the systematic review also searched Chinese Biomedicine
Database, and one trial (75 participants) published in Chinese was included.
However, the “response” in the included trial was defined as an improvement in
diplopa, which was found in 60 participants at baseline.
The present
systematic review included nine randomized clinical trials of IVGC therapy for
GO. The Meta-analysis was performed using the standard methodological guidance
of Cochrane Handbook for Systematic Reviews of Interventions. There is currently
moderate quality evidence which is sufficient to support IVGC for
moderate-to-severe and active GO. In addition, low quality evidence supports
the effect of the combination of orbital radiotherapy with IVGC.
Currently in
the present systematic review, there is moderate quality evidence of to support
the appreciable benefit of rituximab, compared to IVGC. A prospective,
randomized, double-masked, placebo-controlled trial published recently[30], and the finding was compatible with no significant
difference in disease inactivation between rituximab and placebo (RR 1.50,
95%CI 0.60 to 3.74, P=0.38). However, depending on very serious
imprecision and high risk of bias (stopping early for benefit), the evidence of
rituximab versus placebo was downgraded to be of very low quality.
In
conclusion, currently evidence is sufficient to support IVGC for the treatment
of moderate-to-severe and active GO, compared to placebo (low quality) and OGC
(moderate quality). There is evidence of moderate quality to support the use of
rituximab or MMF, which might be a second-line treatment instead of IVGC. In
addition, there is low quality evidence to support orbital radiotherapy as the
combined therapy of IVGC. However, the evidence is very low quality which is
insufficient to support the use of either IVGC or orbital decompression as a
first-line treatment of DON.
Of note is
that the findings of the rituximab versus IVGC trial, which were compatible
with appreciable benefit of rituximab on disease inactivation, conflicted with
those of the rituximab versus placebo trial, which were compatible with no
significant difference between rituximab and placebo on disease inactivation.
Therefore, in order to draw more comprehensive conclusions, much more RCTs
should focus on the benefit and harms of rituximab for the treatment of GO,
compared to IVGC, measuring as the efficacy outcomes such as overall response
defined as an improvement in composite outcome, the improvement and change in
CAS , and adverse outcomes. In addition, it is needed to evaluate the balance
of benefit and harms of between IVGC and orbital decompression for the
treatment of DON.
ACKNOWLEDGEMENTS
Foundation: Supported by National Natural
Science Foundation of China (No.81170874).
Conflicts of
Interest: Zhao LQ, None; Yu DY, None; Cheng JW, None.
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