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Recent therapy for
Gouty Arthritis
경희의료원 류마티스내과
홍승재
case
M/48
CC : pain in right big toe
Onset : 3 days ago, abruptly severe pain
Trauma Hx (-)
Medical Hx : self analgesics, temporary effect
2 times pain Hx. of big toe
but spontaneous subside
Q1. 이와 같은 증상을 보일 때, 가장
먼저 의심할 수 있는 질병은?
① Spondyloarthropathy
② Gout
③ Rheumatoid arthritis
④ Broken toe
P/E : BMI 31 kg/m2 with central obesity
Office worker, few exercise
Diet : mainly red meat, white breads, rice,
pasta, potato etc.
Alcoholic Hx. : Beer or non-diet soda/freq.
Asthma Hx. of childhood : intermittent dyspnea
or development wheezing at current
Family Hx. : Gout (father, retirement state)
Q2. 앞서 보인 환자의 임상 소견 중
통풍의 위험 인자가 아닌 것은?
① Diet
② Asthma
③ Alcohol consumption
④ Body Weight
What are the Risk Factors for Gout?
1. Genetic Factors
genetic variation within SLC2A9
1q21 region of chromosome 1
4q25 region of chromosome 4
estrogen receptor gene thymine-adenine
repeat polymorphism at chromosome 6q25.1
Updated urate transport model in human proximal tubule
incorporating the newly discovered urate transporters by GWAS
genome-wide association studies (GWAS)
Curr Opin Rheumatol.2010 Mar;22(2):144-51
What are the Risk Factors for Gout?
2. Hyperuricemia
Hyperuricemia : SU>6.8 mg/dL, limit of urate
solubility in serum
Associated with gout and increases the risk for
crystal deposition due to urate supersaturation
Asymptomatic hyperuricemia
= hyperuricemia without gout
Becker and Jolly, Rheum Dis Cilin North AM 2006;32:275-93
Plug & Martinez, Curr Opin Rheumatol 2008;20:187-91
Novak et al, Curr Med Res Opin 2007;23:623-30
Hyperuricemia results
Predominantly from:
Decreased
renal uric
acid
excretion
Alone or in
combination with:
Increased
uric acid
synthesis
hyperuricemia without
gout → direct positive
association between SU
and future risk of
developing Gout
Arthritis & Rheumatism 2007;57(7):1324–1328
What are the Risk Factors for Gout?
3. Medications
aspirin : high doses (>3 g/day, uricosuric)
: low doses (1-2 g/day, retention of uric acid)
diuretics : increased risk of gout
Ritonavir, Tacrolimus…
4. Metabolic Syndrome
obesity
hyperinsulinemia
hypertension
5. Diet and Alcohol
Medications as a risk for Gout
Current Opinion in Rheumatology 2011, 23:192–202
Prevalence of the metabolic syndrome according to
presence of gout in adults in the US
Prevalence estimates of comorbidities among
individuals with gout
Current Opinion in Rheumatology 2010, 22:165–172
Q3. 다음 음식 중 통풍 발생의
protective factor인 것은?
① Beer
② Dairy products
③ Red meat
④ Seafood
Lifestyle risk factors of hyperuricemia and gout
Current Opinion in Rheumatology 2010, 22:165–172
Gout risk and a healthy eating pyramid
Current Opinion in Rheumatology 2010, 22:165–172
Life-style modification – dietary:
Low purine diets are not palatable and not effective
Long term dietary recommendations should
take metabolic syndrome into account and be
planned appropriately
Diet becomes high in
carbohydrate and saturated fats
Increased serum urate
Increased risk of insulin
resistance syndrome
Restrict purine intake
BUT
High serum insulin levels
Low purine diet
Reduced renal excretion of urate
Increased serum urate
Choi et al, Am J Med; 120: 442-7
Q4. acute gout에서 가장 흔히
침범하는 관절은?
① Acetabulofemoral joint
② First metatarsophalangeal (MTP) joint
③ Radiocarpal joint
④ Third metacarpophalangeal (MCP) joint
Potential evaluations in a patient presenting
with gout symptoms
Clinical
Family history
Past history of similar events
Medication history
Diet, alcohol use
Metabolic syndrome
Past urolithiasis
Radiographic
Conventional radiographs of
involved joints
Ultrasonographic examination
of involved joints
Examination
Evaluate all joints
Vital signs
Look for tophi
Bursae, tendons
Laboratory
CBC
ESR and/or CRP
Urinalysis
Biochemistry
LFTs, Cr(eGFR), serum
urate
Am J Manag Care 2005;11:S435-42
Synovial fluid analysis for crystals
2 to 20 microns length, needle shaped monosodium urate (MSU) crystals
under compensated polarized light microscopy  “U pay peb”
Joint aspiration: Ideal vs practical
Ideal : Aspirated synovial fluid
Practical : primary care physicians & patients
are reluctant to do routinely
Practical recommendation
1. reasonable doubt → aspirate the joint
Especially gout or septic arthritis
2. preliminary 1977 ACR criteria
or EULAR ladder for acute gout
Ann Rheum Dis 2002; 61: 493-8
Ann Rheum Dis 2006; 65: 1301-11
ACR preliminary criteria
for the diagnosis of gout
~11% patients with suspected gout will undergo joint aspiration,
the ACR produced a set of clinical diagnostic criteria
Six or more of the minor criteria or 1 of the major criteria (tophus or
MSU crystals in synovial fluid) are needed for gout diagnosis
>1 attack of acute arthritis
Maximum inflammation developing within 1 day
Monoarthritis
If septic arthritis is
Redness over joint
suspected, carry out
Painful or swollen 1st MTP joint
joint aspiration
Unilateral attack on 1st MTP joint
immediately
Unilateral attack of tarsal joint
If pseudogout is
Tophus (proven or suspected)
suspected, also
aspirate the joint
Asymmetric swelling within joint on radiograph
Subcortical cysts without erosions on radiograph
Joint fluid culture negative for organisms during attack
Monosodium urate monohydrate microcrystals in joint fluid during
BMJ 2006; 332: 1315-9
attack
Arthritis Rheum 1977; 20: 895-900
EULAR:
Composite diagnostic ladder of gout
A composite approach can provide a more definite
diagnosis of gout
The probability of gout in a patient with “a rapidly
painful, swollen tender joint” is only 0.63%, but with
“erythema” this rise to 1.53% and to over 99% if a full
range of parameters are present
Ann Rheum Dis 2006; 65(10): 1301-11
Q5. 통풍 관절염이 의심되는 환자에서
관절 상태를 보기 위한 검사로
적절하지 않은 것은?
① Ultrasound
② CT/MRI
③ Arthroscopy
④ Plain film X-ray
Plain radiographs of
chronic gout
Current Opinion in Rheumatology 2009, 21:124–131
Gout by ultrasound
Rheumatology 2007;46:1116–1121
Dorsal Lo
Plantar Lo
Medial Lo
Sagittal MRI scan of the 5th MTPJ with
severe tophaceous gout
large tophus with low
signal on T1
variable signal on the short tau
inversion recovery sequence image
patchy enhancement of the tophus
with contrast
Current Opinion in Rheumatology 2009, 21:124–131
Dual-energy CT imaging of tophi in gout
multiple
urate deposits
urate crystal tophi
Nat Rev Rheumatol.2010 Jan;6(1):30-8.
Laboratory investigations
to consider for gout patients
Test
Clinical comment
Serum urate
Level may be normal in an acute gout
attack in up to 40~50% of patients
Complete blood count
Exclude myeloproliferative disorders
Increased WBC may suggest possible
septic arthritis
Renal function
Hyperuricemia occurs in approximately
50% of patients with CKD
Fasting lipids, glucose
and thyroid function
Hyperlipidemia, DM, hypothyroidism
associated with gout
Urinary uric acid
excretion
Uricosurics contraindicated in uric acid
overproducers
BMJ 2006;332:1315-9
Q6. 통풍과 감별해야 할 질병 중,
즉각적인 치료를 필요로 하는 것은?
① Pseudogout
② Rheumatoid arthritis
③ Osteoarthritis
④ Septic arthritis
Major consideration for differential
diagnosis in gout
Gout &
pseudogout
Septic arthritis
Involved joints • 1st MTP, knee
• Knee
Synovial WBC • 2,000~75,000/mm3
• >100,000/mm3
Synovial fluid • Crystal
examination
Radiologic
findings
• Swelling
• Gram
stain/culture(+)
• Effusion, normal
at early stage
Major consideration for differential
diagnosis in gout
Gout
Pseudogout
Sex ratio (M:F)
2-7:1
1:4
Frequent age
40-50
65-75
Frequent joint
1st MTP jt
Knee
Serum uric acid
High
Normal
Radiology
Erosion
Chondrocalcinosis
Crystal
MSUM
CPPD
Morphology
Needle
Small rod-like
Birefringence
Strong, negative
Weak, positive
Q7. 이 환자에서 급성발작을 완화하기
위한 1차 선택약은?
① ACTH
② NSAIDs
③ Colchicine
④ Intra-articular glucocorticoids
Therapeutic choices: Acute gout
Treat at earliest signs of an attack
NSAIDs and colchicine do not prevent MSU tissue deposits and
damage
NSAIDs
Mainstay acute attack
High dose first 24-48 hours
: Taper dose until dose subside
Caution – CHF, CKD, anticoagulation
therapy, ↓hepatic function
Corticosteroids
Useful in CKD or if NSAIDs/
colchicine contraindicated
Concern re-worsening glycemic
control in diabetes
Colchicine
Oral, 0.6mg tid for 1-2 days
Diarrhea and nausea
Avoid in renal/hepatic impairment
Multiple drug interactions
Used less commonly due to drug
toxicity
Other Options
Synthetic ACTH
IL-1 inhibitors
: canakinumab, rilonacept, anakinra
Am J Manag Care 2005;11:S451-8
Pharmacologic Management Options for Acute Gout Attacks.
N Engl J Med.2011 Feb 3;364(5):443-52
Mechanisms of Inflammation in Gout
N Engl J Med.2011 Feb 3;364(5):443-52
일주일 후 재방문
NSAID 사용 후 pain과 swelling 감소
WBC, ESR/CRP 감소
LFTs, BUN/Cr 정상, serum urate 7.5 mg/dL
Plain film X-ray: diffuse soft tissue swelling
Q8. 다음 중 이 환자의 재발을 막기
위해 가장 중요한 치료는?
① Lower WBC and CRP levels to within
normal range
② Ensure patient loses weight
③ Reduce serum urate level to ≤ 6.0 mg/dL
④ No action required at this time
Treatment options for therapeutic goal
Treatment of acute flares
NSAIDs
Acute
Colchicine
gout
Prednisolone
Intra-articular corticosteroids
Adrenocorticotropic hormone
IL-1 inhibitors
(canakinumab, rilonacept, anakinra)
Prophylaxis against acute flares
NSAIDs
Colchicine
IL-1 inhibitors
(canakinumab, rilonacept, anakinra)
Urate-lowering therapy for chronic gout
Xanthine oxidase inhibitors
(allopurinol, febuxostat)
Uricosuric agents
(probenecid, sulfinpyrazone, benzbromarone)
Pegloticase
Chronic
Gout
Nat Rev Rheumatol.2011 Feb;7(2):77-8
환자는 allopurinol 처방받아 복용시작함
100 mg once daily로 시작
4개월에 걸쳐 300 mg once daily까지 증량
요산 농도가 낮아지며 급성 발작이 발생할 수 있
어 예방적으로 NSAID도 함께 사용
4개월 후 재방문
그 사이 몇 차례 gout attack 발생
등과 하지에 rash 발생
serum urate < 6.0 mg/dL
CrCl 56 mg/day
Q9. 이 환자에게 allopurinol을 사용하
면서 발생할 수 있는 문제점은?
① Hypersensitivity
② Drug interaction
③ Poor patient compliance
④ All of the above
Allopurinol dose guidelines
Allopurinol FDA-approved at doses up to
800mg once daily
EULAR and FDA guidelines:
Start at 100mg once daily to avoid gout flares
Increase by 100mg once daily q 1~4 weeks until
target serum urate level reached
Divided allopurinol dose to bid at >300mg once
daily
FDA/NIH web page
Ann Rheum Dis 2006; 35: 1251-60
Q10. Allopurinol에 반응하지 않는 환자
의 경우 다음 중 어떤 요산 강하제를 사
용할 수 있는가?
① Probenecid
② Rasburicase
③ Febuxostat
④ All of the above
Treatment options – Chronic gout
Hypouricemic agent
• allopurinol, febuxostat
Uricosuric agent
• probenecid, sulfinpyrazone, benzbromarone
Uricase
• uricozyme, rasburicase, pegloticase
Pathways of uric acid metabolism and renal elimination, and
primary therapeutic sites of actions of gout medications
Allopurinol, Febuxostat
rasburicase,
pegloticase
probenecid,
benzbromarone,
RDEA594
Nat Rev
Rheumatol.2011
Feb;7(2):77-8
Lancet.2011 Jan
8;377(9760)
:165-77
Therapeutic algorithm for s-urate lowering in gout
Nat Rev Rheumatol.2011 Feb;7(2):77-8
PEG-uricase
: Puricase ®
Pegylated recombinant porcine-like uricase
Decrease immunogenicity relative to nonPEGylated uricase such as rasburicase
Assessed in clinical trials in patients with
treatment failure gout due to:
Uncontrolled hyperuricemia and ongoing symptoms
of gout despite ULT
Dose limiting adverse reaction to other ULTs
Optimal duration of therapy not yet
determined
Curr Rheumatol Rep 2007; 9: 258-64
Febuxostat :
Adenuric® (EU), Uloric ® (US)
Oral, once daily, selective xanthine oxidase
inhibitor
Minimal effect on other enzymes involved in
purine or pyrimidine metabolism
Primarily metabolized by oxidation and
glucuronidation in the liver
Minimal renal component of drug clearance
Mild / moderate renal and hepatic impairment
has little effect on PK or PD
Ann Pharmacother 2006; 40: 2187-94
FACT study: SU at last 3 visits
762 patients with gout and serum urate >8.0mg/dL
received febuxostat 80mg or 120mg qd or allopurinol
300mg qd for 52weeks
Prophylaxis against gout flares with naproxen or
colchicine during weeks 1-8
***
(n=251)
(n=255)
***
(n=250)
FDA approved dose
***p<0.001, febuxostat vs allopurinol
N Eng J Med 2005; 353: 2450-61
APEX study: Allopurinol and placebocontrolled efficacy study of febuxostat
28 week phase III randomized, double blind trial
1067 patients with gout and hyperuricemia
(sUA>8mg/dL) including those with renal impairment
*
*
FDA approved dose
*
n=
134
262
269
134
268
Higher proportions of patients with renal impairment
achieved serum urate < 6.0mg/dL in febuxostat group
vs allopurinol
Arthritis Rheum 2008;59:1540-8
FOCUS study:
Reduction from baseline SU at final visit
n=116; 59 patients completed 5 years of study
Reduction from baseline SUA (%)
FDA approved dose
n=
6
41
11
Rheumatology 2009; 48: 188-94
CONFIRMS trial: The urate-lowering efficacy and
safety of febuxostat of the hyperuricemia of gout
6 months randomized, double blind trial
2269 patients with gout and hyperuricemia (sUA>8mg/dL) including
those with renal impairment
subgroup
achieving
sUA <6.0
mg/dL at
Final Visit
a: P<0.001
Urate-lowering efficacy of febuxostat 80mg exceeded that of febuxostat
40mg and allopurinol (300/200mg).
In subjects with mild/moderate renal impairment, both febuxostat doses
were more efficacious than allopurinol and equally safe
Arthritis Res Ther.2010;12(2):R63. Apr 6.
IL-1 inhibition : anakinra and rilonacept
Ann Rheum Dis 2009;68;1517-1519
Pharmacologic Management Options for Hyperuricemia
Therapy in Gout
Pharmacologic Management Options for Hyperuricemia
Therapy in Gout
Update on gout:
new therapeutic strategies and options
The prevalence of gout has approximately doubled in the past two
decades, along with increases in its severity, treatment complexity
and refractoriness
These advances have the potential to improve risk stratification for
patients with incident gout and to optimize urate-lowering therapy
via pharmacogenomics
Evolution in the evidence base for allopurinol, colchicine and oral
glucocorticosteroid administration has validated improved and costeffective treatment strategies for most patients
Febuxostat and biologic agents in development (interleukin 1
inhibitors and pegloticase) represent substantial therapeutic
advances, particularly for severe, treatment-refractory gout, and
patients with comorbidities or intolerance to other drugs
Nat. Rev. Rheumatol. 6, 30–38 (2010)
Changing points of Harrison 18th
(gout part)
Radiographic Features
: Ultrasound, CT and MRI are being studied and are likely to
become more sensitive for early changes.
Treatment: Gout, Acute Gouty Arthritis
: One useful regimen is one 0.6mg tablet given every 8 h
with subsequent tapering. Intravenous colchicine has been
taken off the market….The most effective drugs are any of
those with a short half-life and include indomethacin, 25–
50mg tid; naproxen, 500mg bid; ibuprofen, 800mg tid; and
diclofenac, 50mg tid. Glucocorticoids given IM or orally.....
Based on recent evidence on the essential role of the
inflammasome and interleukin 1 (IL-1) in acute gout, anakinra
has been used and other inhibitors of IL-1 are under
investigation.
Changing points of Harrison 18th
(gout part)
Treatment: Gout, Hypouricemic Therapy
: the hyperuricemia cannot be corrected by simple means (…
decreased use of fructose-containing foods and beverages…).
Probenecid…increased gradually as needed up to 3g per day to
maintain a serum uric acid level <360mol/L (6mg/dL)….Patients
with mild cutaneous reactions to allopurinol can reconsider the use
of a uricosuric agent or take febuxostat, a new, chemically
unrelated specific xanthine oxidase inhibitor. Febuxostat is
approved at 40 or 80 mg once a day and does not require dose
adjustment in mild to moderate renal disease…..Colchicine should
not be used in dialysis patients and is given in lower doses in
patients with renal disease or with P gylcoprotein or CYP3A4
inhibitors such as clarithromycin that can increase toxicity or
colchicine. Pegloticase is a new urate-lowering biologic agent that
can be effective in patients allergic to or failing xanthine oxidase
inhibitors. New uricosurics are undergoing investigation.