Crystal arthropathies Flashcards
Define gout and pseudogout
- Gout is a chronic disease of deposition of monosodium urate crystals, which form in the presence of increased urate concentrations. The primary clinical manifestation is acute inflammatory arthritis.
- Calcium pyrophosphate deposition disease is arthritis caused by calcium pyrophosphate (CPP) crystals. Until recently, CPPD has been referred to as pseudogout. It may present as an acute inflammatory arthritis.
Describe gout epidemiology and risk factors
- Gout is a common cause of inflammatory arthritis in men over 40 years and women over 55 years.
- Male prevalence is about five times that of females.
- Prevalence rates of asymptomatic hyperuricemia are 5-7.5% in white males, and higher in Pacific Island populations.
- An increasing prevalence of gout has occurred in the last decade, particularly amongst males aged over 65 years.
Gout Risk Factors
- Hyperuricemia
- Male sex if younger than 60 years
- Obesity
- High-purine diet (e.g., red meat, shellfish)
- Alcohol (esp. beer and spirits) and high-fructose drinks
- Medications (esp. thiazide diuretics or cyclosporine)
- Renal insufficiency
- Lead exposure
- Organ transplantation
- Specific diseases (e.g., hypertension, diabetes, hyperlipidemia, hematologic malignant conditions)
- Genetic risk factors
Describe the spectrum of gout
- Asymptomatic hyperuricemia (important part of spectrum)
- Acute gout
- Mono-articular
- Oligoarticular or polyarticular
- Chronic and interval gout - can resemble RA
- Tophaceous gout
- Rare – Axial gout
Describe symptoms and clinical findings in gout
- Warmth, swelling, redness, and severe joint pain.
- First attacks, estimates that 90% are monoarticular
- Common sites of crystal deposition, tophus development: helix of the ear, lower extremities
- Other sites: periarticular structures (bursae, tendons) Crystals more likely in previously diseased/damaged joints. Other forms of arthritis increase gout risk.
- Episodic, self-limited joint pain, swelling, erythema.
- Attack often occurs at night or early morning.
- Trauma may trigger release of crystals into joint space.
- Attacks usually subside in 3 to 14 days without treatment.
- Odds ratios for gout vs non-gout include joint erythema 2.13, difficulty walking 7.34, time to maximal pain <24 hours 1.32, resolution by 2 weeks 3.58, tophus 7.29, and radiograph erosion or cyst 2.49, ultrasound double contour 7.23 - but needs to be performed properly
Describe pathophysiology of gout
- Hyperuricemia can occur as a result of overproduction from hepatic metabolism and cell turnover, or renal underexcretion or extra-renal underexcretion, or both.
- Underexcretion is the dominant cause of hyperuricemia in patients with gout.
- Renal excretion accounts for around two-thirds of urate excretion. Gut excretion accounts for the remainder.
- Secretion and reabsorption coexist along the length of the proximal renal tubule, with roughly 10% of urate that is initially filtered eventually being excreted
Pathophysiology of Gout
- Uric acid - end product of purine metabolism and is present in the serum and tissues in the form of monosodium urate.
- Serum uric acid levels higher than 0.40 mmol/L monosodium urate supersaturates the serum and precipitates into tissues.
- Elevated levels of uric acid do not necessarily translate into clinical disease.
- An acute gouty attack occurs when monosodium urate crystals are released or form de novo in the joint space.
- Trauma, surgery, infections, or initiation of medications such as allopurinol or diuretic agents can abruptly alter uric acid levels and incite an attack of gout.
Describe the role of the inflammasome
- Crystal-induced inflammation.
- Phagocytosis of crystals by monocytes.
- Formation of the NLRP3 inflammasome.
- The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins.
- Release of IL-1beta, IL-6, TNF.
- Downstream mediators of inflammation.
- Resolution involves neutrophils extracellular traps which bind MSU crystals.
- Inflammation - big contributor to pain
List some investigations indicated for gout
- Asymptomatic hyperuricemia: Fasting lipid profile and BSL and 24-hour urine excretion of UA.
- Monoarticular gout: FBC (exclude septic), CRP, and blood cultures; Serum uric acid, EUC, and LFTs; Fasting lipid profile and BSL; Synovial fluid for gram stain, cells, culture, and crystals.
- Pauciarticular and polyarticular gout: Same as for monoarticular gout and Rheumatoid factor, anti-CCP.
Describe diagnosis of gout
- An accurate diagnosis is necessary before initiating lifelong therapy.
- Demonstration of MSU crystals remains the gold standard for diagnosing gout.
- A recent review of imaging modalities in gout – ultrasound and MRI have value in the presence of tophii and larger crystal deposits but no overall improvement in diagnostic sensitivity or specificity.
- Clinically distinguishing gout from septic arthritis is often difficult, and making a diagnosis of septic arthritis is important as delay in treatment is disastrous.
Crystal Analysis
- MSU crystals are more easily detected than CPPD crystals.
- CPPD crystals have a rhomboidal or rectangular shape and have positive birefringence.
- Compared to MSU crystals birefringence is weaker, and some CPPD crystals may not appear birefringent.
- A birefringent CPPD crystal appears blue.
- MSU crystals are brightly birefringent and needle-shaped; MSU crystals appear yellow.
Describe imaging in gout
- Imaging is not necessary for diagnosis but can be helpful in some situations- will see more radiological features with multiple attacks
- X-ray: May show joint space narrowing, subchondral sclerosis, erosions with overhanging edges, and soft tissue masses (tophi). Dual-energy CT (DECT) has high sensitivity and specificity for diagnosing gout and differentiating it from other arthritides.
- Ultrasound: May show double contour sign, tophi, and erosions. It is useful for diagnosing gout in the acute setting and monitoring urate-lowering therapy.
- MRI: Not routinely used but can show bone marrow edema, tophi, and erosions. It may be useful in diagnosing axial gout.
- CT Scan: May show tophi and erosions but is less sensitive than ultrasound or DECT for early changes.
Radiological Features of Gout
1. Erosions with overhanging margins
2. Sclerotic margins
3. Relatively well-preserved joint spaces
4. Soft tissue tophi
List and briefly describe some differential diagnoses for gout
Rheumatoid Arthritis (RA)
- Symmetrical polyarthritis in small joints of hands and feet
- Hand involvement more likely than in gout
- Subcutaneous nodules
- X-ray: soft-tissue swelling, diffuse joint space-narrowing (in a joint), marginal erosions of small joints, symmetrical multiple joint involvement
- Usually osteopenic without signs of repair
Pseudogout (Calcium Phosphate Deposition Disease)
- Appears in unusual places (wrist, elbow) without trauma
- Affects 10% to 15% persons aged 65 years
- X-ray: looks like RA or osteoarthritis but with bony repair
- Cartilage calcification, especially in fibrocartilage
- Triangular cartilage pathognomonic
Septic Arthritis
- Fever, arthritis, great tenderness
- Joint sepsis may occur in previously abnormal joints
- Up to one-half have concomitant rheumatoid arthritis
- Source (skin, lungs) often evident
- X-ray: swelling, effusion
- Treat immediately to avoid joint destruction
Cellulitis
- Erythema, swelling of extremity, very tender, often febrile
- Soft-tissue lymphatic drainage often abnormal due to peripheral venous insufficiency, previous surgery, or infection
- X-ray: soft-tissue swelling
- Often due to Staphylococcus or Streptococcus infection
Describe asymptomatic hyperuricaemia
- 2/3rds of individuals with hyperuricemia asymptomatic
- Approximately 1/3 progress to clinical gout and require treatment
- Clinical relevance of hyperuricemia due to urate-related associations such as HT, insulin resistance, and CVS disease and require screening and lifestyle modification
- In the absence of RCT evidence, routine prophylactic use of anti-hyperuricemic medication not recommended
Intervention
- Intervention in asymptomatic hyperuricemia should include an individual risk assessment for development of gouty arthritis,
- urolithiasis, renal impairment or acute uric acid nephropathy
- underlying overproduction (lymphoproliferative and myeloproliferative disorders, psoriasis, vitamin B12 deficiency etc)
- therapeutic interventions – chemotherapy for leukemia
Describe prevention and non-drug therapy for gout
Primary Prevention
- Dietary modification, weight loss reduces risk factors and lowers serum urate levels (diet changes patient by patient)
- Pharmacologic therapy is not recommended when hyperuricemia is asymptomatic
- Pharmacologic therapy is recommended in patients on chemotherapy for hematologic malignant conditions
- Uric acid-lowering drugs and hydration prevent secondary gout due to tumor lysis
- Without this treatment, uric acid nephropathy with tubular obstruction can develop
Nondrug Therapy in Managing Patients Who Already Have Gout
- Reduce high-purine foods in diet
- Reduce alcohol and high-fructose and sugary drinks
- Lose weight to decrease serum urate levels
- Stay hydrated to reduce recurrence
- Follow diet high in fiber, vitamin C, folate (e.g., fruits and vegetables), and dairy products
- Replace medications that impair uric acid secretion with a substitute drug whenever possible
High in Purine Foods
- High-purine animal and fish sources include red meat (beef, pork, lamb), meat extracts (broth, gravy), organ meats (sweetbreads, liver, kidney), seafood (shrimp, anchovies, mussels, scallops, sardines, herring, fish roe, canned tuna, shrimp, lobster), yeast products (baked goods, beer), mushrooms, spinach, asparagus, cauliflower, and legumes (peas, dried beans)
Describe treatment for gout
- The long-term aim is to reduce Serum Uric Acid (SUA) levels to below 0.36mmol/L
- A “cure” - treatment of the acute attack and preventing recurrence is the cornerstone of management
- Generally, indications for urate-lowering treatment include recurrent attacks, chronic tophaceous gout, presence of radiographic changes, gout and coexisting nephrolithiasis or renal insufficiency, the presence of metabolic syndrome and coexisting gout and diuretic therapy
- A pragmatic clinician is likely to initiate therapy even after a first attack rather than miss the window of opportunity
- Patient education is an important aspect of treatment
Why Treat?
- To prevent growth of crystalline deposits
- Deposits can lead to chronically stiff joints and debilitating arthritis
- Reduce tophi
- To prevent flare recurrence: very common
- Subsequent attacks may involve more joints, tendons
- To prevent nephrolithiasis due to uric acid stones
Treat to Target
- Set target serum urate level according to disease severity: lower if tophi or erosions present
- Commence urate-lowering therapy early
- Monitor serum urate level frequently until serum urate target achieved
- Adjust urate-lowering therapy dose or agent until serum urate target is achieved
- Ensure continuous supply of urate-lowering therapy
- Once serum urate target is achieved, monitor serum urate level intermittently to ensure target concentration is maintained
Current Therapies – Reduce SUA
- Xanthine oxidase (XO) inhibitors (reduced production): Allopurinol, Febuxostat (if allergic to allopurinol)
- Uricase enzyme analogue (reducing SUA by converting to allantoin): Rasburicase (e.g. in presence of haematological malignancy)
- Increasing uric acid excretion: uricosuric agents such as Probenecid, Losartan
- Action on proteins, inhibition of phagocytosis and cell motility: Colchicine
Describe prophylaxis
- When starting urate-lowering therapy, concomitant prophylaxis should be provided for a minimum of six months to prevent flares of gout. ^[also improves odds of adherence]
- It is common for flares of gout to occur when starting treatment and when changing the dose. Preventing these flares is a treatment goal. NSAIDs and low-dose colchicine are first-line, and low-dose prednisolone is second-line.
- Colchicine is equal to NSAIDs for long-term prophylaxis; however, short-term NSAIDs or oral glucocorticoids may be appropriate depending on the patient’s comorbidities and drugs.
Describe treatment in acute attacks
- The management of acute attacks focuses on the prompt treatment of inflammation and pain with anti-inflammatory drugs.
- NSAIDs, colchicine, or corticosteroids are the first-line options, with the choice of drug being influenced by patient comorbidities and concomitant drugs.
- GCs will have multiple actions on different inflammatory processes e.g. ACTH, intra-articulars, systemic
- Blocking PG synthesis: short term NSAIDs– all drugs in this class will have equal efficacy
- Colchicine will act on proteins, inhibit phagocytosis and cell motility
Which Drugs When?
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Non-Steroidal Anti-inflammatories (NSAIDs)
- First-line due to analgesic, anti-inflammatory effects.
- Ibuprofen and naproxen are better-tolerated than indomethacin; do not use aspirin.
- Start at a higher dose; taper over 1 week.
- Side effects: GI bleeding; renal toxicity; hepatotoxicity; increases blood pressure; fluid overload risk, especially with CHF history; reversible platelet dysfunction.
- Avoid in elderly patients.
- Do not use if anticoagulated.
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Colchicine
- Most effective within 12-36 hours after an acute attack starts. Lower doses (0.6 mg 2 to 3 times/day) reduce side effects.
- Side effects: GI intolerance; bone marrow suppression; myopathy, neuropathy; dermatitis; urticaria; alopecia; purpura.
- Reduce dose for renal or hepatic dysfunction; avoid if patient on dialysis.
- Avoid in elderly patients.
- Colchicine is a substrate of both cytochrome P450 3A4 and P-glycoprotein, so it may interact with antineoplastic drugs, calcium channel blockers (diltiazem and verapamil), calcineurin inhibitors, digoxin, dabigatran, macrolide antibiotics, and protease inhibitors.
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Corticosteroids (Oral)
- For polyarticular gout when NSAIDs contraindicated.
- Now first line in some cases.
- Side effects: GI bleeding (esp. in elderly); fluid retention, impaired wound healing; hyperglycemia in diabetes.
- Not for patients with active peptic ulcer disease.
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Corticosteroids (Intra-articular Injection)
- For monoarticular gout when NSAIDs contraindicated.
- Side effects: Risk for damage to nerves, tendons, vascular structures if administered improperly; joint-infection risk; oral corticosteroid side effects.
- Rule out infectious cause before injecting the joint.
