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Arthritis Comparison: RA vs OA vs Reactive Arthritis vs Gout vs Pseudogout

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1. Rheumatoid Arthritis (RA)

Pathophysiology

1. Genetic predisposition via HLA-DR (particularly HLA-DR4 "shared epitope") triggers an immune response against citrullinated self-proteins (e.g., citrullinated vimentin, fibrinogen)
2. Activated T-cells, B-cells, and macrophages infiltrate the synovium → synovial lining cells and subsynovial vessels proliferate → forming pannus (invasive granulation tissue)
3. Pannus secretes matrix metalloproteinases (MMPs) and cytokines (TNF-α, IL-1, IL-6) → cartilage and bone erosion
4. Rheumatoid factor (RF) = IgM autoantibody against Fc portion of IgG; Anti-CCP antibodies = highly specific (95%) and appear years before symptoms
5. TNF-α plays a central role → basis for biologic therapy

Epidemiology

• Prevalence: 1–2% of adults; peak onset 20–50 years
• Women:Men = 3:1 (estrogen effect); 70% have insidious onset
• Higher concordance in monozygotic twins (MHC class II gene influence)

Clinical Features

ACR 1987 Diagnostic Criteria (need ≥4 of 7; symptoms ≥6 weeks)

1. Morning stiffness ≥1 hour
2. Arthritis of ≥3 joint areas
3. Arthritis of hand joints (PIP, MCP, wrist)
4. Symmetric arthritis
5. Rheumatoid nodules
6. Positive RF
7. Radiographic changes (erosions, juxta-articular osteopenia on X-ray)

Investigations

• RF positive: ~70–80% (not specific — can be positive in SLE, Sjögren, infections, elderly)
• Anti-CCP (anti-citrullinated peptide): highly specific (~95%), positive even in seronegative RF
• ESR/CRP: elevated (disease activity markers)
• Synovial fluid: WBC >2,000/mm³ (inflammatory), no crystals
• X-ray: juxta-articular osteopenia → joint space narrowing → erosions → deformities

Treatment

1. NSAIDs: symptomatic only, no disease modification
2. Conventional DMARDs (csDMARDs):
   • Methotrexate (MTX) — anchor drug, 15–25 mg/week; monitor LFTs, CBC
   • Hydroxychloroquine (mild disease): 200 mg BID, ophthalmology follow-up
   • Sulfasalazine: 2–3 g/day in divided doses
   • Leflunomide
3. Biologic DMARDs:
   • Anti-TNF: etanercept, adalimumab, infliximab
   • IL-6 inhibitors: tocilizumab
   • Anti-CD20: rituximab
   • Co-stimulation blocker: abatacept
4. Glucocorticoids: bridge therapy or for flares (not long-term due to side effects)
5. Surgery: joint replacement for end-stage disease

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2. Osteoarthritis (OA)

Pathophysiology

1. Mechanical stress + aging → chondrocyte dysfunction → reduced proteoglycan/collagen II production
2. Subchondral bone remodeling → sclerosis + osteophyte formation
3. Mild inflammation (synovitis) is secondary, driven by locally produced cytokines (IL-1β, IL-6), but NOT the primary pathology
4. Risk factors: age, obesity, prior joint injury, repetitive use, female sex (post-menopause)

Clinical Features

Investigations

• Labs: ESR, CRP, RF — all NORMAL (distinguishes from RA)
• Synovial fluid: non-inflammatory WBC < 2,000/mm³, clear/yellow
• X-ray (4 classic signs):
  1. Joint space narrowing (asymmetric)
  2. Osteophytes (bony spurs)
  3. Subchondral sclerosis
  4. Subchondral cysts (Mnemonic: "JOSS")

Treatment

1. Non-pharmacological: weight loss, physiotherapy, exercise, orthotics
2. Topical NSAIDs: first-line for knee/hand OA
3. Oral NSAIDs: use cautiously (GI/renal risk)
4. Intra-articular corticosteroids: short-term relief
5. Intra-articular hyaluronic acid: modest benefit
6. Duloxetine: for chronic pain component
7. Surgery: osteotomy, joint replacement (TKR/THR)
8. Note: No DMARDs — OA is not autoimmune; NSAIDs/physiotherapy remain cornerstone

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3. Reactive Arthritis (ReA)

Definition & Pathophysiology

• GI pathogens: Salmonella typhimurium, Yersinia enterocolitica, Shigella flexneri, Campylobacter jejuni
• GU pathogen: Chlamydia trachomatis (most common in developed countries)
• Mechanism: Bacterial antigens (fragments or even viable Chlamydia) traffic to the synovium → activate immune response → synovitis. PCR studies have found viable Chlamydia in joints in a metabolically altered state
• HLA-B27 strongly associated (found in 60–80% of cases) — B27 confers risk for onset, axial involvement, and chronicity
• Part of the seronegative spondyloarthropathy spectrum (RF negative)
• Affects 2–7% of those with triggering GI infection; up to 20% in B27-positive individuals

Clinical Features

1. Arthritis: asymmetric oligoarthritis, lower extremity predominance (knee, ankle, MTP)
2. Urethritis/cervicitis: dysuria, urethral discharge (cervicitis may be asymptomatic in women — leads to underdiagnosis)
3. Conjunctivitis/uveitis: bilateral conjunctivitis (painful); acute anterior uveitis (unilateral, less painful)

• Dactylitis ("sausage digit"): diffuse swelling of an entire digit — pathognomonic of spondyloarthropathy
• Enthesitis: Achilles tendinitis, plantar fasciitis
• Keratoderma blennorrhagicum: painless hyperkeratotic papules/plaques on palms and soles — clinically identical to pustular psoriasis
• Circinate balanitis: painless shallow ulcerations on glans penis
• Oral painless ulcers
• Sacroiliitis: asymmetrical (vs. bilateral in AS)
• Nail dystrophy (pitting, onycholysis)

Investigations

• RF and ANA: negative (seronegative)
• HLA-B27: positive in majority
• ESR/CRP/WBC: elevated during acute phase
• Synovial fluid: inflammatory WBC; no crystals; culture negative (aseptic)
• STI screen: urethral/cervical swab for Chlamydia; stool cultures for GI pathogens
• X-ray: periostitis, new bone formation at entheses; asymmetric sacroiliitis (vs. symmetric in AS); "fluffy" periosteal reaction at calcaneus; bulky non-marginal syndesmophytes (vs. marginal in AS)

Treatment

1. NSAIDs: first-line for arthritis symptoms (indomethacin preferred)
2. Antibiotics: for active Chlamydia infection (doxycycline/azithromycin); little effect once arthritis established; prolonged antibiotics (3-month doxycycline/azithromycin) may benefit post-Chlamydia chronic ReA
3. Intra-articular corticosteroids: for persistent monoarticular disease
4. Sulfasalazine or MTX: for chronic/refractory cases (>6 months)
5. Anti-TNF biologics: refractory/severe chronic disease
6. Prognosis: Most resolve in 3–12 months; ~15% develop chronic arthritis; B27-positive patients more likely to develop ankylosing spondylitis

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4. Gout

Pathophysiology

• Uric acid is the end product of purine catabolism (humans lack uricase)
• 90% of patients: reduced renal excretion of uric acid
• 10%: overproduction of uric acid
• Triggers for acute attacks: dietary purines (red meat, shellfish), alcohol (especially beer — ethanol blocks renal urate excretion), dehydration, surgery, diuretics (thiazides, loop), aspirin, trauma
• MSU crystal formation occurs in cooler, more acidic environments → explains predilection for 1st MTP, heel, ankle
• Crystals → phagocytosed by neutrophils → activate NLRP3 inflammasome → IL-1β release → acute inflammatory cascade (neutrophil recruitment, prostaglandins, bradykinin)

Clinical Stages

Clinical Features

• 1st MTP joint (podagra) in 50% of initial attacks; eventually involved in 75–90%
• Also: heel, ankle, knee, midtarsal joints, olecranon bursa
• Severe pain, swelling, erythema, warmth — patient can't tolerate even bedsheet touching the joint
• Attacks often begin at night (↓ temperature, dehydration during sleep)
• Low-grade fever, leukocytosis may accompany severe attacks (can mimic septic arthritis)
• Tophi: chalky-white subcutaneous nodules; common sites = 1st MTP, olecranon bursa, ear helix, Achilles tendon
• Gout in women and elderly: often polyarticular, can mimic RA; tophi mistaken for rheumatoid nodules

Investigations

• Serum uric acid: usually >8 mg/dL during attack (can be normal during acute flare as uric acid redistributes)
• Synovial fluid (GOLD STANDARD): needle-shaped crystals with negative birefringence (yellow when parallel to compensator axis, blue when perpendicular) under polarized light; WBC 10,000–100,000/mm³; culture negative
• 24-hr urine uric acid: distinguishes underexcretion vs. overproduction
• X-ray (chronic gout): "rat-bite" erosions with overhanging edge (punched-out erosions with sclerotic margins), soft tissue tophi; periarticular calcification uncommon (contrast with pseudogout)

Treatment

1. NSAIDs (e.g., indomethacin 50 mg TID): first-line if no contraindications
2. Colchicine: 1.2 mg then 0.6 mg 1 hr later (first 36 hours most effective); inhibits microtubule polymerization → inhibits neutrophil migration
3. Corticosteroids: (oral, IM, or intra-articular) if NSAIDs/colchicine contraindicated; prednisone 0.5 mg/kg/day tapering over 7–10 days
4. IL-1 inhibitors (anakinra, canakinumab): refractory/polyarticular attack

• Indications: ≥2 attacks/year, tophi, uric acid nephropathy/stones, radiographic erosions
• Allopurinol (xanthine oxidase inhibitor): start low (100 mg/day), titrate; paradoxically can trigger attacks if started during active gout
• Febuxostat: alternative XOI, more potent; cardiovascular concerns in some guidelines
• Probenecid: uricosuric; second-line (avoid if GFR <50 or uric acid stones)
• Pegloticase (IV recombinant uricase): refractory tophaceous gout
• Target: serum uric acid <6 mg/dL (<5 mg/dL with tophi)
• Prophylaxis during ULT initiation: low-dose colchicine or NSAID for 3–6 months (mobilization flares)

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5. Pseudogout (CPPD — Calcium Pyrophosphate Crystal Deposition Disease)

Pathophysiology

1. Degradation of articular cartilage proteoglycans (which normally inhibit mineralization) allows CPP crystallization around chondrocytes
2. Crystals form in cartilage matrix → rupture → seed the joint → NLRP3 inflammasome activation → IL-1β → acute inflammation (like gout)
3. Even without inflammation, crystals disrupt cartilage structure/function
4. ANKH gene mutation: encodes inorganic pyrophosphate transporter — linked to familial CPPD
5. Sporadic (idiopathic) vs. hereditary vs. secondary

• Hyperparathyroidism (↑ Ca²⁺)
• Hemochromatosis (↑ Fe²⁺ inhibits pyrophosphatase)
• Hypomagnesemia (Mg²⁺ normally inhibits CPP crystallization)
• Hypothyroidism
• Ochronosis (alkaptonuria)
• Diabetes mellitus
• Previous joint damage/trauma

Epidemiology

• Age: predominantly >50 years; prevalence rises sharply with age — up to 60% of those ≥85 years
• Equal sex distribution (vs. gout's male predominance)
• Often asymptomatic (incidental chondrocalcinosis on X-ray)

Clinical Features

• Unlike gout, CPPD commonly affects the knee (gout prefers 1st MTP)
• Large joint predominance: knee > wrist > shoulder > ankle
• Attacks may be triggered by: illness, surgery, trauma, IV contrast, bisphosphonates

Crystal Characteristics

Investigations

• Synovial fluid: rhomboid crystals with weak positive birefringence (blue when parallel to axis under compensated polarized light); WBC 10,000–50,000/mm³
• X-ray: chondrocalcinosis — linear/punctate radiopaque calcifications in hyaline cartilage or fibrocartilage (knee menisci, wrist TFCC, symphysis pubis) — pathognomonic
• Ultrasound: hyperechoic deposits within the substance of hyaline cartilage (vs. gout's "double contour" sign on cartilage surface)
• Dual-energy CT (DECT): can color-code CPPD from MSU crystals
• Metabolic screen: calcium, PTH, magnesium, iron/ferritin, TFTs, blood glucose (for secondary causes)

Treatment

1. NSAIDs: high-dose (indomethacin, naproxen)
2. Colchicine: effective (same mechanism as gout)
3. Intra-articular corticosteroids: excellent if septic arthritis ruled out and ≤2 joints involved; aspiration alone also provides symptomatic relief
4. Systemic corticosteroids: polyarticular or contraindications to above
5. IL-1 inhibitors: refractory cases

• Low-dose colchicine (0.5–1 mg/day): reduces frequency of recurrent attacks
• Hydroxychloroquine or MTX: for chronic inflammatory CPPD mimicking RA
• No equivalent of ULT for CPPD: no treatment currently prevents or reverses crystal formation

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Comprehensive Comparison Table

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Key Distinguishing Pearls

1. Morning stiffness >1 hr → think RA (or other inflammatory arthritis); <30 min → think OA
2. DIP involvement → OA (Heberden's) or psoriatic arthritis; MCP/wrist sparing DIP → RA
3. 1st MTP sudden overnight pain → GOUT until proven otherwise
4. Knee calcification (chondrocalcinosis) on X-ray → PSEUDOGOUT
5. Urethritis + conjunctivitis + arthritis + recent GI/GU infection → REACTIVE ARTHRITIS
6. Sausage digit (dactylitis) → reactive arthritis, psoriatic arthritis (spondyloarthropathy)
7. Negatively birefringent needle crystals → GOUT; positively birefringent rhomboid crystals → PSEUDOGOUT
8. Tophi on ear helix → chronic gout; subcutaneous nodules on extensor surface → RA nodules
9. Seronegative + HLA-B27 + sacroiliitis → spondyloarthropathy (ReA, AS, psoriatic)
10. Metabolic screen for pseudogout: always check hyperparathyroidism, hemochromatosis, hypomagnesemia, hypothyroidism

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