Clinical Learning Notes: Immunology & Rheumatology

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TOPIC 1: MECHANISM OF AUTOIMMUNITY

What is Autoimmunity?

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Normal Self-Tolerance: How the Body Prevents Autoimmunity

1. Central Tolerance (in generative lymphoid organs)

• T cells - mature in the thymus. Autoreactive T cells that bind self-antigens with high affinity are deleted by apoptosis (negative selection). Some become regulatory T cells (Tregs) instead.
• B cells - mature in the bone marrow. Autoreactive B cells either:
  • Undergo apoptosis (clonal deletion)
  • Switch to new, non-self-reactive antigen receptors (receptor editing)

2. Peripheral Tolerance (in peripheral tissues)

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Why Tolerance Fails: Mechanisms of Autoimmunity

Genetic Susceptibility

• Inheritance of genes that disrupt tolerance pathways
• HLA associations are the most important genetic link:
  • HLA-DR4, DR3 - Rheumatoid Arthritis
  • HLA-DR2, DR3 - SLE
  • HLA-B27 - Ankylosing Spondylitis (>90% of AS patients)
• Non-HLA genes (e.g., PTPN22, STAT4, CTLA-4 variants) also contribute

Environmental Triggers

• Infections can trigger autoimmunity via:
  • Molecular mimicry - microbial antigens share structural similarity with self-antigens; antibodies cross-react with host tissues (e.g., Strep → rheumatic fever)
  • Bystander activation - local inflammation activates APCs and dendritic cells, releasing self-antigens in an inflammatory context
  • Epitope spreading - initial immune response to a foreign antigen spreads to target nearby self-antigens
• Tissue injury and UV radiation (e.g., in SLE) - exposes nuclear antigens that are normally sequestered
• Drugs can induce drug-related lupus (e.g., hydralazine, procainamide, isoniazid)

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Key Autoimmune Effector Mechanisms

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Specific Autoantibodies: High-Yield Summary

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TOPIC 2: CONNECTIVE TISSUE DISEASES

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2A. Systemic Lupus Erythematosus (SLE)

Definition & Pathogenesis

• Excessive generation or persistence of nuclear antigens from cell death (e.g., UV-induced apoptosis fails to clear nuclear debris)
• Abnormal signalling by nucleic acid-recognising Toll-like receptors (TLRs) - TLR-7 and TLR-9 are activated by single- and double-stranded RNA/DNA
• Excessive production of type I interferons (IFN-α) amplifies the autoimmune response
• Defective clearance of apoptotic cells exposes nuclear antigens to the immune system

Epidemiology

• Women of reproductive age (15-40 years) predominantly affected
• Female:male ratio: ~2:1 before puberty, 4:1 after puberty
• More common and severe in African American women (up to 1 in 250)
• 5-year survival rate: ~90%
• Strong familial tendency; associated with HLA-DR2, DR3, DR4, DR5

Diagnosis: ACR Criteria (need 4 of 11)

Clinical Manifestations by System

• Classic butterfly (malar) rash - erythema over cheeks and bridge of nose, sparing nasolabial folds (contrast with dermatomyositis, which involves the nasolabial folds)
• Photosensitivity
• Discoid lupus - scarring plaques
• Subacute cutaneous LE (SCLE) - annular or papulosquamous on sun-exposed areas; associated with anti-Ro antibodies

• Most serious organ manifestation
• WHO/ISN classification I-VI
• Caused by immune complex deposition in glomeruli → complement activation
• Presents as proteinuria, haematuria, hypertension, declining GFR
• Class III/IV (diffuse proliferative) = most severe; treat with cyclophosphamide or mycophenolate

• Non-erosive arthritis/arthralgia (≥90%)
• Jaccoud arthropathy - reversible deformity from ligamentous laxity (not erosive)

• Haemolytic anaemia (Coombs positive)
• Leucopenia, lymphopenia
• Thrombocytopenia
• Antiphospholipid syndrome (APLS) → thrombosis, recurrent pregnancy loss

• Libman-Sacks endocarditis (sterile, verrucous vegetations on both sides of mitral valve)
• Pericarditis (most common cardiac manifestation)
• Accelerated atherosclerosis

• "Neuro-lupus" - mechanisms not fully elucidated
• Seizures, psychosis, cognitive dysfunction, headache

Treatment Principles

• Hydroxychloroquine - backbone of therapy; reduces flares and mortality, cardioprotective
• NSAIDs - arthritis, serositis, mild disease
• Corticosteroids - moderate-severe flares; short-term preferred
• Mycophenolate mofetil / Cyclophosphamide - lupus nephritis (induction)
• Azathioprine - maintenance
• Belimumab (anti-BLyS) - biologic for active SLE
• Sunscreen/sun avoidance

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2B. Sjögren Syndrome (SS)

Definition

• Keratoconjunctivitis sicca - dry eyes
• Xerostomia - dry mouth

Diagnosis

• Schirmer II test - measures tear production (wetting <8mm/5min abnormal)
• Rose bengal staining - detects corneal/conjunctival damage
• Minor salivary gland biopsy - characteristic lymphocytic focus score ≥1 (definitive test)
• Serology: Anti-Ro (SS-A) and Anti-La (SS-B) antibodies; elevated ANA (>1:320), elevated RF

Complications

• Lymphoma (B cell non-Hodgkin's) - most feared; 40× increased risk
• Peripheral neuropathy
• Renal tubular acidosis
• Vaginal dryness, fatigue

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2C. Systemic Sclerosis (Scleroderma)

Definition

1. Immune activation (T cells and macrophages)
2. Vascular injury (Raynaud's, endothelial damage)
3. Fibroblast activation → excess collagen deposition

Two Major Subtypes

Key Clinical Features

• Raynaud's phenomenon - often the first manifestation; triphasic colour change (white → blue → red)
• Skin thickening (induration) - starts in fingers (sclerodactyly), progresses proximally in diffuse disease
• GI: Oesophageal dysmotility (heartburn, dysphagia), gastroparesis, constipation, SIBO
• Lung: Pulmonary fibrosis (ILD) in diffuse; pulmonary arterial hypertension in limited
• Renal crisis: Sudden hypertension + AKI - treat with ACE inhibitors (captopril)
• Cardiac: Myocardial fibrosis, arrhythmias

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2D. Polymyositis (PM) / Dermatomyositis (DM)

Definition

• Heliotrope rash - violaceous discoloration of periorbital skin
• Gottron's papules - raised erythematous papules over MCP/PIP joints (pathognomonic)
• V-sign / Shawl sign - erythema on chest/upper back
• Mechanic's hands - hyperkeratotic, cracked skin on lateral fingers (associated with anti-synthetase syndrome)

Key Antibody: Anti-Jo-1 (anti-synthetase)

Malignancy Association

• DM especially associated with underlying malignancy (screen for occult cancer at diagnosis)

Investigations

• Elevated CK, aldolase, LDH
• Anti-Jo-1, anti-Mi-2 antibodies
• EMG: myopathic pattern
• MRI: muscle inflammation
• Muscle biopsy: perivascular inflammation (DM) vs endomysial inflammation (PM)

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TOPIC 3: INFLAMMATORY ARTHRITIS / OSTEOARTHRITIS

3A. Rheumatoid Arthritis (RA)

Definition & Pathogenesis

1. Synovial inflammation - immune cells (T cells, macrophages, B cells) infiltrate the synovium
2. Pannus formation - hyperplastic synovial tissue (pannus) invades and erodes cartilage and bone
3. Cytokine-driven destruction - TNF-α, IL-1, IL-6 drive inflammation and joint damage
4. Autoantibody production - RF (IgM anti-IgG) and anti-CCP antibodies

Epidemiology

• Prevalence: 1-2% of adults
• Female:male ratio: ~3:1
• Peak incidence: 20-50 years
• RF-positive, polyarticular RA: >70% develop joint erosions within 2 years without treatment

Clinical Features

• Symmetric synovitis - bilateral, equal joint involvement
• Morning stiffness >1 hour (improves with activity - "gel phenomenon"); contrast with OA (<30 minutes, worsens with use)
• Constitutional symptoms: fatigue, malaise, weight loss, low-grade fever

• Hands: MCP, PIP joints predominantly; DIP joints usually spared
• Wrists, elbows, shoulders, ankles, MTPs
• Spares DIP joints (contrast with OA, psoriatic arthritis)
• Cervical spine: atlantoaxial subluxation (risk during intubation - important!)

• Swan-neck deformity - PIP hyperextension, DIP flexion
• Boutonniere deformity - PIP flexion, DIP hyperextension
• Ulnar deviation at MCPs
• Z-thumb deformity
• Forefoot deformities - hallux valgus, claw toes

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

1. Morning stiffness ≥1 hour
2. Arthritis in ≥3 joint areas
3. Arthritis of hand joints (wrist, MCP, or PIP)
4. Symmetric arthritis
5. Rheumatoid nodules
6. Serum RF positive
7. Radiographic changes (erosions or periarticular osteopaenia)

Investigations

• RF - positive in ~70-80% (not specific; also positive in SS, SLE, hepatitis, normal elderly)
• Anti-CCP - more specific (~95%), positive earlier, predicts erosive disease
• ESR, CRP - elevated (disease activity markers)
• FBC - normocytic normochromic anaemia; thrombocytosis in active disease
• X-ray - periarticular osteopaenia → joint space narrowing → erosions (marginal/periarticular) → deformities
• MRI/USS - detect synovitis and erosions earlier than plain X-ray

Treatment (Treat-to-Target Strategy)

• Methotrexate (MTX) - first-line anchor DMARD; weekly dosing; supplement with folic acid
• Hydroxychloroquine - least toxic; useful for mild disease
• Sulfasalazine
• Leflunomide

• Anti-TNF agents: Etanercept, Adalimumab, Infliximab, Certolizumab, Golimumab
• Anti-IL-6: Tocilizumab, Sarilumab
• B cell depletion: Rituximab (anti-CD20)
• T cell co-stimulation blockade: Abatacept (CTLA-4-Ig)

• Baricitinib, Tofacitinib, Upadacitinib

• NSAIDs (symptom control only, no disease modification)
• Short-course corticosteroids (bridge therapy or flares)
• Physical and occupational therapy
• Joint replacement surgery for advanced disease

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3B. Other Inflammatory Arthritides (Seronegative Spondyloarthropathies)

Ankylosing Spondylitis (AS)

• HLA-B27 positive in >90%
• Males 5:1, onset in 20s-30s
• Chronic inflammatory axial arthritis: sacroiliac joints and spine
• Morning stiffness relieved by exercise (inflammatory pattern)
• Bamboo spine on X-ray (late): vertebral fusion from ossification
• Enthesitis (inflammation at tendon/ligament insertions) is characteristic
• Extra-articular: anterior uveitis (iritis) - most common; aortitis; cardiac conduction defects
• Treatment: NSAIDs (1st line, may slow radiographic progression), physiotherapy, anti-TNF biologics

Psoriatic Arthritis

• Arthritis in setting of psoriasis (usually skin precedes joints)
• DIP joint involvement is characteristic (helps distinguish from RA)
• "Sausage digits" (dactylitis)
• Nail changes (pitting, onycholysis)
• Seronegative (RF negative)
• Patterns: oligoarticular, polyarticular, axial, DIP dominant, arthritis mutilans

Reactive Arthritis (formerly Reiter Syndrome)

• Triad: Arthritis + Urethritis + Conjunctivitis ("Can't see, can't pee, can't climb a tree")
• Triggered by GI (Salmonella, Shigella, Campylobacter, Yersinia) or urogenital infections (Chlamydia)
• HLA-B27 associated
• Usually self-limited; NSAIDs, physiotherapy

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3C. Osteoarthritis (OA)

Definition & Pathogenesis

• Matrix metalloproteinase (MMP) activation → cartilage breakdown
• Subchondral bone remodelling
• Synovial inflammation (mild, secondary to debris)
• Genetic, metabolic, and mechanical factors

Epidemiology

• Most common cause of work disability in the USA (17%)
• Affects 20% of the U.S. population
• Radiographic OA present in nearly all 75-year-olds (mostly asymptomatic)
• Equal in men and women age 45-55; more common in women after age 55

Risk Factors

• Age (primary risk factor)
• Obesity
• Previous joint injury/trauma
• Repetitive occupational loading (kneeling: miners, carpet layers)
• Genetic factors (collagen gene defects)
• Secondary causes: haemochromatosis, Wilson's disease, CPPD, Paget's disease, acromegaly, prior inflammatory arthritis, neuropathic joints

Joint Distribution (Important for Exam!)

• Heberden's nodes - bony swellings at DIP joints (familial in women)
• Bouchard's nodes - bony swellings at PIP joints

Clinical Features

• Pain: worsens with activity, relieved by rest (opposite to RA)
• Morning stiffness: <30 minutes and localised
• Gel phenomenon - stiffness after rest resolves within minutes of activity
• No constitutional symptoms (no fever, no systemic inflammation)
• Crepitus, bony enlargement, reduced range of motion
• No significant joint warmth or erythema (minimal inflammation)

Investigations

• X-ray (plain radiograph) is the standard:
  • Joint space narrowing
  • Osteophytes (bone spurs)
  • Subchondral sclerosis (increased bone density)
  • Subchondral cysts
• Blood tests: Normal (ESR, CRP, RF all normal - important distinction from RA)
• Synovial fluid: non-inflammatory (<2000 WBC/mm³)

Treatment

• Patient education
• Weight loss (most important modifiable risk factor)
• Low-impact aerobic exercise and quadriceps strengthening
• Physiotherapy, occupational therapy
• Assistive devices

• Paracetamol (acetaminophen) - first-line analgesia (up to 1000mg QDS if no liver disease)
• NSAIDs - more effective than paracetamol for pain; use with PPI in high-risk patients (age >65, PUD history, anticoagulants)
• Topical NSAIDs/capsaicin - knee OA
• Intraarticular corticosteroids - useful when NSAIDs contraindicated or insufficient; short-term benefit (2× more likely to improve vs placebo); max 4 injections/joint/year
• Tramadol - adjunct; allows dose reduction of NSAIDs
• Opioids - reserved for acute exacerbations; avoid long-term
• Intraarticular hyaluronic acid - evidence weak, some benefit in knee OA

• Arthroscopic debridement/lavage (limited evidence)
• Osteotomy (realignment)
• Total joint arthroplasty - definitive treatment for severe OA; hip and knee most common

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TOPIC 4: CRYSTAL ARTHROPATHIES

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4A. Gout (Monosodium Urate / MSU Crystal Arthropathy)

Pathophysiology

Purines → Xanthine → Uric acid (via xanthine oxidase)

Causes of Hyperuricaemia

Epidemiology

• 95% male
• Men: typically 4th-6th decade
• Women: postmenopausal (oestrogen is uricosuric)
• Asymptomatic hyperuricaemia is common (19% in USA/UK); only 1 in 8 with urate 7-8 mg/dL develops clinical gout over 14 years
• Risk increases significantly with urate >9 mg/dL

Clinical Stages

• Not a disease; no treatment required
• Average 20 years of hyperuricaemia before first attack

• Sudden onset severe pain, erythema, swelling, warmth in a joint
• Podagra - first MTP joint (great toe) involved in 50% of first attacks, eventually in 75-90%
• Also: ankle, knee, midfoot, heel, wrist, elbow (olecranon bursa)
• Resolves spontaneously within days-weeks even without treatment
• Patient is asymptomatic between attacks (intercritical period)
• Serum uric acid may be normal during an acute attack - do not use for diagnosis

• Period between attacks
• Attacks become more frequent, polyarticular, and severe over time

• Joints no longer pain-free between attacks
• Tophi - chalky white deposits of urate crystals in soft tissues:
  • Classic locations: ear helix, olecranon bursa, Achilles tendon, finger pads
  • Can be mistaken for rheumatoid nodules
• Chronic joint erosion and deformity
• Renal: urate nephropathy, uric acid nephrolithiasis

Diagnosis

• Needle-shaped crystals
• Negatively birefringent under polarised light (yellow when parallel to compensator axis)

• Soft tissue swelling (acute)
• "Punched out" erosions with overhanging edges (chronic tophaceous) - not at joint margins (unlike RA)
• Preserved joint space (until late)
• Periarticular soft tissue opacification (tophi)

Management

• NSAIDs (e.g., naproxen, indomethacin) - first-line if no contraindications
• Colchicine - inhibits microtubule polymerisation → inhibits neutrophil migration; effective within 24 hours; GI side effects
• Corticosteroids (oral, intra-articular, or IM) - when NSAIDs and colchicine contraindicated (e.g., renal failure)
• Do NOT start urate-lowering therapy during an acute attack (fluctuation in urate can prolong/worsen attack)

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4B. Pseudogout (Calcium Pyrophosphate Deposition Disease / CPPD)

Pathophysiology

• Deposition of calcium pyrophosphate dihydrate (CPP) crystals in joint cartilage (chondrocalcinosis) and synovial fluid
• Crystals activate the NLRP3 inflammasome similarly to MSU crystals
• Less well understood than gout

Associations (Remember: "The 5 H's + Haemo" or WHOA CHIP)

• Hyperparathyroidism
• Hypothyroidism
• Haemochromatosis (iron deposition in cartilage)
• Hypomagnesaemia
• Hypophosphataemia
• Wilson's disease, Acromegaly, Gout

Clinical Presentations

1. Acute pseudogout - acute inflammatory monoarthritis, typically the knee (most common; contrast with gout → 1st MTP)
2. Chronic pyrophosphate arthropathy - resembles OA; typically large joints
3. Crowned dens syndrome - CPP deposits around odontoid process → neck pain, fever, meningism (mimic meningitis)
4. Asymptomatic chondrocalcinosis

Diagnosis

• Synovial fluid microscopy:
  • Rhomboid (rhombus-shaped) crystals
  • Positively birefringent under polarised light (blue when parallel)
• X-ray: Chondrocalcinosis - calcification of cartilage (menisci of knee, triangular fibrocartilage of wrist most common)
• Bloods: check calcium, phosphate, PTH, Mg, TSH, ferritin (screen for secondary causes)

Crystal Comparison Table (High-Yield Exam)

Management of Acute Pseudogout

• Same as acute gout: NSAIDs > Colchicine > Corticosteroids
• No disease-modifying treatment available to dissolve CPP crystals
• Treat underlying metabolic cause if identified

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4C. Basic Calcium Phosphate (BCP) / Hydroxyapatite Crystal Deposition

• Hydroxyapatite crystals deposit in periarticular tissues and tendons
• Causes calcific tendinitis (supraspinatus most common - "Milwaukee shoulder" if severe)
• Crystals do not show birefringence under polarised light (use alizarin red staining)
• Treatment: NSAIDs, aspiration, ultrasound-guided lavage, physiotherapy

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KEY COMPARISONS FOR EXAMS

Differentiating the Arthritides

RA vs OA Key Distinctions

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PHARMACOLOGY QUICK REFERENCE

DMARDs in Inflammatory Arthritis

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What's in Your Notes

• Central vs. peripheral tolerance mechanisms (thymic deletion, Tregs, CTLA-4/PD-1, anergy)
• Why tolerance fails: genetic susceptibility (HLA), molecular mimicry, bystander activation, epitope spreading
• Four hypersensitivity mechanisms driving autoimmune disease
• High-yield autoantibody table for all major CTDs

• SLE: pathogenesis (TLRs, IFN-α, nuclear debris), ACR 11 criteria, all organ system manifestations (nephritis classes, APLS, Libman-Sacks), treatment ladder
• Sjögren Syndrome: primary vs secondary, diagnostic criteria, lymphoma risk
• Systemic Sclerosis: limited (CREST/anti-centromere) vs diffuse (anti-Scl-70), Raynaud's, scleroderma renal crisis
• Polymyositis/Dermatomyositis: Gottron's papules, heliotrope rash, anti-Jo-1, malignancy screening

• RA: pannus formation, HLA-DR4, ACR criteria, classic deformities, extra-articular features, treat-to-target DMARDs → biologics → JAK inhibitors
• Seronegative spondyloarthropathies: AS (bamboo spine, HLA-B27), psoriatic arthritis (DIP/dactylitis), reactive arthritis (Reiter triad)
• OA: pathogenesis, risk factors, Heberden's/Bouchard's nodes, X-ray findings, full treatment pyramid

• Gout: hyperuricaemia staging, NLRP3 inflammasome, 4 clinical stages, podagra, negatively birefringent needle crystals, acute management vs ULT (allopurinol/febuxostat), lifestyle
• Pseudogout (CPPD): metabolic associations, knee > 1st MTP, positively birefringent rhomboid crystals, chondrocalcinosis on X-ray
• Side-by-side comparison tables for quick revision