Clinical cases

Case report n. 1

Patient Woman, aged 78 years Affected by polyarticular pain and swelling of the distal interphalangeal joints for 10 years First diagnosis: osteoarthritis of the hand, Heberden’s nodes with recurrent inflammatory reactions Treatment: NSAIDs for flares (3-4 per year) Response: good Five years later psoriasis at elbow and on scalp New diagnosis: psoriatic arthritis Treatment: chronic therapy with NSAIDs + omeprazole Response: unsatisfactory (continuous pain) Three years later: atrial fibrillation (warfarin) Treatment: NSAIDs stopped → prednisone 5 mg/daily Response: moderate

After 2 years, she presented at the emergency room with painful swelling of her second distal interphalangeal joints, bilaterally; the joints were also red, warm and tender By kind permission of L. Punzi, Rheumatology Unit, University of Padua

When pressure was applied, a toothpaste-like, white, chalky substance was easily expressed By kind permission of L. Punzi, Rheumatology Unit, University of Padua

Thus, a definitive diagnosis of gout was made When analysed by polarised light microscopy, this chalky substance was found to consist of needle-shaped, highly birefringent crystals (Figure A) Using a first order red compensator, these crystals had a negative optical appearance typical of urate crystals (Figure B) Thus, a definitive diagnosis of gout was made Figure A. Polarised light Figure B. First order red compensator By kind permission of L. Punzi, Rheumatology Unit, University of Padua

The acute symptoms subsided rapidly after 1 week Laboratory investigations indicated normal renal and hepatic function; serum uric acid 600 μmol/l (10mg/dl) Colchicine at low dose (0.5 mg x 2 daily) was added to prednisone 5 mg/daily The acute symptoms subsided rapidly after 1 week Allopurinol was then introduced at a low dose (50 mg/daily for 2 weeks, then 100 mg daily) together with colchicine at prophylactic doses (0.5 mg daily) and prednisone 5 mg daily After 1 month, serum uric acid was 400 μmol/l (6.7 mg/dl) Allopurinol was increased to 150 mg daily, while continuing with colchicine 0.5 mg daily and prednisone 5 mg daily After another month, the serum uric acid was 320 μmol/l (5.4 mg/dl) Colchicine was continued and prednisone was reduced to 2.5 mg daily Three months later the patient stopped prednisone and after 1 month also stopped the colchicine treatment

Case report n. 2

A man, aged 50 years, presented with acute inflammatory polyarthritis characterised by painful swelling, redness, warmth and tenderness of many joints, including those of the hands and wrists bilaterally, shoulders, knee and feet. He had never experienced such an episode before By kind permission of L. Punzi, Rheumatology Unit, University of Padua

- Allopurinol was further increased to 450 mg/day Serum urate was 625 μmol/l (10.5 mg/dl), serum creatinine clearance 90 ml/min and clearance of uric acid was 6.5 ml/min. An overproduction mechanism rather than decreased elimination is supposed to be involved in inducing hyperuricaemia A synovial fluid examination revealed urate crystals, so gout was diagnosed Colchicine 0.5 mg x 2 daily and allopurinol in increasing doses from 100 up to 300 mg/day in 3 months was started After 3 months serum urate levels were still above the therapeutic target: 380 μmol/l (6.4 mg/dl) - Allopurinol was further increased to 450 mg/day Serum urate levels of 291 mol/l (4.9 mg/dl) have been reached but the patients complained malaise and a slight increase in eosinophils to 600/µl - The allopurinol night dose of 150 mg was withdrawn At an allopurinol dose of 300 mg/day, the patient’s serum urate returned to 380 μmol/l (6.4 mg/dl) and he still had chronic complaints and suffered gout flares

Allopurinol was stopped and febuxostat was introduced at a dose of 80 mg/day Serum urate levels lowered to 320 μmol/l (5.4 mg/dl) and gout attacks ceased After three months the patient continued to stay well

Case report n. 3

Man, aged 57 years, presented at our emergency room with a 2-day exacerbation of a painful, swollen elbow He had a history of some years of classical gout for which he had been successfully treated with NSAIDs On examination, the patient was febrile and had an inflamed olecranon bursa at the left elbow By kind permission of L. Punzi, Rheumatology Unit, University of Padua

Purulent-looking fluid was aspirated from his swollen elbow and sent for microbiological studies The synovial fluid analysis revealed a white blood cell content of 60,000/mm3 and many intra- and extra-cellular urate crystals The microbiological cultures grew group C haemolytic streptococci Other investigations included a haemoglobin of 9 g/dl, urea of 28.5 mmol/l and creatinine of 221 mmol/l. His creatinine clearance was 20 ml/min, erythrocyte sedimentation rate 130 mm/h and C-reactive protein 150 g/l, urate 357 μmol/l (6.0 mg/dl) He was taking enapril for hypertension and had recently had an NSAID introduced for treatment of his gout. This and the infection had presumably precipitated the patient’s renal failure He was treated with i.v. benzylpenicillin, and both enapril and NSAID were discontinued On this treatment, his pyrexia settled

The rash disappeared after allopurinol was discontinued His serum creatinine improved to the normal range and creatinine clearance to 44 ml/min Allopurinol 100 mg/day and colchicine 0.5 mg/day were introduced. Nifedipine sustained release 20 mg bid was started as his new antihypertensive treatment One month later, he developed a generalized florid rash for which he was readmitted to hospital The rash disappeared after allopurinol was discontinued On admission, his serum urate had been 464 μmol/l (7.8 mg/dl) Probenecid was introduced but the patient was unable to tolerate it because of dyspepsia Despite continuous treatment with colchicine 0.5 mg bid he suffered frequent inflammatory episodes of gout with serum urate levels varying from 450 to 900 μmol/l (87.5-15.1 mg/dl)(normal range, 160-420 μmol/l – 2.6-7.0 mg/dl) In recent months, he was noted to have proteinuria with a slightly raised serum creatinine of 240 mmol/l

In view of persistent symptoms and concern over the possibility of gouty nephritis, allopurinol was recommenced in a desensitization regime After restarting allopurinol, the serum uric acid decreased to a normal level The regime was tolerated well up to a dose of 200 mg daily, when the patient developed a mild, macular rash. This settled after allopurinol was discontinued Febuxostat at 80 mg daily was then introduced Six months later he was well, and colchicine has been stopped The patient’s proteinuria has disappeared and his serum urate levels have fallen to 300 μmol/l (5 mg/dl)

Comments Severe allopurinol-induced toxic effects occur in less than 2% of treated patients but can be life-threatening, with a mortality rate of about 20% They also develop early and seem to arise mainly in patients with renal failure, in those on high doses of allopurinol, in patients on concomitant diuretic treatment and when the drug is reintroduced after skin intolerance Patients with a history of severe skin rash induced by allopurinol should, therefore, never be given the drug again. Several strategies to control uricaemia in these patients have been proposed, including the use of febuxostat and uricosuric drugs when not contraindicated In cases of mild skin reaction, allopurinol desensitisation might be successful but it is recommended only if the alternatives fail Desensitisation should not be attempted in patients with severe reactions or renal or hepatic failure

Case report n. 4

Patient A 68-year-old female with well-controlled type 2 diabetes, chronic kidney disease, and chronic gout Experiencing increasingly frequent gout attacks She presented with sub-acute pain, swelling, redness and tenderness in joints of the left foot, left hand and pre-patellar bursa Symptoms resolved slowly following aspiration and steroid injection into the pre-patella bursa

At examination the patient had polyarticular gout characterised by acute pain, swelling, redness and tenderness of different affected joints By kind permission of L. Punzi, Rheumatology Unit, University of Padua

Diagnostic procedures A bursal aspirate revealed urate crystals and no infection Laboratory investigations indicated poor renal function (creatinine clearance 30 ml/min/1.73 m2) and elevated serum urate levels (10 mg/dl - 595 μmol/l) Medical consideration Therapeutic options for symptomatic treatment of this patient’s gout flares and for the management of her chronic gout and hyperuricaemia required careful consideration in view of her compromised renal function and diabetes

The patient was treated with allopurinol, starting at a dose of 100 mg/day, and with low dose colchicine for prophylaxis of flares The allopurinol dose was adjusted according to the patient’s creatinine clearance After 3 months of allopurinol treatment urate levels had decreased only to 8.0 mg/dl (476 μmol/l) and the patient still experienced flares. Allopurinol was stopped and benzbromarone was started at a dose of 50 mg/day after the patient’s liver function had been evaluated

Unfortunately, the patient developed an extensive skin rush and benzbromarone was stopped immediately By kind permission of L. Punzi, Rheumatology Unit, University of Padua

Febuxostat at 80 mg daily was then introduced and colchicine prophylaxis was continued for 6 months After 1 month of treatment the patient’s serum urate level had reached 6.1 mg/dl (363 μmol/l) After a further 3 months the serum urate level was 4.9 mg/dl (292 μmol/l) and the patients felt well and had no further flares

Comments Urate lowering therapy is strongly indicated in patients with frequent gout flares and persistent hyperuricaemia Gout management can be difficult in patients with impaired renal function (associated with diabetes in this case) NSAIDs should be avoided and colchicine and corticosteroids used with caution for the symptomatic management of flares Since allopurinol and its metabolites are excreted by the kidney, the dose must be reduced in patients with impaired renal function. Allopurinol should be started at a low dose Since this patient had impaired renal function, low-dose colchicine was more appropriate than NSAIDs for prophylaxis Benzbromarone is likely to be effective in patients with impaired renal function, but carries a small risk of liver toxicity Febuxostat is an effective and well tolerated urate-lowering drug and can be used with no dose adjustments in patients with mild and moderate renal impairment