Crystal Arthropathies Flashcards
Gout is a common disorder of…?
Uric acid metabolism (uric acid is a product of purine breakdown)
How many % of the population does gout affect?
1%
Is gout more common in males or females?
Why?
Males
Uric acid levels in the blood need to be elevated for about 20 years before onset of gout. The levels rise in men at puberty, but not until menopause in women, so women would have to be about 70-80 before onset of gout.
What crystals get deposited in soft tissues in gout?
Monosodium urate crystals
If gout is left untreated, what can it lead to? (2)
Joint destruction
Renal damage
Where do 50% of cases of gout start?
First MTP (big toe)
Presence of urate crystals in synovial fluid is not sufficient to cause flares of gouty arthritis - how is this explained?
Clumps (microtophi) of highly negatively charged and reactive monosodium urate crystals are normally coated with serum proteins (ApoE or B) – these proteins inhibit the binding of crystals to cell receptors, so they are inert.
What can trigger a gout attack?
Either a release of uncoated crystals, or a sudden large change in concentration
After a gout attack is triggered, what happens?
The naked crystals (not coated with serum proteins) interact with intracellular and surface receptors of dendritic cells and macrophages, activating the innate immune system.
This causes the production of IL-1, which initiates the production of a cascade of proinflammatory cytokines (e.g. IL-6, IL-8, and TNF-alpha).
Neutrophils phagocytose crystals and burst, releasing their intercellular contents.
This lowers the PH, due to release of lysosomes, and also leads to more inflammatory mediation production. A lower pH leads to more precipitation, which sets up the spiral.
Gout is unlikely before…?
30 years of age
How does gout usually present?
Acute monoarticular (90% of cases) Small lower extremity joints Podagra - inflammation of 1st MTP joint (50% of cases) Begins suddenly and reach maximum intensity with 8-12 hours
What joints are commonly affected? (4)
1st MTP (90% of individuals) = podagra
Ankle
Knee = gonagra
Elbow
What other complications of gout are there? (4)
Renal damage/stones
Deposition of crystals in cartilage (tophi) – ear, hands
Gout osteoarthropathy
Olecranon bursitis
What does the patient present with in terms of the joint history?
Red, hot, tender.
Pain starts acutely and usually at night.
Intermittent cycles – the first attacks resolve spontaneously in less than two weeks.
If gout is untreated…? (5)
Attacks become polyarticular
More proximal and upper extremity joints involved
Attacks more frequent and last longer
Chronic polyarticular arthritis almost symmetrical
Can affect other synovial structures
What can be seen on x-ray and on examination in gout?
Tophi
‘Rat bite’ erosions on x-ray
What are tophi? How many untreated patients do they develop in?
Urate crystals in soft tissues
50% after 10 years
What do these tophi look like on histology?
Foreign body-type giant cells seen (reaction to the deposited crystals)
The crystalline nature of this material is not obvious in formalin-fixed specimen as the crystals get washed out, but you can see some brown deposit
Macrophages (histocytes) wall off (palisading) the central crystals, and you get lymphocytes around this.
How many mg/dL of purines do we get from diet? How much is synthesised?
600mg/dL
Purine nucleotides and bases 300-600mg/dL, plus tissue nucleotide synthesis 300-600mg/dL
How do humans remove uric acid?
Renal excretion (600mg/dL) and faeces (200mg/dL)
When excretion is insufficient to maintain serum urate levels below what level does hyperuricemia develop?
6.8mg/dL
Is gout usually due to overproduction or under excretion?
What can cause this? (3)
Under excretion (90% of cases) Renal insufficiency, dehydration, thiazide diuretics
What foods are high in purines?
Beef, pork, lamb, seafood, beer, alcoholic beverages…
What are the gout risk factors? (6)
Male Age Obesity Ethnicity (Pacific Islanders) Genetics (polymorphisms) Kidney disease
What are potential sources of elevated purines? (3)
Catabolism of purines
Tumour lysis syndrome
Diet
What are the related risks of hyperuricemia? (5)
Joint inflammation, kidney or bladder stones, nephropathy, CV disease, metabolic syndrome
What causes decreased renal clearance of uric acid? (4)
Drugs (aspirin, HTZ), fructose, genetic factors, kidney disease
How is gout diagnosed using the 11 variables (used by GPs)?
Need more than 6 out of 11 - if it is less than 4 it isn’t gout. If it is between 4 and 8, do synovial fluid analysis.
Includes more than one attack of acute arthritis, monoarthritic, redness, first MTP painful or swollen, hyperuricemia etc.
What is definitive gout?
Definitive gout = urate crystals in joint fluid during attack and joint fluid culture negative for organisms during attack
What are the differential diagnoses for gout?
RA, pseudogout, psoriatic arthritis, septic arthritis, reactive arthritis
What counts as hyperuricemia?
Serum uric acid level more than 5.88mg/dL
How is gout diagnosed using synovial fluid?
High WBC count (greater than 2000/μL and possibly greater than 50,000/μL) – due to polymorphonuclear neutrophils that phagocytose crystals
The fluid appears white and cloudy
May see crystals – shine under polarising light, sharp, needle-like, high negatively birefringent
How is gout diagnosed using serum uric acid? Why?
It isn’t really – presence of hyperuricemia is NOT diagnostic.
This is because 5-8% of population have elevated serum uric acid levels (>7mg/dL), but only 5-20% of these people develop gout
If it is higher than 11mg/Dl it should be treated
How is gout diagnosed using imaging?
X-rays – ‘rat bite’ erosions (have overhanging edges), maintenance of joint space, erosion outside joint capsule
Ultrasound – erosions, can see active inflammation, soft tissue swelling, increased blood flow
What is a feature of all erosive/inflammatory arthropathies?
Joint damage
How do tophaceous deposits lead to bone erosions?
Crystals surrounded by granulomatous tissue reaction
Produce pro-inflammatory cytokines (IL-1, TNF, IL-6) that initiate the production of RANKL and so stimulate osteoclasts.
How are acute gout attacks treated? (4)
NSAIDs
Colchicine
Corticosteroids
IL-1 biologicals
What is colchicine? Why is it now second line?
Anti-mitotic
Narrow therapeutic window and risk of toxicity
When are corticosteroids given?
If patient can’t use NSAID or colchicine
Give 3 examples of IL-1 biologicals?
Rilonacept, canakinumab, anakinra
How do IL-1 biologicals help? What patients are these used in?
Reduces length of attack and reoccurrences
Patients who have severe and frequent flares
How is chronic gout treated?
Low purine diet
Allopurinol
Probenecid
Rasburicase
How does allopurinol work?
Blocks xanthine oxidase - reduces generation of uric acid
How does probenecid work?
What is its benefit over allopurinol?
Uricosuric - increases uric acid excretion
Fewer significant adverse effects
How does rasburicase work?
Catalyses conversion of uric acid to allantoin
What is pseudogout?
Calcium pyrophosphate deposition disease (CPDD):
- Metabolic arthropathy
- Chondrocalcinosis
- Acute deposition of calcium pyrophosphate crystals in and around joints
How many % of people over 85 years have evidence of chondrocalcinosis?
Around 50%
Pseudogout is either pseudo-osteoarthritis or asymptomatic. Explain this.
Pseudo-osteoarthritis (50% of cases) with osteophytes and soft tissue calcification on radiographs
Or
Asymptomatic where only radiographic findings and no other symptoms
Explain the process of pseudogout.
Release of CPPD crystals into joint space followed by phagocytosis of crystals by monocyte-macrophages or neutrophils which then release cytokines and cause inflammation.
What joint is most commonly affected by pseudogout?
Knee
What can trigger acute attacks of pseudogout? (2)
Trauma
Rapid reduction of serum calcium concentration
How is pseudogout diagnosed using synovial fluid?
Mild to moderate inflammation
10,000-50,000 WBCs/μL 90% polymorphonuclear neutrophils
Rhomboid shaped weakly birefringent crystals
How is gout diagnosed using ultrasound?
Can see calcification within soft tissue and within the articular cartilage (parallel with condyle).
In pseudogout there is chondrocalcinosis of… and atypical OA of…?
It is associated with … in same or neighbouring joints.
Articular disc
Hands
OA
How is pseudogout treated?
Intra-articular corticosteroids
NSAIDs
How do gout and pseudogout differ?
Gout much more common in men (7:1), pseudogout a little more common in women
Serum urate is elevated in gout, not in pseudogout
There are tophi, erosions (rat bite), needle shaped crystals in gout
Chondrocalcinosis, and rhomboid shaped crystals in pseudogout
The joints involved are different – gout affects first MTP, fingers, bursa etc, whereas pseudogout affects the knees and wrists
