How to manage multiple sclerosis (MS) in patients experiencing immunosenescence with no disease activity while off MS therapy?

Managing Multiple Sclerosis in Patients with Immunosenescence and No Disease Activity Off Therapy

For MS patients experiencing immunosenescence with no disease activity while off therapy, treatment discontinuation may be appropriate, particularly in those over 55 years of age, as the benefits of continuing immunosuppressive therapy may be outweighed by increased risks of infections and other adverse effects.

Understanding Immunosenescence in MS

• Immunosenescence refers to age-related immune system changes characterized by reduced responsiveness, which naturally occurs as people age and may be accelerated in MS patients 1, 2
• MS disease activity typically declines with age as inflammatory processes diminish, making continued immunosuppressive therapy potentially unnecessary in older patients 3
• Premature immunosenescence has been demonstrated in MS patients, which may affect both disease progression and treatment response 2

Assessment Algorithm for MS Patients with No Disease Activity Off Therapy

Key Factors to Consider:

1. Patient Age

   • Patients >55 years show significantly reduced inflammatory MS activity 3
   • Age is a critical modifier of drug efficacy and risk profile 3, 1

2. Duration of Disease Stability

   • Assess length of time with no clinical relapses 3
   • Evaluate MRI stability (no new T2 lesions or gadolinium-enhancing lesions) 4

3. MRI Monitoring

   • Regular brain MRI scans are essential for monitoring disease progression 4
   • Follow-up scans should include contrast-enhanced T1-weighted and T2-weighted sequences 4
   • MRI subtraction techniques can help detect new lesions across serial scans 4

Management Options:

1. Treatment Discontinuation

• Most appropriate for:

  • Patients >55 years with stable disease (no clinical or MRI activity) 3
  • Patients with evidence of immunosenescence 1, 2
  • Patients at higher risk for treatment-related adverse effects 3

• Monitoring after discontinuation:

  • Follow-up brain MRI at least annually 4
  • Regular clinical assessments for any signs of disease reactivation 4

2. Treatment De-escalation

• Consider for patients with intermediate risk profiles:
  • Extended interval dosing (particularly for natalizumab or ocrelizumab) 3
  • Switching from high-efficacy DMTs with higher risks to moderately effective DMTs with lesser risks 3

3. Continue Current Therapy

• Consider for:
  • Younger patients (<45 years) 4
  • Patients with short disease duration (<10 years) 4
  • Patients with history of highly active disease before stabilization 4

Evidence Supporting Treatment Decisions

• A 2-year randomized controlled discontinuation study in stable MS patients >55 years found only a small increased risk of new MRI activity upon discontinuation compared to continued treatment 3
• Extended interval dosing of ocrelizumab has been shown to mitigate the decline of immunoglobulin levels while maintaining efficacy 3
• Retrospective studies demonstrate that older patients who discontinued treatment were more likely to maintain a stable disease course compared to younger patients 3

Monitoring Recommendations

• For patients who discontinue therapy:

  • Brain MRI should be performed at least annually 4
  • More frequent monitoring (every 3-4 months) may be appropriate initially after discontinuation 4
  • MRI protocol should include T2-weighted images, T2-FLAIR, and contrast-enhanced T1-weighted sequences 4

• For patients who de-escalate therapy:

  • Follow-up brain MRI should be performed 12 months after changing treatment regimen 4
  • Compare with a reference scan obtained after the treatment change has taken effect 4

Potential Pitfalls and Caveats

• Individual variability in immunosenescence may not correlate perfectly with chronological age 2, 5
• Disease stability off therapy should be confirmed with both clinical and MRI assessments before making treatment decisions 4
• Sex and cytomegalovirus status can influence age-sensitive immune biomarkers and should be considered when evaluating immunosenescence 5
• If breakthrough disease occurs after discontinuation, prompt reinitiation of therapy should be considered, with evidence showing good response to both natalizumab and immunosuppressants in patients with breakthrough disease 6