For a patient with Behçet’s disease requiring systemic immunosuppression, which is preferred as first‑line therapy, methotrexate or mycophenolate mofetil?

Methotrexate versus Mycophenolate for Behçet's Disease

For patients with Behçet's disease requiring systemic immunosuppression, neither methotrexate nor mycophenolate mofetil is recommended as first-line therapy—azathioprine combined with corticosteroids is the established standard of care for posterior segment eye disease, which is the most critical manifestation requiring aggressive immunosuppression. 1

Primary Recommendation: Azathioprine as First-Line

The 2018 EULAR guidelines explicitly state that any patient with Behçet's disease and inflammatory eye disease affecting the posterior segment should receive azathioprine combined with systemic corticosteroids as the foundational treatment regimen. 1 This represents a Grade A recommendation based on level IB evidence from randomized controlled trials. 1

• Azathioprine demonstrates superior efficacy specifically in Behçet's uveitis, with moderate efficacy in inflammation control, significant steroid-sparing effects, and only 2% discontinuation rates due to adverse events. 1
• For severe posterior uveitis (defined as >2 lines of visual acuity drop or retinal vasculitis/macular involvement), azathioprine should be combined with either cyclosporine A or infliximab, plus corticosteroids. 1

When Methotrexate or Mycophenolate May Be Considered

Methotrexate

Methotrexate is a reasonable second-line alternative when azathioprine is contraindicated, not tolerated, or has failed. 1

• Methotrexate demonstrates efficacy in inflammation control, steroid-sparing ability, and maintenance/improvement of visual acuity in noninfectious uveitis (Grade B recommendation). 1
• Long-term data (up to 15 years) in 682 Behçet's patients showed visual acuity improvement in 46.5% of eyes, posterior uveitis improvement in 75.4%, and retinal vasculitis improvement in 53.7%. 2
• Typical dosing: 7.5-15 mg/week combined with prednisolone 0.5 mg/kg/day, then tapered. 2

Mycophenolate Mofetil

Mycophenolate mofetil is generally inferior to both azathioprine and methotrexate for Behçet's disease and should be reserved for specific scenarios. 1

• Comparative studies show no significant differences in uveitis control between methotrexate and mycophenolate, but both are less established than azathioprine in Behçet's disease specifically. 1
• Recent evidence suggests mycophenolate monotherapy is inadequate for remission induction in refractory Behçet's uveitis—it may only be effective when combined with a biologic agent (anti-TNF). 3
• Among 12 Behçet's uveitis patients treated with mycophenolate, those on monotherapy continued to have ocular attacks, while combination with anti-TNF prevented further attacks. 3
• Mycophenolate may serve as a maintenance option in select patients who are relapse-free, but 3 of 5 patients experienced breakthrough attacks during maintenance therapy. 3

Critical Comparative Evidence

Azathioprine has higher discontinuation rates due to side effects compared to methotrexate and mycophenolate in general uveitis populations (24% vs lower rates with the other two agents), but this finding comes from non-Behçet's specific studies. 1 However, in Behçet's disease specifically, azathioprine showed only 2% discontinuation rates and superior tolerability. 1

Practical Algorithm for Drug Selection

1. First-line for posterior uveitis/panuveitis: Azathioprine + corticosteroids 1
2. If severe disease (>2 lines VA loss, retinal vasculitis, macular involvement): Add cyclosporine A or infliximab to azathioprine + corticosteroids 1
3. If azathioprine contraindicated/intolerant: Methotrexate + corticosteroids 1, 2
4. If methotrexate fails or contraindicated: Consider mycophenolate + anti-TNF biologic (not mycophenolate monotherapy) 3
5. For mucocutaneous/articular disease only (no eye involvement): Colchicine remains first-line 1

Common Pitfalls to Avoid

• Do not use mycophenolate as monotherapy for active Behçet's uveitis—it is inadequate for remission induction and should only be combined with biologics. 3
• Avoid cyclosporine A if any neurological involvement is present—it is contraindicated due to neurotoxicity risk. 1, 4
• Do not delay escalation to biologics (infliximab/adalimumab) in severe posterior uveitis—these are now recommended as first-line therapy combined with azathioprine for sight-threatening disease. 1, 5
• Monitor for secondary cataracts with long-term methotrexate use—this was the main cause of visual acuity deterioration despite inflammation control. 2