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Colchicine – an Established Medication with New Purpose (An Old Drug with New Purpose)

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Colchicine – an Established Medication with New Purpose (An Old Drug with New Purpose) Leader in digital CPD Earn 3 for Southern African Pain healthcare professionals free CEUs Colchicine – an established medication with new purpose (an old drug with new purpose) Learning objectives You will learn: • Emerging research on new therapeutic uses of colchicine, beyond the treatment of gout • The mechanism of action of colchicine, and current understanding of its anti-inflammatory and antiviral effects • Updates to the American College of Rheumatology (ACR) guidelines on the management of gout • The value of colchicine in cardiovascular disease, with a focus on pericarditis and lowering the risk of ischaemic cardiovascular events after myocardial infarction (MI) • Current research on the use of colchicine in the treatment of COVID-19. Introduction Colchicine is currently approved for the prevention and treatment of gout flares in adults. However, off-label uses for colchicine are many and include the treatment of acute calcium pyrophosphate arthritis (pseudogout), sarcoid and psoriatic arthritis, New therapeutic Behcet’s disease and pericarditis; recent studies have shown its efficacy in preventing uses of colchicine, major adverse cardiovascular events in patients who have suffered a recent MI. beyond gout, are being Consequently, new therapeutic uses of colchicine, beyond gout, are being explored. explored Currently, ten colchicine clinical trials are in progress for the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.1,2 This report was made possible by an unrestricted educational grant from Cipla. The content of the report is independent of the sponsor. ©shutterstock/670482994 © 2020 deNovo Medica NOVEMBER 2020 I 1 Colchicine – an established medication with new purpose Mechanism of action Colchicine is an inhibitor of mitosis and such as cell division, maintenance of cell microtubule assembly. It binds to soluble, shape, cell signalling, signal transduction, cell non-polymerised tubulin heterodimers to migration and cellular transport, colchicine form a tight tubulin-colchicine complex. can inhibit these functions. Furthermore, Colchicine interferes with microtubule for- inhibition of amoeboid motility by col- mation and elongation when used at lower chicine prevents disruption of membrane- doses; at higher doses, it promotes microtu- dependent functions, such as chemotaxis and bule depolymerisation. Since microtubules phagocytosis.1 are involved in a variety of cellular processes The colchicine- Colchicine interferes with several inflammatory pathways tubulin complex Most of the anti-inflammatory effects of • Inhibition of neutrophil chemotaxis, adhe- may block both colchicine are probably due to the disruption sion and mobilisation viral entry and of microtubule function; hence, cells with • Disruption of superoxide production replication of high proliferative rates are disproportionately • Inflammasome inhibition coronaviruses affected by the drug. The anti-inflammatory • Reduction of tumour necrosis factor effects are diverse (Figure 1) and include:1 (TNF)-α and its receptors. Neutrophils Colchicine Chemotaxis Adhesion Mobilisation NLRP3 Inflammasome ROS Tubulin-colchicine complex Caspase-1 lower colchicine dose Polymerisation NF- B Il-1β Pro-Il-1β κ higher colchicine dose TNF-α Depolymerisation Figure 1. Anti-inflammatory mechanism of action – colchicine1 Colchicine has antiviral properties Tubulin ligands have the potential to inhibit and may influence HIV viral load. The the replication of viruses that depend on colchicine-tubulin complex may block both the microtubule network for intracellular viral entry and replication of coronaviruses, transport of viral particles in the host cell. and animal studies indicate that colchicine Colchicine has been reported to cause a sig- reduces replication of respiratory syncytial nificant decrease in replication of flaviviruses virus.1 2 I NOVEMBER 2020 Colchicine – an established medication with new purpose Colchicine in the pharmacotherapy of gout Gout is one of the commonest forms of extremely sensitive to any touch. The first inflammatory arthritis that affects adults metatarsophalangeal (big toe) is the joint and is associated with impaired quality of most often affected, accounting for 50% of all life. Gout is caused by the chronic accumula- attacks. Gout flares usually self-resolve within tion of monosodium urate (MSU) crystals, 7-10 days and are interspersed with asympto- which preferentially deposit within joints and matic periods. Over time, prolonged hyperu- periarticular structures. This occurs as a con- ricaemia may result in more frequent and sequence of hyperuricaemia, an excess of uric severe flares that also affect the upper limbs acid (Table 1). It is important to note that the and multiple joints (polyarticular flares).2 majority of individuals with hyperuricaemia do not develop gout.2 Tophi or subcutaneous deposits usually develop over time in the absence of urate-low- Table 1. Causes of hyperuricaemia ering therapy (ULT), approximately 10 years after the initial gout flare. The transition • Over-production of uric acid (±10% of sufferers) from normouricaemia to clinically evident – Haematological malignancies, haemolysis, gout occurs in a number of stages (Figure 2). psoriasis Factors that contribute to the transition from – Rare genetic disorders (e.g. Lesch-Nyhan hyperuricaemia to clinically evident gout are syndrome) not well understood.2 • Under-excretion of uric acid (±90% of attacks) – Diets high in purine-rich foods (seafood, Atypical manifestations of gout occur more offal, alcohol particularly beer), sweetened frequently in women and elderly individuals. It is important processed foods and drinks) These may include the development of tophi – Metabolic syndrome including hypertension, without accompanying flares, occasionally to note that diabetes, obesity and dyslipidaemia observed in patients who are receiving corti- the majority of – Genetic predisposition costeroids for other conditions, and first pres- – Drugs: diuretics, low-dose aspirin, cyclosporine. individuals with entation as a flare that involves several joints hyperuricaemia symmetrically distributed. Uncommonly, do not develop The gout flare represents an acute inflam- gout may involve proximal large joints other gout matory response to deposited MSU crystals; than the knee and the spine.2 the affected joint is swollen, red, hot and Clinical manifestation Disease progression Risk factor or cause No disease Normouricaemia • Genetic factors (e.g. SNPs in urate transporter genes) • Environmental factors (e.g. diet and BMI) • Impaired kidney function Hyperuricaemia • Increasing age • Male sex • Medications Asymptomatic state • High cell turnover states, etc. MSU crystal deposition • Reduced solubility of urate EARN FREE • Increased nucleation of MSU CPD POINTS Recurrent gout flares crystals Join our CPD community at • Growth of MSU crystals Symptomatic disease www.denovomedica.com Acute inflammatory response to deposited MSU crystals and start to earn today! Chronic gouty arthritis and tophaceous gout Chronic granulomatous Symptomatic disease inflammatory response to with complications deposited crystals SNP: single-nucleotide polymorphism; Figure 2. Disease progression in gout2 BMI: body mass index; MSU: monosodium urate NOVEMBER 2020 I 3 Colchicine – an established medication with new purpose Management of gout Several randomised clinical trials were con- findings led to the 2020 update of the ACR ducted in recent years and provide additional guidelines.3 evidence on the management of gout; these What are the ACR recommendations for the management of gout flares? Colchicine, nonsteroidal anti-inflammatory either ineffective, poorly tolerated or con- drugs (NSAIDs) or glucocorticoids are traindicated. Adrenocorticotropic hormone is recommended as first-line therapy, depend- recommended for patients who are unable to ing on renal function. When colchicine is take oral medications.3 the chosen agent, low-dose colchicine over high-dose colchicine is strongly recom- Canakinumab is also an effective therapy for mended given similar efficacy and a lower gout flares but its use is limited by cost; it is risk of adverse effects, particularly diarrhoea. currently reserved for patients in whom other Using an interleukin-1 (IL-1) inhibitor over options are ineffective or contraindicated. no therapy (beyond supportive/analgesic The IL-1 receptor antagonist, anakinra, has treatment) is conditionally recommended for been shown to be non-inferior to colchicine, patients experiencing a gout flare in whom NSAIDs and prednisone in the management colchicine, NSAIDs and glucocorticoids are of acute gout flares.2 What are the indications for initiation of ULT? Sustained reduction in serum urate (SU) there may be the added benefit of using ULT levels using ULT is vital in the long-term to prevent progression of renal disease. management of gout, which aims to reduce gout flares and resolve tophi. Indications for The ACR recommends against initiation of ULT are outlined in Table 2.3 ULT in patients experiencing their first flare of ‘uncomplicated’ gout, noting, however, There is a high certainty of evidence regard- that there may be specific patients who would ing the efficacy of ULT in reducing flare prefer or benefit from ULT, underscoring frequency, tophi and SU concentrations in the need for shared decision-making between patients with subcutaneous tophi, radio- practitioner and patient. Because the major- graphic damage attributable to gout or ity of patients
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