Gout

Sohrab’s MRCP pearls:

H/O CKD/ Thiazide/Pyrazinamide + Sudden severe pain, swelling in the 1st MTP joint +
Hyperuricemia + Synovial fluid showing MSUM crystals (Needle shaped negative birefringence crystals in plain
polarized light) + Synovial fluid WBC- 10,000-50,000/mm3+ Punchedout erosion on X-ray. Diagnosis : Gout

Gout is a form of microcrystal synovitis caused by the deposition of monosodium urate monohydrate (MSUM)
crystals in the synovium. It is caused by chronic hyperuricemia (uric acid > 450 μmol/l). Around 70% of first attacks
affect in the first metatarsophalangeal (MTP) joint, others affected joints are ankle, wrist & knee.

Þ Predisposing factors:

1. Decreased excretion of uric acid: (90% of cases of primary gout)

- Chronic kidney disease
- Lead toxicity
- Pre-eclampsia
- Drugs: diuretics (Thiazides), low dose aspirin, pyrazinamide
- High alcohol intake (more than 20 units for men, more than 15 units for women).

2. Increased production of uric acid:

- Lesch-Nyhan syndrome
- Myeloproliferative / lymphoproliferative disorder
- Cytotoxic drugs
- Severe psoriasis

Þ Lesch-Nyhan syndrome:
. Hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) deficiency
. X-linked recessive disorder
. Features: gout, renal failure, neurological deficits, learning difficulties, self mutilation
. Patients with Lesch-Nyhan syndrome often take allopurinol for lifelong.

3. Drug causes:
- Diuretics: Furosemide, Thiazides
- Low dose ASA.
- Cytotoxic agents: cyclosporine, tacrolimus
- Pyrazinamide

Note:
- Low dose aspirin may exacerbate gout but high dose aspirin is uricosuric.
- Aspirin in a dose of 75-150mg is not thought to have a significant effect on plasma urate levels.
- The British Society for Rheumatology recommends it should be continued if required for cardiovascular prophylaxis.

Main causes of gout:

CKD, Thiazide, pyrazinamide ,Alcohol, Aspirin low dose, Lesch-Nyhan syndrome, Cyclosporine, tacrolimus

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)

Þ Features:
1. Acute gouty arthritis:
- acute sever pain, erythema, swelling, warmth, High fever.
- usually occur at night, movement restricted.
- commonly affect the joint. first metatarsophalangeal (MTP) joint.

2. Chronic gouty arthritis:

- Progressive joints destruction.
- Tophi formation: Bone tophi (elbow, knees), soft tissue tophi (ear pina, tendon sheath)
- Uric acid nephrolithiasis and uric acid nephropathy may be developed

Þ Investigations:

1. Synovial fluid analysis: ( gold standard test )

- Joint fluid aspiration (choice of investigation) > Needle shaped negative birefringence
crystals under polarized light Microscopy with neutrophil.

2. Uric acid:
- should be checked once acute episode settle down (typically two weeks later), as may high,
normal, or low during acute attack.
- Hyperuricemia may be found.

3. x-ray:
. joint effusion is an early sign.
. well define ‘punched out’ erosions with sclerotic margins (rat bite erosion)
. relative preservation of joint space ,until late disease
. eccentric erosions
. no osteopenia (in contrast to rheumatoid arthritis)
. soft tissue tophi may be seen.

4. WBC & ESR are typically elevated

Þ Management:

Rx of Gout in short:
1. In acute attack
1st line: NSAIDs , Colchicine, Steroids
- Colchicine (if NSAIDs are contraindicated like patient has CKD, PUD).
- Steroids (contraindicated in DM)

2. Urate lowering agents / prophylaxis:

1st line: Allopurinol (give after 1st attack) > if not tolerated or ineffective > Febuxostat.
2nd line: Uricosurics (Benzbromarone / Probenecid)
3rd line: Uricase (Pegloticase)

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)

 Management Acute gout flare

1st line drugs: NSAIDs or colchicine or glucocorticoids

1. NSAIDs:
- contraindicated in CKD (use Colchicine in mild to moderate CKD and prednisolone in severe CKD)
- gastroprotection (e.g., a proton pump inhibitor) may also be indicated.

2. Colchicine:
- Mechanism of action: inhibit microtubule polymerization by binding to tubulin, interfering with
mitosis. Also inhibits neutrophil motility and activity.
- Useful: in patient taking warfarin or patients have mild to moderate CKD but contraindicated in Severe CKD
- Side effect: Diarrhea (main side effect), myopathy, neuropathy, arrhythmias, cardiac toxicity, myelosuppression.
- Drug interactions: with statins due p450 3A4 inhibitor >>> causes Myotoxicity >>> so reduced the dose of statins
- Colchicine has a slower onset of action. The main side-effect is diarrhoea.
- The BNF advises to reduce the dose by up to 50% if creatinine clearance is less than 50 ml/min and
to avoid if creatinine clearance is less than 10 ml/min.

3. Glucocorticoids: Prednisolone, methylprednisolone, intraarticular administrations.

- can be used mild to severe CKD
- preferable where intolerance or inadequate response to NSAIDs or Colchicine.
- avoided in diabetics because it would adversely affect the diabetic control
- intraarticular steroids are preferred for NPO patients.
- a patient with acute gout and cannot take NSAIDs as he has PUD, so Intraarticular steroid injection
is the best alternative.
4. IL-1 blocker:
- Canakinumab for patients with contraindication to NSAIDs or colchicine or glucocorticoids

5. Rest the affected joints

If the patient is already taking allopurinol, it should be continued & add NSAIDs in acute flare

Þ Rasburicase:
It is a recombinant urate oxidase which may be given during an acute gouty attack without the initial worsening of
symptoms. It is also effective newer therapy in urate nephropathy in patients undergoing chemotherapy for
haematological malignancy, it prevent and treat hyperuricaemia associated with tumour lysis syndrome.
Rasburicase breakdown of uric acid to allantoin (allantoin is water-soluble and therefore can be renally excreted).

Management of Chronic gouty arthritis

Þ Urate lowering agents / prophylaxis:

1st line: Allopurinol (give after 1st attack) > if not tolerated or ineffective > Febuxostat.
2nd line: Uricosurics (Benzbromarone / Probenecid)
3rd line: uricase (Pegloticase)

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)

Þ Indications for urate-lowering therapy (ULT)
- the British Society of Rheumatology Guidelines now advocate offering urate- lowering therapy to all
patients after their first attack of gout.
Þ ULT is particularly recommended if:
1. >= 2 attacks in 12 months
2. tophi present
3. renal disease
4. uric acid renal stones
5. prophylaxis if on cytotoxics or diuretics

Urate-lowering therapy (ULT)

1st line: Allopurinol & Febuxostat ® xanthine oxidase inhibitor

Urate-lowering therapy should not be started until 2 weeks after an acute attack, as starting too early may precipitate
a further attack. Commencement of ULT is best delayed until inflammation has settled as ULT is better discussed when
the ‘patient is not in pain'. Initial dose of 100 mg od, with the dose titrated every few weeks to aim for a serum uric
acid of < 300 µmol/l. Lower initial doses should be given if the patient has a reduced eGFR. The BSR guidelines
suggest this may need to be continued for 6 months. when allopurinol is not tolerated or ineffective febuxostat (also
a xanthine oxidase inhibitor) is an alternative choice.

2nd line: Uricosurics: Benzbromarone / Probenecid

- Uricosurics ( Benzbromarone) Act by blocking the URAT-1 ( Uric acid transporter-1 in Proximal Renal Tubule)

- Action: Inhibition of uric acid reabsorption in renal proximal convoluted Tubules → increased renal
elimination of Uric acid

- Contraindications
- Nephrolithiasis
- Moderate to severe CKD
- Side effects: Urolithiasis (uric acid stones)
- Interactions: Inhibits penicillin secretion in the proximal convoluted tubule

3rd line: Recombinant Uricase (Pegloticase)

Action: Breakdown of uric acid to allantoin (allantoin is water-soluble and therefore can be renally excreted)

Contraindications: G6PD deficiency, Congestive heart failure

Uricase (urate oxidase) is an enzyme that catalyzes the conversion of urate to the degradation product of allantoin
which can easily pass through urine. Patients who have persistent symptomatic and severe gout despite the
adequate use of urate-lowering therapy, pegloticase (polyethylene glycol modified mammalian uricase) can achieve
rapid control of hyperuricemia. It is given as an infusion once every two weeks.

Þ Lifestyle modifications
- reduce alcohol intake and avoid during an acute attack
- lose weight if obese
- avoid food high in purines e.g., Liver, kidneys, seafood, oily fish (mackerel, sardines) and yeast products

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)

 Allopurinol

Þ Side effects of allopurinol:

1) Allopurinol hypersensitivity syndrome (AHS)
- Non-blanching purpuric rash, hepatic and renal dysfunction, eosinophilia, and vasculitis. Allopurinol develop
itchy maculopapular rashes, GIT dysfunction, and deranged liver function tests (LFTs).
2) 20% of patients on allopurinol, who are prescribed amoxicillin or ampicillin ® develop a rash.

Þ Allopurinol vs Wafarin vs Colchicine:

- Allopurinol increases the anticoagulant effect of warfarin

- If patient was on warfarin > Colchicine will be the drug of choice.
- Colchicine had little or no interaction with warfarin, but a case series was recently published that suggested
INR may be increased in some patients prescribed colchicine,
- patients on warfarin with acute gout > 1st choice: colchicine, 2nd choice: Rasburicase

Þ Allopurinol, Azathioprine interaction

Allopurinol Inhibit xanthine oxidase. Azathioprine metabolised to active compound of 6-mercaptopurine.

Xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid. Allopurinol inhibit
xanthine oxidase can therefore lead to high levels of 6-mercaptopurine. As a result, azathioprine toxicity develop
(Bone marrow suppressed).

The combination of allopurinol and azathioprine leads to increased bone marrow toxicity

Þ Gout in patient with DM and CKD:

1. Colchicine
Useful in patients with renal impairment who develop gout as NSAIDs are relatively contraindicated. The
BNF advises to reduce the dose by up to 50% if creatinine clearance is less than 50 ml/min and to avoid if
creatinine clearance is less than 10 ml/min.

2. Prednisolone
- Adversely affect of diabetic control.
- Prednisolone can be used instead of NSAIDS if it is contraindicated as in case of renal impairment
or elderly with an increased risk of bleeding with warfarin.
- Corticosteroids are highly effective, and can be used where NSAIDs are not tolerated, or in refractory
disease (intra-articular, oral, intramuscular, IV).
- a patient with acute gout and cannot take NSAIDs as he has PUD, so Intraarticular steroid injection is the best alternative.

Þ Gout + HTN
If diuretics (thiazides) are being used to treat hypertension an alternative antihypertensive should be considered,
consideration should be given to stopping precipitating drugs (such as thiazides) , losartan has a specific uricosuric action
and may be particularly suitable for the many patients who have coexistent hypertension

Note:
® Acute gout pain with congestive cardiac failure and renal impairment, developed severe diarrhoea
with colchicine. The treatment of choice → Prednisolone
® Most patients with hyperuricaemia never develop gout or stones. Treatment of these patients is not recommended.

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)

 MRCP Guidelines Academy
Admission is going on for MRCP part-1 & part-2.
Call + what’sApp : +8801740163296
Facebook Group: MRCP guidelines with drsohrab
Mentor: Dr. Sohrab

Admission is going on for MRCP part1&2, FCPS part-1, +8801740163296 (call+what’sapp)