A 35-year-old man with a history of rheumatoid arthritis presents with fever (38.5°C), joint pain, and a maculopapular rash on his trunk and extremities appearing 10 days after starting a new anti-TNF monoclonal antibody (infliximab). He also complains of malaise and mild lymphadenopathy. Laboratory investigations show elevated ESR (68 mm/hr), CRP 12 mg/dL, and mild hepatic transaminitis. A skin biopsy shows small vessel vasculitis with IgG and C3 deposition in vessel walls. Which type of hypersensitivity reaction best explains this clinical presentation?

Explanation

## Type III Hypersensitivity: Immune Complex Disease This patient presents with **serum sickness-like reaction**, a classic manifestation of **Type III (immune complex) hypersensitivity**, triggered by the monoclonal antibody infliximab. ### Clinical Features Consistent with Type III **High-Yield:** The **classic triad** of serum sickness: 1. **Fever** — systemic inflammatory response 2. **Arthralgia/arthritis** — immune complex deposition in synovial joints 3. **Rash** — urticarial or maculopapular eruption from vasculitis **Additional features in this case:** - **Timing**: 10 days after drug exposure (Type III typically occurs 7–21 days post-exposure) - **Lymphadenopathy**: Regional lymph node involvement from antigen processing - **Elevated inflammatory markers**: ESR and CRP reflect systemic inflammation - **Hepatic involvement**: Immune complex deposition in liver causing transaminitis - **Histology**: Small vessel vasculitis with IgG and C3 deposition — **pathognomonic for Type III** ### Pathophysiology of Type III Hypersensitivity ```mermaid flowchart TD A[Antigen exposure<br/>e.g., infliximab]:::outcome --> B[Antibody formation<br/>IgG or IgM]:::action B --> C[Antigen-Antibody<br/>Complex formation]:::action C --> D[Immune complex<br/>deposition in tissues]:::action D --> E{Complement<br/>activation?}:::decision E -->|Yes| F[C3a, C5a release<br/>Neutrophil recruitment]:::action E -->|No| G[Direct vasculitis<br/>from IC deposition]:::action F --> H[Vasculitis<br/>Tissue damage]:::urgent G --> H H --> I[Fever, rash,<br/>arthralgia, organ injury]:::outcome ``` ### Mechanism in Detail 1. **Sensitization**: Infliximab (foreign protein) is recognized as antigen 2. **Antibody formation**: B cells produce IgG antibodies against infliximab 3. **Complex formation**: Antigen + IgG form **small, soluble immune complexes** (optimal ratio ~1:1) 4. **Tissue deposition**: Complexes deposit in: - Blood vessel walls (small vessels → vasculitis) - Joints (synovitis) - Kidneys (glomerulonephritis) - Skin (leukocytoclastic vasculitis) 5. **Complement activation**: Complexes activate classical complement pathway - C3a and C5a released → chemotaxis of neutrophils - C3b opsonizes complexes → enhanced phagocytosis - Membrane attack complex (MAC) → direct cell lysis 6. **Inflammation**: Neutrophil infiltration → tissue damage and vasculitis ### Histopathology Correlation **Key Point:** The **gold standard** for Type III diagnosis is **immunofluorescence microscopy** showing: - **IgG deposition** in vessel walls (antibody component) - **C3 deposition** in vessel walls (complement activation) - **Fibrinoid necrosis** of small vessel walls This distinguishes Type III from Type II (which shows IgG without C3) and Type IV (which shows no antibody or complement, only T cell infiltration). ### Comparison of Hypersensitivity Types | Feature | Type I | Type II | Type III | Type IV | |---------|--------|---------|----------|----------| | **Mediator** | IgE | IgG/IgM | IgG/IgM + Complement | T cells | | **Onset** | Minutes to hours | Hours to days | 7–21 days | 24–72 hours | | **Mechanism** | Mast cell degranulation | Cytotoxic antibodies | Immune complex deposition | T cell infiltration | | **Histology** | Mast cell infiltration | Cell lysis, antibody binding | Vasculitis, IC deposition, C3 | Lymphocytic infiltration | | **Example** | Anaphylaxis, urticaria | Hemolytic anemia, Graves' | Serum sickness, SLE, post-streptococcal GN | Contact dermatitis, TB | **Mnemonic:** **"Type III = 3 weeks"** — serum sickness typically appears 7–21 days after antigen exposure (in this case, 10 days fits perfectly). ### Clinical Pearl Monoclonal antibodies (infliximab, rituximab, adalimumab) and serum-derived biologics (antivenom, immunoglobulin) are classic triggers of Type III reactions because they are foreign proteins that elicit robust IgG responses. The incidence increases with repeated exposures and in patients with pre-existing antibodies.