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 hyperuricemia2. Acute intermittent gout3. 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 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

The night is spent in torture !

• 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 1st and 2nd 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 arthritis3. 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 non-gout 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 compression and 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 over-

weight• 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 inhibitorsAllopurinol:

• 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:• 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:• 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:• Trauma • Hyperparathyroidism• Hypomagnesemia• Hypophosphatasia• Hypothyroidism• Hemochromatosis

• Differential dx:1. Crystal-induced arthritis:

• Gout• Hydroxyapatite• Calcium oxalate

2. Infectious arthritis3. 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:• 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