Outline: Uric acid pathway Pharmacotherapy in Gout and ...Uric acid pathway Gout vs. hyperuricemia How to manage acute gout attack? Gout Chronic management of gout Hyperuricemia -Who

Pharmacotherapy in Gout and Osteoarthritis

Thitima Doungngern, PharmD, MPharm, BCPSFaculty of Pharmaceutical Sciences

Prince of Songkla University

การประชมุวชิาการ วทิยาลยัเภสชับําบัดแหง่ประเทศไทยเรื=อง Contemporary Review in Pharmacotherapy 2013

วันที= 17 มกราคม พ.ศ.2556

Outline:

� Uric acid pathway

� Gout vs. hyperuricemia

� How to manage acute

gout attack?

Gout

gout attack?

� Chronic management

of gout

� Hyperuricemia - Who

should be treated?

Purine synthesis

300-600 mg/d

PURINE

600 mg/d+ H+

Uric acid

GI tract 200 mg/d

• Mostly degraded by colonic bacteria

Urine 600 mg/d

Uric acid

1200 mg/d

Uric acid (pool)

1200 mg/d

• Glomerular filtration

• Proximal reabsorption and

secretionUrate transporters:

URAT1 (gene SLC22A12)

GLUT9 (gene SCL2A9)

URAT1 = urate/organic anion exchanger 1GLUT9 = glucose transporter 9

Gout & Hyperuricemia

� Hyperuricemia: uric acid level > 6.8 – 7.0 mg/Dl

� Chronic hyperuricemia � precipitation of MSU crystals

� + Predisposing factors e.g., trauma, surgery

Release of MSU crystals to joint space � inflammation

• Gout: presence of monosodium urate (MSU) crystals in joints, bones, and soft tissues

Hyperuricemia

Asymptomatic hyperuricemia(progressive MSU deposition)

Acute gouty arthritis

Intercritical (interval) gout

Gout

∼ 10-30%

Intercritical (interval) gout

Chronic recurrent gout

Tophaceous gout

http://health-fts.blogspot.com

Prevalence of Gout

� Male > Female

� Increase with age

Clin Rheumatol 2012;31:13-21

Clinical Presentation

• Arthritis, > 1 joint(s)

• Tophus or tophi

• Renal

• Urolithiasis


• Urolithiasis

• Chronic interstitial

nephropathy (rare)

Case

A 54 y/o male presents with extreme pain in his right toe that began overnight

PMH: HTN, CAD, MI, HLD, PUD and obesity

Current med: lisinopril 40 mg/d, ASA 81 mg/d, Current med: lisinopril 40 mg/d, ASA 81 mg/d, clopidogrel 75 mg/d, metoprolol 50 mg BID, famotidine 20 mg/d, simvastatin 40 mg/d, and fenofibrate 160 mg/d

SH: Drinks 2-3 cans of beer 5-7 night/weekEnjoy eating red meat, low-fat dairy products

almost daily

Which one of the following is the best way to diagnose the patient’s gout ?

A. Check joint for presence of monosodium urate

(MSU) crystals

B. Obtain synovial fluid gram stain and culture

C. Check serum uric acid concentration

D. Assess clinical symptoms

Criteria for diagnosis of gout

� Rome criteria (1963)

� New York criteria (1966)

American College of Rheumatology � American College of Rheumatology

preliminary criteria for gout (1977)

ACR preliminary criteria of diagnosis of acute gout

Meet at one of the following: � MSU crystals in synovial fluid during attack � Presence of proven tophous� At least 6 of the following criteria:

� More than 1 acute arthritis attack� Maximal inflammation developed within 1 day� Monoarthritis attack� Redness observed over joints� Redness observed over joints� First MTP joint attack � Unilateral first metatarsophalangeal joint attack � Unilateral tarsal joint attack� Suspected tophous� Asymmetric swelling within a joint on a radiograph � Subcortical cysts without erosions on a radiograph� Hyperuricemia � Synovial fluid culture negative for organisms during attack

Arthritis Rheum 1977;20:895-900.http://www.physio-pedia.com/Gout

metatarsophalangeal (MTP) joint

TophousTophous


Differential Diagnosis of Acute Gout

Diagnosis Synovial fluid finding

WBC /mm3

Gram stain/ culture

Synovial fluid crystal

Gout 2,000 –50,000

Negative MSU crystals(needle shaped, negative birefringence)negative birefringence)

Pseudogout 2,000 –50,000

Negative CPPD crystals(rhomboid shaped, weak positive birefringence)

Septicarthritis

> 50,000 Positive No crystals

MSU = monosodium urate, CPPD = Ca pyrophosphate dihydrate

Am Fam Phys 2007;76:801-808.

Monosodium urate (MSU) crystal

Needle shaped, negative birefringent crystals

Clev Clin J Med 2008;78:s17-s21.

Pseudogout

Calcium pyrophosphate dihydrate (CPPD) crystal

Rhomboid shaped, weakly positive birefringent crystal

Clev Clin J Med 2008;78:s17-s21.

IL-1ββββ

Clin Rheumatol 2012;31:13-21

Which one of the following is the best initial treatment regimen for the patient’s attack ?

A. Prednisolone 10 mg PO daily

B. Triamcinolone 20 mg IA into affected joint

C. Colchicine 1.2 mg PO, followed by 0.6 mg in 1

hour

D. Naproxen 500 mg PO BID

ACR 2012 Recommendations

Acute Gouty Arthritis

� Severity….based on self-reported pain (0-10 VAS)

Mild < 4Moderate 5 – 6 Severe > 7

� Extent… based on number of active joints

One or few small joints1 or 2 large joints (ankle, elbow, wrist, hip, shoulder)

Polyarticular (> 3 large joints or > 4 joints involving > 1 region)

Arthritis Care & Research 2012: 64:1431–1446.

Assess severity

Initial Therapy of Acute Gout AttackInitial Therapy of Acute Gout Attack

MonotherapyMild-moderate

Combination therapySevere

• NSAID + Colchicine• PO steroid + Colchicine• IA steroid + …..

* For acute gout if started w/in 36 hours of symptom onset

Monotherapy

NSAIDs/COX-2 inhibitor

Systemic corticosteroids

Colchicine*

• IA steroid + …..


NSAIDs/COXNSAIDs/COX--2 2 inhibitorsinhibitors

� All oral NSAIDs/COX-2 inhibitors are effective

� Low dose aspirin (75 – 150 mg/d) does not significantly

affect urate concentrations and should be continued if

required for cardiovascular prophylaxis

ACR 2012 recommendation

required for cardiovascular prophylaxis

� No consensus on the topical NSAIDs and IM ketorolac

for the treatment of acute gout


ColchicineColchicine

� Acute gout attack (within 36 hours of symptom onset)

� LD: 1.2 mg, then 0.6 mg 1 hour later

� MD (prophylaxis): 0.6 mg once or twice daily

– start 12 hours later, until gout attack resolved


� Avoid in patients with severe renal or hepatic impairment � bone marrow suppression or neuromyopathy

Colchicine dosing reduction: • CKD• CYP 3A4 and P-glycoprotein inhibitors


CorticosteroidsCorticosteroids

� Extent of joint involvement

� Oral prednisolone 0.5 mg/kg/day

� for 5 – 10 days and then stop OR

� for 2 – 3 days of full dose � taper for 7 – 10 days then


� for 2 – 3 days of full dose � taper for 7 – 10 days then stop

� 1-2 large joint(s): Intra-articular corticosteroids

� + oral corticosteroids/ NSAID/ colchicine

� Dose varies by the size of involved joint(s)


Inadequate

Inadequate Response of an Initial TherapyInadequate Response of an Initial Therapy

•< 20% improvement in pain score w/in 24 hours•< 50% improvement in pain score > 24 hours after initiating pharmacotherapy

Combination therapyInadequate response

Switch to another monotherapy

Combination therapy

Refractory to other agents+ IL-1 inhibitors (Ankinra 100 mg SC daily x 3 days)


Should Uric Lowering Therapy be Initiated?

� ACR 2012, recommend uric acid lowing therapy (ULT) for

gouty arthritis patients with one of the following:

� Tophus or tophi by clinical exam or imaging study

� Frequent acute gouty arthritis attacks (> 2 attacks/yr)

CKD stage 2 or worse� CKD stage 2 or worse

� Past urolithiasis (uric acid stone)

Target of serum uric acid after treatment < 6 mg/dL< 5 mg/dL may be needed to improve S/Sx


Case 2

A 48 y/o male was prescribed allopurinol 100 mg QD and colchicine 0.6 mg BID a few days ago because of 3 episodes of acute gout attack in the past year.

Recent Labs: uric acid 9.3 mg/dL SCr 1.1 mg/dL LFT-WNL

He presents to your pharmacy with redness, swelling, and He presents to your pharmacy with redness, swelling, and intense pain in his right foot about 12 hours. He tells you that he never taken colchicine. He states “I didn’t understand why I needed two medications, so I only took allopurinol. Now I wonder if I should even take allopurinol because it isn’t working.”

Which one of the following is the most appropriate intervention for this patient ?

A. Discontinue allopurinol and start and NSAIDs

B. Discontinue allopurinol and start and colchicine

C. Continue allopurinol and start and NSAIDs

D. Continue allopurinol and start and a corticosteroid

LongLong--Term Management of GoutTerm Management of Gout

� Initiate ULT 1 – 2 weeks after the inflammation of the acute attack has resolved

� ULT may precipitate gout attack

� Use prophylaxis against acute attacks when initiating ULT:ULT:

� Colchicine 0.6 – 1.2 mg/d for up to 6 months OR

� NSAIDs/COX-2 inhibitors (for not more than 6 weeks)

� Consider losartan and fenofibrate for HTN and hyperlipidemia respectively, for their modest uricouriceffects

Uric Lowering Therapy

Xanthine oxidase inhibitors • Allopurinol• Allopurinol• Febuxostat (not available)

Uricosuric• Probenecid• Benzbromarone• Sulfinpyrazone

Recombinant urate-oxidase enzyme• Pegloticase (not available)

Allopurinol Allopurinol

� Xanthine oxidase inhibitor

� 1st line therapy for hyperuricemia

� Dose:

� starting dose < 100 mg/day for any patient � starting dose < 100 mg/day for any patient

� 50 mg/day for CKD > 4

� gradually titrate every 2-5 weeks

� dose can be raised above 300 mg/day, even in

those with renal impairment

� Serious ADR: Allopurinol hypersensitivity syndrome

Allopurinol Hypersensitivity Syndrome

� Fever with rash is the most common clinical findings

� Severe cutaneous reaction may be found

� Mortality rate ∼ 20 – 25%

� HLA-B*5801 polymorphism� Han Chinese, Thai, Korean

http://www.cmaj.ca/content/182/5/476.full.pdf+html

Reported HLAReported HLA--B*B*5801 5801 for for allopurinolallopurinol--induced cutaneous ADRinduced cutaneous ADR

Race Reactions Selectivity

Han Chinese (Taiwan) SJS/TEN orDIHS/DRESS

51/51

Thai SJS/TEN 27/27

J Dermatol 2011;38:246-254.

Thai SJS/TEN 27/27

Caucasians SJS/TEN 15/27

Japanese SJS/TEN/DIHS 3/3

Japanese SJS/TEN 4/10

HLA-B*5801 Allele Frequencies

http://www.cmaj.ca/content/182/5/476/F5.large.jpg

HLA-B*5801 Testing

HLA-B*5801 testing

Positive Negative

Allopurinol-SJS/TEN 400 0Allopurinol tolerant 14,940 84,660Allopurinol tolerant 14,940 84,660

Predictive value 2.7% 100%

Pharmacogenomics. 2010;11:973-987.

� HLA-B*5801 is more evenly distributed among

difference ethnic group

� weaker association

HLB*5801 – Apply to Clinical Practice

� NOT routinely recommended as a screening tool

before starting allopurinol therapy

� Possible use to confirm the diagnosis

FebuxostatFebuxostat

� Dose: 40 – 80 mg/day� Gout flare prophylaxis is recommended when

initialing therapy� Can use in patient with HLA-B*5801 polymorphism� Thromboembolic events (MI, stroke) have been � Thromboembolic events (MI, stroke) have been

reported !! � DI: azathioprine, mercaptopurine (↑ level)

Probenecid

� Initial dose:

� 250 mg BID x 1 week � 500 mg BID

� Absent of gout attack for > 6 months � may gradually decrease dose to maintain normal uric acid level (< 6 mg/dL)decrease dose to maintain normal uric acid level (< 6 mg/dL)

� ? Subtherapeutic dose -- may inhibit renal urate secretion

Benzbromarone

� Inhibit proximal renal tubular urate reabsorption �↑ urinary urate excretion

� ↓ uric acid levels by 33–59% (dose-dependent)

� Usual dose: 50–200 mg PO daily

� Serious ADR: liver failure (require liver transplantation)

Sulfinpyrazone

� Dose � Initial: 100–200 mg BID for 1–3 wks � 200–400 mg BID � Absent of gout attack for > 6 months � may gradually

decrease dose to maintain normal uric acid level (< 6 mg/dL)

� CrCl < 10 mL/min � loss of uricouric effect

� Platelet aggregation inhibitor (unclear MOA)

� CI: phenylbutazone allergy

peptic ulcer disease (may aggravate)

serious blood disorders

Uricosuric agents – Class Effects (probenecid, benzbromarone, sulfinpyrazone)

� Urolithiasis (urate stone) ∼ 10%

Prevention:

� Adequate fluid intake (10 – 12 glasses /day)

Maintain high urine pH � Maintain high urine pH

↑↑↑↑ urine pH … a diet high in citrus fruits, vegetables, or dairy products

↓↓↓↓ urine pH … a diet high in meat products or cranberries

� + Aspirin …. ↓ uricosuric effect

…. ↑ risk of bleeding (↓ aspirin excretion)

Pegloticase, IV � Pegylated recombinant form of urate-oxidase

enzyme (uricase)urate-oxidase

uric acid allantoin (water soluble metabolite)

� Approved for refractory gout � Approved for refractory gout � NOT for asymptomatic hyperuricemia � Prophylaxis gout flare (NSAID or colchicine) 1 week before

pegloticase and may continue for up to 6 months

� CI: G6PD deficiency � ? Risk of anaphylaxis and infusion-related reactions

� Premedicated with antihistamine + corticosteroid� Slow infusion in > 2 hours

Drug-induced Decreased Renal Urate Clearance

� Diuretics (Thiazides and Loops)

� Cyclosporin, Tacrolimus

� Low dose aspirin (< 325 mg/day)

� Ethambutol

Pyrazinamide� Pyrazinamide

� Ethanol (esp. beer and spirit, but not wine)

� Levodopa

� Methoxyflurane

� Laxative abuse (alkalosis)

� Salt restrictionhttp://health-fts.blogspot.com

DietDiet & Lifestyle for Gout Patients& Lifestyle for Gout Patients

� งดอาหารที= purine สงู เชน่ � เครื=องในสตัว ์เนืzอเป็ด/ไก ่กุง้ หอย ปลา (เชน่ ปลาดกุ ปลา

อนิทรยี ์ปลาซารด์นีกระป๋อง) กะปิ นํzาซปุตา่งๆ � ผัก เชน่ เห็ด กระถนิ ชะอม ขีzเหล็ก หน่อไม ้เห็ด

หน่อไมฝ้รั=ง ดอกกะหลํ=า� ถั=วดํา ถั=วแดง ถั=วเขยีว ถั=วเหลอืง � ถั=วดํา ถั=วแดง ถั=วเขยีว ถั=วเหลอืง � เบยีร ์ขนมปังผสมยสีต ์

� หลกีเลี=ยงเครื=องดื=ม alcohol � Alcohol � lactic acid � ↓ การขบั uric

Low purine diet

Gout: Summary

� Acute onset of severe joint pain. � Swelling, effusion, warmth, erythema, and/or

tenderness of the involved joint(s).� Arthrocentesis with synovial fluid analysis shows

strongly MSU crystal.

� Acute onset of severe joint pain. � Swelling, effusion, warmth, erythema, and/or

tenderness of the involved joint(s).� Arthrocentesis with synovial fluid analysis shows

strongly MSU crystal.� NSAIDs, colchicine, or corticosteroids are used to treat

acute disease. � Allopurinol, uricosuric agents are used as uric acid-

lowering drugs when long-term prevention of crystal deposition is indicated.

� Complications include joint destruction, kidney disease, and urolithiasis.

� NSAIDs, colchicine, or corticosteroids are used to treat acute disease.

� Allopurinol, uricosuric agents are used as uric acid-lowering drugs when long-term prevention of crystal deposition is indicated.

� Complications include joint destruction, kidney disease, and urolithiasis.

Outlines:

� Overview

� Update ACR 2012

guideline

Osteoarthritis

� Glucosamine +

chondroitin in OA

� IA Hyaluronic acid in OA

Osteoarthritis (OA) is a disorder of diarthrodial joints that is characterized clinically by pain and functional limitations, radiographically by osteophytes and joint space narrowing, and histopathologically by alterations in cartilage and subchondral bone integrity.

OAOA

� Most prevalent form of arthritis

� Highly associated with aging (usually after age 40 - 50)

� Women > Men

� Commonly affected large weight bearing joints

� Exact cause of OA

– remains unclear

Pathophysiology of OA

MMP = metalloproteinasehttp://www.mdconsult.com

Clinical Manifestations� Pain

� [Early stage] exacerbated by activity and relieved by rest

� [Advanced disease] progressively less activity �

occurring at rest and at night

� Joint stiffness � Joint stiffness

� morning – usually resolved within 30 min

� after periods of inactivity Typical hand deformities in OA. Heberden's nodes are seen on the distal interphalangeal joints, and Bouchard's nodes are at the proximal interphalangeal joints.

http://www.mdconsult.com

Classification of OA

Idiopathic (Primary)Idiopathic (Primary)

� Localized � Hands, feet, knees,

hips, spine, shoulder � Generalized (> 3 areas)

SecondarySecondary

� Post-trauma� Congenital � Other diseases:

� Gout, RA, osteoporosis, � Mineral deposition

diseases� CPPD depostion� Hydroxyapatite

arthropathy� Destructive disease

� Gout, RA, osteoporosis, Paget’s diseases, ischemic necrosis

� DM, hypothyroid � Mechanical (e.g., obesity,

enequal lower ext length) � Etc.

Therapy Goals

� Relieve pain

� Maintain or improve joint function

� Prevent loss of function� Prevent loss of function

� Maintain or improve quality of life

ACR 2012

Non-pharmacological Recommendations

� Weight reduction (for overweight patients)

� Exercise

� Joint protection techniques� Joint protection techniques

� Use of thermal modalities

� Provide assistive devices, as needed

� Surgery

Case 3W.F. is an 85-year-old man who presents to his physician with pain from hip OA. He also has HTN, CAD, and BPH. For his OA, W.F. has been taking acetaminophen 650 mg 3 times/day. W.F. reports that paracetamol helps, but he still experiences pain that limits his ability to walk.

Which one of the following is the best next step in analgesic therapy for W.F.?

A. Change the analgesic to ibuprofenB. Change the analgesic to celecoxibC. Add paracetamol + codeineD. Add glucosamine

Pharmacological Treatments

� Topical capsaicin or NSAIDs

� Oral analgesics

� Paracetamol

�NSAIDs & COX2 inhibitors

�Tramadol

�Opioids

� Glucosamine sulfate + Chondroitin

Pharmacologic recommendations:

Initial management

Hand OAHand OA

� Should use� Topical capsaicin � Topical NSAIDs

Oral NSAIDs/COX inhibitors � Oral NSAIDs/COX2 inhibitors � Tramadol

� NOT use � IA therapies � Opioids

Arthritis Care & Research. 2012;64:465-474.


Initial management

Knee OAKnee OA

� Should use� Paracetamol � Topical NSAIDs

Oral NSAIDs/COX inhibitors


� Oral NSAIDs/COX2 inhibitors � Tramadol � IA corticosteroids

� NOT use � Glucosamine + chondroitin � Topical capsaicin


Initial management

Hip OA

� Should use� Paracetamol� Oral NSAIDs/COX2 inhibitors

Tramadol � Tramadol � IA corticosteroids

� NOT use � Glucosamine + chondroitin


Glucosamine

� Amino sugar … precursor of glycosaminoglycans(part of cartilage)

� Presumably maintain elasticity, strength, and resiliency in joint cartilage

Glucosamine sulfate + Chondroitin Glucosamine sulfate + Chondroitin

resiliency in joint cartilage

� Produced commercially by the hydrolysis of crustacean exoskeletons

� Avoid: shellfish allergy !!

� ↑ bleeding risk

Glucosamine sulfate + Chondroitin Glucosamine sulfate + Chondroitin

Chondroitin

� Hydrophilic gel � polysaccharide macromolecule

� Improve compressive resistance of the cartilage (↑ cartilage thickness)

� ↑ bleeding risk � avoid in patients with hemostaticproblems or h/o bleeding

Meta-analysis

10 RCTs (n = 3803)

Drugs vs. placebo

Pain intensity (VAS) • Glucosamine: –0.4 cm

Meta-analysis

10 RCTs (n = 3803)

Drugs vs. placebo

Pain intensity (VAS) • Glucosamine: –0.4 cm

BMJ 2010;341:c4675 doi:10.1136/bmj.c4675.

• Glucosamine: –0.4 cm (95% CI: -0.7 to -0.1 cm)

• Chondroitin: –0.3 cm (95% CI: -0.7 to 0.0 cm)

• Combination: –0.5 cm (95% CI: -0.9 to 0.0 cm)

• Glucosamine: –0.4 cm (95% CI: -0.7 to -0.1 cm)

• Chondroitin: –0.3 cm (95% CI: -0.7 to 0.0 cm)

• Combination: –0.5 cm (95% CI: -0.9 to 0.0 cm)

Hyaluronic acid (HA)Hyaluronic acid (HA)

� Polysaccharide (nonsulfated glycosaminoglycan) in synovial fluid � Lubricant

� 1/3 of hyaluronan in the body is degraded and synthesized every day synthesized every day

� In patients with OA, synovial hyaluronic acid is depolymerized and cleared at high rate � decrease of molecular weight and concentration

Ann Intern Med. 2012;157:180-91.

Systematic review & Meta-analysis

71 RCTs (n = 9,617)

Patients with symptomatic knee OA

Systematic review & Meta-analysis

71 RCTs (n = 9,617)

Patients with symptomatic knee OA

IA hyaluronic acid vs. Control

• Pain intensity (VAS): –0.37 cm (95% CI: -0.46 to -0.28 cm)

Phet < 0.001 • Risk of flare up: 1.51 (95% CI: 0.84 to 2.72) • Risk of serious ADR: 1.41 (95% CI: 1.02 to 1.97)

IA hyaluronic acid vs. Control

• Pain intensity (VAS): –0.37 cm (95% CI: -0.46 to -0.28 cm)

Phet < 0.001 • Risk of flare up: 1.51 (95% CI: 0.84 to 2.72) • Risk of serious ADR: 1.41 (95% CI: 1.02 to 1.97)

Ann Intern Med. 2012;157:180-91.

Acute PainAcute Pain

Paracetamol + Topical analgesic

NSAIDs/COX2 inhibitor + Topical analgesic

Tramadol

Exacerbation

IA corticosteroid

SURGERY

Tramadol + Topical analgesic

Opioid !!

Persistent pain despite multiple treatment modalities or with severe disability

Joint Replacement Surgery

OA: Summary

� A degenerative joint disorder; prevalence increases with age.

� Most commonly affected joints are the knee, hip, hands, and lumbar and cervical spine.

� Presents with joint pain and stiffness that is typically worse with activity.

� A degenerative joint disorder; prevalence increases with age.

� Most commonly affected joints are the knee, hip, hands, and lumbar and cervical spine.

� Presents with joint pain and stiffness that is typically worse with activity.worse with activity.

� Radiographs show loss of joint space, subchondralsclerosis, and osteophytes.

� Treatments are non-pharmacological and pharmacological.

� Joint replacement surgery is effective for controlling the pain of osteoarthritis in advanced disease.

worse with activity.� Radiographs show loss of joint space, subchondral

sclerosis, and osteophytes.� Treatments are non-pharmacological and

pharmacological.� Joint replacement surgery is effective for controlling

the pain of osteoarthritis in advanced disease.

Documents

Outline: Uric acid pathway Pharmacotherapy in Gout and ...Uric acid pathway Gout vs. hyperuricemia How to manage acute gout attack? Gout Chronic management of gout Hyperuricemia -Who