1. 통풍 진단 및 치료의 최신지견
분당서울대학교병원
류마티스내과
하유정

2. Gout (통풍, 痛風) A clinical disease associated with hyperuricemia
Inflammatory reaction caused by the deposition of monosodium urate (MSU) crystals in and around the tissues of joints
Also non-articular (soft tissue): tophi, urolithiasis
“Punch cures the gout, the colic, and the ‘tisick” (anonymous). Historical sterotypes of gout persist and can act as barriers to adequate care.

3. Uric acid pool Metabolism of uric acid and risk factors for gout
Nat Rev Rheumatol. 2014;10:271-62

4. Hyperuricemia Definition : serum uric acid (SUA) ≥ 7.0 mg/dL Exogenous
1/3
GI excretion
Purine rich diet
Alcohol (Beer)
2/3
Uric acid
Renal excretion
체내 urate pool
1200 mg/day
Glomerular filtration
Endogenous
(purine metabolism)
Proximal tubules
100% S1
98-100%, Reabsorption
Enzyme deficiency
Hematologic disease
Tissue hypoxia
Drugs S2
50%, Secretion
50% S3
40-45%, Reabsorption
5-10%

5. MSU crystal formation About 6.8 mg/dL in serum at 37ºC
Temperature (◦C) 20 28 36
5.0
10.0
Uric acid concentration (mg/dL)
Temperature
in the ankle joint
Ann Rheum Dis. 1983;42 Suppl 1:12-5
Curr Rheumatol Rep. 2014;16:400

6. Clinical features of gout
Podagra
Chronic tophaceous gout
Rapid onset
Excruciating pain
Resolve in 1-2 weeks
Site: lower limb - 1st MTP (m/c) - midfoot, ankle, knee - wrist, elbow, bursa (less common)
Mono-articular (esp. early course) ~ Oligo-articular
A through F, Radiographs of damage to joints due to gout. A, Erosions at the third proximal interphalangeal and fourth distal interphalangeal joints of the hand. B, Discrete punched-out lesion at the first metatarsophalangeal (MTP) joint. C, More advanced disease at the first MTP joint with periarticular tophaceous material. D, Erosion at the fifth MTP joint. E and F, Severe destruction with malalignment.
Radiograph of joint damage

7. Prevalence
Nat Rev Rheumatol. 2015;11:649-62

8. Change in gout prevalence according to the age and gender group
Gout in Korea
Prevalence per 100,000 persons
Gout prevalence in the NHIC database
Year
Change in gout prevalence according to the age and gender group
Age group
Prevalence ratio from 2001 to 2008
대한류마티스학회지. 2011;18:94

9. The Normative Aging Study Annual incidence of gout
Hyperuricemia & gout
High levels of uric acid increase the risk of clinically apparent gout
Serum UA level could be normal during acute attack
The Normative Aging Study
(2046 previously healthy men [initial average age 42] followed for 14.9 years)
Initial U.A level
Annual incidence of gout
≥ 9 mg/dL (n=141)
4.9%
7 – 8.9 mg/dL (n=1642)
0.5%
< 7 mg/dL (n=5249)
0.1%
Ame J Med 1987;82:421-6
Normal serum UA level in 43% during acute episode
Arthritis Rheum. 1977;20:
Ann Rheum Dis. 1997;56:696-7

10. Natural history of gout
~ 1 yr: 62%
1 ~ 2 yr: 16%
2 ~ 5 yr: 11%
5 yr ~ : 13%
Asymptomatic hyperuricemia
Asymptomatic MSU deposits
Intermittent flares
Chronic gout
Curr Opin Rheumatol 2014;26:181-91
Primer on the Rheumatic Diseases. 12th ed.

11. Gold standard in diagnosis of gout
Definitive Dx.: demonstration of MSU crystal in synovial fluid or tophus aspirate
Needle-shaped negative birefringence on compensated polarized microscopy (yellow, when parallel to the axis of compensator)
◈ Limitations
Poorly accessible to joint aspiration or polarizing microscope – small joints or non-expertise
MSU crystal identification is dependent on an operator (requires adequate training).
SF MSU crystals are present in some patients with asymptomatic hyperuricemia without over clinical features of gout.
MSU crystals may be present in patients presenting with joint inflammation due to concomitant rheumatic conditions such as septic arthritis.
Compensator axis
Nat Rev Rheumatol. 2014;10:271-62

12. Diagnostic criteria for gout
1963 Rome
1966 New York
1977 ACR
2010 Mexico
2010 Netherland
MSU crystal
sUA > 7 (M) or >6 (F)
Hyperuricemia
sUA > 5.88 (3.5)
Tophus
Tophus (13)
Attacks of painful joint swelling with abrupt onset and resolution within 2 wks
≥ 2 attacks of painful joint swelling with complete resolution within 2 wks
≥ 2 attacks of acute arthritis
Previous patient-reported arthritis attack (2)
Maximum inflammation within 1 day
Rapid onset of pain and swelling (less than 24 h)
Onset within 1 day (0.5)
Redness over joints
Joint erythema
Joint redness (1)
Complete termination of attack
H/O or observation of podagra
1st MTP joint pain or swelling
Podagra
1st MTP involvement (2.5)
Unilateral 1st MTP attack
Unilateral tarsal attack
Oligoarthritis attack
Mono and/or oligoarticular attacks
Asymmetrical swelling in a joint (x-ray)
Subcortical cysts without erosions (x-ray)
Rapid response to CCC (within 48 h)
Male sex (2)
HTN or ≥ 2 CVD (1.5)
≥ 2 criteria
≥ 2/4 criteria or MSU
≥ 6/12 criteria or MSU
≥ 4/8 criteria or MSU
Score > 8

13. Limitation of previous criteria
Lack of
Specificity
Classifiability
Robust validation
Ann Rheum Dis 2016;75:178-82

14. Advances in imaging modalities
Ultrasound
Dual-energy CT (DECT)
Rheumatology (Oxford) 2007;46:
Ann Rheum Dis 2012;71:

15. 2015 ACR/EULAR Gout Classification Criteria
Categories
score
CLINICA
Pattern of joint/bursa involvement
Ankle OR midfoot (mono-/oligo-) 1
1st MTP (mono-/oligo-) 2
Characteristics of episode(s) ever
One characteristic
Two characteristic
Three characteristics 3
Time-course of episode(S) ever
One typical episode
Recurrent typical episodes
Clinical evidence of tophus
Present 4
LAB
Serum Urate
6 - <8 mg/dL
8 - <10 mg/dL
≥ 10 mg/dL
IMAGE
Imaging evidence of urate deposition
Present (U/S DCS or DECT)
Imaging evidence of gout-related joint damage
Present (X-ray gouty erosion)
SUA<4: -4 / MSU-ve: -2
Maximum Total Score 23
Score ≥ 8 ⇒ High sensitivity (92%) and specificity (89%)
Arthritis Rheumatol. 2015;67:

16. Management of Gout General management Acute gouty arthritis
Urate-lowering therapy (ULT)
Prophylaxis
→ Based on ‘2012 ACR recommendations’
‘2016 EULAR recommendations’
Arthritis Care Res. 2012;75:
Ann Rheum Dis. 2017;76:29-42

17. Baseline recommendations
Patient education: appropriate diet & lifestyle
Weight loss
Avoidance of alcohol (esp. beer and spirits), sugar-sweetened drinks, heavy meals, and excessive intake of meat and seafood
Regular exercise
Consider secondary causes of hyperuricemia (“Co-morbidity Checklist”)
Consider elimination of non-essential prescription medications that induce hyperuricemia
Clinically evaluate gout disease burden (palpable tophi, frequency & severity of acute/chronic sx & signs)
Comorbidity checklist
Obesity, dietary factors
Excessive alcohol intake
Metabolic syndrome, Type 2 DM
Hypertension
Hyperlipidemia
Serum urate-elevating medications
History of urolithiasis
Chronic kidney, glomerular, or interstitial renal disease
In selected cases, potential genetic or acquired cause of UA overproduction
Arthritis Care Res. 2012;75:
Ann Rheum Dis. 2017;76:29-42

18. General health, diet and lifestyle measures
Arthritis Care Res. 2012;75:

19. Management of an acute gout attack
<2012 ACR recommendation>
Acute gouty arthritis attacks should be treated with pharmacologic therapy
To provide optimal care, pharmacologic treatment should be initiated within 24 hrs of acute gout attack onset
Ongoing pharmacological ULT should not be interrupted during an attack

20. Management of an acute gout attack
<2016 EULAR recommendation>
Acute flares of gout should be treated as early as possible. Fully informed patients should be educated to self-medicate at the first warning symptoms. The choice of drugs should be based on the presence of contraindications, the patient’s previous experience with treatments, time of initiation after flare onset and the number and type of joint(s) involved.
Recommended first-line options for acute flares are colchicine (within 12 hours of flare onset) at a loading dose of 1 mg followed 1 hour later by 0.5 mg on day 1 and/or an NSAID (plus PPI if appropriate), oral corticosteroid (30–35 mg/day of equivalent prednisolone for 3–5 days) or articular aspiration and injection of corticosteroids.
Colchicine and NSAIDs should be avoided in patients with severe renal impairment.
Colchicine should not be given to patients receiving strong P-glycoprotein and/or CYP3A4 inhibitors such as cyclosporin or clarithromycin.
Ann Rheum Dis 2017;76:29-42

21. Ann Rheum Dis 2017;76:29-42 Cyclosporin Clarithromycin Verapamil
Ketoconazole
Canakinumab
rilonacept
Ann Rheum Dis 2017;76:29-42

22. Choice of drugs for attack
Agents
Advantages
NSAIDs
Any NSAID is effective at the appropriate dose
Colchicine
(CCC)
Fast-acting control when used early (within 6-12 h)
Synergism with other agents
Able to abort flares during prodromal phase
Steroids
Useful with renal and/or GI contraindications to other therapies
Available via multiple routes (oral, IA, IM, IV)
Limitation
NSAIDs
CCC
Steroids
Gastropathy ○
Renal dysfunction
△ (GFR< 30mg/min)
CNS dysfunction
Fluid retention
Platelet inhibition
Impaired wound healing
Hyperglycemia
Flares after discontinuing

23. IL-1 blockade Anakinra Rilonacept Canakinumab (approved in Europe)
Ann Rheum Dis 2012;71:

24. Urate-lowering therapy (ULT)
Indications
[2012 ACR]
Tophus by clinical exam or imaging study
Frequent acute gout attacks (≥2/yr)
CKD stage 2-5 or ESRD
Past urolithiasis
[2016 EULAR] +
Young age (<40yrs)
Very high SUA level (>8 mg/dL)
Comorbidities
⇒ ULT should be started at a low dose and the titrated upwards the SUA target is reached. SUA target should be maintained lifelong.
Renal impairment, HTN, Ischemic HD, HF

25. Xanthine oxidase (XO) inhibitors
Mechanisms of ULT
Hypoxanthine
Allopurinol
Oxypurinol
Febuxostat
Xanthine oxidase (XO) inhibitors
Xanthine
Allopurinol
Oxypurinol
Febuxostat
Uricolytics
Uric acid
Probenecid
Benzbromrone
Losartan
Fenofibrate
Rasburicase
Pegloticase
Uricase
URAT1
Uricosuric agents
Allantoin
Renal excretion
Urinary excretion
URAT1, urate transporter 1 (SLC22A12)

26. XO inhibitors Characteristic Allopurinol Febuxostat Action Elimination
Nonspecific XOI
Specific XOI
Elimination
Renal
Hepatic
Daily dose
(50mg), 100~300 (900) mg
40mg, 80mg, (120mg)
DRESS/SCAR
Rare, but serious
(RF: Asian population, HLA-B*5801, renal impairment)
Extremely rare
Cautions
Severe renal impairment
Heart failure (NYHA class III or IV), hepatic failure, eGFR <30ml/min/1.73m2
Interactions
Cytotoxic drugs metabolized by XO (eg. azathioprine, mercaptopurine) Warfarin
Cytotoxic drugs metabolized by XO (eg. azathioprine, mercaptopurine)
Cost (1 tablet)
KW 26
KW 221

27. Adopting dose of allopurinol
British J Clin Pharmacol 2016;81:277-89

28. Febuxostat
Greater efficacy than allopurinol 300mg/day  more gout attacks during treatment
Extensive hepatic metabolism and renal function does not affect elimination.
Hepatotoxicity, diarrhea, nausea, headache

29. Uricosuric agent Probenecid Benzbromarone Typical maintenance dosemg mg
Route and schedule
Orally twice daily
Orally once daily
Half-life
3-8 hrs (500mg);
6-12 hrs (larger doses)
3 hrs (~30 hours for the active metabolite)
Primary site of metabolism
Liver
Liver (CYP2C9)
Primary sites of elimination
Liver and kidney
Limitations
Drug-drug interactions; limited efficacy in renal insufficiency
Safety concerns (several liver toxicity)

30. Benzbromarone
A potent inhibitor of URAT1 in proximal tubules  inhibits post-secretory reabsorption
100mg benzbromarone vs. 300mg allopurinol
Effective in moderate renal impairment (Ccr > 30 mL/min)
Contraindicated with tophi, stone hx, severe renal impairment, or in overproducers.
May cause urinary stone or hepatotoxicity

31. Pegloticase Mammalian recombinant uricase 2010 FDA approved RCT
42% 8mg biweekly infusion group achieved plasma UA < 6mg/dL vs. 0% in placebo
40% biweekly infusion group had complete resolution of ≥1 tophus vs 7% in PBO
Considered ‘3rd line’ in 2012 ACR & 2016 EULAR treatment guidelines
JAMA ;306:711-20
Arthritis Rheumatol. 2002;47:356-60

32. Other agent with uricosuric or anti-uricosuric effects
Estrogen
Losartan
Fenofibrates
Amlodipine
Statins
Diuretics
Salicylates
Cyclosporine
Pyrazinamide
Ethambutol
Substitute loop or thiazide diuretics if possible
HTN: losartan, CCBs
Hyperlipidemia: statin or fenofibrate

33. Tophi, chronic arthropathy, frequent attacks
SUA target
2016 EULAR
2012 ACR
2010 Japan
2007 BSR
6 mg/dL or
5 mg/dL
Tophi, chronic arthropathy, frequent attacks
요산 수치를 많이 낮추면 낮출수록 좋은가요?
Uric acid might protect against various neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis)
Does not recommend lowering continuously the SUA level to <3 mg/dL for several years
Am J Epidemiol ;169:1064-9
Am J Epidemiol ;166:561-7
Int J Geriatric Psychiatry. 2006;21:344-8

34. Ann Rheum Dis 2017;76:29-42

35. Prophylaxis
Anti-inflammatory prophylaxis against gout attcks is recommended when ULT is initiated (up to 6 months)
Low dose colchicine : colchin 0.6mg qd or bid
Interaction with strong P-glycoprotein and/or CYP3A4 inhibitors
Awareness of potential neurotoxicity and/or muscular toxicity in case of renal impairment or statin treatment
Low dose NSAIDs : NSAIDs half-dose or one-dose
eg.; naproxen 250mg bid
Low dose prednisolone : prednisolone 2.5~5mg/d

36. Prophylaxis
Arthritis Care Res. 2012;75:

37. How can we treat gout better?
Suboptimal treatment
Poor adherence
Not at target

38. Are we doing enough treatment?
Cumulative Probability of Eligibility and Receipt of Prescription for ULT
At 5 years
87% indication for ULT
57% had ever received
30% were on ULT
JAMA ;312:2684-6

39. Poor adherence
Drug adherence rates across 7 medical conditions from 2001 to 2004 in USA.
Medication possession ratio
80~100% ~79% ~59% ~39% ~19%
Pharmacotherapy. 2008;28:437-43

40. Poor adherence Continuing suboptimal management of gout in UK
Partially adherent
At 6 months
Adherent
Standardized % of patients on ULT
Adherence of ULT treated patients
At 12 months
Non-adherent
Ann Rheum Dis. 2015;74:661-7

41. Emerging therapeutics
ULT
Lesinurad: uricosuric (inhibits URAT1 and OAT4)
Ulodesine: PNP (purine nucleoside phosphorylase) inhibitor
Topiroxostat: novel XOI
Dual-acting: anti-inflammatory + ULT
Arhalofenate (PPARγ modulator) : uricosuric (inhibits URAT1, OAT4, OAT10), IL-1β inhibition
Anti-inflammatory therapies
Caspase inhibitors
Ther Adv Musculoskel Dis. 2016;8:145-59

42. Topiroxostat Novel XO inhibitor
RCT, 120mg/d is non-inferior to allopurinol 200mg in UA lowering
160mg/d effectively reduced SUA level in the hyperuricemic stage 3 CKD pt w or wo gout
Clin Exp Nephrol. 2014;18:876-84
J Clin Pharm Ther. 2016;41:290-7

43. Lesinurad Selectively inhibits renal UA resoption via URAT1 and OAT4
With allopurinol, lesinurad mg/d reduced sign and UA in gout
FDA licensed in Dec 2015
At dose 200mg in combination with XOI
Ann Rheum Dis. 2016;75:
Arthritis Rheumatol. 2017;69:203-12

44. Arhalofenate
Uricosuric (block UA reabsorption by inhibition of URAT1 & OAT) + anti-inflammatory (suppress local release of IL-1β)
Decrease sUA level
Decrease gout flares
Arthritis Rheumatol. 2016;68:

45. Summary Diagnosis Treatment
Not dependent only on serum UA levels
MSU crystal detection (but consider a false negativity) or based on clinical features ⇒ 2015 ACR classification criteria
Treatment
Management of comorbid conditions, Wt control, hydration
Avoid organ meats, high fructose beverages, and alcohol
Acute gout attack : NSAIDs, CCC, steroid
ULT + prophylaxis
Indication: tophi, frequent attacks, CKD, or urolithiasis (+ young age, very high SUA level, comorbidities)
Target: SUA levels < 5~6 mg/dL with long-term ULT
Curable disease, but inappropriately treated