1. Clinical cases

2. Case report n. 1

3. 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

4. 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

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

6. 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

7. 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

8. Case report n. 2

9. 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

10. - 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

11. 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

12. Case report n. 3

13. Man, aged 57 years, presented at our emergency room with a 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

14. 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

15. 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 ( mg/dl)(normal range, μmol/l – mg/dl)
In recent months, he was noted to have proteinuria with a slightly raised serum creatinine of 240 mmol/l

16. 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)

17. 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

18. Case report n. 4

19. 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

20. 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

21. 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 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

22. 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

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

24. 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

25. 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