1 Introduction
Osteoarthritis (OA) is the most frequent form of arthritis, and one of the leading causes of disability among older adults worldwide [
1]. For individuals, the burden of OA also includes persistent background pain (aching) and intermittent but generally more intense pain. Together with disability, pain contributes to a significant reduction in quality of life.
The management of OA includes pharmacological therapies, which are mostly symptomatic [
2]. Paracetamol is the first-line oral analgesic, whilst oral non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, are the mainstay of therapy [
3,
4]. These drugs are considered as rapid-acting drugs in OA and are recommended by rheumatology societies [
2,
5,
6] and government agencies [
7].
Symptomatic slow-acting drugs for OA (SYSADOAs) such as glucosamine, chondroitin sulphate and diacerein are used for non-acute treatment. Although there is relative general agreement on many OA management recommendations across organisations, there is still no consensus on the place of SYSADOAs. In general, they are considered supplementary to analgesics and NSAIDs, whereas the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) places SYSADOAs as pharmacological background treatment; that is, first chronic therapy that may improve or control symptoms [
8].
Diacerein is an anthraquinone derivative, of which the active metabolite is rhein. Its positioning in the algorithm established by the ESCEO [
8] had not been formalised because, at the time of publication, diacerein was under review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA). Following the assessment of the PRAC, the ESCEO felt the need to evaluate the role of diacerein in clinical practice and constituted a panel of experts to define its place in the management of OA. This article expresses the reasoned conclusions drawn by the ESCEO working group on diacerein.
2 ESCEO Working Group Process
The ESCEO invited 11 experts in musculoskeletal diseases (rheumatologists, clinical epidemiologists and scientists) to be part of the working group. Four members had already been involved in clinical or preclinical research on diacerein, two of them being current diacerein prescribers; all were proficient in analysing and interpreting clinical trial evidence related to OA.
Five of the participants were entrusted with the task of preparing a review on the mode of action, efficacy and safety of diacerein in the treatment of OA. A literature search was conducted in May 2015 using the MEDLINE/PubMed database. The search strategy included a combination of the following terms: ‘diacerein’, ‘diacetylrhein’, ‘diacerhein’, ‘rhein’ and ‘osteoarthritis’. Filter settings were ‘English’, ‘French’, ‘German’, ‘Spanish’ or ‘Italian’ languages. This literature search yielded 179 hits, of which 108 (57 original research papers, 51 reviews, meta-analyses or opinion-based articles) were retrieved according to their relevance to the topics mentioned above: 42 were related to the mode of action of diacerein, 60 dealt with its clinical efficacy, and 45 contained information on the safety of diacerein. Additional references were selected from the reference lists of the retrieved articles to broaden the literature search.
The outcome of this review was finally discussed by the 11 experts at a one-day meeting in June 2015.
6 Discussion
The overall analysis of randomised controlled clinical studies and meta-analyses confirmed the efficacy of diacerein in the symptomatic treatment of knee and hip OA. An ES on pain of 0.24 (95 % CI 0.08–0.39) has been reported [
52], a value considered to be low but clinically relevant in OA [
66]. Furthermore, as the ES of diacerein and other anti-OA agents is based on the difference between the placebo and the active drug effects, it is relevant to note that unequivocal evidence for a large placebo response has been demonstrated in randomised clinical trials of OA (ES = 0.51, 95 % CI 0.46–0.55) [
67]. The ES of diacerein should therefore be assessed bearing in mind this large placebo response.
Although NSAIDs have shown a more rapid onset of action than diacerein, efficacy of these drugs on pain and joint function was comparable after the first month of treatment. On the other hand, unlike NSAIDs, diacerein has shown a prolonged effect of several months once treatment was stopped. Evidence published by the Osteoarthritis Research Society International (OARSI) indicated that diacerein had a greater efficacy on pain reduction in OA than paracetamol (ES = 0.14, 95 % CI 0.05–0.22), and a similar efficacy compared with NSAIDs (ES = 0.29, 95 % CI 0.22–0.35) [
6].
The use of diacerein is associated with common gastrointestinal disorders (mostly soft stools and diarrhoea), common mild skin reactions, and uncommon hepatobiliary disorders. Frequent cases of severe diarrhoea and rare cases of potentially serious hepatotoxicity were reported; a risk of cutaneous drug reactions could not be excluded [
63].
In order to minimise this risk, it is recommended to start diacerein treatment with half the recommended dose (50 mg/day) for the first 2–4 weeks, the laxative properties of diacerein being dose-dependent [
39]. In the same context, starting a treatment with diacerein is not recommended in patients older than 65 years who are considered to be more vulnerable to diarrhoeal complications [
68]. In parallel, laxatives should be avoided, and concomitant treatment with medicines that can lead to hypokalaemia should be especially monitored. Finally, it is common sense to stop treatment as soon as diarrhoea occurs. To prevent the risk of hepatotoxicity, diacerein is contraindicated in patients with current or a history of liver disease and, therefore, patients should be screened for major causes of active hepatic disease before starting the treatment. Caution should be exercised when diacerein is used concomitantly with products associated with hepatic injury. Treatment should be stopped if elevation of hepatic enzymes or suspected signs or symptoms of liver damage are detected.
Safety of diacerein should be put in the context of paracetamol and NSAID use, drugs that have been shown to cause potentially severe hepatic [
69‐
71], gastrointestinal [
72,
73], renal [
74‐
77], cutaneous [
78] and cardiovascular reactions [
79‐
82]. For example, an incidence of clinically apparent liver injuries of 10.0 per 100,000 patient-years of treatment with NSAIDs has been reported [
83], and paracetamol is responsible for the higher rate of hospitalisations for hepatic failures [
69]. In comparison, the risk of hepatic disorders with diacerein (including elevated hepatic enzymes) was 1.68 per 100,000 patient-years of treatment. Regarding cutaneous reactions, NSAIDs have been reported to be the second most common cause of drug-induced hypersensitivity reaction [
84], and among the drugs that are the most frequently associated with SJS and TEN [
85]. NSAIDs are also known for increasing the risk of cardiovascular events, including congestive heart failure and infarction/stroke [
73,
86,
87].
Several rheumatology societies, such as the European League Against Rheumatism (EULAR) [
2] and the OARSI [
5,
6], have included diacerein in their therapeutic guidelines as a treatment option in OA. However, a review evaluating the benefit–risk ratio of diacerein conducted by the PRAC was initiated in November 2012 following the request of the French Medicines Agency. One year later, the PRAC/EMA initially recommended the suspension of the marketing authorisations for diacerein, but following re-examination, additional proposals to manage the risks of diacerein were considered. As a result, in July 2014, the PRAC/EMA confirmed the safety profile of diacerein, which has not changed in 20 years, and concluded that its benefit–risk balance remained positive in the symptomatic treatment of hip and knee OA [
63].
Based on the opinion of 11 experts in rheumatology, the ESCEO working group underlines the PRAC/EMA conclusions that the benefits of diacerein outweigh its risks and confirms that diacerein is an interesting option in the physician’s armamentarium for treating OA. These conclusions are also in line with those of a review recently published by two independent Australian experts [
88]. Therefore, similarly to other SYSADOAs, the ESCEO positions diacerein as a first-line background pharmacological treatment of OA. However, it should be avoided in patients with a known propensity for diarrhoea, but would be particularly beneficial in patients with contraindications to NSAIDs or paracetamol.
Diacerein is a compound with a long history but whose effects are still not fully understood. Besides the evidence of its efficacy in knee and hip OA, there are very few data on its effect in other OA locations such as the hand, as well as on different types of patient profiles [
89], or OA subtypes. Further research also needs to be performed to define the real potential of diacerein on disease progression with well designed, high quality, structure-modifying clinical trials. Then, depending on the outcomes on cartilage and knowing the proven carry-over therapeutic effect of diacerein, one might question whether continuous or intermittent treatment would be the most reasonable.
Compliance with Ethical Standards
Conflicts of interest
Pr. Pavelka has received lecture fees from Glynn Brothers Chemicals that are not related to the preparation of this manuscript. Pr. Bruyère has received research grants from IBSA, Merck Sharp & Dohme, Novartis, Nutraveris, Pfizer, Rottapharm, Servier, SMB, and Theramex, consulting or lecture fees from Bayer, Genevrier, IBSA, Rottapharm, Servier and SMB, as well as reimbursement for attending meetings from IBSA, Merck Sharp & Dohme, Novartis, Pfizer, Rottapharm, Servier and Theramex. Pr. Cooper has received consulting fees/honoraria from Alliance for Better Bone Health, Amgen, Eli Lilly, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB. Pr. Kanis has received reimbursement for travel expenses from the ESCEO. Dr. Leeb has received consulting and lecture fees from IBSA, Pfizer, Servier and TRB Chemedica that are not related to the preparation opig model of osteoarthritis this manuscript. Dr. Maheu has received reimbursement for travel expenses from the ESCEO. Dr. Monfort declared no conflicts of interest. Pr. Martel-Pelletier and Pr. Pelletier are shareholders in Arthrolab Inc, received reimbursement for travel expenses from the ESCEO, as well as grants, consulting and lecture fees from TRB Chemedica. They also served as expert witnesses during the review of diacerein-containing medicines by the Pharmacovigilance Risk Assessment Committee (PRAC). Pr. Rizzoli declared no conflicts of interest. Pr. Reginster has received consulting fees or payments as an advisory board member from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed-Takeda, NPS, IBSA-Genevrier, Theramex, UCB, Asahi Kasei and Endocyte, lecture fees from Merck Sharp & Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Merckle, Teijin, Teva, Analis, Theramex, Nycomed, NovoNordisk, Ebewee Pharma, Zodiac, Danone, Will-Pharma, and Amgen, and grants from Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Roche, Amgen, Lilly, Novartis, GlaxoSmithKline, Servier, Pfizer, Theramex, Danone, Organon, Therabel, Boehringer, Chiltern and Galapagos.
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