What is the preferred immunomodulator for a patient with generalized Myasthenia Gravis (MG) classified as class 3 or 4, who is also Hepatitis B surface antigen (HBsAg) positive?

Immunomodulator Selection for Generalized MG Class 3/4 with HBsAg Positive Status

Azathioprine is the preferred immunomodulator for HBsAg-positive patients with generalized myasthenia gravis class 3/4, as it carries low risk (<1%) of hepatitis B reactivation and has established efficacy in MG, while corticosteroids and rituximab pose significantly higher reactivation risks requiring antiviral prophylaxis. 1

Risk Stratification of Immunomodulators in HBsAg-Positive Patients

High-Risk Agents (>10% Reactivation Risk) - Require Antiviral Prophylaxis

Corticosteroids (commonly used first-line in MG) carry high reactivation risk when used at moderate-to-high doses (≥10-20 mg prednisone daily) for ≥4 weeks in HBsAg-positive patients. 1 If corticosteroids are necessary, strong antiviral prophylaxis is mandatory and should continue for at least 6 months after discontinuation. 1

Rituximab (B-cell depleting agent) poses the highest reactivation risk (>10%) in HBsAg-positive patients and requires antiviral prophylaxis extending 12 months post-treatment due to prolonged immune reconstitution. 1 While rituximab is increasingly used in refractory MG, particularly MuSK-positive cases, the hepatitis B risk makes it a poor choice without aggressive prophylaxis. 2, 3

Low-Risk Agents (<1% Reactivation Risk) - Preferred Options

Azathioprine is classified as low-risk for HBV reactivation in HBsAg-positive patients, with anticipated reactivation incidence <1%. 1 This makes it the optimal choice as it combines:

• Established efficacy as first-line steroid-sparing agent in MG 4, 5, 3
• Low hepatitis B reactivation risk requiring only monitoring rather than routine prophylaxis 1
• Favorable long-term safety profile in MG populations 3

Methotrexate and 6-mercaptopurine also carry low reactivation risk (<1%) in HBsAg-positive patients. 1 However, these are typically second or third-line agents in MG with less robust efficacy data compared to azathioprine. 2, 6

Moderate-Risk Agents (1-10% Reactivation Risk) - Use with Caution

Mycophenolate mofetil is not specifically categorized in the hepatitis guidelines reviewed, but as a traditional immunosuppressant similar to azathioprine, it likely carries low-to-moderate risk. 1 It is increasingly used as a steroid-sparing agent in MG. 4, 2, 5

Cyclosporine and tacrolimus (immunophilin inhibitors) carry moderate reactivation risk and would require careful monitoring or prophylaxis. 1 These are typically reserved for refractory MG cases. 2, 6, 3

Practical Management Algorithm

Step 1: Initiate Azathioprine as Primary Immunomodulator

• Start azathioprine 2-3 mg/kg/day as the steroid-sparing immunosuppressant of choice 4, 5, 3
• Monitor HBV DNA levels every 3 months rather than routine antiviral prophylaxis (given low-risk classification) 1
• Check baseline HBV DNA, ALT, and complete hepatitis panel before starting 1

Step 2: Minimize or Avoid High-Dose Corticosteroids

• If corticosteroids are required for initial disease control, use the lowest effective dose (<10 mg prednisone daily) for shortest duration (<4 weeks) to remain in low-risk category 1
• If moderate-to-high dose steroids (≥10-20 mg daily for ≥4 weeks) are unavoidable, initiate antiviral prophylaxis with entecavir or tenofovir before starting steroids 1
• Continue antiviral prophylaxis for 6 months after steroid discontinuation 1

Step 3: Reserve Rituximab Only for Refractory Cases with Mandatory Prophylaxis

• Consider rituximab only if patient fails azathioprine, mycophenolate, and other conventional agents 2, 3
• Mandatory antiviral prophylaxis with entecavir or tenofovir starting before rituximab and continuing 12 months post-treatment 1
• Monitor HBV DNA monthly during and after rituximab therapy 1

Step 4: Monitoring Protocol for HBsAg-Positive Patients on Low-Risk Agents

• HBV DNA quantification every 3 months 1
• ALT/AST monitoring every 1-2 months 1
• If HBV DNA rises >2000 IU/mL or ALT elevation occurs, initiate preemptive antiviral therapy immediately 1

Critical Pitfalls to Avoid

Do not assume all immunosuppressants carry equal hepatitis B risk. The reactivation risk varies dramatically from <1% with azathioprine to >10% with rituximab or high-dose corticosteroids in HBsAg-positive patients. 1

Do not use corticosteroid monotherapy long-term without antiviral prophylaxis. Even moderate-dose prednisone (10-20 mg daily) for ≥4 weeks triggers high reactivation risk requiring prophylaxis. 1

Do not delay azathioprine initiation. Starting azathioprine early allows for corticosteroid tapering and minimizes cumulative steroid exposure and hepatitis B risk. 4, 5, 3

Do not use rituximab without hepatology consultation and antiviral prophylaxis. The prolonged B-cell depletion creates reactivation risk extending 12+ months post-treatment. 1

Alternative Considerations for Refractory Disease

If azathioprine fails and additional immunosuppression is needed, mycophenolate mofetil represents a reasonable next choice given its likely low-to-moderate hepatitis B risk profile and established MG efficacy. 4, 2, 5

For truly refractory cases requiring more aggressive therapy, eculizumab (complement inhibitor) may be considered as it does not appear in high-risk categories for hepatitis B reactivation, though specific data are limited. 2

Intravenous immunoglobulin (IVIG) and plasma exchange remain safe options for acute exacerbations or bridging therapy in HBsAg-positive patients, as they do not increase hepatitis B reactivation risk. 4, 6