Urate-lowering therapy and gout prevention

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Use the first prevention appointment to confirm the diagnosis and quantify burden. Record flare number, duration and joints over the previous year, tophi, erosive or chronic synovitis, kidney stones, CKD, transplant status, diuretics, cardiovascular disease, alcohol, weight, current serum urate and previous ULT response. Ask what the patient believes caused gout and what happened with earlier prescriptions. A respectful explanation that biology and medicines matter prevents the conversation becoming a dietary reprimand.

NICE offers ULT using treat-to-target for multiple or troublesome flares, CKD stages 3 to 5, current diuretic use, tophi or chronic gouty arthritis. For anyone outside these groups after a first or later flare, discuss benefits and burdens rather than withholding the option. ULT is not generally prescribed for isolated asymptomatic hyperuricaemia. Start two to four weeks after a flare settles when practical; if attacks are frequent, it can begin during one with adequate flare treatment and prophylaxis.

Choose between xanthine-oxidase inhibitors transparently. Allopurinol is inexpensive, has wide dose flexibility and is NICE first-line when there has been myocardial infarction, stroke or unstable angina. Febuxostat reaches effect rapidly and uses 80 mg and 120 mg steps, but MHRA advises caution in pre-existing major cardiovascular disease, especially at initiation or with heavy crystal burden. Severe prior allopurinol hypersensitivity prohibits rechallenge rather than simply favouring slower titration.

Start allopurinol 100 mg once daily in most adults; consider 50 mg once daily or a longer initial interval in advanced renal impairment under specialist care. Increase by 100 mg increments approximately every two to four weeks, checking monthly serum urate and safety until target. Licensed dosing extends to 900 mg daily in severe disease, generally divided when a single daily dose exceeds 300 mg. Renal function informs cautious starting and monitoring but should not leave a patient permanently at an ineffective dose.

Febuxostat starts at 80 mg orally once daily. Recheck serum urate after two to four weeks and consider 120 mg once daily if it remains above 357 micromol/L. It should not be used during pregnancy or breastfeeding, and severe hepatic impairment lacks adequate evidence. Check liver tests, rash and cardiovascular symptoms and review azathioprine or mercaptopurine because xanthine-oxidase inhibition can cause dangerous accumulation; those combinations need specialist alternatives, not casual dose adjustment.

The general target is below 360 micromol/L. Choose below 300 for tophi, chronic gouty arthritis or ongoing frequent attacks despite a value below 360. Monthly results drive dose increases until stable; do not accept clinical quietness while urate stays above target because crystals remain. Photograph and measure tophi and record flare outcomes. After target is achieved and maintained, extend review and consider annual urate measurement while continuing therapy lifelong.

Key points

Urate-lowering therapy is crystal-dissolving treatment, not an analgesic. Benefits require a serum-urate target, gradual titration, flare prophylaxis and continuation after the patient feels well.
Offer treat-to-target ULT for multiple or troublesome flares, CKD stages 3–5, diuretic therapy, tophi or chronic gouty arthritis; discuss it after a first or later flare in other patients.
NICE usually starts ULT two to four weeks after a flare has settled; frequent flares can justify starting during an attack while adequate anti-inflammatory treatment and prophylaxis continue.
Aim below 360 micromol/L. Consider below 300 micromol/L for tophi, chronic gouty arthritis or persistent frequent flares despite remaining below 360.
NICE accepts allopurinol or febuxostat as first-line in most adults after comorbidity and preference review, but allopurinol is specifically first-line when major cardiovascular disease is present.
Start low and measure serum urate monthly while increasing treatment. Allopurinol 300 mg is not a universal ceiling; many adults need careful higher licensed doses to reach target.
Start allopurinol commonly at 100 mg once daily and lower in important renal impairment; increase according to urate and tolerance rather than estimating the final dose from eGFR alone.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Persistent urate supersaturation

Gout continues when the average serum urate permits crystal persistence; symptom-free intervals do not mean the deposited reservoir has disappeared.

Underexcretion and medicine effects

Kidney impairment, diuretics, ciclosporin, tacrolimus and inherited transporter variation commonly limit urate clearance and may require higher long-term treatment intensity.

Overproduction and high cell turnover

Tumour lysis, myeloproliferative disease, psoriasis and rare enzyme disorders increase production; these contexts need disease-specific renal and oncology protocols.

Treatment and adherence barriers

Fixed low allopurinol dosing, absent serum-urate monitoring, early titration flares, misinformation and fragmented follow-up allow crystals to persist despite a prescription.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Xanthine oxidase inhibition
Allopurinol and febuxostat reduce conversion of hypoxanthine and xanthine to uric acid, lowering extracellular urate and shifting tissue deposits toward dissolution.
2
Treat-to-target dissolution
Maintaining serum urate below saturation creates a sustained concentration gradient out of tophi and cartilage; lower targets accelerate clearance in high-burden disease.
3
Early mobilisation flares
As deposits remodel during initial lowering, exposed crystals can trigger inflammation, so early attacks may increase before falling after months of target control.
4
Slow reservoir clearance
Serum urate falls within weeks but established tophi and joint deposits take months or years to dissolve, requiring continued therapy after symptoms improve.
5
Rebound after withdrawal
Stopping effective treatment permits urate to rise, crystals to redeposit and flares to recur, which is why urate lowering is usually lifelong.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Mandatory-offer phenotype

Troublesome recurrence, CKD stages 3–5, diuretic use, tophi or chronic gouty arthritis meets NICE criteria for an offer of treat-to-target therapy.

High crystal burden

Multiple tophi, chronic synovitis, erosions and frequent flares indicate a large reservoir and support the lower serum-urate target below 300 micromol/L.

Allopurinol hypersensitivityRed flag

New rash with fever, facial swelling, mucosal disease or internal-organ injury after exposure is an emergency and prohibits rechallenge after severe reaction.

Early mobilisation flare

An attack after starting or increasing ULT reflects crystal remodelling rather than medicine failure; continue the stable ULT dose and treat the attack separately.

Red flags requiring action

Rash, mucosal pain, blistering, facial swelling, fever or systemic illness after allopurinol requires immediate permanent cessation pending urgent assessment.
Severe diarrhoea, vomiting, proximal weakness, paraesthesia, bruising or infection during colchicine prophylaxis can signal accumulation, neuromyopathy or marrow toxicity.
Chest pain, new focal neurological symptoms or decompensated heart failure during febuxostat treatment requires urgent cardiovascular assessment and medicine review.
Abrupt oliguria, tumour-lysis physiology or uric-acid obstruction needs acute renal and oncology management rather than routine outpatient dose titration.
Pregnancy, conception planning or breastfeeding requires early specialist review because febuxostat should not be used and allopurinol or prophylaxis needs individual benefit-risk assessment.
A hot prosthetic or systemically unwell joint remains a septic-arthritis question even when serum urate is above target and flares are expected during titration.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line baseline urate and safety bloodsFirst stepFirst line
Why
Confirm the treatment baseline and identify prescribing constraints.
Interpretation and limitations
Measure serum urate, FBC, creatinine and eGFR and liver profile; add pregnancy testing, HLA-B*58:01 or other tests only when individual context makes them relevant.
02
Monthly serum urate during titration
Why
Provide the objective signal for dose increases within a treat-to-target strategy.
Interpretation and limitations
Increase a tolerated low dose until below 360 micromol/L or the chosen below-300 target; symptoms alone lag behind tissue crystal burden.
03
HLA-B*58:01 assessment
Why
Reduce severe allopurinol-reaction risk in selected high-prevalence ancestry groups.
Interpretation and limitations
Consider testing particularly in Han Chinese, Thai or Korean ancestry and alongside CKD risk; a negative result does not eliminate SJS, TEN or DRESS.
04
Renal, hepatic and interaction review
Why
Prevent accumulation and identify alternatives before each major change.
Interpretation and limitations
eGFR affects initial allopurinol and colchicine caution, liver status affects febuxostat, and azathioprine or mercaptopurine interaction with xanthine-oxidase inhibitors can be dangerous.
05
Tophus and flare outcome record
Why
Measure clinical crystal dissolution and patient-important benefit.
Interpretation and limitations
Use sites, dimensions, photographs, flare days and function; tophi shrink more slowly than serum urate and should not trigger premature abandonment of effective therapy.
06
Annual stable-phase serum urate
Why
Detect loss of target after titration is complete.
Interpretation and limitations
NICE advises considering annual measurement; an unexpected rise prompts adherence, medicine, kidney and weight or alcohol review before automatic dose escalation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Asymptomatic hyperuricaemia

An isolated raised serum urate without gout or another specific indication does not automatically justify lifelong urate-lowering treatment.

Calcium pyrophosphate disease

Recurrent knee or wrist attacks with CPP crystals will not improve from allopurinol, even when serum urate is also elevated.

Septic arthritis

Flares during titration can be expected, but fever, prosthesis, bacteraemia or atypical non-response requires aspiration and culture rather than dose assumptions.

Chronic inflammatory arthritis

Persistent symmetrical synovitis, psoriasis, enthesitis or prolonged stiffness may represent rheumatoid or psoriatic disease with incidental hyperuricaemia.

Tophus mimics

Rheumatoid nodules, calcinosis, xanthoma and tumoral calcinosis can resemble tophi; aspirate or image an atypical mass before escalating gout treatment.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First-line eligibilityOffer or discuss lifelong crystal dissolutionFirst stepFirst lineGout is confirmed and the acute attack has been reviewed.

1Offer ULT for troublesome recurrence, CKD stages 3–5, diuretic therapy, tophi or chronic gouty arthritis and discuss it with other patients after any flare.
2Explain targets, early mobilisation flares, prophylaxis, likely lifelong duration and why symptom freedom alone is not crystal clearance.
3Obtain baseline urate, renal, hepatic and blood safety data and plan the start usually two to four weeks after the flare settles.

02First-line selectionChoose allopurinol or febuxostat safelyFirst lineThe patient elects to begin treat-to-target urate-lowering therapy.

1Use allopurinol first when major cardiovascular disease is present; otherwise discuss either option using comorbidity, interaction and preference.
2Start allopurinol 100 mg daily, lower when severe renal impairment warrants, or febuxostat 80 mg daily and arrange monthly urate review.
3Offer colchicine prophylaxis while target is approached and supply a separate written plan for treating breakthrough flares without stopping ULT.

03Treat-to-target titrationMove the number, not just symptomsSerum urate remains at or above the chosen target and treatment is tolerated.

1Increase allopurinol by approximately 100 mg every two to four weeks or increase febuxostat to 120 mg after two to four weeks when appropriate.
2Recheck monthly, reviewing rash, interactions, renal or hepatic safety, adherence and prophylaxis at each change.
3Maintain below 360 micromol/L, or below 300 for tophi, chronic gouty arthritis or ongoing frequent attacks despite the standard target.

04Failure or intoleranceVerify then switch or referTarget is not reached, adverse effects occur or flares remain troublesome after adequate treatment.

1Separate predictable early flares from hypersensitivity, toxicity, non-adherence and an incorrect diagnosis; never rechallenge severe allopurinol reaction.
2Optimise the tolerated agent, then switch between allopurinol and febuxostat when target or tolerance requires it, respecting cardiovascular context.
3Refer CKD stage 3b–5, transplant, diagnostic uncertainty or standard-treatment failure for specialist uricosuric, combination or advanced options.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

A NICE first-line xanthine-oxidase inhibitor and the specific first-line ULT for people with major cardiovascular disease; continued treatment is usually lifelong.

Allopurinol

Start 100 mg orally once daily after food in most adults; consider 50 mg once daily in advanced renal impairment. Increase commonly by 100 mg every 2 to 4 weeks against monthly serum urate, up to the licensed maximum 900 mg daily when necessary and tolerated.

Stop immediately for any rash and never rechallenge after DRESS, SJS or TEN. Consider HLA-B*58:01 testing in high-prevalence ancestry, especially with CKD. Review renal and liver function, ACE inhibitor or diuretic context, warfarin and the dangerous azathioprine or mercaptopurine interaction. Use in pregnancy only when no safer alternative and disease itself carries risk.

A NICE first-line alternative in many adults and a switch option when allopurinol is ineffective or not tolerated; allopurinol remains first-line in major cardiovascular disease.

Febuxostat

Give 80 mg orally once daily with or without food; if serum urate remains above 357 micromol/L after 2 to 4 weeks, consider increasing to 120 mg once daily.

Use cautiously in previous myocardial infarction, stroke, unstable angina or other major cardiovascular disease and monitor regularly. Check liver function and rash; avoid azathioprine or mercaptopurine unless a specialist manages the major interaction. Do not use in pregnancy or breastfeeding and avoid severe hepatic impairment.

Reduces mobilisation flares that otherwise undermine adherence while tissue crystals begin to dissolve; this is a licensed prophylactic use during allopurinol or uricosuric initiation.

Colchicine flare prophylaxis

Offer 500 micrograms orally once or twice daily while ULT is started and titrated and the serum-urate target is being reached; BSR commonly continues prophylaxis for up to 6 months, adjusted to burden and tolerance.

Adjust or avoid in renal or hepatic impairment and older frailty. Stop for diarrhoea or vomiting and check macrolide, azole, ciclosporin, verapamil and statin interactions; prolonged exposure can cause cytopenia and neuromyopathy. Pregnancy or breastfeeding requires individual product and specialist review.

NICE alternative prophylaxis when colchicine is contraindicated, not tolerated or ineffective; both prophylactic indications were off-label when NG219 was issued.

Low-dose NSAID or corticosteroid prophylaxis

If colchicine cannot be used, choose a local protocol low-dose NSAID with gastroprotection or low-dose oral prednisolone for only the titration period, with a documented dose, duration and review date.

NSAIDs can cause renal injury, bleeding, fluid retention and cardiovascular harm and are unsuitable in later pregnancy. Steroid can mask infection and worsen glucose, pressure, mood, bone and adrenal health; do not allow temporary prophylaxis to become indefinite unreviewed therapy.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Tophaceous erosive disease

Failure to sustain target urate allows expanding deposits, bone erosion, tendon injury, ulceration, deformity and loss of joint function.

Allopurinol severe cutaneous reaction

DRESS, Stevens-Johnson syndrome and toxic epidermal necrolysis can cause hepatic, renal, pulmonary, marrow and skin failure with substantial mortality.

Colchicine toxicity

Drug accumulation or a major interaction can produce severe gastrointestinal symptoms, marrow suppression, neuropathy, myopathy, rhabdomyolysis and potentially fatal multiorgan failure.

Cardiovascular treatment complexity

Gout and major cardiovascular disease commonly coexist; febuxostat requires caution, while NICE specifically favours allopurinol first in this group.

Loss of trust and adherence

Unexplained early flares or rigid lifestyle messaging can lead patients to stop treatment, recreating urate fluctuation and preventable long-term deposition.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure serum urate monthly during dose escalation and do not stop titration at a conventional tablet dose while the value remains above target and treatment is tolerated.
At each change ask about rash, fever, mucosal symptoms, gastrointestinal toxicity, weakness, adherence and new antibiotics or interacting medicines.
Repeat renal and liver function and FBC at a risk-based interval during escalation, more closely with CKD, frailty, colchicine, high allopurinol dose or febuxostat liver risk.
Record flare frequency, duration and function and explain that the first months can worsen transiently before sustained target control reduces attacks.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Three hundred is not a ceiling

Many adults need more than 300 mg allopurinol daily; a low start improves safety, while the serum-urate target determines the final tolerated dose.

Flares can increase first

Crystal mobilisation during successful lowering can provoke attacks, so prophylaxis and explanation protect adherence through the paradoxical early phase.

Target reflects burden

Below 360 micromol/L suits most gout, while below 300 creates a larger dissolution gradient for tophi, chronic arthritis or persistent flares.

Renal impairment changes pace

CKD warrants cautious initiation and monitoring but does not justify leaving serum urate indefinitely above target without specialist optimisation.

11Common pitfallsFrequent interpretation and management errors.

01
Prescribing allopurinol 100 or 300 mg indefinitely without monthly serum-urate-guided titration.
02
Stopping urate-lowering therapy during a flare and restarting it later, producing avoidable concentration fluctuation.
03
Failing to offer prophylaxis or explain early mobilisation flares, then interpreting poor adherence as patient unwillingness.
04
Using febuxostat casually in major cardiovascular disease despite the NICE allopurinol preference and MHRA caution.
05
Continuing allopurinol after a new rash or rechallenging a previous severe cutaneous reaction.
06
Combining a xanthine-oxidase inhibitor with azathioprine or mercaptopurine without specialist management of potentially fatal toxicity.