Colchicine

Colchicine is an alkaloid derived from extracts of meadow saffron ( Crocus autoimmale ). It is thought that colchicine relieves pain through its binding to tubulin dimers and by inhibiting β-tubulin polymerization into microtubules, thus interfering with neutrophil functions including diapedesis (ameboid movement), mobilization, lysosomal degranulation, and, most importantly, leukocyte chemotaxis. In addition, colchicine suppresses MSU crystal–induced NALP3 inflammasome-driven caspase-1 activation and interleukin (IL)-1β processing.

Colchicine is metabolized in the liver, and excreted in the urine and by the biliary tract. The half-life of oral colchicine in patients with normal renal and hepatic functions is approximately 9 hours, whereas in patients with renal failure it is approximately 24 hours, and in cirrhotic patients with renal failure it is up to 10 times normal (approximately 4 days) and is not removed via hemodialysis.

Despite the widespread use of oral colchicine, it did not gain Food and Drug Administration (FDA) approval until August 2009 following the Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial. The AGREE trial was a randomized, double-blind, placebo-controlled trial of 184 patients with acute gout treated within 12 hours of the onset of an attack. Low-dose colchicine (1.2 mg followed by 0.6 mg 1 hour later for a total of 1.8 mg) was found to be equally effective and better tolerated than high-dose colchicine (1.2 mg followed by 0.6 mg hourly × 6 hours for a total of 4.8 mg). There was a significantly higher incidence of gastrointestinal side effects such as diarrhea, nausea, and vomiting when high-dose colchicine was used, compared with low-dose colchicine and placebo.

Ahern and colleagues studied 43 patients in an earlier placebo-controlled study of colchicine treatment in acute gout. Twenty-two patients were started on colchicine, 1 mg followed by 0.5 mg every 2 hours until complete response or toxicity, and 21 patients were enrolled in the placebo group. No NSAIDs were used during the study. Two-thirds of the colchicine-treated patients improved within 48 hours compared with only one-third of the patients receiving placebo. Colchicine was found to be more effective when used within 24 hours of an acute attack. The problem was the high incidence of adverse events, with more than 80% of patients in the colchicine group experiencing nausea, vomiting, diarrhea, and abdominal pain before full clinical improvement.

The recommended doses of colchicine depend on renal and hepatic functions in addition to colchicine drug-drug interactions. Colchicine is a substrate for both the CYP3A4 enzyme and P-glycoprotein (P-gp) transporter. Therefore, coadministration with drugs known to inhibit CYP3A4 and/or P-gp increases the risk of colchicine-induced adverse events. These agents include cyclosporine, erythromycin, and calcium-channel antagonists such as verapamil and diltiazem. Other examples of P-gp and strong CYP3A4 inhibitors include telithromycin, ketoconazole, itraconazole, human immunodeficiency virus protease inhibitors, and nefazodone. The FDA advises patients treated with P-gp or strong CYP3A4 inhibitor drugs within 14 days of colchicine use for acute gout to reduce the dose or stop colchicine treatment. For treatment of acute gout in patients with mild (glomerular filtration rate [GFR] 50–80 mL/min) to moderate (GFR 30–50 mL/min) kidney disease, adjustment of this recommended dose is not required. For patients with acute gout requiring repeated courses of colchicine, consideration should be given to alternative therapy. For patients undergoing dialysis, the total recommended dose for the treatment of acute gout should be reduced to a single dose of 0.6 mg (1 tablet), and the treatment should not be repeated more than once every 2 weeks. Treatment of gout attacks with colchicine is not recommended in patients with kidney disease receiving colchicine prophylaxis.

A clinical response to colchicine is not pathognomonic for acute gout, and can be seen in other conditions such as acute pseudogout, psoriatic arthritis, and calcific tendonitis.

Oral nonsteroidal anti-inflammatory drugs

NSAIDs are among the most commonly prescribed drugs. These agents differ in their structure and their pharmacokinetic and pharmacodynamic properties, but share the same mode of action. NSAIDs exert their anti-inflammatory action by inhibiting cyclooxygenase (COX), an enzyme that transforms phospholipid-derived arachidonic acid into prostaglandins. NSAIDs may be nonselective, inhibiting both COX-1 and COX-2 (eg, ibuprofen and naproxen), or may be more COX-1 (eg, aspirin) or COX-2 selective (eg, celecoxib).

NSAIDs are commonly used in patients with acute gout who do not have underlying comorbidities. The most important determinant of therapeutic success is not which NSAID is chosen, but rather how soon the NSAID is initiated, and that large enough dosages be given at the onset of symptoms and continued for a long enough period of time. Naproxen, indomethacin, and sulindac are FDA-approved for acute gout; however, several head-to-head studies, some of which were RCTs for acute gout, show equivalence between different NSAIDs. Most of these small trials compared indomethacin with another NSAID including COX-2–selective drugs, which were also found to be effective. In 2 studies comparing etoricoxib with indomethacin, etoricoxib 120 mg once daily was comparable with indomethacin 50 mg 3 times daily in treating acute gout. Studies comparing celecoxib (400 mg and 800 mg) and indomethacin 50 mg 3 times daily show equivalence between celecoxib and indomethacin.

The use of NSAIDs is limited by their side effects. NSAID-related gastrointestinal side effects may lead to bleeding, hospitalizations, and deaths. Coadministration of a proton-pump inhibitor may lessen gastrointestinal side effects. In addition, the use of NSAIDs in patients with heart disease or those thought to be at increased risk of heart disease should be cautioned. All patients taking NSAIDs should be carefully monitored for the development of high blood pressure, worsening heart disease, worsening renal function, fluid retention, gastrointestinal bleeding, and elevations in liver enzymes.

There are no RCTs comparing colchicine with NSAIDs, and such studies comparing their efficacy and adverse events are much needed.

Systemic corticosteroids

CS interfere with the proinflammatory signaling process, suppress the immune response, and inhibit prostaglandins and leukotrienes. One of the most important anti-inflammatory effects of CS is directly inhibiting the activity of transcription factors by a transrepression mechanism, which results in protein-protein interaction. In addition, CS inhibit proinflammatory cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor α, and upregulate genes for lipocortin and vasocortin, which have anti-inflammatory effects by inhibiting phospholipase A2, thereby blocking eicosanoid production and inhibiting various leukocyte inflammatory functions (epithelial adhesion, diapedesis, chemotaxis, phagocytosis, and so forth).

CS can be given orally, intravenously, intramuscularly, and intra-articularly, and are commonly used in patients who cannot be treated with NSAIDs and/or colchicine. CS are commonly used, and often preferred, for polyarticular gout. The ACR TFP recommended oral prednisone or prednisolone at a dose of 0.5 mg/kg/d for 5 to 10 days, or for 2 to 5 days at this full dose followed by a 7- to 10-day taper. It is unclear whether treatment with parenteral CS confers any advantage over other modes of treatment, unless the patient cannot take oral medications.

In a prospective case cohort using systemic CS for acute gout in 13 patients (15 attacks) who had contraindications to NSAIDs, Groff and colleagues noted improvement within 12 to 48 hours. Complete resolution occurred in 11 of 15 attacks within 7 days. Patients with more than 5 involved joints required longer CS courses (mean 17 days).

Several studies compared oral prednisolone with NSAIDs, and found them equivalent for the treatment of acute gout. A study by Man and colleagues compared oral indomethacin given as 50 mg 3 times daily for 2 days followed by 25 mg indomethacin 3 times daily for 3 days plus placebo prednisolone (n = 46), with prednisolone 30 mg daily for 5 days plus placebo indomethacin (n = 44); both arms also received a single dose of diclofenac, 75 mg intramuscularly, and acetaminophen, 1 g every 6 hours as needed over 5 days. In another RCT, Janssens and colleagues compared prednisolone 35 mg daily (n = 60) with naproxen 500 mg twice daily (n = 60) for 5 days in acute gout among patients with MSU crystal–proven gout presenting within 24 hours of an attack. Although 216 subjects were potentially eligible for the trial, 96 were excluded mostly because of current use of NSAIDs or colchicine, or contraindications to NSAIDs. Oral prednisolone was found to be comparably effective with naproxen 500 mg twice daily in treating acute gout. At 90 hours, mean reductions in pain assessed on a VAS were similar in the naproxen and prednisolone groups. Adverse effects during treatment were minor and comparable between groups. At 3-week follow-up, all patients reported complete resolution of pain and disability.

Administration of a single intramuscular dose of triamcinolone acetonide (TA) was addressed in several studies. Alloway and colleagues compared 60-mg intramuscular TA injections with oral indomethacin. Twenty-seven patients presenting within 5 days of the onset of an acute attack were included in the study. Fourteen patients received one 60-mg TA injection, 3 patients received a second injection 2 days after enrollment in the study, and 13 patients received oral indomethacin (50 mg 3 times daily). There was no statistical difference in responses, with resolution of all symptoms occurring at an average of 8 days for the indomethacin-treated patients and 7 days for patients treated with TA. Siegel and colleagues, in a prospective, controlled, unblinded study, compared patients receiving a single 40-IU injection of ACTH intramuscularly (n = 16) with patients receiving a 60-mg intramuscular injection of TA (n = 15) in acute gout. The main efficacy outcome was the number of days to 100% symptom resolution. Both groups had similar mean times to resolution (7.9 and 7.6 days, respectively).

Intra-articular corticosteroids

Intra-articular CS are beneficial and useful in acute gout when 1 or 2 joints are inflamed. This approach is less favored when 2 or more joints are involved or when the involved joint is not easily amenable to aspiration. Ensuring that the joint is not infected before injecting intra-articular CS is of utmost importance. Intra-articular CS should be avoided if septic arthritis is suspected.

This modality has not been well studied, although in an uncontrolled trial small intra-articular doses of TA (10 mg in knees and 8 mg in small joints) helped resolve 20 attacks of acute gout in 19 men. Joints involved were 11 knees, 4 metatarsophalangeal joints, 3 ankles, and 2 wrists. All had an MSU crystal–proven diagnosis. After one intra-articular injection of TA in 11 joints (55%) the attack of acute gout had resolved at 24 hours, and in 9 joints (45%) at 48 hours. All attacks in the 19 patients receiving intra-articular injections of CS improved within 48 hours.

Future studies are needed to compare different injectable CS suspensions and dosages to further the understanding of their efficacy and safety in treating acute gout.

Corticotropin (ACTH)

The exact mechanism of action of ACTH in gouty inflammation is not well understood. ACTH is secreted by the pituitary gland. It affects adrenal CS release, stimulating production of cortisol, corticosterone, and androgens by the pituitary. In addition, ACTH may inhibit gouty inflammation peripherally by activating the melanocortin type 3 receptor (MC3R). Getting and colleagues showed that small fragments of α–melanocyte-stimulating hormone (MSH) and β-MSH inhibit MSU crystal–induced neutrophil migration and release of proinflammatory cytokines and chemokines. These anti-inflammatory effects occurred in a corticosterone-independent manner, hence no reflex stimulation of the hypothalamic-pituitary-adrenal axis was observed.

A retrospective study of 33 patients who received ACTH for their acute gout or pseudogout attacks found the most common regimen (90%) to be 40 IU administered intramuscularly every 8 hours. Duration of therapy was 1 to 14 days; a 97% resolution rate was reported. The mean time to complete resolution was 5.5 days, and a relapse rate of 11% (n = 4) was reported.

In a prospective controlled, unblinded study of 76 patients presenting within 24 hours of the onset of an attack of acute gout, Axelrod and Preston compared intramuscular ACTH (40 IU) with oral indomethacin 50 mg 4 times daily, and found the mean pain interval from administration of the study drug to complete pain relief was 3 ± 1 hour for ACTH-treated patients versus 24 ± 10 hours for indomethacin-treated patients ( P <.0001). The study concluded that patients treated with intramuscular ACTH experienced quicker pain relief than those treated with oral indomethacin for their acute attack.

No blinded RCTs have been conducted comparing ACTH with other modalities. It is not clear whether ACTH or CS are superior to one another or whether they have equivalent efficacy in acute gout. Future studies are needed to compare ACTH treatment with others for acute gout.

Interleukin-1β inhibitors (anakinra, canakinumab, rilonacept)

IL-1β is an important cytokine involved in gouty inflammation. MSU crystals stimulate IL-1 release by monocytes and synovial mononuclear cells, and cause activation of the cryopyrin (NLRP3) inflammasome, an intracellular, multiprotein complex. Cryopyrin regulates the protease caspase-1 and controls IL-1β activation. Once caspase-1 becomes active it cleaves pro–IL-1β to release the mature p17 form of IL-1β, resulting in the active form of IL-1β. IL-1 inhibition has now been shown to have a beneficial effect in gouty inflammation. Current IL-1 inhibitors in trials include anakinra, canakinumab, and rilonacept. Canakinumab is approved for use in acute gout by the European Medicines Agency (EMEA).

Anakinra is a no glycosylated recombinant human IL-1 receptor antagonist (IL-1Ra). IL-1Ra is an endogenous receptor antagonist for the IL-1 receptor (IL-1RI). It binds to IL-1RI and prevents it from associating with its accessory protein, IL-1RAcP, thus preventing signal transduction. Because of its short plasma half-life of approximately 4 to 6 hours following subcutaneous administration, anakinra is administered daily. Anakinra significantly relieved pain associated with acute gout in patients who could not tolerate or had failed standard anti-inflammatory therapies. In an open-label pilot study, So and colleagues studied 10 patients with gout, acute gout, and subacute gout, and their response to treatment with anakinra, 100 mg daily subcutaneously for 3 days. All patients responded and had relief of symptoms within 48 hours of the first anakinra injection. A complete resolution of symptoms was reported in 9 of the 10 patients on day 3 of the study. In a retrospective study of anakinra in the treatment of acute gout, 15 hospitalized patients (22 attacks) who had failed CS treatment or had comorbid limitations to the use of CS were given anakinra, 100 mg daily subcutaneously for 3 days. In 19 of 22 attacks, pain reduction was reported within a day. Anakinra treatment was effective in recurrent acute attacks in the same patients, with no decrement in response to multiple anakinra courses observed.

Canakinumab, a fully selective human anti–IL-1β monoclonal antibody, does not bind IL-1α or IL-1Ra. Canakinumab has a long plasma half-life of 28 days. Two recently published phase III studies (n = 454 patients with gout) compared canakinumab, 150 mg subcutaneously with intramuscular TA. Both studies were 12 weeks long and had a 12-week extension. Canakinumab, 150 mg was found to provide rapid pain relief in comparison with TA, 40 mg intramuscularly. A statistically significant dose response was observed at 72 hours for canakinumab, 150 mg subcutaneously. It was superior to 40 mg of TA intramuscularly in providing pain relief, starting at 24 hours. The median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg, compared with 2 days for the TA group ( P = .0006). Canakinumab is approved by the EMEA for the treatment of adult patients with frequent gout attacks (at least 3 attacks in the previous 12 months) in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate.

Rilonacept (Arcalyst) is an IL-1 trap. It binds to IL-1α and IL-1β with high affinity, as well as IL-1Ra, thus preventing IL-1 from binding to the endogenous IL-1 receptor. Results of an acute gout study comparing indomethacin alone versus rilonacept with indomethacin versus rilonacept alone reported that rilonacept, when combined with indomethacin and when used alone, failed to improve pain and inflammation more than indomethacin alone.