Crystal arthropathies

Crystal arthropathies are a group of joint disorders that are characterised by the deposition of microscopic crystal within the joint and surrounding tissues. The most common types of crystal arthropathies include:

• Gout - caused by monosodium urate crystals.
• Pseudogout - caused by calcium pyrophosphate dihydrate crystals.
• Basic calcium phosphate crystal deposition disease - caused by basic calcium phosphate crystals such as hydroxyapatite.

We will discuss each of these in more detail below…

Gout

Gout is characterised by the accumulation of monosodium urate (MSU) crystals in joints and peripheral tissues. It was historically known as rich man’s disease as it was believed that it was the “rich” diet which was heavy in meat and wine is what caused it. It is now known that it is the accumulation and precipitation of MSU crystals that form the disease.

The most commonly affected joints are:

• Metatarsophalangeal (MTP) joints - especially in the big toe (this is known as podagra).
• Metacarpophalangeal (MCP) joints - this is known as chiragra.
• Radiocarpal (wrist) joint

It can also affect larger joints such as the knee (known as gonagra) and ankle.

Pathophysiology

The primary cause of gout is hyperuricaemia (an increase of serum uric acid levels). Before we discuss how we may get hyperuricaemia, let’s discuss how uric acid is formed:

Uric acid is the end product of purine metabolism in humans. Purines are nitrogen-containing compounds, such as adenine and guanine, that serve as building blocks in DNA and RNA. They are also found in various foods such as meat, seafood, alcohol (especially beer). Purines are metabolised to form uric acid which is then excreted. This metabolism involves a series of enzymes and pathways:

• Purines are broken down into hypoxanthine and then xanthine by the enzyme xanthine oxidase. Xanthine oxidase then converts the xanthine into uric acid.
• Purines are also recycled using the purine salvage pathway. The enzyme hypoxanthine-guanine phosphoribosyltransferaase (HGPRT) converts hypoxanthine into inosine monophosphate (IMP) and converts guanine into guanosine monophosphate (GMP) which therefore prevents degradation into uric acid.

When serum uric acid levels exceed the limit for solubility (around 6.8mg/dL) they begin to form MSU crystal, particularly in cooler areas of the body.

So what causes hyperuricaemia?

1. Increased uric acid production - overproduction can occur due to genetic factors as well as dietary factors. Genetic mutations affecting HGPRT occurs in Lesch-Nyhan syndrome, this leads to an overproduction of uric acid. Dietary factors include eating purine-rich foods such as red meat, seafood, alcohol, and fructose-sweetened beverages.
2. Decreased uric acid excretion - the kidneys maintain urate levels through renal excretion. This contributes to 70% of urate excretion. The other 30% is excreted by the gastrointestinal tract. Renal under-excretion is the most common cause of hyperuricaemia. This may occur due to genetic predispositions, renal insufficiency, hypertension and certain medications. Thiazide-diuretics and low-dose aspirin can impair uric acid excretion.

💡 90% of individuals have hyperuricaemia due to impaired renal excretion, 10% have it due to overproduction and a smaller proportion have a mixture of both under-excretion and overproduction.

When these MSU crystals form they deposit in cooler areas of the body such as the peripheral joints. This leads to an intense inflammatory response. MSU crystals are phagocytoses by synovial macrophages which activates the NLRP3 inflammasome which activates caspase-1 to activate IL-1. IL-1 is a potent pro-inflammatory cytokine that then recruits neutrophils and other inflammatory cells. This is the hallmark of acute gouty arthritis. These cells release reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) which leads to tissue damage, swelling and pain. This mainly occurs in the first MTP joint (podagra). After this first attack, a second attack may occur within one year and chronic symptoms may develop within 10 years. This is known as intercritical gout. Recurrent acute attacks may lead to chronic tophaceous gout which is characterised by the formation of tophi (MSU aggregates surrounded by inflammatory cells and fibrous tissue). These tophi can lead to destruction, deformity and disability of the joint.

⚠️ Risk factors

😷 Presentation

It is important to note that gout can occur in individuals who have normal serum uric acid levels, and furthermore 95% of individuals with hyperuricaemia are asymptomatic (known as asymptomatic hyperuricaemia) and never develop gout. The risk of developing gout increases with serum uric acid levels though.

Gout usually presents as a monoarthritis but can develop into an oligoarthritis/polyarthritis over time. It may be acute or chronic:

• Acute gouty arthritis - this refers to a flare of gout. The initial episode most commonly affects the MTP joint but it is also common in the midfoot, ankle, knee, fingers, wrist and elbows.
• Acute, severe pain of the affected joint usually occurring overnight and waking the patient from sleep. It reaches maximum intensity within 24 hours.
• Overlying erythema, swelling, warmth and decreased range of motion.
• There may be desquamation of the overlying skin during the recovery of an acute flare.
• Chronic gouty arthritis - this is rarer nowadays as the management after an acute flare has reduced the number of cases significantly. It may occur due to poor access to healthcare; lack of compliance with medication; or longstanding, untreated gout.
• Progressive joint destruction - due to repetitive attacks and crystal deposition. This may lead to inability to walk if the first MTP is affected.
• Nephrolithiasis and nephropathy
• Tophi formation these are painless, hard, cutaneous nodules that form due to the deposition of MSU crystals, along with inflammatory cells and fibrous tissue. They are typically seen on the extensor surfaces, Achilles tendon, dorsum of the hands and feet and in the helix of the ears. The tophi may be deposited in the bones or in the soft tissue such as bursae (which may cause bursitis).

🔍 Investigations

⭐️ Gout is a clinical diagnosis that can be made in conjunction with serum uric acid levels. A level of 360micromol/L (6mg/dL) or more confirms the diagnosis. However, in an acute flare the level may be normal as it gets consumed in the process of inflammation. If the level is <360micromol/L but gout is strongly suspected then we should repeat the measurement 2-4 weeks after the flare has settled.

If the diagnosis is still unconfirmed then we can do some investigations in secondary care:

• 🏆 Joint aspiration (arthrocentesis) and polarised light microscopy of synovial fluid - this will show strongly negative birefringent needle-shaped crystals under polarised light.
• Ultrasound or dual energy CT (DECT) scan of the joint - these may show erosions, tophi and a double contour sign.
• X-ray - shows:
• Maintained joint space
• Lytic lesions
• Punched out erosions with sclerotic borders and overhanging edges.

🧰 Management

🚨 Complications

• Chronic arthritis
• Joint damage
• Renal stones
• Trophi
• Cardiovascular disease
• Chronic kidney disease

Pseudogout

Pseudogout, also known as calcium pyrophosphate dihydrate (CPPD) deposition disease is another form of crystal arthropathy that is characterised by CPPD crystals accumulating in the joint. It is called pseudogout as it mimics gout. It more typically affects older adults and involves larger joints (such as the knees, wrists and shoulders).

Pathophysiology

CPPD crystals form due to an excess of inorganic pyrophosphate in the extracellular matrix of cartilage. The excess may occur due to ageing, joint injury and metabolic disturbances. This pyrophosphate combines with calcium to form CPPD crystals. These crystals are deposited in cartilage and synovium which results in inflammation and can be seen on imaging (chondrocalcinosis). Similar to gout it triggers an inflammatory response that is mediated by IL-1, IL-6 and TNF-alpha. Over time, repeated attacks of inflammation may lead to chronic joint damage which is characterised by cartilage degradation, synovial hyperplasia, fibrosis.

⚠️ Risk factors

Most cases are idiopathic with advancing age being the biggest risk factor for primary pseudogout development.

It may also develop secondary to other factors:

• Joint injury/surgery
• Hyperparathyroidism
• Haemochromatosis
• Hypomagnesaemia
• Hypophosphatasia
• Familial chondrocalcinosis - this may be due to mutations in the CCAL1 or CCAL2 genes.

😷 Presentation

• Acute CPPD arthritis:
• Acute onset of pain and swelling
• Monoarthritis (sometimes may be oligoarthritis)
• Commonly affects larger joints such as the knee, wrist, ankles and hips.
• Longer duration than gout
• Self-limiting
• Chronic CPPD arthritis:
• Osteoarthritis-like presentation characterised by progressive joint degeneration but is more severe than osteoarthritis.
• Polyarticular usually and in joints not affected by osteoarthritis typically (such as smaller joints).
• May present with rheumatoid arthritis-like presentation characterised by polyarticular distribution associated with morning stiffness but is rather assymetrical.

🔍 Investigations

• 🏆 Joint aspiration (arthrocentesis) and polarised light microscopy of synovial fluid - this will show positive birefringent rhomboid-shaped crystals under polarised light.

Other first-line investigations to do are:

• X-ray of affected joint - may show chondrocalcinosis. It is not diagnostic of pseudogout but is suggestive of it. It may also show osteoarthritic changes such as:
• Loss of joint space
• Osteophytes
• Subchondral cysts
• Sclerosis


• Serum calcium and serum PTH - to assess for hyperparathyroidism.
• Iron studies - to assess for haemochromatosis.
• Serum magnesium - to assess for hypomagnesaemia.
• Serum alkaline phosphatase - to assess for hypophosphatasia.
• Serum uric acid - to differentiate it from gout.

🧰 Management

Basic calcium phosphate crystal deposition disease

Basic calcium phosphate (BCP) crystal deposition disease, also known as apatite-associated arthropathy, involves the deposition of BCP crystals in and around joints. It manifests in various forms such as Milwaukee shoulder syndrome and calcific tendinitis.

Pathophysiology

The pathophysiology involves the formation of BCP crystals. These are primarily made up of hydroxyapatite (composed of calcium and phosphate). The crystals deposit in joints such as cartilage, synovium and tendons and also lead to inflammation and joint damage. In conditions such as Milwaukee shoulder syndrome, large joint effusions, rotator cuff tears and severe joint destruction are characteristic. This highlights the aggressive nature of BCP crystal-related arthropathy. Other forms of BCP include: octacalcium phosphate and tricalcium phosphate.

⚠️ Risk factors

• Female sex
• Mild trauma or joint overuse
• Gout and pseudogout
• Renal disease
• Metabolic abnormalities - such as hypercalcaemia, hyperphosphataemia, hyophosphatasia.

Milwaukee shoulder syndrome

This subtype of BCP cyrstal-related arthropathy is characterised by non-inflammatory osteoclast-mediated destructive arthritis of the glenohumeral joint. It is accompanied by non-inflammatory joint effusion and rotator cuff deficits.

😷 Presentation

• Shoulder joint pain and swelling
• Restricted range of motion
• Crepitus

🔍 Investigations

• Synovial fluid analysis - may show few WBCs and many RBCs as it is non-inflammatory. It may also show non-specific BCP crystals.
• X-ray and MRI - may show rotator cuff damage/tear, bursitis, joint effusion, joint narrowing.

Calcific tendinitis

Calcific tendinitis is an inflammatory tendinopathy and periarticular soft tissue inflammatory disorder associated with periarticular BCP-crystal deposition.

It affects women more than men and mainly affects those aged 30-60 years old

😷 Presentation

It most commonly affects the rotator cuff (supraspinatus and infraspinatus tendons), but may also affect the hip, spine, hand, wrist etc.

• Acute onset of severe pain with swelling and erythema
• Low-grade fever
• It is typically self-limiting in 2-3 weeks or less with treatment.
• It can have recurrent attacks and a chronic pain syndrome may develop after recurrent attacks.

🔍 Investigations

• X-ray of affected joint - will show large deposits of calcifications within the articular cartilage.
• Arthrography - can confirm rotator cuff injury.

🧰 Management