1. Update on the Management of Gout
Rizwan Rajak
Consultant Rheumatologist
CHS NHS Trust
Jan 2019

2. Content Clinical Case Background Overview
National / International Guideline Updates
Management Overview
Advances

3. Case History 46 year Taxi driver, male, obese
2 -3 years of intermittent joints flares: toes, ankles, knees, fingers, olecranon
Developed tophi over 18 months, Xrays feet – 1st MTPJ ‘punched out’ erosions, urate 650 µmol/L
Symptoms now every day, debilitating, unable to work
GP tried NSAID & Colchicine – not effective, Allopurinol – flares. Referred on Pred 40mg daily (flares at doses below) taken for 4 months

5. Case History Lifestyle review: high sweetened drinks intake (fructose)
No alcohol (previously high), no red meat / shellfish, no renal disease / psoriasis, no iatrogenic causes, no FH
Acute attack(s): IV Steroids?
Rasburicase (uricase) – lowered sUA to unrecordable levels. Allopurinol started but then flared badly within 1 week
Re-tried Rasburicase and then followed with Febuxostat – same issue, mild reaction to uricase
MDT held: Anakinra daily SC – after 2 weeks then Rasburicase, followed immediately by Febuxostat120mg daily. Consider Benzbromarone.

6. Background Overview Most common inflammatory arthritis
UK Incidence steadily increased from 1.5% in 1997 to 2.5% in 2012
More common in men – male:female ratio 4:1
Most important risk factor is sustained hyperuricaemia
Caused by overproduction or under-excretion of urate
Deposition of monosodium urate crystals in joints and tissues
Studies have repeatedly identified increased cardiovascular mortality with gout

7. Epidemiology – prevalence increases with age
100 80 60 40 20
Men
Women
<25
45–54
55–64
65–74
75–84
≥85
25–34
35–44
Prevalence, per 1,000 people
While the incidence of a disease is the proportion of a given population in whom the diagnosis of a disease is made during a specified time period, the prevalence of a disease is the proportion of a specified population who have the disease at a given time.
According to prevalence data on gout in the UK in 1999, the rates peaked in men between the age of 75 and 84 years (7.3%), while in women disease prevalence continued to rise beyond 85 years of age (2.8%). [1]
1. Mikuls TR, et al. Ann Rheum Dis 2005; 64:
Age group (years) 7

8. Risk factors for gout Modifiable High-purine diet Non-modifiable
Alcohol consumption
Obesity
Certain medications
Diuretics
Hyperuricaemia
Non-modifiable
Age
Male gender
Race
Genetic factors
Impaired renal function
The risk factors for gout can be divided into modifiable and non-modifiable.
The non-modifiable risk factors for gout are age, sex, race, genetic factors and chronic renal failure. The incidence of gout increases in direct association with age, and men are affected more frequently than women, because of the uricosuric effect of oestrogens in the latter. Indeed the incidence of gout increases considerably in women after the menopause. A familial tendency to the development of gout is well recognized but still poorly understood. Over 30% of gout sufferers have at least one relative with gout. Certain gene mutations and polymorphisms have been related to the development of gout.
Modifiable risk factors for gout include hyperuricaemia, high purine intake, consumption of purine-rich alcoholic beverages, obesity, and the use of certain medications. 8

9. Modifiable risk factors for gout: purine-rich foods
Relative risk of gout in the highest quintile of purine-rich foods and dairy intake compared to the lowest quintile of intake
Increased risk
Decreased risk
Relative risk of gout
1.41
1.51
0.96
0.56
0.58 1
0.0
0.5
1.0
1.5
2.0
Total
meat
(n=161)
Seafood
(n=171)
Purine-rich vegetables
(n=133)
dairy
(n=102)
Low-fat
(n=101)
High-fat
(n=142)
A diet low in purines can reduce the serum level of uric acid. Notable sources of dietary purines are meat (in particular, dark meat) and seafood.
In a large prospective study, high consumption of meat and seafood were found to be associated with an elevated risk of gout onset (41% and 51%, respectively). High consumption of dairy products, high in protein but very low in DNA and RNA (which contain purine), was associated with a 44% decrease in the incidence of gout. Consumption of the more purine-rich vegetables or a high protein diet per se had no significant correlation. [1]
Another study showed that men who consume two or more sugary soft drinks a day have an 85% higher risk of gout compared with those who drink less than one a month. This is because such beverages contain large quantities of high-fructose corn syrup, a common sweetener and sugar substitute, which results in hyperuricaemia. [2]
1. Choi HK, et al. N Engl J Med 2004; 350:
2. Choi HK, et al. BMJ 2008; 336: 9

10. Modifiable risk factors for gout: alcohol intake
3.0
2.51
2.5
2.0
1.6
Relative risk of gout
1.5
Increased risk
1.05
1.0
Decreased risk
0.5
The risk of gout varies according to the type of alcohol consumed. A study comparing the development of gout in men who regularly drank beer, spirits or wine with those who very rarely drank these alcoholic beverages, showed that the consumption of beer, being rich in purines, conferred a higher risk than drinking spirits. Moderate wine drinking does not increase the risk of gout. In the past, however, lead sugar was used to sweeten wine and some studies have established a statistical connection between gout and lead poisoning, and a significant correlation between levels of lead in the body, urate excretion and gout.
0.0
Beer
(n=45)
Spirits
(n=64)
Wine
(n=18)

11. Modifiable risk factors for gout: obesity5 4
Relative risk of gout
2.97 3
2.33
1.95 2
This study prospectively examined the relationship between adiposity, weight change, hypertension, and diuretic use and incident gout in 47,150 men with no history of gout at baseline over a 12-year period ( ). 730 incident cases of gout were confirmed. [1]
Compared with men with a body mass index (BMI) of , the multivariate relative risks (RRs) of gout were 1.95 (95% CI, ) for a BMI of 25 to 29.9,
2.33 (95% CI, ) for a BMI of 30 to 34.9, and 2.97 (95% CI, ) for a BMI of 35 or greater (P for trend <0.001). Compared with men who had maintained their weight (±4 lb) since age 21 years, the RR of gout for men who had gained 30 lb or more since age 21 years was 1.99 (95% CI, ). In contrast, the multivariate RR for men who had lost 10 lb or more since the study baseline was 0.61 (95% CI, ). [1]
Higher adiposity and weight gain are therefore strong risk factors for gout in men, while weight loss is protective. [1]
1. Choi HK, et al. Arch Intern Med 2005; 165:742-8. 1 1
≥35
BMI (kg/m2) 11

12. Diagnosis Four Stages of Gouty Arthritis Asymptomatic hyperuricaemia
Acute gouty arthritis
Intercritical gout
Chronic tophaceous gout

13. Gout is recurrent and progressive
Gout, if untreated, evolves through various stages. There is a long period (usually years) of asymptomatic hyperuricaemia during which crystals accumulate and the person has no symptoms. This period finishes when the person has a first acute attack (or flare) of gouty arthritis. The initial episode almost always involves a single peripheral joint. The joint becomes swollen, red, hot, shiny and extremely painful. The inflammation resolves slowly over 7-10 days, often with itching and flaking of the overlying skin. In rare cases, the person never has another attack, but most patients will go on to have recurrent flares (62% within 1 year, 78% within 2 years and 89% within 5 years). [1,2] The frequency of attacks, their severity and duration and number of joints involved all increase with time, while the asymptomatic intercritical periods between acute attacks shorten. After an average of about 10 years, permanent joint damage can develop and the patient has advanced gout with chronic pain. Tophi (large monosodium urate crystal deposits) may be present.
1. Wortmann RL, Schumacher HR Jr. Rheumatology 2005; 5:
2. McGill NW. Ballieres Best Pract Res Clin Rheumatol 2000; 14: 13

14. Gold standard Gout diagnosis
Demonstration of monosodium urate crystals by microscopic examination for negatively birefringent crystals in synovial fluid or tophus aspirates permits a definitive diagnosis of gout
Urate crystals are intra- or extracellular
Long needles, typically μm
Crystals examined under a polarizing filter will be:
Yellow when aligned parallel to the axis of the red compensator
Blue when aligned perpendicular to the direction of polarization
The gold standard for the diagnosis of gout is aspiration of synovial fluid or a tophus and microscopic examination for the presence of negatively birefringent crystals.
Urate crystals are intra- or extracellular long needles (typically μm).
Crystals examined under a polarising filter are:
Yellow when aligned parallel to the axis of the red compensator;
Blue when aligned perpendicular to the direction of polarisation.

15. Diagnostics in gouty patients
Clinical examination for tophi
Extensor surface of forearm, olecranon, Achilles tendon, pinna
Imaging
No juxta-articular osteopaenia cf other inflammatory arthritides
Punched out lateral erosions with sclerotic margins and over-hanging edges (so-called “rat-bite erosions”)
sUA measurement
May decrease during an acute attack
Full blood count
To exclude myeloproliferative disorders; raised WBC may suggest septic arthritis
Renal function
Association of renal failure with hyperuricaemia
Lower allopurinol dose in renal impairment
Urinary urate excretion
Risk of renal stones?
Uricosurics contraindicated in patients with high urate excretion
Fasting lipids and glucose
Association of gout with metabolic syndrome
Thyroid function
Association with hypothyroidism and possibly hyperthyroidism
Patients with suspected gout should be examined carefully for the presence of tophi. Imaging techniques are not diagnostically specific but provide objective evidence of the presence and degree of joint damage and deformity.
Blood tests commonly performed are a full blood count, electrolyte assays, renal and thyroid function tests and erythrocyte sedimentation rate, which help to exclude other causes of arthritis, particularly septic arthritis, and to investigate any underlying cause for the hyperuricaemia, as well as indicating whether treatments will need to be modified (e.g., reduction of allopurinol dose in patients with renal impairment).
The serum uric acid level may be normal during a gout flare and should, therefore, be assessed after the acute attack has subsided. 15

16. Men with gout are at risk of other complications
Joint Damage / Deformity
Cardiovascular risk
Kidney Stones
Kidney Damage
In a prospective study of more than 50,000 male health care professionals, at the baseline questionnaire, the prevalence of kidney stone disease was almost two-fold higher in men with a history of gout compared to those without (15% vs 8%). After excluding men who reported a history of kidney stone disease or gout on the baseline questionnaire, the prospective investigation showed that a confirmed diagnosis of gout increased the multivariate relative risk of incident kidney stones. In contrast, a history of kidney stone disease was not associated with an increased risk of gout. 16

17. BMJ review 2018
Acute attack - likely to require treatment with a NSAID + PPI or colchicine
ULT is targeted to patients with recurrent attacks, tophi, urate arthropathy, or renal damage and to symptomatic patients with very high serum uric acid levels
Allopurinol is the first line option
Shared decision making about ULT
All patients taking ULT require regular monitoring of renal function and serum uric acid level to ensure that the dose is appropriate
For most, allopurinol 300 mg daily will be insufficient to achieve target serum uric acid reductions
Despite limited evidence, patients should be encouraged to manage their weight & increase exercise

18. EULAR recommendations 2016
General principles:
(a) Provide education
(b) Implement lifestyle interventions
(c) Screen for co-morbidities (esp CVD)
11 Recommendations:
Treat acute flare asap
1st line acute flare Rx Colchicine, others: NSAIDs, Steroids (PO/IA)
If frequent / recurrent flares: consider IL1 inhibitor
Prophylaxis against flares for 6 months (Colchicine / NSAIDs)
ULT should be considered in all patients with definite Dx esp those with recurrent flares, tophi, urate arthropathy and/or renal stones, CVD risk
With ULT, aim to reduce sUA to <360 µmol/L (<300µmol/L in higher risk cases)
ULT should be started at lower dose and titrated
In normal renal function, 1st line is Allopurinol 100mg / day, increase by 100mg every 2 -4 weeks until sUA target reached. Febuxostat and other medications
In renal disease, consider lower Allopurinol dose, switch to other agents
In patients with crystal-proven, severe debilitating chronic tophaceous gout and poor quality of life, Pegloticase is indicated
If diuretic used, consider losartan or calcium channel blockers; for hyperlipidaemia, consider a statin or fenofibrate

20. BSR Recommendations 2017

21. Lifestyle modifications
Diet
Reduce purine intake (reduce red meat, avoid liver, kidneys, shellfish and pulses)
Reduce fructose-containing drinks
Include skimmed milk, low fat yoghurt, vegetable protein and cherries
Vitamin C is uricosuric
Decrease alcohol consumption (especially beer)
Weight loss
1 kg/month (avoid crash diets)
Avoid high protein diets
Patients with urolithiasis should be encouraged to drink >2 litres of water/day
Moderate exercise
Since there is a clear relationship between diet and lifestyle and the development of hyperuricemia and gout, these disorders are often amenable to changes in diet, lifestyle, and medication. The lifestyle modifications recommended for the treatment or prevention of gout are similar to those for the prevention or treatment of other major chronic disorders. Thus, the net health benefits are expected to be even greater among patients with gout and coexisting insulin resistance syndrome, diabetes, obesity, hypertension and cardiovascular disease.
Given the unfavourable natural history of untreated gout, and the fact that lifestyle modifications are simple and inexpensive, this form of non-pharmacological urate-lowering therapy (ULT) should be initiated in every patient at presentation. However, non-pharmacological ULT usually needs to be combined with drug therapy to achieve maximum control of the disorder.

22. Goals of treatment Acute attacks:
Relieve pain rapidly and reduce inflammation
Non-pharmacological (coldpacks)
NSAIDs or Coxibs (Etoricoxib)
Colchicine
Corticocosteroids
There is no need to discontinue allopurinol during an acute attack
Never commence allopurinol during an acute attack
Long-term treatment (gout is curable by dissolving all crystals and preventing further crystal formation):
Prevent further acute attacks
Prevent joint damage
Eliminate tophi
The treatment of gout is divided into short-term resolution of acute attacks and long-term prophylactic and curative treatment.
The first line of treatment for acute attacks should be to relieve pain and reduce inflammation.
Long-term treatment, aimed at preventing future attacks and associated cumulative tissue damage as well as eliminating existing tophi, include reducing the production of uric acid, dissolving crystals of uric acid so that the uric acid can return to the blood, and increasing the excretion of uric acid from the blood into the urine.

24. Remove prophylactic therapy and maintain patient on ULT
Effective gout management
Initiate long-term urate-lowering therapy (ULT) plus prophylaxis (low-dose colchicine or NSAIDs)
Acute treatment
(NSAIDs, colchicine,
or steroids)
Remove prophylactic therapy and maintain patient on ULT
Asymptomatic
hyperuricaemia
1-2 gout attacks
(2 weeks)
(6 months)
(3 months)
(3 months)
(3 months)
(3 months)
Check initial sUA level
Check sUA level at 3-monthly intervals in first year, annually thereafter
If not below 360µmol/l,
Increase ULT

25. Allopurinol and renal failure
Estimated GFR ml/min/1.73 m2 
Allopurinol starting dose 
<5 
50 mg/week 
5–15 
50 mg twice weekly 
16–30 
50 mg every 2 days 
31–45 
50 mg/day 
46–60 
50 mg and 100 mg on alternate days 
61–90 
100 mg/day 
91–130 
150 mg/day 
>130 
200 mg/day 

26. Advances in Gout New drug targets
IL1 inhibitors – Canakinumab, Anakinra
New approaches to serum urate lowering
Uricases – Pegloticase, Raburicase
Lesinurad - selective, highly potent uric acid reabsorption inhibitor - CLEAR 1, CLEAR 2, CRYSTAL, LIGHT studies showed that Lesinurad + either Allopurinol or Febuxostat was more effective by as much as 2.5-fold
Arhalofenate - pipeline drug with a dual mechanism of action (ULT and anti- inflammatory effects)
New Guidance – ACR, BSR, EULAR
New genetics for screening
HLA-B*58:01 - predicts risk of reaction to Allopurinol (recommended in ACR guidelines for at risk populations)

27. Imaging Advances
Ultrasound
Duel-Energy CT (DECT)

28. Thank You
Now let’s go enjoy a drink!