Gout 2017 by Prof. Professor Sukhbir Uppal Consultant in Medicine/Rheumatology, University Hospital Sharjah, UAE
1. Welcome
to
University Hospital Sharjah
Treating gout with
clinical guidelines
Professor Sukhbir Uppal
Consultant in Medicine/Rheumatology
MBBS,MD, FRCP(UK), FACR (USA)
University Hospital Sharjah, UAE
3. Aims and objectives
• Using the 2016 Eular guidelines as a framework, this
presentation aims to achieve the following
objectives:
– Patient education
– Screening for co-morbidities
– Flare treatment and prophylaxis
– Urate lowering therapy
– Management of asymptomatic hyperuricemia
4. Introduction
• New drugs and new evidence concerning the
use of established treatments have become
available over the last 10 years for the
management of gout.
5. Rheum Dis Clin North Am. 2014 May; 40(2):
155–175.
Increasing incidence of gout in
men and women with serum
urate level
7. Barriers
• Recent studies report that less than half of the
patients with gout receive ULT , and if
prescribed, often at an insufficient dose
• 90% of pts with gout are poorly controlled or
improperly managed
• Full patient education increased adherence to
ULT, leading to a high rate (92%) of effectively
treated patients at 12 months
Rheumatology (Oxford) 2013;52:1623–9; Ann Rheum Dis 2012;71:1490–5.
Ann Rheum Dis 2013;72:826–30; F1000Res. 2017 Mar 10;6:247
8. Overarching principles
• Patient education: GOUT IS CURABLE
• Every person with gout should receive
advice regarding lifestyle:
– Weight loss
– Avoidance of alcohol (especially beer and spirits)
and sugar-sweetened drinks, heavy meals and
excessive intake of meat and seafood.
(Low-fat dairy products, coffee, Vit C are
protective)
• Regular exercise
9. Dietary Factors That Can
Contribute to Hyperuricemia
• Animal sources:
• • Red meat (beef, lamb, pork)
• • Meat extracts (broth, gravy)
• • Organ meats (e.g., sweet breads, liver, and
kidney)
• • Seafood with high-purine content (e.g.,
sardines, anchovies, shellfish (shrimp, lobster)
• Alcohol
• High-fructose corn syrup–sweetened beverages,
sodas
18. Comorbidities
• Every person with gout
should be systematically
screened for associated
comorbidities and
cardiovascular risk
factors:
(Hyperuricaemia and/or
gout are independent
risk factors for these
conditions and for
death due to CV causes)
– Renal impairment
– Coronary heart disease
– Heart failure
– Stroke
– Peripheral arterial
disease
– Obesity
– Hyperlipidaemia
– Hypertension
– Diabetes
– Smoking,
HR for total and CV mortality: 1.42 and 1.58
QJM. 2013;106(7):647-58
19. Metabolic syndrome
• Amongst individuals with gout the prevalence
of metabolic syndrome IS 62.8%, compared
with 25.4% among those without gout (age-
adjusted and sex-adjusted OR = 3.05, 95% CI =
2.01, 4.61).
Arthritis Rheum. 2007;57(1):109-15
21. Treatment of acute flares
• Acute flares of gout should be treated as early
as possible.
• Pill in pocket approach: Patient to self-
medicate at the first warning symptoms.
• The choice of drug (s) should be based on:
– presence of contraindications
– patient’s previous experience with treatments
– time of initiation after flare onset
– number and type of joint(s) involved.
22. Conventional Teaching
• Acute gout flares are treated with 1 tablet of
colchicine hourly until the patient develops
diarrhea or gets better.
22
23. 23
AGREE study: Acute Gout Flare
Receiving ColchicinE Evaluation
• High vs. Low Dose Colchicine for Gout Flare
• Randomized, double-blind, placebo-controlled
study
• Low dose colchicine (1.8mg total over 1 h) 3 tabs
• High dose colchicine (4.8mg total over 6 h) 8 tabs
• Primary end point: >50% pain reduction in 24
hours
• 184 patients intent-to-treat analysis
Terkeltaub, RA., et al. Arthritis Rheum 2010.
24. 24
AGREE study: Acute Gout Flare
Receiving ColchicinE Evaluation
Colchicine
Dose
% >50%
reduction in
pain
P value vs.
placebo
Adverse
Event Rate
% needing
rescue
medications
High dose 32.7% 0.034 76.9% 34.6%
Low dose 37.8% 0.005 36.5% 31.1%
Placebo 15.5% n/a 27.1% 50.0%
Adverse Events High Dose Low Dose Placebo
All GI Events 76.9 25.7 20.3
Diarrhea 76.9 23.0 13.6
Nausea 17.3 4.1 5.1
Vomiting 17.3 0 0
Terkeltaub, RA., et al. Arthritis Rheum 2010.
25. Acute flares
Options:
• Colchicine (within 12 hours of flare onset) at
a loading dose of 1 mg followed 1 hour later
by 0.5 mg
• NSAID (plus proton pump inhibitors if
appropriate)
• Oral corticosteroid (30–35 mg/day of
prednisolone for 3–5 days)
• Joint aspiration and injection of
corticosteroids
• IL-1 blocker
26. IL-1 Blocker
• In patients with frequent flares and
contraindications to colchicine, NSAIDs and
corticosteroids, IL-1 blockers should be
considered for treating flares.
• Current infection is a contraindication to the
use of IL-1 blockers.
Ann Rheum Dis
2012;71:1839–48.
27. Multiple steps in the inflammatory cascade initiated by
monosodium urate (MSU) crystals.
Alexander So, and Nathalie Busso Ann Rheum Dis 2009;68:1517-1519
28. Figure 2. Activation of the NLRP3 inflammasome and the production IL-1β.
Igel TF, Krasnokutsky S and Pillinger MH 2017 [version 1; referees: 2 approved] F1000Research
2017, 6:247 (doi: 10.12688/f1000research.9402.1)
29. Flare Prophylaxis
• Prophylaxis recommended during the first 6
months of ULT.
• Recommended prophylactic treatment:
– Colchicine, 0.5–1 mg/day
– If colchicine not tolerated or contraindicated,
NSAIDs at low dosage, e.g. naproxen 250 mg bid
30. Urate lowering therapy
• ULT indicated from first presentation in.
– Recurrent flares
– Tophi
– Urate arthropathy and/or renal stones
– Patients presenting at a young age (<40 years)
– Very high SUA level (>8.0 mg/dL; 480 mmol/L)
– Comorbidities (renal impairment, hypertension,
ischaemic heart disease, heart failure)
32. ULT: target
• TREAT TO TARGET: SUA <6 mg/dL (360 mmol/L)
• Lower SUA target (<5 mg/dL; 300 mmol/L) for
patients with severe gout
• SUA level <3 mg/dL not recommended
• All ULTs to be started at a low dose and then
titrated upwards
• SUA <6 mg/dL (360 mmol/L) should be
maintained lifelong.
34. 34
Oxypurinol
• Oxypurinol, allopurinol metabolite, cleared by kidney and
accumulates in patients with renal failure
• Increased oxypurinol related to risk of allopurinol
hypersensitivity syndrome
allopurinol oxypurinol
Xanthine
Oxidase
Stevens-Johnson
Syndrome
Allopurinol
Hypersensitivity
Syndrome
Toxic Epidermal
Necrolysis
35. 35
Allopurinol and Renal
Insufficiency
• 1984 Hande, et al published “Severe
allopurinol toxicity: Description and
guidelines for prevention in patients with
renal insufficiency”
– “Avoidance of allopurinol or use of reduced doses in
patients with renal insufficiency according to proposed
guidelines should be adequate to inhibit uric acid
production in most patients and may reduce the
incidence of life-threatening allopurinol toxicity.”
Hande KR, et al. Am J Med, 1984.
36. CrCl (mL/min)
Maintenance Dose of
Allopurinol
0 100mg every 3d
10 100mg every 2d
20 100mg
40 150mg
60 200mg
80 250mg
100 300mg
120 350mg
140 400mg
Maintenance Doses of Allopurinol
for Adults based on CrCl
36Hande KR, et al. Am J Med, 1984.
Stage 1 renal damage with normal GFR
(GFR > 90 ml/min)
Stage 2 Mild CKD (GFR = 60-89 ml/min)
Stage 3 Modererate CKD (GFR = 30-59 ml/min)
Stage 4 Severe CKD (GFR = 15-29 ml/min)
Stage 5 End Stage CKD (GFR <15 ml/min)
37. Allopurinol Hypersensitivity Syndrome
• 2% of all allopurinol users develop cutaneous rash
• Severe cutaneous adverse drug reactions (SCARs) including
Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) rare but serious.
• 20% mortality rate
• Strong association with HLA-B*58.01 (>100-fold) risk
• Life threatening toxicity: vasculitis, rash, eosinophilia,
hepatitis, progressive renal failure
• Treatment: early recognition, withdrawal of drug, supportive
care
– Steroids, N-acetyl-cysteine, dialysis prn
37
Markel A. IMAJ, 2005.
Terkeltaub RA, in Primer on the Rheumatic Disease, 13th ed. 2008.
38. Allopurinol in CRF
• 1st T2T RCT
• Gout patients on CrCL-
based allopurinol dose
for ≥1 month and SU
≥6 mg/dL recruited
• Randomised to
continue current dose
(control= 93) or
allopurinol dose
escalation (n=90) for 12
months.
• At month 12, 32% of
controls and 69% in the
dose escalation had SU
<6 mg/dL.
• There were 43 serious
AEs in 25 controls and
35 events in 22 dose
escalation participants.
Ann Rheum Dis. 2017 Mar 17. pii:
annrheumdis-2016-210872. doi:
10.1136/annrheumdis-2016-210872.
[Epub ahead of print]
39. ULT
• With normal RFT, start allopurinol at 100
mg/day
• Increase by 100 mg increments every 2–4
weeks if required.
• If SUA target not reached, switch to febuxostat
+ uricosuric
40. 40
Allopurinol vs. Febuxostat
Allopurinol Febuxostat (Uloric)
FDA-approved 1966 FDA-approved 2009
Purine-selective XO Inhibitor Non-Purine Selective XO
Inhibitor
Prevents uric acid production Prevents uric acid production
Renal Metabolism Liver Metabolism
41. Uricosurics
• Uricosurics are recommended, where
available, alone or in combination with
allopurinol in patients without proper control
with allopurinol alone
• Benzbromarone (50–200 mg/day) is a more
potent uricosuric as compared with
probenecid (1–2 g/day).
42. Lesinurad
• Uricosuric
• Uric Acid Transporter 1 (URAT1) Inhibitor
• URAT1 is responsible for the majority of the
reabsorption of filtered uric acid from the
renal tubular lumen
Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7
44. Trials
• The regulatory approval of lesinurad is based on
three RCTs - CLEAR 1, CLEAR 2, and CRYSTAL
• Arthritis Rheum 2014;66:3533-4.
• Ann Rheum Dis 2015;74 Suppl 2:778
FDA approval Dec 2015
European approval 2016
45. Effect of Lesinurad in Allopurinol-
refractory Gout
• Investigated in combination with allopurinol or with
febuxostat versus either agent in monotherapy
– Doses studied: 200 mg: in combination with stable
allopurinol 200 – 600 and febuxostat 40 and 80
– Lesinurad was found to be:
• Very effective at achieving normal SUA levels in combination
with allopurinol or febuxostat
– Febuxostat combination better than the allopurinol combination
– Patients receiving concomitant HCTZ fared better than those not
receiving HCTZ
Perez-Ruiz F, et al. Ann Rheum Dis 2016;0:1–7
46. Clinical Application
• Dosing:
– 200mg by mouth daily with XAO
• Indications:
– Only in combination with a xanthine oxidase
inhibitor for the treatment of hyperuricemia
associated with gout
• Place in therapy:
– Patients who have not achieved target serum
uric acid levels with a xanthine oxidase inhibitor
alone
47. Contraindications
• Severe renal impairment, end stage renal
disease, and kidney transplant recipients
• Avoid in patients with CrCl < 45mL/min
• Can cause serum creatinine elevations
(generally reversible) – periodically monitor
• Tumor lysis syndrome or Lesch-Nyhan
syndrome
48. Severe and iatrogenic gout:
Pegloticase
• In patients with severe debilitating chronic
tophaceous gout and poor QOL, in whom the
SUA target cannot be reached with any other
available drug at the maximal dosage
(including combinations), pegloticase is
indicated.
• 8 mg, every 2 weeks
• Allergic reactions in 25%
49. Other drugs and gout
• Diuretics
• Antihypertensives
• Aspirin
50. Diuretics
• 91,530 cases of gout
• Loop and thiazide diuretics increase risk: OR
2.64, 1.70
• Calcium channel blockers or losartan
attenuate risk
Arthritis Rheumatol. 2014 Feb;66(2):427.
51. Antihypertensives
• RR of incident gout with current use of
antihypertensive drugs(n = 29,138)
• RR
– 0.87 for calcium channel blockers
– 0.81 for losartan
– 2.36 for diuretics
– 1.48 for Beta blockers
– 1.24 for ACE inhibitors
– 1.29 for non-losartan ARBs
BMJ. 2012 Jan 12;344
52. Gout with diuretics
• When gout occurs in a patient receiving loop
or thiazide diuretics, substitute the diuretic if
possible; for hypertension, consider losartan
or calcium channel blockers; for
hyperlipidaemia, consider a statin or
fenofibrate.
53. Take Home Points
• Patient education and partnership
• Advice regarding diet, weight loss, exercise
• Screening for co-morbidities
• Treatment of acute flare
• ULT and flare prophylaxis – treat to target
• Colchicine has FDA-approved dosing guidelines for chronic
kidney disease
• Allopurinol doses above recommended CrCl-based dose is
effective with minimal adverse effect
• Febuxostat is an excellent alternative for patients with renal
insufficiency
• Lesinurad is new approved uricosuric
56