Week 5 - Rheumatoid & Osteoarthritis Flashcards
(33 cards)
Describe the aetiopathogenesis of rheumatoid arthritis.
• Chronic, autoimmune, multisystem disorder + arthritis*
- Arthritis is the major part however it does effect other outcomes.
• Inflammatory proliferative synovitis that often progresses to joint destruction and ankylosis (fusion).
- Proliferative - joint destruction.
• Prevalence ~1%, female 4:1.
- Females sensitive to all autoimmune disorders.
• Skin, heart, blood vessels, lungs - similar to SLE etc.
- Major organs involved.
Aetiology - genetic + environment + autoimmune.
• Genetic susceptibility - HLA DRB1 in 75%, PTPN22 gene polymorphism.
• Environmental factor - ?EBV, Borrelia etc.
- Still unknown but infections particularly EBV.
• Autoimmunity - IGM anti IgG (RF). Anti CCP Ab, T lymphocytes against collagen and cartilage glycoprotein 39, macrophages around RF → type III (immune complex), CCP - cyclic citrullinated peptides (collagen, fibrinogen, vimentin etc.)
- Autoimmunity major factor.
- Development of autoantibodies particular IGM antibodies against IgG (known as rheumatoid factor).
- Anti CCP Ab
- T lymphocytes against collagen and cartilage glycoprotein 39.
- CCP - citrullination of collagen, fibrinogen and vimentin - CT proteins - citrullination leads to antibody formation.
Pathogenesis
• HLA DRB1 + environmental factors including smoking → activated lymphocytes and citrullination of self protein (modification) → results in various immune reactions - IL8 and VEGF produce excess proliferation of blood vessels, TNF and interferon gamma for inflammation → produce proliferation of synovium forming the pannus which leads to destruction of bone, cartilage, fibrosis.
- Exposure of a genetically susceptible individual to an arthritogenic antigen.
- Breakdown of immunological self-tolerance and a chronic inflammatory reaction.
• Auto-T lymphocytes → type II collagen & superantigen → cytokines → inflammation.
• B cells → formation autoantibodies (IgM against IgG ‘rheumatoid factor’) → immune complex deposition → joint injury.
• Macrophages surround immune complexes → type III injury → cytokines → inflammation + proliferation of chondrocytes. - Inflammation, cytokines & immune complex deposition cause destruction of bone, cartilage & fibrosis in the joints → arthritis.
Describe proliferative synovitis.
• Proliferative synovitis with papillary projections, lymphocytes, plasma cells and macrophages Pannus.
- All these together known as Pannus.
• Neutrophils in fluid (non suppurative inflam, sterile).
- Only seen in the synovial fluid. Non suppurative inflammation.
• Organising fibrin in joint - rice bodies.
- Organising fibrin in the joint space can form rice bodies.
• Juxta-articular osteopenia, erosions, cysts, fibrosis (sclerosis) and ankylosis (fibrous mainly, rarely bony).
- All because of the inflammation extending. That also damages the articular cartilage.
• Loss of articular cartilage.
RA pathogenesis.
- Initially, starts producing proliferation fingerlike projections, plenty of chronic inflammatory cells and acute inflammatory cells in the fluid along with B lymphocytes and plasma cells.
- This hypertrophy of the synovium damages the cartilage.
- Inflammation extending into the articular cartilage (lower end of femoral condyles). Slowly gradually progresses from early stage to late stage to severe deformity.
- In RA, inflammation starts from the synovium, extends and damages the cartilage.
- In OA, starts in the cartilage and then the damage extends to the synovium.
Describe the swan neck deformity seen in RA joints.
- Swan neck deformity is because of inflammation, scarring and contraction of muscles and tendons.
- Flexion of distal interphalangeal joint (DIP) and extension of proximal interphalangeal joint (PIP).
- Notice loss of joint space and loss of bone tissue - cyst formation, marked osteopenia.
- Characteristic swan neck deformity.
Identify the clinical features of rheumatoid arthritis.
- Start with malaise, fatigue, MSK pains (IL-1, TNF).
• Due to inflammatory mediators. - Morning stiffness (syn. inflam. fluid).
• Joint involvement starts as morning stiffness - early synovial inflammation and excess fluid. With movement, the fluid gets absorbed → patient feels better. Morning stiffness improved by activity very typical of early stage RA. - Arthritis in 3 or more joints.
• Gradually develops, usually symmetric. - Symmetric arthritis (systemic).
- Rheumatoid nodules - skin.
• Appear in skin. - Serum Rheumatoid Factor.
• Can be detected. - Radiographic changes (swan neck).
Outline the diagnosis of rheumatoid arthritis.
- Characteristic radiographic findings.
- Sterile, turbid synovial fluid, decreased viscosity, decreased mucin clot formation and neutrophils with inclusions.
- The combination of RF and anti-CCP antibody (80% of patients).
Common joints involved in RA - hands, feet, knees.
- Diagnosis is based on clinical criteria - is no single diagnostic test
- Management: physical rest, targeted anti-inflammatory therapy & passive exercises.
*See clinical algorithm.
Identify the extra-articular manifestations of RA.
• Almost every organ can be involved with inflammation - systemic autoimmune disorder.
- Rheumatoid nodules.
• Degeneration of the collagen tissue surrounded by macrophages - granuloma. Occurs in pressure points. - Iridocyclitis, uveitis, SICCA syndrome (dry eyes).
- Vasculitis.
- Pleuritis, pericarditis.
- Tendonitis.
- Lung - fibrosing alveolitis.
Discuss the lab diagnosis and drugs for RA.
• Discovery of ACPAs/anti CCP improved understanding and diagnosis of RA.
- Anti citrullinated protein antibodies or anti CCP - theory is that the citrullination of collagenous proteins leads to sensitisation and the production of antibodies against the citrullinated proteins.
• Tests for ACPAs - (Anti Citrullinated Protein Ab)
- Ab to cyclic citrullinated peptide (anti-CCP 1st 2nd and 3rd gen tests).
- Ab to modified citrullinated vimentin (anti-MCV).
- Sensitivity upto 92% and specificity upto 98%.
• Novel Biologic agents in therapy (targeting the new understanding):
- anti-TNFα - etanercept, infliximab, golimumab, pegol.
- anti-B-cell - rituximab.
- T cell costimulation blocker - abatacept.
- anti-IL - anakinra (IL-1 RA) and tocilizumab (anti IL-6)
• Long term complications
- Immunosuppressive therapy → infections.
• Because immunosuppressive therapy is commonly used including steroids, patients are susceptible to chronic infections.
- Amyloidosis - 5-10%.
• Excess antibodies in the body for a long time produces secondary amyloidosis.
Describe the morphology of rheumatoid arthritis.
Gross: • Joints - Synovium becomes thickened. - Covered by fronds. - Juxta-articular erosions. - Cysts and fibrosis (sclerosis). - Fibrous ankylosis (joint fusion).
• Extra-articular manifestations - Rheumatoid nodules o Firm & non-tender o Skin (subcutaneous tissue) o Central necrosis - Vasculitis (esp. digital arteries) - Pleuritis - Pericarditis - Tendonitis - Fibrosing alveolitis
Microscopy: • Proliferative synovitis - Lymphocytes (CD4) - Plasma cells - Macrophages • Increased vascularity due angiogenesis • Organising fibrin (“rice bodies”) • Neutrophils • Osteoclastic activity in underlying bone • Pannus formation - Mass of synovium & synovial stroma - Granulation tissue, inflammation, fibrosis - Causes erosion of articular cartilage
Differentiate between RA & OA.
Rheumatoid arthritis • Inflammatory autoimmune disease. • Inflammation starts in synovium. • Young, small joints. • Autoimmune/recurrent. • Synovial inflammation. • Synovium → cartilage. Clinical: • Sharp, severe pain relieved by activity. • Morning pain and stiffness. • Reduce with activity (early). • Swan neck deformity.
Osteoarthritis • Degenerative disease. • Degeneration starts in cartilage. • Old age, large joints. • Degenerative/progressive. • Cartilage degeneration. • Cartilage → synovium. Clinical: • Deep, mild pain exacerbated by activity. • Morning stiffness and crepitus. • Increases with activity. • Heberden's nodes.
Common end result - destruction, deformity and ankylosis.
Outline osteoarthritis.
• “Cartilage degeneration” - degenerative disease of the cartilage.
• 95% primary/idiopathic, ageing >80% in >80y
- 95% idiopathic due to ageing.
• 5% secondary in young: trauma, obesity, deformity.
- Rarely 5% secondary to trauma, obesity, deformity.
• Weight bearing/most used joints. Knees and hands in women, hips and spine in men - common.
- Most common in the weight bearing/most used joints.
• Stiffness, mild pain (morning*), increase with activity.
- Stiffness, mild pain in the morning (stiffness remains for >1 hour), pain increases with activity - differentiates from rheumatoid arthritis.
• Limited range of movements, deformity, instability.
- Weight bearing joints.
• Progressive loss of chondrocyte - erosion and fibrillation of articular cartilage → forms loose bodies.
- Pathogenesis - progressive loss of chondrocyte - ageing, metabolic, genetic - leading to erosion and fibrillation (breaking down) of articular cartilage.
Explain the pathogenesis of osteoarthritis.
Aetiology
• Ageing (most occur without an apparent initiating cause). Contributing factors include genetics, physical activity and nutrition, menopause (due ↓oestrogen, ↑ IL-1 & IL-6, ↑ osteoclast activity), ageing (due ↓osteoprogrenitor cell replication, ↓osteoblasts, ↓growth factors, ↓physical activity).
Pathogenesis (3 stages):
1. Chondrocyte injury - genetics, wear and tear.
- Early OA - inflammation, proliferation, proteases, soft.
• Inflammation, proliferation of chondrocytes, release of proteases, leading to softening of the cartilage. - Late OA - loss of chondrocytes and matrix → fissuring “eburnation”, subarticular cyst, sclerosis and osteophytes.
• Late stage - total loss of chondrocyte and damage to matrix → fissuring (breaking down of the cartilage) - leads to entry of synovial fluid into the cartilage and bone → leads to various changes known as ‘eburnation’, subarticular cyst, sclerosis and osteophytes. - Chondrocyte injury (due to ageing, genetic and biochemical factors).
- Chondrocytes proliferate, produce inflammatory mediators → remodel cartilage + inflammation.
- Repetitive injury & chronic inflammation lead to ↓ chondrocytes, loss of cartilage & bone changes.
• Progressive erosion & fibrillation of articular cartilage → form loose bodies.
• Hardened articular bone → eburnation & subarticular cyst formation in bone.
Describe the morphology of osteoarthritis.
Gross: 1. Eburnation. • Thickening of exposed bone. 2. Subchondral cyst. • Large cysts due to entry of the synovial fluid proteases leading to dissolution of the bone. 3. Residual cartilage. 4. Sclerosis. • Thickening of the bone surrounding in response to damage.
- Occurs in large weight-bearing joints
- Eburnation of bone (polished ivory appearance)
- Subchondral cyst
- Residual cartilage
- Erosion of articular cartilage
- Small fractures through articular bones
Microscopy:
1. Cartilage fissuring.
2. Loss of chondrocytes.
Loose bodies (joint mice).
- Erosion & fibrillation of articular cartilage
- Loose bodies (cartilage and subchondral bone)
- Hardened articular bone
- Periarticular osteophyte formation
- Inflammatory cells
- Thick trabeculae
N.B. Features of advanced OA - cartilage loss, osteophyte, bone cyst, sclerosis, thick trabeculae.
Identify the radiological features of osteoarthritis.
- Non-uniform joint space loss.
- Loose bodies - cartilage.
- Deformity, osteophyte (bone spur).
- Subchondral cyst and sclerosis (due to synovial fluid).
- X-ray - weight bearing joints most common - lose joint space due to loss of cartilage - exposure of the bone.
- Formation of cysts, sclerosis, surface eburnation and osteophyte formation (due to grinding of the bone and the reactive new bone formation surrounding).
- Chemical mediators, new bone formation. The exposed surface area gets grinded down and the edges start projecting out (known as bone spurs or osteophytes).
- Non-uniform joint space loss.
- Osteophyte formation.
- Cyst formation.
- Subchondral sclerosis.
- Sclerosis, ankylosing and deformity.
Identify the clinical features of osteoarthritis.
- Commonly asymptomatic in middle-aged or older people.
- Intermittent joint pain related to movement affecting 1 or a few joints.
- Mainly affects large weight-bearing joints.
- Functional restriction - instability of joints; crepitis, muscle spasm, tendon/capsular contractions.
- Pain worsens with activity and improves on rest.
- Mild inflammation.
- Painful early morning stiffness lasts 1 hour or more.
- Bony overgrowths evident – interphalangeal joints distal (Herberden’s) & proximal (Bouchard’s).
Describe osteoarthritis of the fingers.
- Early morning stiffness lasts 1 hour or more.
- Pain worsens with activity and improves on rest.
- Limitation of motion (muscle, tendon and capsular thickening).
- Fusiform bony overgrowth at interphalangeal joints distal (Heberden nodes), proximal (Bouchard’s). Osteophytes.
Describe osteoarthritis of the hip.
• Ankylosis - fusion of joints.
- Fibrous ankylosis.
- Bony ankylosis.
Outline crystal induced arthritis.
Endogenous (crystals):
• Monosodium urate - gout (most common)
• Calcium pyrophosphate - pseudo gout.
Exogenous:
• Corticosteroids, silicone, polyethylene etc.
- Anything injected into the joint.
Outline gout.
• Only humans, 1% of population, males, adults.
• Increased uric acid → purine metabolism, uricase.
- Due to increased uric acid levels in the body - end product of purine metabolism (protein breakdown) through the enzyme uricase.
• Monosodium urate crystals in joints.
- Deposition of crystals specifically in the joints. Only 2 organs affected - joints then kidney.
• Primary Gout 90%, genetic (unknown). Increased production (common)/decreased excretion (rare).
- Commonest clinically - 90% of cases - genetic (unknown) - usually due to increased production or occasionally due to decreased excretion, ultimately leading to increased uric acid (hyperuricaemia).
• Secondary Gout 10% - cell breakdown (cancers), renal disease, high protein diet, alcohol abuse, obesity, thiazide diuretics, lead toxicity.
- Secondary gout usually due to cell breakdown e.g. cancers (leukaemias, lymphomas), renal disease (no excretion), high protein diet etc.
• Acute → repeated → chronic.
- Usually occurs as an acute attack followed by a remission then repeated attacks → then can become chronic.
• Large deposits in chronic Tophaceous.
- In chronic phase, there is usually large deposits of uric acid known as tophus.
• Activation of inflammation → extensive cartilage and joint damage. Acute neutrophils → chronic granuloma + Giant cells (chronic).
- Uric acid crystals activate inflammation both acute and chronic macrophages → release inflammatory mediators e.g. IL-1 → resulting ultimately in inflammation (acute or chronic - both effect the joint).
Explain the pathogenesis of gout.
- Accumulation of urates due to increased production of uric acid or decreased excretion.
- Accumulation of urates within joint synovium (possibly due to trauma etc.)
- Precipitation of (monosodium) urate crystals into the joints (N.B. as synovial fluid is a poorer solvent for monosodium urate than plasma it becomes supersaturated more easily).
- This triggers neutrophils, macrophages, cytokine response → inflammation & tissue injury.
- Repeated attacks of acute arthritis eventually lead to chronic arthritis.
What are the 4 clinical stages of gout?
- Asymptomatic hyperuricemia.
- Acute arthritis.
- Asymptomatic resolution.
• Asymptomatic phase of resolution then recurrent attacks of acute then becomes chronic tophaceous gout, - Chronic tophaceous gout.
• Chronic granulomatous inflammation.
Identify the renal complications of gout.
• Renal complications - gout nephropathy, lithiasis, renal colic, pyelonephritis. Renal failure. (Commonest is nephropathy and lithiasis).
Describe the morphology of gout.
• Acute: neutrophils + intracytoplasmic crystals.
• Chronic: tophi + granuloma (macrophages).
1. MSU crystals (tophi).
2. Macrophages + Giant cells.
3. Fibrosis.
Gross:
• Joint inflammation.
• Joint deformity.
• Oedema.
Microscopy: • Acute arthritis. - Neutrophil infiltrate. - Monosodium crystals in synovium. - Oedema.
• Chronic tophaceous arthritis (repetitive cases)
- Urates encrust articular surface.
- Hyperplastic, fibrotic.
- Inflammatory cells.
- Fibrosis → loss of joint function.
• Tophi
- Large aggregates of urate crystals surrounded by inflammatory reaction.
Identify the clinical features and management of gout.
Clinical features
• Single joint affected.
• Rapid onset of severe pain, extreme tenderness and marked swelling.
• Self-limiting over 5-14 days.
Management
• Acute attack: fast acting NSAID with ice-pack + joint aspiration.
• Chronic management: weight loss, reduction excess alcohol intake etc.
