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

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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

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

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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

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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 with asymptomatic hyperuri- frequent gout flares. For patients who have caemia (including those with comorbid infrequent flares and no tophi, the potential CKD, cardiovascular disease, urolithiasis clinical benefit of ULT is lower than for those or hypertension) are unlikely to progress to with more burdensome gout.2,3 gout within five years, the ACR recommends against the initiation of ULT as the benefits In patients with moderate-to-severe chronic would not outweigh potential treatment costs kidney disease (CKD) stage ≥3, SU >9mg/dl or risks for the large number of patients or urolithiasis, who are experiencing their unlikely to progress to gout. This is also the first gout flare, there may be benefit to initiat- case for patients with asymptomatic hyperuri- ing ULT as there is a higher likelihood of caemia with MSU crystal deposition, as gout progression and the development of noted on imaging tests such as ultrasound or clinical tophi in these patients. Furthermore, dual-energy computed tomography.

Table 2. Indications for pharmacological ULT – ACR guidelines

Strongly recommend initiating ULT over no ULT • Frequent gout flares (≥2/year) • Subcutaneous tophi • Radiographic damage (any modality) attributable to gout. Conditionally recommend initiating ULT over no ULT • Previously experienced >1 flare but have infrequent flares (<2/year) and no tophi • For patients experiencing their first flare and CKD stage ≥3, SU >9mg/dl, or urolithiasis. Conditionally recommend against initiating ULT over no ULT • First flare of ‘uncomplicated’ gout • For patients with asymptomatic hyperuricaemia (SU >6.8mg/dl with no prior gout flares or subcutaneous tophi).

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When it is decided that ULT is indicated A treat-to-target strategy is strongly recom- while the patient is experiencing a gout flare, mended for all patients receiving ULT. This the ACR conditionally recommends start- includes ULT dose titration and subsequent ing low-dose ULT during the gout flare over dosing guided by serial SU measurements to starting ULT after the gout flare has resolved. achieve and maintain a target SU of <6mg/dl Patients are likely to be motivated to take (<0.36 mmol/l), and lower (<0.30mmol/l) ULT due to the symptoms related to the if there is a heavy burden of tophi. ULT current flare, and concerns about prolonging titration should occur over a reasonable time the flare by initiating ULT during one are frame of weeks to months, not years, in order unfounded. A lower starting dose of any ULT to prevent ‘treatment inertia’. Models of care, reduces the risk of flare associated with initia- such as nurse-led strategies that focus on tion, as well as specific safety issues such as patient engagement and education, substan- allopurinol hypersensitivity syndrome.4 tially improve clinical outcomes and now rep- resent best practice for gout management.2,3 What are the ACR recommendations for choice of ULT? An increasing number of urate-lowering safety and lower cost. Febuxostat is useful for drugs are available and can be grouped based patients with allopurinol hypersensitivity syn- on their mechanism of action. The xanthine drome. Probenecid is useful if XOIs are not oxidase inhibitors (XOIs), allopurinol and tolerated, or in combination with allopurinol. Patients are febuxostat, inhibit urate formation; uricosu- likely to be ric drugs (e.g. probenecid) inhibit renal urate In the patient with CKD stage ≥3, either motivated to transporters; and the recombinant uricase, allopurinol or febuxostat can be used; initiate pegloticase, inhibits enzymes that metabolise treatment at a low dose (allopurinol ≤100mg/ take ULT due to urate.2 day, febuxostat ≤40mg/day) with subsequent the symptoms dose titration. If using probenecid, initiate at related to Allopurinol is the preferred first-line agent a low dose (500mg once to twice daily), with the current for ULT based on its efficacy, tolerability, subsequent dose titration. flare, and Anti-inflammatory prophylaxis therapy with ULT concerns about Because ULT may precipitate gout flares, courses of ‘handbag’ NSAIDs or corticos- prolonging concomitant anti-inflammatory prophylaxis teroids) continued for 3-6 months after ULT the flare by (e.g. daily or twice-daily colchicine, short initiation is strongly recommended. initiating ULT Management of lifestyle factors in patients with gout during one are Conditional recommendations include extremely difficult to maintain in the long unfounded limiting intake of alcohol, purine-rich foods term and has minimal effect on SU levels. and high-fructose corn syrup, regardless of Low-dose aspirin and diuretic use should be disease activity, as is using a weight loss pro- assessed and minimised where possible, but gramme (avoiding crash diets, which may pre- may be necessary to manage cardiovascular cipitate flares) for those who are overweight risk, hypertension and heart failure.2,3 or obese. However, dietary modification is

What is the value of colchicine in cardiovascular EARN FREE CPD POINTS disease? Join our CPD community at Pericarditis www.denovomedica.com Acute pericarditis is usually a self-limiting constriction and post-pericardiotomy syn- process with negligible mortality but signifi- drome (PPS).5,6 and start to earn today! cant morbidity. A minority of cases develop recurrent or incessant symptoms, but only a Meta-analysis of 10 randomised trials assess- few progress to chronic constriction. Recent ing the efficacy and safety of colchicine in evidence on therapeutic targets in pericarditis 1 981 patients with pericarditis or PPS has demonstrated that NLRP3 inflamma- confirms that colchicine is efficacious and some blockade is the cornerstone of the clini- safe for the prevention of recurrent pericar- cal benefits of colchicine, which extend from ditis, with significant reductions in the risk acute and recurrent pericarditis to transient of recurrence, the risk of rehospitalisation

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due to pericarditis, as well as the number of colchicine adverse events, so careful medica- patients with persistent symptoms after 72 tion reconciliation is advised before prescrib- hours. Colchicine is effective in reducing both ing colchicine in the cardiac patient to avoid the risk of PPS and the rehospitalisation rate potentially harmful interactions. after PPS but has not been associated with a significant reduction of postoperative peri- With regard to colchicine dosing in the cardial effusion when compared to placebo.7 management of pericarditis, clinical guidelines recommend adjunctive low doses (0.6mg The use of adjunctive colchicine in the man- twice a day, or 0.6mg once a day if weight agement of inflammatory pericardial diseases <70kg) for at least three months during an is standard of care in current practice. Many episode of acute pericarditis and at least six cardiovascular drugs have the pharma- months for recurrent episodes.5,6 cokinetic potential to increase the risk for

MI Because acute coronary syndromes are associ- The Colchicine Cardiovascular Outcomes The use of ated with higher risks of recurrent events and Trial (COLCOT) evaluated the effects of col- exacerbated inflammation, anti-inflammatory chicine on cardiovascular outcomes in adjunctive treatment may reduce the risk of atheroscle- 4 745 patients who were recruited within colchicine in the rotic events among patients with coronary 30 days after a MI. Patients were randomly management of artery disease. In the Low-Dose Colchicine assigned to receive either low-dose colchicine inflammatory (LoDoCo) trial,8 patients with stable coro- (0.5mg once daily) or placebo, and followed pericardial nary disease treated with colchicine (0.5mg for a median of 22.6 months. Treatment with once daily) had fewer cardiovascular events colchicine led to a significantly lower risk of diseases is than those not receiving colchicine. However, ischaemic cardiovascular events than placebo standard of that trial enrolled only 532 patients and was (Figure 3). This result was due predominantly care in current not placebo controlled. to a lower incidence of strokes and urgent practice hospitalisations for angina leading to coronary revascularisation.9

100 15 Hazard ratio, 0.77 (95% CI, 0.61–0.96) 90 P=0.02

80 10 Placebo 70

60 Colchicine 5 50 Cumulative Incidence %) 40 0 30 0 7 14 21 28 35 42

Cumulative Incidence %) 10

0 0 7 14 21 28 35 42

Months since Randomisation No. at Risk Placebo 2 379 2 261 1 854 1 224 622 144 0 Colchicine 2 366 2 284 1 868 1 230 628 153 0

Figure 3. COLCOT – cumulative incidence of cardiovascular events (intention-to-treat population)9 Shown are the Kaplan–Meier event curves for the primary efficacy composite endpoint of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalisation for angina leading to coronary revascularisation in the colchicine group and the placebo group in a time-to-event analysis. The inset shows the same data on an enlarged y-axis.

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Colchicine and COVID-19 COVID-19 results in an intense inflamma- trial, randomised 105 patients hospitalised tory response, predominantly affecting the with COVID-19 in a 1:1 allocation to either respiratory system. NLRP3 inflammasome standard medical treatment or the addition activation has been implicated in acute lung of colchicine (1.5mg loading dose followed injury or acute respiratory distress syndrome by 0.5mg after 60 minutes and maintenance in certain patients infected with COVID-19. doses of 0.5mg twice daily) with stand- Within this pathophysiological framework, ard medical treatment, for as long as three colchicine is a potential candidate for treat- weeks. Participants who received colchicine ment of COVID-19 as it possesses potent had a statistically significant time to clini- anti-inflammatory action, an element of cal improvement. There were no significant which is NLRP3 inflammasome inhibition, differences in high-sensitivity cardiac tro- without the adverse effects of steroids and ponin or C-reactive protein levels; of interest, NSAIDs.1,10 however, there was an attenuated D-dimer increase in patients treated with colchicine The Greek Study in the Effects of Colchicine compared with those in the control arm, in COVID-19 Complications Prevention which suggests an anti-inflammatory and (GRECCO-19),10 a prospective, open-label antithrombogenic effect.

Colchicine is a potential Using colchicine safely – drug interactions candidate for As new therapeutic uses for colchicine are (P-gp) substrate. As such, P-gp inhibitors treatment of explored, safe use of the drug should remain (Table 3) have been reported to cause colchi- COVID-19 as of primary importance, particularly as many cine toxicity. Life-threatening and fatal drug it possesses patients may be on therapies for comorbidi- interactions have been reported in patients potent anti- ties. It must be remembered that colchicine treated with colchicine given with P-gp and is metabolised in the liver and the intestine; potent CYP3A4 inhibitors.1 inflammatory colchicine is a CYP3A4 and P-glycoprotein action, an element of Table 3. P-gp inhibitors causing colchicine toxicity which is NLRP3 inflammasome • Antacids, such as cimetidine • Antibiotics, such as erythromycin and tetracycline inhibition, • Calcium channel blockers, such as diltiazem and verapamil without the • Immunosuppressants, such as cyclosporine and tacrolimus adverse effects • HIV protease inhibitors, such as lopinavir and ritonavir of steroids and • Azole antifungals, such as itraconazole and ketoconazole • Anti-arrhythmic drugs, such as amiodarone and quinidine NSAIDs • Selective oestrogen receptor modulators, such as tamoxifen.

Key learnings

EARN FREE • There are many off-label uses for colchicine CPD POINTS • Colchicine is an inhibitor of mitosis and microtubule assembly; it interferes with several inflammatory Join our CPD community at pathways and has antiviral properties • Colchicine is used in the treatment of acute gout flares; the ACR also recommends its use in patients with www.denovomedica.com chronic disease, as prophylaxis concomitant with ULT and start to earn today! • Colchicine is safe and efficacious for the treatment of recurrent pericarditis, and there is evidence of a significantly lower risk of ischaemic cardiovascular events when used in patients with recent MI • Colchicine is a potential candidate for the treatment of COVID-19 • Colchicine is a CYP3A4 and P-gp substrate; caution is required when concurrently prescribing medicines that inhibit this pathway.

NOVEMBER 2020 I 7 Colchicine – an established medication with new purpose

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References EARN FREE Click on reference to access the scientific article CPD POINTS 1. Schlesinger N, Firestein BL, Brunetti L. Colchicine in COVID-19: 7. Lutschinger LL, Rigopoulos AG, Schlattmann P, et al. an old drug, new use. Curr Pharmacol Rep 2020; 6: 137-145. Meta-analysis for the value of colchicine for the therapy Are you a member of 2. Dalbeth N, Choi HK, Joosten LAB, et al. Gout. Nat Rev Dis of pericarditis and of postpericardiotomy syndrome. BMC Southern Africa’s leading Primers 2019; 5(1): 69. Cardiovasc Disord 2019; 19: 207. digital Continuing 3. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American 8. Nidorf SM, Eikelboom JW, Budgeon CA, et al. Low-dose Professional Development College of Rheumatology guideline for the management of colchicine for secondary prevention of cardiovascular disease. J website earning FREE gout. Arthritis Care Res (Hoboken) 2020; 72(6): 744-760. Am Coll Cardiol 2013; 61: 404-410. CPD points with access to 4. Hill EM, Sky K, Sit M, et al. Does starting allopurinol prolong 9. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low- best practice content? acute treated gout? A randomized clinical trial. J Clin dose colchicine after myocardial infarction. N Engl J Med 2019; Rheumatol 2015; 21(3): 120-125. 381(26): 2497-2505. Only a few clicks and 5. Schenone AL, Menon V. Colchicine in pericardial disease: from 10. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect you can register to start the underlying biology and clinical benefits to the drug-drug of colchicine vs standard care on cardiac and inflammatory earning today interactions in cardiovascular medicine. Curr Cardiol Rep 2018; biomarkers and clinical outcomes in patients hospitalized with 20(8): 62. coronavirus disease 2019: The GRECCO-19 randomized clinical 6. Ismail TF. Acute pericarditis: Update on diagnosis and trial. JAMA Netw Open 2020; 3(6): e2013136. Visit management. Clin Med (Lond) 2020; 20(1): 48-51. www.denovomedica.com

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This CPD-accredited programme was written for deNovo Medica by Glenda Hardy BSc(Hons) Medical Cell Biology Reviewed by Professor Bridget Hodkinson MBBCh, PhD, FCP (SA), Cert Rheum Professor and Head, Rheumatology Disclaimer Published by © 2020 deNovo Medica Division, Department of Medicine, The views and opinions expressed in the article are those of the presenters and do not necessarily reflect Reg: 2012/216456/07 University of Cape Town and Groote those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the 70 Arlington Street, Everglen, Cape Town, 7550 Schuur Hospital product insert documentation as approved by relevant control authorities. Tel: (021) 976 0485 I [email protected]

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