AUTHORS: Omar Karim, BS and Caroline P. Meehan, MD
Gout refers to a group of disease states caused by deposition of monosodium urate (MSU) in tissue, resulting from prolonged hyperuricemia. Clinical manifestations of gout include acute and chronic arthritis, soft tissue inflammation, tophus formation, gouty nephropathy, and nephrolithiasis. Untreated hyperuricemia in patients with gout may lead to chronic destructive deforming arthritis.
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Self-reported prevalence in the U.S. is estimated at 3.9% of adults.1 In the U.S., gout has been diagnosed in more than 10 million adults.2
Male:female ratio ∼4:1. However the prevalence of gout among women has increased in past decade. Compared with men, gout in women is more likely to be associated with diabetes, coronary heart disease, and chronic kidney disease.3
TABLE 1 Gout Promoters and Inhibitors∗
Crystal formation | Seed nucleus (particulate) Immunoglobulin Phagocytes Low temperature Low pH Cation concentration Intraarticular dehydration Other (unknown) macromolecules | ||
Triggering the acute flare (local factors) | Rapid change in urate level Microcrystal release IgG coat (apolipoproteins B, E inhibitory) Complement activation (classical, alternate, MAC) Inflammasome activation Cytokine and chemokine release Endothelial activation (e-selectin, ICAM-1, VCAM-1) Local trauma | ||
Presence of susceptible phagocytes, mast cells (systemic events) | Surgery, trauma Infections, other intercurrent systemic illness Alcohol, dietary intake Drugs that raise or lower circulating urate level |
ICAM-1, Intercellular adhesion molecule 1; Ig, immunoglobulin; MAC, membrane attack complex; VCAM-1, vascular cell adhesion molecule 1.
∗A diverse array of proteins and other mediators have been identified on the surfaces of urate crystals. In addition to their proinflammatory effect through opsonizing existing crystals, immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies may promote crystal formation by providing a stable molecular platform for crystal nucleation and growth. Apolipoproteins are antiinflammatory molecules that coat crystals. The characteristics of the phagocytes encountering the crystals may be crucial; macrophages that are more differentiated are less likely to elicit proinflammatory cytokines.
From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Figure E1 Many signals impact the critical points in this pathway.
Patients with hyperuricemia do not necessarily form urate crystals. Crystals ingested by phagocytes sometimes elicit remarkably little inflammation, and the inflammation is often low grade or clinically silent in advanced gout, indicating robust regulation of the pathways shown. Factors leading to the spontaneous termination of the acute gout flare are incompletely understood. AMPK, Adenosine monophosphate-activated protein kinase; apo, apolipoprotein; IgG, immunoglobulin G; IL, interleukin; MCR, melanocortin receptor; NET, neutrophil extracellular trap; NLRP3, nucleotide-binding oligomerization domain-like receptor 3; NO, nitric oxide; PPAR, peroxisome proliferator-activated receptor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α.
From Hochberg MC: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Figure E2 Initial phases of monosodium urate (MSU) crystal-induced activation.
IL, Interleukin.
The presence of fresh MSU crystals, resulting either from spontaneous precipitation or the liberation of crystals from established pools, results in direct complement activation and activation of resident cells in the synovium including macrophages, fibroblasts, and mast cells. Activated cells produce IL-1β and other cytokines, as well as multiple other mediators (not all illustrated) that in turn activate both bloodstream neutrophils and endothelial cells. These responses permit neutrophils to adhere to and traverse the endothelium, resulting in neutrophil influx and the further propagation of inflammation as neutrophils undergo direct activation by MSU crystals (not illustrated). See text for additional details.
From Firestein GS et al: Firestein & Kelleys textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.
Figure E3 Propagation of the acute gouty response by activated neutrophils.
Neutrophils that enter the joint migrate toward and phagocytose crystals. In the case of crystals coated with immunoglobulins and complement, the resultant activation results in synthesis and/or release of inflammatory mediators such as interleukin-1β (IL-1β), IL-8, and tumor necrosis factor, as well as proteases and reactive oxygen species. In the case of uncoated crystals, the crystal frequently interacts with and lyses the membrane of the phagolysosome, spilling toxic contents and leading to cell lysis. In both cases, the result is local tissue damage and recruitment of additional neutrophils from the bloodstream in an explosive inflammatory cycle. LTB4, Leukotriene B4.
From Firestein GS et al: Firestein & Kelleys textbook of rheumatology, ed 11, Philadelphia 2021, Elsevier.
BOX 1 Acute Gout: Clinical Pearls
From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
BOX 2 Chronic Gout: Clinical Pearls
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From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Figure E4 Advanced tophaceous gout with multiple intra-articular and periarticular tophi.
Tophi observed on bilateral first metatarsophalangeal joints (A) (right greater than left) and the hand (B) in a patient with severe tophaceous gout.
From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Section II describes the differential diagnosis of acute monoarticular and oligoarticular arthritis.
Figure E6 Chronic tophaceous gout. Asymmetric large eccentric soft tissue lumps (tophi).
Underlying gouty erosions are seen at several sites, particularly the distal interphalangeal joint of the right little finger and the carpometacarpal joint of the thumb.
From Adam A et al: Grainger & Allisons diagnostic radiology, ed 5, London, 2007, Churchill Livingstone; in Grant LA: Grainger & Allisons diagnostic radiology essentials, ed 2, Philadelphia 2019, Elsevier.
Figure E7 Classic radiographic findings of gout in a 69-yr-old man.
Note the asymmetric, well-marginated erosions in the head of the first metatarsal and lesser erosions in the opposing phalanx (solid arrows). The medial erosions are characteristically larger than the lateral erosions. There is a hook sign on the inferior margin of the large medial erosion of the head of the metatarsal (dashed arrow). The joint space is preserved, and there is no osteopenia.
From Pope TL et al: Musculoskeletal imaging, ed 2, Philadelphia, 2014, WB Saunders.
TABLE 2 Therapeutic Options for Acute Gouty Inflammation
Drug Option | Level of Evidence | Typical Regimens |
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COX-nonselective NSAIDs | Grade A evidence for each regimen listed | Naproxen, 750-1000 mg/day PO in divided doses for 3 days; then 500-750 mg total daily for 4-7 days Sulindac, 300-400 mg/day in divided doses for 7-10 days |
Indomethacin, 150-200 mg/day PO in divided doses for 3 days; then 100 mg/day PO in divided doses for 4-7 days | ||
COX-2-selective NSAIDs | Grade A | For example: Celecoxib, 800 mg; then 400 mg on day 1, followed by 400 mg bid for 7 days |
Systemic corticosteroids | Grade A evidence for oral prednisolone, 35 mg/day for five or six doses; lower evidence grades for other regimens | Prednisone, 30-60 mg/day for 3 days; then taper every 3 days by 10-15 mg less as a daily dose until discontinuation |
Oral prednisolone, 35 mg/day for 5-7 days | ||
Medrol dose pack (for less severe flares) or to initiate therapy | ||
In an NPO patient: | ||
Intraarticular corticosteroids | Grade C evidence | Particularly useful for flares in a single large joint |
Triamcinolone acetonide preparations are especially useful | ||
Dose titrated to the size of the joint | ||
ACTH | Grade C evidence | 25 USP units of synthetic ACTH SC for less severe flares; 40 USP units IM or IV once for more severe flares (including larger joint flares and polyarticular gout) |
One or two repeated doses of synthetic ACTH at intervals of 12 h are often required with each of these regimens | ||
Oral colchicine | Grade A evidence for FDA-approved regimen | In the U.S: To treat an early acute gout flare: 1.2 mg once followed by 0.6 mg in 1 h and then 12 h later; oral low-dose colchicine at prophylaxis doses until the acute gout flare resolves |
Outside the U.S: 0.5 mg tid for several days is the EULAR-recommended dosing regimen | ||
Oral colchicine treatment of acute gout should be limited to once every 2 wk in those already taking a maintenance low dose of colchicine | ||
Off-label use in U.S: IL-1 antagonism | Grade C for anakinra; grade A for canakinumab | Use of anakinra (e.g., 100 mg/day SC for 3 days) or canakinumab (150 mg SC as single dose) for acute gout flare is not approved by the FDA, but canakinumab is approved by the EMA for this indication |
ACTH, Adrenocorticotropic hormone; bid, twice a day; COX, cyclooxygenase; EMA, European Medicines Agency; EULAR, European League Against Rheumatism; FDA, U.S. Food and Drug Administration; IL-1, interleukin-1; IM, intramuscularly; IV, intravenously; NPO, nothing by mouth; NSAID, nonsteroidal antiinflammatory drug; PO, by mouth; SC, subcutaneously; tid, three times a day; USP, U.S. Pharmacopeia.
From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Acute Gout | Interval Gout | Treatment of Hyperuricemia |
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NSAIDs (preferred): Indomethacin 50 mg qid or ibuprofen 800 mg tid (or other NSAID in full doses). Contraindicated in patients with renal insufficiency and gastrointestinal disorders. Or Colchicine, oral: 1.2 mg followed by a second dose of 0.6 mg 1 h later. Contraindicated in patients with renal insufficiency and gastrointestinal disorders Or Intraarticular steroids (Treatment of choice for large joint monoarthritis): Triamcinolone 40 mg or equivalent for knee Or Systemic steroid therapy (for patients in whom NSAIDs and colchicine are contraindicated) Prednisone 30-50 mg/day PO or in divided doses. May use lower dose in diabetic or postsurgical patients. | Colchicine, oral: 0.6-1.2 mg/day as prophylaxis against recurrent attacks. NSAIDs may also be used for prophylaxis. Hypouricemic agent: Indicated for patients with recurrent attacks despite prophylaxis, severe hyperuricemia, presence of tophi, urolithiasis, or gouty arthritis Other: Weight loss, reduce alcohol (especially beer), diet low in seafood, red meat, organ meat, and fructose | Colchicine, oral: 0.6-1.2 mg/day for 4-6 wk before initiating hypouricemic therapy and for several months afterward to prevent recurrent attacks during initiation of hypouricemic therapy And Allopurinol: Initial dose 100 mg/day in patients with renal insufficiency or very high uric acid levels. Increase dose as needed to attain uric acid less than 6 mg/dl Or Uricosuric agent (Use only in patients with good renal function and <600 mg uric acid in a 24-h collection): Probenecid, 0.5-1 g bid, or sulfinpyrazone 100 mg tid or qid Other: Consider febuxostat for patients allergic to allopurinol and the addition of lesinurad in patients resistant to xanthine oxidase inhibitors. Pegloticase may be useful for selected patients with severe tophaceous gout |
bid, Twice a day; NSAID, nonsteroidal antiinflammatory drug; PO, by mouth; qid, four times a day; tid, three times a day.
The American College of Rheumatology, as well as most international rheumatology guidelines, recommend that every patient with gout who has tophi, more than two attacks of gout per year, chronic kidney disease, or nephrolithiasis be treated with pharmacologic urate-lowering therapy. Serum uric acid should be monitored on a regular basis and urate-lowering therapy intensified until a target of less than 6 mg/dl is reached. In most cases, urate-lowering therapy should be continued for life. Fig. E8 summarizes pharmacologic serum urate-lowering treatment.1
The American College of Physicians Guidelines recommends a more conservative approach based on recurrence of symptoms. These guidelines have been criticized for ignoring the progressive nature of gout and perpetuating the well-documented underuse and under-dosing of urate-lowering therapy.
The algorithm, discussed in the text, summarizes the first-, second-, and third-line approaches to pharmacologic urate-lowering therapy, including management of refractory hyperuricemia in difficult gout. CKD, Chronic kidney disease; PCR, polymerase chain reaction.
From Hochberg MC et al: Rheumatology, ed 7, Philadelphia, 2019, Elsevier.
Lifestyle and dietary modification should always be a component of therapy for patients with gout, but this is rarely effective without concomitant pharmacologic urate-lowering therapy, as dietary modification can lower uric acid only about 1 mg/dl. Recommendations include reducing ingestion of red meat, kidney, liver, yeast extract, shellfish, and overall protein along with restricting alcohol intake. Discontinuation of diuretic therapy may help lower serum uric acid. Women with normal weight and best adherence to dietary approaches to stop hypertension (DASH) diet have a 68% lower risk for gout than women who are overweight or obese and are least adherent to the DASH diet.3
Allopurinol is very effective and safe when used properly. Correct dosing and patient compliance are essential elements in the prevention of erosive and tophaceous gout. Patients with renal insufficiency are at increased risk for allopurinol hypersensitivity, which manifests as fever, rash, and hepatitis occurring most commonly in the first 3 months of therapy. The rash may progress to life-threatening toxic epidermal necrolysis if not recognized early.
Traditionally, therapy with allopurinol is initiated several weeks after the acute attack has resolved. However, initiation of allopurinol at presentation may improve long-term compliance without reducing the efficacy of acute treatment. The initial dose should be low (≤100 mg/day depending on creatinine clearance) in patients with renal insufficiency and those with very high uric acid levels.8 High initial doses are associated with increased incidence of allopurinol hypersensitivity. The serum uric acid should be reevaluated after 4 to 6 wk of therapy, and the allopurinol dose adjusted to reduce the serum uric acid to <6 mg/dl. The most common therapeutic dosage of allopurinol is 300 mg/day, but the dose may be increased by 50 to 100 mg every 2 to 3 wk until the target serum uric acid level is achieved. There is evidence that increasing allopurinol doses in patients with renal insufficiency does not result in significant toxicity, but concurrent use with statins and colchicine is associated with a higher incidence of adverse effects. Some authors have reported using doses as high as 800 mg/day without excess toxicity. It is recommended that patients of Han Chinese, Thai, and Korean ancestry be tested for HLA-B∗5801 before initiating allopurinol as these individuals are at high risk of allopurinol hypersensitivity if this allele is present.1
Febuxostat is a xanthine oxidase inhibitor that has been shown to be more potent than allopurinol 300 mg/day for reducing serum uric acid. The chemical structure of febuxostat is different from allopurinol, making cross-reactive allergy unlikely. The metabolism of febuxostat is primarily hepatic, which obviates the need for dose adjustments because of renal insufficiency. Some cases of hepatic toxicity have been reported, and it is recommended that liver function tests be monitored. Febuxostat may help preserve renal function in patients with chronic kidney disease (CKD) but has not been tested in patients with severe renal failure.1
The primary indication for febuxostat is demonstrated allergy to allopurinol. The cost of febuxostat may be as much as 40 times that of allopurinol, and there is some evidence suggesting that febuxostat may be associated with higher cardiovascular and all-cause mortality than allopurinol in patients with cardiovascular risk factors. In 2019 the FDA added a boxed warning for increased risk of death with febuxostat.9
Uricosuric agents may be used in patients with good renal function and urinary uric acid <600 mg in a 24-h collection. Probenecid can be used in patients with intolerance to xanthene-oxidase inhibitors. Compliance is poor due to the necessity of taking the drug more often than once daily.1
Lesinurad is a URAT1 and OAT4 inhibitor approved by the FDA in 2015 for gout-associated hyperuricemia unresponsive to xanthine oxidase inhibitor monotherapy, to be taken in combination with a xanthine oxidase inhibitor.10 This drug was withdrawn in 2019 because of business-related reasons without safety concerns noted.
Intravenous PEGylated uricase is FDA approved for treatment of severe refractory tophaceous gout. It is a PEGylated recombinant mammalian uricase that rapidly degrades urate when given intravenously. Use is limited by very high cost and potential toxicities, including frequent gout flares and anaphylaxis. Rasburicase is a nonpegylated uricase used in tumor lysis syndrome and is not indicated for gout treatment.11
It is essential that patients, families, physicians, and other members of the health care team appreciate the importance of compliance with a daily allopurinol regimen if recurrent flares and progression to chronic arthritis and tophi are to be avoided. Allopurinol should be discontinued only for symptoms suggesting hypersensitivity; otherwise, it should be continued during flares, medical illnesses, and surgical procedures.14