Challenge in Management of Hyperuricemia and Goutmedinfo2.psu.ac.th/internalmed/med61/work/hotmed... · gout patients - Any alcohol use in gout during periods of frequent gout attacks,

Challenge in Management of Hyperuricemia and Gout

พญ.ปริฉัตร เอื้ออารีวงศา

พญ.สิริพร จุทอง

หน่วยโรคข้อและรูมาติสซั่ม ภาควิชาอายุรศาสตร์

คณะแพทยศาสตร์ มหาวิทยาลัยสงขลานครินทร์

Case 1

• ชายอายุ 40 ปี ได้รับการตรวจสุขภาพประจ าปี พบว่า serum uric acid = 8.0 mg/dL

• ผู้ป่วยมาปรึกษา เนื่องจาก• ผู้ป่วยกลัวว่าจะเป็นเกาต์ • สงสัยว่าต้องกินยาลดกรดยูริกหรือไม่ ต้องหลีกเลี่ยง

อาหารอะไรบ้าง• ท่านจะให้ค าแนะน าหรือให้การรักษาอย่างไร

ประวัติเพิ่มเติม

• ไม่เคยปวดข้อมาก่อน

• ไมม่ีโรคประจ าตัว

• ไม่มีประวัติโรคเกาต์ในครอบครัว

• ไม่เคยปัสสาวะผิดปกติ

• ดื่มสุราและสูบบุหรี่ตามงานเลี้ยง

• BP 130/85 mmHg

• BW 75 Kg, HT 170 cm (BMI 26)

• Physical examination: WNL

• Lab: Cr 0.9 mg/dl, UA normal

Asymptomatic Hyperuricemia

Hyperuricemia

• Physiochemical definition, ≥ 6.8 mg/dl

• Statistical definition, ≥ 7 mg/dl for men and ≥ 6.0 for women

• Clinically relevant definition, ≥ 6 mg/dl

NH

NHNH

NH

O

O

O

Asymptomatic Hyperuricemia

Hyperuricemia without symptoms or signs of MSU crystal deposition disease, such as gout, or uric acid renal disease

Urate crystal deposition disorders

• Gout

Consequence of hyperuricemia



• Gout

• Urate nephropathy Deposition of sodium urate crystals in the medullary interstitium induced chronic inflammatory response, potentially leading to interstitial fibrosis and chronic kidney disease.

CluesHyperuricemia out of proportion to the degree of renal insufficiency • Uric > 9 mg/dl if Cr <1.5 mg/dl • Uric > 10 mg/dl if Cr 1.5 - 2 mg/dl• Uric > 12 mg/dl if Cr > 2 mg/dl


• Gout

• Urate nephropathy

• Acute uric acid nephropathy

Most often seen in patient with lymphoma, leukemia, or myeloproliferative disease, particularly after chemotherapy or radiation has induced rapid cell lysis.

Serum uric acid > 15 mg/dL



• Gout



• Nephrolithiasis

Incidence of urolithiasis ~50% in patients in whom urinary uric acid excretion > 1100 mg/dayRisk of nephrolithiasis • Hyperuricemia• Hyperuricosuria • Low urine volume• Low urine pH



• Gout



• Nephrolithiasis

Non-crystal deposition disorders

• Chronic kidney disease

• Hypertension

• Cardiovascular disease

• Insulin resistant


Hyperuricemia is an independent risk factor of

• All cause mortality

• Cardiovascular mortality

• Stroke mortality

• Cardiovascular events

• Progressive nephropathy

• Allograft dysfunction


Asymptomatic hyperuricemia: treat or not treat?

No universal agreement but expert recommended

• No treatment with specific anti-hyperuricemic agents until

symptoms develop.

• Rare exceptions include

• Hereditary cause of uric acid overproduction

• Patients at risk for acute uric acid nephropathy (tumor lysis syndrome)

11

Expert opinion

Marked hyperuricemia

Serum urate level > 13 mg/dl in men , > 10 mg/dl in women

Marked hyperuricosuria

Urinary uric acid excretion > 1100 mg/day

Asymptomatic hyperuricemia: treat or not treat?

No universal agreement but expert recommended

• No treatment with specific anti-hyperuricemic agents until

symptoms develop.

• Rare exceptions include

• Hereditary cause of uric acid overproduction

• Patients at risk for acute uric acid nephropathy

• Causes and associated factors should be addressed.

• Secondary hyperuricemia

• Obesity, hyperlipidemia, alcoholism, and especially hypertension

12

Lifestyle modification – hyperuricemia / gout

Risk factorsDirection of risk

Risk of hyperuricemia Risk of goutAdiposity

BMIWaist-to-hip ratioWeight gain

Purine-rich foodsMeatsSea foodsPurine-rich vegetables/nuts

ND

Alcohol (beer, liquor)

Fructose Sugar-sweetened beveragesSweet fruits/fruit juices

Coffee/decaffeinated coffee

Dairy productsLow-fat dairy productsHigh-fat dairy products

ND

Vitamin C supplements

Cherry ND NDOmega-3 fatty acid ND ND

Case 1: Hyperuricemia

• Symptomatic vs Asymptomatic

• Identify risk factor of hyperuricemia, comorbidity

• Life style modification

• No indication of Urate lowering agent

Case 2

ชายอายุ 45 ปี ปวดข้อเท้าซ้ายมา 2 วัน เดินกะเผลก

PE: BW 90 kg, height 165 cm, afebrile

Left ankle : redness, swelling , tender

โรคประจ าตัว : ไม่มี

Case 2 ประวัติเพิ่มเติม

ชายอายุ 45 ปี ปวดข้อเท้าซ้ายมา 2 วัน

เคยมีอาการปวด บวมที่ข้อเท้า ข้อโคนนิ้วเท้าเป็นๆหายๆ ซื้อยาแก้ปวดกินเอง ครั้งละ 2-5 วัน มา 3 ปี ช่วงแรกเป็นปีละ 1-2 ครั้ง ปีก่อนเป็นมา 3 ครั้ง

เคยตรวจเลือดพบกรดยูริกสูง = 9 mg/dL เมื่อปีที่แล้ว

Clinical features of gout

New onset gout Long standing gout

Typical patients Hyperuricemia, men aged > 30 ypostmenopausal women

Elderly men or women

Onset of attacks Acute Acute, subacute, or chronic

Joint distribution Monoarthritis Monoarthritis, oligoarthritis, or polyarthritis

Joint affected Toe (especially 1st MTP), mid foot, ankle

Any joint but especially digits, mid foot, ankle, knee, wrist

Symptom duration 3 to 5 days, self-limited 5 days to weeks

Associated findings Fever, elevated white blood cell count, elevated inflammatory markers

Tophi

2015 ACR/EULAR gout classification criteria

Entry criterion:

At least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa

Sufficient criterion:

Presence of MSU crystals in a symptomatic joint or bursa or tophus

Clinical, Laboratory, and Imaging criteria (score ≥ 8)

Clinical criteriaClinical Categories Score

Pattern of joint/bursa involvement during symptomatic episode(s)

•Ankle or mid-foot•1st MTP joint

12

Characteristics of symptomatic episode(s) ▸ Erythema overlying affected joint ▸ Can’t bear touch or pressure to affected joint▸ Great difficulty with walking or inability to use

•1 characteristic•2 characteristics•3 characteristics

123

Time course of typical episode(s) Presence of ≥ 2, ▸ Time to maximal pain <24 hours▸ Resolution of symptoms in ≤14 days▸ Complete resolution between episodes

•1 typical episode•>1 typical episodes

12

Clinical evidence of tophus •Present 4

19

Neogi T, et al. Ann Rheum Dis 2015;74:1789–1798

Laboratory criteria

Laboratory Categories Score

Serum urate: Measured by the uricase method. Ideally should be scored at a time when the patient was not receiving urate-lowering treatment and it was >4 weeks from the start of an episode

•<4 mg/dL •6–<8 mg/dL •8–<10 mg/dL •≥10 mg/dL

- 4234

Synovial fluid analysis of a symptomatic (ever) joint or bursa (should be assessed by a trained observer)

•MSU negative - 2

20


Imaging criteria

Imaging Categories Score

Imaging evidence of urate deposition in symptomatic (ever) joint or bursa: Ultrasound evidence of double-contour sign or DECTdemonstrating urate deposition

•Present (either modality) 4

Imaging evidence of gout-related joint damage: Conventional radiography of the handsand/or feet demonstrates at least 1 erosion

•Present 4

21


What is the treatment for acute flare?

• Colchicine (within 12 hours of flare onset) at a loading dose of 1.2 mg followed 1 hour later by 0.6 mg on day 1 following by prophylaxis dose (0.6 mg once or twice daily)

and/or

• NSAID (plus proton pump inhibitors if appropriate)

• Oral corticosteroid (30–35 mg/day of equivalent prednisolone for 3–5 days)

• Articular aspiration and injection of corticosteroids.

Safety concern • Colchicine 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 clarithromycin or cyclosporin

• NSAIDs : • Efficacy traditional NSAIDs = COX2 inhibitor • renal, cardiovascular and GI safety

What is the appropriate long term treatment?

• Non pharmacologic

• Pharmacologic

Comorbid checklists for gout patients

• Obesity, dietary factors

• Excessive alcohol intake

• Metabolic syndrome, type 2 diabetes mellitus

• Hypertension

• Hyperlipidemia, modifiable risk factors for coronary artery disease or stroke

• Serum urate–elevating medications

• History of urolithiasis

• Chronic kidney, glomerular, or interstitial renal disease (e.g., analgesic nephropathy, polycystic kidney disease)

• In selected cases, potential genetic or acquired cause of uric acid overproduction (e.g., inborn error of purine metabolism or psoriasis, myeloproliferative, or lymphoproliferative disease, respectively)

• Lead intoxication

- Weight loss for obese patients, to achieve BMI that promotes general health

- Healthy overall diet

- Stay well hydrated

- Exercise (achieve physical fitness)

- Smoking cessation

General health, diet and life style measures for gout patients

Avoid Limit Encourage

Organ meats high in purine content(eg. Sweetbreads, liver, kidney)

Serving sizes of- beef, lamb, pork- Seafood with high purine content (eg.

Sardine, shellfish)

- Low fat or non-fat dairy produced

High fructose corn syrup-sweetened sodas, other beverages, or foods

- Serving of naturally sweet fruit juices - Table sugar, and sweetened beverages

and desserts- Table salt, including in sauces and

grevies

- Vegetables

-alcohol overuse (defined as more than 2 servings per day for male and 1 serving per day for a female) in all gout patients- Any alcohol use in gout during periods of frequent gout attacks, or advanced gout under poor control

- Alcohol (particularly beer, but also wine and spirits) in all gout patients

General health, diet and life style measures for gout patients

B B B

C C C

B

BC

ACR Guidelines for Gout Management: Part 1

Grade of EvidenceLevel A Supported by multiple randomized clinical trials or meta‐analysisLevel B Derived from a single randomized trials, or nonrandomized studiesLevel C Consensus opinion of experts; case studies or standard of care


• แพ้ยา : allopurinol ผื่น คัน ทั้งตัว

• ดื่มเหล้าหรือเบียร์สังสรรค์ ปีละ 3-4 ครั้ง

• ไม่เคยปัสสาวะเปน็นิ่ว

• ปฏิเสธโรคประจ าตัว ไม่มียาที่กินประจ า

• Lab : Cr 0.8, uric acid 9, AST 12, ALT 10

Lowering the uric acid level is important

To

Prevent long-term joint damage and tophus development

Indication for pharmacologic ULT

Patient with establish diagnosis of gouty arthritis and

¤ Tophus or Tophi

¤ Frequent attack of acute gouty arthritis (≥2attack/yr)

¤ CKD stage 2 or worse

¤ Past urolithiasis

ULT could be considered : gout at age <40 years, uric acid levels > 8 mg/dL, or coexisting diseases such as HT, CVD, or HF

ACR2012, EULAR 2016

sUA saturation point : 6.8 mg/dL

Treat to target strategy

Set of uric acid target and maintaining

No TophiKeep <6 mg/dL

TophiKeep <5 mg/dL

Sustained uric acid levels lower than 3 mg/dL should be avoided

Urate-lowering treatment options

Xanthine oxidase

inhibitors• Allopurinol, Febuxostat

Uricosurics • Probenecid,

• Benzpromarone

Uricases • Pegloticase

ULT indicated

Start allopurinol 50-100 mg/d (50; if CrCl<30)

WITHProphylatic treatment

Slow titrate up to maximum allowed dose

Achieve target

continue

Allergy to allopurinol or HLA B*5801+

Start Febuxostator Uricosuric

Consider combined therapy (with uricosuric)

or Switch to

Febuxostat or Uricosuric

Refer to rheumatologist

yes

no

Can not achieve target

no attack 3-6 mo.Off prophylactic treatmentContinue ULT; FU q 6 mo.

Monitoring:- AE : rash, AHS*- SUA (q 1mo)- AST, ALT, Cr

(q 3-6mo)- Uricosuric : +Urine pH, stone

Adapted from ACR 2012

Initiate after gout flare was

controlled

Urate lowering agentsAllopurinol Febuxostat Probenecid Benzbromarone

กลไกการออกฤทธิ์

ลดการสร้างยูริก(XOI)

ลดการสร้างยูริก(XOI)

เพ่ิมการขับยูริกทางไต(uricosuric)

เพ่ิมการขับยูริกทางไต(uricosuric)

ขนาดยา 50-800 mg/d 40-80 mg/d 500-2000 mg/d 50-200 mg/d

ผลข้างเคียงที่ส าคัญ

ผื่นแพ้ยา 2%ชนิดรุนแรง <0.1%

Abnormal LFT นิ่วในระบบทางเดินปัสสาวะ

นิ่วในระบบทางเดินปัสสาวะhepatotoxicity

การติดตาม Serum urate, Cr, LFT Serum urate, Cr, LFT

Serum urate, Cr, ,Urine pH

Serum urate, CrLFT ,Urine pH

หมายเหตุ สามารถปรับขนาดยาเหนือกว่า ขนาดตามCrCl และมากกว่า 300 มก.ต่อวัน เพ่ือให้ได้เป้าหมาย ควบคู่กับการติดตามผลข้างเคียง

-การแพ้ยาเกิด ขึ้นซ้ าน้อย ในผู้ป่วยที่มีประวัติ AHS มาก่อน-มีข้อมูลความปลอดภัยในผู้ป่วยไตบกพร่องปานกลางถงึรุนแรง

Adequate hydration with keep alkalinized urine

Adequate hydration with keep alkalinized urine

• People with gout receiving at least (CrCL)-based allopurinol dose for ≥1 month and SU ≥6 mg/dL

• Continue current dose (control) vs Allopurinol dose escalation

• 12 months

• The Primary endpoints: reduction in SU & adverse events

• Baseline: mean urate 7.15 mg/dL, allopurinol dose 269 mg/day; 52% CrCL<60 mL/min

• Final visit: mean ∆ SU −0.34 mg/dL(control group) and −1.5 mg/dL (dose escalation group) (p<0.001) with a mean difference of 1.2 mg/dL (95%CI 0.67-1.5, p<0.001)

69%

32%

Safety : AE, SAE ( not difference), no cases of AHSMild elevations in LFTs were common in both groups *

Conclusions : Higher than CrCL-based doses of allopurinol can effectively lower SU to treatment target in most people with gout. Allopurinol dose escalation is well tolerated

Allopurinol hypersensitivity

Stamp LK, et al. Nature reviews Rheumatology. 2016;12(4):235-42.

AHS mortality 9-20%

Risk factors for AHS

Category Factor information

Time-relatedfactors

Recent commencement ofallopurinol

90% occurred within the first 180 days; Ramasamy et al. median time 3 wks, with 90% within 9 wks

Genetic factors HLA-B*58:01 ↑ risk of developing allopurinol-inducedDRESS, SJS/TEN (OR of 80–580)

Drug-concentrationfactors

Starting dose** Starting dose adjust by CrCl(Hande et al.1984, Stamp LK 2012, ACR 2012)Renal impairment

Diuretic therapy

Stamp LK, et al. Nature reviews Rheumatology. 2016;12(4):235-42.

HLA-B*5801 and AHS

• The frequency of HLA-B*5801 in Thailand is 8-16%

• Strong association between HLA-B*5801 and STS-TEN in Thai population OR 348.3 (95%CI 19.2-6336.9)

• HLA-B*58:01 & STS/TEN (OR 579), DRESS(OR 430), MPE (OR 144)

Tassaneeyakul W, et al. Pharmacogenetics and genomics. 2009Puangpetch A, et al. Frontiers in genetics. 2014

Saokaew S, et al. PloS one. 2014Sukasem C, et al. Frontiers in pharmacology. 2016

Can the risk of AHS be reduced?

Indication for ULT : NOT for Asymptomatic hyperuricemia

Screening for HLA-B*58:01 allele(high risk population-ACR2012)

Allopurinol should be avoided if HLA-B*58:01+

Modifying the dosing strategy : STARTING DOSE (adjusted by eGFR)

with monitoring AE ( if rash occured STOP allopurinol immediately)

Alternative ULT: febuxostat, uricosuric (if kidney function is not too bad)

‘tolerance induction protocol’ (Jung, J. et al.2015)

28-day allopurinol desensitization protocol

Uricosuric agents

• Second-line urate-lowering therapy

• CrCl check

probenecid eGFR must > 50 mL/min per 1·72 m²

benzbromarone must > 30 mL/min per 1·72 m²

• No KUB stone

• Adequate hydration

• Need monitoring and keep urine pH > 6

Anti-inflammatory prophylaxis during initiation of ULT

¤ Low dose colchicine (0.6-1.2mg/d, please adjust CrCl) or

¤ Low dose Non-steroidal anti-inflammatory drug

¤ third line: low dose corticosteroids (prednisolone ≤ 10 mg/d)

For …..

at least 6 months or

until 3 months after achieving target serum urate ( if no tophi) or

until 6 months after achieving target (if tophi+)


• ชายอายุ 45 ปี ปวดข้อเท้าซ้ายมา 2 วัน เดินกะเผลก

• PE: BW 90 kg, height 165 cm, left ankle arthritis

• แพย้า : allopurinol ผื่น คัน ทั้งตัว

• ดื่มเหล้าหรือเบียร์สังสรรค์ ปีละ 3-4 ครั้ง

• ไม่เคยปัสสาวะเปน็นิ่ว

• ปฏิเสธโรคประจ าตัว ไม่มียาที่กินประจ า

• Lab : Cr 0.8, uric acid 9, AST 12, ALT 10

ULT indicated

Slow titrate up to maximum allowed dose

Achieve target

continue

yes

no attack 3-6 mo.Off prophylactic treatmentContinue ULT; FU q 6 mo.

Monitoring:- AE : rash- SUA (q 1mo)- AST, ALT, Cr

(q 3-6mo)- Uricosuric : +Urine pH, stone

Adapted from ACR 2012

Gout with Hxallopurinol-MP rash

Attack ≥ 2 times/yr Cr 0.8

If KUB stone+, CrCl<30Febuxostat Uricosuric

Case 3

•ชายอายุ 70 ปี admit มาท า CAG ระหว่างนอน รพ.มีอาการปวดข้อเข่าขวา และมีไข้ 2 วัน • โรคประจ าตัว : เบาหวาน ความดันโลหิตสูง ไขมันสูง

• ผู้ป่วยเคยมีอาการปวด บวมที่ข้อเท้า ข้อเข่า เป็นๆ หายๆ มา 10 ปี ซื้อยาแก้ปวดกินเอง

• ยาเดิม: Metformin, HCTZ, simvastatin

• PE: T 38.5 C , BP 110/60 mmHg P 100/min

• Left knee arthritis

• Lab : Cr 2.2, eGFR 25

ชายอายุ 70 ปี admit มาท า CAG ระหว่างนอน รพ.มีอาการปวดข้อเข่าขวา และมีไข้ 2 วัน

Synovial fluid analysis

• WBC 25,000 cell/mm3, N 95% L 5%

• Many intracellular and extracellular MSU crystals were found.

• Gram stain : no organism

Management

• Acute gouty arthritis in CKD with CVD

X NSAIDs

Colchicine low dose

Systemic steroid or intra-articular steroid

• Long term management; CKD (eGFR 25) with CVD

Indication ULT: frequent attack

ULT: allopurinol (high risk AHS), HLA B*5801+

if negative try allopurinol, if positive febuxostat;

no benefit of uricosuric agent

Allopurinol low dose : 50 mg/d + monitor rash

Colchicine prophylaxis : colchicine dose adjusted CrCl

Monitor SUA +AE and Titrate ULT until reach target

Management

Documents

Challenge in Management of Hyperuricemia and Goutmedinfo2.psu.ac.th/internalmed/med61/work/hotmed... · gout patients - Any alcohol use in gout during periods of frequent gout attacks,