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)
"Be temperate in wine, in
eating, girls, and sloth, or
the Gout will seize you and
plague you…"
-- Franklin
MAJOR ARTHRITOGENIC
CRYSTALS
• Monosodium urate
• Calcium pyrophosphate
dihydratte
• Hydroxyapatite
• Corticosteroid esters
• Calcium oxalate
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 (xlinked)
• Beta aldolase deficiency
• Sarcoidosis
• B12 deficiency
• Down syndrome
• Glycogen storage dis. 3, 5, 7
• Fever, post-op state
Risk Factors for Gout
•
•
•
•
•
Obesity, metabolic syndrome
Ethanol
Diuretics
Fructose ingestion
Excessive purine ingestion
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
• 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
• 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
Hyperuricemia & Gout
Serum Uric Acid
(mg/dl)
< 7.0
Annual Incidence
of Gout (%)
0.1
7.0 – 8.9
0.5
> 9.0
4.9
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?
• 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
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.
• In experimental models,
hyperuricemia causes:
– Hypertension
– Reduced perfusion
– Endothelial dysfunction
– Renal dysfunction
• Reversible with hypouricemics
Frequent Clinical
Associations with Gout
•
•
•
•
•
Hypertension
Diabetes
Hyperlipidemia
Obesity
Ethanol – the fuel
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
AKA:
• Familial medullary cystic kidney
disease, type 2.
• Familial juvenile hyperuricemic
nephropathy.
• Uromodulin storage disease.
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
• 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
•
•
•
•
•
•
MSU
CPPD
Hydroxyapatite
Septic
Psoriatic, Reiter’s
Rheumatoid
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
• Treat acute attack
• Prevent new attacks
• Reduce uric acid level
(sometimes)
Phase 1 - Termination
•
•
•
•
•
NSAID
Colchcine
Intra-articular steroids
Systemic steroids
IL-1 inhibitors
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
• One or a few joints.
• Not useful for polyarticular or
soft-tissue gout.
• Make sure infection not
present.
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
•
•
•
•
•
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)
• 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
•
•
•
•
•
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
• 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
• 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
• 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
•
•
•
•
•
•
•
Allopurinol
Febuxostat
Probenecid
Pegloticase
Losartan (off-label)
High-dose salicylates (off-label)
Vitamin C (off-label)
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
• 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
• Don’t treat it (this advice may
change in future)
• Exception: Patients getting
chemotherapy for leukemia,
lymphoma.
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!)
• 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
• Allopurinol
– calcium and uric acid
stones
• Potassium citrate
– calcium and uric acid
stones
– direct inhibitor of
nucleation
• Fluids!
Treatment of Stones
in Gouty Patients
• Allopurinol
– calcium and uric acid stones
• Potassium citrate
– calcium and uric acid stones
– direct inhibitor of nucleation
• Fluids!
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
Mean Reduction in Tophus Area
Group
% Area Reduction
P Value
Feb 80 mg
83
P = .08 (NS)
Feb 120 mg
66
P = 0.16 (NS)
Allop 300mg
50
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
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.
Febuxostat
• Adverse Reactions
– Nausea
– Gout flare (must be on prophylaxis!)
– Elevated ALT, AST (3% > 3xULN)
– Elevated CRP
– Rash
– Elevated CK
Febuxostat: Best Use
• Allopurinol failures
• Renal insufficiency
• Tophaceous gout
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
• For refractory chronic gout
• Dissolves tophi in weeks
to months
• Problems:
– Anaphylaxis
– Antibody formation
– Not in G6PD defic.
– $$$$
This is chronic
refractory
gout!
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)
• 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 offlabel).
• Don’t forget vitamin C (500 mg BID)
Gout
Yellow
Negative (when parallel)
GYN
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:
•
•
•
•
Cell count
Crystals
Culture
Glucose
Lavendar top
Green top
Red top, no preserv.
Red top
• Protein, pH, complement – not
helpful
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.
On to
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
• Knees
• Pelvis
• Hands
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
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
• Aspiration (more important
than in gout!)
• Rest
• Intra-articular steroids
• NSAIDs
• Systemic steroids
• Colchicine?
• IL-1 Inhibitors?
Pseudogout Prevention
•
•
•
•
Colchicine
NSAID
Magnesium?
There’s no allopurinol for
pseudogout (unfortunately).
The Basic (Non-Acidic)
Calcium Phosphates
•
•
•
•
Hydroxyapatite
Calcium carbonate
Octacalcium phosphate
Tricalcium phosphate
(whitlockite)
• Hydroxyapatite is nonbirefringent.
Syndromes Associated
with Hydroxyapatite
• Acute monoarthritis
(pseudopseudogout)
• Acute calcific tendinitis, bursitis
• Scleroderma, dermatomyositis
• Heterotopic calcification
• Milwaukee shoulder
• Crowned Dens Synd.
Acute Apatite
Monoarthritis
(Pseudopseudogout)
• Is usually a peri-arthritis.
• Intense inflammation (looks septic)
• Synovial fluid often noninflammatory.
• Often causes podagra (especially in
younger women).
• Look for the telltale calcifications on
radiographs.
CROWNED DENS SYNDROME
Crowned Dens Synd
•
•
•
•
Headache
Pain with head rotation
Shoulder myalgias
Very elevated sed rate
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
• Iatrogenic crystal arthritis.
• Starts several hours after intraarticular steroid injection.
• Septic arthritis usually takes
longer.
• Usually short-lived.
• Ice it; may drain it, but don’t
operate on it.
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 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.
THE END