gout

historical perspective

Described by Hippocrates
Podagra was the foot goddess, a bad tempered virgin, who attacked victims after they overindulged.
Autumn crocus used to Rx arthritis in 6th Century
For many centuries, thought to be confined to men who had indulged in dietary or sexual excess.
Benjamin Franklin's advice:
- “Be temperate in wine, eating, girls & sloth or the gout will seize you & plague you both”
Sydenham wrote the classic description of the disease in 1684.
colchicine isolated 1820
Probenecid developed to inhibit penicillin excretion in 1951

pathophysiology & epidemiology:

gout is deposition of uric acid crystals from a supersaturated extracellular fluid.
risk of gout attacks correlates with serum uric acid levels although “healthy levels” of less than 0.42mM is not as important as whether the concentration places the patient at risk of crystal formation.
only 20% of people with hyperuricaemia develop gout but the higher the level the greater the risk
more than half of patients with acute gout have normal serum uric acid levels ¹⁾
the crystals are ingested by PMNLs resulting in inflammatory reaction
uric acid can be over-produced (eg. myeloproliferative/lymphoproliferative diseases) or under-excreted by the kidneys.
calcium channel blockers and Losartan appear to mildly reduce incidence of gout while other antihypertensives especially diuretics may increase the risk²⁾
metabolism and immune systems developed hand-in-hand from an evolutionary and survival perspective as resisting starvation and mounting an immune response to pathogens was paramount, nutrients use the pathogen-sensing systems to trigger inflammatory responses. Most humans do not have to face food scarcity, thus, once beneficial, uric acid metabolism triggers the accumulation of fats and inflammation even without infection, a biological process driving renal impairment. A metabolomic analysis in 2023 found a characteristic metabolite profile for gout, in which 10 of 46 metabolites showed marked differences, and nearly all were related to metabolic inflammation: ³⁾
- DL-2-aminoadipic acid, an intermediate lysine metabolism metabolite, plays a key role in glucose and lipid metabolism, thus, its elevated concentrations promote fat consumption. However, that damages renal function in gout patients by enhancing their metabolism
- hypoxanthine could cause inflammation in the kidneys
- adenosine, a purine metabolite, bound different purinergic receptors to regulate interleukin-1beta (IL-1β) secretion and played an anti-inflammatory role in gout development and remission
- kynurenic acid (KYNA), a byproduct of the tryptophan metabolism, regulates immune system cells and several immune-mediated diseases - chronic stress or mild inflammation could promote KYNA production and immunomodulatory actions
- they suggest changes in the levels of metabolites, such as UA, hypoxanthine, adenosine, creatinine, and DL-2-aminoadipic acid, form the basis of gout development and confirmed the significance of metabolic inflammation in gout pathogenesis. The authors found that the signaling pathways used by metabolic and traditional inflammation were relatively consistent and originated from the energy metabolism pathways finding related biomarkers in the evolutionary journey, which could help detect or prevent gout attacks

risk factors include:

obesity or weight gain in young adulthood
hypertension
diabetes
alcohol consumption
proximal loop diuretics
thiazide diuretics
beta adrenergic blockers
lead exposure
GTN infusions (? due to alcohol in mixture)
post-menopausal women (oestrogens increase renal excretion of uric acid)
renal insufficiency
polycythaemia rubra vera

precipitants of acute attacks:

stress of illness or surgery
alcohol or dietary excess
organ transplant patients taking cyclosporine
diuretics

clinical features:

acute gouty arthritis:

occurs most commonly in middle-aged men & postmenopausal women
increased serum uric acid levels are usually present for 20yrs before the 1st attack
gouty attacks most often affect the 1st MTP jt (up to 75%), the tarsal joints, ankle & knee
40% have polyarticular involvement
rarely, it may involve the spine and tophi may mimic an epidural abscess (half are lumbar, quarter each in Tx and Cx spine) and ~20% have fevers, and may cause radicular pain or acute spinal cord compression⁴⁾
pain is excruciating at the onset & some cannot tolerate even the weight of a sheet on the joint
fever may be present but serum uric acid level may be normal during acute attack
without Rx, self-limiting lasting several days to weeks & followed by an intercritical period of wks-yrs.
subsequent attacks get closer together, involve more jts & last longer

systemic inflammatory polyarticular gout syndrome (SIPGS)

an uncommon severe acute presentation of gout involving at least 5 joints and usually bilateral
usually presents with very high C reactive protein (CRP) > 80
may develop acute kidney injury (AKI) / acute renal failure (ARF)
responds poorly to non-steroidal anti-inflammatory drugs (NSAIDs)
use corticosteroids or colchicine
may need inpatient management due to severe pain or renal issues
https://www.jscimedcentral.com/Arthritis/arthritis-2-1024.pdf

long-term sequelae:

renal calculi
tophi (foreign body granulomas with the crystal as the nidus)
- form in the musculotendinous unit:
  - olecranon bursa, Achilles tendon, ulnar surface of forearm, hands, feet, toes, finger, helix of ear
nephropathy
bone erosions with overhanging margins

treatment:

acute gout attack:

is it possible that joint is infected or is joint easy to aspirate? if so, aspirate joint looking for urate crystals (must be done within 24hrs of aspirate to avoid degradation)
otherwise treat as gout:
- early Rx within hours is probably more important than which anti-inflammatory:
  - corticosteroids such as prednisolone 50mg/d for 5 days is as efficacious as non-steroidal anti-inflammatory drugs (NSAIDs) and has less adverse effects (ICEM2004)
  - non-steroidal anti-inflammatory drugs (NSAIDs) for 1wk after symptoms have settled if no C/I such as PU, renal/cardiac/liver failure; post-op. state, anticoagulant Rx or poorly controlled HT
  - if C/I to NSAIDS then consider either:
    - corticosteroids
      - eg. oral prednisone 10mg bd for 3-5 days then taper
      - if cannot tolerate oral, a single IM steroid dose can be used
      - intra-articular methylprednisolone if no sepsis on aspirate eg. 40mg for knee joint
      - low dose colchicine 0.5mg bd if healthy adult over 50kg to prevent short term recurrence
        
        avoid colchicine in the elderly, weight < 50kg or severe liver or renal impairment.
  - if C/I to NSAIDs and steroids and no C/I to colchicine then:
    - colchicine if no severe liver or renal impairment:
      - low dose Rx regime: 1 mg orally initially, then 500 micrograms 1 hour later, as a single one-day course (total dose is 1.5 mg) (as per eTG 2024), OR,
      - prolonged low dose regime: 500 micrograms orally, 8- to 12-hourly until symptoms abate [maximum of 6 mg over 4 days];
      - total dose of colchicine given in an acute attack should not exceed 6 mg over 4 days
      - reduce dosage in renal impairment
  - avoid changing anti-gout Rx as any sudden change in uric acid levels (esp. a fall) will exacerbate the attack.
  - pts taking hypouricaemic Rx should continue and those not on any should not start until the acute attack is over.
  - consider concurrent low dose colchicine 0.5mg bd to cover high risk starting phase of new hypouricaemic Rx
  - assess & Mx associated disorders of obesity, excess alcohol intake, hypertension, hyperlipidaemia & renal insufficiency.

chronic gout:

Rx if either frequent attacks, tophi, joint destruction, or renal stones:
- take baseline U&E, uric acid level
- reduce alcohol consumption to reduce risk of acute attacks as there is dose-related risk:
  - 1.36 (95% CI: 1.00 to 1.88) times higher for >1-2 alcoholic beverages/day
  - 1.51 (95% CI: 1.09 to 2.09) times higher for >2-4 alcoholic beverages/day⁵⁾
- commence Rx to reduce uric acid levels:
  - historically, the choice of drug is allopurinol starting at 200mg/day and increasing to 600mg/day
  - assuming there is no evidence of acute gout but be aware of risks of allopurinol Rx:
    - precipitation of acute gout attack
    - rarely, a potentially fatal syndrome 1-6wks after starting Rx of:
      - exfoliative rash
      - fever
      - hepatitis
      - renal failure
      - NB. this syndrome is more likely if pre-existing renal insufficiency or concomitant diuretics
  - in 2015, a new Rx, febuxostat was introduced and trials suggest it may be more effective than allopurinol but does risk cessation due to causing abnormal LFTs, and commencement needs to be covered with NSAIDs or colchicine for 6 months as flare ups at commencement are more likely.
    - for patients with tophi, start at 40mg/d, if urate levels > 0.36mM after 2-4wks Rx, then increase to 80mg/d
  - may also consider probenecid
- plus non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine 0.6mg bd for 6-12mths if frequent attacks
  - BUT note that NSAIDs may have very limited efficacy for prevention of attacks
Risk of no Rx:
- further exacerbation of gouty nephropathy
- renal stones
- gouty arthritic attacks
- further tophi
- joint destruction