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Efficacy of Diacerein in Osteoarthritis

Some studies showed that diacerein has the potential to treat osteoarthritis. Osteoarthritis (OA) is the most common type of arthritis and is one of the main contributors to disability in geriatric populations throughout the world.

Management of mild Osteoarthritis is symptomatic by administering analgesic (paracetamol or analgesic nonsteroidal anti-inflammatory drugs), and lifestyle modification.

However, long-term use of paracetamol is associated with impaired liver function risk, whereas NSAIDs increase the risk of gastrointestinal bleeding and cardiovascular adverse events. Moreover, neither paracetamol nor NSAIDs affect the pathologic process of OA. Therefore, developed second-line therapy known as symptomatic slow-acting drugs for OA (SYSADOA). The drugs included in this group are glucosamine sulfate, glucosamine hydrochloride, hyaluronic acid, chondroitin sulfate, and diacerein. 

Efficacy of Diacerein in Osteoarthritis
Diacerein

Diacerein (also known as diacetylrhein) is an anthraquinone derivative with active metabolites of rhein. The principal mechanism of action of diacerein is inhibiting interleukin-1 beta (IL-1ß) and downstream signaling related to IL-1ß. Diacerein affects the IL-1ß system via decreased IL-1 converting enzyme production, reduces sensitivity to IL-1 by reducing the number of IL-1 receptors on the surface of chondrocyte cells, and indirectly increases IL-1 receptor antagonist production. Diacerein also inhibits the activation of NF-kappa beta transcription factors induced by IL-1ß.

In addition to anti-inflammatory effects, diacerein has anticatabolic and pro anabolic effects that affect the cartilage and synovial membranes, and also has a protective effect against the process of remodeling subchondral bone.

Clinical data of the efficacy of diacerein in osteoarthritis

Clinical data on the efficacy of diacerein in osteoarthritis (OA) is discussed according to pain reduction and improvement of physical function, structure-modifying effect, and safety aspects.

Efficacy of Diacerein for Pain Reduction and Improvement of Physical Function

The meta-analysis result of 19 studies covering 2637 patients by Rintelen et al., showed the superiority of diacerein over placebo in reducing pain and improving physical function at the end of the study period. These effects carry-over after stopping treatment.

Using the Cochrane reviews, Fidelix et al. conducted a meta-analysis of 10 randomized controlled trials that included 2210 participants. The result of the meta-analysis found that mean-weighted differences tended to be better in the diacerein group than in the placebo. The authors summarize that diacerein has a small but significant effect on OA pain relief after therapy.

In another meta-analysis of six clinical studies covering 1533 patients, the effect size was estimated by Hedges' standardized mean difference; diacerein seems to be superior to placebo for pain reduction or improvement in physical function of patients. 
Efficacy of Diacerein for Structure-Modifying Effect

Two clinical studies examined the effect of diacerein on structure-modifying effects that were reflected in the radiological sign of OA, namely the ECHODIAH (Evaluation of the Structure-Modifying Effects of Diacerein in Hip Osteoarthritis) and Pham studies.

The ECHODIAH study was a multicenter, randomized, double-blind, placebo-controlled study that lasted for 3 years in 507 patients with pelvic OA. The result of the study showed the superiority of diacerein against placebo in 3 of the 4 co-primary endpoints in terms of repairing narrowing joint space but failed to demonstrate the overall structure-modifying effect in pelvic OA patients.

Whereas, the Pham study applied a randomized, double-blind, placebo-controlled, three-arm design for 1 year to evaluate the effects of hyaluronic acid injection versus diacerein versus placebo in 301 patients with knee OA. The result of this study found no statistically significant differences between the three groups in the aspect of the structure-modifying effect.

Comparison of the efficacy of diacerein and glucosamine

The result of a network meta-analysis by Kongtharvonskul et al. from 31 clinical research data published in PubMed and Scopus showed that the efficacy of diacerein and glucosamine is comparable for improvement in pain scores and WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index).

Clinical Data on Safety of Diacerein 

The main side effect of using diacerein, which is widely reported, is diarrhea. It is caused by the laxative effect of the chemical structure of anthraquinone diacerein. Mild to moderate degree of diarrhea is reversible after stopping the administration of diacerein. Bartels et al. calculated the risk ratio (RR) of diarrhea for diacerein compared to the placebo of 3.51. These results are similar to the study report by Fidelix et al.

Report data from 15 published clinical trials indicate that the side effects of diacerein for cutaneous events were 1.8-9.4%. The most commonly reported cutaneous reactions are skin rashes, pruritus, and atopic dermatitis. Post-marketing data have published a small number of severe cases of cutaneous events in the form of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

Of the 15 published clinical trials results in diacerein, only Zheng et al. reported an abnormality in liver function tests that was marked by a mild increase in liver transaminase enzymes without an increase in bilirubin due to diacerein use.

Diacerein does not cause toxicity to the cardiovascular system. Both toxicology study data and post-marketing surveillance data. To date, there have been no reports of cardiovascular problems caused by diacerein use.

Recommendation

Based on available clinical data, some rheumatology experts such as the European League Against Rheumatism (EULAR), European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), and Osteoarthritis Research Society International (OARSI) have recognized and included diacerein in the management of Osteoporosis and Osteoarthritis. However, by the reports of side effects, the use of diacerein should be applied according to the benefit and risk ratio, especially in patients with a high propensity for diarrhea. 

Conclusion
Many studies have shown the efficacy of diacerein in the management of osteoarthritis, especially linked with pain relief and improvement in physical function compared to the placebo. The efficacy is reported to be similar to nonsteroidal anti-inflammatory drugs (NSAIDs), but without the risk of gastrointestinal bleeding and cardiovascular disease, and reported to be better than paracetamol. However, it should be noted that diacerein is associated with various side effects, such as diarrhea, rashes, pruritus, eczema, and cutaneous allergic reactions.

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