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Gout

Management of Acute Gouty Arthritis

Robert Terkeltaub, MD; N. Lawrence Edwards, MD, MACP, MACR; Puja Khanna, MD, MPH 
Reviewed on July 16, 2024
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Principal Goals of Treatment

The specific treatment goals for acute flares of gouty arthritis are rapid analgesia and inhibition of inflammation, such that a swift return of pain-free function can be restored for the involved joint(s) in a safe, highly effective and cost-efficient manner. The anti-inflammatory therapies employed to treat acute gout do reduce pain as well as inflammation in this condition, and analgesics (typically acetaminophen and, in selective cases, opiates) and local measures (e.g., rest, elevation, topical ice) can be employed as adjunctive therapies. The treatment options discussed in detail in this section are specifically designed to treat the active inflammatory manifestations of acute gouty arthritis. Further details, by synopsis of the 2020 American College of Rheumatology (ACR) treatment guidelines for management of gout, are available in The 2020 American College of Rheumatology Guidelines for the Management of Gout. In addition, the algorithm shown in…

Principal Goals of Treatment

The specific treatment goals for acute flares of gouty arthritis are rapid analgesia and inhibition of inflammation, such that a swift return of pain-free function can be restored for the involved joint(s) in a safe, highly effective and cost-efficient manner. The anti-inflammatory therapies employed to treat acute gout do reduce pain as well as inflammation in this condition, and analgesics (typically acetaminophen and, in selective cases, opiates) and local measures (e.g., rest, elevation, topical ice) can be employed as adjunctive therapies. The treatment options discussed in detail in this section are specifically designed to treat the active inflammatory manifestations of acute gouty arthritis. Further details, by synopsis of the 2020 American College of Rheumatology (ACR) treatment guidelines for management of gout, are available in The 2020 American College of Rheumatology Guidelines for the Management of Gout. In addition, the algorithm shown in Figure 6-1 summarizes the FDA-approved therapy options for acute gout, while Figure 6-2 shows the algorithm for gout flare management from the 2016 European League Against Rheumatism (EULAR) guidelines on gout management.

Pathogenic inflammatory pathways of acute gouty arthritis (Disease Definition and Overview) stem from the capacity of urate crystals to activate resident cells in the joint (e.g., synovial lining cells, mast cells and macrophages). The subsequent cascade of urate crystal–induced ingress and activation of leukocytes (principally neutrophils, monocytes and macrophages) in the joint space prolongs acute gouty inflammation. There are many individual targets for anti-inflammatories in gouty arthritis (Disease Definition and Overview). However, the primary systemic evidence-based treatment choices (e.g., NSAIDs, corticosteroids, colchicine) inhibit multiple inflammatory pathways, ultimately suppressing endothelial function and inflammatory cell activation, and further neutrophil and monocyte recruitment into the joint space. Key targets of gout anti-inflammatory therapeutics include inflammatory signaling (including NLRP3 inflammasome and NF- κB activation) and the related expression, secretion and signaling of inflammatory cytokines, such as IL-1b and IL-8, particularly as they impact on endothelial activation and neutrophil adhesion, migration and activation.

Enlarge  Figure 6-1: Anti-Inflammatory Treatment Strategy Options Using FDA-Approved Agents
Figure 6-1: Anti-Inflammatory Treatment Strategy Options Using FDA-Approved Agents
Enlarge  Figure 6-2: The 2016 EULAR Gout Flare Management Algorithm. Strong P-glycoprotein or CYP3A4 inhibitors are cyclosporin, clarithromycin, ketoconazole and ritonavir. IL, interleukin; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; ULT, urate-lowering therapy. Source: Adapted from Richette P, et al. Ann Rheum Dis. 2017;76(1):29-42.
Figure 6-2: The 2016 EULAR Gout Flare Management Algorithm. Strong P-glycoprotein or CYP3A4 inhibitors are cyclosporin, clarithromycin, ketoconazole and ritonavir. IL, interleukin; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; ULT, urate-lowering therapy. Source: Adapted from Richette P, et al. Ann Rheum Dis. 2017;76(1):29-42.

Choice of Treatment Regimens

Acute gout flares are inherently self-limited due to adaptive mechanisms to the innate immune response, such that spontaneous resolution of the flare is typical within 1 to 2 weeks. The natural course of untreated acute gout serves as a benchmark to assess efficacy of treatments since most patients have improvement in pain and tenderness by 1 week, although full resolution of pain occurs spontaneously only in a minority of patients by 1 week. As such, assessment of drug efficacy is challenging in clinical trials of acute gout. Moreover, such trials often are designed to primarily examine response of an index joint, whereas more intensive therapy appears to be needed for polyarticular and large-joint gout flares in comparison with monoarticular small-joint flares of gout.

Not all treatments employed in the clinic for acute gout are fully evidence based. Fortunately, there are multiple effective options (and dosing regimens) for anti-inflammatory/analgesic treatment in acute gout (Table 6-1). Moreover, novel and effective treatments are emerging in clinical development and trials. However, there remains no single standard therapy for the gout flare, and selection of the most appropriate option, including combinations of therapies for more severe flares, is individualized to the patient, and takes into account patient comorbidities and patient and provider preferences. Clinical research advances of the last decade supply guidance on choosing treatment regimens.

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Factors in Selecting the Gouty Arthritis Treatment Regimen for the Individual Patient

Comorbidities and the potential for drug-drug interactions are perhaps the most important considerations in selecting treatment of acute gout. For example, limits to nonsteroidal anti-inflammatory drug (NSAIDs) and cyclooxygenase (COX)-2–selective inhibitors are imposed by renal, cardiac, respiratory, and upper gastrointestinal (GI) tract diseases, as well as anticoagulant use. Systemic corticosteroid use is limited in part by hyperglycemia, fluid retention, central nervous system (CNS) side effects, and concurrent infection. Conversely, corticosteroids are a particularly useful treatment option for gout in chronic kidney disease (CKD) at stage 3 or beyond in severity. Colchicine appears most effective when employed in early gout flares (i.e., within the first day or two of the flare). Corticosteroid injection of joints for treatment of acute gout is limited by accessibility to the joint space, physician expertise and practice patterns and patient preferences and should not be employed when there is suspicion of bacterial cellulitis rather than sterile gout-related skin inflammation in the differential diagnosis.

Patient expectations for the speed of resolution of gout flares need to be kept in line. Specifically, NSAIDs, systemic corticosteroids and colchicine render the excruciating pain of the gout flare more bearable and do so within 24 hours, but the therapeutic responses are incomplete. For example, the typical response of acute gout to oral NSAIDs sees sustained reduction of the level of pain by ~50% by 48 to 72 hours (Figure 6-2). Moreover, preliminary studies of injectable NSAID therapy have not yet shown any advantage in early pain relief in comparison with oral NSAIDs.

Enlarge  Figure 6-2: The 2016 EULAR Gout Flare Management Algorithm. Strong P-glycoprotein or CYP3A4 inhibitors are cyclosporin, clarithromycin, ketoconazole and ritonavir. IL, interleukin; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; ULT, urate-lowering therapy. Source: Adapted from Richette P, et al. Ann Rheum Dis. 2017;76(1):29-42.
Figure 6-2: The 2016 EULAR Gout Flare Management Algorithm. Strong P-glycoprotein or CYP3A4 inhibitors are cyclosporin, clarithromycin, ketoconazole and ritonavir. IL, interleukin; NSAID, non-steroidal anti-inflammatory drug; PPI, proton pump inhibitor; ULT, urate-lowering therapy. Source: Adapted from Richette P, et al. Ann Rheum Dis. 2017;76(1):29-42.

NSAIDs and COX-2–Selective Inhibitors

In several dozen appropriately designed clinical trials, NSAIDs have been demonstrated to be effective in treatment of acute gout. Indomethacin had been the gold standard and clearly provides particularly effective analgesia in acute gout. However, both CNS (including dizziness and headache) and GI side effects often limit indomethacin use. Many clinicians now prefer to treat acute gout with naproxen or other NSAIDs rather than indomethacin. Numerous other NSAIDs are effective alternatives, including full doses of sulindac, diclofenac and ibuprofen. Sample treatment regimens and core principles of NSAID therapy for acute gout flares are listed in Table 6-2.

The most studied COX-2–selective inhibitors to date in acute gout are etoricoxib and lumiracoxib, which appeared to be comparably effective as indomethacin in randomized, controlled clinical trial evaluations. However, etoricoxib and lumiracoxib are not FDA-approved agents and are not available in the United States.

Use of celecoxib is an option for the acute pain linked to inflammation in gouty arthritis, but requires much higher doses than the standard doses used for chronic arthritis in order to give a change in pain scores from baseline to day 2 comparable to indomethacin 50 mg tid. Cardiovascular safety of both NSAIDs and COX-2–selective inhibitors remains a major concern, since even short-term NSAID use can significantly increase cardiovascular and renal adverse events and these include myocardial infarction.

Use of high doses of aspirin (acetylsalicylic acid) or of nonacetylated salicylates is not recommended for acute gout. These agents have not been formally evaluated for this condition. The time needed for aspirin to reach therapeutic serum levels for adequate analgesia in gout is not optimal. Moreover, high-dose salicylates are uricosuric and substantial lowering of serum urate is an undesirable change in acute gout due to the potential to worsen the inflammation via remodeling and destabilization of tophi.

Side effects, drug-drug interactions, precautions in use and contraindications of NSAID and COX-2–selective inhibitor therapy have been reviewed elsewhere. Table 6-3 summarizes major potential NSAID adverse events specifically in short-term therapy for acute gout. There is no evidence that gastric cytoprotection is generally necessary when using NSAIDs in the absence of known peptic ulcer disease or GI intolerance of NSAIDs. However, alcohol use increases the risk of GI bleeding with NSAIDs.

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Systemic Corticosteroids

Oral Therapy

NSAIDs and oral corticosteroids are comparable in efficacy for acute gout. Prednisone is a valuable frontline treatment for acute gout, but best practice guidelines are for clinicians to employ a starting dose of at least 0.5 mg/kg prednisone on the first day (Table 6-4). The fact that severe flares of acute gout develop in many major-organ transplant patients maintained on low-dose daily prednisone (in the range of 7.5 to 10 mg daily) is a striking illustration of the need for relatively high initial doses of systemic corticosteroids to effectively treat acute gouty arthritis. Sample regimens include 40 to 60 mg prednisone daily for 3 days (depending on severity of the flare), then decreasing by 10 to 15 mg/day every 3 days until discontinuation.

Alternatively, for relatively mild flares of acute gout, a methylprednisolone dose pack is sometimes employed in clinical practice to, at a minimum, initiate therapy, but this is not an evidence-based regimen. In randomized, controlled clinical trials, prednisolone 35 mg daily for 5 days and naproxen 500 mg twice daily for 5 days were similar in efficacy and tolerance for acute gout, and prednisolone (six doses of 30 mg over 5 days) was similar in efficacy to indomethacin and was superior in tolerance. Table 6-3 summarizes and compares major potential adverse effects of NSAIDs and corticosteroids in short-term therapy for acute gout. Side effects of systemic corticosteroid therapy, specifically in acute gout treatment, are summarized elsewhere.

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Parenteral Systemic Corticosteroid Therapy

In severe cases of acute polyarticular gout or when the patient is nothing by mouth (NPO) (i.e., unable to ingest oral medication), an abbreviated course of intravenous (IV) methylprednisolone appears to be an appropriate strategy. Using 100 to 150 mg IV methylprednisolone as an initial dose, followed by 50 to 75 mg twice daily for a few days is thought to be a reasonable starting point for acute gout. A single dose of 60 mg intramuscular (IM) triamcinolone acetonide has been suggested to be effective for acute gout, but the evidence basis is limited, and continuation with oral prednisone after the intramuscular triamcinolone is good clinical practice. A single dose of only 40 mg IM triamcinolone acetonide (TA) was inferior to single-dose subcutaneous canakinumab 150 mg for acute gout in a direct comparative study and, although biologically active, such TA dosing is not a preferred regimen.

Rebound Flares of Gout After Discontinuation of Systemic Corticosteroids

The use of prednisone (as well as triamcinolone) and adrenocorticotropic hormone (ACTH) (which induces adrenal corticosteroid production) for primary treatment of acute gout flare is associated with the potential for rebound flares of acute gout when short courses of treatment are stopped. There is a likely scientific basis for the rebound flares, since corticosteroids induce expression of NLRP3 in macrophages. Thus the best practice is to initiate or continue low-dose colchicine for gout-flare prophylaxis as an adjunct to therapy when systemic corticosteroids are used to treat acute gout, particularly in the setting of recent initiation of urate-lowering therapy (ULT). This practice is much preferable to having to administer sustained or multiple courses of systemic corticosteroids, even at low doses, in patients with gout.

Colchicine

Mechanism of Action

Colchicine, by binding tightly to tubulin and inhibiting microtubule elongation and function in the cytoskeleton of phagocytes and endothelium, exerts multiple effects on pathways that drive the acute neutrophil-mediated inflammation in gout (and pseudogout). Notably, colchicine becomes readily concentrated in neutrophils. At low drug doses, these effects include suppression of multiple macrophage inflammatory responses to urate crystals and inhibition of neutrophil adhesion to endothelium promoted by E-selectin; neutrophil migration and inflammatory mediator release are inhibited by higher doses of the drug. Many of the primary anti-inflammatory effects of colchicine are mediated by the ability of colchicine to increase the activation of the nutritional biosensor adenosine monophossphate (AMP) activated protein kinase.

Best Practice for Use of Colchicine in Acute Gout

Oral colchicine appears most effective when self-administered promptly by the patient after gout-flare symptom onset, ideally within the first 12 to 36 hours of an acute gout flare, by a well-educated patient with a prescribed supply of the drug on hand (Table 6-5). Because colchicine elimination is slow, it is not advisable to add oral colchicine for acute gout flare in those already loaded with the drug (i.e., on a sustained course of low-dose daily colchicine for gout-flare prophylaxis). The use of lower-dose and abbreviated colchicine regimens reduces risks of clinically significant drug-drug interactions. However, caution is required when administering colchicine for acute gout in those with severe chronic kidney disease, and/or taking established drugs with the potential for pharmacokinetic interaction with colchicine (e.g., clarithromycin, erythromycin, cyclosporine, tacrolimus, disulfiram and multiple antineoplastics); a specific dose reduction algorithm has been recommended, based on pharmacokinetic studies in healthy volunteers. Dose adjustments for colchicine due to drug-drug interactions are discussed in greater detail, including as a guide in chronic use of colchicine for gout flare prophylaxis, in Prophylaxis of Acute Gout Flares.

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Dosing Guidelines for Acute Gout

Dosing guidelines and the evidence basis for colchicine in acute gout treatment are well-accepted (Table 6-5 and Table 6-6). Earlier high-dose colchicine dosing regimens are no longer advocated, due to GI toxicity, including severe diarrhea, that is dose-limiting and develops before the ideal target level of 50% reduction in pain is attained in the majority of those with acute gout. Such regimens, in which patients are essentially inundated in a prolonged manner with colchicine, also should not be used in pseudogout.

The sizeable, randomized, placebo-controlled multicenter study (the Acute Gout Flare Receiving Colchicine Evaluation [AGREE] trial) compared low-dose with extended-dose colchicine regimens in subjects with well-preserved renal function. The low-dose and high-dose colchicine regimens rapidly achieved the same maximal serum concentration (Cmax) of ~6 ng/mL, but total drug exposure was proportionate to colchicine dose (Figure 6-3). Importantly, low-dose colchicine was similar to high-dose colchicine in efficacy of pain relief at 24 hours, and this was independent of the extent of the pain response. However, low-dose colchicine did not differ from placebo for diarrhea (mild or severe), nausea, or other GI adverse events. In contrast, high-dose colchicine caused significantly more GI adverse events, including severe diarrhea, than did placebo. The results suggest that attainment of ~6 ng/mL serum Cmax of colchicine is central to therapeutic effect in acute gout, whereas adverse events are more related to total drug exposure.

More clinical study is needed to ascertain the evidence basis and ideal dosing amount and length for continuation of oral colchicine after the first day of using low-dose colchicine to treat the acute gout flare. Best practice is to start low-dose colchicine prophylaxis (Prophylaxis of Acute Gout Flares), if indicated, beginning 12 hours after the use of the low-dose colchicine regimen for acute gout; at this point in time, colchicine blood levels markedly decline after use of the low-dose colchicine regimen. Renal and hepatobiliary function and potential drug-drug interactions need to be considered when extending colchicine treatment of acute gout.

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Enlarge  Figure 6-3: Effect of NSAIDs and Oral Corticosteroids on Pain in Acute Gout Flare (in an emergency department setting in a large randomized controlled trial of oral indomethacin vs oral prednisolone). In the indomethacin group, patients initially received 50 mg (two 25-mg tablets) of oral indomethacin 3 times a day, followed by 25 mg of indomethacin three times a day for 3 days. In the prednisolone group, patients initially received 30 mg (three 10-mg tablets) of oral prednisolone once a day, followed by 30 mg (three 10-mg tablets) of prednisolone once a day for 3 days. All patients were prescribed oral paracetamol (1 g) to be taken every 6 hours as needed. Mean early pain scores, and pain scores over 2 weeks, are shown in the figure panels. Data were analyzed per protocol. The means and 95% CIs of the coefficients (slopes) of change in pain over unit time for patients in each group were compared using the t test. A. Pain score at rest in the emergency department phase. The study authors found no statistically or clinically significant differences between groups (P=0.69). The mean decrease in pain score was 6.54 mm/h (95% CI, 5.02 to 8.06 mm/h) for indomethacin and 5.05 mm/h (CI, 3.56 to 6.55 mm/h) for prednisolone (mean difference, -1.49 mm/h [CI, 0.64 to –3.61 mm/h]). B. Pain score with activity in the emergency department phase. We found no statistically or clinically significant differences between groups (P=0.56). The mean decrease in pain score was 11.69 mm/h (CI, 10.10 to 13.28 mm/h) for indomethacin and 11.38 mm/h (CI, 9.98 to 12.79 mm/h) for prednisolone (mean difference, –0.31 mm/h [CI, 1.80 to –2.42 mm/h]). C. Pain score at rest from days 1 to 14. We found no statistically or clinically significant differences between groups (P=0.80). The mean decrease in pain score was 1.80 mm/d (CI, 1.46 to 2.13 mm/d) for indomethacin and 1.68 mm/d (CI, 1.39 to 1.97 mm/d) for prednisolone (mean difference, –0.12 mm/d [CI, 0.32 to –0.55 mm/d]). D. Pain score with activity from days 1 to 14. We found no statistically or clinically significant differences between groups (P = 0.20). The mean decrease in pain score was 2.96 mm/d (CI, 2.62 to 3.30 mm/d) for indomethacin and 3.19 mm/d (CI, 2.85 to 3.52 mm/d) for prednisolone (mean difference, 0.22 mm/d [CI, 0.70 to –0.25 mm/d]). Source: Rainer TH, et al. Ann Intern Med. 2016;164(7):464-471.
Figure 6-3: Effect of NSAIDs and Oral Corticosteroids on Pain in Acute Gout Flare (in an emergency department setting in a large randomized controlled trial of oral indomethacin vs oral prednisolone). In the indomethacin group, patients initially received 50 mg (two 25-mg tablets) of oral indomethacin 3 times a day, followed by 25 mg of indomethacin three times a day for 3 days. In the prednisolone group, patients initially received 30 mg (three 10-mg tablets) of oral prednisolone once a day, followed by 30 mg (three 10-mg tablets) of prednisolone once a day for 3 days. All patients were prescribed oral paracetamol (1 g) to be taken every 6 hours as needed. Mean early pain scores, and pain scores over 2 weeks, are shown in the figure panels. Data were analyzed per protocol. The means and 95% CIs of the coefficients (slopes) of change in pain over unit time for patients in each group were compared using the t test. A. Pain score at rest in the emergency department phase. The study authors found no statistically or clinically significant differences between groups (P=0.69). The mean decrease in pain score was 6.54 mm/h (95% CI, 5.02 to 8.06 mm/h) for indomethacin and 5.05 mm/h (CI, 3.56 to 6.55 mm/h) for prednisolone (mean difference, -1.49 mm/h [CI, 0.64 to –3.61 mm/h]). B. Pain score with activity in the emergency department phase. We found no statistically or clinically significant differences between groups (P=0.56). The mean decrease in pain score was 11.69 mm/h (CI, 10.10 to 13.28 mm/h) for indomethacin and 11.38 mm/h (CI, 9.98 to 12.79 mm/h) for prednisolone (mean difference, –0.31 mm/h [CI, 1.80 to –2.42 mm/h]). C. Pain score at rest from days 1 to 14. We found no statistically or clinically significant differences between groups (P=0.80). The mean decrease in pain score was 1.80 mm/d (CI, 1.46 to 2.13 mm/d) for indomethacin and 1.68 mm/d (CI, 1.39 to 1.97 mm/d) for prednisolone (mean difference, –0.12 mm/d [CI, 0.32 to –0.55 mm/d]). D. Pain score with activity from days 1 to 14. We found no statistically or clinically significant differences between groups (P = 0.20). The mean decrease in pain score was 2.96 mm/d (CI, 2.62 to 3.30 mm/d) for indomethacin and 3.19 mm/d (CI, 2.85 to 3.52 mm/d) for prednisolone (mean difference, 0.22 mm/d [CI, 0.70 to –0.25 mm/d]). Source: Rainer TH, et al. Ann Intern Med. 2016;164(7):464-471.

Colchicine Side Effects in the Treatment of Acute Gout

GI symptoms (e.g., diarrhea [which can be severe], nausea, and less frequently, vomiting) are the most common side effects with oral colchicine (Table 6-7), but are far more common with previous high-dose colchicine regimens than with the Food and Drug Administration (FDA)-approved low-dose colchicine regimen for acute gout. In acute colchicine overdose, bone marrow depression can develop, usually with a nadir at 1 week after onset of therapy. In acute (and chronic) colchicine overdose, colchicine myopathy, affecting proximal more than distal muscles and typically associated with elevated creatine kinase (CK) serum levels in the early phase (weeks to months) and with variable degrees of neuropathy, can mimic inflammatory muscle disease. In more severe colchicine overdose, cardiac toxicity, cardiovascular (CV) collapse, hepatotoxicity and alopecia can occur. Importantly, colchicine is incompletely cleared by dialysis. Overdose of the drug has the potential to cause severe or lethal side effects.

Severe colchicine overdose is managed by supportive care. The use of granulocyte colony-stimulating factor (G-CSF) treatment for colchicine-induced neutropenia is rational in this clinical context but has not been assessed in a controlled clinical trial.

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Intra-articular Corticosteroids

Intra-articular injection of a depot glucocorticosteroid for gout affecting one or two large joints is supported by small, open-label studies. This option is considered the best practice in those in whom the oral therapies highlighted above are contraindicated or are not working into the course of a flare and is useful in the nothing by mouth (NPO) patient. Importantly, lack of response of a gout flare to the frontline oral treatment modalities discussed above should always first trigger suspicion of a diagnosis other than gout, and often warrants diagnostic arthrocentesis and synovial fluid analysis.

ACTH

In small clinical studies, ACTH has appeared effective within hours for monoarticular and polyarticular gout flares. Some clinical studies suggest that ACTH may have particularly rapid onset of action in acute gout. This may be due to peripheral, non-adrenal effects of ACTH, since ACTH exerts peripheral anti-inflammatory effects on phagocytes via melanocortin receptor activation. ACTH may be of particular value in some hospital inpatient flares of gout, including the NPO patient. However, there is no evidence that systemic anti-inflammatory doses of corticosteroids and ACTH differ significantly in efficacy. Moreover, ACTH is many times more expensive than oral corticosteroids. Hence, ACTH therapy is generally reserved for those unable to take oral or parenteral corticosteroids.

When employed for acute gout, porcine ACTH has a small risk of hypersensitivity reaction. ACTH also is expected to be far less effective in those with chronic adrenal suppression via sustained oral corticosteroid therapy. Dose recommendations are for 25 USP Units of ACTH subcutaneously (SC) as a starting dose for acute, small joint monoarticular gout and a typical starting dose is 40 USP Units SC once for larger-joint acute gout or for polyarticular gout. With each of these ACTH dosing regimens, one or a few repeat doses of ACTH may be required at up to 6- or 8-hour intervals.

Canakinumab

IL-1β appears to be critical to experimental urate (and CPPD) crystal–induced inflammation and more central to these processes than TNF-α (Disease Definition and Overview). Canakinumab, a IL-1 inhibitor, is the most recent agent to receive FDA approval for the symptomatic treatment of gout flares (in August 2023). Canakinumab, at a single subcutaneous dose of 150 mg, was superior to a single injection of 40 mg IM triamcinolone acetate for decrease in intensity of pain of gout flare at multiple time points between 1 to 7 days after treatment in clinical trials. Canakinumab was also associated with markedly fewer recurrent gout flares, compared with IM triamcinolone, for many weeks following the initial gout flare treated, and canakinumab improved certain parameters of inflammation and health-related quality of life. However, canakinumab is also associated with increased risk of serious infections.

Combinations of Therapies

The use of low prophylactic doses of oral colchicine (Prophylaxis of Acute Gout Flares) as an adjunct to an NSAID, systemic or local corticosteroid, or ACTH treatment of an acute gout flare is generally appropriate. Continuation of low-dose oral prophylactic colchicine as the gout flare resolves can help to suppress rebound flares after any treatment. Other drug combinations in acute gout are not yet evidence-based. Clinicians should avoid combining NSAIDs and systemic corticosteroids in acute gout since, for example, this combination can enhance GI toxicity and fluid retention.

Other Modalities

Topical ice, previously subjected to randomized clinical trial evaluation (in which it was used in conjunction with colchicine and prednisone), appears to be of benefit in reducing the level of pain in acute gout. Some patients benefit from selective use of opiates as adjuncts for severe, acute pain in early gout-flare treatment, although no controlled study has been conducted, and opiates are not recommended in first-line gout therapy.

Emerging Treatments

IL-1 inhibitors other than canakinumab (anakinra, gevokizumab, rilonacept) have yet to receive FDA approval for the treatment of gout, though further clinical trials may lead to approval of one or more of these agents. Notably, anakinra was shown in 2019 to be non-inferior to the usual treatment (colchicine, naproxen, or prednisone) with respect to change from baseline in a 5-point pain score. Anakinra was also shown to be noninferior to triamcinolone for acute gout pain management.

There is no evidence basis to employ biologic tumor necrosis factor alpha (TNF-α) antagonists for gouty inflammation, since only anecdotal reports have suggested TNF-α antagonism to be beneficial for refractory human gouty arthritis, and pseudogout has been reported to break through on established etanercept therapy.

Other anti-inflammatory agents of potential future value in acute gout management include caspase inhibitors (pralnacasan, a reversible caspase‐1 inhibitor, and emricasan, an irreversible pancaspase inhibitor; both inhibit IL‐1β secretion), NLRP3 inflammasome inhibitors (e.g. dapansutrile, an oral β‐sulfonyl nitrile molecule), and AAT-Fc, a recombinant human alpha‐1 anti‐trypsin immunoglobulin G1 Fc fusion protein (which targets the proteases involved in the extracellular processing of IL‐1β).

Treatment of Pseudogout

There are marked limitations in the evidence basis of pseudogout treatment, but expert opinion suggests the efficacy of comparable frontline approaches to those discussed above for acute gout, with intra-articular corticosteroids being a mainstay of therapy for large joint arthritis in pseudogout. ACTH also may be effective in pseudogout and colchicine appears to be useful in prophylaxis of recurrent flares of pseudogout.

Take-Away Messages

  • NSAIDs (or coxibs, but with many of the same precautions as NSAIDs), colchicine and prednisone are the front-line therapy options for the acute gout attack. However, there remains no single therapy standard among these for the gout flare and selection is individualized, with comorbidities and potential drug-drug interactions as important considerations.
  • NSAIDs and oral corticosteroids are comparable in efficacy for acute gout.
  • Indomethacin is effective in acute gout, but both CNS (including dizziness) and GI side effects limit indomethacin use. Naproxen and many other NSAIDs are good alternatives, and some coxibs have been shown to be effective, but celecoxib requires a high-dose regimen.
  • Use of high doses of aspirin (acetylsalicylic acid) or of nonacetylated salicylates is not recommended for acute gout.
  • When prednisone is used to treat acute gout, the best practice guidelines are for a starting dose of at least 0.5 mg/kg prednisone per day.
  • The use of prednisone for acute gout flare is associated with the potential for rebound flares of acute gout, and low-dose colchicine gout-flare prophylaxis should be considered as an adjunct to therapy.
  • Oral colchicine appears most effective when self-administered promptly by the patient after gout-flare symptom onset, ideally in the first 12 to 36 hours of an acute gout flare by a patient who is well educated in its use with a prescribed supply of the drug on hand.
  • The dosing regimen of colchicine for treating an acute early attack of gout (within 12 hours) should be limited to 1.2 mg orally followed by 0.6 mg 1 hour later. Prophylactic colchicine dosing can be added, starting 12 hours later. Higher colchicine doses and more extended early-dosing regimens concentrated over a few hours do not add efficacy and markedly increase toxicity in early gout-flare treatment.
  • Parenteral (IV or IM) corticosteroids, intra-articular corticosteroids and subcutaneous ACTH are particularly useful options for the NPO patient, such as hospital inpatients pre-operatively or postoperatively.

References

  • Terkeltaub R, Edwards NL, Khanna P. Gout: Diagnosis and Management of Gouty Arthritis and Hyperuricemia. 5th ed. Professional Communications Inc. 2024
  • Daoussis D, Antonopoulos I, Andonopoulos AP. ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action. Semin Arthritis Rheum. 2014;43(5):648-653.
  • Daoussis D, Antonopoulos I, Yiannopoulos G, et al. ACTH as first line treatment for acute gout in 181 hospitalized patients. Joint Bone Spine.2013;80(3):291-294.
  • Fisher MC, Pillinger MH, Keenan RT. Inpatient gout: a review. Curr Rheumatol Rep. 2014;16(11):458.
  • FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760.
  • Getting SJ, Lam CW, Chen AS, Grieco P, Perretti M. Melanocortin 3 receptors control crystal-induced inflammation. FASEB J. 2006;2(13):2234-2241.
  • Ilaris [package insert]. East Hanover, NJ: Novartic Pharmaceuticals Corporation. 08/2023.
  • James R, Paul BJ. New and emerging therapies in gout. Rheumatology Autoimmunity. 2023;3:70-77.
  • Janssen CA, Oude Voshaar M, Vokeman HE, et al. Anakinra for the treatment of acute gout flares: a randomized, double-blind, placebo-conrolled, active-comparator, non-inferiority trial. Rheumatology. 2019;58:1344-1352.
  • Janssens HJ, Janssen M, van de Lisdonk EH, et al. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008;371(9627):1854-1860.
  • Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. Cochrane Database Syst Rev. 2008;(2):CD005521.
  • Josefina M, Ana CJ, Ariel V, Silvio AA. Development of pseudogout during etanercept treatment. J Clin Rheumatol. 2007;13(3): 177.
  • Keenan RT, O’Brien WR, Lee KH, et al. Prevalence of contraindications and prescription of pharmacologic therapies for gout. Am J Med. 2011;124(2):155-163.
  • Khanna PP, Gladue HS, Singh MK, et al. Semin Arthritis Rheum. 2014;44:31-38.
  • Kingsbury SR, Conaghan PG, McDermott MF. The role of the NLRP3 inflammasome in gout. J Inflamm Res. 2011;4:39-49.
  • Man CY, Cheung IT, Cameron PA, Rainer TH. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med. 2007;49(5):670-677.
  • Neogi T. Clinical practice. Gout. N Engl J Med. 2011;364(5):443-452.
  • Neogi T. Interleukin-1 antagonism in acute gout: is targeting a single cytokine the answer? Arthritis Rheum. 2010;62(10):2845-2849.
  • Patrono C. Cardiovascular effects of nonsteroidal anti-inflammatory drugs. Curr Cardiol Rep. 2016;18(3):25.
  • Rainer TH, Cheng CH, Janssens HJ, et al. Oral prednisolone in the treatment of acute gout. A pragmatic, multicenter, double-blind, randomized trial. Ann Intern Med. 2016;164(7):464-471.
  • Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76:29-42..
  • Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum. 2004;50(2):598-606.
  • Saag KG, Khanna PP, Keenan RT, et al. A randomized, phase II study evaluating the efficacy and afety of anakinra in the treatment of gout flares. Arthritis Rheumatol. 2021;73(8):1533-1542.
  • Schlesinger N, De Meulemeester M, Pikhlak A, et al. Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat gouty arthritis by suppressing inflammation: results of a randomized, dose-ranging study. Arthritis Res Ther. 2011;13(2):R53.
  • Schlesinger N, Detry MA, Holland BK, et al. Local ice therapy during bouts of acute gouty arthritis. J Rheumatol. 2002;29(2):331-334.
  • Schlesinger N. Overview of the management of acute gout and the role of adrenocorticotropic hormone. Drugs. 2008;68(4):407-415.
  • Schumacher HR, Berger MF, Li-Yu J, et al. Efficacy and tolerability of celecoxib in the treatment of acute gouty arthritis: a randomized controlled trial. J Rheumatol. 2012;39(9):1859-1866.
  • Shrestha M, Chiu MJ, Martin RL, Cush JJ, Wainscott MS. Treatment of acute gouty arthritis with intramuscular ketorolac tromethamine. Am J Emerg Med. 1994;12(4):454-455.
  • Shrestha M, Morgan DL, Moreden JM, Singh R, Nelson M, Hayes JE. Randomized double-blind comparison of the analgesic efficacy of intramuscular ketorolac and oral indomethacin in the treatment of acute gouty arthritis. Ann Emerg Med. 1995;26(6):682-686.
  • Slobodnick A, Shah B, Pillinger MH, et al. Colchicine: old and new. Am J Med. 2015;128(5):461-470.
  • So A, De Meulemeester M, Pikhlak A, et al. Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: results of a multicenter, phase II, dose-ranging study. Arthritis Rheum. 2010;62(10):3064-3076.
  • So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther. 2007;9(2):R28.
  • Steiger S, Harper JL. Mechanisms of spontaneous resolution of acute gouty inflammation. Curr Rheumatol Rep. 2014;16:392.
  • Tausche AK, Richter K, Grassler A, Hansel S, Roch B, Schroder HE. Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Ann Rheum Dis. 2004;63(10):1351-1352.
  • Terkeltaub R. Update on gout: new therapeutic strategies and options. Nat Rev Rheumatol. 2010;6(1):30-38.
  • Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High vs low dosing of oral colchicine for early acute gout flare: Twenty-four hour outcome results of the first randomized, placebo-controlled, dose comparison colchicine trial. Arthritis Rheum. 2010;62(4):1060-1068.
  • Terkeltaub RA, Furst DE, Digiacinto JL, et al. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors [published correction appears in Arthritis Rheum. 2011;63(11):3521]. Arthritis Rheum. 2011;63(8):2226-2237.
  • Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum. 2009;38(6):411-419.
  • Wang Y, Viollet B, Terkeltaub R, et al. AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis. 2016;75(1):286-294.
  • Wason S, Mount D, Faulkner R. Single-dose, open-label study of the differences in pharmacokinetics of colchicine in subjects with renal impairment, including end-stage renal disease. Clin Drug Investig. 2014;34(12):845-855.
  • Winzenberg T, Buchbinder R. Cochrane Musculoskeletal Group review: acute gout. Steroids or NSAIDs? Let this overview from the Cochrane Group help you decide what’s best for your patient. J Fam Pract. 2009;58(7):E1-E4.
  • Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-1324.
  • Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011;70(4):571-575.
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