A 42-year-old man with a history of rheumatoid arthritis develops fever, arthralgia, and a maculopapular rash 10 days after starting sulfasalazine. Serum complement levels (C3 and C4) are low, and circulating immune complexes are elevated. Anti-nuclear antibody (ANA) is negative. Which type of hypersensitivity reaction best explains this drug-induced adverse event?

Explanation

## Type III Hypersensitivity: Immune Complex-Mediated Reaction ### Clinical Presentation **Key Point:** This patient presents with serum sickness, a classic Type III hypersensitivity reaction characterized by the formation and deposition of antigen–antibody complexes in tissues, typically occurring 7–14 days after drug exposure. ### Pathophysiology of Type III Hypersensitivity ```mermaid flowchart TD A[Drug exposure]:::action --> B[Antigen-specific IgG/IgM production]:::outcome B --> C[Antigen-antibody complex formation]:::outcome C --> D{Immune complex size}:::decision D -->|Small complexes| E[Circulate in blood]:::outcome D -->|Deposit in tissues| F[Vessel walls, joints, kidneys]:::outcome E --> G[Complement activation]:::action F --> G G --> H[C3a, C5a release]:::outcome H --> I[Neutrophil chemotaxis & inflammation]:::action I --> J[Vasculitis, arthritis, rash]:::outcome ``` ### Key Diagnostic Features | Feature | Type III | Type I | Type II | Type IV | |---------|----------|--------|---------|----------| | **Onset** | 7–14 days | Minutes–hours | Hours–days | 24–72 hours | | **Antibody** | IgG, IgM | IgE | IgG | T-cell mediated | | **Complement** | ↓ C3, C4 | Normal | ↓ C3, C4 | Normal | | **Circulating IC** | ↑ Elevated | Normal | Normal | Normal | | **Skin findings** | Maculopapular rash | Urticaria, angioedema | Bullae, necrosis | Delayed erythema | | **Systemic symptoms** | Fever, arthralgia, lymphadenopathy | Anaphylaxis | Hemolysis, thrombocytopenia | Contact dermatitis | ### Mechanism in This Case 1. **Sensitization**: Sulfasalazine acts as a hapten, conjugating to carrier proteins and triggering IgG and IgM antibody production (days 3–7). 2. **Complex formation**: Antigen–antibody complexes form in slight antigen excess, creating small, soluble immune complexes (day 7–10). 3. **Complement activation**: Immune complexes activate the classical complement pathway, consuming C3 and C4 (explaining the low levels). 4. **Tissue deposition**: Complexes deposit in: - Blood vessel walls → vasculitis (rash) - Joint synovium → arthritis (arthralgia) - Glomeruli → glomerulonephritis (if severe) 5. **Inflammation**: Complement fragments (C3a, C5a) recruit neutrophils, causing local inflammation and tissue damage. **High-Yield:** Low complement levels (C3, C4) with elevated circulating immune complexes are the hallmark laboratory findings of Type III hypersensitivity. ANA negativity rules out systemic lupus erythematosus (SLE), which can present similarly. **Clinical Pearl:** Serum sickness is self-limited; symptoms typically resolve 1–2 weeks after discontinuation of the offending drug as immune complexes are cleared by the reticuloendothelial system. ### Mnemonic for Type III Hypersensitivity **ACID** — **A**ntigen–antibody **C**omplexes, **I**mmune-mediated, **D**elay (7–14 days)