MSK, Rheumatology & Imaging System
MSK & Rheumatology
High-yield musculoskeletal, rheumatology, imaging, and immunology for USMLE Step 2/3 — inflammatory arthritis, autoimmune connective tissue disease, CT contrast decision rules, and hypersensitivity mechanisms, organized by cluster for exam performance.
Inflammatory Arthritis
Rheumatoid arthritis and its DMARD pharmacology appear on every shelf and board exam. RR-68 delivers the RA framework plus Parvo B19 polyarthritis. EP619 covers elbow, neck, and back pathology with a clinical-scenario focus — lateral epicondylitis vs medial epicondylitis, cervical radiculopathy levels, and lumbar disc herniation patterns.
RR 68EP358
Rheumatoid Arthritis, DMARDs & Parvo B19 Arthritis
- RA diagnosis: Symmetric small joint (MCP, PIP) polyarthritis + morning stiffness >1 hour. Rheumatoid factor (IgM against IgG Fc) and anti-CCP antibodies (more specific). Hands, wrists, feet — spares DIP joints (DIP = OA, gout, psoriatic)
- RA extra-articular: Rheumatoid nodules (subcutaneous, at extensor surfaces), pericarditis, scleritis, Felty syndrome (RA + splenomegaly + neutropenia), Caplan syndrome (RA + pneumoconiosis with large nodules)
- DMARD stepladder: MTX first (folic acid antagonist → mouth sores, hepatotoxicity, pneumonitis — give folate supplement). Add hydroxychloroquine (retinal toxicity → annual eye exam). Leflunomide (teratogen, hepatotoxic). Sulfasalazine
- Biologics (anti-TNF): Etanercept, infliximab, adalimumab. Screen for latent TB (PPD/IGRA) before starting — TNF blockade can reactivate TB. Also screen hepatitis B. Risk of opportunistic infections
- IL-6 inhibitor: Tocilizumab (blocks IL-6 receptor). Rituximab (anti-CD20, depletes B cells) — used if anti-TNF fails
- Parvo B19 arthritis: Symmetric polyarthritis mimicking RA, occurring in adults (daycare workers, pediatricians, pregnant women). Self-limited. "Slapped cheek" rash in children. Single-stranded DNA virus. Aplastic crisis in hemoglobinopathy patients
RA vs Other Inflammatory Arthritides
| Condition | Joint Pattern | Key Feature | HY Distinguisher |
|---|---|---|---|
| Rheumatoid Arthritis | Symmetric, small joints (MCP, PIP, wrist); spares DIP | RF, anti-CCP; morning stiffness >1h | Bilateral hand/wrist symmetry; ulnar deviation |
| Osteoarthritis | Weight-bearing joints; DIP (Heberden's nodes), PIP (Bouchard's nodes) | No morning stiffness; worse with activity | DIP involvement; no RF; asymmetric |
| Gout | First MTP (podagra) classically; acute monoarthritis | Urate crystals (needle-shaped, negatively birefringent) | Hyperuricemia; alcohol/purine triggers; tophi |
| Pseudogout (CPPD) | Knee most common; wrist | Calcium pyrophosphate crystals (rhomboid, weakly + birefringent) | Chondrocalcinosis on X-ray; elderly; associated with hemochromatosis, hyperparathyroidism |
| Reactive arthritis | Asymmetric oligoarthritis; lower extremity | Post-infection (Chlamydia, Shigella, Salmonella, Campylobacter) | Can't see, can't pee, can't climb a tree |
| Psoriatic arthritis | DIP involvement + nail pitting; asymmetric | Skin psoriasis (not always present before joints) | Sausage digits (dactylitis); pencil-in-cup deformity on X-ray |
| Septic arthritis | Monoarthritis; hot, red, swollen joint | WBC >50,000 in synovial fluid; fever; Staph aureus #1 | Gonorrhea in young sexually active; Staph most common overall |
DMARD Side Effects — Must Know
Methotrexate: Folic acid antagonist → mouth ulcers, hepatotoxicity, pulmonary toxicity (interstitial lung disease), teratogen (category X). Always supplement folate. Check LFTs regularly.
Hydroxychloroquine: Retinal toxicity (irreversible). Annual ophthalmology exam mandatory. Also used in lupus.
Leflunomide: Teratogen (washout needed before pregnancy). Hepatotoxic. Similar to MTX in mechanism (pyrimidine synthesis inhibitor).
Anti-TNF agents: Screen for latent TB (IGRA) before starting. Risk of serious infections. Demyelination risk with TNF inhibitors (do not use in MS). CHF worsening.
Crystal Arthropathy Comparison
| Feature | Gout (MSU) | Pseudogout (CPPD) |
|---|---|---|
| Crystal shape | Needle-shaped (monosodium urate) | Rhomboid (calcium pyrophosphate) |
| Birefringence | Negative (yellow parallel, blue perpendicular to polarizer) | Weakly positive (blue parallel, yellow perpendicular) |
| Common joint | First MTP, ankle, knee | Knee, wrist; chondrocalcinosis on X-ray |
| Association | Hyperuricemia, alcohol, thiazides, aspirin (low dose), cyclosporine | Hemochromatosis, hyperparathyroidism, hypomagnesemia, elderly |
| Acute treatment | Indomethacin/NSAIDs, colchicine, or steroids | NSAIDs or steroids |
| Prophylaxis | Allopurinol (xanthine oxidase inhibitor) or febuxostat; avoid during acute attack | No specific prophylaxis |
EP619
USMLE MSK Series: Elbow, Neck & Back
- Lateral epicondylitis (tennis elbow): Pain at lateral epicondyle; worse with wrist extension and gripping. Affects common extensor origin. Treat: rest, NSAIDs, PT. Cortisone injection if refractory
- Medial epicondylitis (golfer's elbow): Pain at medial epicondyle; worse with wrist flexion. Affects common flexor origin. Associated with ulnar nerve entrapment (cubital tunnel syndrome) — ring/little finger numbness
- Cervical radiculopathy levels: C5 = deltoid weakness, shoulder pain. C6 = biceps weakness, thumb/index paresthesia. C7 = triceps weakness (most common), middle finger. C8 = hand intrinsic weakness, ring/little finger. Check reflexes: C5–6 = biceps, C7 = triceps
- Lumbar disc herniation: L4 = knee extension weakness, medial leg/foot paresthesia, knee reflex ↓. L5 = foot dorsiflexion (foot drop), great toe extension, lateral leg. S1 = plantarflexion weakness, lateral foot, ankle reflex ↓ (most common)
- Cauda equina syndrome: Central disc herniation L4–S1 → bilateral leg weakness + saddle anesthesia (perineum) + bowel/bladder dysfunction (urinary retention). Emergency — surgical decompression. MRI is imaging of choice
- Spinal stenosis: Neurogenic claudication — pain/weakness with walking, relieved by sitting or forward flexion (opens spinal canal). Distinguish from vascular claudication (no relief with flexion; no pulses)
Cervical vs Lumbar Radiculopathy — Root Level Table
| Root | Motor | Reflex | Sensory | Level Disc |
|---|---|---|---|---|
| C5 | Deltoid (shoulder abduction) | Biceps ↓ | Lateral arm | C4–5 |
| C6 | Biceps, wrist extensors | Brachioradialis ↓ | Thumb, index finger | C5–6 |
| C7 (most common) | Triceps, wrist flexors | Triceps ↓ | Middle finger | C6–7 |
| C8 | Hand intrinsics, finger flexors | None | Ring + little finger | C7–T1 |
| L4 | Quadriceps (knee extension) | Knee reflex ↓ | Medial leg + foot | L3–4 |
| L5 | Foot dorsiflexion, great toe ext. | None reliable | Lateral leg, dorsum foot | L4–5 |
| S1 (most common lumbar) | Plantarflexion (standing on toes) | Ankle reflex ↓ | Lateral foot, heel | L5–S1 |
Cauda Equina — Surgical Emergency
Saddle anesthesia + bilateral leg weakness + urinary retention (overflow incontinence) = cauda equina syndrome. This is a surgical emergency. MRI lumbosacral spine immediately. Decompressive surgery within hours. Do NOT delay for more imaging if clinical picture is clear.
Neurogenic vs Vascular Claudication
| Feature | Neurogenic (Spinal Stenosis) | Vascular (PAD) |
|---|---|---|
| Trigger | Walking AND prolonged standing | Walking only (fixed distance) |
| Relief | Sitting, bending forward (opens canal) | Standing still (rest); no position effect |
| Pulses | Normal | Diminished or absent |
| Imaging | MRI spine → canal narrowing | ABI (<0.9), duplex ultrasound |
| Bicycle test | Can ride bicycle (flexion helps) | Cannot ride bicycle (claudication with any exertion) |
Autoimmune & Connective Tissue Disease
SLE is the most integrative rheumatology topic on the boards — it touches nephrology (lupus nephritis classes), hematology (ITP, hemolytic anemia), and cardiology (Libman-Sacks endocarditis). Antiphospholipid syndrome has a deceptive lab paradox that trips up students. Vasculitis is tested by vessel size and associated conditions.
RR 113EP527
SLE, Antiphospholipid Syndrome & Osteoarthritis
- SLE criteria mnemonic (DOPAMINE RASH): Discoid rash, Oral ulcers, Photosensitivity, Arthritis (non-erosive), Malar rash, Immunologic (anti-dsDNA, anti-Smith, antiphospholipid, direct Coombs+), Neurologic (seizures, psychosis), Endocarditis (Libman-Sacks), Renal (nephritis), Anemia (hemolytic), Serositis (pleuritis, pericarditis), Hematologic (leukopenia, thrombocytopenia)
- Key antibodies: ANA (sensitive, not specific). Anti-dsDNA (specific, tracks with disease activity). Anti-Smith (highly specific, not sensitive). Anti-Ro/SSA, anti-La/SSB (Sjogren's also; neonatal lupus → congenital heart block)
- Lupus nephritis: Class III/IV (diffuse proliferative) = worst. Hematuria + proteinuria + RBC casts. Treat with hydroxychloroquine + mycophenolate or cyclophosphamide. Class V (membranous) = nephrotic syndrome
- Antiphospholipid syndrome (APLS): Paradox: prolonged aPTT in lab (antibody interferes with test) but thrombosis in vivo (antibody activates platelets). Recurrent arterial/venous clots + recurrent pregnancy loss. Treat with warfarin (long-term). Lupus anticoagulant, anticardiolipin, anti-β2GP1 antibodies
- Libman-Sacks endocarditis: Sterile vegetations on BOTH sides of mitral valve (vs rheumatic fever = just on leaflet). Non-infectious, associated with APLS and SLE. High embolic risk
- OA management: First-line = acetaminophen. NSAIDs if inadequate. Topical NSAIDs for knees. Intraarticular steroids for acute flares. Arthroplasty for end-stage. Glucosamine/chondroitin: no proven benefit on USMLE
SLE — Antibody Specificity Guide
| Antibody | Sensitivity | Specificity | Associated Condition / HY Pearl|
|---|---|---|---|
| ANA | High (95%) | Low | Screen first; negative ANA makes SLE very unlikely |
| Anti-dsDNA | Moderate | High | Tracks with lupus nephritis activity; titers ↑ with flares |
| Anti-Smith (Sm) | Low | Very high (SLE-specific) | Pathognomonic for SLE; doesn't track activity |
| Anti-Ro/SSA + Anti-La/SSB | Moderate | Moderate | Sjogren's primary; SLE with secondary Sjogren's; neonatal lupus (congenital heart block) |
| Lupus anticoagulant / Anticardiolipin | Moderate | High for APLS | Paradox: prolongs aPTT in vitro, thrombosis in vivo |
| Anti-histone | High | Drug-induced lupus | Hydralazine, procainamide, isoniazid, quinidine. Anti-dsDNA negative in drug-induced |
APLS Paradox — The Trick on Every Exam
Antiphospholipid antibodies interfere with the phospholipid-dependent steps of the coagulation cascade in the test tube → prolonged aPTT. But in the body, they activate platelet and endothelial surfaces → thrombosis. So: prolonged aPTT + thrombosis (not bleeding) + recurrent miscarriage = antiphospholipid syndrome. Treatment: warfarin (INR target 2–3 for venous; 3–4 for arterial).
Lupus Nephritis WHO Classification (High Yield)
| Class | Pattern | Clinical | Treatment |
|---|---|---|---|
| Class I–II | Minimal/mesangial | Mild proteinuria or normal | Hydroxychloroquine; no aggressive immunosuppression |
| Class III (focal) | Focal proliferative (<50% glomeruli) | Hematuria, proteinuria, HTN | Mycophenolate or low-dose cyclophosphamide |
| Class IV (diffuse) — worst | Diffuse proliferative (>50% glomeruli) | Nephritic syndrome, RBC casts, ↓GFR | High-dose steroids + mycophenolate or cyclophosphamide |
| Class V (membranous) | Immune complex sub-epithelial deposits | Nephrotic syndrome (heavy proteinuria) | Mycophenolate; consider RAAS inhibitor |
RR 115EP536
Vasculitis, Pneumoconiosis & Cyclophosphamide
- Large vessel vasculitis: Giant cell arteritis (GCA) — age >50, temporal headache, jaw claudication, ESR >50, risk of blindness (anterior ischemic optic neuropathy). Start steroids immediately — don't wait for biopsy. Temporal artery biopsy confirms. Associated with polymyalgia rheumatica (PMR — proximal muscle pain, not weakness)
- Medium vessel vasculitis: Polyarteritis nodosa (PAN) — spares lung and kidney glomeruli (involved renal artery, not glomerulonephritis). HBV association. Livedo reticularis, mononeuritis multiplex, abdominal angina, renovascular hypertension. ANCA negative
- Small vessel (ANCA+): GPA (Wegener's): upper + lower respiratory + renal triad; c-ANCA (anti-PR3). MPA: lung + kidney; p-ANCA (anti-MPO). EGPA (Churg-Strauss): asthma + eosinophilia + p-ANCA. Treat GPA/MPA with rituximab or cyclophosphamide + steroids
- Cyclophosphamide toxicity: Hemorrhagic cystitis (prevent with mesna + adequate hydration). Transitional cell carcinoma of bladder (long-term risk). Bone marrow suppression. SIADH. Bladder toxicity is the key distinguishing side effect
- Kawasaki disease: <5 years old, fever >5 days + 4 of 5 CRASH features (Conjunctivitis, Rash, Adenopathy cervical, Strawberry tongue, Hands/feet swelling/desquamation). IVIG + aspirin. Risk: coronary artery aneurysm (get echo at diagnosis, 6 weeks, 6 months)
- Takayasu arteritis: Large vessel; young Asian women; subclavian/aortic involvement; absent radial pulse; arm claudication; treat with steroids
Vasculitis — Size-Based Classification
| Size | Disease | ANCA | Key Feature | Treatment |
|---|---|---|---|---|
| Large | Giant Cell Arteritis (GCA) | Negative | Age >50; jaw claudication; blindness risk | High-dose prednisone immediately |
| Large | Takayasu Arteritis | Negative | Young Asian women; absent pulse; arm claudication | Steroids ± methotrexate |
| Medium | Polyarteritis Nodosa (PAN) | Negative | HBV; spares lungs; renal artery (not GN) | Steroids ± cyclophosphamide |
| Medium | Kawasaki disease | Negative | Children; CRASH; coronary aneurysm | IVIG + aspirin |
| Small | GPA (Wegener's) | c-ANCA (PR3) | Sinuses + lungs + kidneys; saddle-nose deformity | Rituximab or cyclophosphamide + steroids |
| Small | MPA | p-ANCA (MPO) | Pulmonary-renal syndrome; no upper airway | Rituximab or cyclophosphamide |
| Small | EGPA (Churg-Strauss) | p-ANCA (MPO) | Asthma + eosinophilia + vasculitis | Steroids; mepolizumab (anti-IL5) |
| Small | IgA vasculitis (HSP) | Negative | Children; purpura on buttocks/legs, arthritis, GI, nephritis; post-URI | Supportive; steroids for severe GI/renal |
GCA vs PMR — The Classic Pairing
GCA and PMR occur together in 50% of cases. PMR = bilateral aching of shoulder and hip girdle in patients >50, dramatically responsive to LOW-dose prednisone (20mg/day). GCA requires HIGH-dose prednisone (1mg/kg/day). Both have elevated ESR and CRP. PMR alone has no headache and no cranial artery involvement.
Imaging Principles
CT contrast decisions are formulaic and high-yield — infection/inflammation/cancer/vascular = use contrast. Stroke/stone/fracture/ILD screening = no contrast. EP610 extends this to breast imaging, vascular procedures (embolectomy vs TPA), and IVC filters — clinical imaging integration that appears frequently on Step 2/3.
EP478
CT with Contrast vs CT without Contrast
- NO contrast for: Stroke (blood is its own contrast; contrast obscures hemorrhage on CT head). Kidney stone (calcium-containing stones already radio-dense). Fractures / musculoskeletal injury. Non-penetrating trauma without vascular concern. ILD / high-resolution lung CT. Lung cancer screening (low-dose CT). CT colonography (colon cancer screening)
- YES contrast for: Cancer (any type, except lung cancer screening and CT colonography). Infection or inflammation (-itis anything: pancreatitis, diverticulitis, appendicitis). Penetrating trauma or suspected vascular injury. Infarction/ischemia anywhere except brain. Any vascular abnormality (aneurysm, dissection, embolus)
- Oral/rectal contrast: Only when suspecting GI tract perforation. Prefer gastrografin over barium (water-soluble; if barium leaks into peritoneum → barium peritonitis). Never give oral contrast to a vomiting patient
- Contrast-induced nephropathy: Acute intrinsic renal failure after contrast. Prevention = IV normal saline (fluids first, not N-acetylcysteine). Risk factors: pre-existing CKD, diabetes, volume depletion
- Allergic contrast reaction: Biggest risk factor = prior allergic contrast reaction. Second = atopic disease (asthma). Treatment: IV steroid + antihistamine. Anaphylaxis → epinephrine
- Angiography terms: Any imaging with "angiography" in the name = involves contrast. CTA (CT angiography) = IV contrast. DSA (digital subtraction angiography) = invasive + contrast
CT Contrast Decision Table
| Clinical Scenario | Contrast | Reasoning |
|---|---|---|
| Acute stroke | No contrast (CT head) | Blood is own contrast; contrast hides hemorrhage |
| Kidney stone | No contrast (CT abdomen/pelvis) | Calcium radio-dense; contrast adds nothing |
| Fracture evaluation | No contrast | Bone already radio-dense |
| ILD evaluation | No contrast (HRCT) | High-res CT gives adequate detail without contrast |
| Lung cancer screening | No contrast (low-dose CT) | Protocol is low-dose; contrast not required for screening |
| Appendicitis / diverticulitis | With IV contrast | Infection/inflammation → contrast enhances |
| Cancer workup | With IV contrast | Tumor vascularity demonstrated with contrast |
| Aortic dissection | With IV contrast (CTA) | Vascular abnormality requires contrast |
| Pulmonary embolism | With IV contrast (CT-PA) | Vascular emergency; contrast fills pulmonary arteries |
| Penetrating trauma | With IV contrast | Vascular injury assessment requires contrast |
| Suspected GI perforation | Oral gastrografin (not IV) | Water-soluble oral contrast; not IV |
The Lymphoma Exception
Most cancers → contrast CT. Lymphoma is an exception — lymphoma does not typically require IV contrast for initial workup. The lymph node enlargement is visible without contrast enhancement. PET-CT is preferred for lymphoma staging.
EP610
Imaging & The USMLEs — Part 1
- Breast imaging algorithm: Age <30 → ultrasound (denser tissue, mammogram less sensitive). Age >30 → mammogram. Recent negative mammogram + new palpable mass → ultrasound (not repeat mammogram). Palpable mass + negative imaging → biopsy anyway. BRCA mutation → annual breast MRI from age 25, add mammogram from age 30
- Malignant mammographic features: Irregular or spiculated margins. Radio-dense. Varying morphology. Calcifications: linear, coarse, segmented, or clustered
- Benign mammographic features: Round/oval, well-circumscribed. Radiolucent (oil cyst, lipoma, galactocele). Popcorn calcifications (pulmonary hamartoma in lungs; fibroadenoma in breast). Layered/teacup calcifications = milk of calcium. Vascular calcification pattern. Scattered calcifications
- IVC filter: DVT + contraindication to anticoagulation (recent major hemorrhage, severe active bleeding) → place IVC filter. Does not treat DVT; prevents PE. Not equivalent to anticoagulation
- Embolectomy vs TPA: Acute limb ischemia → anticoagulate first → CTA of extremity → surgical embolectomy. If embolectomy not listed → TPA. Saddle PE → embolectomy (not TPA for massive saddle PE). Ischemic stroke <4.5h → TPA (not embolectomy)
- Central line indications: Long-term antibiotics (endocarditis, osteomyelitis — 6-week courses). Chemotherapy. TPN. Most common complication of TPN → central line-associated bloodstream infection (CLABSI), not acalculous cholecystitis (common distractor)
Mammographic Calcification Patterns
| Pattern | Type | Classic Association |
|---|---|---|
| Linear / segmental | Malignant | Ductal carcinoma; follows duct system |
| Coarse / clustered | Malignant (worrisome) | Suspicious; biopsy required |
| Popcorn | Benign | Fibroadenoma (breast); pulmonary hamartoma (lung) |
| Milk of calcium / layered | Benign | Teacup or crescent orientation; harmless |
| Vascular | Benign | Follows vessel path; atherosclerosis of breast vessels |
| Scattered | Benign | No coherent pattern; not concerning |
Reperfusion Injury — When TPA Works Too Late
After delayed vascular restoration (TPA or embolectomy for acute limb ischemia): oxygen returns to ischemic tissue → free radical burst → rhabdomyolysis → myoglobinuria (red/brown urine) + hyperkalemia + acute kidney injury + EKG changes (peaked T waves, wide QRS). Treat hyperkalemia first with IV calcium gluconate (membrane stabilization), then treat the rhabdomyolysis with IV fluids.
Immunology & Hypersensitivity
The four hypersensitivity types are tested through clinical recognition — asthma and anaphylaxis are Type 1; hemolytic anemia and rheumatic fever are Type 2; serum sickness and post-streptococcal GN are Type 3; TB skin test and contact dermatitis are Type 4. Know the mechanism, not just the category, and you can derive any question.
EP359
The Clutch Hypersensitivity Reactions Podcast
- Type 1 (IgE-mediated): First exposure → sensitization (Th2 cells → IL-4 → class switch to IgE → IgE binds Fc epsilon receptors on mast cells/basophils). Second exposure → allergen cross-links IgE → mast cell degranulation → histamine, bradykinin → vasodilation, bronchoconstriction. Examples: asthma, anaphylaxis, food allergy, hay fever, IgA-deficient anaphylactic transfusion reaction
- Type 2 (antibody-mediated cytotoxic): IgG and IgM bind cell surface antigens → complement activation → MAC → cell lysis. Examples: autoimmune hemolytic anemia (Coombs+), ITP (anti-GP2B3A), Goodpasture (anti-type IV collagen), rheumatic fever (molecular mimicry against strep), acute hemolytic transfusion reaction
- Type 3 (immune complex): Mobile antigen-antibody complexes deposit in vessel walls/kidneys → complement activation → inflammation. Examples: serum sickness (3–14 days after monoclonal antibody infusion), post-streptococcal GN, lupus nephritis, most vasculitides, Arthus reaction (local)
- Type 4 (delayed, T-cell mediated): CD4+ Th1 cells → macrophage activation via IFN-γ → tissue destruction. 24–72 hour delay. Examples: TB skin test, contact dermatitis (poison ivy, nickel), rheumatoid arthritis, Hashimoto's thyroiditis, MS, Crohn's, celiac. Granulomas = Type 4
- IgA deficiency + anaphylaxis: IgA-deficient patients lack IgA → receive blood product with IgA → form anti-IgA IgE → second transfusion → anaphylaxis. Treat with washed RBCs (remove IgA) or IgA-deficient donor products
- Hyper-IgM syndrome: Class-switching defect (CD40L mutation, X-linked) → cannot switch from IgM to IgG/IgA/IgE → low all immunoglobulins except IgM. Recurrent bacterial infections in boys. Prone to Pneumocystis (since T-cell help for class switching also impairs CD40-dependent macrophage activation)
Hypersensitivity Types — Master Reference
| Type | Mediator | Mechanism | Classic Examples | Time Course |
|---|---|---|---|---|
| Type 1 (Anaphylactic) | IgE → mast cells/basophils | Allergen cross-links IgE → degranulation → histamine | Asthma, anaphylaxis, food allergy, hay fever | Minutes (immediate) |
| Type 2 (Cytotoxic) | IgG, IgM | Antibody binds cell surface → complement → MAC lysis | AIHA, ITP, Goodpasture, rheumatic fever, ABO mismatch | Hours |
| Type 3 (Immune complex) | IgG antigen-antibody complexes | Complexes deposit → complement → neutrophil recruitment | Serum sickness, post-strep GN, SLE, many vasculitides | Days (3–14 days for serum sickness) |
| Type 4 (Delayed/Cell-mediated) | T cells (CD4+ Th1, CD8+) | Th1 → IFN-γ → macrophage activation; granuloma formation | TB skin test, contact dermatitis, RA, MS, Crohn's, celiac | 24–72 hours (delayed) |
Granuloma = Type 4 Hypersensitivity (Almost Always)
When an NBME question shows granuloma formation on pathology → think Type 4 hypersensitivity reaction. The macrophage is the key cell: activated by IFN-γ from Th1 cells → forms giant cells → coalesces into granuloma. This applies to TB, sarcoidosis, Crohn's, berylliosis, and fungal infections (when chronic immune response develops).
Mast Cell Degranulation Products and Effects
| Mediator | Effect | Clinical Result |
|---|---|---|
| Histamine | Vasodilation, increased vascular permeability, bronchoconstriction | Urticaria, angioedema, wheezing, hypotension |
| Bradykinin | Pain, vasodilation, bronchoconstriction | Angioedema (different from histamine-mediated) |
| Heparin | Anticoagulation | Prolonged bleeding if massive degranulation |
| Prostaglandins | Bronchoconstriction, vasodilation, fever | Late-phase asthma response |
| Leukotrienes (C4, D4, E4) | Sustained bronchoconstriction, increased mucus | Late-phase reaction; target of montelukast |
RR 130EP622
Immune Response, Inflammatory Pathways & Autoimmune Pathophysiology
- Complement cascade — classical vs alternate: Classical = IgG/IgM trigger (C1q binds Fc). Alternate = direct pathogen surface activation (LPS, fungi). Lectin = MBL binds carbohydrates. All converge at C3 → C3a (anaphylatoxin → mast cell) + C3b (opsonin). C5b-9 = MAC
- Complement deficiencies: C1q deficiency → SLE-like (classical pathway clears immune complexes). C3 deficiency → recurrent encapsulated bacterial infections (no opsonization). C5–9 (MAC) deficiency → recurrent Neisseria (Neisseria gonorrhoeae and meningitidis need MAC for killing). DAF/CD59 deficiency → PNH (complement destroys own RBCs)
- TNF-α role: Master inflammatory cytokine. Produced by macrophages. Causes fever (via IL-1, IL-6, PGE2), cachexia, shock (massive vasodilation in septic shock). Target of infliximab, etanercept, adalimumab in RA/IBD/psoriasis
- IL-1 and IL-6: Fever inducers (act on hypothalamus via PGE2). IL-6 drives acute phase reactants (CRP, fibrinogen, haptoglobin → elevated ESR). Tocilizumab blocks IL-6 receptor
- NK cells: Kill cells missing MHC-I (virally infected + tumor cells downregulate MHC-I to escape CD8+ T cells → NK cells recognize "missing self"). ADCC via CD16 (Fc receptor) — mechanism also used by trastuzumab
- Primary immunodeficiencies — key patterns: B cell defects → recurrent encapsulated bacteria after age 6 months (maternal IgG wanes). T cell defects → opportunistic infections (Candida, PCP, CMV) from birth. Combined → both. Complement → Neisseria. Phagocyte (CGD) → catalase-positive organisms (Staph, Aspergillus, Nocardia)
Complement Deficiency → Infection Pattern
| Deficient Component | Infection Risk | Mechanism |
|---|---|---|
| C1q (SLE association) | Recurrent infections + SLE-like disease | Classical pathway fails to clear immune complexes → SLE. Also recurrent encapsulated bacteria |
| C3 | Recurrent encapsulated bacteria (Strep pneumo, H. influenzae, N. meningitidis) | No opsonization (C3b is main opsonin). Also increased susceptibility to all pyogenic bacteria |
| C5–C9 (MAC) | Recurrent Neisseria (gonorrhea and meningitidis) | MAC is required for killing gram-negative diplococci; C3b/opsonization insufficient for Neisseria |
| DAF / CD59 (PNH) | Not infections — complement attacks own RBCs | GPI-anchor defect → complement lyses own RBCs and platelets → hemolysis + thrombosis + cytopenias |
| MBL (lectin) | Recurrent infections in early childhood | Lectin pathway cannot clear pathogens; significant in neonates before adaptive immunity matures |
Immunodeficiency Pattern Quick Reference
Recurrent Neisseria → Terminal complement (C5–9) deficiency
Recurrent encapsulated bacteria after 6 months → B cell defect (XLA, CVID)
Opportunistic infections from birth → T cell defect (SCID, DiGeorge)
Catalase+ organisms (Staph, Serratia, Aspergillus, Nocardia, Candida) → CGD (NADPH oxidase defect)
SLE-like + infections → C1q deficiency