gout and crystalline advances in... · 2020. 5. 8. · acute gouty arthritis: helpful facts 1. uric...

Gout and Crystalline

Diseases

Derrick J. Todd, M.D., Ph.D.

Chief, Clinical Rheumatology: Brigham and Women’s Faulkner Hospital

Associate Physician: Brigham and Women’s Hospital

Dept. of Medicine, Div. of Rheumatology, Inflammation, and Immunity

Instructor of Medicine: Harvard Medical School

Disclosures

• UpToDate, Author and reviewer

“When an arthritis

patient walks in the

front door, I feel like

leaving by the back…”

Objectives

1. Review of uric acid metabolism

2. The many faces of hyperuricemia and gout• Asymptomatic hyperuricemia

• Acute gouty arthritis

• Chronic tophaceous gouty arthropathy

• Uric acid nephropathy and nephrolithiasis

3. Management of hyperuricemia and gout

Uric Acid Metabolism

1. Produced in the liver as the end-product of

purine metabolism

2. Excreted via kidney (2/3) and gut (1/3)

3. Urate pool: ~1200 mg men, ~600 mg women

4. Solubility ~6.8 mg/dL

5. Normally balanced intact and excretion

Uric Acid: Renal Excretion

1. Only 10% of filtered urate load is excreted

2. Four-compartment model• Glomerular filtration

• Pre-secretory reabsorption (~100%)

• Secretion (~50%)

• Post-secretory reabsorption (~40%)

3. URAT1 & GLUT9: the major urate transporters

4. Most hyperuricemia is due to under-excretion

Uric Acid: Renal Excretion

Terkeltaub 2009 Arthritis Res Ther

Manifestations of Hyperuricemia

1. Asymptomatic hyperuricemia

2. Acute gouty arthritis

3. Chronic (tophaceous) gouty arthropathy

4. Uric acid nephropathy and nephrolithiasis

Asymptomatic Hyperuricemia

1. Urate >7.0 mg/dL in the absence of symptoms• Often exists for decades prior to symptoms

2. Primary hyperuricemia is an adult issue• Uric acid levels increase with age

• In men, starts at adolescence

• In women, starts post-menopausal - estrogen

inhibits urate reabsorption in proximal tubule

3. Secondary hyperuricemia can occur at an

earlier age in association with genetic

conditions, disease states, or medications

Uric Acid

1. Uric acid level stratifies a patient’s risk for

developing clinical gout over a lifetime• Hyperuricemia is not diagnostic of gout

• Normal uric acid does not exclude gout

2. Many factors affect a spot serum uric acid• Hydration and dietary status

• Acute changes in renal function

• Medications (esp. diuretics)

• Active gout attack

3. Uric acid should also be used as a target of

treatment in a patient with established gout. • Goal: uric acid <6 mg/dL, or <5 mg/dL if tophi

Hyperuricemia: Risk Factors

1. Un-modifiable risk factors• Family history of gout or hyperuricemia

• Older age and male gender

• Co-morbidities: cardiac disease, renal insufficiency,

heme malignancy, inherited metabolic defects

2. Modifiable risk factors• Diet: alcohol (beer), shellfish, organ meat, red meat,

heavy dairy, high-fructose corn syrup

• Medications: diuretics, cyclosporine, HAART

• Obesity

• Lead exposure

Myth #1: Busted?

Asymptomatic hyperuricemia is a benign condition.

True, False, or Maybe?

1. Is it really asymptomatic hyperuricemia• Risk factor for acute gouty arthritis and chronic

tophaceous gouty arthropathy

• Increased risk of nephrolithiasis (>1100 mg/24 hr)

• Association with CKD, HTN, CVD, and DM

• Inverse association with Alzheimer’s Disease

2. Does correcting uric acid help?• Not clear, but clinical trials are underway in HTN,

CHF, DM, and psychiatric diseases

• Currently not recommended: medications are not

without some risk of adverse effect

Maybe…

Acute Gout

1. Acute inflammatory arthritis/tendinitis/bursitis• Usually mono- or oligo-articular

• Aspirate: inflammatory fluid with uric acid crystals

2. Triggers are mostly unpredictable• Recent trauma or repetitive overuse

• Systemic inflamed state: surgery, infection

• Fluctuations in uric acid: fluid shifts, diuretics, or

someone messed with the allopurinol!

• Dietary indiscretion?

3. Treatment: Target the inflammation!

Acute Gout: Diagnosis

Myth #2: Busted?

Joint fluid WBC >50,000 cells/mm3 always

warrants an orthopedic consult for septic joint


1. In both septic joint and sterile gout, joint fluid

WBC can exceed 50,000 cells/mm3.• WBC differential usually >95% PMN in both

• Be careful! Both conditions can co-exist.

2. Fluid analysis should include crystal search,

cell count, gram stain, and culture• Positive crystals with negative gram stain should

often be watched for culture results rather than

automatically sent to the OR for a washout.

False!

Polarized Light Microscopy

Monosodium Urate Crystals

Don’t Forget THIS Possibility

Calcium Pyrophosphate Dihydrate (CPPD)

1. Indistinguishable from acute gout or infection

2. Usually affects elderly or those with risk factors

3. Prior pseudogout attack or radiographic presence of

chondrocalcinosis may be helpful (will not see on MRI)

4. Triggers: concurrent trauma or any inflamed state

5. Risks for CPPD: altered metabolism• Hemochromatosis

• Hyper-PTH

• Thyroid abnormalities

• Low phosphate or magnesium

• Acromegaly

• Rare genetic states (ANKH mutation)

Calcium Pyrophosphate Dihydrate (CPPD)

Myth #3: Busted?

Colchicine is a good option for acute gouty arthritis

because it has relative few adverse effects.


1. Requires relatively high doses to achieve

desired effect in managing ACUTE gout.• Often reach diarrhea before pain relief…uh oh

• Greater toxicity in those with renal impairment

• Expect a few days to “kick in”

2. Better for prevention of acute gout• Prophylaxis discussed later.

Mostly False

Acute Crystalline Arthritis: Basics

Management principles in acute gout/pseudogout1. Early treatment favors and early recovery

2. Rest, ice, and analgesics help almost everyone

3. It gets better on its own with time

4. Try to avoid the ortho service

5. Don’t mess with allopurinol in patients with acute gout

Acute Crystalline Arthritis: Medications1. NSAIDS: assess co-morbidities and risks

2. Corticosteroids: low doses are safe and effective• Intra-articular: directed therapy

• Oral: 20-40 mg daily, tapered by 5-10 mg every 4 days

• Quick: IM/IV methylprednisolone 40 mg x1, then oral

3. Oral colchicine (NEVER INTRAVENOUSLY)• 0.6 mg BID-TID for 1-2 days, then QD-BID

• Do NOT dose to the point of diarrhea

• CAUTION in renal compromised patients

• CAUTION with medication interactions

• Neuromyotoxicity can be a missed toxicity

Acute Gouty Arthritis: Helpful Facts

1. Uric acid level is not always helpful in acute gout.

2. Distribution of involvement may be helpful:• Most common site: Peripheral extremities

• Can include tendon sheaths and bursae

• Rarely occurs centrally: SI joints, pubis, or discs

3. May co-exist with septic arthritis or other forms of

crystalline arthritis (CPPD)

4. In bad polyarticular disease, patients can

demonstrate features of sepsis.

5. Management of hyperuricemia is often

unnecessary in the acute setting.

Case: Polyarthralgias


58 y.o. overweight male attorney on celecoxib for

chronic degenerative back pain, who presents

with 4 months of progressively severe pain and

swelling in his bilateral ankles and feet.• Examination: swollen feet and ankles with preserved

ROM of ankles. Mildly tender MTP squeeze.

What are the possible diagnoses?A. Distractor #1

B. Distractor #2

C. Distractor #3

D. Distractor #4

E. A rather atypical presentation of chronic gouty

arthropathy in a patient with multiple risk factors for

hyperuricemia (age, gender, weight) and chronic

NSAID usage, which can suppress episodes of what

might have ordinarily presented at a younger age as

attacks of acute gouty arthritis.


What are the possible diagnoses?A. Osteoarthritis

B. Rheumatoid arthritis

C. Systemic lupus erythematosus

D. Spondyloarthritis (e.g. psoriatic arthritis)

E. Carpal/tarsal tunnel syndrome

F. Gout

G. Pseudogout

H. Overuse syndrome

I. Viral arthritis

J. Lyme arthritis

K. Infectious arthritis

L. Other inflammatory arthritis (e.g. sarcoid, amyloid, etc.)


What are the possible diagnoses?A. Osteoarthritis

B. Rheumatoid arthritis

C. Systemic lupus erythematosus

D. Spondyloarthritis (e.g. psoriatic arthritis)

E. Carpal/tarsal tunnel syndrome

F. Gout

G. Pseudogout

H. Overuse syndrome

I. Viral arthritis

J. Lyme arthritis

K. Infectious arthritis

L. Other inflammatory arthritis (e.g. sarcoid, amyloid, etc.)

Case: Demographics? Distribution? Timing?






• Normal metabolic and hematologic parameters.

• RF/CCP negative, CRP 10.0 mg/L, ESR 32 mm/hr.

• Uric acid 7.2 mg/dL










• Radiographs: Degenerative changes at 1st MTP

joints. No erosive changes.












• Left MTP1 aspirate: monosodium urate crystals












• Left MTP1 aspirate: monosodium urate crystals

• Diagnosis: Chronic gouty arthropathy


THE GOUCH

1. Result of many years of chronic hyperuricemia

2. Can occur in joints, tendons, and soft tissues• Sometimes a “surprise diagnosis” in the OR

• Biopsy requires specimen fresh or in 100% EtOH

3. Additional risk factors almost always present• Chronic kidney disease

• Congestive heart failure

• Culprit medications: cyclosporine

• Chronic use of NSAIDs or corticosteroids

• Noncompliant patient, unobservant physician, or both

Chronic Tophaceous Gouty Arthropathy

Chronic/Recurrent Gout

1. A disease of hyperuricemia• Treating only inflammatory episodes is effective for

symptomatic gout but insufficient for chronic disease

• Hyperuricemia associated with many disease states:

chronic arthropathy, chronic kidney disease,

hypertension, and cardiovascular disease

2. In whom do we start urate-lowering therapy?• All patients with clinical gout should be encouraged to

modify risk factors: weight, diet, and possibly diuretics

• Indicators for urate lowering therapy: multiple attacks,

high risk for recurrence, tophi, erosive arthropathy,

uric acid nephropathy, or nephrolithiasis

• New ACP recommendations are highly controversial.

1. Radiography– Rarely diagnostic for gout, but can be suggestive

– Useful for determining extent of any gouty arthropathy

Role of Imaging in Diagnosis of Gout



2. Ultrasound (MSKUS)– Advantages: relatively inexpensive; no radiation;

assess multiple sites; sensitive to gouty changes

– Disadvantages: operator dependent


Gout: Ultrasound

R Thiele 2007, Rheumatology

Tophaceous Gout: Ultrasound



2. Ultrasound (MSKUS)– Advantages: relatively inexpensive; no radiation;

assess multiple sites; sensitive to gouty changes

– Disadvantages: operator dependent

3. Dual energy CT scan (DECT)– Advantages: standardized; can assess entire

foot/ankle; can see “through” bone

– Disadvantages: cost; radiation; availability; familiarity


Dual-Energy CT

http://www.dsct.com/index.php/dual-energy-imaging

Gout: Advanced Imaging

A Huppertz 2014, Rheumatol Int

Ultrasound versus DECT

A Ogdie 2014, Ann Rheum Dis

1. Acute uric acid nephropathy• AKI from uric acid precipitation in tubules

• Feature of myeloproliferative disorders, especially

after chemotherapy (tumor lysis syndrome)

• Prevented with allopurinol or recombinant uricase

2. Chronic urate nephropathy• Crystal deposition in the medullary interstitium with

secondary chronic inflammatory changes

• Uric acid elevated out of proportion to kidney disease

Uric Acid Nephropathy

1. Not limited to just uric acid stone formation• OR 1.5 – 1.9 for stones of any type (NHANES III)

2. Metabolic disturbances: H+ + urate- uric acid

• Elevated urine uric acid secretion

• Acidic urine

3. Treatment of uric acid stones• Increase fluids

• Alkalinize urine: acetazolamide, potassium citrate

• Urate lowering therapy

Hyperuricemia and Nephrolithiasis

Management of Hyperuricemia





1. Reduce purine-rich foods• Beer and spirits

• Red meats and shellfish

• Heavy dairy

• High fructose corn syrup

2. Beneficial foods?• Light dairy

• Vitamin C

3. Exercise and weight loss

4. Medication compliance

Management: Diet and Lifestyle

thegoutkiller.com

Myth #4: Busted?

Once an acute gout attack is resolved, it is

appropriate to stop anti-inflammatory therapy and

start urate lowering therapy.


Myths #5 and #6: Busted?

Allopurinol is directly toxic to the kidney.

Allopurinol dose should be limited to 300 mg daily

in patients with normal renal function, and 100 mg

daily in patients with impaired renal function.


Myth #7: Busted?

Other potential offending medications should

always be eliminated in patients with

complications of chronic gout: diuretics, low-dose

aspirin, cyclosporine, protease inhibitors.


1. Reduce uric acid to prevent complications of

hyperuricemia: tophi, erosions, nephropathy,

nephrolithiasis• Driven by hyperuricemia

• Urate-lowering therapy

2. Treat/prevent acute gout• Driven by inflammation

• Anti-inflammatory agents

Pharmacologic Management

Medications for Chronic Gout

1. Treat hyperuricemia!• Explain that treatment is usually “for life”

• Goal uric acid: <6 mg/dL, or <5 mg/dL if tophi present

• Almost all compliant patients can achieve this!

2. The agents• Xanthine oxidase inhibitors: allopurinol, febuxostat

• Uricosurics: probenacid, losartan, Vit C, lesinurad

• Recombinant uricase: pegloticase, rasburicase

3. Don’t lose your patient to a gout attack!!• Early in treatment: patients at high risk for gout attack

• Almost always co-prescribe an anti-inflammatory such

as low-dose colchicine, typically for months.

Allopurinol: Myth-busting

1. Properly used, allopurinol is the most effective and

safest urate-lowering therapy for most patients• Allopurinol is generally safe, even at high doses.

• I often titrate to >300 mg daily, even in patients with CKD.

• Rapid change in allopurinol can trigger gout attack!

• Start low and go slow, especially in CKD.

• Inadequate dose most likely reason for “treatment failure”

2. Allopurinol toxicity• Renal excretion, and only very rarely nephrotoxic

• Changes in LFTs or blood counts can be dose limiting

• Rash is rare, but can portend a more serious reaction

• Hypersensitivity: SJS, TEN, DRESS, DIL, ANCA vasculitis

• HLA-B*5801 high-risk allele (Korean, Han Chinese, Thai)

My Conclusions

1. Allopurinol remains the preferred xanthine oxidase

inhibitor when choosing a urate lowering therapy.

2. Allopurinol is generally safe in doses greater than

that traditionally thought.

3. Febuxostat should not be cast aside entirely• Important role as the only feasible option in most patients

with allopurinol hypersensitivity

• Studies have shown conflicting evidence about mortality

risk in patients on febuxostat compared to allopurinol

• Reserve extra time for conversation about risks/benefits,

especially in patients with cardiovascular risk factors

Myth #4: Busted?

Once an acute gout attack is resolved, it is

appropriate to stop anti-inflammatory therapy and

start urate lowering therapy.


1. Attacks of acute gout are very common in

patients starting anti-hyperuricemic therapy

unaccompanied by prophylactic therapy• Colchicine

• NSAIDs

• Low-dose steroids

2. Patients lose faith

3. Overlap treatment by 6-12 months

False

Myths #5 and #6: Busted?


Allopurinol is directly toxic to the kidney.

Allopurinol dose should be limited to 300 mg daily

in patients with normal renal function, and 100 mg

daily in patients with impaired renal function.

1. Allopurinol is rarely toxic to the kidney, and its

urate lowering effect may actually benefit renal

function in chronic urate nephropathy• Dose may need to be titrated up to 600-900 mg daily

• Monitor hepatic and bone marrow toxicity

• Renal toxicity is described but very rare, limited to

the allopurinol hypersensitivity syndrome

• Risk factors for hypersensitivity include age, diabetes

mellitus, impaired renal function, and HLA-B*5801

• Can sometimes de-sensitize if rash develops

• An abrupt change in allopurinol dose can precipitate

a gout attack, often polyarticular and severe.

Mostly False

Myth #7: Busted?


Other potential offending medications should

always be eliminated in patients with

complications of chronic gout: diuretics, low-dose

aspirin, cyclosporine, protease inhibitors.

1. Consider changing if good alternatives exist,

but we now have enough treatment options for

gout to allow for continuing these other very

important medications, even if “offensive” to us!

Mostly False

1. Asymptomatic hyperuricemia may be bad, but

we do not have evidence that risk of treatment

outweighs any potential benefit

2. Acute gouty arthritis is difficult-if-not-impossible

to distinguish clinically from septic arthritis

3. Unless contraindications exist, corticosteroids

and NSAIDs are better options than colchicine

for acute gouty arthritis

Summary

4. Embarking on urate lowering therapy usually

requires co-prescribing of a prophylactic agent

against acute gout attacks (e.g. colchicine)

5. Allopurinol is rarely toxic to the kidney, and the

dose need not be limited to 300 mg daily

6. Rheumatologists are nice people. We don’t

mess with other people’s meds, so please don’t

change ours unless there is obvious toxicity…

Summary

Conclusions: Gout

1. Try to secure a crystal-proven diagnosis

2. Non-invasive imaging modalities help diagnose

gout and determine extent of disease burden

3. Treat inflammatory phase of acute gouty

arthritis with anti-inflammatory agents• NSAIDs, corticosteroids, colchicine, ice, rest

4. Use anti-hyperuricemic agents when indicated• Tophi, erosions, nephrolithiasis, multiple attacks

• Allopurinol, febuxostat, probenecid, pegloticase

5. Overlap #3 and #4, often for months

6. PLEASE don’t mess with my allopurinol

Summary: Don’t Hesitate to Call!

[email protected], BWH 617-732-5325, Faulkner 617-983-7720

Questions?

[email protected], BWH 617-732-5325, Faulkner 617-983-7720

gout and crystalline advances in... · 2020. 5. 8. · acute gouty arthritis: helpful facts 1. uric...

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