Prophylaxis of Acute Gout Flares

Introduction

The goals of therapy in gout include not simply active and rapid treatment of acute gout flares but also prevention of acute gout attacks, whose major precipitating factors are listed in Table 9-1. Acute gout flares in the early phase of urate-lowering therapy (ULT) or intensification of established ULT are most likely due to inflammatory effects in joint tissue due to remodeling and altered stability of tophi in the joint brought on by rapid lowering of serum urate. Local trauma to the joint, including the biomechanical effects of excess load on the first metatarsophalangeal (MTP) joint, also could act by destabilizing tophi and stimulating inflammation and fluid and solute shifts in the joint. Dehydration, via associated fluctuations in serum urate also may be central to precipitating gout flares in many instances may, along with subclinical joint trauma via increased physical activity, account for seasonal increases in gout-flare rates in spring and summer.

A general algorithm for gout flare prophylaxis, broadly based on the clinical practice preferences of the authors of this handbook is presented in Figure 9-1. However, please note that gout flare prophylaxis should be individualized for the patient. Moreover, we recommend following the general principles of the 2020 American College of Rheumatology (ACR) guidelines for management of gout, a synopsis of which is presented in The 2020 American College of Rheumatology Guidelines for the Management of Gout. Some patients averse to taking ULT drugs prefer and elect to manage their gout by indefinite periods of flare prophylaxis alone, via monitoring diet and alcohol frequently, by use of folk remedies and other complementary medical approaches. By itself, this is rarely an adequate strategy for clinical practice, where gout-flare prophylaxis should be combined with a ULT program in most patient with active disease. Some clinicians elect to use pharmacologic therapy with colchicine or prescribed or over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), without prescribing ULT disease modification therapy. This strategy is not endorsed by the authors nor by major society guidelines such as from the ACR.

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Nonpharmacologic Approaches

Importance of Diet and Alcohol Moderation and of Hydration in Preventing Flares

Precipitating factors for gout flares include dehydration, seasonal factors including high ambient temperature (at extremes of humidity), and nocturnal factors (e.g., obstructive sleep apnea), with a disproportionate fraction of acute flares developing between midnight and the early morning hours (Table 9-1). In one study, the risk of acute gout flares during the night and early morning was 2.4 times higher than in the daytime.

Gout flares are clearly triggered by a variety of excesses in diet and alcohol intake, which not only induce rapid rise and fall of serum urate that could lead to changes in articular crystal deposits, but also can modify hydration and inflammatory processes. Periods of high dietary purine intake, more so from meat and seafood than from vegetables and legumes, are associated with markedly increased gout flare activity. All forms of alcohol promote gout flares when ingested in a condensed period of time. In an internet-based case-crossover study, five or more standard-sized servings of alcohol (beer, wine, or spirits) in a 24- or 48-hour period at least doubled the risk of gout flare, with dose response more evident for consumption patterns within 24 hours.

Recent use of low-dose aspirin (~2-fold increased risk) and of diuretic medication (~3-4 fold increased risk) also are linked to acute gout flares (Table 9-1). Conversely, consumption of water to maintain hydration was associated with decreased risk of gout flares in an internet-based case-crossover study. In that study, consumption of five to eight glasses (250 mL each) of water in a 24-hour period was associated with an adjusted (for diuretic use purine and alcohol intake) odds ratio (OR) of gout flare of 0.6 (95% CI 0.4-0.9) and drinking more than eight glasses per day with adjusted OR 0.54 (95% CI 0.32-0.9) (P=0.02). Hospitalization for cause other than gout is associated with ~4-fold elevated risk of developing an acute gout flare. Maintenance of adequate hydration should be a particular consideration in preventing gout flares during intercurrent medical illness and also in the postoperative state, in which gout flares typically occur in the first 1 to 2 days after general surgery.

Nonpharmacologic aspects of gout flare prophylaxis being investigated include the anti-inflammatory effects of omega-3 fatty acids (which act in part by suppression of activation of the NLRP3 inflammasome), of milk product extracts, and of cherry products (putatively mediated by anthocyanins). In this context, cherry and cherry juice or extract consumption were associated with a ~35% decrease in acute gout attacks in an internet case-crossover study these findings clearly warrant further investigation. In gout patients, decreased anti-inflammatory effects of gut microbiome-derived short chain fatty acid generation (e.g., butyrate), also is undergoing further study. The value of judicious choice of footwear in gout-flare prophylaxis merits consideration in clinical practice. Effects of some dietary gout flare triggers are potentially mediated through inhibition of activity of AMP-activated protein kinase (AMPK), a nutritional biosensor, which serves as a “master regulator” of gout-like inflammation in vivo. Caloric restraint, physical fitness exercise increase tissue AMPK activity, whereas tissue AMPK activity is decreased in obesity, type 2 diabetes metabolic syndrome.

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Precipitation of Gout Flares by ULT

Unfortunately, the most common adverse event caused by starting ULT is early precipitation of acute gout flares. Furthermore, the more intensive and rapid the ULT regimen is, the more acute flares are precipitated in early treatment (defined as the first 6 months of ULT), as seen in the Febuxostat Versus Allopurinol Control Trial in Subjects With Gout (FACT) of urate lowering with allopurinol vs febuxostat (Figure 9-2). Specifically, acute gout flares occurred in ~30% to 45% of subjects between weeks 8 and 16 of this ULT trial. Hence, a general principle of starting ULT is to start low and gradually build up the ULT dose (reviewed in Pharmacologic Urate-Lowering Therapy). For example, this is done with allopurinol, febuxostat probenecid regimens, in which the initial doses are 100 mg daily, 40 mg daily 250 mg twice daily, respectively, with upward dose adjustments started after the first 2 weeks of therapy.

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Best-Practice Guidelines on Starting and Terminating Gout-Flare Prophylaxis When Initiating ULT

For prophylaxis of acute gout, low-dose colchicine therapy or low-dose NSAID therapy is commenced 1 to 2 weeks before initiation of serum ULT and continued for at least 3-6 months (if successful serum urate lowering to target [usually <6 mg/dL] is achieved) (Table 9-2). It is noted that in the FACT trial, prophylactic low-dose colchicine or low-dose NSAID therapy was discontinued 8 weeks into the ULT gout flares spiked several fold shortly thereafter. In contrast, in the CONFIRMS trial of the same ULT agents, in which there was continuation of gout-flare prophylaxis therapy through 6 months, acute gout flares did not spike. Gout-flare prophylaxis is continued >6 months in situations where gout flares are likely to persist (ie, until visible tophi resolve or if serum urate lowering to target has not yet been achieved). Patient expectations should be addressed in detail when starting ULT to optimize treatment adherence, since early gout flares contribute to decreased adherence (Table 9-3).

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Colchicine in Gout-Flare Prophylaxis

Low-dose prophylactic colchicine treatment decreases total leukocyte and absolute neutrophil counts in asymptomatic gouty knee joints. Hence, colchicine acts by suppressing both the baseline level of subclinical inflammation in the joint with gout and augmentation of the level of inflammation.

Evidence Basis for Colchicine in Flare Prophylaxis

The evidence basis for low-dose colchicine prophylaxis of acute gout flares after starting ULT is clear from comparison of the FACT and CONFIRMS trial data.It is buttressed by a small (n=43), randomized, placebo-controlled study of patients starting allopurinol as ULT (Figure 9-3), in which acute gout flares developed in 33% of patients on colchicine 0.6 mg twice daily and 77% of patients taking placebo (P=0.008); the severity of gout flares was significantly less with colchicine relative to placebo (P=0.018). In that study, colchicine was continued for at least 3 months beyond the point at which the serum urate target level was reached subjects maintained on colchicine for 6 months retained significant clinical benefit. Results from the Febuxostat Outcome Research Towards Urate Lowering in the Next Decade (FORTUNE-1) trial (n=255) suggest that a stepwise dose increase of febuxostat (compared to fixed high-dose febuxostat, with or without concomitant colchicine) may be an effective alternative to low-dose colchicine prophylaxis during ULT initiation. However, colchicine (0.5 mg/day) was shown to significantly improve flare prevention in another study (n=200) of its efficacy during initiation of ULT with allopurinol.

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Colchicine Dosing Guidelines for Gout-Flare Prophylaxis

Colchicine 0.6 mg twice daily for at least 6 months is the recommended dosage in average-sized younger patients with intact renal and hepatobiliary function and no predicted drug-drug interactions. However, the minimum effective dose of colchicine for gout-flare prophylaxis is not established, and in the FACT and CONFIRMS ULT trials, colchicine 0.6 mg daily was the dose employed. In the ULT-induced gout-flare prophylaxis study of Borstad and colleagues, some subjects developed diarrhea while taking colchicine 0.6 mg twice daily, which resolved by lowering colchicine to 0.6 mg once daily. Similarly, ~40% of patients in one ULT initiation trial needed to reduce oral prophylactic colchicine from 0.6 mg twice daily to 0.6 mg once daily.

Side Effects of Low-Dose Colchicine in Gout-Flare Prophylaxis Therapy

Even the low doses used in daily prophylactic colchicine treatment may be associated with severe toxicities, principally bone marrow suppression and combined myopathy and neuropathy. Hence, routine surveillance of creatine kinase (CK) and complete blood count and differential (hemogram) is advised during sustained colchicine gout-flare prophylaxis therapy, particularly with chronic kidney disease (CKD) or potential drug-drug interactions. GI side effects and alopecia can develop. Colchicine can induce reversible oligospermia/azoospermia, but this is rare. Effects of colchicine on chromosomal integrity of sperm are not clear, or of colchicine taken during pregnancy on chromosomal abnormalities, birth defects, or pregnancy complications effects of colchicine on breast-fed infants.

Dosing of Prophylactic Colchicine With Age and Renal Impairment and Standard Use of CK and Hemogram to Monitor for Toxicity

The bioavailability of colchicine is similar in young and older individuals, but its pharmacokinetics differ. The volume of drug distribution at steady state (V_ss) and total body clearance are significantly reduced, with the plasma C_max significantly higher at comparable colchicine doses in elderly individuals. The dose of prophylactic colchicine is routinely lowered in CKD, but dosing adjustments are not well defined for patients with age >70 years. Gout is common in patients with renal impairment and in elderly patients the risk of NSAID toxicity is increased in subjects related to advanced age and CKD. Therefore, colchicine is particularly useful in gout-flare prophylaxis in elderly patients and those with CKD, but attention to dosing recommendations clearly is required for CKD. A good starting point is to reduce the colchicine dose for gout-flare prophylaxis by ~50% in those with CrCl <50 and to monitor CK and hemogram every 3 months in that circumstance. A non–evidence-based low-dose prophylactic colchicine dosing schedule, calibrated to renal function and tuned to drug safety, is presented in Table 9-4.

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Understanding Colchicine Clinical Pharmacology to Avoid Drug-Drug Interactions

As illustrated in Figure 9-3, after uptake in the small bowel, oral colchicine is readily bioavailable. The fat-soluble characteristics of colchicine facilitate uptake by cells, allowing colchicine to bind its primary target tubulin, which also serves as body reservoir of the drug. Elimination of colchicine is predominately mediated by the multidrug resistance transporter P-glycoprotein (P-gp)/ABCB1 occurs in the feces and by biliary excretion (Figure 9-4). Pumping of colchicine out of cells (including intestinal lining cells), enterohepatic recirculation intensive drug enrichment in bile are central to colchicine elimination. Plasma membrane P-gp/ABCB1 extrudes numerous drugs and other compounds out of cells in an ATP-driven manner thereby mediates certain clinically significant drug-drug interactions (Figure 9-5), which have the potential to develop with time, even in those on low-dose colchicine therapy. Cyclosporine, clarithromycin disulfiram are major examples of potent P-gp/ABCB1 inhibitors.Importantly, most drugs that inhibit P-gp/ABCB1 also inhibit cytochrome P-450 3E4 (CYP3A4), an enzyme that demethylates colchicine to inactive metabolites in the liver preceding hepatobiliary colchicine elimination. In the clinic, it should be noted that colchicine neuromyopathy can develop in a matter of weeks after starting cyclosporine. Moreover, cyclosporine and certain other drugs can delay or mask colchicine-induced diarrhea, making identification of colchicine intolerance more difficult. Since the calcineurin inhibitors cyclosporine and tacrolimus are frequently associated with severe gout in patients with major organ transplant, colchicine is useful in gout-flare prophylaxis in many cyclosporine- and tacrolimus-treated patients. However, attention to dosing and monitoring the CK and hemogram are essential in this situation, especially with concurrent renal or hepatobiliary disease.

The macrolide antibiotics clarithromycin and erythromycin promote severe colchicine toxicity, including ~60 reports of death due to clarithromycin-colchicine drug-drug interaction. In general, clarithromycin, erythromycin disulfiram should be avoided in those taking colchicine. Moreover, colchicine use should be avoided (or, if colchicine use is absolutely indicated, the colchicine dose should be reduced) in patients on clarithromycin and erythromycin. It is not yet known how one would safely adjust colchicine dosage in patients on disulfiram. In contrast, azithromycin appears to be safe to use with colchicine since azithromycin only weakly inhibits P-gp/ABCB1 and does not significantly increase plasma concentration of colchicine in healthy volunteers.

A sample dosing model for oral-maintenance low-dose colchicine in acute gout and gout-flare prophylaxis is shown in Table 9-5. Such models are incomplete. For example, although demethylation of colchicine plays a small role relative to P-gp/ABCB1 in colchicine disposition, CYP3A4 becomes more important in eliminating the drug with aging (due to decreased P-gp/ABCB1 expression) and with hepatobiliary dysfunction. Drugs that interfere with both P-gp/ABCB1 and CYP3A4 (e.g., erythromycin, clarithromycin, cyclosporine, lovastatin, simvastatin, atorvastatin) particularly have the potential to potentiate colchicine toxicity in subjects with renal impairment. Moreover, statins and colchicine can exert synergistic effects to promote myopathy, and CK levels should be monitored every few months in patients concurrently taking both statins and colchicine. Dose reduction of sustained prophylactic colchicine by 50% also is advised in those on the calcium channel blockers diltiazem and verapamil.

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Colchicine and Cardiovascular Event Prevention

In the last decade, data have emerged from trials in non-gout populations to support a cardioprotective role for low-dose colchicine that make it an even more attractive option for gout prophylaxis. Supportive evidence comes from three double-blind, randomized trials: Low Dose Colchicine for Secondary Prevention of Cardiovascular Disease (LoDoCo), LoDoCo2 Colchicine Cardiovascular Outcomes Trial (COLCOT).

The LoDoCo trial, published in 2013, provided the first hint of the cardioprotective potential of colchicine. This study randomized (1:1) 532 patients with stable coronary artery disease (CAD) to receive 0.5 mg of colchicine a day or no colchicine. The primary endpoint (acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke) occurred in 5.3% of participants in the colchicine group, compared to 16.0% in the control group (P<0.001). However, the LoDoCo study had several weaknesses that limited its impact on clinical practice, above all the lack of a placebo in the no colchicine group. The second line of evidence came from the COLCOT trial, a placebo-controlled, investigator-initiated trial that recruited a slightly different population than LoDoCo: adult patients who had experienced a myocardial infarction (MI) within 30 days before enrollment. A total of 4745 patients were randomized (1:1) to receive either colchicine (at a daily dose of 0.5 mg) or a placebo. Clinical assessments were conducted at the 1-month and 3-month marks following randomization then continued every 3 months for a median of 22.6 months. The primary efficacy end point was a composite of death from cardiovascular (CV) causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. Colchicine significantly reduced the risk of CV adverse events compared to the placebo, with primary endpoints occurring in 5.5% of the colchicine group and 7.1% of the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02).

Finally, in 2020, results from LoDoCo2, a larger and more thoroughly executed trial than its predecessor, were published. This trial randomized (1:1) a total of 5522 patients (of whom ~8% had a history of gout) to receive 0.5 mg of colchicine once daily or a matching placebo. Patients were eligible to enter the study if they had evidence of CAD on invasive coronary angiography or CT angiography, or had a coronary-artery calcium score of ≥400 Agatston units on a coronary artery calcium scan. Clinical evaluations were scheduled at the time of randomization at 6-month intervals until the completion of the trial (median follow-up of 28.6 months). The primary end point was a composite of CV death, spontaneous (nonprocedural) MI, ischemic stroke, or ischemia-driven coronary revascularization. A primary end-point event occurred in 6.8% of patients in the colchicine group, compared to 9.6% of those in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years, respectively; hazard ratio, 0.69; 95% CI, 0.57 to 0.83; P<0.001). Two additional retrospective studies in US veterans with gout support the cardioprotective properties of colchicine. Binita and colleagues followed 722 male patients (446 colchicine users and 276 nonusers) without established CAD and discovered a lower rate of incident CAD in patients without chronic kidney disease, as well as a lower rate of the composite of incident CAD and MI. Similarly, Ho et al. followed 335 male patients (239 colchicine users and 116 nonusers) with preexisting CAD. They found that chronic colchicine users had a higher baseline CV risk than nonusers, but that both groups experienced similar rates of major adverse CV events. Additionally, patients who consistently used colchicine throughout the study period showed the most significant protective benefits, especially during active use periods.

Low-Dose NSAID Prophylaxis of Gout Flares

Examples of low-dose NSAID gout-flare prophylaxis regimens employed in clinical practice include naproxen 250 mg twice daily, indomethacin 25 mg twice daily ibuprofen 600 mg twice daily;other NSAID and selective COX-2 inhibitor regimens can be used in the clinic. However, low-dose NSAID therapy is not fully evidence-based for gout prophylaxis at this point. Proton pump inhibitor therapy may need to be used as cytoprotection when chronic NSAIDs are prescribed based on risk factors such as past peptic ulcer disease, current GI symptoms age. The potential for NSAIDs and COX-2 inhibitors to induce decline in renal function and fluid retention to impact on management of hypertension and CHF to increase risk of myocardial infarction in coronary artery disease, needs to be considered and monitored in gout patients.

Other Pharmacologic Approaches for Gout-Flare Prophylaxis

Use of low-dose prednisone (i.e., up to 10 mg daily) for gout-flare prophylaxis should be avoided, with use only as a last resort. In this context, chronic low-dose prednisone is often insufficient to prevent gout flares in major organ transplant patients, as one striking example. It is difficult to taper off prednisone in gout patients since gout flares can rebound when corticosteroids are discontinued (mediated likely in part by the capacity of corticosteroids to induce NLRP3 in macrophages). Hence, low-dose prednisone therapy for gout prophylaxis is only employed as a last resort.

Approaches Under Investigation

We need additional treatment options for prophylaxis of acute gout flares. This is a particularly important consideration for patients with intolerance to colchicine and NSAIDs, or where colchicine or NSAIDs fail to adequately prevent gout flares. The latter scenario appears to arise more frequently in the first few months of more intensive urate lowering in patients with more severe disease, such as in chronic, tophaceous gouty arthropathy. Currently, there are several pharmacologic options being investigated for gout flare prophylaxis.

IL-1 Inhibition

Biologic IL-1 inhibition therapyhas been studied in advanced clinical trials for prophylaxis of gouty arthritis, but it is not yet approved by the FDA. In clinical trials, there was marked (~80%) and significant reduction of ULT-induced early gout-flare frequency (compared with placebo) using weekly SC injection of the IL-1α and IL-1β inhibitor rilonacept, a soluble receptor form of IL-1 inhibition therapy. A placebo-controlled, randomized, double-blind, phase 2 trial demonstrated that rilonacept 80 mg or 160 mg once per week reduced the occurrence of gout flares ~80% over 16 weeks during initiation of ULT with allopurinol and did so with an acceptable safety and tolerability profile. However, rilonacept also did not gain FDA approval.

The monoclonal antibody to IL-1β, canakinumab, provided relative risk reduction, compared to triamcinolone acetate (40 mg), of 94% for recurrent gout flare at 8 weeks postdose for treatment of acute gout flare. Moreover, 16 weeks of canakinumab compared favorably to colchicine in a large (432 randomized patients) double-blind study of gout-flare prevention in patients starting allopurinol therapy. Canakinumab is approved for acute gout treatment in Europe and received FDA approval in 2023 for this indication (see Management of Acute Gouty Arthritis), but is not approved by either the FDA or the EMA for gout flare prophylaxis.

Arhalofenate

Arhalofenate is a partial agonist of PPARg, a receptor involved in not only insulin sensitization and other metabolic effects but also modulation of inflammation (including suppression of gout-like inflammation in vivo). In a phase 2b clinical trial, 800 mg daily arhalofenate, which also has uricosuric activity via suppression of URAT1, significantly decreased gout flare frequency when compared to allopurinol 300 mg/day alone and to placebo. There was no statistical difference in gout flare rate between arhalofenate 800 mg/day and the combination of allopurinol 300 mg/day combined with colchicine. These results indicated that arhalofenate has intrinsic anti-inflammatory activities clinically associated with improvement in gout flares. Arhalofenate is moving forward in clinical development as a combination therapy ULT and anti-inflammatory flare prophylaxis therapy for gout with hyperuricemia refractory to standard ULT.

SGLT2 Inhibitors

Interestingly, SGLT2 inhibitors – agents typically used for glycemic control and for their cardio- and renoprotective effects in patients with type 2 diabetes (T2D) – have also demonstrated serum urate-lowering efficacy (Pharmacologic Urate-Lowering Therapy), and their effects on gout flares have more recently been assessed. A study published in 2022 showed that SGLT2 inhibitors, compared to dipeptidyl peptidase 4 inhibitors (another class of antihyperglycemic medications), were associated with a lower rate of gout flares (rate ratio [RR] 0.66) and gout-primary emergency department visits (RR 0.52) among patients with T2D. It is unknown whether this protective effect extends to individuals without T2D.

Take-Away Messages

• Pharmacologic gout flare prophylaxis is a valuable component in overall management of gout, in conjunction with initiation or intensification of gout flare therapy, particularly with high flare activity, particularly severe gout flares, or with palpable tophi present. This measure is underutilized in primary care contributes to non-adherence with ULT.
• Patient education to limit or avoid factors that precipitate gout flares is an essential best practice measure.
• Precipitating factors for gout flares include excesses in diet and alcohol intake, which induce rapid rise and fall of serum urate that could modify tophus structure and also could have other pro-inflammatory effects.
• All forms of alcohol promote gout flares when ingested in a condensed period of time (eg, more than three servings in a 24-hour period).
• Dehydration and its associated rises in serum urate high ambient temperature and extremes of humidity, also may be central to precipitating many gout flares and may account for seasonal increases in gout-flare rates in spring and summer.
• The patient can help lessen gout flares by moderating food portion sizes and content, by not drinking alcohol in excess in short time periods by staying well hydrated (five to eight 250-mL servings of water daily unless medically contraindicated).
• The most common adverse event caused by starting ULT is precipitation of acute gout flares in the first months of therapy. In clinical practice, gout-flare prophylaxis always should be combined with a ULT program.
• Acute gout flares early in ULT are most likely due to inflammatory effects in joint tissue due to remodeling and altered stability of tophi in the joint brought on by rapid lowering of serum urate.
• A general principle of starting oral ULT to help prevent gout flares is to start low and gradually build up the ULT dose.
• For prophylaxis of acute gout, low-dose colchicine therapy or, as second choice, low-dose NSAID therapy (eg, naproxen 250 mg bid) is commenced 1 to 2 weeks before initiation of serum ULT and continued for at least 6 months (if successful serum urate lowering <6 mg/dL is achieved).
• For gout-flare prophylaxis, colchicine 0.6 mg twice daily for at least 3-6 months is the recommended dose in average-sized younger patients with intact renal and hepatobiliary function and no predicted drug-drug interactions.
• Even the low doses used in daily prophylactic colchicine treatment may be associated with toxicities. Colchicine dose should be reduced in CKD, where certain drug-drug interactions are likely in the elderly.
• In patients with moderate to severe CKD at substantial risk for colchicine toxicity during gout prophylaxis, the hemogram and CK should be monitored to screen for bone marrow suppression and myopathy.
• Cyclosporine and clarithromycin are major examples of drugs that interact adversely with colchicine can give very serious adverse events due to this interaction. Importantly, azithromycin does not appear to affect colchicine pharmacokinetics.
• Use of low-dose prednisone for gout-flare prophylaxis should be avoided only employed as a last resort.
• Patient expectations should be addressed in detail when starting ULT since early gout flares contribute to decreased adherence.