A 28-year-old man with ocular myasthenia gravis (OMG) presents with persistent ptosis and diplopia despite 3 months of prednisolone therapy. He wishes to avoid long-term corticosteroids due to side effects. What is the preferred second-line agent to add for steroid-sparing effect?

Explanation

## Steroid-Sparing Agents in Myasthenia Gravis **Key Point:** Azathioprine is the preferred steroid-sparing agent to add to prednisolone in myasthenia gravis because of its proven long-term efficacy, acceptable safety profile, and extensive clinical experience in MG, despite its slow onset. ### Why Azathioprine is First-Line Steroid-Sparer 1. **Mechanism**: Inhibits purine synthesis, reducing T-cell and B-cell proliferation and anti-AChR antibody production 2. **Onset**: 3–6 months, but when combined with prednisolone, allows gradual steroid tapering 3. **Evidence base**: Largest body of clinical trial data in MG; proven to reduce relapse rates and allow 50% reduction in prednisolone dose 4. **Cost**: Inexpensive and widely available 5. **Dosing**: 1–2.5 mg/kg/day (usual range 50–150 mg/day), requires baseline CBC, LFTs, and TPMT testing ### Comparison of Second-Line Agents | Agent | Onset | Mechanism | Advantages | Disadvantages | Role | |-------|-------|-----------|-----------|---------------|------| | **Azathioprine** | 3–6 mo | Purine antagonist | Proven efficacy, cheap, oral | Slow onset, hepatotoxicity, myelosuppression | **First-line steroid-sparer** | | **Mycophenolate mofetil** | 2–3 mo | IMPDH inhibitor | Faster than AZA, fewer drug interactions | Less long-term data in MG | Alternative if AZA intolerant | | **Cyclosporine** | 4–8 weeks | Calcineurin inhibitor | Faster onset | Nephrotoxicity, hypertension, expensive | Refractory disease | | **Tacrolimus** | 4–8 weeks | Calcineurin inhibitor | Faster onset, less nephrotoxic than CSA | Limited MG data, expensive | Refractory/resistant cases | | **IVIG** | Days–weeks | Antibody modulation | Rapid effect in crisis | Temporary effect only; not for chronic use | Myasthenic crisis, acute exacerbation | **High-Yield:** IVIG and plasmapheresis are **acute therapies** for myasthenic crisis or rapid deterioration, not chronic steroid-sparing agents. They provide temporary benefit (2–4 weeks) and must be combined with long-term immunosuppression. ### Clinical Pearl **Warning:** A common exam trap is confusing acute therapies (IVIG, plasmapheresis) with chronic steroid-sparing agents. IVIG provides rapid improvement but does not allow steroid tapering — azathioprine does. ### Steroid-Sparing Strategy in MG ```mermaid flowchart TD A[Patient on prednisolone for MG]:::outcome --> B{Steroid side effects or dose intolerance?}:::decision B -->|Yes| C[Add azathioprine 1-2.5 mg/kg/day]:::action C --> D[Check TPMT, baseline CBC/LFTs]:::action D --> E[Gradual prednisolone taper over 6-12 months]:::action E --> F[Assess response at 3-6 months]:::decision F -->|Good response| G[Continue maintenance azathioprine]:::action F -->|Inadequate response| H[Add mycophenolate or consider cyclosporine]:::action B -->|No| I[Continue prednisolone monotherapy]:::action ``` ### Monitoring During Azathioprine Therapy - **TPMT genotyping**: Before initiation (homozygous deficiency = contraindication) - **CBC**: Baseline, then monthly for 3 months, then quarterly - **LFTs**: Baseline and every 3 months - **Clinical response**: Expected at 3–6 months; full benefit may take 12 months