What is the role of disease modifying therapy in treating multiple sclerosis?

The goal of disease-modifying therapies (DMTs) is to prevent accumulation of multiple sclerosis (MS) lesions, decrease relapse activity, and lessen overall disability accrual. There are now over two dozen MS drugs within nine diverse drug classes. DMTs exert their benefits through an array of anti-inflammatory effects, ultimately altering the immune system to prevent disease activity. Efficacy rates of current DMTs, defined by reduction in annualized relapse rates compared with placebo or active comparators, range anywhere from 29%-68% depending on drug class [1]. While there are clear benefits of DMTs in relapsing MS for preventing relapse activity and subsequent accrual of disability, there is less evidence for DMTs in progressive MS forms. Only one DMT (ocrelizumab) is FDA approved for primary progressive MS (PPMS) and all DMTs are approved for SPMS with activity. Historically, MS DMT treatment duration has been thought of as long term, potentially even lifelong, but there is currently no consensus guidelines on recommended length of treatment. Additionally, the risk/benefit ratio of these treatments evolves for the individual patient over time, and the role of DMTs in patients later in the disease course with no evidence of active inflammatory disease (relapses and/or new MRI lesions) becomes less clear [2]. 

What is the rationale for considering DMT discontinuation?

There are several potential benefits of DMT discontinuation in the appropriate subset of individuals. One of greatest benefits would be reduction of DMT-associated adverse events, including risk of both minor and serious infections. Depending on the DMT, infections include common entities such as respiratory infections and urinary infections or more serious such as sepsis or central nervous system infections (e.g. progressive multifocal leukoencephalopathy). Evidence supports that patients with MS are at a significantly higher risk of outpatient and serious infections, and that infection risk increases with age and number of years exposed to the drug [3–7]. Additionally, there are other adverse effects of DMTs depending on drug class that may include hypertension, hepatotoxicity, macular edema, heart block, infusion reactions, and malignancy risk [8]. Ultimately, individual risk profile depends on a variety of factors, including the particular DMT class and the individual patient; for specific DMT class risks please see MS Disease Modifying Therapy section of the Mellen Center Multiple Sclerosis Approaches.

The avoidance of side effects once stopping DMT could lead to improved quality of life for patients. Depending on the DMT that has been discontinued, there is also the potential for patients to mount a more robust vaccine response; this could be of benefit particularly to those in their 5th or 6th decades given increased number of vaccines typically needed. 

In terms of DMT costs, nationally, prescription drugs account for 10-15% of total healthcare expenditure, but for people with MS prescription drugs account for more than two-thirds of total healthcare costs [9, 10]. Outside of the other mentioned prospective benefits for the appropriate patient who discontinues DMT, there is also the potential to lessen the economic burden for the patient, including their direct out of pocket costs.

What is the biological rationale supporting DMT discontinuation?

Controlling and/or preventing active MS disease is an attainable target for the current MS DMTs. Over time, however, the biology that drives relapse and focal inflammatory demyelination becomes less pronounced, while the biology that drives progression and neurodegeneration becomes more apparent [11]. This pathophysiology of neurodegeneration that occurs in later stages of MS and progressive phenotypes is not well targeted with the current DMTs available [12, 13]. Additionally, immunosenescence, defined as a dynamic process within the immune system where some immune functions become reduced, whereas others remain unchanged or increased, occurs as part of the normal aging process independent of MS [14]. Together, these processes ultimately alter the immune response and thus have implications on DMT utility. Given the shift to a more significant risk profile with diminished biological benefit for DMT use as MS patients age, transitioning older MS patients off their DMT is a more common issue today in clinical practice.

What is the observational evidence supporting DMT discontinuation?

Multiple cohort studies have examined DMT discontinuation in MS patients. There appears to be growing evidence in support of DMT discontinuation for older patients who have been on DMT for multiple years without new inflammatory disease activity, however results of studies remain mixed. In one study evaluating patients on injectable DMTs (interferon-beta or glatiramer acetate), there was a similar relapse rate between patients who discontinued versus stayed on DMT (36.4% versus 37.8% respectively). In this same study, confirmed disability progression was 50% higher in DMT stoppers relative to stayers [15]. Another study evaluating patients with a mean age 45 years with RRMS treated with DMT for >2 years with no clinical or radiographic relapse for >2 years found that discontinuation was not associated with time to clinical relapse, MRI event, disability progression or disease activity (clinical relapse or MRI event). This study also noted that patients >45 years had significantly less likely to experience a new clinical relapse or MRI event than younger patients suggesting that older MS patients may be able to safely stop their DMTs [16].

Finally, a recent observational study evaluating discontinuation of first-line DMTs in patients with median age of 47.8 found that patients with NEDA-3 (absence of relapses, disability worsening, new brain lesions) for a period of >5.5 years while on treatment prior to discontinuation had a 7.7% chance of new disease activity in 4.6 years of follow-up [17]. 

Altogether these studies and others suggested that older patients with no recent inflammatory disease who discontinue their DMT have similar relapse rate to those who continue DMT. Although it is important to note that there were mixed results for the impact of discontinuation on progression promoting evaluation in more robust prospective randomized trials to evaluate outcomes. 

What is the randomized clinical trial evidence supporting DMT discontinuation?

Discontinuation of Disease Modifying Therapies in Multiple Sclerosis (DISCOMS, NCT03073603) was a multicenter, randomized, non-inferiority trial which sought to evaluate the safety of DMT discontinuation. Patients who were age 55 or older, had no relapse for at least 5 years, no new MRI lesion for at least 3 years, and on DMT continuously for at least 5 years were randomized to continue or discontinue their DMT and followed for 2 years of follow-up. A total of 259 patients were enrolled, with a median age of 63 (interquartile range of 59-67) and average of 14.5 years from last documented relapse in the discontinuation arm. The most common DMT at time of randomization in both groups was Interferon beta-1a. Results showed that patients who discontinued DMT had a 7% higher rate of disease activity, defined as either new lesions on MRI or a relapse, compared to those who continued DMT, and thus failed to meet its primary outcome of non-inferiority. Most of the primary outcome events were new brain MRI lesions, and there was no noted difference in disability progression between the two trial arms (11% in DMT continuation arm versus 12% in DMT discontinuation arm) [18]. 

Discontinuation of First-Line Disease-Modifying Therapy in Stable Multiple Sclerosis (DOT-MS, NCT04260711) is a clinical trial investigating discontinuation of DMTs in participants with clinical and radiographic stability for 5 years. Preliminary data including 89 participants with average age in their early fifties showed that in the discontinuation arm 17.8% had notable new disease activity, 7 of which had signs of substantial MRI activity, defined as three or more new total lesions or two or more new lesions with active inflammation [19]. These findings ultimately lead to trial termination in March 2024, and participants will continue to be followed in an observational matter after restarting their previous DMT. STOP-I-SEP (NCT03653273), another clinical trial currently underway in France, is evaluating discontinuation of DMT in participants SPMS age 50 or older with clinical and radiographic stability for 3 or more years; completion is currently estimated for early 2028.  Altogether, the randomized clinical trial evidence highlights the risk of recurrent disease activity after DMT discontinuation and the need for careful patient selection when considering discontinuation. 

What are the potential risks of discontinuing DMT in patients with MS?

The most obvious risk of DMT discontinuation in MS patients is disease reactivation. Multiple observational studies provide evidence for relative safety of DMT discontinuation in older stable MS populations, however more recent clinical trial data through DISCO-MS and DOT-MS highlight ongoing risks, particularly in patients with more recent MRI or clinical activity [15]. In addition, the potential of ongoing disability accrual also remains. 

Furthermore, certain DMT classes that block immune cell trafficking, such as sphingosine 1-phosphate receptor (S1PR) modulators and natalizumab, pose a particular risk for rebound activity post discontinuation, and additional consideration must be paid in these individuals [20, 21].

What patient scenarios might we consider for DMT discontinuation?

Based on the current evidence cited above, here at the Mellen Center we raise the possibility of stopping DMT only after the patient reaches mid-fifties and has been stable on current DMT without evidence of inflammatory activity for 5 or more years. This decision is done with careful counseling with each individual patient and family of the associated risks of DMT discontinuation including recurrent disease activity and risks of DMT continuation (e.g. infection). In our experience, the decision of DMT discontinuation must be made on an individualized basis weighing the risks, benefits, and individual patient preferences.  Due to the mixed data currently available, there is heterogeneity in clinical practice and a shared decision-making approach between care team and patient remains of the utmost importance.

How do we clinically monitor MS patients after discontinuing DMT?

We monitor patients closely post DMT discontinuation with an initial MRI brain at the time of discontinuation and then 6-12 months following discontinuation of DMT. If stable, annual MRI brain surveillance scans are obtained for several years thereafter. Patients are counseled on clinical signs of MS relapse and when to contact their care team with concerns regarding new symptoms. If the patient has no recurrent inflammatory disease activity (relapses or new MRI lesions) for several years we consider spacing out the frequency of surveillance MRI scans. 

It is important to note that in addition to MS disease activity surveillance, patients should continue to receive consistent monitoring every 6 to 12 months with clinic visits to help address other ongoing symptomatic and functional needs. When discussing the potential of DMT discontinuation, we find it important to stress that while there is a change in the MS care plan, this does not mean the patients’ overall MS care is ending. 

What are the alternative approaches to DMT discontinuation?

Many patients may be counselled to continue their DMT. Beyond continuation another approach is de-escalation. De-escalation would be defined as changing from a higher efficacy DMT to a less potent DMT as MS disease activity lessens and/or risks of DMT use increases. For example, this approach may be employed in patients who are incurring frequent infections on their current higher efficacy DMT but there is a substantial concern for relapse upon discontinuation given recent MS activity. Another potential scenario involves a need for DMT switch or discontinuation but there is concern about rebound potential due to DMT class that is being prescribed (such as S1PR modulators or natalizumab). Despite these potential scenarios, there is uncertainty that de-escalation to a lower efficacy agent ultimately confers more safety. Further randomized clinical trials would be needed for a head-to-head comparison of de-escalation to both discontinuation and continuation to assess its efficacy and overall role in MS DMT management.

References

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