GOUT

• Gout is the most common inflammatory arthri2s in men and in • It is caused by deposi2on of monosodium urate monohydrate
older women. crystals in and around synovial joints.

Epidemiology

• The prevalence of gout is approximately 1–2%, with a greater • SUA levels are higher in men, increase with age and are
than 5 : 1 male preponderance. posi2vely associated with body weight.
• Gout has become progressively more common over recent years • Levels are higher in some ethnic groups (such as Maoris and
in affluent socie2es due to the increased prevalence of obesity Pacific islanders).
and metabolic syndrome, of which hyperuricaemia is an integral • Although hyperuricaemia is strong risk factor for gout, only a
component. minority of hyperuricaemic individuals actually develop gout.
• The risk of developing gout increases with age and with serum
uric acid (SUA) levels. These are normally distributed in the
general popula2on and hyperuricaemia is defined as an SUA of
>2 standard devia2ons above the mean for the popula2on.

Pathophysiology

• About 1/3 of the body uric acid pool is derived from dietary • The associa2on between OA and gout is thought to be due to a
sources and 2/3 from endogenous purine metabolism. reduc2on in levels of proteoglycan and other inhibitors of crystal
• The concentra2on of uric acid in body fluids depends on the forma2on in osteoarthri2c car2lage, predisposing to crystal
balance between endogenous synthesis, and elimina2on by the forma2on.
kidneys (2/3) and gut (1/3). • Some pa2ents develop gout because they over-produce uric
• Purine nucleo2de synthesis and degrada2on are regulated by a acid. The mechanisms are poorly understood, except in the case
network of enzyme pathways, but xanthine oxidase plays a of a few single gene disorders where there are muta2ons in
pivotal role in catalysing the conversion of hypoxanthine to genes that regulate purine metabolism.
xanthine and xanthine to uric acid. • Lesch–Nyhan syndrome is an X-linked recessive form of gout that
• In over 90% of pa2ents, the main abnormality is reduced uric is also associated with mental retarda2on, self-mu2la2on and
acid excre2on by the kidney, which is gene2cally determined. choreoathetosis. An inherited cause should be suspected if other
Impaired renal excre2on of urate also accounts for the clinical features are present or there is an early age at onset with
occurrence of hyperuricaemia in chronic renal failure, and for a posi2ve family history.
hyperuricaemia associated with thiazide diure2c therapy. • Severe hyperuricaemia can also occur in pa2ents with
• Other risk factors for gout include metabolic syndrome, high haematological and other cancers who are undergoing
alcohol intake (predominantly beer, which contains guanosine), chemotherapy due to increased purine turnover (tumour lysis
generalised OA, and a diet rela2vely high in game, offal, seafood, syndrome). This is seldom connected with gout but can be
red meat and fructose, or low in vitamin C. associated with acute kidney injury.
• Lead poisoning may cause gout (saturnine gout).
Clinical features

• The classical presenta2on is with an acute monoarthri2s, which • Some people never have a second episode and in others several
affects the first MTP joint in over 50% of cases. Other common years may elapse before the next one. In many, however, a
sites are the ankle, midfoot, knee, small joints of hands, wrist second afack occurs within 1 year and may progress to chronic
and elbow. The axial skeleton and large proximal joints are rarely gout, with chronic pain and joint damage, and occasionally
involved. Typical features include: severe deformity and func2onal impairment.
- Rapid onset, reaching maximum severity in 2–6 hours, and • Pa2ents with uncontrolled hyperuricaemia who suffer mul2ple
o`en waking the pa2ent in the early morning. afacks of acute gout may also progress to chronic gout.
- Severe pain, o`en described as the ‘worst pain ever’. • The presenta2on of gout in the elderly may be atypical with
- Extreme tenderness, such that the pa2ent is unable to wear chronic symptoms rather than acute afacks.
a sock or to let bedding rest on the joint. • Crystals may be deposited in the joints and so` 2ssues to
- Marked swelling with overlying red, shiny skin. produce irregular firm nodules called tophi. These have a
- Self-limi2ng over 5–14 days, with complete resolu2on. predilec2on for the extensor surfaces of fingers, hands, forearm,
• During the afack, the joint shows signs of marked synovi2s, elbows, Achilles tendons and some2mes the helix of the ear.
swelling and erythema. • Tophi have a white colour, differen2a2ng them from rheumatoid
• There may be accompanying fever, malaise and even delirium, nodules. Tophi can ulcerate, discharging white grify material,
especially if a large joint such as the knee is involved. become infected or induce a local inflammatory response, with
• As the afack subsides, pruritus and desquama2on of overlying erythema and pus in the absence of secondary infec2on. They
skin are common. are usually a feature of long-standing gout but can some2mes
• The main differen2al diagnosis is sep2c arthri2s, infec2ve develop within 12 months in pa2ents with chronic renal failure.
celluli2s or reac2ve arthri2s. Occasionally, tophi may develop in the absence of previous
• Acute afacks may also manifest as bursi2s, tenosynovi2s or acute afacks, especially in pa2ents on thiazide therapy who
celluli2s, which have the same clinical characteris2cs. have coexis2ng OA.
• Many pa2ents describe milder episodes las2ng just a few days. • In addi2on to causing musculoskeletal disease, chronic
• Some have afacks in >1 joint. Others have further afacks in hyperuricaemia may be complicated by renal stone forma2on
other joints a few days later (cluster afacks), the first possibly and, if severe, renal impairment due to the development of
ac2ng as a trigger. inters22al nephri2s as a result of urate deposi2on in the kidney.
• Simultaneous polyar2cular afacks are unusual. This is par2cularly common in pa2ents with chronic tophaceous
gout who are on diure2c therapy.

Inves=ga=ons

• The diagnosis of gout can be confirmed by the iden2fica2on of • Acute gout is characterised by an elevated ESR and CRP and with
urate crystals in the aspirate from a joint, bursa or tophus. In a neutrophilia, all of which return to normal as the afack
acute gout, the synovial fluid may be turbid due to an elevated subsides. Tophaceous gout may be accompanied by a modest
neutrophil count. In chronic gout, the appearance is more but chronic eleva2on in ESR and CRP.
variable but occasionally the fluid appears white due to the • X-rays are usually normal in acute gout but well-demarcated
presence of urate crystals. Between afacks, aspira2on of an erosions may be seen in pa2ents with chronic or tophaceous
asymptoma2c first MTP joint or knee may s2ll reveal crystals. gout. Tophi may also be visible on X-rays as so` 2ssue swellings.
• A biochemical screen, including renal func2on, uric acid, glucose • In late disease, destruc2ve changes may occur that are similar to
and lipid profile, should be performed because of the those in other forms of advanced inflammatory arthri2s.
associa2on with metabolic syndrome.
• Hyperuricaemia is usually present in gout but levels may be
normal during an afack because serum urate falls during
inflamma2on.
Management
Management should focus on first dealing with the acute afack and then giving prophylaxis to lower SUA and prevent further afacks.

Acute gout

• Oral colchicine given in doses of 0.5 mg twice or 3 2mes daily is • The IL-1β inhibitor canakinumab is effec2ve but extremely
the treatment of first choice in acute gout. It works by inhibi2ng expensive and so seldom given.
microtubule assembly in neutrophils. The most common adverse • Local ice packs can also be used for symptoma2c relief.
effects are nausea, vomi2ng and diarrhoea. • Pa2ents with recurrent episodes can keep a supply of an NSAID,
• Oral NSAIDs are also effec2ve but are used less commonly since colchicine or prednisolone and take it as soon as the first
many pa2ents affected by acute gout have coexis2ng symptoms occur, con2nuing un2l the afack resolves.
cardiovascular, cerebrovascular or chronic kidney disease. • Joint aspira2on can give pain relief, par2cularly if a large joint is
• Oral prednisolone (15–20 mg daily) or IM methylprednisolone affected, and may be combined with an intra-ar2cular
(80–120 mg daily) for 2–3 days are highly effec2ve and are a glucocor2coid injec2on if the diagnosis is clear and infec2on can
good choice in elderly pa2ents where there is an increased risk be excluded.
of toxicity with colchicine and NSAID.

Prophylaxis

• Pa2ents who have had a single afack of gout do not necessarily • The risk of flares can be reduced by prophylaxis with oral
need to be given urate-lowering therapy, but individuals who colchicine (0.5 mg twice daily) or an NSAID for the first few
have >1 acute afack within 12 months and those with months. Alterna2vely, pa2ents can be given a supply of
complica2ons such as tophi or erosions should be offered it. colchicine, an NSAID or prednisolone to be taken at the first sign
of an acute afack.
• In the longer term, annual monitoring of uric acid levels is
recommended. In most pa2ents, urate-lowering therapy needs
to be con2nued indefinitely.
• Febuxostat also inhibits xanthine oxidase. It is typically used in
pa2ents with an inadequate response to allopurinol, and when
allopurinol is contraindicated or causes adverse effects.
• The long-term therapeu2c aim is to prevent afacks occurring by Febuxostat undergoes hepa2c metabolism and no dose
bringing uric acid levels below the level at which monosodium adjustment is required for renal impairment. It is more effec2ve
urate monohydrate crystals form. than allopurinol but commonly provokes acute afacks when
• A therapeu2c target of 360 μmol/L (6 mg/dL) is recommended in therapy is ini2ated. The usual star2ng dose is 80 mg daily,
the Bri2sh Society of Rheumatology guidelines, whereas the increasing to 120 mg daily in pa2ents with an inadequate
European League Against Rheuma2sm guidelines recommend a response. Prophylaxis against acute afacks should be given on
threshold of 300 μmol/L (5 mg/dL). ini2a2ng therapy, as described for allopurinol.
• Allopurinol is the drug of first choice. It inhibits xanthine oxidase, • Uricosuric drugs, such as probenecid, sulfinpyrazone and
which reduces the conversion of hypoxanthine and xanthine to benzbromarone, lower urate levels but are seldom used in
uric acid. The recommended star2ng dose is 100 mg daily, or 50 rou2ne clinical prac2ce. They are contraindicated in over-
mg in older pa2ents and in renal impairment. The dose of producers and those with renal impairment or urolithiasis and
allopurinol should be increased by 100 mg every 4 weeks (50 mg require pa2ents to maintain a high fluid intake to avoid uric acid
in the elderly and those with renal impairment) un2l the target crystallisa2on in the renal tubules.
uric acid level is achieved, side-effects occur or the maximum
recommended dose is reached (900 mg/day).
• Acute flares of gout o`en follow ini2a2on of urate-lowering
therapy. The pa2ent should be warned about this and told to
con2nue therapy, even if an afack occurs.
 • Peglo2case is a biological treatment in which the enzyme uricase • Lifestyle measures are equally important as drug therapy in the
(oxidises uric acid to 5-hydroxyisourate, which is then converted treatment of gout. Pa2ents should be advised to lose weight
to allantoin) has been conjugated to monomethoxypolyethylene where appropriate and to reduce excessive alcohol intake,
glycol. It is indicated for the treatment of tophaceous gout especially beer.
resistant to standard therapy and is administered as an IV • Several an2hypertensive drugs, including thiazides, β-blockers
infusion every 2 weeks for up to 6 months. It is highly effec2ve at and ACE inhibitors, increase uric acid levels, whereas losartan
controlling hyperuricaemia and can cause regression of tophi. has a uricosuric effect and should be subs2tuted for other drugs
The main adverse effects are infusion reac2ons (which can be if possible.
treated with an2histamines or glucocor2coids) and flares of gout • Pa2ents should be advised to avoid large amounts of seafood
during the first 3 months of therapy. A limi2ng factor for longer- and offal, which have a high purine content, but a highly
term treatment is the development of an2bodies to peglo2case, restric2ve diet is not necessary.
which occur in a high propor2on of cases and are associated
with an impaired therapeu2c response.