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PA32.5-7 | Arthritis (RA, OA, Gout) & Bone Morphology — SDL Guide (Part 2)

Gouty Arthritis — Pathogenesis, Morphology & Complications

Gout is caused by hyperuricemia and the deposition of monosodium urate (MSU) crystals in joints and soft tissues, triggering intense acute inflammation.

Pathogenesis of hyperuricemia:
• Primary gout (90%): Idiopathic, usually underexcretion of uric acid by the kidney; predominantly middle-aged men.
• Secondary gout: Overproduction (myeloproliferative disorders, tumour lysis syndrome, enzyme defects — HGPRT deficiency in Lesch-Nyhan syndrome) or underexcretion (renal failure, diuretics, low-dose aspirin, cyclosporin).
• Uric acid = end product of purine catabolism via xanthine oxidase.

How crystals cause disease:
1. MSU crystals deposit in synovial fluid and are phagocytosed by neutrophils → NLRP3 inflammasome activation → IL-1β release → explosive neutrophilic inflammation.
2. Crystals are needle-shaped, negatively birefringent under polarised light (appear yellow when parallel to the slow ray of the compensator).
3. Compare: Calcium pyrophosphate crystals (pseudogout) are rhomboid/rod-shaped and positively birefringent (blue when parallel to slow ray).

Clinical phases:

Asymptomatic hyperuricemia — elevated serum uric acid without symptoms; most people with hyperuricemia never develop gout.
Acute gouty arthritis — sudden-onset, exquisitely tender, red, hot, swollen joint; podagra (first MTP joint) in 50% of initial attacks; self-limiting (resolves in days–weeks); triggered by alcohol, dietary purine load, dehydration, trauma, surgery.
Intercritical gout — asymptomatic intervals between attacks (may last years).
Chronic tophaceous gout — persistent hyperuricemia leads to tophi deposition in soft tissues (ears, Achilles tendon, bursae, finger pads, extensor surfaces); persistent low-grade joint inflammation.

Morphology:

Tophus — a collection of MSU crystals surrounded by a granulomatous reaction: foreign-body type giant cells, macrophages, fibroblasts, and chronic inflammatory cells encircling the needle-like crystal deposits.

Two-panel H&E histology diagram of a gouty tophus showing amorphous pale urate deposits surrounded by foreign-body giant cells and granulomatous macrophage reaction at low and high magnification. — **Panel A:** Tophus (central amorphous pale/white zone — dissolved urate deposits); Granulomatous reaction (peripheral cellular rim); Foreign-body giant cells (large, multinucleated); Macrophages/epithelioid cells (surrounding mononuclear); Fibrous stroma (background collagen). **Panel B:** Multinucleated giant cell (8–15 peripheral nuclei); Pale urate ghost zone (tophus edge); Epithelioid macrophages (oval nuclei, pink cytoplasm); Giant cell–tophus interface.

Three-panel diagram: Panels A and B show polarized-light photomicrograph simulations of MSU (needle-shaped, negative birefringence, yellow parallel to slow axis) and CPPD (rhomboid, positive birefringence, blue parallel to slow axis) crystals respectively with labeled features; Panel C is a structured comparison table of both crystal types covering shape, birefringence sign, color, location, disease, and serum marker. — **Panel A:** Needle-shaped MSU crystals; yellow color parallel to slow axis (negative birefringence); blue color perpendicular; slow axis direction arrow; birefringence color key inset. **Panel B:** Rhomboid CPPD crystals; blue color parallel to slow axis (positive birefringence); yellow color perpendicular; slow axis direction arrow; birefringence color key inset. **Panel C:** Comparison table rows — crystal shape icons, birefringence sign (negative vs positive), color parallel to slow axis (yellow vs blue), anatomical location, associated disease (Gout vs Pseudogout), serum marker (uric acid vs Ca²⁺/phosphate).

Complications:
• Urate nephropathy — MSU crystal deposition in renal medullary interstitium → tubular obstruction, inflammation, chronic renal failure ("gouty nephropathy").
• Uric acid nephrolithiasis — radiolucent renal stones (unlike calcium oxalate/phosphate stones which are radio-opaque).
• Acute uric acid nephropathy — massive crystal precipitation in collecting ducts during tumour lysis → acute oliguric renal failure.

Acute attack: aspiration findings — cloudy fluid, WBC >20,000 (predominantly neutrophils), negatively birefringent needle crystals; uric acid often not elevated during acute attack (crystals deposit as levels fall).

SELF-CHECK

A 55-year-old woman has symmetric swelling of her MCP and PIP joints with morning stiffness >1 hour. Serology shows high-positive anti-CCP. X-ray shows juxta-articular osteopenia with marginal erosions but NO osteophytes. Her DIP joints are NORMAL. What is the most likely diagnosis and which joint-sparing pattern clinches it?

A. Osteoarthritis — Heberden's nodes at DIPs are the hallmark

B. Rheumatoid arthritis — DIP sparing with symmetric MCP/PIP involvement and erosions

C. Gout — negatively birefringent crystals in joint fluid confirm it

D. Psoriatic arthritis — DIP involvement distinguishes it from RA

Reveal Answer

Answer: B. Rheumatoid arthritis — DIP sparing with symmetric MCP/PIP involvement and erosions

RA classically spares the DIP joints and involves MCPs, PIPs, and wrists symmetrically. The anti-CCP is highly specific (95%), juxta-articular osteopenia and marginal erosions without osteophytes are characteristic radiologic findings. OA affects DIPs (Heberden's nodes) and is not erosive. Gout is typically monoarticular initially and confirmed by crystal analysis. Psoriatic arthritis involves DIPs (the opposite of RA).

RA vs OA vs Gout — Comparison Table

This table is high-yield for theory and clinical exams. Memorise the contrasting columns.

Feature	Rheumatoid Arthritis	Osteoarthritis	Gout
Type	Autoimmune/inflammatory	Degenerative	Crystal-induced inflammatory
Age / Sex	30–50 yrs; F > M (3:1)	>65 yrs; F > M	40–60 yrs; M > F (95%)
Joints	Symmetric; MCPs, PIPs, wrists	Asymmetric; hips, knees, DIPs	First MTP (podagra); acute monoarthritis
DIP involvement	Spared	Heberden's nodes (DIP), Bouchard's (PIP)	Can be affected in tophaceous stage
Onset	Gradual; morning stiffness >1 hr	Gradual; stiffness <30 min; worse with use	Acute, sudden, nocturnal; exquisitely tender
Synovium	Hyperplastic; pannus; lymphocytic infiltrate	Mild secondary inflammation	Acute: neutrophilic; Chronic: granulomatous tophus
Cartilage loss	Pannus-mediated; enzymatic	Mechanical/biochemical; fibrillation	Secondary to crystal-induced inflammation
X-ray	Osteopenia, erosions, no osteophytes	Osteophytes, sclerosis, subchondral cysts	Punched-out erosions ("rat-bite") with overhanging edges in chronic
Serology	RF +, anti-CCP +	Negative	Serum uric acid elevated (not always during attack)
Key lab/aspiration	Anti-CCP, ↑ESR, ↑CRP	Usually normal	Negatively birefringent needle crystals; WBC >20,000
Extra-articular	Nodules, amyloidosis, vasculitis, ILD	Local (subchondral cysts, loose bodies)	Tophi, urate nephropathy, nephrolithiasis
Treatment target	TNF-α, IL-6, JAK (DMARDs)	Symptom management; joint replacement	Colchicine (acute); allopurinol (chronic)

Three-panel radiograph-style illustration comparing hand X-ray features of rheumatoid arthritis (marginal erosions, juxta-articular osteopenia, no osteophytes), osteoarthritis (Heberden nodes, DIP joint-space narrowing, subchondral sclerosis), and chronic gout (punched-out erosions with sclerotic margins and overhanging edges at first MCP). — **Panel A:** RA Hand — juxta-articular osteopenia (periarticular bone pallor at MCPs), marginal erosions (notched defects at 2nd/3rd MCP joint margins), uniform MCP and wrist joint-space narrowing, ulnar deviation of fingers, absence of osteophytes (explicitly noted). **Panel B:** OA Hand — Heberden nodes (osteophytes at DIP joints), Bouchard nodes (osteophytes at PIP joints), subchondral sclerosis at DIP and PIP margins, asymmetric DIP/PIP joint-space narrowing, first CMC joint involvement, relative MCP sparing. **Panel C:** Chronic Gout Hand — punched-out erosions with well-defined sclerotic white margins at first MCP, characteristic overhanging bony edge projecting over erosion, periarticular soft-tissue tophus density, relative preservation of joint space in early/intermediate disease.

CLINICAL PEARL

The 'treat-to-target' trap in gout: Serum uric acid is often normal or even low during an acute gouty attack because crystals are precipitating out of solution as levels fall — do NOT use a normal uric acid to rule out gout acutely. The target for chronic gout management is uric acid <6 mg/dL (below the saturation point for MSU crystal formation). Allopurinol paradoxically can trigger acute attacks when first started (by mobilising crystals) — always co-prescribe prophylactic colchicine for 3–6 months when initiating allopurinol.

SELF-CHECK

During microscopic examination of a joint aspirate from a 60-year-old man with acute knee swelling, you see rhomboid/rod-shaped crystals that appear BLUE when aligned parallel to the slow axis of the compensator under polarised light. What is the diagnosis?

A. Gout — monosodium urate crystals showing negative birefringence

B. Pseudogout — calcium pyrophosphate crystals showing positive birefringence

C. Septic arthritis — gram-positive cocci confirmed by culture

D. RA — fibrin crystals in the synovial fluid

Reveal Answer

Answer: B. Pseudogout — calcium pyrophosphate crystals showing positive birefringence

Calcium pyrophosphate dihydrate (CPPD) crystals in pseudogout are rhomboid-shaped and POSITIVELY birefringent (blue when parallel to the slow axis, yellow when perpendicular). Monosodium urate crystals in gout are needle-shaped and NEGATIVELY birefringent (yellow when parallel, blue when perpendicular). The shape and birefringence pattern here — rhomboid + blue (positive) — diagnose pseudogout (chondrocalcinosis), often affecting the knee in elderly patients.

Bone Morphology Practical — Systematic Pattern Recognition

PA32.7 requires you to identify bone lesions morphologically. The practical examiner will give you a slide — you must name the lesion and justify it from the features you see. This section walks through the six patterns you must own.

Approach every bone slide in this order: (1) Is there normal bone? (2) What is the cellular infiltrate or matrix abnormality? (3) Is there destruction, new bone formation, or both? (4) What pattern does that make?

1. Acute Osteomyelitis / Sequestrum

Etiology: Haematogenous spread (children: metaphysis; Staphylococcus aureus ~80%); or contiguous spread.

Gross key features:
• Involucrum — reactive new bone shell surrounding the infected area
• Sequestrum — devitalised, dead bone fragment within the abscess cavity (avascular, no cells, basophilic outlines)
• Cloaca — opening in involucrum through which pus drains

Microscopic key features:
• Acute: neutrophilic infiltrate, bone necrosis (empty lacunae, basophilic dead bone)
• Chronic: lymphocytes, plasma cells, fibrosis, new bone formation

Two-panel medical illustration: Panel A shows a longitudinal cross-section of a tibia with chronic osteomyelitis labelling the involucrum (outer reactive new bone shell), sequestrum (pale dead bone inside the abscess cavity), and cloaca (drainage opening); Panel B shows a high-power H&E histology diagram of the sequestrum with empty osteocyte lacunae in necrotic bone surrounded by neutrophilic acute inflammatory exudate. — **Panel A:** Involucrum (outer reactive periosteal new bone shell), Sequestrum (pale avascular dead bone fragment within abscess cavity), Cloaca (sinus channel opening through involucrum for pus drainage), Abscess cavity, Normal medullary canal (superior and inferior to lesion for orientation). **Panel B:** Empty osteocyte lacunae in necrotic lamellar bone (no viable nuclei), Acute inflammatory exudate — dense neutrophilic infiltrate surrounding necrotic trabeculae.

2. Paget Disease — Mosaic Pattern

Etiology: Probable paramyxoviral trigger + RANK pathway dysregulation; older adults.

Gross: Enlarged, deformed bone — hat size increases, "chalk-stick" fractures; skull enlargement.

Microscopic hallmark: Mosaic (jigsaw) pattern — irregular cement lines in lamellar bone giving the appearance of a crazy-paving or mosaic; both osteoblasts and osteoclasts are increased (alternating phases of resorption and chaotic deposition).

Three-panel H&E histology diagram of Paget disease bone showing the characteristic mosaic cement line pattern at medium power (Panel A), multinucleated osteoclasts within Howship's lacunae at high power (Panel B), and prominent osteoblasts lining new osteoid seams at high power (Panel C). — **Panel A:** Mosaic cement lines (basophilic reversal lines), lamellar bone matrix (pale pink), marbled/jigsaw pattern of irregular bone segments. **Panel B:** Multinucleated osteoclasts (10–12 nuclei), Howship's lacunae (scalloped resorption bays), resorption surface of trabecula. **Panel C:** Osteoblasts (plump cuboidal cells with eccentric nuclei), osteoid seam (new uncalcified bone), reversal cement line at base.

3. Osteosarcoma — Malignant Osteoid

Definition: Malignant tumour in which the tumour cells directly produce osteoid (unmineralised bone matrix). Most common primary malignant bone tumour in children/adolescents; metaphysis of distal femur or proximal tibia.

Gross: Metaphyseal destructive mass; Codman's triangle (periosteal elevation); sunburst pattern on X-ray.

Microscopic hallmark: Malignant osteoid — pink, homogeneous, amorphous matrix directly produced by pleomorphic, hyperchromatic malignant osteoblasts. The key question: "Are these atypical cells making bone?" Yes → osteosarcoma.

Three-panel H&E histology diagram of osteosarcoma: Panel A shows low-power view with pleomorphic malignant cells directly producing pink amorphous osteoid without lamellar organisation; Panel B shows high-power view with atypical mitotic figures and hyperchromatic nuclei; Panel C shows normal lamellar bone for comparison. — **Panel A:** Malignant osteoid (pink amorphous matrix), pleomorphic tumour cells (hyperchromatic irregular nuclei), high N:C ratio bracket, disorganised stroma replacing lamellar architecture — low-power H&E field. **Panel B:** Atypical mitotic figure (tripolar/scattered chromosomes), binucleate malignant cell, hyperchromatic nucleus with coarse chromatin — 40× high-power inset. **Panel C:** Normal lamellar bone (concentric Haversian lamellae), osteocyte lacunae in orderly arrangement, Haversian canal centre — comparison reference panel.

4. Giant-Cell Tumour (GCT) — Osteoclast-Type Giant Cells

Definition: Locally aggressive tumour of the epiphysis (young adults, 20–40 years); distal femur, proximal tibia most common.

Gross: Epiphyseal, eccentric, soap-bubble lytic lesion on X-ray.

Microscopic hallmark: Uniformly distributed osteoclast-type multinucleated giant cells (may contain 50–100 nuclei) in a background of ovoid to spindle mononuclear stromal cells; nuclei of giant cells and stromal cells look similar (same appearance — key feature).

Two-panel H&E histopathology diagram of giant-cell tumour showing low-power uniform distribution of osteoclast-type giant cells among spindle stromal cells (Panel A) and high-power detail demonstrating nuclear morphological similarity between giant cells and stromal cells (Panel B). — **Panel A:** Osteoclast-type giant cells (large, pale eosinophilic cytoplasm, 50–100 evenly distributed nuclei); spindle-shaped mononuclear stromal cells uniformly interspersed; absence of malignant osteoid or necrosis; panel title 'A. Low-power view — uniform GCT architecture'. **Panel B:** High-power inset of single giant cell showing 8–12 oval nuclei with open chromatin and inconspicuous nucleoli; adjacent stromal cell nuclei shown side-by-side for morphological comparison; callout annotation 'Nuclear similarity — key diagnostic feature'; panel title 'B. High-power detail — nuclear morphology'.

5. Ewing Sarcoma — Small Round Blue Cells

Definition: Malignant tumour of bone (and soft tissue); children/adolescents; diaphysis (contrast GCT = epiphysis, osteosarcoma = metaphysis).
Genetics: t(11;22)(q24;q12) → EWSR1-FLI1 fusion; CD99 positive (MIC-2 antigen).

Gross: Diaphyseal, onion-skin periosteal reaction on X-ray; can mimic osteomyelitis clinically (fever, ↑WBC).

Microscopic hallmark: Sheets of uniform small, round, blue cells with scant cytoplasm and round nuclei; no matrix production; PAS-positive glycogen granules in cytoplasm; CD99 strongly positive on IHC.

Two-panel histopathology illustration of Ewing sarcoma: Panel A shows H&E photomicrograph with sheets of uniform small round blue cells with scant cytoplasm and round nuclei and no osteoid or cartilage matrix; Panel B inset shows CD99 (MIC-2) immunohistochemistry with diffuse membranous brown positivity. — **Panel A:** Small round blue cells (sheets), scant cytoplasm, round nuclei with finely stippled chromatin, absent osteoid matrix, absent cartilage matrix; H&E ×200; scale bar 50 µm. **Panel B:** CD99 (MIC-2) immunohistochemistry; diffuse strong membranous positivity (brown DAB); hematoxylin counterstain (blue nuclei); scale bar 50 µm.

6. Bone Metastases

Context: Most common malignant bone tumour overall (more common than primary tumours). Common primaries: Breast, Lung, Prostate, Kidney, Thyroid (mnemonic: BLPKiT; or Breast Likes Killing Prostate/Thyroid).

Pattern:
• Lytic (osteoclast activation dominant): lung, kidney, thyroid, myeloma
• Sclerotic/blastic (osteoblast stimulation): prostate, carcinoid
• Mixed: breast

Microscopic key: Clusters or sheets of cohesive epithelial cells (carcinoma cells forming glands, nests, or solid sheets) in a fibrotic stroma — within a background of normal or reactive bone. The 'wrong' cell in bone tissue.