Crystal arthropathies
Maya Mattar, MD
09/15/2014
Gout
Epidemiology
• Ancient disease : “the king of diseases and the disease of kings”
• first identified by the Egyptians
• 5thcentury BC: Hippocrates referred to gout as “unwalkable disease”
and noted links between gout & lifestyle, demographics & other
variables
• Crystals from tophi were first described during the 18th and 19th
centuries
• In the mid 20th century the role of excess urate production and
impaired excretion in the pathogenesis of hyperuricemia were
reported.
• Finally, McCarty and Hollander showed that crystals from the synovial
fluid of patients with gout were composed of MSU
• Rates of gout in USA increased during the 1990s—especially for men
older than 75 years in whom rates nearly doubled from 2.1% in 1990
to 4.1% in 1999.
• In USA 2.6 million in 2005, projected to increase to 3.6 million in 2025
• The prevalence of gout is much higher in men than in women and
rises with age.
Wallace K, Riedel A, Joseph-Ridge N, Wortmann R. J Rheumatol 2004; 31: 1582–87.
Stages of classic gout
1. Asymptomatic hyperuricemia
2. Acute intermittent gout
3. Advanced gout (chronic tophaceous gout)
Asymptomatic hyperuricemia
• Clinical laboratories define hyperuricemia as > 8-8.5 mg/dl
• In physiologic terms , any levels > 6.8 mg/dl because it exceeds the
soluble concentration of MSU in body fluid
• Incidence of gout increases with age as well as degree of
hyperuricemia
• Over time, high serum urate
levels lead to gout
• Normative Aging Study:1858
previously healthy men (average
initial age 42) followed for 14.9
years
Campion et al. Am J Med. 1987;82:421-426.
• However vast majority of people with hyperuricemia never develop
symptoms associated with uric acid excess .
Acute intermittent gout
• Decades of untreated, chronic hyperuricemia increases body urate
stores, advancing the severity of the disease:
•
•
•
•
Flares last longer
Flares occur more often
Intercritical segments (flare free periods) decrease
Persistent pain and stiffness occur
Primer on the Rheumatic Diseases. 12th ed. Arthritis
Foundation; 2001:313.
Description of acute attack:
The night is spent in torture !
• The victim goes to bed and sleeps in good health. About 2 am he is
awakened by a severe pain in the great toe; more rarely in the heel ,
ankle, or instep. The pain is like that of a dislocation, and yet the parts
feel as if cold water were poured over them…..Now it is a violent
stretching and tearing of the ligaments…. So exquisite and lively
meanwhile is the feeling of the part affected , that it cannot bear the
weight of bedclothes nor the jar of a person walking in the room.
Primer on the Rheumatic Diseases. 12th ed. Arthritis Foundation; 2001:313.
Thomas Sydenham, 17th century
• In Their Own Words
• “It is by far the most horrendous pain one should have to endure.”
• “I can’t believe how much this hurts.”
• “I've broken legs, arms, ribs, all nothing compared to my big toe. Even a bed
sheet hurts.”
• “There’s worse things, but they don’t hurt as much as gout.”
A typical attack of gout:
• Rapid development of warmth, swelling, erythema and pain in the
affected joint
• Pain escalates to most intense level in 8-12 hrs
• Initial attack is usually monoarticular and >50% cases involve the 1st
MTP joint.
• Other joints involved in early stage: midfoot, ankles, heels and knees.
Less commonly wrists , fingers and elbows.
• Systemic symptoms such as fever > 38 C can be seen in 30% of
patients with acute gout attacks, chills, and malaise.
• It also triggers a systemic inflammatory response manifesting with
leukocytosis, elevated ESR and CRP.
• Solubility of urate in joint fluids depends on:
• the articular hydration state
• Temperature
• pH, concentration of cations, and presence of extracellular matrix proteins
such as proteoglycans, collagens, and chondroitin sulphate.
• these factors might explain:
• The 1st MTP joint involvement (a peripheral joint with low temperature)
• Osteoarthritic joints (joints with decreased collagen and proteoglycan
content)
• The nocturnal onset of pain (because of intra-articular dehydration)
Choi HK, Mount DB, Reginato AM. Ann Intern Med 2005; 143: 499–516.
Roddy E, Zhang W, Doherty M. Ann Rheum Dis 2007; 66: 1374–77.
Intervals between
st
1
and
nd
2
acute flares:
Yu et al. Ann IntMed. 1961;55:179-192
• Acute attacks can be precipitated:
•
•
•
•
•
•
•
Increased alcohol consumption (especially beer)
Trauma
Use of diuretics
Dehydration
Cyclosporine
Diet (organ meat, shellfish)
Drugs that can lead to sudden changes (increase or decrease) in urate levels,
such as hypouricemic agents
• If left untreated , acute gout varies from episodes of mild pain “petits
attacks” to several attacks that last 1 to 2 weeks.
• Over time, attacks typically become more frequent, longer in
duration, and involve more joints, and spread to the upper limbs.
• Intercritical period:
• Previously involved joints are virtually free of symptoms
• Despite this, MSU crystals often can be identified in the synovial fluid of
previously inflamed joints which reflect ongoing subclinical inflammation
Differential dx:
1. Crystal-induced arthritis:
• CPPD
• Hydroxyapatite
• Calcium oxalate
2. Infectious arthritis
3. Systemic diseases:
• Psoriatic arthritis
• RA
• Reactive arthritis
Advanced gout
• It is characterized by chronic destructive polyarticular involvement
with low-grade joint inflammation, joint deformity, and tophi
• Tophaceous gout develops within 5 years of onset of gout in 30% of
untreated patients
• Tophi are painless and rarely become infected but function and
health-related QoL can be severely affected with chronic gout
Patient
Society
↓QOL with gout progression, worse QOL scores
with >1 tophi vs no tophi
Estimated 2.6 million (2005) with estimate of 3.6
million (2025)
Inter-critical periods:
25% report pain when not experiencing flare
$27.4 million = estimated annual direct cost for
new cases of acute gout in US
Nearly half of all gout pts have difficulty in
recreation & other QOL activities, but some will
also have difficulty with even basic activities of
daily living
Near doubling of claims cost for Rx, sick leave, short
term disability and workman’s comp in gout vs nongout pts ($6970 vs $3705)
Higher rate of all-cause mortality in those with
gout vs without
More absence days per year and lower mean
annual productivity
• Tophi are frequently seen in:
•
•
•
•
•
•
Helix of the ear
Over the olecranon processes
On the Achilles tendons
Within and around the toe or finger joints
Around the knees, and within the pre-patellar bursae
Spinal involvement can lead to nerve root or cord compressionand might also
mimic epidural infection
• Median nerve, which leads to carpal tunnel syndrome
• Rare locations: eyes,breast,vocal cords,heart,and colon
Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
Diagnosis (EULAR recs)
• A typical presentation of gout is highly suggestive of crystal inflammation,
although not specific for gout
• Identification of MSU crystals in synovial fluid or tophus aspirates allows a
definitive diagnosis of gout
• Gout and sepsis can coexist, so gram stain and culture of synovial fluid
should still be done when septic arthritis is even if MSU crystals are
identified
• Serum uric acid concentrations do not confirm or exclude gout because
many people with hyperuricemia do not develop gout, and during acute
attacks serum concentrations might be within the normal range in a third
of patients
• Radiographs useful for differential diagnosis and might show typical
features in chronic gout, but are not useful for confirmation of
diagnosis of early or acute gout
• Risk factors for gout and associated comorbidity should be assessed,
including features of metabolic syndrome (obesity, hyperglycemia,
hyperlipidemia, and hypertension)
Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
Lancet. 2010 Jan 23;375(9711):318-28. doi: 10.1016/S0140-6736(09)60883-7
Treatment
• Lifestyle modifications:
• Obesity is the commonest comorbid risk factor for gout ->address overweight
• Protective food: coffee, dairy products, and vitamin C
• Causative (beer but not wine, meat and seafood, and fructose)
• Adhering to lifestyle advice alone can have a small urate lowering
effect but carry additional benefits in terms of overall health, with
regard to the metabolic syndrome.
• Further treatment is divided into acute and chronic gout treatment
• Acute treatment:
• Main aim of acute treatment is to provide rapid relief of pain and
inflammation and exclude joint sepsis
• Affected joints should be rested and treated with ice, which has a significant
anti-inflammatory effect
• NSAIDs are the most commonly used first-line treatment
• Head-to-head studies show few differences between drugs
• Full doses of NSAID should be initiated immediately and tapered after
resolution of symptoms
Kelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
• Avoid NSAIDs:
•
•
•
•
•
G-I ulcer
Bleeding or perforation
Renal insufficiency
Heart failure
Use of oral anticoagulants
• Co-administration of a proton pump inhibitor should be considered
• Colchicine:
• Blocks microtubule assembly in neutrophils reducing phagocytosis and
transport of MSU crystals.
• Affects neutrophil migration into joints by reducing adhesion molecules on
endothelial cells and neutrophils in response to IL-1 or TNF-a.
• Reduces NALP3 inflammasome-driven caspase-1 activation by microtubule
inhibition which decreases MSU delivery
• low-dose colchicine (1.8 mg over 1 hour) can be utilized effectively
and safely in acute gout flare
• Adverse events of colchicine:
•
•
•
•
Abdominal cramps
Nausea, vomiting
Bone marrow suppression
Neuropathy and myopathy
• IV colchicine is no longer as it has a 2% mortality rate.
Kelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
• Reduced dosing in elderly or those with renal or hepatic impairment
• Toxicity can be caused by drugs interacting with its metabolism and
clearance, which include macrolides, cyclosporine and protease
inhibitors
• No trials have directly compared NSAIDs and colchicine.
• Corticosteroids:
• Intraarticularly (preferred route if one or two joints affected)
• Orally
• Intramuscularly or intravenously.
• Corticosteroids are a good alternative where NSAID and colchicine
cannot be used or in refractory cases
• Studies showed equal efficacy between corticosteroid and NSAIDs,
with no reported side-effects with short-term use of corticosteroid
Kelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
• The anti-IL-1 drugs: anakinra
• Subcutaneous injections of anakinra 100mg daily for 3 days is well tolerated
and efficacious treatment of flares.
• Used in case gout is refractory to other available options, or NSAIDs ,
colchicine or steroids cannot be used
• Expensive
• Not for preventive use
Kelsey Jordan.Curr Opin Rheumatol 2012, 24:145–151
• In certain cases narcotics are only options for treatment of acute gout
flares (neutropenia, advanced renal failure, infection, malignancy)
• Chronic treatment:
• Prevent recurrent attacks and alleviate complications of chronic gouty
arthritis
• ‘Treat to target’ to prevent MSU crystal saturation and dissolve crystals
already deposited in joints and soft tissue (goal serum urate < 6 mg/dl)
• Assess and modify contributing risk factors (HTN, DM type 2, DLP, CHF,
obesity, OA, drugs (diuretics and ciclosporin)
• Provide long-term follow-up and monitoring of gout including serum urate
checks
• It has long been advocated that urate-lowering therapy (ULT) should
not be initiated until after an acute gout flare has resolved
• The absolute risks of these complications have not been established ,
and some experts have suggested that ULT can occasionally be started
together with anti-inflammatory therapy during an acute attack
Taylor TH, et al Am J Med. 2012 Nov;125(11):1126-1134.
• Uricostatic agents: xanthine oxidase inhibitors
Allopurinol:
• The most commonly used dose is 300mg daily, with the maximum dose of
900mg daily.
• Introducing at a dose of 100mg daily and increased by 100mg ,may reduce
flare on initiation
• Commencing at a low dose and slowly incrementing can reduce the risk of
allopurinol hypersensitivity reaction .
• Adverse events of allopurinol:
•
•
•
•
•
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Rash (2%)
Vasculitis
Eosinophilia
Life-threatening hypersensitivity reaction
Hepatitis
Decreased renal function and bone-marrow suppression.
• In transplant patients be aware of the dangerous drug interaction
between allopurinol and azathioprine, because xanthine oxidase is
related to metabolism of azathioprine (and 6-mercaptopurine).
• Mycophenolate mofetil, which is not metabolised by xanthine
oxidase, can be substituted for azathioprine to ensure safe use of
allopurinol.
Febuxostat (Uloric):
• new nonpurine selective xanthine oxidase inhibitor.
• It is primarily metabolized in the liver and therefore no dose
reduction in moderate renal function is required.
• Efficacy: at 52 weeks s uric acid < 6 mg/dl -> 53% of the patients on
80mg of febuxostat, 62% on 120mg of febuxostat and only 21% in
those receiving allopurinol 300 mg daily.
• Its place in treatment should be as a second-line agent where
allopurinol has failed to reduce s uric acid or contraindicated.
Uricosuric agents :These drugs enhance the renal clearance of urate
• Probenicid:
Can be effective as an add-in therapy when allopurinol alone is insufficient,
contraindicated in nephrolithiasis and inefficient in renal failure
• Oral colchicine can reduce the frequency of recurrent episodes of
acute gouty arthritis (0.6 mg orally once or twice daily for patients
with normal renal function)
• colchicine is continued for six months after normal serum urate
values have been obtained in patients without tophi
• Other interventions: discontinuation of diuretics and use of the
uricosuric drugs losartan and fenofibrate for HTN and DLP.
• Studies have shown only 30–60% of patients are still prescribed
allopurinol 1 year after initiation of therapy and that management of
gout is frequently inappropriate.
• Patient education:
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•
•
•
Disease nature
Targets and practicalities of drug therapy
How to prevent and handle flares
Importance of lifestyle and dietary factors
Pseudogout
• calcium pyrophosphate dehydrate (CPPD) crystals deposit in joints
and soft tissue, resulting in inflammation and tissue damage
• It is not commonly encountered at a younger age without a previous
history of trauma or surgery, is seen more commonly after age 50
years, and it has no definite ethnic or gender predilection
• Clinical manifestations:
•
•
•
•
Ranges from asymptomatic to gout like (pseudogout)
Rheumatoid arthritis–like (pseudo-rheumatoid arthritis)
Osteoarthritis-like (pseudo-osteoarthritis)
PMR-like (pseudo-PMR)
• Acute or subacute attacks can involve one or multiple joints
• Systemic features such as fever, malaise, leukocytosis, and elevated
ESR and CRP can be present
• Pseudogout and gout can share similar joint predilection, but
pseudogout affects larger joints more commonly than gout (knee
joints, wrists, elbows, shoulders)
• It is often difficult to differentiate gout and pseudogout without a
synovial fluid analysis
• Diagnosis:
• Synovial fluid analysis:
• CPPD crystals might not be as evident as MSU crystals.
• Detection might not be as accurate if fluid analysis is delayed.
• In addition, because pseudogout and gout can coexist, MSU crystals might also be observed
• Radiographs:
• Chondrocalcinosis in the joint involved and other more typical joints even if pseudogout
is not clinically active at the time of presentation
• They are not required to make the diagnosis once CPPD crystals are seen under polarized
light
• Conditions associated with pseudogout:
•
•
•
•
•
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Trauma
Hyperparathyroidism
Hypomagnesemia
Hypophosphatasia
Hypothyroidism
Hemochromatosis
• Differential dx:
1. Crystal-induced arthritis:
• Gout
• Hydroxyapatite
• Calcium oxalate
2. Infectious arthritis
3. Systemic diseases:
•
•
•
•
Psoriatic arthritis
RA
Reactive arthritis
PMR
Treatment:
• Acute:
• If one or two joints: joint aspiration and IA steroid injection
• If more than two joints are involved treatment is directed more toward
systemic therapy (NSAIDs, corticosteroids, colchicine)
• Chronic:
• In patients with three or more attacks a year colchicine at a dose of 0.6 mg
once or twice daily to reduce the number of attacks in a year.
• There are no hypouricemic equivalents to improve the long-term control of
pseudogout and to prevent or reverse CPPD crystal deposit disease.
Other crystal arthropathies:
• Milwaukee shoulder:
• Seen mainly in older females with advanced DJD
• Severe destructive shoulder arthropathy
• Fluid is non inflammatory, and is due to basic calcium phosphate crystals
(hydroxyapatite)
• Steroid induced arthritis:
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•
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Iatrogenic crystal arthritis
Develop within few hours after IA cortisteroid injection
Septic arthritis takes longer to develop
Short lived
Symptomatic treatment: rest and ice application