Fidelix Et Al-2014-Cochrane Database of Systematic Reviews

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Diacerein for osteoarthritis (Review)
Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V
Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V.

Diacerein for osteoarthritis.
Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD005117.
DOI: 10.1002/14651858.CD005117.pub3.
www.cochranelibrary.com

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 7
METHODS..................................................................................................................................................................................................... 7
RESULTS........................................................................................................................................................................................................ 10
Figure 1.................................................................................................................................................................................................. 11
Figure 2.................................................................................................................................................................................................. 13
Figure 3.................................................................................................................................................................................................. 14
DISCUSSION.................................................................................................................................................................................................. 18
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 19
ACKNOWLEDGEMENTS................................................................................................................................................................................ 20
REFERENCES................................................................................................................................................................................................ 21
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 24
DATA AND ANALYSES.................................................................................................................................................................................... 37
Analysis 1.1. Comparison 1 DIACEREIN VS PLACEBO, Outcome 1 Visual analogic Scale for Pain.................................................... 39
Analysis 1.2. Comparison 1 DIACEREIN VS PLACEBO, Outcome 2 Lequesne Impairment Index...................................................... 39
Analysis 1.3. Comparison 1 DIACEREIN VS PLACEBO, Outcome 3 WOMAC total............................................................................... 40
Analysis 1.4. Comparison 1 DIACEREIN VS PLACEBO, Outcome 4 WOMAC subscore (Pain)............................................................. 41
Analysis 1.5. Comparison 1 DIACEREIN VS PLACEBO, Outcome 5 WOMAC subscore (stiffness)....................................................... 41
Analysis 1.6. Comparison 1 DIACEREIN VS PLACEBO, Outcome 6 WOMAC subscore (Physical Function)........................................ 42
Analysis 1.7. Comparison 1 DIACEREIN VS PLACEBO, Outcome 7 Radiographic Progression.......................................................... 42
Analysis 1.8. Comparison 1 DIACEREIN VS PLACEBO, Outcome 8 Adverse Effects........................................................................... 43
Analysis 1.9. Comparison 1 DIACEREIN VS PLACEBO, Outcome 9 Drop Out..................................................................................... 44
Analysis 2.1. Comparison 2 DIACEREIN VS NSAIDs, Outcome 1 WOMAC subscore (Physical Function)........................................... 45
Analysis 2.2. Comparison 2 DIACEREIN VS NSAIDs, Outcome 2 Quality of Life................................................................................. 45
Analysis 2.3. Comparison 2 DIACEREIN VS NSAIDs, Outcome 3 Adverse Effects............................................................................... 46
Analysis 2.4. Comparison 2 DIACEREIN VS NSAIDs, Outcome 4 Drop Out......................................................................................... 46
Analysis 2.5. Comparison 2 DIACEREIN VS NSAIDs, Outcome 5 Pain VAS 0 to 100............................................................................ 47
Analysis 2.6. Comparison 2 DIACEREIN VS NSAIDs, Outcome 6 Womac Pain.................................................................................... 47
Analysis 2.7. Comparison 2 DIACEREIN VS NSAIDs, Outcome 7 Pain on walking 20 m..................................................................... 47
Analysis 3.1. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA), Outcome 1 Visual 48
analogue scale for pain........................................................................................................................................................................
Analysis 3.2. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA), Outcome 2 Lequesne 49
Impairment Index..................................................................................................................................................................................
Analysis 3.3. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA), Outcome 3 49
Radiographic progression.....................................................................................................................................................................
Analysis 3.4. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA), Outcome 4 Adverse 50
effects.....................................................................................................................................................................................................
Analysis 3.5. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA), Outcome 5 Dropout..... 51
Analysis 4.1. Comparison 4 Diacerein versus Placebo/ Sensitivity, Outcome 1 Pain on VAS (0 to 100 mm).................................... 51
Analysis 5.1. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 1 Pain on VAS 0 to 100 mm....................................... 52
Analysis 5.2. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 2 WOMAC A (Pain)..................................................... 53
Analysis 5.3. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 3 WOMAC B (Stiffness)............................................... 53
Analysis 5.4. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 4 WOMAC C (Physical function)................................ 53
APPENDICES................................................................................................................................................................................................. 53
WHAT'S NEW................................................................................................................................................................................................. 55
HISTORY........................................................................................................................................................................................................ 55
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 55
DECLARATIONS OF INTEREST..................................................................................................................................................................... 55
Diacerein for osteoarthritis (Review) i
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SOURCES OF SUPPORT............................................................................................................................................................................... 55
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 56
INDEX TERMS............................................................................................................................................................................................... 56
Diacerein for osteoarthritis (Review) ii

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[Intervention Review]
Diacerein for osteoarthritis
Tania S.A. Fidelix1, Cristiane R Macedo2, Lara J Maxwell3, Virginia Fernandes Moça Trevisani4
1Internal Medicine and Therapeutic, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Bernardo, Brazil. 2Brazilian
Cochrane Centre, Centro de Estudos de Medicina Baseada em Evidências e Avaliação Tecnológica em Saúde, São Paulo, Brazil.
3Centre for Global Health, Institute of Population Health, University of Ottawa, Ottawa, Canada. 4Rheumatology/Internal Medicine and
Therapeutics, Universidade Federal de São Paulo, São Paulo, Brazil
Contact address: Tania S.A. Fidelix, Internal Medicine and Therapeutic, Escola Paulista de Medicina, Universidade Federal de São Paulo,
Rua Mediterraneo, 290 sl 13, São Bernardo, São Paulo, 09750 420, Brazil. [email protected].
Editorial group: Cochrane Musculoskeletal Group

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 2, 2014.
Citation: Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V. Diacerein for osteoarthritis. Cochrane Database of Systematic
Reviews 2014, Issue 2. Art. No.: CD005117. DOI: 10.1002/14651858.CD005117.pub3.
ABSTRACT
Background
Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases. There is currently no consensus on what is the best treatment to
improve OA symptoms and slow disease progression. Diacerein is an anthraquinone synthesised in 1980 that interferes with interleukin-1,
an inflammatory mediator. It has been proposed that diacerein acts as a slow-acting, symptom-modifying and perhaps disease-structure-
modifying drug for OA. This is an update of a Cochrane review first published in 2006.
Objectives
To assess the benefits and harms of diacerein for the treatment of adults with OA when compared with placebo and other
pharmacologically active interventions (nonsteroidal anti-inflammatory drugs (NSAIDs) and other symptom-modifying, slow-acting drugs)
for OA.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library, Issue 10, 2013, MEDLINE (1966 to 2013),
EMBASE (1980 to 2013), LILACS (1982 to 2013), and ACP Journal Club, and we handsearched reference lists of published articles. We also
searched the World Health Organization International Clinical Trials Platform ( http://www.who.int/trialsearch/Default.aspx) to identify
ongoing trials and screened reference lists of retrieved review articles and trials to identify potentially relevant studies. All searches were
up to date as of March 2013. Pharmaceutical companies and authors of published articles were contacted. We searched the websites of
the regulatory agencies using the keyword ‘diacerein’ in November 2013. No language restrictions were applied.
Selection criteria
Studies were included if they were randomised or quasi-randomised controlled trials that compared diacerein with placebo or another
active pharmacological intervention in participants with OA.
Data collection and analysis

Data abstraction and quality assessment were performed by two independent investigators, and their results were compared. The
Cochrane risk of bias tool was used. The quality of evidence obtained was assessed using the GRADE approach.
Diacerein for osteoarthritis (Review) 1

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Main results
We identified three new trials (141 participants), and this updated review now includes 10 trials, totalling 2,210 participants. The most
frequent risk of bias was incomplete outcome data, identified in approximately 80% of the studies. Allocation concealment and random
sequence generation were unclear in 90% and 40% of the studies, respectively, because of poor reporting.
Low-quality evidence from six trials (1,283 participants) indicates that diacerein has a small beneficial effect on overall pain (measured on
a 100 mm visual analogue scale) at three to 36 months (mean difference (MD) -8.65, 95% confidence interval (CI) -15.62 to -1.68), which
is equivalent to a 9% pain reduction in the diacerein group (95% CI -16% to -2%) compared with the placebo group. This benefit may not
be clinically significant.
No statistically significant differences in physical function (4 studies, 1006 participants) were noted between the diacerein and placebo
groups (Lequesne impairment index, 0 to 24 points) (MD -0.29, 95% CI -0.87 to 0.28).
Low-quality evidence from two trials (616 participants) on slowing of joint space narrowing (a decrease greater than 0.50 mm) in the knee
or hip favoured diacerein over placebo (risk ratio (RR) 0.85, 95% CI 0.72 to 0.99), with an absolute risk difference of -6% (95% CI -15% to
2%) and a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 8 to 203). Analysis of the knee joint alone (1
study, 170 participants) did not reach statistical significance (RR 0.94, 95% CI 0.51 to 1.74).
None of the trials of diacerein versus placebo measured quality of life. According to one trial (161 participants), which compared diacerein
versus non-steroidal anti-inflammatory drugs (NSAIDs), the quality of life of participants in the two groups (as assessed by the Short Form
(SF)-36 health survey questionnaire (0 to 800 sum score)) did not differ significantly (MD -40.70, 95% CI -85.20 to 3.80).
Low-quality evidence from seven trials showed significantly more adverse events in the diacerein group compared with the placebo group
after two to 36 months, mainly diarrhoea (RR 3.52, 95% CI 2.42 to 5.11), with an absolute risk increase of 24% (95% CI 12% to 35%), and a
number needed to treat for an additional harmful outcome (NNTH) of 4 (95% CI 3 to 7).
No statistically significant differences in participant withdrawal due to adverse events were seen at two to 36 months for diacerein
compared with placebo (RR 1.29, 95% CI 0.83 to 2.01).
A search of regulatory websites found a recommendation from the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment
Committee (PRAC) that the marketing authorization of diacerein should be suspended across Europe because of harms (particularly the
risk of severe diarrhoea and potentially harmful effects on the liver) outweighing benefits. However, this guidance is not final as the PRAC
recommendation will be re-examined.
Authors' conclusions
In this update, the strength of evidence for effectiveness outcomes was low to moderate. We confirmed that symptomatic benefit provided
by diacerein in terms of pain reduction is minimal. The small benefit derived in terms of joint space narrowing is of questionable clinical
relevance and was observed only for OA of the hip. With respect to adverse effects of diacerein, diarrhoea was most frequent. Given the
recent guidance issued by the EMA recommending suspension of diacerein in Europe, the EMA website should be consulted for further
recommendations regarding the use of diacerein.
PLAIN LANGUAGE SUMMARY
Diacerein for osteoarthritis
What is osteoarthritis and what is diacerein?
Osteoarthritis (OA) is the most common form of arthritis. In OA, the cartilage that protects the ends of the bones breaks down, causing
pain and swelling. OA can affect any joint, but the knees, hips and hands are the joints most often studied in clinical trials. In all, 10% of
the world’s population aged 60 or older have pain or disability from OA.
Diacerein is a slow-acting drug taken as a pill that may slow the breakdown of cartilage and relieve pain and swelling.
The review searched for studies up to March 2013 about primary osteoarthritis affecting men and women (18 years and older) of any disease
severity.
The review shows that in people with osteoarthitis:
- Pain may improve slightly more in people taking diacerein.
- Improvement in physical function is about the same for people taking diacerein,- or a placebo (fake pill). This may have happened by
chance.

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- Diacerein may slow the process of joint space narrowing slightly of the hip but may have little or no difference on the knee joint as it is
seen on an x-ray.
- Diacerein may cause side effects in the lower digestive tract, such as diarrhoea.
Further research is very likely to have an important impact on our confidence in these findings and is likely to change the estimates.
Best estimate of what happens to people with osteoarthritis who take diacerein
Pain after three to 36 months
- People who took diacerein rated their pain to be 9 points lower on a scale of 0 (no pain) to 100 (extreme pain) after taking the medication
for three to 36 months (9% absolute improvement).
- People who took diacerein rated their pain to be 34 on a scale of 0 to 100 after taking the medication compared to people who took a fake
pill and rated their pain to be 43 points on a scale of 0 to 100.
Physical function after two to 36 months (lower score means worse function)
- People who took diacerein rated their physical function to be 0.30 points lower on a scale of 0 to 24 after taking the medication for two
to 36 months (0% absolute improvement).
- People who took diacerein rated their physical function to be 9.3 on a scale of 0 to 24 after taking the medication compared to people
who took a fake pill and rated their physical function to be 9 points on a scale of 0 to 24.
Radiographic progression - how the joint looks on an x-ray (reduction in joint space narrowing of at least 0.5 mm)
- Seven more people who took placebo had radiographic progression (absolute difference of 7%).
- 42 of every 100 people who took diacerein experienced reduction in joint space narrowing of at least 0.5 mm compared to 49 of every
100 people who took a fake pill.
Quality of life
- The review authors found no studies about quality of life of people who took diacerein compared with placebo.
- There was no difference in quality of life of people who took diacerein compared with non-steroidal anti-inflammatory drugs (NSAIDs).
This may have happened by chance.
Side effects
- Twenty-six more people who took diacerein experienced diarrhoea as a side effect (absolute difference of 26%).
- 36 of every 100 people who took diacerein experienced diarrhoea as a side effect compared to 10 of every 100 who took a fake pill.
Diarrhoea was the most common side effect and usually occurred during the first two weeks after the start of diacerein.
People who took diacerein were not more likely than people who took a placebo to stop taking the medication because of side effects.
In November 2013, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) recommended that the
marketing authorisation of diacerein should be suspended across Europe because of harms outweighing benefits. However, this guidance
is not final as the PRAC recommendation will be re-examined.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Diacerein compared with placebo for osteoarthritis
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Diacerein compared to placebo for osteoarthritis
Patient or population: participants with osteoarthritis

Settings: outpatient
Intervention: diacerein
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Comparison: placebo
Outcomes Illustrative comparative risks* (95% CI) Relative ef- No of partici- Quality of the Comments
fect pants evidence
Assumed risk Corresponding risk (95% CI) (studies) (GRADE)
Placebo Diacerein
Pain overall visual analogue scale Mean pain overall Mean pain overall visual 1,283 ⊕⊕⊕⊝ NNTB 6 (4 to 30)5
for pain visual analogue analogue scale for pain in (six studies) low1,2
Scale from: 0 to 100 scale for pain in the intervention groups was Absolute risk difference
Follow-up: three to 36 months control groups 8.65 points lower -9% (-16% to -2%)
was (15.62 to 1.68 lower)
43 mm Relative percentage
change -19% (-34% to
-4%)
Physical function—Lequesne Impair- Mean physi- Mean physical function— 1,006 ⊕⊕⊕⊝ NNTB: non–statistical-
ment Index cal function— Lequesne Impairment Index (four studies) moderate2 ly significant5 Absolute
Scale from: 0 to 24 Lequesne Impair- in intervention groups was risk difference 0% (-4%
Follow-up: two to 36 months ment Index in 0.29 points lower to 1%)
control groups (0.87 lower to 0.28 higher)
was Relative percentage
9 points change -4% (-11% to

4%)
Radiographic progression—mini- 494 per 1000 420 per 1000 RR 0.85 616 ⊕⊕⊝⊝ NNTB 14 (8 to 203)5
mum joint space width (355 to 489) (0.72 to 0.99) (two studies) low2,3
Absolute risk difference
(decreased over 0.50 mm during the -6% (-15% to 2%)
study period)
Relative percentage
Follow-up: 12 to 36 months change -15% (-28% to
-1%)
4

Quality of Life not measured See comment See comment Not estimable - See comment This outcome was not
measured.6
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Adverse event: diarrhoea 102 per 1000 359 per 1000 RR 3.52 1.462 ⊕⊕⊕⊝ NNTH 4 (7 to 3)7
Follow-up: two to 36 months (247 to 521) (2.42 to 5.11) (seven stud- low2,4
ies) Absolute risk difference
24% (12% to 35%)
Relative percentage
change 252% (142% to
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411%)
Withdrawal due to adverse events 118 per 1000 153 per 1000 RR 1.29 1,476 ⊕⊕⊝⊝ NNTH: non–statistically
Follow-up: two to 36 months (98 to 238) (0.83 to 2.01) (seven stud- low3,4 significant7
ies)
Absolute risk difference
0% (-3% to 4%)
Relative percentage
change 0% (-29% to
41%)
Total number of serious adverse See comment See comment Not estimable - See comment This outcome was not
events not measured measured in any of our
studies8
*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; RR: Risk ratio.
GRADE Working Group grades of evidence.

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.
1High heterogeneity (I2 = 84%). Reduction of heterogeneity could be explained by post hoc sensitivity analysis between studies, with follow-up lasting longer than six months.
2No allocation concealment in most studies.
3Total number of events is less than 300.
4Unexplained heterogeneity.
5NNTB: number needed to treat for an additional beneficial outcome.
6One study compared diacerein versus non-steroidal anti-inflammatory drugs (NSAIDs) and there was no difference in the quality of life of participants in the two groups (MD
-40.70, 95% CI -85.20 to 3.80).
7NNTH: number needed to treat for an additional harmful outcome.
5

8Although diacerein is known to cause diarrhoea as a side effect, the PRAC (http://www.ema.europa.eu) on 8 November 2013, concluded that there was a high number of cases,
particularly of severe diarrhoea, which sometimes led to complications. The Committee was also concerned about liver problems that had been reported in some patients taking
the medicine.
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BACKGROUND cartilage-degrading enzymes. In addition, cytokines can be

produced by synovial tissue cells and subchondral osteoblasts.
Description of the condition IL-1beta and tumour necrosis factor (TNF)-alfa are key cytokines in
the catabolic process of cartilage (Berembaum 2010).
Osteoarthritis (OA) is the most prevalent musculoskeletal disease
(ACR 2000; Picavet 2003). The World Health Organization (WHO) In vitro and in vivo studies have demonstrated that diacerein
Scientific Group on Rheumatic Diseases estimates that 10% of acts not only on cartilage but in all tissues involved in
the world’s population aged 60 or older have significant clinical the pathogenesis of OA, including synoviocytes, the synovial
problems attributed to OA (Woolf 2003). As the incidence and membrane, subchondral bone and chondrocytes. Besides its
prevalence of OA increase with age, the increase in life expectancy inhibitory effects on IL-1, diacerein reduces other important
will result in an increase in OA in the future (Sun 2007; Woolf 2003), mediators such as metalloproteinases, nitric oxide, ADAMTS (a
making this disease an ever growing public health problem. More disintegrin and metalloproteinase with thrombospondin motifs)-4
than 10% of the US adult population had clinical OA in 2005, and and ADAMTS-5 (Pelletier 2010).
in 2009, OA was the fourth most common cause of hospitalisation.
OA is the leading indication for joint replacement surgery; 905,000 Why it is important to do this review
knee and hip replacements were performed in 2009 at a cost of
$42.3 billion (Murphy 2012). Obesity is a strong risk factor for OA of Currently, clinical management of OA typically entails a
the knee and hip (Murphy 2012). combination of treatment options to reduce pain and improve
tolerance to functional activity. Existing pharmacological therapies
OA remains an enigmatic disease. It is defined as a condition for OA help to reduce symptoms but are only moderately effective
characterised by focal areas of loss of articular cartilage and leave patients with substantial pain and functional burden
within the synovial joints, associated with hypertrophy of (Hunter 2011).
the bone (osteophytes and subchondral bone sclerosis) and
thickening of the capsule (Lawrence 1998; Zhang 2001). Recently, Starting in 1982 (Lingetti 1982), several trials tested diacerein
OA has been relabeled as a whole organ disease because for the treatment of OA, and since 1994, the drug has been
pathological abnormalities such as periarticular muscle weakness, marketed around the world, except in the United States of America.
lax ligaments, low-grade synovitis, meniscal degeneration and Based on the findings of several studies, it has been proposed
neurosensory system alteration are often present in these patients that diacerein is a slow-acting, symptom-modifying and perhaps
(Bijlsma 2012). disease/structure-modifying drug for OA. However, the importance
of diacerein as an option for the treatment of OA needs to
Description of the intervention be clarified. Despite the long time elapsed since its discovery,
published studies have not defined a clear place for the use of
Treatments for OA include pharmacological and non- diacerein in the treatment of this disease as a symptom modifier or
pharmacological therapies and surgical procedures. as a disease-modifying agent that could retard the loss of cartilage.
Pharmacological therapies consist of topical agents, oral (systemic)
agents, adjunct therapies and nutraceuticals (Bellamy 2006; We performed a review of these studies to gather up-to-date
Towheed 2006; Towheed 2008). evidence to clarify the role of diacerein in the treatment of OA.
Although some drugs and/or compounds have been available for OBJECTIVES
several decades and are integrated as standard practice in many
countries, their efficacy has been demonstrated only over the past To assess the benefits and harms of diacerein for the
decade. Revision of drug registries by health authorities in various treatment of adults with OA when compared with placebo and
European countries in the 1990s led to appropriate clinical trials other pharmacologically active interventions (nonsteroidal anti-
for available drugs (such as avocado extract), as well as drugs inflammatory drugs (NSAIDs) and other symptom-modifying, slow-
in development at that time (such as diacerein). This action of acting drugs) for OA.
health authorities greatly improved knowledge regarding the level
of evidence and characteristic treatment effects of these drugs METHODS
(onset of action, carry-over effect) (Hochberg 2001).
Criteria for considering studies for this review
Current therapies for OA, including non-steroidal anti-
Types of studies
inflammatory drugs (NSAIDs), although effective against symptoms
of the disease, are palliative and do not stop disease progression. Studies with the following characteristics were eligible for inclusion
However, promising agents and compounds have been shown to in the review.
reduce the severity of the disease, as well as the symptoms. Among
them is diacerein, an oral interleukin (IL)-1beta inhibitor. Its active 1. Randomised controlled trials (RCTs) evaluating the benefits and
derivative, rhein, is an anthraquinone found in plants of the genus harms of diacerein for OA.
Cassia. It has moderate anti-inflammatory and analgesic activities 2. Both placebo-based and comparative studies were eligible.
(Spencer 1997).
Types of participants
How the intervention might work All adults (age 18 years and older) with a diagnosis of primary OA at
Although OA is considered a non-inflammatory disease, numerous any site, including the axial and peripheral skeleton, who fulfilled
studies have shown that inflammatory cytokines provide essential the American College of Rheumatology (ACR) criteria (Altman 1986;
biochemical signals that simulate chondrocytes to release Altman 1990) were eligible for inclusion. Primary OA is any OA for

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which a definite etiology (cause) is not found. Secondary OA is 2. Walking disability.

diagnosed when a specific cause for the disease can be identified, 3. WOMAC disability subscore.
such as trauma or hypermobility; this type of OA was not included 4. Composite disability scores other than WOMAC.
in this review.
5. Disability other than walking.
Types of interventions 6. WOMAC global scale.
Studies evaluating benefits and/or harms of diacerein compared 7. Lequesne Osteoarthritis Index global score.
with: 8. Other algofunctional scale.
1. placebo; and 3. Radiographic joint structure changes.

2. other active treatments (non-steroidal anti-inflammatory drugs Radiographic progression of OA in studies lasting longer than one
or other slow-acting arthritis drugs). year include the following.
Types of outcome measures 1. Minimum joint space width.
Seven important outcomes were selected for reporting. 2. Median joint space width.
3. Semi-quantitative measurement.
1. For benefit, the outcomes were (1) pain, (2) physical function, (3)
radiographic joint structure changes and (4) quality of life. 4. Quality of life.
2. For safety, the outcomes were (5) number of participants
experiencing any adverse event, (6) number of participants Quality of life data were extracted from the following instruments.
who withdrew because of adverse events and (7) number of
participants experiencing any serious adverse event. 1. Short Form (SF)-12.
2. Short Form (SF)-36.
Benefits
Safety
1. Pain.
The toxicity of diacerein was also considered a relevant outcome
The measure of effectiveness was pain relief. To assess this outcome and was measured by the following.
in accordance with the latest review of the OMERACT (international
initiative to improve outcome measurement in rheumatology)-3 5. Number of participants experiencing any adverse event.
(Bellamy 1997), the OMERACT-6 (Pham 2003) recommends the use
of standardised, validated instruments such as visual analogue 6. Number of participants who withdrew because of adverse
scales (VASs) (Carlsson 1983), the Lequesne Functional Severity events.
Index (Lequesne 1987) or the pain scales included in the Western 7. Number of participants experiencing any serious adverse
Ontario and McMaster Universities Osteoarthritis Index (WOMAC) event.
(Bellamy 1988).
Search methods for identification of studies
If data on more than one pain scale were provided for a trial, data
were extracted on the pain scale that is highest in the following For identification of relevant studies, detailed search strategies
list, according to a previously described hierarchy of pain related were developed for each specific database to be searched.
outcomes. These strategies were based on the search strategy developed
for MEDLINE (OVID) (Appendix 1) and revised appropriately for
1. Pain overall. each database. The following databases were searched: Cochrane
2. Pain on walking. Central Register of Controlled Trials (CENTRAL, The Cochrane
3. WOMAC pain subscale. Library, Issue 3, 2013) (Appendix 2), MEDLINE (1966 to March 2013),
4. Pain on activities other than walking. EMBASE (1980 to March 2013) (Appendix 3), ACP Journal Club (1991
to 2013) (Appendix 2), LILACS (1982 to March 2013) (Appendix 4) and
5. WOMAC global scale.
International Clinical Trials Register (World Health Organization,
6. Lequesne Osteoarthritis Index global score. March 2013) (Appendix 5).
7. Other algofunctional scale.
8. Patient’s global assessment. The reference lists of all identified citations were manually
searched. In addition, letters were sent to study authors and to
9. Physician’s global assessment.
content experts to ask for assistance in retrieving additional RCTs,
10.Other outcome. especially those that were unpublished. The manufacturers of
11.No continuous outcome reported. diacerein (Negma-Lerads and TRB-Pharma) were contacted for
additional trials. For this version of the Cochrane Review, the search
2. Physical function. was updated to March 2013.
If data on more than one physical function scale were provided for For safety assessments, we searched the websites of the regulatory
a trial, data were extracted according to the hierarchy presented in agencies (US Food and Drug Administration-MedWatch (http://
the following list. www.fda.gov/Safety/MedWatch/default.htm) , European Medicines
1. Global disability score. Evaluation Agency (http://www.ema.europa.eu), Australian
Adverse Drug Reactions Bulletin (http://www.tga.gov.au/safety/
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ews-monitoring.htm), and UK Medicines and Healthcare products included each group of participants only once in the meta-analysis,
Regulatory Agency (MHRA) pharmacovigilance and drug safety in accordance with the procedure recommended in the Cochrane
updates (http://www.mhra.gov.uk/Safetyinformation/index.htm) Handbook for Systematic Reviews of Interventions (Higgins 2011).
using the keyword ‘diacerein’ on 26 November 2013.
Dealing with missing data
No language or date of publication restrictions were applied.
As far as possible, data were analysed on an intention-to-treat
Data collection and analysis (ITT) basis, and attempts were made to obtain missing data from
the original trial lists. When some data were unavailable, only the
Selection of studies available data were analysed.
Two review authors (TSAF and CRM) independently reviewed the For dichotomous outcomes that measured adverse events (e.g.
references identified through the search strategy and selected number of withdrawals due to adverse events), the withdrawal
those that fulfilled the selection criteria. Differences regarding rate was calculated using the number of participants who
selection were solved by a third review author (VFMT). received treatment as the denominator (worst-case analysis). For
dichotomous outcomes that measured benefits, the worst-case
Data extraction and management
analysis was calculated using the number of randomly assigned
Two review authors (TSFA and CRM) independently extracted data participants as the denominator. For continuous outcomes (e.g.
from eligible studies. Review authors were not masked to report pain), we calculated mean difference (MD) or the SMD using the
authors, journals, dates of publication, sources of financial support number of participants analysed at the time point. If the number
or results. Any disagreements were resolved through discussion of participants analysed was not presented for each time point,
with or by seeking the opinion of a third review author (VFMT). the number of randomly assigned participants in each group at
Data extracted included study characteristics and outcome data. baseline was used.
For studies with more than one publication, the main trial report
was used as the reference, and additional details were derived from When possible, missing standard deviations were computed
secondary papers. from other statistics such as standard errors. CIs or P values
were calculated according to the methods recommended in the
Assessment of risk of bias in included studies Cochrane Handbook for Systematic Reviews of Interventions (Higgins
2011). If it was not possible to calculate standard deviations, we
This updated version of the review assessed independently and
imputed them, for example, from other studies in the meta-analysis
in duplicate the risk of bias in included studies using the risk of
(Higgins 2011).
bias tool described in Chapter 8 of the Cochrane Handbook for
Systematic Reviews of interventions, version 5.1.0 (Higgins 2011). Assessment of heterogeneity
The domains investigated included the following.
Heterogeneity was measured by Tau2 and I2 and by calculating a
1. Sequence generation. Chi2 test with P < 0.10 considered significant. The I2 cutoff point for
2. Allocation concealment. considering substantive heterogeneity is 50% (Higgins 2003).
3. Blinding of participants.
Assessment of reporting biases
4. Blinding of outcome assessment.
5. Incomplete outcome data addressed. In future updates, if sufficient numbers of studies (more than 10)
6. Selective outcome reporting. are eligible for inclusion, a funnel plot (Egger 1997) will be used to
assess publication bias.
Each domain was classified as having 'low risk of bias', 'high risk of
bias' or 'unclear risk of bias'. Data synthesis
For clinically homogeneous studies, we pooled outcomes in a meta-
Measures of treatment effect analysis using the random-effects model as a default.
For dichotomous outcomes, results were expressed as a risk ratio
(RR), that is, the proportion of events in the treatment group in Subgroup analysis and investigation of heterogeneity
relation to the proportion of events in the control group, with When possible, subgroup analysis was done as follows: different
95% confidence intervals (95% CIs). When overall results were doses of diacerein, hip OA versus knee OA versus spine OA versus
significant, the number needed to treat for an additional beneficial hand OA and different functional classes of OA. Studies analysing
outcome (NNTB) was calculated. The NNTB is the number of knee and hip OA were separated to assess whether results changed
participants who need to be treated with the intervention to in the meta-analysis graphics (subgroup analyses). In this update,
prevent one event. The NNTB was also calculated for radiographic subgroup analyses for spine versus hand OA and for different
progression. Continuous outcomes were analysed according to functional classes of OA were not performed because RCTs included
standardised mean differences (SMDs), using an inverse variance in this review did not provide these data.
with random approach.
Sensitivity analysis
Unit of analysis issues
Sensitivity analysis was carried out to explore heterogeneity.
The unit of analysis was the participant. For studies containing Studies of longer than six months' duration were pooled together
more than two intervention groups, to make multiple pair-wise to explore effect size differences and robustness of the results.
comparisons between all possible pairs of intervention groups, we Sensitivity analysis according to length of follow-up was not

Informed decisions.

included in the original protocol because it was decided post hoc 4. Imprecision of results (wide confidence intervals).
that this would be performed. 5. High probability of publication bias.
In future updates, if sufficient studies are eligible, other sensitivity Summary of findings tables
analyses could be carried out. Heterogeneity in the results of the
meta-analysis should be assessed both by inspecting graphical The summary of findings tables present the main findings in this
presentations (funnel plot) (Egger 1997) if more than 10 studies updated review. They provide key information concerning quality
are included and by calculating a Chi2 test with P values < of the evidence, magnitude of effect of the interventions examined
0.1 considered as significant. In future updates of this review, and the sum of available data on the main outcomes. Seven
differences in populations, interventions and assessments of important outcomes were included in the summary of findings
outcomes could be explored in analyses of heterogeneity. tables.
Grading of Evidence 1. Pain.

2. Physical function.
The Cochrane Collaboration has adopted the principles of the
3. Radiographic joint structure changes.
GRADE approach for evaluating the quality of evidence for
outcomes reported in systematic reviews (Grade 2008). The GRADE 4. Quality of life.
approach specifies four levels of quality. The highest quality 5. Number of participants experiencing any adverse event.
rating is for randomised trial evidence. However, review authors 6. Number of participants who withdrew because of adverse
can downgrade randomised trial evidence to moderate, low or events.
even very low quality evidence, depending on the presence of 7. Number of participants experiencing any serious adverse event.
the five factors. Usually, quality ratings will fall by one level for
each factor, up to a maximum of three levels for all factors. If RESULTS
very severe problems are noted for any one factor (e.g. when
assessing limitations in design and implementation, all studies Description of studies
were unconcealed, were unblinded and lost more than 50% of their
Results of the search
participants to follow-up), randomised trial evidence may fall by
two levels because of that factor alone. The search retrieved 324 (25 Cochrane Central Register of
Controlled Trials (CENTRAL, The Cochrane Library, Issue 10, 2013),
These five factors that constitute the GRADE approach include the 184 MEDLINE, 90 EMBASE, 24 LILACS, 1 ACP Journal) references,
following. and nine additional reports were obtained through other sources
(eight reference lists and one abstract from a conference meeting),
1. Limitation in the design or implementation of available studies,
which after de-duplication resulted in 272 citations. After the titles
suggesting high level of bias.
and abstracts of these references were screened, 40 full-text articles
2. Indirecteness of evidence (indirect population, intervention, were selected; 30 of these studies were excluded, and 10 fulfilled
control and outcomes). the selection criteria. Three new studies were included in this
3. Unexplained heterogeneity or inconsistency of results (including updated version of the 2006 systematic review. See the study flow
problems with subgroup analysis). diagram for further details (Figure 1).


Informed decisions.

Figure 1. Study flow diagram.


Informed decisions.

Figure 1. (Continued)

Included studies Five trials analysed treatment carry-over effect (Brahmachari 2009;
Lequesne 1998; Louthrenoo 2007; Pavelka 2007; Zheng 2006) for
The 10 identified studies are listed in the Characteristics of
up to two months after cessation of the intervention. The carry-
included studies table. Years of publication ranged from 1994
over effect refers to the remaining effect of the drug after its
to 2009. All were double-blinded, randomised, parallel-group
discontinuation.
trials and included a total of 2,210 adults with a mean age of
59.69 (± 8.90) years. A total of 996 participants were randomly Good overall agreement was reached between two investigators
assigned to treatment with diacerein, and 1,214 were randomly (TSAF and CRM) regarding data extracted from the 10 RCTs.
assigned to one of the comparator groups (NSAIDs or placebo Consensus was reached for all discrepancies.
or other symptom-modifying, slow-acting drugs for OA). These
studies were performed in France (Chantre 2000; Dougados 2001; Excluded studies
Lequesne 1998; Nguyen 1994; Pham 2004), the UK (Pham 2004),
A total of 30 studies were excluded for the following reasons:
Canada (Pelletier 2000), Israel (Pelletier 2000), China (Zheng
inadequate study design for this review (Adami 1985; Bogliola 1991;
2006), the Czech Republic (Pavelka 2007), Thailand (Louthrenoo
Carrabba 1987; Delcambre 1994; Fagnani 1998; Kay 1980; Linguetti
2007) and India (Brahmachari 2009). Seven of the ten studies
1982; Mantia 1987; Marcolongo 1988; Mathieu 1999; Mazzaro 1989;
compared diacerein with placebo (Brahmachari 2009; Dougados
Renapurkar 2010; Sharma 2008), duplicate publication (Delcambre
2001; Lequesne 1998; Nguyen 1994; Pavelka 2007; Pelletier 2000;
1996; Leblan 2000; Tang 2004; Valat 1997), incomplete data
Pham 2004 ), two compared diacerein with other symptom-
and unsuccessful personal contact with authors (Ascherl 1994;
modifying, slow-acting drugs for OA—Harpadol and the hyaluronic
Fioravanti 1985; Mattara 1985; Mordini 1986; Pietrogrande 1985;
acid compound NRD101 (Chantre 2000; Pham 2004) and three
Portioli 1987; Schulitz 1994; Seisenbayev 2012) and inappropriate
compared diacerein with NSAIDs: tenoxicam (Nguyen 1994),
inclusion criteria (Baliga 2010; Singh 2012). The studies Vignon
diclofenac (Zheng 2006) and piroxicam (Louthrenoo 2007).
2002, Villani 1998 and Villermay 1994 are not clinical trials. Reasons
Only knee or hip OA was evaluated in the 10 included studies. for exclusion are listed in the Characteristics of excluded studies
None of the studies evaluated OA in other segments such as table.
hands or spine. In two studies, only the hip joint was evaluated
One study (Shin 2013) is awaiting classification depending on the
(Dougados 2001; Nguyen 1994). The knee was evaluated in six RCTs
response of the study authors regarding information necessary to
(Brahmachari 2009; Louthrenoo 2007; Pavelka 2007; Pelletier 2000;
the process of inclusion.
Pham 2004; Zheng 2006), and two RCTs (Chantre 2000; Lequesne
1998) assessed both knee and hip joints.
Risk of bias in included studies
Participants with primary OA were evaluated in all studies, and Pre randomisation inclusion and exclusion criteria were provided
radiographs of the target joint were obtained in nine of the ten by all 10 RCTs. Study authors and pharmaceutical companies were
studies. In all included studies, the diagnosis of OA was based on contacted to provide data.
valid clinical and radiographic findings in accordance with the ACR
criteria; one study also included the Lequesne criteria (Lequesne The most frequent risk of bias was incomplete outcome data,
1998). The Kellgren and Lawrence radiographic gradation of OA was identified in approximately 80% of the studies, followed by lack of
used to evaluate the radiographic diagnosis of OA (Kellgren 1957). blinding of clinical outcome assessment in about 20% and selective
reporting in 10% of the studies. Almost all (90%) studies did not
Duration of the studies ranged from two months to three years. provide details on allocation concealment (unclear).
Six studies (Brahmachari 2009; Chantre 2000; Dougados 2001;
Louthrenoo 2007; Nguyen 1994; Pelletier 2000) mentioned the Approximately 40% of the included studies were unclear about
duration of disease, and the mean was 4.69 years. The number random sequence generation. See the risk of bias graph and the risk
of participants randomly assigned ranged from 64 (Brahmachari of bias summary for additional details (Figure 2; Figure 3).
2009) to 521 (Dougados 2001), and the number of dropouts in the
diacerein groups ranged from three of 86 (Louthrenoo 2007) to 65
of 262 (Dougados 2001).


Informed decisions.

Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.


Informed decisions.

Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.


Informed decisions.

Figure 3. (Continued)

Allocation Incomplete outcome data
Allocation sequences were adequately described with low risk of Two studies (Chantre 2000; Nguyen 1994) were classified as having
bias in six studies (Brahmachari 2009; Dougados 2001; Louthrenoo low risk of bias on this item because all randomly assigned
2007; Pavelka 2007; Pelletier 2000; Pham 2004). Three studies used participants were included in the ITT analyses.
computer-generated number lists as their randomisation method
(Brahmachari 2009; Louthrenoo 2007; Pavelka 2007), two studies Seven studies were classified as having high risk of bias (Dougados
used blocked randomisation (Dougados 2001; Pelletier 2000) and 2001; Lequesne 1998; Louthrenoo 2007; Pavelka 2007; Pelletier
one study used central randomisation (Pham 2004). 2000; Pham 2004; Zheng 2006). In three of these studies
(Brahmachari 2009; Dougados 2001; Pelletier 2000), ITT analysis
Four studies (Chantre 2000; Lequesne 1998; Nguyen 1994; Zheng was used for all participants who took at least one dose of
2006) were classified as having unclear risk of bias for this domain. the medication, and the last observation carried forward (LOCF)
method was used for those with missing values.
Allocation concealment was not described (unclear risk of bias) in
any of the studies, except one. The author of Brahmachari 2009 Pham 2004 evaluated efficacy outcomes using ITT analysis (all
replied to our contact and informed that he had used sealed opaque randomly assigned participants); however, radiographic evaluation
envelopes. was done only for participants who had at least two different X-rays
to compare.
Blinding
Two studies (Louthrenoo 2007; Pavelka 2007) reported different
Six studies (Brahmachari 2009; Chantre 2000; Dougados 2001;
numbers of participants in the baseline and outcomes tables. These
Nguyen 1994; Pavelka 2007; Pham 2004) were classified as having
studies provided no information on the reasons for exclusion of
low risk of bias for blinding of participants and personnel. Four of
these participants at the end of the study.
these studies (Dougados 2001; Chantre 2000; Pavelka 2007; Pham
2004) described adequate double-blinding processes. Brahmachari Lequesne 1998 evaluated pain using a 0 to 100-mm VAS for all
2009 blinded only participants. randomly assigned participants. The number of participants for the
second effectiveness outcome in this study (Lequesne Impairment
Four studies provided no information on blinding of participants
Index) was different, and the authors provided no explanation for
and personnel and therefore were categorised as having unclear
this discrepancy.
risk of bias (Lequesne 1998; Louthrenoo 2007; Pelletier 2000; Zheng
2006). No studies were categorised as having high risk of bias for Selective reporting
performance bias.
All proposed outcomes were evaluated in nine studies
Seven studies provided no information on blinding of clinical (Brahmachari 2009; Chantre 2000; Lequesne 1998; Louthrenoo
outcome assessors and therefore were categorised as having 2007; Nguyen 1994; Pavelka 2007; Pelletier 2000; Pham 2004; Zheng
unclear risk of bias (Chantre 2000; Dougados 2001; Lequesne 1998; 2006). One study (Dougados 2001) was classified as having high
Louthrenoo 2007; Pelletier 2000; Pham 2004; Zheng 2006). Two risk of bias on this domain because it did not provide data for the
studies were categorised as having high risk of bias for detection outcome "patient evaluation of the treatment" using a 0 to 5 Likert
bias (Brahmachari 2009; Nguyen 1994). scale .
Two studies (Dougados 2001; Pham 2004) were classified as Effects of interventions
having low risk of bias for blinding of radiographic outcome
assessment because they described adequate blinding processes See: Summary of findings for the main comparison Diacerein
for radiographic outcomes: The radiologists were unaware of compared with placebo for osteoarthritis
the identity of the participants when they read their X-rays to
evaluate structural outcomes. The other eight studies, which did
not evaluate radiographic outcomes, were classified as having low
risk of bias.

Informed decisions.

Comparison 1: diacerein compared with placebo Analysis 1.8. The number needed to treat for an additional harmful
outcome (NNTH) for diarrhoea was 4 (95% CI 3 to 7). The absolute
Benefits
risk difference was 24% (95% CI 12% to 35%), and the relative
1. Pain. percentage change was 252% (95% CI 142% to 411%).
• Visual analog scale for pain (0 to 100 mm); 1,283 participants 6. Number of participants who withdrew because of adverse
from six studies:Brahmachari 2009; Dougados 2001; Lequesne events.
1998; Nguyen 1994; Pelletier 2000; Pham 2004 (Analysis 1.1).
The pooled RR (random effect) for withdrawals due to adverse
The pooled summary MD (random effect) of these six studies was effects was 1.29 (95% CI 0.83 to 2.01) in 733 participants taking
-8.65 (95% CI -15.62 to -1.68), with high heterogeneity (I2 = 84%). diacerein versus 743 participants using placebo (seven studies). See
A negative MD in this case means that diacerein was superior to Analysis 1.9. The NNTH was not calculated, as the result was not
placebo in reducing pain. The absolute risk difference was -9% (95% statistically significant. The absolute risk difference was 0% (95%
CI -16% to -2%), and the relative percentage change was -19% (95% CI -3% to 4%), and the relative percentage change was 0% (95% CI
CI -34% to -4%). -29% to 41%).
The effect of diacerein was similar to that of placebo in the two 7. Number of participants experiencing any serious adverse
studies that followed participants for longer than six months, event.
according to the post hoc sensitivity analysis. The pooled MD This outcome was not described in the studies included in this
of these two studies was 0.48 (95% CI -3.90 to 4.86) with no comparison.
heterogeneity (I2 = 0%). See Analysis 4.1.
Comparison 2: diacerein compared with non-steroidal anti-
2. Physical function. inflammatory drugs (NSAIDs)
• Lequesne Impairment Index (0 to 24 points); 1,006 Benefits
participants from four studies:Dougados 2001; Lequesne
1998; Nguyen 1994; Pham 2004 (Analysis 1.2). Three RCTs (Louthrenoo 2007; Nguyen 1994; Zheng 2006) with 150,
184 and 161 participants, respectively, compared diacerein with
The pooled summary MD (random effect) of these four studies was NSAIDs. The Nguyen study evaluated hip OA, and the other two
-0.29 (95% CI -0.87 to 0.28). A negative MD in this case means that studies evaluated knee OA.
diacerein was superior to placebo in terms of its ability to improve
Lequesne Index scores, but this effect did not reach statistical 1. Pain.
significance. The absolute risk difference was 0% (95% CI -4% to • Visual analog scale for pain (0 to 100 mm); 150 participants
1%), and the relative percentage change was -4% (95% CI -11% to from one study:Nguyen 1994.
4%).
No statistically significant differences were noted between the
3. Radiographic joint structure changes. two interventions. Only one study (Nguyen 1994) evaluated pain
• Minimum joint space width decreased over 0.50 mm reduction according to a 0 to 100-mm VAS scale and reported no
during the study period; 616 participants from two differences between the two interventions. The summary MD was
studies:Dougados 2001; Pham 2004 (Analysis 1.7). 2.00 (95% CI -6.48 to 10.48).
When diacerein was compared with placebo for changes in • WOMAC pain subscale; 184 participants from one
minimum joint space width for the knee or hip, the summary RR study:Louthrenoo 2007.
(random effect) was 0.85 (95% CI 0.72 to 0.99). Diacerein slowed the
radiological progression for hip OA (the most representative study One study evaluated this outcome over 16 weeks of treatment by
was Dougados 2001, with RR 0.84, 95% CI 0.71 to 0.99) but not for comparing diacerein versus piroxicam; no statistically significant
knee OA (RR 0.94, 95% CI 0.51 to 1.74). The number needed to treat difference was observed between the two interventions. The
for an additional beneficial outcome (NNTB) was 14 (95% CI 8 to summary MD was 14.00 (95% CI -10.15 to 38.15).
203). The absolute risk difference was -6% (95% CI -15% to 2%), and • Pain on walking 20 m; 231 participants from one study:Zheng
relative percentage change was -15% (95% CI -28% to -1%). 2006.
4. Quality of life. One study did not show statistically significant differences between
This outcome was not reported by the studies included in this diacerein and diclofenac. The summary MD was 1.30 (95% CI -3.81
comparison. to 6.41).
Safety 2. Physical function.

5. Number of participants experiencing any adverse event. • WOMAC disability subscore; 345 participants from two
studies:Louthrenoo 2007; Zheng 2006 (Analysis 2.1).
The pooled RR (random effect) for diarrhoea was 3.52 (95% CI 2.42
to 5.11) in six studies (726 participants taking diacerein and 736 The summary MD was 29.50 (95% CI -23.17 to 82.17).
taking placebo). The RR for dyspepsia was 0.98 (95% CI 0.61 to
1.58) when 526 participants in the diacerein group were compared 3. Radiographic joint structure changes.
with 533 participants in the placebo group (four studies). See
No study assessed this outcome.
Informed decisions.

4. Quality of life. to 1.71), and for the comparison between diacerein and Harpadol,
the pooled MD (random effect) was 1.20 (95% CI -3.01 to 5.41).
• SF-36 (sum score 0-800): 374 participants in two
studies:Louthrenoo 2007; Zheng 2006. 3. Radiographic joint structure changes.
Only one study provided data on SF-36 results allowing analysis • MInimum joint space width decreased by more than 0.50
Louthrenoo 2007. Afer 16 weeks of active treatment, there were no mm during the study period; 216 participants from one
statistically significant differences between the groups. At the end study:Pham 2004.
of the treatment, both groups had similar variations in the scores
for each dimension of the SF-36 health survey questionnaire. MD Radiographic progression was assessed in one study (Pham 2004),
was -40.70 (95% confidence interval; -85.20 to 3.80) (Analysis 2.2). and no statistically significant difference was noted between
diacerein and NRD101: RR (random effect) 1.07 (95% CI 0.60 to 1.91)
Zheng 2006 informed that there were no statistically significant after one year of observation.
differences between both intervention groups without reporting
specific numerical data. 4. Quality of life.
None of the studies assessed this outcome.
Safety
5. Number of participants experiencing any adverse event. Safety
The pooled RR (random effect) for diarrhoea was 3.20 (95% CI 1.58 5. Number of participants experiencing any adverse event.
to 6.49) with 77 of 253 participants in the diacerein group versus 23 The most frequent adverse event was diarrhoea, with RR 4.26 (95%
of 252 participants in the NSAIDs group (three studies). The RR for CI 2.54 to 7.16) (Analysis 3.4).
dyspepsia was 0.69 (95% CI 0.29 to 1.61) in three studies (Analysis
2.3). 6. Participants who withdrew because of adverse events.
6. Participants who withdrew because of adverse events. The proportion of dropouts in the diacerein groups was similar
to that in the SYSADOA group; RR was 1.42 (95% CI 0.78 to 2.58)
The pooled RR (random effect) for withdrawals due to adverse (Analysis 3.4).
events was 0.96 (95% CI 0.38 to 2.44) in three studies with 534
participants (Analysis 2.4). 7. Participants experiencing any serious adverse event.
7. Participants experiencing any serious adverse event. This outcome was not reported by the studies.
None of the studies analysed this outcome. Subgroup analysis: carry-over effect
Comparison 3: diacerein compared with other symptomatic Five studies (Brahmachari 2009; Lequesne 1998; Louthrenoo 2007;
slow-acting drugs for osteoarthritis (SYSADOA) Pavelka 2007; Zheng 2006) analysed the carry-over effect. The
time for outcome measurement without the drug was four weeks
Two RCTs (Chantre 2000; Pham 2004) consisting of 338 participants (Brahmachari 2009), eight weeks (Lequesne 1998), four weeks
compared diacerein versus two SYSADOA drugs: intra-articular (Louthrenoo 2007), 12 weeks (Pavelka 2007) and four weeks (Zheng
NRD101 (a hyaluronic acid high-molecular-weight, -1.900 kDa 2006).
polysaccharide) for 12 months versus Harpadol or devil's claw (a
perennial South African herbaceous plant with anti-inflammatory 1. Pain.
and analgesic effects attributed to its iridoid glycoside) for four
months. • Visual analog scale for pain (0 to 100 mm); 470 participants
from three studies:Brahmachari 2009; Lequesne 1998; Zheng
Benefits 2006 (Analysis 5.1).
1. Pain. The summary MD was -13.19 (95% CI -24.25 to -2.13).

• Visual analog scale for pain (0 to 100 mm); 338 participants • WOMAC Index subscale pain; 339 participants from two
from two studies:Chantre 2000; Pham 2004 (Analysis 3.1). studies:Louthrenoo 2007; Pavelka 2007 (Analysis 5.2).
For pain assessed through a VAS scale, the comparison between The summary MD was -80.37 (95% CI -153.26 to -7.47).
diacerein and NRD101 resulted in a subgroup MD (random effect)
of 4.50 (95% CI -4.67 to 0.13.67), and the comparison between 2. Physical function.
diacerein and Harpadol resulted in a subgroup MD (random effect)
of 0.40 (95% CI -7.73 to 6.93). • WOMAC Index subscale physical function; 381 participants
from three studies:Brahmachari 2009; Louthrenoo 2007;
2. Physical function. Pavelka 2007 (Analysis 5.4).
• Lequesne Impairment Index (0 to 24 points); 338 participants The summary MD was -233.30 (95% CI -363.30 to -103.30).
from two studies:Chantre 2000; Pham 2004 (Analysis 3.2).
Only one study (Pelletier 2000) studied different doses of diacerein,
For the Lequesne Index, comparison between diacerein and and the only reported difference between groups was related
NRD101 yielded a pooled MD (random effect) of 0.27 (95% CI -1.17 to adverse events. Participants who received 50 mg/d had
significantly fewer adverse effects than the group treated with 100

Informed decisions.

mg; participants treated with 150 mg/d had the highest overall Diacerein compared with NSAIDs was statistically non-significant
rate of withdrawals (20% in the 150-mg diacerein group vs 10 % in for physical function measured by the WOMAC Index, with MD 29.50
the placebo group). This is why we did not perform this subgroup (95% CI -23.17 to 82.17).
analysis.
According to studies that analysed the carry-over effect
Results from search of regulatory websites: (Brahmachari 2009; Lequesne 1998; Louthrenoo 2007; Pavelka
2007; Zheng 2006), diacerein remains effective for at least two
The FDA MedWatch, Australian Adverse Drug Reactions Bulletin,
months after treatment interruption. Reasons for this were not
and UK Medicines and Healthcare products Regulatory Agency,
explained. Pooled results of three of these studies (Brahmachari
did not have any warnings regarding diacerein. However, a
2009; Lequesne 1998; Zheng 2006) for pain reduction produced MD
notice on the European Medicines Agency (EMA) website, dated
of -13.19 (95% CI -24.25 to -2.13) on a 0 to 100-mm VAS.
November 8, 2013, from the Pharmacovigilance Risk Assessment
Committee (PRAC) recommended that the marketing authorization A statistically significant increase in the risk of adverse effects was
of diacerein should be suspended across Europe because of noted for participants allocated to diacerein compared with those
harms (particularly the risk of severe diarrhoea and potentially given placebo, mainly diarrhoea. The NNTH for diarrhoea was 4, but
harmful effects on the liver) outweighing benefits (PRAC 2013). This this did not lead to a statistically significant increase in withdrawals
guidance is not final and the EMA website should be consulted for due to adverse events (RR 1.29, 95% CI 0.83 to 2.01).
future guidance on this issue.
No difference between diacerein and placebo was reported in terms
Liver adverse effects was not an outcome pre-specified for of upper gastrointestinal symptoms. The second most prevalent
this review. However, after becoming aware of the PRAC adverse effect was urine discolouration (25% in the diacerein group
recommendation, we re-assessed the included studies for this vs 1.7% in the placebo group)—a clinically irrelevant effect. It
outcome. We did not find evidence of liver adverse effects in the should be noted that this effect is unrelated to renal function.
studies included in this review. Blood samples were collected to Allergic events affecting the skin (pruritus, rash) were more
evaluate liver function in all studies, except two (Chantre 2000; frequent in the diacerein groups (Analysis 1.8).
Lequesne 1998). Only one patient discontinued the diacerein
treatment due to deterioration in hepatic function (ALT up to 97 U/ In November 2013, the European Medicines Agency
L) in the Zheng study (Zheng 2006). Pharmacovigilance Risk Assessment Committee (PRAC)
recommended that the marketing authorization of diacerein
DISCUSSION should be suspended across Europe because of harms (particularly
the risk of severe diarrhoea and potentially harmful effects on
Summary of main results the liver) outweighing benefits (PRAC 2013). However, the website
This updated systematic review identified 10 randomised states that this recommendation will be re-examined.
controlled trials. We found that the symptomatic benefit of
diacerein in participants with OA of the knee or hip was minimal Overall completeness and applicability of evidence
or none when compared with placebo. Minimal benefit was noted This review has several limitations. First of all, most of the included
in terms of joint space narrowing for hip OA, and was uncertain studies were small and were too short in duration, given that the
for knee OA. Adverse effects related to the gastrointestinal tract therapeutic effects of diacerein start after approximately six to eight
(diarrhoea) were frequent, and safety concerns could make use of weeks of use. Only three of the 10 studies lasted longer than 24
this drug non-beneficial. weeks. Second, all studies allowed participants to take analgesics
and even NSAIDs during the trial, and this could have influenced the
This review included trials published between 1994 and 2009 that results related to pain and evaluation of adverse effects. Finally, in
allocated and analysed 2,210 participants with knee or hip OA. daily clinical practice, OA can affect other joints besides the knees
The average age of participants was 60 years, and 63% of them and hips, but these other joints were not evaluated in the included
were women. These participants were treated with diacerein (996 studies.
participants) compared with placebo or other active interventions
(1,214 participants). Quality of the evidence
Six studies were pooled for analysis of pain reduction assessed All studies included in this review had some type of risk of bias:
through a 0 to 100-mm VAS. When diacerein and placebo were selection bias or detection bias or attrition bias. Five randomised
compared, the MD was -8.65 (95% CI -15.62 to -1.68, P < 0.01), trials had lower risk of bias in most of the categories (Brahmachari
supporting mild efficacy of diacerein as opposed to placebo. This 2009; Chantre 2000; Nguyen 1994; Pavelka 2007; Pham 2004),
result is based on studies with large heterogeneity (I2 = 84%). but their primary outcomes were different. Brahmachari 2009
No significant reduction in heterogeneity was observed when the evaluated the primary efficacy and safety of diacerein compared
previously described sensitivity analysis was performed. Diacerein with placebo over a short time; Chantre 2000 evaluated the
was statistically non-significant in reducing the Lequesne Index non-inferiority of Harpagophytum procumbens compared with
score according to five comparisons: MD was -0.29 (95% CI -0.87 to diacerein for pain and functional disability improvement; Pham
0.28) without heterogeneity (I2 = 0%). 2004 evaluated the efficacy and safety of a hyaluronic acid
intra-articular compared with placebo and diacerein in a long-
Radiographic progression of disease was less pronounced for hip term study; Nguyen 1994 evaluated the efficacy and safety of
OA (RR 0.84, 95% CI 0.71 to 0.99) than for knee OA (RR 0.94, 95% CI diacerein compared with non-steroidal anti-inflammatory drugs;
0.51 to 1.74). and Pavelka 2007 analysed the carry-over effect after three months

Informed decisions.

of therapy. This diversity of bias can reduce the meaning of the because they compared diacerein associated with other effective
results. drugs versus standard treatment (Fagnani 1998; Marcolongo 1988).
Over the past three years, we have repeatedly contacted authors
Only one (Pavelka 2007) of the 10 studies blinded assessors for of those eight studies and representatives of the pharmaceutical
clinical outcomes; all studies were classified as having low risk for industry to ask for additional details and unpublished data, but
radiographic outcomes. Radiological progression of OA is evaluated we have received no reply. The pharmaceutical company that
in long-term studies, and this review retrieved two studies that sponsored several of these studies did not send us the complete
included this analysis. Radiographic joint space width, measured data for analyses. Bartels et al (Bartels 2010) also did not include
in millimetres, is currently considered the preferred technique these studies in their meta-analyses.
to evaluate the structural progression of OA, which is required
by regulatory agencies (Hellio 2009). Unfortunately, the studies Results of this updated review coincide with those reported by
evaluated different joints. Radiological progression of knee OA Bartels (Bartels 2010), who analysed six of these studies and
was evaluated after one year (Pham 2004) with no statistically reported a small beneficial effect of diacerein in the treatment of
significant differences noted, and hip OA was evaluated after three OA. As in our review, those authors found a small reduction in pain
years, with a small difference favouring diacerein over placebo and lower efficacy in the studies of longest duration.
(Dougados 2001).
As mentioned in our Results, the EMA PRAC recommended that the
Compliance gives an indication of drug tolerability and marketing authorization of diacerein should be suspended because
acceptability by participants. Although all studies described in their of harms related to the risk of severe diarrhoea and potentially
Methods section that compliance was assessed by pill counting, harmful effects on the liver (PRAC 2013). While the results of this
investigators did not analyse this parameter, thereby hindering review found evidence of an increased risk of diarrhea, a post-hoc
estimations of drug tolerability. Included studies do not provide assessment of the included studies for liver adverse effects was not
information on how often or what doses of analgesics or NSAIDs found in these RCTs.
were used by randomly assigned participants. This information
would be important in assessing the overall effectiveness and AUTHORS' CONCLUSIONS
safety of the treatment.
Implications for practice
Only one of the 10 studies (Brahmachari 2009) had adequate
There is low quality evidence that diacerein provides a small
allocation concealment, and six (Brahmachari 2009; Dougados
symptomatic benefit in pain improvement that may not be
2001; Louthrenoo 2007; Pavelka 2007; Pelletier 2000; Pham 2004)
clinically significant. Another small benefit (of low quality, as
used an adequate method to generate a random sequence. Eight of
assessed by GRADE) in terms of joint space narrowing was noted in
ten studies had high risk of bias for incomplete outcome data. Only
hip OA while the result for knee OA was not statistically significant.
one study(Dougados 2001) was selective in its reporting of results
There was low quality of evidence indicating that diacerein can
and data. Consequently, evidence was downgraded to moderate
cause adverse effects such as diarrhoea, which was described as the
for physical function/Lequesne impairment and to low for all other
most frequent adverse event by all studies that documented and
outcomes, using the GRADE assessment of quality (Summary of
analysed this outcome.
findings for the main comparison).
The European Medicines Agency Pharmacovigilance Risk
Potential biases in the review process Assessment Committee (PRAC) recommended the suspension of
Strengths of this review include the detailed electronic search diacerein-containing medicines across Europe because of harms
strategy; all important databases were included in the search. outweighing benefits. However, this guidance is not final as the
At least two independent investigators were involved in all PRAC recommendation will be re-examined.
steps of the review, from screening of retrieved references, to
reading, abstraction and quality assessment of included studies. An Implications for research
additional investigator was consulted to solve discrepancies until This review provides the most recent evidence on (1) the clinical
consensus was reached. effectiveness of diacerein for pain reduction and physical function
improvement in patients with OA and (2) the effect of this drug on
Weaknesses of this review include a low response rate when
the radiographic progression of hip and knee OA.
attempts were made to contact authors of the included studies.
In addition, the pharmaceutical companies contacted (TRB This evidence, however, is based on studies with methodological
Chemedica, Negma Lerads) did not reply to our questions regarding shortcomings, qualifying the evidence as low and moderate. These
missing data. findings show that additional trials are needed to further assess the
effectiveness of this drug for pain reduction and physical function.
Agreements and disagreements with other studies or These outcomes are better measured by WOMAC scales and/or the
reviews Lequesne Index, as well as by patient global evaluation (Dworkin
Eight studies retrieved from the reference list of another review 2011).
(Rintelen 2006) were excluded from our review. They were
Structural variables usually assess the rate and extent of cartilage
unpublished reports (Mantia 1987; Portioli 1987) or presentations
breakdown revealed by radiographic space width or cartilage
from the Italian Society of Rheumatology (Mattara 1985; Mordini
volume, as measured by magnetic resonance imaging. Such
1986; Pietrogrande 1985), except one study that did not show data
outcome variables are accurate, have high intrinsic validity and
consistent with other studies (Mattara 1985) and two others that
were already excluded in the first version of this review (2006)
Informed decisions.

are usually considered as the primary outcome to be assessed in VAS pain scale, the quality of life index and global assessment by
studies of disease-modifying OA drugs (Dougados 2004). participants and investigators should be included in future studies.
It is very important that researchers design studies of good ACKNOWLEDGEMENTS

methodological quality, lasting longer than six months and
providing blinding of outcome assessors, including radiographic We would like to thank the Cochrane Musculoskeletal Editorial
progression and symptomatic improvement. In addition to the Team, mainly Ms Elizabeth Ghogomu, for their thoughtful
comments and suggestions of ways to minimise bias in the review.

Informed decisions.

REFERENCES

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Schulitz KP. Clinical investigation of the efficacy and tolerance
Linguetti 1982 {published data only}
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Linguetti M, D'Ambrosio PL, Di Grezia F, Sorrentino P, Lingetti E. knee. Köln, Germany: Madaus AG. Unpublished final clinical
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Palermo Hospital, Palermo, Italy; 1987. Postmarketing Evaluation of the Efficacy and Tolerability of
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Marcolongo R, Fioravanti A, Adami S, Tozzi E, Mian M,
Zampieri A. Efficacy and Tolerability of Diacerhein in the Singh 2012 {published data only}
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Mathieu 1999 {published data only}
Mathieu P. Interleucine 1 - Results of a pilot study with diacerein Tang 2004 {published data only}
(ART 50) for Knee Osteoarthrosis [L'interleukine 1 - Résultats Tang FL, Wu DH, Lu ZG, Huang F, Zhou YX. The efficacy and
d'une étude "pilote" avec la diacerhéine (ART 50) dans la safety of diacerein in treatmnet of painful osteoarthritis of the
gonarthrose]. La Revue du Praticien 1999;49:S15-S18. knee. 11º Asia Pacific League of Associations for Rheumatology
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osteoartosi ]. Relazione presentata al LXXXVI Congresso Naz. Valat-JP. Diacerein Pragmatic Study: Clinical, Life quality and
Società Ital. Medicina Interna - Sorrento. 1985; Vol. S:59. socio- economic analysis [Étude pragmatique de la diacerheine:
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[Valutazione clinica della Diacereina nel Trattamento Vignon E. Results of ECHODIAH study in hip osteoarthritis
dell'osteoartrosi]. Minerva Medica 1989;80(9):1025-1027. [Résultats de l'essai thérapeutique ECHODIAH dans l"arthrose
de hanche]. La Presse Médicale 2002;31(1):7-9.
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Abstract presented at: The 27th Congress of the Italian Society symptomatic slow-acting drugs given for osteoarthritis
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* Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Brahmachari 2009
Methods Randomised controlled trial
Single-blind (participants were blinded)
Placebo-controlled

Informed decisions.

Brahmachari 2009 (Continued)
Participants Individuals between 35 and 70 years of age, with primary, symptomatic, tibiofemoral OA fulfilling ACR
criteria and Kellgren-Lawrence grades II and III with pain score ≥ 35 mm on a 100-mm VAS scale
Interventions Diacerein 50-mg capsules twice daily or placebo capsules twice daily
Duration eight weeks with evaluation and after 12 weeks without treatment
Outcomes Pain on movement in 0 to 100 mm VAS
WOMAC stiffness and physical function
Clinical global impression by investigator on a 5-point Likert scale
Use of rescue medication
Notes The study drug was provided by Macleods Pharmaceuticals Ltd
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Diacerein and placebo arms were randomly assigned using a computer-gener-
tion (selection bias) ated random number list
Allocation concealment Low risk Opaque sealed envelopes

(selection bias)
Blinding of participants Low risk Blinding only for the participants

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- High risk Single blind. Each participant was followed up at monthly intervals for 12
sessment (detection bias) weeks. Outcomes assessed were pain, WOMAC subscores for stiffness and
Clinical outcomes physical function, clinical global assessment by the physician and use of res-
cue medication
Blinding of outcome as- Low risk Not applicable

sessment (detection bias)
Radiographic outcomes
Incomplete outcome data High risk Analysis used a modified intention-to-treat method, including all participants
(attrition bias) who attended at least one postbaseline visit. Missing values were dealt with by
All outcomes the last observation carried forward method
Selective reporting (re- Low risk Appropriate methods to compare results were used and well described
porting bias)

Chantre 2000
Double-blind
Multi-centre (30 centres)
Parallel-group
Participants Outpatients with OA of hip or knee

Informed decisions.

Chantre 2000 (Continued)
Country: France
N = 122
Mean age, years: 61.5
Female 63%; male 37%
Interventions Diacerein 50 mg BID + six capsules of placebo per day versus six capsules of Harpadol(R) + two capsules
of placebo per day.
Duration: 16 weeks
Outcomes Pain (0 to 100 VAS scale)

Lequesne Functional Index
Use of NSAIDs
Notes Arkopharma Laboratories is represented as the first author
Risk of bias
Random sequence genera- Unclear risk Randomisation in blocks of four to ensure uniform distribution to the treat-
tion (selection bias) ment groups at each study centre. Trial samples were numbered consecutive-
ly and were handed out to participants in the order of inclusion. Treatment
groups were matched with respect to age, gender, weight and duration of
arthrosis
Allocation concealment Unclear risk Not described

(selection bias)
Blinding of participants Low risk Double blind. Medications were packaged individually and labelled with the
and personnel (perfor- study number, the participant number and the randomisation number
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Not described

Clinical outcomes

Incomplete outcome data Low risk ITT participants and per-protocol participants were described without dispari-
(attrition bias) ties
All outcomes
Selective reporting (re- Low risk All data were properly reported
porting bias)

Dougados 2001
Double-blind

Informed decisions.

Dougados 2001 (Continued)
Parallel-group
Participants Outpatients with hip OA
Country: France
N = 507
Mean age, years: 62 ± 7
Female 60%;
male 40%
Interventions Diacerein 50 mg BID versus placebo BID
Duration: three years of treatment
Outcomes Radiography once a year (JWS measurement)
Pain (100-mm VAS)
Functional Lequesne Index
Analgesic use
Need for signal hip joint replacement
Notes Supported in part by a grant from Negma Ltd
Risk of bias
Random sequence genera- Low risk The centralised allocation schedule was prepared using a blocked randomisa-
tion (selection bias) tion technique (blocking factor of 4)
Allocation concealment Unclear risk No description

(selection bias)
Blinding of participants Low risk Double-blind. Participants were randomly assigned to receive one indistin-
and personnel (perfor- guishable capsule of placebo or diacerein
mance bias)
All outcomes
Blinding of outcome as- Unclear risk No reference was made to assessors' blinding in evaluating clinical outcomes
Clinical outcomes
Blinding of outcome as- Low risk A central reader expert radiologist was unaware of participants' identity, study
sessment (detection bias) group, signal hip and sequence of radiographs
Incomplete outcome data High risk 252 participants were randomly assigned to placebo and 255 to diacerein.
(attrition bias) ITT analysis in 247 placebo and 246 diacerein participants. PP analysis in 138
All outcomes placebo and 131 diacerein
Selective reporting (re- High risk Outcomes were analysed at baseline and at the end of the study. One evalua-
porting bias) tion described in the baseline table was not reported at the end of the study:
participant assessment on the Likert scale

Informed decisions.


Lequesne 1998
Double-blind
Parallel-group
Participants Outpatients with knee or hip OA
Country: France
N = 183
Mean age, years: 61.5 ± 10.9
Interventions Zero to two months: diacerein 50 mg BID + diclofenac 50 mg BID versus placebo + diclofenac 50 mg BID
Two to six months: diacerein 50 mg BID versus placebo
Six to eight months: without treatment (carry-over effect evaluation)
Outcomes Pain (0 to 100-mm VAS scale)

Functional Lequesne Impairment Index
Global efficacy evaluation for participant and physician (participant scale 0 to 7 and physician scale 0
to 5)
Safety scale 0 to 4 at the end of the study
Analgesic and NSAID use
Notes
Risk of bias
Random sequence genera- Unclear risk Randomisation not described

tion (selection bias)
Allocation concealment Unclear risk Allocation not described

(selection bias)
Blinding of participants Unclear risk Not described

mance bias)
All outcomes

Clinical outcomes

Incomplete outcome data High risk 93 participants in the placebo group and 90 in the diacerein group. ITT analysis
(attrition bias) was done for only some outcomes
All outcomes

Informed decisions.

Lequesne 1998 (Continued)
porting bias)

Louthrenoo 2007
Multi-centre (five medical schools in Thailand)
Double-blind
Piroxicam-controlled
Parallel-group
Participants Participants with tibiofemoral X-ray confirmed Kellgren-Lawrence grade II or III OA according to ACR
criteria between 40 and 65 years of age, with knee pain of at least 40 mm on at least two items of the
WOMAC A, on a 0 to 100-mm VAS scale, for at least 15 days
Interventions Diacerein 100 mg/ d (N = 86) versus piroxicam 20 mg/d (N = 85). 16 weeks
Outcomes WOMAC A, B, C
SF-36
Paracetamol consumption
Notes Supported by a grant from TRB Chemedica International
Risk of bias
Random sequence genera- Low risk Each participant was randomly assigned to a treatment group using a ran-
tion (selection bias) domisation table generated by a validated computer software

(selection bias)

mance bias)
All outcomes

Clinical outcomes

Incomplete outcome data High risk A good description of withdrawals and the reasons for them were provided.
(attrition bias) 171 were randomly assigned (diacerein 86 and control 85); however, ITT analy-
All outcomes sis was performed in only 161 (82 diacerein, 79 control). 10 participants (four
diacerein, six control) were excluded from ITT because they did not take any
dose of medication. 150 participants completed the study

Informed decisions.

Louthrenoo 2007 (Continued)
porting bias)

Nguyen 1994
Allocation concealment
Double-blind
Placebo-controlled
Parallel-group
Multi-centre
Participants Outpatients with hip OA
Country: France
N = 288; included in this review: 221
Mean age, years: 60 ± 16
Female 57%;
male 43%
Interventions One capsule (50-mg capsule of diacerein or matching placebo capsules) twice daily and one tablet (20-
mg tablet of tenoxicam or matching placebo tablets)
Duration: eight weeks
Outcomes Pain (100-mm VAS scale)
Functional Lequesne Impairment Index
Analgesic consumption
Participant overall assessment (0 to 4 scale)
Notes Supported in part by Negma Pharma Ltd
Risk of bias
Random sequence genera- Unclear risk Not described


(selection bias)
Blinding of participants Low risk Pills were unidentifiable and all participants were allowed to take analgesics
mance bias)
All outcomes
Blinding of outcome as- High risk The same investigator did the clinical evaluation and applied questionnaires
Clinical outcomes

Informed decisions.

Nguyen 1994 (Continued)
Incomplete outcome data Low risk Withdrawn participants were well described, and all randomly assigned partic-
(attrition bias) ipants were evaluated
All outcomes
porting bias)

Pavelka 2007
Double-blind
Placebo-controlled
Multi-centre
Participants Outpatients with tibiofemoral OA (knee) according to ACR criteria
Interventions Diacerein 50 mg twice a day (N = 82) versus placebo (N = 83)
Outcomes WOMAC for pain (A), WOMAC B, WOMAC C and total WOMAC
Tenderness of target knee on palpation 100 mm VAS
Acetaminophen intake, tablets/d
Notes Supported by a joint grant from TRB Chemedica International and Glynn Brothers Chemicals AG
Risk of bias
Random sequence genera- Low risk Computer generated


(selection bias)
Blinding of participants Low risk Double-blind for participants and personnel

mance bias)
All outcomes
Blinding of outcome as- Low risk Blinding for assessors

Clinical outcomes


Informed decisions.

Pavelka 2007 (Continued)
Incomplete outcome data High risk 168 participants were randomly assigned; however, 165 participants were in-
(attrition bias) cluded in the ITT analysis
All outcomes
porting bias)

Pelletier 2000
Double-blind
Parallel-group four-arm trial
Participants Outpatients with knee OA

Country: Canada and Israel, N = 484; included in this review: 236
Mean age, years: 63.5 ± 8.9
Female 79.6%;
male 20.4%
Interventions Diacerein 25 mg twice daily versus diacerein 50 mg twice daily versus diacerein 75 mg twice daily ver-
sus placebo (one capsule twice daily)
Duration 16 weeks
Outcomes Pain (0 to 100-mm VAS scale)

WOMAC Index
Handicap (0 to 100-mm VAS)
Participant and physician overall assessment on a 0 to 100-mm VAS at the end of the study
Knee joint swelling (0 to 3)
Duration of morning stiffness in minutes
Joint mobility assessed with a goniometer
Safety evaluation
Notes Supported by a grant from Les Laboratoires Negma
Risk of bias
Random sequence genera- Low risk The centralised allocation schedule was prepared by using a blocked randomi-
tion (selection bias) sation technique (blocking factor eight). Treatments were divided between
the two countries (treatments 1 to 500 in Israel and 600 to 1000 in Canada) and
were allocated to each centre

(selection bias)

mance bias)
All outcomes

Informed decisions.

Pelletier 2000 (Continued)
Clinical outcomes

Incomplete outcome data High risk Three populations were evaluated: one for safety and two for efficacy
(attrition bias)
All outcomes Safety population received the medications at least once. An intention-to-treat
population was evaluated with at least one postbaseline visit. A per-protocol
population with all postbaseline visits completed was also evaluated. Four
participants were excluded from ITT analysis
porting bias)

Pham 2004
Double-blind
Three arms

Country: France and UK
N = 301
Mean age, years: 65

Female 70%;
male 30%
Interventions Diacerein 50 mg BID + 3 × 3 intra-articular injections of saline solution versus 3 × 3 HA intra-articular in-
jections (NRD101) and placebo capsules versus 3 × 3 intra-articular injections of saline solution and dai-
ly placebo capsules
Duration: one year
Outcomes Pain (0 to 100-mm VAS)

Lequesne Impairment Index
Participants' global assessment (0 to 100 VAS)
Percentage of painful days (0 to 100 VAS)
Assessment of treatment efficacy by participant and investigator (0 to 5 scale) at the end of the study
Radiography after one year (JWS measurement)
Notes
Risk of bias

Informed decisions.

Pham 2004 (Continued)
Random sequence genera- Low risk The randomised allocation schedule was centralised (Cassene Laboratories)

(selection bias)
Blinding of participants Low risk Double-blinding of participants and personnel

mance bias)
All outcomes
Blinding of outcome as- Unclear risk No reference about assessors' blinding to evaluate clinical outcomes
Clinical outcomes
Blinding of outcome as- Low risk Two observers who were unaware of participants' identity, study group, signal
sessment (detection bias) knee and sequence of radiographs
Incomplete outcome data High risk Intention-to-treat analysis was done for efficacy outcomes. Structural evalu-
(attrition bias) ation was analysed only in participants with X-rays in the baseline table. Nine
All outcomes participants were excluded from the analysis
porting bias)

Zheng 2006
Double-blind
Parallel-group
Multi-centre

Country: China
N = 184
Mean age, years: 58.5
82% female;
18% male
Interventions Diacerein 2 × 50 mg capsules and three tablets of placebo versus diclofenac 3 × 25 mg tablets and two
tablets of placebo
Duration: three months with a follow-up period of one month
Outcomes Pain on walking 20 m on a 100-mm VAS

WOMAC Index
Effusion or swelling of soft tissue/tenderness of target joint
Efficacy judgements by participants and investigators
Notes Diacerein and diclofenac were provided by Kunming Jida Pharmaceutical Co

Informed decisions.

Zheng 2006 (Continued)
Risk of bias
Random sequence genera- Unclear risk Not described


(selection bias)
Blinding of participants Unclear risk The same packaging boxes were used for both groups with the medications
mance bias)
All outcomes

Clinical outcomes

Incomplete outcome data High risk ITT analysis was not performed
(attrition bias)
All outcomes
porting bias)
BID: twice a day.

HA: hyaluronic acid.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Adami 1985 Not a randomised controlled trial
Ascherl 1994 Unpublished study. Diacerein versus placebo for knee OA. Unsuccessful TRB Chemedica contact
Baliga 2010 Inappropriate inclusion criteria
Bogliola 1991 Not a randomised controlled trial

The study describes diacerein 50 mg/d every 60 days versus a 30-day interval compared with falgo
balneo therapy for one year
Carrabba 1987 Not a randomised controlled trial. Study analysed use of diacerein 100 mg/d in a group of 31 par-
ticipants with OA without defined joint for four weeks, in another group of 20 OA participants us-
ing diacerein 100 mg/d in a cross-over arm with naproxen 500 mg/d and in a third group of 20 fi-
bromyalgia participants using diacerein 100 mg/d five days/wk for 12 weeks. The three cohorts
were analysed for outcomes on a 0 to 3 scale
Delcambre 1994 Not a randomised controlled trial. Study evaluated 1,221 participants with radiological OA of hip,
knee or cervical or lumbar spine using diacerein 100 mg/d for three months as isolated therapy or

Informed decisions.

Study Reason for exclusion

associated with analgesic or NSAIDs. Outcome measurements inadequate for analysis (VAS 0 to 100
in five grades)
Delcambre 1996 Duplication of the Delcambre 1994 publication
Fagnani 1998 Randomised non blinded study using diacerein and standard therapy for OA including other slow
acting anti osteoarthritic drugs plus several procedures that could cause confusion on improve-
ment of end point measurements
Fioravanti 1985 Report of diacerein effectiveness. Symposium presentation not published. Unsuccessfull TRB
Chemedica contact
Kay 1980 Not a randomised controlled trial
Leblan 2000 Duplication of the publication of Chantre 2000
Linguetti 1982 Not a randomised controlled trial
Mantia 1987 Clinical study report. Diacerein versus diclofenac for knee and hip OA. Data not available. Unsuc-
cessfull TRB Chemedica contact
Marcolongo 1988 Review on diacerein treatment. No specific data are available for analysis
Mathieu 1999 Case series
Mattara 1985 Data not available. Unsuccessful TRB Chemedica contact
Mazzaro 1989 Not a trial
Mordini 1986 Clinical study. Data not available. Unsuccessful TRB Chemedica contact
Pietrogrande 1985 Data not available. Unsuccessful TRB Chemedica contact
Portioli 1987 Data not available. Unsuccessful TRB Chemedica contact
Renapurkar 2010 Not a randomised controlled trial
Schulitz 1994 Data not available. Unsuccessful TRB Chemedica contact
Seisenbayev 2012 Data not available. Unsuccessful personal contact
Sharma 2008 Not a randomised controlled trial
Singh 2012 Inappropriate inclusion criteria
Tang 2004 Congress abstract later published by Zheng (Zheng 2006) with additional data
Valat 1997 Duplication of the Fagnani study (Fagnani 1998)
Vignon 2002 Comments about ECHODIAH study
Villani 1998 Comment about placebo effects in trials using slow-acting drugs for OA
Villermay 1994 Comment about the large trial involving 1,221 participants described by Delcambre

Informed decisions.


Characteristics of studies awaiting assessment [ordered by study ID]

Shin 2013
Methods Double-blind, randomised, controlled study; allocation concealment
Participants 84 participants > 40 years of age, had at least one tender joint and had a joint pain visual analogue
scale of 30 mm
Interventions Participants received diacerein (50 mg) or placebo BID for 12 weeks
Outcomes The primary end point was the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain score
at four weeks. Secondary end points were AUSCAN pain score at 12 weeks and AUSCAN physical
function and stiffness score, participant and physician global assessments, functional index of
hand OA scores and multi-dimensional health assessment questionnaire results at four weeks and
12 weeks
Notes The following additional information is pending:
• Description of the process used for allocation concealment

• Details of outcomes

DATA AND ANALYSES

Comparison 1. DIACEREIN VS PLACEBO
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Visual analogic Scale for 6 1283 Mean Difference (IV, Random, 95% CI) -8.65 [-15.62, -1.68]
Pain
1.1 Hip 1 146 Mean Difference (IV, Random, 95% CI) -8.0 [-16.11, 0.11]
1.2 Hip change score 1 507 Mean Difference (IV, Random, 95% CI) 0.0 [-5.23, 5.23]
1.3 Hip and/or knee 1 171 Mean Difference (IV, Random, 95% CI) -11.60 [-18.98, -4.22]
1.4 Knee 1 55 Mean Difference (IV, Random, 95% CI) -28.60 [-38.31, -18.89]
1.5 Knee change score 2 404 Mean Difference (IV, Random, 95% CI) -4.04 [-11.78, 3.70]
2 Lequesne Impairment In- 4 1006 Mean Difference (IV, Random, 95% CI) -0.29 [-0.87, 0.28]
dex
2.1 Hip 2 216 Mean Difference (IV, Random, 95% CI) -0.79 [-1.98, 0.40]
2.2 Hip - change score 1 507 Mean Difference (IV, Random, 95% CI) 0.0 [-0.71, 0.71]
2.3 Knee 1 113 Mean Difference (IV, Random, 95% CI) -1.10 [-2.91, 0.71]
2.4 Knee - change score 1 170 Mean Difference (IV, Random, 95% CI) 0.10 [-4.66, 4.86]

Informed decisions.


studies partici-
pants
3 WOMAC total 2 399 Mean Difference (IV, Random, 95% CI) -58.69 [-173.90, 56.52]
3.2 Knee change score 1 234 Mean Difference (IV, Random, 95% CI) -20.00 [-33.38, -6.62]
4 WOMAC subscore (Pain) 2 399 Mean Difference (IV, Random, 95% CI) -29.33 [-48.45, -10.20]
5 WOMAC subscore (stiff- 3 454 Mean Difference (IV, Random, 95% CI) -15.79 [-26.21, -5.37]
ness)
6 WOMAC subscore (Physi- 3 454 Mean Difference (IV, Random, 95% CI) -110.92 [-173.88, -47.97]
cal Function)
6.2 Knee- change score 1 234 Mean Difference (IV, Random, 95% CI) -107.50 [-187.51, -27.49]
7 Radiographic Progression 2 616 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.72, 0.99]
7.1 Hip 1 446 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.71, 0.99]
7.2 Knee 1 170 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.51, 1.74]
8 Adverse Effects 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only
8.1 Diarrhoea 7 1462 Risk Ratio (M-H, Random, 95% CI) 3.52 [2.42, 5.11]
8.2 Dyspepsia 4 1059 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.61, 1.58]
8.3 Rash or Pruritus 4 878 Risk Ratio (M-H, Random, 95% CI) 1.99 [0.94, 4.23]
8.4 Urine Descolouration 2 677 Risk Ratio (M-H, Random, 95% CI) 13.01 [5.96, 28.40]
8.5 Epigastralgia 2 316 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.44, 2.09]
9 Drop Out 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only
9.1 Ineffective intervention 2 757 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.49, 0.87]
9.2 Adverse effect 7 1476 Risk Ratio (M-H, Random, 95% CI) 1.29 [0.83, 2.01]
9.3 Other 2 750 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.49, 1.61]

Informed decisions.


Analysis 1.1. Comparison 1 DIACEREIN VS PLACEBO, Outcome 1 Visual analogic Scale for Pain.
Study or subgroup Favours treatment Placebo Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Random, 95% CI Random, 95% CI
1.1.1 Hip
Nguyen 1994 75 40 (26) 71 48 (24) 15.97% -8[-16.11,0.11]
Subtotal *** 75 71 15.97% -8[-16.11,0.11]
Heterogeneity: Not applicable
Test for overall effect: Z=1.93(P=0.05)

1.1.2 Hip change score
Dougados 2001 255 -3 (30.2) 252 -3 (29.9) 18.28% 0[-5.23,5.23]
Subtotal *** 255 252 18.28% 0[-5.23,5.23]
Test for overall effect: Not applicable

1.1.3 Hip and/or knee
Lequesne 1998 85 38.5 (23.9) 86 50.1 (25.3) 16.59% -11.6[-18.98,-4.22]
Subtotal *** 85 86 16.59% -11.6[-18.98,-4.22]
Test for overall effect: Z=3.08(P=0)

1.1.4 Knee
Brahmachari 2009 28 30.7 (16.4) 27 59.3 (20.1) 14.6% -28.6[-38.31,-18.89]
Subtotal *** 28 27 14.6% -28.6[-38.31,-18.89]
Test for overall effect: Z=5.77(P<0.0001)

1.1.5 Knee change score
Pelletier 2000 110 -18.3 (19.3) 124 -10.9 (19.3) 18.48% -7.4[-12.35,-2.45]
Pham 2004 85 -33.9 (25.7) 85 -34.5 (27.4) 16.08% 0.6[-7.39,8.59]
Subtotal *** 195 209 34.55% -4.04[-11.78,3.7]
Heterogeneity: Tau2=20.5; Chi2=2.78, df=1(P=0.1); I2=64.07%

Total *** 638 645 100% -8.65[-15.62,-1.68]
Heterogeneity: Tau2=62.12; Chi2=30.9, df=5(P<0.0001); I2=83.82%
Test for subgroup differences: Chi2=27.96, df=1 (P<0.0001), I2=85.69%
Favours treatment -50 -25 0 25 50 Favours control

Analysis 1.2. Comparison 1 DIACEREIN VS PLACEBO, Outcome 2 Lequesne Impairment Index.
Study or subgroup Diacerein Placebo Mean Difference Weight Mean Difference
1.2.1 Hip
Lequesne 1998 31 8.2 (4.5) 39 9.2 (4.9) 6.8% -1[-3.21,1.21]
Nguyen 1994 75 7.7 (4.6) 71 8.4 (4.1) 16.62% -0.7[-2.11,0.71]
Subtotal *** 106 110 23.42% -0.79[-1.98,0.4]
Heterogeneity: Tau2=0; Chi2=0.05, df=1(P=0.82); I2=0%

Informed decisions.



1.2.2 Hip - change score
Dougados 2001 255 -0.5 (4) 252 -0.5 (4.2) 64.99% 0[-0.71,0.71]
Subtotal *** 255 252 64.99% 0[-0.71,0.71]
Test for overall effect: Not applicable

1.2.3 Knee
Lequesne 1998 59 7.5 (4.9) 54 8.6 (4.9) 10.13% -1.1[-2.91,0.71]
Subtotal *** 59 54 10.13% -1.1[-2.91,0.71]

1.2.4 Knee - change score
Pham 2004 85 -18.8 (14.7) 85 -18.9 (16.9) 1.46% 0.1[-4.66,4.86]
Subtotal *** 85 85 1.46% 0.1[-4.66,4.86]

Total *** 505 501 100% -0.29[-0.87,0.28]
Test for overall effect: Z=1(P=0.32)
Test for subgroup differences: Chi2=2.1, df=1 (P=0.55), I2=0%

Analysis 1.3. Comparison 1 DIACEREIN VS PLACEBO, Outcome 3 WOMAC total.
1.3.1 Knee
Pavelka 2007 82 834 (507.5) 83 982 (530.1) 30.22% -148[-306.34,10.34]
Subtotal *** 82 83 30.22% -148[-306.34,10.34]

Pelletier 2000 110 -36.7 (52.3) 124 -16.7 (51.9) 69.78% -20[-33.38,-6.62]
Subtotal *** 110 124 69.78% -20[-33.38,-6.62]

Total *** 192 207 100% -58.69[-173.9,56.52]
Test for overall effect: Z=1(P=0.32)
Test for subgroup differences: Chi2=2.49, df=1 (P=0.11), I2=59.88%


Informed decisions.

Analysis 1.4. Comparison 1 DIACEREIN VS PLACEBO, Outcome 4 WOMAC subscore (Pain).

1.4.1 Knee
Pavelka 2007 82 153 (103.3) 83 191 (112.2) 33.79% -38[-70.9,-5.1]
Subtotal *** 82 83 33.79% -38[-70.9,-5.1]

Pelletier 2000 110 -58.8 (92.5) 124 -33.9 (90.5) 66.21% -24.9[-48.41,-1.39]
Subtotal *** 110 124 66.21% -24.9[-48.41,-1.39]

Total *** 192 207 100% -29.33[-48.45,-10.2]

Analysis 1.5. Comparison 1 DIACEREIN VS PLACEBO, Outcome 5 WOMAC subscore (stiffness).
1.5.1 Knee
Brahmachari 2009 28 52.7 (64.9) 27 54.2 (77.6) 7.57% -1.5[-39.38,36.38]
Pavelka 2007 82 75 (476) 83 85 (489) 0.5% -10[-157.25,137.25]
Subtotal *** 110 110 8.07% -2.03[-38.71,34.65]

Pelletier 2000 110 -27.3 (42.3) 124 -10.3 (42.4) 91.93% -17[-27.87,-6.13]
Subtotal *** 110 124 91.93% -17[-27.87,-6.13]

Total *** 220 234 100% -15.79[-26.21,-5.37]


Informed decisions.

Analysis 1.6. Comparison 1 DIACEREIN VS PLACEBO, Outcome 6 WOMAC subscore (Physical Function).
1.6.1 Knee
Brahmachari 2009 28 601 (402) 27 778 (431) 8.16% -177[-397.46,43.46]
Pavelka 2007 82 606 (368.8) 83 706 (385.3) 29.93% -100[-215.08,15.08]
Subtotal *** 110 110 38.09% -116.49[-218.5,-14.47]

1.6.2 Knee- change score
Pelletier 2000 110 -193.3 (318) 124 -85.8 61.91% -107.5[-187.51,-27.49]
(304.4)
Subtotal *** 110 124 61.91% -107.5[-187.51,-27.49]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Total *** 220 234 100% -110.92[-173.88,-47.97]

Analysis 1.7. Comparison 1 DIACEREIN VS PLACEBO, Outcome 7 Radiographic Progression.
Study or subgroup Diacerein Placebo Risk Ratio Weight Risk Ratio
n/N n/N M-H, Random, 95% CI M-H, Random, 95% CI
1.7.1 Hip
Dougados 2001 112/221 136/225 93.04% 0.84[0.71,0.99]
Subtotal (95% CI) 221 225 93.04% 0.84[0.71,0.99]
Total events: 112 (Diacerein), 136 (Placebo)

1.7.2 Knee
Pham 2004 16/85 17/85 6.96% 0.94[0.51,1.74]
Subtotal (95% CI) 85 85 6.96% 0.94[0.51,1.74]

Total (95% CI) 306 310 100% 0.85[0.72,0.99]
Favours treatment 0.2 0.5 1 2 5 Favours control


Informed decisions.

Analysis 1.8. Comparison 1 DIACEREIN VS PLACEBO, Outcome 8 Adverse Effects.

1.8.1 Diarrhoea
Brahmachari 2009 1/28 0/27 1.35% 2.9[0.12,68.15]
Dougados 2001 117/255 31/252 26.4% 3.73[2.61,5.32]
Lequesne 1998 35/90 11/93 17.98% 3.29[1.78,6.07]
Nguyen 1994 31/75 3/71 8.22% 9.78[3.13,30.58]
Pavelka 2007 13/82 7/83 12.12% 1.88[0.79,4.47]
Pelletier 2000 33/111 17/125 20.56% 2.19[1.29,3.7]
Pham 2004 41/85 6/85 13.37% 6.83[3.06,15.24]
Subtotal (95% CI) 726 736 100% 3.52[2.42,5.11]

1.8.2 Dyspepsia
Dougados 2001 11/255 17/252 35.73% 0.64[0.31,1.34]
Nguyen 1994 7/75 8/71 22.29% 0.83[0.32,2.17]
Pelletier 2000 7/111 4/125 14.69% 1.97[0.59,6.55]
Pham 2004 11/85 8/85 27.29% 1.38[0.58,3.25]
Subtotal (95% CI) 526 533 100% 0.98[0.61,1.58]

1.8.3 Rash or Pruritus
Brahmachari 2009 1/28 1/27 7.51% 0.96[0.06,14.65]
Dougados 2001 17/255 7/252 62.58% 2.4[1.01,5.69]
Nguyen 1994 2/75 3/71 17.43% 0.63[0.11,3.67]
Pham 2004 6/85 1/85 12.48% 6[0.74,48.78]
Subtotal (95% CI) 443 435 100% 1.99[0.94,4.23]

1.8.4 Urine Descolouration
Dougados 2001 79/255 6/252 92.55% 13.01[5.78,29.29]
Pham 2004 6/85 0/85 7.45% 13[0.74,227.2]
Subtotal (95% CI) 340 337 100% 13.01[5.96,28.4]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=1); I2=0%

1.8.5 Epigastralgia
Nguyen 1994 6/75 8/71 59.8% 0.71[0.26,1.94]
Pham 2004 6/85 4/85 40.2% 1.5[0.44,5.13]
Subtotal (95% CI) 160 156 100% 0.96[0.44,2.09]
Test for subgroup differences: Chi2=41.14, df=1 (P<0.0001), I2=90.28%

Informed decisions.


Analysis 1.9. Comparison 1 DIACEREIN VS PLACEBO, Outcome 9 Drop Out.
1.9.1 Ineffective intervention
Dougados 2001 48/262 71/259 80.12% 0.67[0.48,0.92]
Pelletier 2000 12/111 23/125 19.88% 0.59[0.31,1.12]
Subtotal (95% CI) 373 384 100% 0.65[0.49,0.87]

1.9.2 Adverse effect
Brahmachari 2009 1/28 1/27 2.46% 0.96[0.06,14.65]
Dougados 2001 65/262 29/259 27.8% 2.22[1.48,3.31]
Lequesne 1998 29/90 34/93 27.83% 0.88[0.59,1.32]
Nguyen 1994 6/75 4/71 9.6% 1.42[0.42,4.82]
Pavelka 2007 7/82 4/83 9.99% 1.77[0.54,5.82]
Pelletier 2000 11/111 14/125 17.78% 0.88[0.42,1.87]
Pham 2004 2/85 2/85 4.55% 1[0.14,6.94]
Subtotal (95% CI) 733 743 100% 1.29[0.83,2.01]

1.9.3 Other
Dougados 2001 11/262 14/252 60.12% 0.76[0.35,1.63]
Pelletier 2000 8/111 8/125 39.88% 1.13[0.44,2.9]
Subtotal (95% CI) 373 377 100% 0.89[0.49,1.61]
Test for subgroup differences: Chi2=6.51, df=1 (P=0.04), I2=69.28%

Comparison 2. DIACEREIN VS NSAIDs

studies partici-
pants
1 WOMAC subscore (Physical 2 345 Mean Difference (IV, Random, 95% CI) 29.50 [-23.17, 82.17]
Function)
1.1 Knee 2 345 Mean Difference (IV, Random, 95% CI) 29.50 [-23.17, 82.17]
2 Quality of Life 1 Mean Difference (IV, Random, 95% CI) Subtotals only
3 Adverse Effects 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only

Informed decisions.


studies partici-
pants
3.3 Dizziness 3 505 Risk Ratio (M-H, Random, 95% CI) 0.86 [0.18, 4.15]
3.4 Bowel Motility Disorders 2 321 Risk Ratio (M-H, Random, 95% CI) 6.95 [2.11, 22.89]
3.5 Rash or Pruritus 1 150 Risk Ratio (M-H, Random, 95% CI) 5.0 [0.24, 102.42]
4 Drop Out 3 534 Risk Ratio (M-H, Random, 95% CI) 0.96 [0.38, 2.44]
5 Pain VAS 0 to 100 1 150 Mean Difference (IV, Fixed, 95% CI) 2.0 [-6.48, 10.48]
6 Womac Pain 1 161 Mean Difference (IV, Fixed, 95% CI) 14.0 [-10.15, 38.15]
7 Pain on walking 20 m 1 213 Mean Difference (IV, Fixed, 95% CI) 1.30 [-3.81, 6.41]

Analysis 2.1. Comparison 2 DIACEREIN VS NSAIDs, Outcome 1 WOMAC subscore (Physical Function).
Study or subgroup Diacerein NSAID Mean Difference Weight Mean Difference
2.1.1 Knee
Louthrenoo 2007 82 301 (299.1) 79 265.4 37.07% 35.6[-50.91,122.11]
(260.2)
Zheng 2006 92 656.2 92 630.3 62.93% 25.91[-40.48,92.3]
(216.1) (242.6)
Subtotal *** 174 171 100% 29.5[-23.17,82.17]

Total *** 174 171 100% 29.5[-23.17,82.17]

Analysis 2.2. Comparison 2 DIACEREIN VS NSAIDs, Outcome 2 Quality of Life.
Louthrenoo 2007 82 517.9 79 558.6 0% -40.7[-85.2,3.8]
(146.7) (141.4)
Favours control -100 -50 0 50 100 Favours experimental


Informed decisions.

Analysis 2.3. Comparison 2 DIACEREIN VS NSAIDs, Outcome 3 Adverse Effects.

Study or subgroup Diacerein NSAID Risk Ratio Weight Risk Ratio
2.3.1 Diarrhoea
Louthrenoo 2007 31/86 9/85 36.89% 3.4[1.73,6.71]
Nguyen 1994 31/75 5/75 29.66% 6.2[2.55,15.08]
Zheng 2006 15/92 9/92 33.45% 1.67[0.77,3.61]
Subtotal (95% CI) 253 252 100% 3.2[1.58,6.49]
Total events: 77 (Diacerein), 23 (NSAID)

2.3.2 Dyspepsia
Louthrenoo 2007 19/86 28/85 54.96% 0.67[0.41,1.11]
Nguyen 1994 7/75 5/75 31.63% 1.4[0.47,4.21]
Zheng 2006 1/92 7/92 13.4% 0.14[0.02,1.14]
Subtotal (95% CI) 253 252 100% 0.69[0.29,1.61]

2.3.3 Dizziness
Louthrenoo 2007 5/86 4/85 58.09% 1.24[0.34,4.44]
Nguyen 1994 1/75 0/75 19.47% 3[0.12,72.49]
Zheng 2006 0/92 4/92 22.44% 0.11[0.01,2.03]
Subtotal (95% CI) 253 252 100% 0.86[0.18,4.15]

2.3.4 Bowel Motility Disorders
Louthrenoo 2007 11/86 2/85 65.22% 5.44[1.24,23.8]
Nguyen 1994 11/75 1/75 34.78% 11[1.46,83.08]
Subtotal (95% CI) 161 160 100% 6.95[2.11,22.89]

2.3.5 Rash or Pruritus
Nguyen 1994 2/75 0/75 100% 5[0.24,102.42]
Subtotal (95% CI) 75 75 100% 5[0.24,102.42]

Analysis 2.4. Comparison 2 DIACEREIN VS NSAIDs, Outcome 4 Drop Out.
Louthrenoo 2007 3/86 7/85 29.99% 0.42[0.11,1.58]

Informed decisions.


Nguyen 1994 6/75 2/75 23.99% 3[0.63,14.39]
Zheng 2006 9/106 10/107 46.02% 0.91[0.38,2.15]

Total (95% CI) 267 267 100% 0.96[0.38,2.44]

Analysis 2.5. Comparison 2 DIACEREIN VS NSAIDs, Outcome 5 Pain VAS 0 to 100.
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Nguyen 1994 75 40 (26) 75 38 (27) 100% 2[-6.48,10.48]

Total *** 75 75 100% 2[-6.48,10.48]
Favours diacerein -100 -50 0 50 100 Favours NSAID

Analysis 2.6. Comparison 2 DIACEREIN VS NSAIDs, Outcome 6 Womac Pain.
Louthrenoo 2007 82 84.7 (85.8) 79 70.7 (70) 100% 14[-10.15,38.15]

Total *** 82 79 100% 14[-10.15,38.15]

Analysis 2.7. Comparison 2 DIACEREIN VS NSAIDs, Outcome 7 Pain on walking 20 m.
Zheng 2006 106 28.6 (19.7) 107 27.3 (18.3) 100% 1.3[-3.81,6.41]

Total *** 106 107 100% 1.3[-3.81,6.41]


Informed decisions.

Comparison 3. DIACEREIN VS OTHER SYSADOA(Symptom modifier slow acting drug for OA)

studies partici-
pants
1 Visual analogue scale for pain 2 312 Mean Difference (IV, Random, 95% 1.51 [-4.22, 7.23]
CI)
1.1 Knee and/or hip 1 96 Mean Difference (IV, Random, 95% 4.50 [-4.67, 13.67]
CI)
1.2 Knee-change score 1 216 Mean Difference (IV, Random, 95% -0.40 [-7.73, 6.93]
CI)
2 Lequesne Impairment Index 2 311 Mean Difference (IV, Random, 95% 0.37 [1.00, 1.73]
CI)
2.1 Knee and/or hip 1 95 Mean Difference (IV, Random, 95% 0.27 [-1.17, 1.71]
CI)
2.2 Knee-change score 1 216 Mean Difference (IV, Random, 95% 1.20 [-3.01, 5.41]
CI)
3 Radiographic progression 1 216 Risk Ratio (M-H, Random, 95% CI) 1.07 [0.60, 1.91]
4 Adverse effects 2 Risk Ratio (M-H, Random, 95% CI) Subtotals only
4.1 Total 2 338 Risk Ratio (M-H, Random, 95% CI) 1.41 [0.60, 3.34]
4.2 Knee pain after intra-articular in- 1 216 Risk Ratio (M-H, Random, 95% CI) 0.35 [0.16, 0.75]
jection
4.5 Dizziness 1 216 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.20, 1.90]
4.6 Influenza-like and respiratory 1 216 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.46, 1.50]
symptoms
4.7 Urine discolouration 1 216 Risk Ratio (M-H, Random, 95% CI) 19.95 [1.14, 349.67]
5 Dropout 2 338 Risk Ratio (M-H, Random, 95% CI) 1.42 [0.78, 2.58]

Analysis 3.1. Comparison 3 DIACEREIN VS OTHER SYSADOA(Symptom
modifier slow acting drug for OA), Outcome 1 Visual analogue scale for pain.
Study or subgroup Diacerein SYSADOA Mean Difference Weight Mean Difference
3.1.1 Knee and/or hip
Chantre 2000 44 35.8 (22.8) 52 31.3 (22.9) 38.95% 4.5[-4.67,13.67]
Subtotal *** 44 52 38.95% 4.5[-4.67,13.67]

Informed decisions.



3.1.2 Knee-change score
Pham 2004 85 -33.9 (25.7) 131 -33.5 (28.5) 61.05% -0.4[-7.73,6.93]
Subtotal *** 85 131 61.05% -0.4[-7.73,6.93]

Total *** 129 183 100% 1.51[-4.22,7.23]

modifier slow acting drug for OA), Outcome 2 Lequesne Impairment Index.
3.2.1 Knee and/or hip
Chantre 2000 43 7.4 (3.2) 52 7.2 (4) 89.49% 0.27[-1.17,1.71]
Subtotal *** 43 52 89.49% 0.27[-1.17,1.71]

3.2.2 Knee-change score
Pham 2004 85 -18.8 (14.7) 131 -20 (16.5) 10.51% 1.2[-3.01,5.41]
Subtotal *** 85 131 10.51% 1.2[-3.01,5.41]

Total *** 128 183 100% 0.37[-1,1.73]

modifier slow acting drug for OA), Outcome 3 Radiographic progression.
Study or subgroup Diacerein NRD101 Risk Ratio Weight Risk Ratio
Pham 2004 16/85 23/131 100% 1.07[0.6,1.91]

Total (95% CI) 85 131 100% 1.07[0.6,1.91]
Total events: 16 (Diacerein), 23 (NRD101)

Informed decisions.

Study or subgroup Diacerein NRD101 Risk Ratio Weight Risk Ratio


modifier slow acting drug for OA), Outcome 4 Adverse effects.
Study or subgroup Diacerein SYSADOA Risk Ratio Weight Risk Ratio
3.4.1 Total
Chantre 2000 21/60 10/62 42.98% 2.17[1.12,4.22]
Pham 2004 71/85 107/131 57.02% 1.02[0.9,1.16]
Subtotal (95% CI) 145 193 100% 1.41[0.6,3.34]
Total events: 92 (Diacerein), 117 (SYSADOA)

3.4.2 Knee pain after intra-articular injection
Pham 2004 7/85 31/131 100% 0.35[0.16,0.75]
Subtotal (95% CI) 85 131 100% 0.35[0.16,0.75]

3.4.3 Diarrhoea
Chantre 2000 16/60 5/62 30.52% 3.31[1.29,8.46]
Pham 2004 34/85 11/131 69.48% 4.76[2.56,8.88]
Subtotal (95% CI) 145 193 100% 4.26[2.54,7.16]

3.4.4 Dyspepsia
Chantre 2000 3/60 3/62 21.3% 1.03[0.22,4.92]
Pham 2004 11/85 10/131 78.7% 1.7[0.75,3.82]
Subtotal (95% CI) 145 193 100% 1.53[0.74,3.13]

3.4.5 Dizziness
Pham 2004 4/85 10/131 100% 0.62[0.2,1.9]
Subtotal (95% CI) 85 131 100% 0.62[0.2,1.9]

3.4.6 Influenza-like and respiratory symptoms
Pham 2004 14/85 26/131 100% 0.83[0.46,1.5]

Informed decisions.


Subtotal (95% CI) 85 131 100% 0.83[0.46,1.5]

3.4.7 Urine discolouration
Pham 2004 6/85 0/131 100% 19.95[1.14,349.67]
Subtotal (95% CI) 85 131 100% 19.95[1.14,349.67]

modifier slow acting drug for OA), Outcome 5 Dropout.
Chantre 2000 18/60 12/62 87.32% 1.55[0.82,2.93]
Pham 2004 2/85 4/131 12.68% 0.77[0.14,4.12]

Total (95% CI) 145 193 100% 1.42[0.78,2.58]

Comparison 4. Diacerein versus Placebo/ Sensitivity

studies partici-
pants
1 Pain on VAS (0 to 100 mm) 2 677 Mean Difference (IV, Fixed, 95% CI) 0.48 [-3.90, 4.86]
1.1 Longer studies (longer than six 2 677 Mean Difference (IV, Fixed, 95% CI) 0.48 [-3.90, 4.86]
months)

Analysis 4.1. Comparison 4 Diacerein versus Placebo/ Sensitivity, Outcome 1 Pain on VAS (0 to 100 mm).
4.1.1 Longer studies (longer than six months)
Dougados 2001 255 -3 (30.2) 252 -3 (29.9) 69.97% 0[-5.23,5.23]
Pham 2004 85 -33.9 (25.7) 85 -35.5 (27.4) 30.03% 1.6[-6.39,9.59]
Favours experimental -100 -50 0 50 100 Favours control

Informed decisions.


Subtotal *** 340 337 100% 0.48[-3.9,4.86]

Total *** 340 337 100% 0.48[-3.9,4.86]

Comparison 5. Subgroup Analysis_Carry over effect

studies partici-
pants
1 Pain on VAS 0 to 100 mm 3 451 Mean Difference (IV, Random, 95% -13.19 [-24.25, -2.13]
CI)
2 WOMAC A (Pain) 2 326 Mean Difference (IV, Random, 95% -80.37 [-153.26, -7.47]
CI)
3 WOMAC B (Stiffness) 3 381 Mean Difference (IV, Random, 95% -20.42 [-30.52, -10.31]
CI)
4 WOMAC C (Physical function) 3 381 Mean Difference (IV, Random, 95% -233.30 [-363.30, -103.30]
CI)

Analysis 5.1. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 1 Pain on VAS 0 to 100 mm.
Study or subgroup diacerein carry over control carry over Mean Difference Weight Mean Difference
Brahmachari 2009 28 33.4 (20.8) 27 60 (22.5) 28.12% -26.6[-38.06,-15.14]
Lequesne 1998 90 36.8 (25.5) 93 48.5 (26.8) 33.88% -11.7[-19.28,-4.12]
Zheng 2006 106 1.1 (14.2) 107 5.7 (17.5) 38% -4.6[-8.88,-0.32]

Total *** 224 227 100% -13.19[-24.25,-2.13]
Heterogeneity: Tau2=79.07; Chi2=13.44, df=2(P=0); I2=85.12%


Informed decisions.

Analysis 5.2. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 2 WOMAC A (Pain).
Louthrenoo 2007 82 82.9 (88.3) 79 201.3 48.88% -118.4[-158.82,-77.98]
(161.5)
Pavelka 2007 82 148 (109.8) 83 192 (113.1) 51.12% -44[-78.01,-9.99]

Total *** 164 162 100% -80.37[-153.26,-7.47]

Analysis 5.3. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 3 WOMAC B (Stiffness).
Brahmachari 2009 28 47.2 (50.7) 27 62 (81.3) 7.89% -14.8[-50.76,21.16]
Louthrenoo 2007 82 36.1 (37.2) 79 56.9 (56.2) 46.73% -20.8[-35.58,-6.02]
Pavelka 2007 82 67 (46.8) 83 88 (51.4) 45.38% -21[-36,-6]

Total *** 192 189 100% -20.42[-30.52,-10.31]

Analysis 5.4. Comparison 5 Subgroup Analysis_Carry over effect, Outcome 4 WOMAC C (Physical function).
Brahmachari 2009 28 581 (538) 27 757 (427) 18.45% -176[-432.23,80.23]
Louthrenoo 2007 82 297.8 79 639 (516.5) 38.59% -341.2[-474.83,-207.57]
(322.9)
Pavelka 2007 82 544 (366.1) 83 705 (392.1) 42.96% -161[-276.73,-45.27]

Total *** 192 189 100% -233.3[-363.3,-103.3]

APPENDICES
Appendix 1. MEDLINE search strategy

1. exp osteoarthritis/
2. osteoarthr$.tw.
3. (degenerative adj2 arthritis).tw.
4. arthrosis.tw.
5. or/1-4
6. Diacetylrhein/
Informed decisions.

7. Diacerein.tw.
8. Diacerhein.tw.
9. Rhein.tw.
10. Diacetylrhein.tw.
11. Anthraquinone Derivative/
12. Anthraquinone$.tw.
13. or/6-12
14. 5 and 13
Appendix 2. CENTRAL search strategy

CDSR, ACP, DARE, HTA
1. exp osteoarthritis/
2. osteoarthr$.tw.
3. (degenerative adj2 arthritis).tw.
4. arthrosis.tw.
5. or/1-4
6. Diacetylrhein.tw.
7. Diacerein$.tw.
8. Diacerhein.tw.
9. Rhein.tw.
10. Anthraquinone Derivative.tw.
11. exp Anthraquinones/
12. Anthraquinone$.tw.
13. or/6-12
14. 5 and 13
Appendix 3. EMBASE search strategy

1. 'osteoarthritis'/exp
2. osteoarthr*:ab,ti
3. (degenerative NEAR/2 arthritis):ab,ti
4. arthrosis:ab,ti
5. #1 OR #2 OR #3 OR #4
6. 'diacerein'/exp
7. diacerein*:ab,ti
8. diacerhein:ab,ti
9. diacetylrhein:ab,ti
10. 'anthraquinone derivative'/exp
11.'anthraquinone derivative':ab,ti
12. anthraquinon*:ab,ti
13. rhein:ab,ti

Informed decisions.

14. #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13
15. #6 AND #14
Appendix 4. LILACS search strategy

((TW:Osteoarthritis) OR (TW:Osteoartrite) OR (TW: 'Arthritis, Degenerative') OR (MH:C05.550.114.606$) OR (MH:C05.799.613$) OR
(TW:osteoarthr$) OR (TW: 'degenerative arthritis') OR (TW: 'artrite degenerativa') OR (TW:arthrosis) OR (TW:artrose)) AND
((TW:Diacetylrhein) OR (TW:Diacerein$.) OR (TW:Diacerhein) OR (TW:rhein) OR (TW: 'Anthraquinone Derivative') OR (TW:Anthraquinone$)
OR (TW:Antraquinonas) OR (TW:Antraquinonas) OR (TW:Anthracenediones) OR (MH:D02.455.426.559.847.117.159$) OR (MH:D02.806.100$)
OR (MH:D04.615.117.159$))
Appendix 5. International Clinical Trials Register search strategy

Keywords CONTAINS: (Osteoarthritis) OR (degenerative arthritis OR (arthrosis)) AND ((Diacetylrhein) OR (Diacerhein) OR (rhein) OR
(Anthraquinone Derivative) OR (Anthraquinone))
WHAT'S NEW

Date Event Description
14 January 2014 New search has been performed With the addition of three new trials including 141 participants,
the updated review now reports findings of a total of 10 studies
including 2,210 participants. New tools used in the review down-
graded the quality of the evidence.
14 January 2014 New citation required and conclusions Two new review authors, Cristiane Rufino Macedo and Lara
have changed Maxwell, were included in this update.

HISTORY
Protocol first published: Issue 1, 2005
Review first published: Issue 1, 2006

Date Event Description
2 April 2008 Amended CMSG ID C028-R
1 April 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Tania Sales de Alencar Fidelix (TSAF), Cristiane Rufino Macedo (CRM), Lara Maxwell (LM) and Virginia Fernandes Moça Trevisani (VFMT)
contributed to the updated version of this review.
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• UNIFESP Escola Paulista de Medicina, Brazil.
• Brazilian Cochrane Centre, Brazil.

Informed decisions.

External sources
• No sources of support supplied
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
No differences were noted between the objectives and methods described in the protocol and those included in the first published
review. In this updated version, the review authors adhered to the current recommendations of the Cochrane Handbook for Assessment
of Methodological Quality of Studies and included post hoc sensitivity analyses of studies with follow-ups lasting longer than six months.
Therefore, the Jadad scores described in the protocol were not used. As well, the search included a search of four main regulatory agency
websites as per the current CMSG guidance.
INDEX TERMS
Medical Subject Headings (MeSH)

Anthraquinones [*therapeutic use]; Anti-Inflammatory Agents, Non-Steroidal [*therapeutic use]; Osteoarthritis [*drug therapy];
Randomized Controlled Trials as Topic [standards]
MeSH check words

Humans


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Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V

Fidelix TS, Macedo CR, Maxwell LJ, Fernandes Moça Trevisani V.

Diacerein for osteoarthritis (Review) ii

Diacerein for osteoarthritis

Editorial group: Cochrane Musculoskeletal Group

Data collection and analysis

Diacerein for osteoarthritis (Review) 1

Diacerein for osteoarthritis

What is osteoarthritis and what is diacerein?

The review shows that in people with osteoarthitis:

- Pain may improve slightly more in people taking diacerein.

Diacerein for osteoarthritis (Review) 2

Pain after three to 36 months

Diacerein for osteoarthritis (Review) 3

Patient or population: participants with osteoarthritis

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence.

Cochrane Database of Systematic Reviews

BACKGROUND cartilage-degrading enzymes. In addition, cytokines can be

Diacerein for osteoarthritis (Review) 7

which a definite etiology (cause) is not found. Secondary OA is 2. Walking disability.

1. placebo; and 3. Radiographic joint structure changes.

Diacerein for osteoarthritis (Review) 9

Grading of Evidence 1. Pain.

Diacerein for osteoarthritis (Review) 10

Figure 1. Study flow diagram.

Diacerein for osteoarthritis (Review) 11

Diacerein for osteoarthritis (Review) 12

Diacerein for osteoarthritis (Review) 13

Diacerein for osteoarthritis (Review) 14

Diacerein for osteoarthritis (Review) 15

Safety 2. Physical function.

1. Pain. The summary MD was -13.19 (95% CI -24.25 to -2.13).

Diacerein for osteoarthritis (Review) 17

Diacerein for osteoarthritis (Review) 18

It is very important that researchers design studies of good ACKNOWLEDGEMENTS

Diacerein for osteoarthritis (Review) 20

Diacerein for osteoarthritis (Review) 21

Diacerein for osteoarthritis (Review) 22

Villermay 1994 {published data only} Berembaum 2010

Diacerein for osteoarthritis (Review) 23

Hunter 2011 PRAC 2013

Lequesne 1987 Spencer 1997

Characteristics of included studies [ordered by study ID]

Single-blind (participants were blinded)

Diacerein for osteoarthritis (Review) 24

Outcomes Pain on movement in 0 to 100 mm VAS

WOMAC stiffness and physical function

Clinical global impression by investigator on a 5-point Likert scale

Use of rescue medication

Notes The study drug was provided by Macleods Pharmaceuticals Ltd

Bias Authors' judgement Support for judgement

Allocation concealment Low risk Opaque sealed envelopes

Blinding of participants Low risk Blinding only for the participants

Blinding of outcome as- Low risk Not applicable

Participants Outpatients with OA of hip or knee

Diacerein for osteoarthritis (Review) 25

Mean age, years: 61.5

Female 63%; male 37%