Gout

Image of “The Gout”, by James Gillray. Wikimedia Commons, CC BY

Natural History of Gout

Risk factors for gout

3 clinical classical stages

1. Gout flare – acute arthritis induced by MSU crystals
2. Intercritial gout – asymptomatic period after or between gout flare
3. Chronic gouty arthritis +/- tophi – joint deformity e.g. fixed flexion deformity

• 1st presentation of acute gout: typically acute monoarthritis of the 1st MTP joint (podagra), midfoot or ankle.
• Less commonly with oligoarthritis;
• Acute gout is generally self-limiting, lasting about 1 – 2 weeks.
• If hyperuricemia persist –> recurrent flares –> polyarticular gout (including those of upper limb)
• Common sites of tophi: 1st MTP joint, Achilles tendon, peroneal tendon, helix of the ear, olecranon bursa & finger pad.

Extra-articular manifestation: Urolithiasis, Chronic nephropathy (Thus, don’t forget to assess also patient’s Renal Function)

Diagnosis 🔬

Laboratory investigations

Mainly serum uric acid (SU)
– Cut-off level to diagnose hyperuricemia: > 6.8 mg/dL (408 umol/L; 0.408 mmol/L) at physiological pH & body temperature.

Keep in mind that:
– Diagnosis of gout should not be made based on hyperuricemia alone.
– A normal/low SU during flare does not exclude gout as level may be normal during flare. If clinical suspicion is high, SU may be repeated 2 weeks or more after complete resolution of flare.

Imaging modalities – X-ray & ultrasound

Typical radiographic features of gout on plain radiograph:
– Bone erosions with overhanging edges and a sclerotic rim (“punched out”/”rat bite” erosions)
– Bony proliferation
– Joint space are generally preserved until late stages of the disease
– No peri-articular osteopenia
– Soft tissue tophi +/- calcification

Co-morbidities

Gout is an independent risk factor for mortality due to coronary heart disease & kidney disease.
Screening for comorbidities e.g. HTN, DM, Dyslipidemia, CHD, & renal disease including urolithiasis should be done upon diagnosis & during follow up.
Below are the suggested baseline investigations which include screening for comorbidities as given in our Malaysia CPG guidelines.

Baseline investigations

Differential diagnosis

1. Septic arthritis
   – Commonly involves knee joint (other sites: hip, shoulder, ankle, wrist)
   systemic features e.g. fever, ill or septic-looking
   – Risk factors e.g. concomitant bacteria infection, recent intra-articular injection
   – Leucocytosis and increased CRP
   
2. Acute calcium pyrophosphate crystal arthritis
   – Age > 60 y/o
   – Involvement of a degenerative joint
   – Plain radiograph: chondrocalcinosis
   
3. Psoriatic arthritis
   
4. Reactive arthritis
   – Recent genitourinary or GI infection.
   – Presence of urethral discharge or ulcer, rash on soles, conjunctivitis.

Prevention of gout

• Maintenance of healthy body weight
• Avoid alcohol
• Adherence to Dietary Approaches to Stop Hypertension (DASH) which:
  – Discourages purine-rich red meat, fructose-rich foods, full-fat dairy products & saturated fat.
  – Encourages vegetables, fruits, whole grains, fat-free or low-fat dairy products, fish, poultry, beans, nuts & vegetable oils.
• Diuretics should be avoided if possible, or replaced by an alternative drug when used as an antihypertensive agent.

Dietary recommendations🥗

Management of gout flare 🔥

Mainstay of treatment: pain relief
The following monotherapy may be used:

1. Colchicine
2. NSAIDs/COX-2 inhibitors
3. Corticosteroids

Combination of the above may be used if response to monotherapy is insufficient.

Indications for Urate-Lowering Therapy (ULT)

Established indications:

• Recurrent gout flares (≥ 2 flares in 12 months) OR
• Presence of ≥1 tophi OR
• Presence of radiographic damage attributable to gout

Other conditional recommendations for ULT initiation after first gout flares:

– Moderate to severe CKD (Stage ≥ 3) OR
– SU concentration of > 9mg/dL (540 umol/L) OR
– Urolithiasis

Available ULT options

1. Xanthine oxidase inhibitors – allopurinol & febuxostat
2. Uricosuric agents – benzbromarone & probenecid
   – Contraindicated in patient with urolithiasis & are not recommended in severe renal impairment.
3. Recombinant uricase – pegloticase
4. Others – ? Ural sachet

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Allopurinol

• 1st line
• Start at low dose & increase gradually.
• Severe cutaneous adverse reaction (SCAR) is the more serious A/E. There was a strong dose-response relationship between starting dose of allopurinol and Allopurinol Hypersensitivity Syndrome (AHS). Therefore always start low, go slow.
• Start low dose 50 mg or 100 mg & increase slowly every 4 weeks.

Febuxostat

2nd line

Can be used in patient with renal impairment (eGFR 15 – 89)

Dosing & Titration

• Initial dose: 40 mg OD
• Titration: if SU is still > 6.0 mg/dL after 2 – 4 weeks, consider increasing to 80 mg OD
• Maintenance: 40 mg or 80 mg OD
• Maximum: 120 mg OD if clinically indicated

Dosage modifications

Potential Side Effects (AEs)

• Common: Rash, diarrhea, nausea & liver function abnormalities
• Serious skin reactions: Risk of DRESS, Stevens-Johnson Syndrome (SJS), & Toxic Epidermal Necrolysis (TEN)
• Cardiovascular Black Box Warning: Gout patients with established CV disease treated with Febuxostat have shown a higher rate of CV death compared to Allopurinol.

Major Drug Interactions

• Azathioprine/Mercaptopurine: Contraindicated. Concurrent use increases plasma concentrations of these drugs which can lead to severe toxicity.
• Methotrexate: May enhance hepatotoxic effects of methotrexate

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Flare prophylaxis

Initiation of ULT leads to dissolution of MSU deposits which causes dispersion of crystals resulting in increased gout flares.
Concomitant anti-inflammatory agents should be started to reduce flares.
Preferred choice: Stepwise dose increase of ULT &/or concomitant colchicine (0.5 mg OD or BD).
Prophylaxis should be used for at least 3 – 6 months when initiating ULT.

Treat-to-Target (T2T) 🎯

Aim for serum urate< 360 umol/L (0.36 mmol/L) should be applied in treatment of all patients.
– A lower SU target of < 5mg/dL (300 umol/L; 0.30 mmol/L) for faster dissolution of crystals is recommended in severe gout (tophi, chronic arthropathy, frequent flares)
– However, some studies have suggested that urate might be protective against various neurodegenerative disease, thus prolonged SU < 3 mg/dL (180 umol/L; 0.18 mmol/L) is not recommended.

Gout in CKD patients

Follow up

Monitoring during Treat-to-Target

• SU, RP, LFT, FBC: Every 4 weeks during dose titration, then every 6 months once dose is stable.
• Screen/Monitor comorbidities at least annually: FBS, FSL, HbA1c

Indications for referral

• Diagnosis uncertainty
• Refractory to conventional therapy despite drug adherence
• Complicated gout with destructive joint changes
• Hypersensitivity or intolerance to allopurinol
• Gout in pregnancy
• Surgical management of tophi when there is uncontrolled infection, entrapment neuropathy & risk of permanent joint damage
• Gout with urolithiasis should be assessed by urologist

Summary Algorithm

References

Ministry of Health Malaysia. (2021). Clinical practice guidelines: Management of gout. Putrajaya: Ministry of Health Malaysia.