Cardiovascular Disease
Cardiovascular disease risk has been shown to increase with the use of COX-2 inhibitors. This risk may be present for all NSAIDs. Current FDA labeling suggests limiting NSAID and COX-2 inhibitor use in patients with a history of myocardial infarction (MI), congestive heart failure, or stroke. Given the potential impact on cardiovascular risk factors, including hypertension, T2DM, and hyperlipidemia, glucocorticoids may not be ideal for patients with known CVD or those at high risk.
Recent evidence has shown that colchicine use is associated with a lower risk of MI among patients with gout.21 These results, in addition to a proposed dual role of IL-1 in both gout and CVD, suggest that either colchicine or IL-1 inhibitors may be rational agents in the treatment of acute gout in the context of CVD.22
Hepatic Impairment and GI Bleeding
Patients with cirrhosis should avoid NSAID use due to the potential increased bleeding risk from underlying coagulopathy. Additionally, colchicine clearance may be reduced in patients with severe liver impairment, mandating close surveillance when this agent is used. If hepatic impairment is mild to moderate, judicious use of any of the first-line therapies may be appropriate.
Patients with GI bleeding or a history of peptic ulcer disease should avoid NSAID use because of increased bleeding risk. If an NSAID is used, proton pump inhibitors decrease the risk of NSAID-associated mucosal damage.
Drug Interactions
Colchicine is metabolized by the cytochrome P450 3A4 enzyme (CYP3A4) and is a substrate for P-glycoprotein (P-gp). Therefore, concomitant use of colchicine with potent inhibitors of CYP3A4 or P-gp should be avoided when possible. These agents include macrolide antibiotics (clarithromyocin), calcium channel blockers (verapamil and diltiazem), and cyclosporine (commonly used in transplant patients who are at high risk for gout). New evidence-based dosing recommendations indicate that no dose reduction is required with azithromyocin.23
Nonsteroidal anti-inflammatory drugs are contraindicated with the concomitant use of angiotensin-converting enzyme (ACE) inhibitors and/or diuretics. Prostaglandin production is decreased while using NSAIDs, resulting in increased constriction of afferent renal arterioles and decreased glomerular filtration pressure. This physiologic effect of NSAIDs can be exacerbated when used in combination with ACE inhibitors or diuretics, both of which can also reduce glomerular filtration pressures. Combination therapy with either ACE inhibitors or diuretics increases the risk for NSAID-mediated acute kidney injury. Additionally, NSAID use should be avoided in patients taking anticoagulants such as warfarin or heparin due to increased bleeding risk.
Diagnosis
Diagnosis is a key component of proper treatment of acute gout. A gout diagnosis is usually made based on clinical signs and symptoms, including sudden onset of pain that peaks within 24 hours, past history of acute self-limited attacks of arthritis, first MTP involvement, and an elevated sUA. However, not all these factors must be present. In a study conducted by Janssens and colleagues, these factors plus additional demographics had a sensitivity of 90% and specificity of 65% when compared with crystal diagnosis.24 However, a normal sUA level does not exclude gout as a diagnosis due to the uricosuric effect of the inflammatory process.25 In fact, one observational cohort recorded an average sUA decrease from baseline of 2 mg/dL during an acute gout attack.26
Alternative diagnoses, including septic arthritis, should be considered, particularly in the context of treatment failure (< 50% reduction in pain) within the first 24 to 48 hours. A definitive diagnosis is made by identifying negatively birefringent crystals in the synovial fluid of the affected joint (using polarized microscopy) with negative cultures. In the absence of crystal confirmation, there is an emerging role for imaging in gout diagnosis, including the use of ultrasound and dual-energy computed tomography.27
Long-term Treatment Considerations
During treatment for acute gout attacks, urate-lowering therapy that was initiated before the attack should not be discontinued.28 There is no evidence to suggest that current urate lowering has any AEs during attacks. However, removing treatment may increase sUA levels, precipitating attacks in other joints by “destabilizing” crystals still present. Current recommendations also state that urate-lowering therapy may be started during an attack despite traditionally being deferred until the attack has resolved.28 In a randomized trial comparing a group starting allopurinol 300 mg during an attack vs a placebo group (with all patients receiving anti-inflammatory treatment for the acute attack), there was no difference in pain outcomes.29 Regardless of the chosen timing, lowering and maintaining sUA ≤ 6.0 mg/dL is the primary method for minimizing long-term risk of gout attacks.28
Health care providers should discuss with patients the likely need for indefinite urate-lowering therapy while noting that attacks related to therapy initiation are relatively common.30 Current guidelines recommend starting urate-lowering therapy in low doses (≤ 100 mg/d for allopurinol) and titrating to achieve and maintain the target sUA level. Along with the judicious use of anti-inflammatory prophylaxis, this may minimize attacks related to therapy initiation.3,28 By lowering and maintaining sUA below the target level, monosodium urate crystals will dissolve, thereby eliminating the major inciting factor of acute attacks.
Other day-to-day triggers such as alcohol, meat or seafood consumption, and dehydration exist for some patients with gout. Patients should be informed of these inciting factors, as they could potentially be avoided, reducing the risk of future gout attacks. It is important to recognize, however, that dietary or behavioral interventions have generally yielded only modest sUA reductions. For the majority of patients, therefore, reduction and maintenance of sUA ≤ 6.0 mg/dL requires pharmacologic intervention.
Conclusions
Gout attacks should be treated immediately with pharmacologic treatment when contraindications are absent. First-line treatment options include NSAIDs, colchicine, and systemic glucocorticoids. Use of these modalities can be complicated because of comorbidity and concomitant medication use that is prevalent among patients with gout. Comorbidities commonly limiting treatment choice include hypertension (NSAIDs, glucocorticoids), CKD (NSAIDS, colchicine), CVD (NSAIDs, COX-2 inhibitors, glucocorticoids), T2DM (glucocorticoids), and liver disease (NSAIDs, colchicine). Careful consideration must be given to these comorbidities and contraindications as well as patient preferences.