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Crystal-Induced Arthritis. “All the Pearls in 50 Minutes ”. Gerald F. Falasca, M.D. Johnson City, TN. March 27, 2012. The risk factors for gout were known to the ancients. Ben Franklin (1706 -1790).

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Crystal induced arthritis

Crystal-Induced Arthritis

“All the Pearls in 50 Minutes”

Gerald F. Falasca, M.D.

Johnson City, TN

March 27, 2012



Ben franklin 1706 1790
Ben Franklin (1706 -1790)

"Be temperate in wine, in eating, girls, and sloth, or the Gout will seize you and plague you…"

-- Franklin


Major arthritogenic crystals
MAJOR ARTHRITOGENIC CRYSTALS

  • Monosodium urate

  • Calcium pyrophosphate dihydratte

  • Hydroxyapatite

  • Corticosteroid esters

  • Calcium oxalate


Major arthritogenic crystals1
MAJOR ARTHRITOGENIC CRYSTALS

  • Monosodium urate

  • Calcium pyrophosphate dihydratte

  • Hydroxyapatite

  • Corticosteroid esters

  • Calcium oxalate


Risk factors for gout

Underexcretors (80%)

Male gender

Postmenopausal females

Obesity, metabolic synd.

Ethanol

Renal insufficiency

Plumbism

Medications (see separate)

Dehydration/low flow

Filipino ancestry

Fructose ingestion

Uromodulin kidney dis.

Overproducers (20%)

Ethanol

High cell turnover states (psoriasis, myeloprolif. disorders)

Excessive purine ingestion

PRPP overactivity (x-linked)

HGPRT underactivity (x-linked)

Beta aldolase deficiency

Sarcoidosis

B12 deficiency

Down syndrome

Glycogen storage dis. 3, 5, 7

Fever, post-op state

Risk Factors for Gout


Risk factors for gout1

Obesity, metabolic syndrome

Ethanol

Diuretics

Fructose ingestion

Excessive purine ingestion

Risk Factors for Gout


Hyperuricemia and gout
Hyperuricemia and Gout

  • Dairy consumption is protective.

  • Estrogen protective (suppresses URAT1, the proximal renal tubule epithelial cell anion exchanger ).

  • Beer much worse than wine.


Overproducers
Overproducers

  • 15-20% of gouty patients are overproducers.

  • Distinguished by 24 hour uric acid excretion:

    • > 800 mg/d on regular diet.

    • > 600 mg/d on purine-free diet.


Drugs associated with hyperuricemia

Diuretics (loop and thiazide types)

Low-dose aspirin

Cyclosporine, tacrolimus

Ethanol

Ethambutol

Pyrazinamide

Ritonavir, darunavir, didanosine

Levodopa

Nicotinic acid, niacin

Pancreatic enzymes

Rituximab

Basiliximab

Teriparatide

Filgrastim

Sildenafil

Diazoxide

Cytotoxic chemotherapy

Drugs Associated with Hyperuricemia


Drugs associated with hyperuricemia1

Diuretics (loop and thiazide types)

Low-dose aspirin

Cyclosporine, tacrolimus

Ethanol

Ethambutol

Pyrazinamide

Ritonavir, darunavir, didanosine

Levodopa

Nicotinic acid, niacin

Pancreatic enzymes

Rituximab

Basiliximab

Teriparatide

Filgrastim

Sildenafil

Diazoxide

Cytotoxic chemotherapy

Drugs Associated with Hyperuricemia



Hyperuricemia and gout1
Hyperuricemia and Gout

  • Hyperuricemia (>7.0 mg/dl) in 5% - 8% of male population.

  • Most (about ⅔) are forever asymptomatic.

  • 80% of gouty patients have uric acid < 9 mg/dl.

  • Above 10 mg/dl, risk rises rapidly.

  • Gout is the most common cause of monarthritis in middle-aged and elderly men (8% yearly prevalence).


Who almost never gets gout
Who Almost Never Gets Gout?

  • Pre-pubertal children

  • Pre-menopausal women

  • Look for enzyme defects in these patients.

  • Look for familial kidney disease


Provocative factors adding insult to injury

Ethanol

Cessation of ethanol

Purine overindulgence

Surgery

Trauma

Overexercise

Fasting

Fever

Provocative Factors“Adding Insult to Injury”


The fructose connection
The Fructose Connection

  • Fructose raises uric acid levels in minutes.

  • Biggest source of fructose: high fructose corn syrup.

  • Sucrose does not seem to raise uric acid.


Link to cardiovascular dis
Link to Cardiovascular Dis.

  • In experimental models, hyperuricemia causes:

    • Hypertension

    • Reduced perfusion

    • Endothelial dysfunction

    • Renal dysfunction

  • Reversible with hypouricemics


Frequent clinical associations with gout
Frequent Clinical Associations with Gout

  • Hypertension

  • Diabetes

  • Hyperlipidemia

  • Obesity

  • Ethanol – the fuel


Gout kidney disease
Gout & Kidney Disease

  • Stones - Uric acid and calcium

  • Urate nephropathy - chronic interstitial disease, not well defined.

  • Uric acid nephropathy – acute tubular deposition of uric acid, with renal failure, not seen in gout.


Uromodulin associated kidney disease
Uromodulin-associated kidney disease

AKA:

  • Familial medullary cystic kidney disease, type 2.

  • Familial juvenile hyperuricemic nephropathy.

  • Uromodulin storage disease.


Uromodulin cont d
Uromodulin (cont’d)

  • Uromodulin (Tamm-Horsfall protein) accumulates in the thick ascending portion of Loop of Henle.

  • Reduced excretion of uric acid.

  • No renal deposition of urates.

  • Autosomal dominant.


A typical attack of gout
A Typical Attack of Gout

  • Lasts several days to several weeks.

  • May spread from joint to joint.

  • Often accompanied by fever, leukocytosis.

  • Gets worse as the years go on.

  • Pain appears last, disappears first.

  • Petite attacks occur (lasting hours).


Causes of podagra
Causes of Podagra

  • MSU

  • CPPD

  • Hydroxyapatite

  • Septic

  • Psoriatic, Reiter’s

  • Rheumatoid


Radiographic hallmarks of gout
Radiographic Hallmarks of Gout

  • Overhanging edges

  • Punched out lesions with sclerotic borders.

  • Preservation of joint space (till late)

  • Degenerative changes


The “Double Contour Sign” of Gout.

Filippucci E, Grassi W Department of Rheumatology, University of Ancona, Italy


The three phases of gout treatment
The Three Phases of Gout Treatment

  • Treat acute attack

  • Prevent new attacks

  • Reduce uric acid level (sometimes)


Phase 1 termination
Phase 1 - Termination

  • NSAID

  • Colchcine

  • Intra-articular steroids

  • Systemic steroids

  • IL-1 inhibitors


Nsaids
NSAIDs

  • Treatment of choice in otherwise healthy patient.

  • Avoid in renal insufficiency and in peptic ulcer disease.

  • Avoid salicylates (these cause swings in serum uric acid).


Intra articular steroids
Intra-Articular Steroids

  • One or a few joints.

  • Not useful for polyarticular or soft-tissue gout.

  • Make sure infection not present.


Oral colchicine
Oral Colchicine

  • 1.2 mg followed by 0.6 mg 2 hrs later.

  • Loading dose same in renal insufficiency.

  • Maintenance (preventive) dose 0.6 mg qd or bid.

  • 0.3 mg 2-3 times per week in dialysis patients (preventive).


Systemic steroids
Systemic Steroids

  • Polyarticular attacks or fever.

  • Longstanding attacks (>3-5 days).

  • Need divided doses.

  • Taper over 7-10 days.

  • Start prophylactic agent (colchicine) as soon as possible.


Anakinra off label
Anakinra (Off-Label)

  • Effective for acute attack in studies.

  • Best in pts who cannot take steroids or colchcine.

  • Expensive but 1 week of treatment may be affordable.

  • Not for preventive use.

  • Other interleukin-1 inhibitors currently in trials (rilonacept & canakinumab)


Adjunctive measures
Adjunctive Measures

  • Rest

  • Ice

  • Elevation

  • Analgesics

  • Anti-motility agents (if using colchicine or indomethacin)

  • Continue hypouricemic agent if patient has been taking it.


Phase 2 preventive therapy
Phase 2 - Preventive Therapy

  • Colchicine or NSAID.

  • Always use when beginning a hypouricemic drug.

  • Continue several weeks to years (depending on tophi, serum uric acid).

  • Always use before surgery in previously gouty patient.


Phase 3 hypouricemic therapy
Phase 3 - Hypouricemic Therapy

  • Not every patient needs it.

  • May not need it in:

    • Very elderly

    • Non-compliant

    • Infrequent attacks and no tophi

  • May exacerbate attacks early on


Goals of hypouricemic treatment
Goals of Hypouricemic Treatment

  • Aim for serum uric acid under 6, preferably near 5 for some chronic gouty patients.

  • But remember:

    • allopurinol toxicity more likely with higher dose.

    • More likely with renal insufficiency.


Hypouricemic agents
Hypouricemic Agents

  • Allopurinol

  • Febuxostat

  • Probenecid

  • Pegloticase

  • Losartan (off-label)

  • High-dose salicylates (off-label)

  • Vitamin C (off-label)


Hypouricemic therapy
Hypouricemic Therapy

  • Don’t start hypouricemic agent during acute attack.

  • Use probenecid first; it’s safer.

  • Don’t use probenecid if:

    • overproducer

    • creat clearance < 35-50 ml/min.

    • history of kidney stones.


Reasons for hypouricemic treatment failure
Reasons for Hypouricemic Treatment Failure

  • Need lower uric acid levels than “normal.”

  • Non-compliance.

  • Renal insufficiency.

  • Rapid dissolution of tophi.

  • Rapid elimination of oxypurinol (may occur with combined allopurinol and probenecid).


Asymptomatic hyperuricemia
Asymptomatic Hyperuricemia

  • Don’t treat it (this advice may change in future)

  • Exception: Patients getting chemotherapy for leukemia, lymphoma.


Major toxicities of allopurinol
Major Toxicities of Allopurinol

  • Increased gout attacks early on (use prophylaxis)

  • Rash (may be severe)

  • Stevens-Johnson syndrome

  • Vasculitis

  • Hepatitis

  • Renal failure (interstitial nephritis)

  • Bone marrow suppression


Allopurinol hypersensitivity syndrome

Fever

Rash

Renal Failure

Hepatic injury

Leukocytosis

Eosinophilia (the tipoff!)

Allopurinol Hypersensitivity Syndrome

  • May be fatal. Hard to treat.

  • Serious reactions to allopurinol reported

  • in 1 of 260 patients.Arthritis Rheum 29:82, 1986


Treatment of stones in gouty patients
Treatment of Stonesin Gouty Patients

  • Allopurinol

    • calcium and uric acid stones

  • Potassium citrate

    • calcium and uric acid stones

    • direct inhibitor of nucleation

  • Fluids!


Treatment of stones in gouty patients1
Treatment of Stonesin Gouty Patients

  • Allopurinol

    • calcium and uric acid stones

  • Potassium citrate

    • calcium and uric acid stones

    • direct inhibitor of nucleation

  • Fluids!


Febuxostat
Febuxostat

  • Non-xanthine inhibitor of XO and XD.

  • Better tolerated than allopurinol.

  • Lower uric acid levels than allopurinol (53% vs. 21% met target of 6.0 mg/dl).

  • Better dissolution of tophi.


Tophus reduction
Tophus Reduction

Mean Reduction in Tophus Area

Becker MA. N Engl J Med. 2005 Dec 8;353(23):2450-61. Febuxostat compared with allopurinol in patients with hyperuricemia and gout.


Febuxostat vs allopurinol
Febuxostat vs. Allopurinol

Percentage of Patients Achieving Serum Uric Acid < 6 mg/dl

Study 1: Allopurinol dosed at 300 mg/d for ClCr ≥ 60 ml/min or 200 mg/d for 30 ≤ ClCr ≤ 59 ml/min.


Febuxostat1
Febuxostat

  • Adverse Reactions

    • Nausea

    • Gout flare (must be on prophylaxis!)

    • Elevated ALT, AST (3% > 3xULN)

    • Elevated CRP

    • Rash

    • Elevated CK


Febuxostat best use
Febuxostat: Best Use

  • Allopurinol failures

  • Renal insufficiency

  • Tophaceous gout


Allopurinol febuxostat drug interactions
Allopurinol & Febuxostat Drug Interactions

  • Life threatening interaction with azathioprine, 6-mercaptopurine.

    • Reduce dose of purine analogue by approximately 2/3.

  • Theophylline

  • Other interactions also


Pegloticase
Pegloticase

  • For refractory chronic gout

  • Dissolves tophi in weeks to months

  • Problems:

    • Anaphylaxis

    • Antibody formation

    • Not in G6PD defic.

    • $$$$



Resistant hyperuricemia
Resistant Hyperuricemia?

  • Try febuxostat 40 mg BID instead of 80 mg qd (off-label use).

  • Short half-life supports this dosing.

  • Currently in clinical trials


Losartan vit c off label
Losartan & Vit C (Off-Label)

  • Lowers uric acid 0.3 – 1.3 mg/dl (dose range 25 – 200 mg/d).

  • Uricosuric mechanism.

  • Useful when 24 hour uric acid is < 800 mg/d.

  • Maintain good hydration.

  • Effect is not seen with other ARBs.

  • Also consider fenofibrate (quite good actually) and atorvastatin (both off-label).

  • Don’t forget vitamin C (500 mg BID)


Gout

Yellow

Negative (when parallel)

G Y N


Synovial fluid in gout
Synovial Fluid in Gout

  • May be cloudy or clear.

  • Inspect for tophaceous deposits.

  • WBC – 2000 – 50,000 or more…

  • Glucose normal.

  • Between attacks, may have free crystals.

  • Don’t forget to culture it.


Send synovial fluid for
Send Synovial Fluid for:

  • Cell count Lavendar top

  • Crystals Green top

  • Culture Red top, no preserv.

  • Glucose Red top

  • Protein, pH, complement – not helpful


Reasons msu crystals may not be seen
Reasons MSU Crystals May Not Be Seen

  • Needle in crystal-less sac.

  • Ultramicroscopic size (need EM).

  • Spherules.

  • Settled out.

  • Lack of time to search.

  • Lack of experience.



Gout vs pseudogout
Gout vs. Pseudogout

  • Gout

    • hallux, ankle, knee, hand

    • younger, male

  • Pseudogout

    • knee, wrist, ankle

    • older, female

  • Almost any joint can be affected by either disease!


Screening films to get in pseudogout patient
Screening Films to Getin Pseudogout Patient

  • Knees

  • Pelvis

  • Hands


Cppd deposition
CPPD Deposition

  • Wrist: triangular ligament

  • Pelvis: symphysis pubis

  • Knee: menisci

  • Also: annulus fibrosis, articular capsules, bursae, ligaments, tendons


Clinical associations with psuedogout

Aging

Previous joint surgery

Previous joint trauma

Familial types

Gout

Amyloidosis

Hyperpara

Hemochromatosis

Hypomagnesemia

Familial hypocalciuric hypercalcemia

Hypophosphatasia

Wilson’s disease

Ochronosis

Clinical Associations with Psuedogout


Pseudo djd pattern of cppd
Pseudo-DJD Pattern of CPPD

  • 50% of CPPD patients.

  • Wrists, MCPs, elbows, shoulders, knees. Note difference from usual DJD pattern.

  • Heberden’s or Bouchard’s frequently found.

  • May be acute or chronic.


Treatment of acute psuedogout
Treatment of Acute Psuedogout

  • Aspiration (more important than in gout!)

  • Rest

  • Intra-articular steroids

  • NSAIDs

  • Systemic steroids

  • Colchicine?

  • IL-1 Inhibitors?


Pseudogout prevention
Pseudogout Prevention

  • Colchicine

  • NSAID

  • Magnesium?

  • There’s no allopurinol for pseudogout (unfortunately).


The basic non acidic calcium phosphates
The Basic (Non-Acidic) Calcium Phosphates

  • Hydroxyapatite

  • Calcium carbonate

  • Octacalcium phosphate

  • Tricalcium phosphate (whitlockite)

  • Hydroxyapatite is non-birefringent.


Syndromes associated with hydroxyapatite
Syndromes Associated with Hydroxyapatite

  • Acute monoarthritis (pseudopseudogout)

  • Acute calcific tendinitis, bursitis

  • Scleroderma, dermatomyositis

  • Heterotopic calcification

  • Milwaukee shoulder

  • Crowned Dens Synd.


Acute apatite monoarthritis pseudopseudogout
Acute Apatite Monoarthritis(Pseudopseudogout)

  • Is usually a peri-arthritis.

  • Intense inflammation (looks septic)

  • Synovial fluid often non-inflammatory.

  • Often causes podagra (especially in younger women).

  • Look for the telltale calcifications on radiographs.



Crowned dens synd
Crowned Dens Synd

  • Headache

  • Pain with head rotation

  • Shoulder myalgias

  • Very elevated sed rate


Milwaukee shoulder
Milwaukee Shoulder

  • Severe, destructive shoulder arthropathy.

  • Seen in elderly females with DJD of shoulder.

  • High-riding humeral head on radiographs (large rotator cuff tear).

  • Non-inflammatory fluid with BCP crystals.


Steroid crystal arthritis
Steroid Crystal Arthritis

  • Iatrogenic crystal arthritis.

  • Starts several hours after intra-articular steroid injection.

  • Septic arthritis usually takes longer.

  • Usually short-lived.

  • Ice it; may drain it, but don’t operate on it.


Take home msgs
Take Home Msgs

  • Always give prophylaxis (colchicine or NSAID) before reducing uric acid.

  • Longer courses of prednisone in divided doses for severe gout.

  • Consider anakinra for acute treatment in some cases.

  • Febuxostat is more effective than allopurinol in renal insufficiency.


Take home msgs1
Take Home Msgs

  • The “crowned dens” is a cause of severe headaches, and a mimicker of PMR/GCA.

  • Pseudopseudogout mimicks gout in young persons.

  • CPPDD is associated with destructive osteoarthritis; consider methotrexate.



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