1

Difficult gout.Gout in the elderly

and drug-induced gout

2Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

Increasing prevalence of gout and hyperuricaemia among elderly subjects

3Wallace KL, et al. J Rheumatol 2004;31:1582-1587.

Annual gout prevalence stratified by age

4

UK prevalence of gout

Mikuls, et al. Ann Rheum Dis 2005;64:267-272.

M

F

>75 years

Men: 7.3%Women: 2.8%

M

F

Overall1.4%

5

Perception of disease and health-related quality of life in elderly patients with gout

Lee SJ. Rheumatology 2009;48:582-586.

SF-36: Physical Component Summary (PCS) and Mental Component Summary (MCS)

6

Clinical features of gout in the elderly

• Increased prevalence

• Women more frequently affected

• Small joints of the fingers more frequently involved

• Polyarticular onset more common

• Tophi occur earlier in the course of gout, often in atypical locations

• Frequently associated with other joint diseases (OA, CPPD)

• Comorbidities more common

• Increased association with diuretic use

By kind permission of L. Punzi, Rheumatology Unit, University of Padua

Wise CM. Rheum Dis Clin N Am 2007;33:33-55.De Leonardis F, et al. Rheumatol Int 2007;28:1-7.

7

• A high association with diuretic use and renal insufficiency has been noted in most elderly populations with gout

• Diuretic use has been reported in more than 75% of patients who have elderly onset gout, with a frequency of 95% to 100% in women

• Most small series of elderly patients who have atypical finger joint disease or tophaceous deposits report a consistent majority of patients taking diuretics

• A retrospective cohort study documented an almost two-fold increase in the risk of initiation of anti-gout therapy in patients within 2 years of starting thiazide diuretics for hypertension compared to patients given non-thiazide therapy

• Because of a lack of direct comparison to other elderly patients, it is unclear whether a decrease in renal function is peculiar to patients who have gout or merely reflects the trend seen in elderly populations in general

Increased association with diuretic use

Scott JT, Higgins CS. Ann Rheum Dis 1992;51:259-261.Fam AG, et al. J Rheumatol 1996;23:684-689.

Gurwitz JH, et al. J Clin Epidemiol 1997;50:953-959.Janssens HJ, et al. Ann Rheum Dis 2006;65:1080-1083.

8Hanly JG, et al. J Rheumatol 2009;36:822-830.

Healthcare utilisationin older adults with gout

9Wu EQ, et al. J Manag Care Pharm 2008;14(2):164-175.

Total all-cause health care costsamong gout patients

10

Reasons why gouty patients presentat an emergency department

• Severity of the acute attack

• Attack during the night

• Elderly age

• Comorbidity

• Polypharmacy

• Flares after the introduction of urate-lowering therapy

By kind permission of L. Punzi,Rheumatology Unit,University of Padua

Wise CM. Rheum Dis Clin N Am 2007;33:33-55.De Leonardis F, et al. Rheumatol Int 2007;28:1-7.

11

Management of gout in the elderly: general aspects

• Atypical presentation may make diagnosis difficult and hence may delay initiation of treatment

• Colchicine is less effective

• Use of NSAIDs or colchicine is limited by their side-effect profile

• Use of uricosuric agents may be limited due to the presence of co-morbidities including renal disease

• Restricting diet to eliminate purine-rich food is often challenging, and is of limited benefit

• Drug interactions are more likely, as polypharmacy is common

• Social, economic, and cognitive factors can affect compliance with medications and with laboratory monitoring

• Trials on newer therapies often do not include elderly subjects

Singh H, Torralba HB. Geriatrics 2008;63(7):13-8,20.

12

Management of acute gout attacksin the elderly: the colchicine dilemma

Morris I, et al. BMJ 2003;327:1275-1276.

13

Colchicine in acute gout

Morris I, et al. BMJ 2003;327:1275-1276.

14

Incidence of adverse events according to colchicine dose

Terkeltaub R, et al. Arthritis & Rheumatism 2010;62:1060-1068.

Colchicine dose

High (n=52) Low (n=74) Placebo (n=59)

Adverse events 40 (76.9) 27 (36.5) 16 (27.1)

Gastrointestinal adverse events 40 (76.9) 19 (25.7) 12 (20.3)

Diarrhoea (all occurences) 40 (76.9) 17 (23.0) 8 (13.6)

Nausea (all occurences) 9 (17.3) 3 (4.1) 3 (5.1)

Vomiting (all occurences) 9 (17.3) 0 (0) 0 (0)

Severe intensity adverse events 10 (19.2) 0 (0) 1 (1.7)

Diarrhoea (only severe intensity) 10 (19.2) 0 (0) 0 (0)

Melena (only severe intensity) 1 (1.92) 0 (0) 0 (0)

Nausea (only severe intensity) 1 (1.92) 0 (0) 0 (0)

Gout (only severe intensity) 0 (0) 0 (0) 1 (1.7)

Serious adverse events 0 (0) 0 (0) 0 (0)

15

Allopurinol is an appropriate long-term urate lowering therapy. It should be started at low doses (e.g. 100 mg daily) and

increased by 100 mg every 2-4 weeks if required. The dose should be adjusted in those with renal impairment.

If allopurinol toxicity occurs, options include other xanthine oxidase inhibitors, a uricosuric agent or allopurinol desensitisation (the latter

only in cases of mild rash).

Management of chronic gout in the elderly: focus on allopurinol

EULAR recommendations 2006 for the management of gout

9

Zhang W, et al. Ann Rheum Dis 2006;65:1312-1324.

16

Management of chronic gout in the elderly: allopurinol toxicity

• Minor self-limiting drug reactions are relatively common, being estimated to occur in up to 10% of patients, and include itching, rash and gastrointestinal problems

• The more serious, indeed potentially fatal, allopurinol hypersensitivity syndrome (ASH) is far less common, being estimated to occur in 0.4% of patients

• ASH includes features such as eosinophilia, liver and renal dysfunction, vasculitis, bone marrow suppression and rash

• Known risk factors for developing AHS include renal impairment, older age, comorbidities, use of thiazide diuretics and a genetic predisposition

Kumar A, et al. Br Med J 1996;312:173-4.Fam AG, et al. Arthritis Rheum 2001;44:231-8.

Rider TG, Jordan KM. Rheumatology 2010;49:5-14.

17

Clinical use of febuxostat

No dose adjustment needed in:• Elderly

• Mild to moderate renal function impairment

• Mild to moderate (caution) liver function impairment

No dose adjustment needed while on:

• Colchicine, indomethacin, naproxen

• Warfarin

• Hydrochlorothiazide

• CYP 2D6 substrates

SmPC febuxostat.

18

Special precautions

Febuxostat is not recommended in:• patients with ischaemic heart disease or congestive heart failure

• patients being treated with mercaptopurine or azathioprine

• patients with severe renal function impairment (no experience)

• patients with moderate or severe liver impairment

Caution is required when febuxostat is used in:• patients being treated with theophylline

• patients with thyroid disorders

SmPC febuxostat.

19

Summary of the managementof gout in the elderly

Treatment options Notes

Acute attacks

Colchicine (oral) At low doses (0.5-1 mg/day) colchicine is safe also in the elderly. Adminster with caution in concomitance with strong inhibitors of p-glycoprotein and cytochrome P450, such as clarithromycin, erythromycin or cyclosporine

NSAIDs With caution, NSAIDs should be taken at low doses, for limited periods, and by patients with normal renal function; consider a COX-2 inhibitor or adding a gastroprotective agent to reduce gastrointestinal toxicity to avoid in patients treated with anticoagulants

Corticosteroids (intra-articular, oral, parenteral)

Preferable in patients who have comorbid conditions, with caution in diabetes

Corticotropin (ACTH) (parenteral) Similar to corticosteroids, availability limited to some patients

Short-term prophylaxis

Colchicine Safe at low doses

NSAIDs See above

Urate-lowering therapy

Uricosuric agents Seldom effective in elderly patients because of renal dysfunction

Allopurinol Reduce dosage based on creatinine clearance, titrate dose

Febuxostat Better tolerated than allopurinol in the elderly. May be considered in mild to moderate renal impairment (creat. clear. 20-60 ml/min) and/or non-alcoholic hepatic impairment

Zhang W, et al. Ann Rheum Dis 2006;65:1301-1311.Richette P, et al. Lancet 2010;375:318-328.

Terkeltaub R. Nature Rev Rheumatol 2010:6:30-38.

20

Drug-induced gout

21

Drugs potentially inducing hyperuricaemia by a reduction of renal excretion

Cyclosporine

Alcohol

Nicotinic acid

Thiazides

Lasix (furosemide) or other loop diuretics

Ethambutol

Aspirin (low dose)

Pyrazinamide

Andrew JK, et al. Am J Manag Care 2005;11:S435-S442. Underwood M. BMJ 2006;332:1315-9.

22

• Drugs– Thiazides– Loop diuretics– Aspirin (low-dose)– Ethanol– Levodopa

• Renal– Hypertension– Chronic renal failure (any aetiology)

• Metabolic/endocrine– Obesity– Hypothyroidism– Hyperparathyroidism– Dehydration

Frequent causes of decreased renal excretion of urate in the elderly

Wise CM. Rheum Dis Clin N Am 2007;33:33-55.Perez-Ruiz F. Rheumatology 2009;48:ii9-ii14.

23

Cyclosporine and tacrolimus

• Calcineurin inhibitors– Both drugs can impair renal uric acid excretion – High sUA/decreased UA excretion (reduced fractional

excretion)– Mg leakage via tubular dysfunction (high fractional

excretion)

• Gout in organ transplant recipients– Heart and kidney tranplantation: higher sUA/MSU deposits

along with ageing, chronic kidney disease, diuretics– Liver transplantation: 10-50% hyperuricaemia; low gout

prevalence (2.6-6%)

Perez-Ruiz F, et al. Transplantation 2001;71:696-698.Shibolet O, et al. Transplantation 2004;77:1576-1580.

Fernández-Molina G, et al. Transplantation 2008;86:1543-1547.

24

Anti-tuberculous drugsand hyperuricaemia

• Pyrazinamide

– Hyperuricaemic effect due to modulation of urate transport via the proximal tubules

– Quickly reversible after the drug is stopped

• Ethambutol

– Effect not dependent on the dose

– Reversible within 15 days after the drug is stopped

• Rifampicin

– Seen less frequently

Merriman TR, et al. Joint Bone Spine 2011;78:35-40.