Gout and pseudogout

• Gout is crystal arthritis caused by deposits of monosodium urate (MSU) crystals in and around joints, driven by long-standing high serum uric acid.
• Gout declares itself as sudden painful flares, most classically podagra (the first metatarsophalangeal joint), and later as tophi and joint damage if untreated.
• Diagnosis rests on finding needle-shaped, negatively birefringent MSU crystals in synovial fluid; serum uric acid supports but does not prove it.
• Acute flares are treated with NSAIDs, colchicine or glucocorticoids. Long-term, treat to a serum uric acid target below 6 mg/dL using allopurinol first line, with anti-inflammatory prophylaxis for 3 to 6 months. ^[1]
• Pseudogout (calcium pyrophosphate deposition disease, CPPD) is a similar crystal arthritis from calcium pyrophosphate crystals, which are shorter, often rhomboid, and positively birefringent.

By the end of this page you should be able to:

1. Explain urate handling, why some people make crystals and others do not, and how a flare starts and stops.
2. Recognise the clinical patterns of acute and chronic gout, including tophi, and the sites they favour.
3. Perform or interpret a synovial fluid crystal examination and distinguish MSU from calcium pyrophosphate crystals.
4. Choose first-line, second-line and last-line urate-lowering therapy, with starting doses, titration targets and safety cautions.
5. Manage a gout flare, including when each drug is contraindicated, and when to aspirate a joint.
6. Recognise CPPD (pseudogout), compare it with gout in a table, and know how its treatment differs.
7. Apply the current named guidelines (ACR 2020, EULAR 2016, BSR 2017) and discuss where they differ.

Hyperuricaemia means a serum uric acid above the solubility threshold; in practice a serum uric acid of 6.8 mg/dL or higher. ^[4] Pathological urate deposition is supersaturation in extracellular fluid: MSU crystallises in cooler, more acidic, less vascular tissue such as the first toe, where urate concentration, pH and water content lower crystal solubility. ^[4]

Classification by stage is the most useful for a student. ^[4][1]

• Asymptomatic hyperuricaemia. High serum uric acid without crystals documented. Pharmacologic urate-lowering therapy is generally not started here. ^[1]
• Acute gouty arthritis. A sudden, intensely painful mono- or oligoarthritis peaking within hours.
• Intercritical gout. The patient is symptom-free between attacks, but low-grade inflammatory activity and stored crystals remain.
• Chronic tophaceous gout. Repeated poorly controlled disease with tophi, radiographic erosions and joint damage.

Pseudogout, properly called calcium pyrophosphate deposition disease (CPPD), is not gout. It is crystal arthritis (and cartilage calcification, chondrocalcinosis) caused by calcium pyrophosphate (CPP) crystals. ^[5] It can mimic gout acutely and coexists with it. Mixed crystal arthritis is a real diagnostic trap: MSU and CPP crystals can be found together in the same joint. ^[5][4]

Gout is the most common inflammatory arthritis in many populations. Reported general prevalence is 1 to 4% of the adult population, with higher figures in western countries (3 to 6% in men, 1 to 2% in women) and up to 10% in some countries. Over age 80 years, prevalence is up to 10% in men and 6% in women. Annual incidence is about 2.68 per 1000 persons, with men affected 2 to 6 times as often as women. ^[4] In the United States, NHANES 2015-16 estimated 9.2 million adults (3.9%) had gout and NHANES 2017-18 estimated 12.1 million (5.1%). ^[1][8]

Risk rises with age, male sex, menopause, obesity, metabolic syndrome, chronic kidney disease, hypertension, diabetes and the use of loop or thiazide diuretics, low-dose aspirin, cyclosporine and transplantation. ^[4][1] Gout also co-occurs with osteoarthritis: damaged cartilage seems to permit urate crystal nucleation. ^[4]

Purine overproduction accounts for about 10% of gout and is due to rare enzyme defects (hypoxanthine-guanine phosphoribosyltransferase deficiency, phosphoribosyl pyrophosphate synthetase superactivity) or high cellular turnover. ^[4] Most gout (about 90%) is from under-excretion by the kidney and intestine. ^[4]

CPPD becomes common with age, often on a background of osteoarthritis, and is associated with hyperparathyroidism, haemochromatosis and hypomagnesaemia. Recent data suggest its prevalence in developed countries is growing, partly through longer life, more osteoarthritis and possibly magnesium-depleting drugs (loop and thiazide diuretics, proton pump inhibitors). ^[5]

Uric acid is the end product of purine metabolism in humans, who lack uricase. It circulates mainly as urate. Rising serum urate, sustained over time, leads to formation and deposition of MSU crystals in cooler peripheral tissues. Crystal deposition alone is usually silent until tissue-resident immune cells encounter free crystal surfaces. ^[4][6]

A gout flare is a short, explosive inflammatory burst, not slow cartilage wear. MSU crystals are phagocytosed by macrophages and monocytes, damage lysosomes, release pro-inflammatory cytokines and activate the NLRP3 inflammasome, which releases interleukin-1beta. ^[6] Reported activation mechanisms include lysosomal disruption with cathepsin release and altered ion flux: monosodium urate crystals, on reaching lysosomes, raise intracellular sodium, causing water influx and cellular swelling, which lowers intracellular potassium concentration below the threshold that licenses inflammasome assembly. ^[6] Neutrophils are recruited rapidly, which explains the dramatic onset and the pain. ^[4]

Flares are self-limited because well-differentiated macrophages later clear crystals and debris, and anti-inflammatory cytokines such as transforming growth factor beta terminate signalling; urate levels actually fall slightly during an acute attack. ^[4] Repeated inflammation produces chronic synovitis, tophi (aggregations of crystals with a surrounding granuloma), cartilage damage and the classic overhanging-edge erosions. ^[4]

Genetic variation matters. URAT1 and other renal urate transporters (SLC2A9, ABCG2) determine how much urate is excreted; common variants explain why hyperuricaemia clusters in families. ^[4] Secondary causes include major cell turnover, malignancy, chemotherapy and obesity-driven endogenous production. ^[4]

Figure 1Gout.IMG 0364

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Long description

A clinical photograph of gout presenting in the metatarsophalangeal joint of the big toe, with redness of the skin overlying the joint.

An acute gout flare is a step-change in pain. The patient often wakes at night; the joint is, in the patient's words, "the worst pain I have ever had". It begins within hours and peaks within a day, with striking erythema and swelling, often of the first metatarsophalangeal joint (podagra). Lower-limb joints (ankle, mid-foot, knee) are the usual early targets. ^[4]

Other presentations:

• Monoarticular flare is classic; polyarticular flares occur, more often in postmenopausal women or long-standing disease. ^[4]
• Systemic features such as fever and malaise can mimic septic arthritis, so both can coexist in the same joint. ^[4]
• Intercritical flares may be followed by months or years of freedom, then recur.
• Chronic tophaceous gout shows persistent lumps, bony deformity and mechanical pain.
• Extra-articular crystal deposition includes olecranon bursitis, Achilles tenosynovitis and, clinically important, renal colic from uric acid stones. Patients on loop or thiazide diuretics may have diuretic-precipitated gouty bursitis. ^[4]

• Acutely: a hot, red, exquisitely tender joint with shiny overlying skin and swelling; range of motion is lost.
• Chronic gout: palpable tophi (chalky white material under skin, common at helix of ear, olecranon, fingers and toes), joint deformity and bony erosions with overhanging edges on examination/imaging.
• Tophi can be mistaken for rheumatoid nodules, Heberden/Bouchard nodes, lipomas or xanthomas; a needle aspirate showing MSU crystals confirms them. ^[4]

Examine for comorbidity as part of the joint consultation: blood pressure, body mass index, signs of chronic kidney disease, hypertension and dyslipidaemia, because these drive treatment choices. ^[1][4]

The gold standard is polarised light microscopy of synovial fluid or tophus aspirate showing MSU crystals. ^[4][5] In practice, diagnosis is often clinical with a compatible history plus high serum uric acid, but aspiration should be performed whenever septic arthritis is possible or the presentation is atypical. ^[4]

Synovial fluid is examined as soon as possible (ideally within 6 hours, or kept at 4 degrees Celsius for up to 24 hours). Crystals are visible with ordinary light at 600x to 1000x magnification; compensated polarised light improves detection and lets you read birefringence. ^[4]

The named guidelines used here are the ACR 2020 gout guideline, the EULAR 2016 updated recommendations (published 2017), and the BSR 2017 guideline. ^[1][2][3] They agree on treat-to-target and allopurinol first line, and differ in detail: for example, on whether colchicine should be used within 12 (EULAR) or 24 (ACR) hours of flare onset, and on how aggressively to lower urate in severe gout. ^[4] A patient leaflet and lifestyle advice accompany drug therapy in all three.

Start treatment early; all flare drugs work much better in the first 12 to 24 hours. ^[4] Choose one, or combine in severe disease. ^[4]

• NSAIDs (or COX-2 inhibitors) at full analgesic dose, with proton pump inhibitor cover when indicated. Efficacy is well accepted although placebo-controlled trials are lacking. ^[4]
• Colchicine. When taken within 12 hours of onset, 1.8 mg total (1.2 mg then 0.6 mg one hour later) is as effective as older high-dose regimens. ^[4] It has a narrow therapeutic window; diarrhoea, nausea or vomiting are usually the first toxic signs and should prompt dose reduction or stopping. ^[4] Renal dosing differs by source: Ragab 2017 (Ref 4) advises 0.5 to 0.6 mg daily for eGFR 30 to 60 and 0.5 to 0.6 mg every 2 to 3 days for eGFR 15 to 30, with avoidance in stage 5 CKD; the UK SmPC contraindicates severe renal impairment and advises caution and dose reduction in moderate impairment; the US product label does not require adjustment in mild to moderate impairment and uses reduced starting doses with monitoring in severe impairment and dialysis. ^[4][9] Reduce in hepatic impairment. It interacts with CYP3A4 and P-glycoprotein inhibitors (macrolides, azole antifungals, cyclosporin, diltiazem, verapamil), which raises toxicity; muscle and nerve toxicity can occur with long-term low-dose use in CKD. ^[4][1]
• Glucocorticoids. Oral prednisone 30 mg daily for 7 days is effective and is recommended by ACR and EULAR as a first-line option, especially in CKD or where NSAIDs/colchicine are unsuitable; intra-articular steroid injection is highly effective for mono- or oligo-articular flares. ^[2][4] Steroids can worsen hypertension and diabetes. ^{[4] [1]}
• IL-1 blockers are reserved for patients with frequent flares who cannot tolerate colchicine, NSAIDs or steroids. ^[2] They are not first-line.
• During the flare: keep the joint rested, use ice, analgesia and fluids; aspiration rules out sepsis. ^[4]

Pharmacologic urate-lowering therapy is strongly recommended for: any subcutaneous tophus, radiographic damage attributable to gout, or frequent flares defined as 2 or more per year. It is conditionally recommended for more than 1 prior flare with infrequent flares (fewer than 2 per year), and conditionally recommended against after a single uncomplicated flare, except when CKD stage 3 or worse, serum uric acid above 9 mg/dL, or urolithiasis is present. ^[1]

Choice of agent. Allopurinol is the preferred first-line agent, including in moderate-to-severe CKD, because of efficacy at appropriate doses, safety and cost. ^[1] Start at 100 mg daily or less, and 50 mg daily or less in CKD stage 3 or worse, then titrate. ^[1] It is metabolised to oxypurinol and can reach a maximum FDA-approved dose of 800 mg daily. ^[1] Testing for HLA-B*5801 is conditionally recommended before starting allopurinol in patients of Southeast Asian descent (Han Chinese, Korean, Thai) and in African American patients, in whom prevalence is 7.4% and 3.8% respectively versus 0.7% in white and Hispanic patients, because of the risk of allopurinol hypersensitivity syndrome. ^[1]

Febuxostat is an alternative xanthine oxidase inhibitor. Start at 40 mg daily or less and titrate. ^[1] Switch patients with a cardiovascular history or a new cardiovascular event to an alternative agent where possible, because of the FDA boxed warning and the CARES trial signal (cardiovascular death and all-cause mortality). ^[1] The absolute cardiovascular risk attributable to febuxostat remains uncertain. ^[1]

Uricosurics (probenecid) are an option when a second drug is needed; start at 500 mg once to twice daily. ^[1] Alkalinising urine is not recommended, but adequate hydration and counselling about stones are. ^[1] Switching to a second xanthine oxidase inhibitor is conditionally preferred over adding a uricosuric when the first has failed. ^[1]

Treat to target. Use serial serum uric acid measurements to guide dose titration rather than fixed doses, toward a serum uric acid below 6 mg/dL, and below 5 mg/dL in severe or tophaceous disease. ^[1][2] This nurse- or pharmacist-led augmented care improves adherence and outcomes. ^[1] Continuing therapy indefinitely is conditionally recommended over stopping, even in clinical remission. ^[1]

Pegloticase is strongly recommended against as first line, and strongly recommended (over continuing current therapy) for refractory disease after xanthine oxidase inhibitors, uricosurics and other options have failed, in patients with frequent flares or non-resolving tophi; it is strongly recommended against where flares are infrequent and there are no tophi. ^[1]

Prophylaxis against flares on starting ULT (colchicine, NSAID or prednisone/prednisolone, chosen by patient factors) is strongly recommended for 3 to 6 months, with reassessment. ^[1] Starting ULT during a flare (rather than waiting) is conditionally recommended. ^[1]

For asymptomatic hyperuricaemia (serum uric acid 6.8 mg/dL or higher with no prior flare or tophus), pharmacologic ULT is conditionally recommended against, even when MSU deposition is seen on imaging, because the absolute risk of progression is low. ^[1] (Urate 9 mg/dL over 5 years progresses to gout in only about 20% of people. ^[1]) Lifestyle advice still applies. ^[1]

• Educate the patient and provide a written flare plan; self-treatment of early flares is encouraged. ^[2][4]
• Reduce purine-rich foods (especially animal and seafood sources), limit alcohol (beer worst, spirits less, wine least), and favour weight loss, exercise and waist reduction. ^[4]
• Favour high vitamin C and low-fat dairy, vegetables and plant oils; these do not need restriction. ^[4]
• For medication-related hyperuricaemia, when feasible switch hydrochlorothiazide to another antihypertensive, prefer losartan, do not stop low-dose aspirin taken for a correct indication, and do not add fenofibrate for gout. ^[1]
• Treat comorbidities (hypertension, diabetes, hyperlipidaemia, chronic kidney disease, obesity) aggressively; they matter as much as the gout. ^[1][4]

• Septic arthritis in a gouty joint (co-infection occurs; aspirate and culture). ^[4]
• Renal colic and uric acid stones from high urinary urate; stone prophylaxis with hydration and stone-directed therapy. ^[4]
• Joint destruction, tophi and deformity from uncontrolled disease. ^[4]
• Erosions with characteristic overhanging edges on radiograph. ^[4]
• Allopurinol hypersensitivity syndrome (serious and potentially fatal) - mitigated by low starting dose and HLA-B*5801 screening in Asian and African American patients. ^[1]
• Colchicine toxicity, especially with renal failure or interacting drugs. ^[4][1]
• Cardiovascular implications of febuxostat (boxed warning). ^[1]

With consistent treat-to-target therapy the outlook is excellent: flares stop, tophi dissolve, radiographic progression slows. ^[1][2] About 13% of patients in stable remission whose serum uric acid stayed below 7 mg/dL without therapy had no flares over 5 years, which argues for continuing therapy in most patients. ^[1] Flare frequency and tophus burden are the clinically important outcomes that guide intensity of therapy. ^[1][2]

There is no population screening test for gout. Prevention means identifying hyperuricaemia risk factors: family history, renal impairment, medication review, diet, alcohol, obesity and metabolic syndrome. ^[4][1] Patients with gout should be monitored for CKD and cardiovascular risk. ^[1][4] Low vitamin C and low-fat dairy intake, weight control and avoiding excess beer and spirits modify risk. ^[4]

Pregnancy. Gout in pregnancy is uncommon and needs specialist care; decisions about flares and urate-lowering therapy should be made jointly with obstetrics and rheumatology, following local guidance. ^[1]

Children and adolescents. Gout is rare in children and, when it occurs, suggests an inborn error of purine metabolism; tophi in a child or young adult should prompt a search for familial disease, and renal/genetic evaluation. ^[4]

Older adults. Chronic kidney disease, polypharmacy, diuretic use and under-nutrition are common; colchicine and NSAID doses must be reduced, and drug interactions checked; tophi may be long-standing. ^[1][4]

Renal impairment. Allopurinol remains first line but starts lower and titrates cautiously; colchicine and NSAIDs are restricted; febuxostat has boxed CV concerns. ^[1][4]

Where joint aspiration is unavailable, use clinical features plus serum uric acid, and treat the flare empirically while considering sepsis. Crystal confirmation and radiographs may be unavailable; an ultrasound (double contour sign, tophus aggregates) and basic biochemistry often suffice. Colchicine is inexpensive but has a narrow safety window; low-dose regimens are safer and effective. ^[1][4]

Plain text placeholders until topics are verified: rheumatoid arthritis; osteoarthritis; septic arthritis; urinary stone disease; chronic kidney disease; metabolic syndrome; hyperparathyroidism; haemochromatosis.