Recognizing When a Treatment Change Is Warranted in Relapsing MS

Key Takeaways:

• Breakthrough disease is one of several signals that warrant reassessing therapy. Tolerability, adherence, and life-stage change are equally actionable.
• Guideline thresholds for an efficacy-driven switch assume the patient has been adherent and on therapy long enough for it to work. Confirm both before escalating.
• Matching the next agent to the primary reasons for switching is what makes a change hold.

In addition to insufficient efficacy as assessed by new clinical relapses or new MS lesions on MRI, the American Academy of Neurology (AAN) practice guideline gives equal recommendation-level weight to tolerability, laboratory abnormalities, and safety-monitoring findings when it comes to considerations for switching disease-modifying therapy (DMT).¹

Signals that should prompt reassessment

The efficacy threshold recommended by the AAN for considering switching from one DMT to another is relatively specific. The AAN recommends offering a change when a patient has experienced 1 or more confirmed clinical relapses, 2 or more unequivocally new MRI-detected MS lesions, or increased MS disability on examination over a 1-year period.¹ Two conditions are attached to it: that the patient has been adherent to their DMT, and that the agent has had adequate time to take effect. UpToDate places this adequate interval to be about 6 months, though this may vary for different DMTs, and notes that a single mild relapse or a single new lesion within that window is usually insufficient to prompt a DMT change on its own.²

The non-efficacy triggers for switching DMT therapy carry the same Level B recommendation. Adverse events affecting adherence, persistent laboratory abnormalities, a rising John Cunningham virus antibody index (for natalizumab), malignancy, and recurrent or serious infections are each named as potential grounds for a DMT change. Patient preference is also critical to consider when selecting initial therapy or switching therapies. The AAN guideline recommends at Level A that clinicians ascertain and incorporate preferences on safety, route of administration, lifestyle, cost, efficacy, and tolerability in the choice of therapy, and that they engage in ongoing dialogue about treatment decisions throughout the disease course.¹

Tolerability and adherence as clinical data

Adherence is critical to ascertain and confirm prior to considering any switch in DMT therapy. Real-world data shows how often adherence is a major issue. In a United States claims analysis of 4,121 MS patients making a first therapy switch, adherence fell from 91 percent at 3 months to 75 percent at 6 months and 55 percent at 12 months.³ A therapy the patient has stopped taking will likely mirror the same clinical and imaging outcomes as therapy that has failed due to insufficient efficacy.

Tolerability of a therapy, laboratory abnormalities, and safety are also potential reasons to consider switching DMT therapies. In the AAN guidelines, clinicians are directed to evaluate readiness and reluctance before starting a new therapy, to counsel on adherence during treatment, and to monitor for and treat adverse events that interfere with adherence and tolerability as grounds for a change in their own right.¹ None of that requires waiting for clinical or radiologic evidence of efficacy.

Matching the next agent to the reason

The reason for the DMT change should help guide the decision for the next DMT choice. A switch driven by breakthrough inflammatory activity may suggest the need for a higher efficacy tier or a drug with a different mechanism of action; a switch driven by intolerance may argue for a different profile within a comparable tier. Oral fumarates, sphingosine-1-phosphate (S1P) receptor modulators, teriflunomide, and oral cladribine each carry distinct monitoring and adverse-effect profiles, and each differs again from the higher-efficacy monoclonal antibody options.^5-8 Life stage narrows the field further: teriflunomide and cladribine both carry boxed warnings for embryofetal toxicity and teratogenicity, and teriflunomide requires an accelerated elimination procedure before conception rather than simple discontinuation.^7,8

Transition safety and monitoring

Some DMT transition considerations are related to specific safety and monitoring considerations. Stopping an S1P receptor modulator carries a warning for severe increase in disability as a result of rebound relapses shortly after discontinuation, generally within 12 weeks and reported up to 24 weeks.⁶ In line with this, the AAN gives its only Level A switching recommendation to counseling patients about the risk of rebound disease activity after stopping natalizumab.¹ Fumarates and cladribine both require lymphocyte monitoring on a defined schedule. Other DMTs require other specific monitoring for safety both before and/or after switching.^5,8

When considering whether to continue a DMT therapy or switch, it is important to consider several factors including patient preference, adherence, tolerability, and safety in addition to efficacy.