Note from the National Guideline Clearinghouse (NGC): This article concentrates on two of the four gout domains that the American College of Rheumatology (ACR) requested for evaluation of pharmacologic and nonpharmacologic management approaches: analgesic and antiinflammatory management of acute attacks of gouty arthritis and pharmacologic antiinflammatory prophylaxis of acute attacks of gouty arthritis. Part 1 of the guidelines focused on systematic nonpharmacologic measures (patient education, diet and lifestyle choices, identification and management of comorbidities) that impact hyperuricemia, and made recommendations on pharmacologic urate-lowering therapy (ULT) in a range of case scenarios of patients with disease activity manifested by acute and chronic forms of gouty arthritis, including chronic tophaceous gouty arthropathy (see the NGC summary of the ACR guideline 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia).
The levels of evidence supporting the recommendations (A-C) are defined at the end of the "Major Recommendations" field.
Recommendations for Pharmacologic Therapy for Attacks of Acute Gout
General Principles for Treatment of the Acute Attack of Gouty Arthritis ("Acute Gout" Management)
Figure 2 in the original guideline document summarizes the overall recommendations on treatment of an acute gouty arthritis attack. The Task Force Panel (TFP) recommended that an acute gouty arthritis attack should be treated with pharmacologic therapy (evidence C), and that treatment should be preferentially initiated within 24 hours of onset of an acute gout attack (evidence C). The latter recommendation was based on consensus that early treatment leads to better patient-reported outcomes. The TFP also recommended continuing established pharmacologic ULT without interruption during an acute attack of gout (evidence C), i.e., do not stop ULT therapy during an acute attack. The TFP also recommended patient education, not simply on dietary and other triggers of acute gout attacks, but also providing the patients with instruction so that they can initiate treatment upon signs and symptoms of an acute gout attack, without the need to consult their health care practitioner for each attack (evidence B). Moreover, fundamental patient education includes discussion that gout is caused by body excess of uric acid, and that only effective ULT is potentially "curative" (evidence B).
Initial Pharmacologic Treatment of the Acute Attack of Gouty Arthritis
The TFP recommended that the choice of pharmacologic agent should be based upon severity of pain and the number of joints involved (see Figure 2 in the original guideline document). For attacks of mild/moderate gout severity (≤6 of 10 on a 0–10 pain visual analog scale [VAS]) particularly those involving 1 or a few small joints or 1 or 2 large joints, the TFP recommended that initiating monotherapy was appropriate, with recommended options being oral nonsteroidal antiinflammatory drugs (NSAIDs), systemic corticosteroids, or oral colchicine (evidence A for all therapeutic categories) (see Figure 2 in the original guideline document). The TFP also voted that combination therapy was an appropriate option to consider when the acute gout attack was characterized by severe pain, particularly in an acute polyarticular gout attack or an attack involving 1–2 large joints (evidence C) (see Figure 2 in the original guideline document). The TFP did not rank one therapeutic class over another. Therefore, it is at the discretion of the prescribing physicians to choose the most appropriate monotherapy based on the patient's preference, prior response to pharmacologic therapy for an acute gout attack, and associated comorbidities. Recommendations for appropriate combination therapy options are highlighted in Table 1 in the original guideline document and discussed below. The TFP did not vote on case scenarios for specific renal or hepatic function impairment–adjusted dosing and individual contraindications or drug–drug interactions with pharmacologic therapies.
For NSAIDs, the TFP recommended full dosing at either the Food and Drug Administration (FDA)– or European Medical Agency–approved antiinflammatory/analgesic doses used for the treatment of acute pain and/or treatment of acute gout (evidence A–C) (see Figure 3A in the original guideline document). The FDA has approved naproxen (evidence A), indomethacin (evidence A), and sulindac (evidence B) for the treatment of acute gout. However, analgesic and antiinflammatory doses of other NSAIDs may be as effective (evidence B and C). For cyclooxygenase 2 (COX-2) inhibitors, as an option in patients with gastrointestinal contraindications or intolerance to NSAIDs, published randomized controlled trials support the efficacy of etoricoxib (evidence A) and lumiracoxib (evidence B), but these agents are not available in the U.S., and lumiracoxib has been withdrawn from use in several countries due to hepatotoxicity. A randomized controlled trial of a single comparison of celecoxib versus indomethacin suggested effectiveness of a high-dose celecoxib regimen (800 mg once, followed by 400 mg on day 1, then 400 mg twice daily for a week) in acute gout. The TFP recommended this celecoxib regimen as an option for acute gout in carefully selected patients with contraindications or intolerance to NSAIDs (evidence B), keeping in mind that the risk/benefit ratio is not yet clear for celecoxib in acute gout.
The TFP did not reach a consensus to preferentially recommend any one specific NSAID as first-line treatment. The TFP did recommend continuing the initial NSAID inhibitor treatment regimen at the full dose (if appropriate) until the acute gouty attack completely resolved (evidence C). The option to taper the dose in patients with multiple comorbidities/hepatic or renal impairment was reinforced by the TFP, without specific TFP voting or more prescriptive guidance. Last, there was no TFP consensus on the use of intramuscular ketorolac or topical NSAIDs for the treatment of acute gout.
The TFP recommended oral colchicine as one of the appropriate primary modality options to treat acute gout, but only for gout attacks where the onset was no greater than 36 hours prior to treatment initiation (evidence C) (see Figure 3B in the original guideline document). The TFP recommended that acute gout can be treated with a loading dose of 1.2 mg of colchicine followed by 0.6 mg 1 hour later (evidence B), and this regimen can then be followed by gout attack prophylaxis dosing 0.6 mg once or twice daily (unless dose adjustment is required) 12 hours later, until the gout attack resolves (evidence C). For countries where 1.0 mg or 0.5 mg rather than 0.6 mg tablets of colchicine are available, the TFP recommended, as appropriate, 1.0 mg colchicine as the loading dose, followed by 0.5 mg 1 hour later, and then followed, as needed, after 12 hours, by continued colchicine (up to 0.5 mg 3 times daily) until the acute attack resolves (evidence C). In doing so, the TFP rationale was informed by pharmacokinetics of the low-dose colchicine regimen, where the exposure to the drug in plasma becomes markedly reduced approximately 12 hours after administration in healthy volunteers. The TFP also evaluated prior European League Against Rheumatism (EULAR) recommendations on a colchicine dosing regimen for acute gout (0.5 mg 3 times daily) and the British Society for Rheumatology (BSR)-recommended maximum dosage for acute gout of 2 mg colchicine per day.
The algorithm in Figure 3B in the original guideline document outlines recommendations for colchicine based on FDA labeling and TFP deliberations and votes, including specific recommendations for patients already receiving colchicine acute gout attack prophylaxis. For more specific prescriptive guidance, practitioners should consult the FDA-approved drug labeling, including recommended dosing reduction in moderate to severe chronic kidney disease (CKD), and colchicine dose reduction (or avoidance of colchicine use) with drug interactions with moderate to high potency inhibitors of cytochrome P450 3A4 and of P-glycoprotein; major colchicine drug interactions include those with clarithromycin, erythromycin, cyclosporine, and disulfiram. Last, the TFP did not vote on use of intravenous colchicine, since the formulation is no longer available in the U.S., due to misuse and associated severe toxicity.
Systemic and Intraarticular Corticosteroids and Adrenocorticotropic Hormone (ACTH)
When selecting corticosteroids as the initial therapy, the TFP recommended to first consider the number of joints with active arthritis. For involvement of 1 or 2 joints, the TFP recommended the use of oral corticosteroids (evidence B); the TFP additionally recommended the option of intraarticular corticosteroids for acute gout of 1 or 2 large joints (evidence B) (see Figure 3C in the original guideline document). For intraarticular corticosteroid therapy in acute gouty arthritis, it was recommended that dosing be based on the size of the involved joint(s), and that this modality could be used in combination (see Table 1 in the original guideline document) with oral corticosteroids, NSAIDs, or colchicine (evidence B). Specific doses for intraarticular corticosteroid therapy in specific joints were not considered during TFP voting.
Where intraarticular joint injection is impractical (e.g., polyarticular joint involvement, patient preference, or injection of the involved joint site is not in the scope of the provider's usual practice), the TFP recommended oral corticosteroids, prednisone, or prednisolone at a starting dosage of at least 0.5 mg/kg per day for 5–10 days, followed by discontinuation (evidence A), or alternately, 2–5 days at the full dose, followed by tapering for 7–10 days, and then discontinuation (evidence C). Acknowledging current prevalence of usage, the TFP recommended, as an appropriate option according to provider and patient preference, the use of an oral methylprednisolone dose pack for initial treatment of an acute attack of gout (evidence C).
The TFP also recommended, as appropriate in each case scenario, an alternative regimen of intramuscular single-dose (60 mg) triamcinolone acetonide, followed by oral prednisone or prednisolone (evidence C). However, there was no consensus by the TFP on the use of intramuscular triamcinolone acetonide as monotherapy. Last, the TFP vote also did not reach a consensus on use of ACTH (evidence A) for acute gout in patients able to take medications orally, but did consider ACTH in separate voting, as described below, for patients unable to take oral antiinflammatory medications.
Initial Combination Therapy for Acute Gout
For patients with severe acute gout attack (≥7 of 10 on a 0–10 pain VAS) and patients with an acute polyarthritis or involvement of more than 1 large joint, the TFP recommended, as an appropriate option, the initial simultaneous use of full doses (or, where appropriate, a full dose of one agent and prophylaxis dosing of the other) of two of the pharmacologic modalities recommended above. Specifically, the TFP recommended the option to use combinations of colchicine and NSAIDs, oral corticosteroids and colchicine, or intraarticular steroids with any of the other modalities (evidence C). The TFP was not asked by the Core Expert Panel (CEP) to vote on use of NSAIDs and systemic corticosteroids in combination, given CEP concerns about synergistic gastrointestinal tract toxicity of that drug combination.
Inadequate Response of an Acute Gout Attack to Initial Therapy
There is a lack of a uniform definition of an inadequate response to the initial pharmacologic therapy for an acute attack of gouty arthritis. Clinical trials in acute gout have defined variable primary end points for therapeutic response, such as percent improvement in pain on a Likert scale or VAS. To define inadequate response for scenarios in this section, the CEP asked the TFP to vote on various percent improvement definitions at time points such as 24, 48, or 72 hours. The TFP voted that the following criteria would define an inadequate response of acute gout to pharmacologic therapy in case scenarios: either <20% improvement in pain score within 24 hours or <50% improvement in pain score ≥24 hours after initiating pharmacologic therapy.
For the scenario of a patient with an acute attack of gouty arthritis not responding adequately to initial pharmacologic monotherapy, the TFP advised, without a specific vote, that alternative diagnoses to gout should be considered (see Figure 2 and Table 1 in the original guideline document). For patients not responding to initial therapy, the TFP also recommended switching to another monotherapy recommended above (evidence C) or adding a second recommended agent (evidence C). Use of a biologic interleukin-1 (IL-1) inhibitor (anakinra 100 mg subcutaneously daily for 3 consecutive days; evidence B) or canakinumab 150 mg subcutaneously as an option for severe attacks of acute gouty arthritis refractory to other agents was graded as evidence A in the systematic review. Given a lack of randomized studies for anakinra and the unclear risk/benefit ratio and lack of FDA approval for canakinumab at the time this was written, the authors, independent of TFP discussion, assessed the role of IL-1 inhibitor therapy in acute gout as uncertain.
Case Scenarios for the Nothing by Mouth (NPO) Patient
Acute gout attacks are common in the in-hospital setting, where patients may be NPO due to different surgical and medical conditions. In such a scenario, the TFP recommended intraarticular injection of corticosteroids for involvement of 1 or 2 joints (with the dose depending on the size of the joint; evidence B) (see Figure 4 in the original guideline document). The TFP also recommended, as appropriate options, intravenous or intramuscular methylprednisolone at an initial dose at 0.5–2.0 mg/kg (evidence B).
The TFP also recommended, as an appropriate alternative for the NPO patient, subcutaneous synthetic ACTH at an initial dose of 25–40 IU (evidence A), with repeat doses as clinically indicated (for either ACTH or intravenous steroid regimens). There was no voting by the TFP on specific followup ACTH or an intravenous steroid dosing regimen, given a lack of evidence. In the scenario of the NPO patient with acute gout, there was no consensus on the use of intramuscular ketorolac or intramuscular triamcinolone acetonide monotherapy. Biologic IL-1 inhibition therapy remains an FDA-unapproved modality for NPO patients, without specific past evaluation in this population.
Critical Drug Therapy Adverse Event Considerations in Acute Gout
It was not possible to evaluate every permutation of gout treatment and comorbid disease, given the constraints of the project. The treating clinician will need to carefully weigh the complexities of each unique patient. TFP discussions emphasized that potential drug toxicities due to comorbidities and drug–drug interactions are considerable in treatment of acute gout. Some examples include underlying moderate and severe CKD (NSAIDs, COX-2 inhibitors, colchicine), congestive heart failure (NSAIDs, COX-2 inhibitors), peptic ulcer disease (NSAIDs, COX-2 inhibitors, corticosteroids), anticoagulation or antiplatelet aggregation therapy (NSAIDs), diabetes mellitus (corticosteroids), ongoing infection or high risk of infection (corticosteroids), and hepatic disease (NSAIDs, COX-2 inhibitors, colchicine).
Complementary Therapies for Acute Gout Attack
The TFP recommended topical ice application to be an appropriate adjunctive measure to one or more pharmacologic therapies for acute gouty arthritis (evidence B). The TFP voted, as inappropriate, the use of a variety of oral complementary agents for the treatment of an acute attack (cherry juice or extract, salicylate-rich willow bark extract, ginger, flaxseed, charcoal, strawberries, black currant, burdock, sour cream, olive oil, horsetail, pears, or celery root).
Recommendations for Pharmacologic Antiinflammatory Prophylaxis of Attacks of Acute Gout
The TFP recommended pharmacologic antiinflammatory prophylaxis for all case scenarios of gout where ULT was initiated, given high gout attack rate frequencies in early ULT (evidence A) (see Figure 5 in the original guideline document). For gout attack prophylaxis, the TFP recommended, as a first-line option, use of oral colchicine (evidence A). The TFP also recommended, as a first-line option (with a lower evidence grade than for colchicine), the use of low-dose NSAIDs (such as naproxen 250 mg orally twice a day), with proton-pump inhibitor therapy or other effective suppression therapy for peptic ulcer disease and its complications, where indicated (evidence C).
In their evaluation of colchicine evidence in gout attack prophylaxis, the TFP specifically recommended low-dose colchicine (0.5 mg or 0.6 mg orally once or twice a day, with dosing further adjusted downward for moderate to severe renal function impairment and potential drug–drug interactions) as appropriate for gout attack prophylaxis. The TFP did not vote on specific quantitative renal function impairment–adjusted dosing of oral colchicine. Since a pharmacokinetic analysis suggesting colchicine dose should be decreased by 50% below a creatinine clearance of 50 ml/minute is unpublished in peer-review form, specific quantitative colchicine dose adjustment in CKD is the decision of the treating clinician.
The TFP, in discussion without a specific vote, recognized the evidence that colchicine and low-dose NSAID prophylaxis fail to prevent all gout attacks in patient populations after initiation of ULT. As an alternative gout attack prophylaxis strategy in patients with intolerance or contraindication or refractoriness to both colchicine and NSAIDs, the TFP recommended use of low-dosage prednisone or prednisolone (defined here as ≤10 mg/day) (evidence C). Nevertheless, concerns were raised in discussion among the TFP and by the other authors regarding particularly sparse evidence for efficacy of this low-dose strategy. Given the known risks of prolonged use of corticosteroids, the authors urge clinicians to be particularly attentive in reevaluating the risk/benefit ratio of continued corticosteroid prophylaxis as the risk of acute gout attack decreases with time in conjunction with effective ULT. The TFP voted the use of high daily doses (i.e., >10 mg daily) of prednisone or prednisolone for gout attack prophylaxis to be as inappropriate in most case scenarios, and there was a lack of TFP consensus for more severe forms of chronic tophaceous gouty arthropathy. Last, there was a lack of TFP consensus on the risk/benefit ratio for off-label use of biologic IL-1 inhibition (evidence A) for antiinflammatory gout attack prophylaxis in patients who previously failed or had intolerance or contraindications to low doses of colchicine, NSAIDs, and prednisone or prednisolone for gout attack prophylaxis.
Duration of Antiinflammatory Prophylaxis of Acute Gout Attacks
The TFP recommended to continue pharmacologic gout attack prophylaxis if there is any clinical evidence of continuing gout disease activity (such as 1 or more tophi detected on physical examination, recent acute gout attacks, or chronic gouty arthritis), and/or the serum urate target has not yet been achieved. Specifically, the TFP voted to continue the prophylaxis for the greater of: 1) 6 months' duration (evidence A), 2) 3 months after achieving the target serum urate level for the patient without tophi detected on physical examination (evidence B), or 3) 6 months after achieving the target serum urate level, where there has been resolution of tophi previously detected on physical examination (evidence C) (see Figure 5 in the original guideline document).
Levels of Evidence
Level A: Recommendations supported more than one randomized clinical trials or one or more meta-analyses
Level B: Recommendations derived from a single randomized trial or nonrandomized studies
Level C: Consensus opinion of experts, case studies, or standard of care