Background

Multiple sclerosis (MS) is a variably debilitating disease characterized by demyelination (deterioration of the protective myelin sheaths covering nerve cell processes in the brain and spinal cord) and axon loss within the central nervous system. The lesions created by the myelin destruction and resulting scar tissue interfere with normal transmission along nerve fibers within the brain and to and from the brain. This results in classic symptoms associated with MS. The condition affects 2.5 million individuals worldwide and approximately 400,000 in the United States.¹ About 40 percent of people with MS receive some form of disability income.² Twice as many women as men are affected, and diagnosis usually occurs between the ages of 20 and 50.¹ Symptoms and disease course are highly individual, depending on where the lesions occur within the central nervous system and the type of MS. Clinically definite MS types include the following:

• Relapsing-remitting MS (RRMS) is the most common form, affecting approximately 85 percent of patients. Patients typically are diagnosed in their 20s or 30s. Neurologic symptoms of a relapse typically develop over a course of days, stabilize, and spontaneously improve. However, over time permanent disability often accrues, with further relapses. Many patients with RRMS eventually transition to secondary progressive MS (below). Estimates of the median time from RRMS onset to this transition range from 15 to 29 years.³
• Secondary progressive MS (SPMS) is characterized by worsening disability with or without relapses. Patients may have exacerbations, but the trend over time is a relatively steady progression of disease and disability.¹
• Primary progressive MS (PPMS) represents about 15 percent of patients and affects women and men about equally. This form has the worst prognosis and is characterized by gradual and progressive worsening of function without distinct relapses.¹
• Progressive relapsing MS (PRMS) affects about 5 percent of patients. This form is usually diagnosed first as PPMS due to a steady worsening of functioning and changed to PRMS when the patient experiences a relapse. Recently, a recommendation has been made to eliminate PRMS as a type, classifying these patients as having PPMS.⁴

People with clinically isolated syndrome (CIS), a first neurologic episode consistent with an MS relapse, may or may not go on to develop MS. CIS involves neurologic symptoms such as vision loss, numbness, or weakness that last at least 24 hours and are caused by inflammation or demyelination in one (monofocal) or more (multifocal) sites in the central nervous system. In a cohort of 107 CIS patients followed for 20 years, 60 patients with three or more lesions (seen via magnetic resonance imaging [MRI]) converted to definite MS, while only 7 with normal baseline MRI converted.⁵

MS cannot be cured with current therapies. Disease-modifying treatments (DMTs) comprise immunomodulating and immunosuppressant medications aimed at slowing the progression of MS and improving quality of life. The working hypothesis is that reducing or preventing new lesions and their sequelae slows the worsening of the disease. DMTs currently approved by the Food and Drug Administration (FDA) for RRMS include interferon (IFN) beta-1a and -1b (some formulations also approved for CIS), glatiramer acetate, mitoxantrone (also approved for SPMS and PRMS), natalizumab, fingolimod, and dimethyl fumarate.

A 2013 Cochrane overview review and network analysis of 44 2- to 3-year trials of DMTs for MS found moderate- to high-quality evidence that DMTs are effective against recurrence of relapses in RRMS during the first 24 months of treatment compared with placebo.⁶ The network analysis ranked natalizumab as the most effective drug, followed in order by IFNbeta-1a (Rebif^®), mitoxantrone, glatiramer acetate (Copaxone^®), and IFNbeta-1b (Betaseron^®). Confidence in the evidence dropped to moderate for direct comparisons of mitoxantrone or IFNbeta-1b versus placebo and very low for glatiramer acetate versus placebo. Further, natalizumab and IFNbeta-1b were more effective than IFNbeta-1a in reducing the number of RRMS participants with disease progression, as measured with surrogate markers. In patients with progressive MS, both pairwise and network analysis found that no DMT analyzed prevented disability progression over 2 or 3 years. The overview and network analysis were too recent to include the newest approved drugs, such as fingolimod or dimethyl fumerate.

Unfortunately, the efficacy of MS treatments appears to correlate with the frequency and severity of side effects.⁷ The injectable treatments, the IFN drugs and glatiramer acetate, were modestly efficacious and side effects were tolerable by many patients.⁶ Mitoxantrone, an escalation medication, has a lifetime maximum dosage due to cardiotoxicity and risks of leukemia.⁷ Natalizumab, the first monoclonal antibody approved for treating MS, can induce the potentially fatal brain infection progressive multifocal leukoencephalopathy (PML). Risk for PML increases with natalizumab use longer than 2 years, anti-JC virus antibody status, and prior use of immuosuppressive agents.⁸ People taking natalizumab may take a drug holiday or discontinue use completely if their risk for PML increases, assessed by a positive test for the anti-JC virus antibody status.

Women considering pregnancy face special considerations for drug holidays. There are no class A drugs (drugs safe for use during pregnancy according to the FDA) for MS. Women and their physicians must weigh the possible risks of DMT exposure to the unborn fetus against the maternal risk of disease progression if they discontinue DMT.

The optimal duration of DMT use remains an open and controversial question. Many patients do not use these medications throughout their entire life after diagnosis. However, with few exceptions (such as natalizumab use or intended pregnancy), patients who opt for DMT for MS may end up using it for several years to decades, as long as they tolerate the treatment and the DMT seems effective. Patients may switch between DMTs in order to find one that is more effective or more tolerable, and studies have found high rates of switching between drugs.⁹ Some patients cannot tolerate any of the DMTs, but if a tolerable drug regime is determined, treatment generally continues until the individual reaches a disease stage where DMTs are no longer considered to be helping. Such a point may be reached when it is determined that a person is nonresponsive to the medication due to disease progression. Determining when DMT is no longer helpful is challenging. Thus, major questions of interest are whether or not DMTs for MS alter the natural history of the disease in the long run and when (if ever) to discontinue DMT. The related question addresses the influence of patient values, beliefs, and preferences regarding discontinuing DMTs. Such information should support clinicians, patients, consumer advocates, and other decisionmakers on decisions to discontinue treatment.

Scope and Key Questions

This review examines the long-term (more than 3 years) consequences of continuing or discontinuing DMT. We looked for evidence that directly assessed discontinuing versus continuing DMT and also evidence for long-term (more than 3 years) benefits and harms for either continuing or discontinuing, since that decision can be informed by the benefits or harms directly linked to either course of action. This information would extend understanding beyond the short-term trials examined in the 2013 Cochrane review. We were also interested in the reasons for discontinuing treatment reported in the long-term studies.

We concentrated on outcomes that patients notice or factor directly into their decisionmaking, such as relapse rates and changes in disability level, rather than intermediate outcomes such as lab tests for neutralizing antibodies. MRI to identify MS-related lesions has been shown to correlate with short-term relapse rates (6 months to 2 years).⁷ However, long-term MRI followup results as a surrogate marker for relapse rates or, more importantly, disease progression, currently lack evidence.^10,11 Further, short-term MRI followup as a predictor of long-term disability progression answers a different research question—i.e., does short-term treatment affect long-term outcomes—than the research questions asked for this review. Thus, we did not use MRI results as a long-term outcome in this review. However, we included MRI results as a short-term outcome in the subset of patients discontinuing natalizumab due to risk of PML.

People with MS commonly switch between the available DMTs, depending on tolerance, presence of adverse effects, and perceived helpfulness of the treatment. The pertinent clinical question for switching medications is how to define the threshold of disease activity for changing medications. This important question is qualitatively different from that of when, if ever, to stop DMT completely. To adequately address the question of when to switch medications will likely require a review of both short- and long-term research. Therefore, questions related to switching between DMTs are outside the scope of this review.

We synthesized the evidence in the published literature to address the following two Key Questions (KQs):

KQ1: What are the consequences of discontinuing disease-modifying treatments in adult patients?

1. What is the evidence for benefits for continuing versus discontinuing treatment?
2. What is the evidence for long-term harms?
3. What reasons for discontinuation of disease-modifying treatments have been reported in long-term observational cohort studies?

KQ2: What are individual values, beliefs, and preferences regarding discontinuing disease-modifying treatments?

1. What are patient and provider preferences for discontinuation of disease-modifying treatments?
2. What are patient and provider preferences for participation in shared decisionmaking to discontinue disease-modifying treatments?

Figure A provides a conceptual framework that links the KQs. At the top it depicts the logic path both physicians and patients must travel when considering DMT:

Figure A

Conceptual framework for Key Questions. KQ = Key Question

• Does it work?
• What drug should I start with?
• When should I switch to a new drug and what should that drug be?
• When should I discontinue DMT?

This logic path describes the context within which patients and clinicians consider clinical factors—tolerability of the medication, disease characteristics at the time of discontinuation (relapses, progression, MRI activity), risk of ongoing disease treatment, other impediments to continued medication use (difficulty in obtaining, injecting, or ingesting, cost, etc.)—and make decisions about DMT or, in the case of this review, discontinuation (KQ1). The lower part of the figure, the conceptual basis for KQ2, depicts the progression from an individual's internal decision context and process (such as preferences, values, knowledge, beliefs, and cognitive behaviors and habits) to an interpersonal decision context and processes between the physician and patient. The overlapping ovals representing the clinician and the patient indicate information shared between the two parties versus information and other cognitive processes specific to one individual. Any overlap depends in part on the level of sophistication a patient brings to the decisionmaking process and in part on how well a physician understands a patient's beliefs, values, goals, and preferences. For example, a patient newly diagnosed with MS in the novice phase of learning about MS would likely have a smaller overlap.¹² The interaction between the physician and patient results in decisions that can vary in their level of concordance.

Figure B provides an analytic framework describing the treatment path and long-term benefits and harms of continuing versus discontinuing DMT for KQ1.

Figure B

Analytic framework for discontinuing disease-modifying treatments for MS. DMT = disease-modifying treatment; KQ = Key Question; MS = multiple sclerosis

Methods

The methods for this review follow the methods suggested in the Agency for Healthcare Research and Quality “Methods Guide for Effectiveness and Comparative Effectiveness Reviews” (available at www.effectivehealthcare.ahrq.gov). We used Technical Brief methods for KQ2. A complete description of the methods can be found in the full report. All methods and analyses were determined a priori.

Results

We identified 4,359 unique citations in searching from 1990 to August 2014. After excluding articles at the title and abstract phase, full texts of 198 articles were reviewed to determine final inclusion. Seven articles were added through hand-search. Of the 61 articles retained for KQ1, 11 were specific to discontinuing natalizumab due to increased risk and 12 were specific to discontinuing due to pregnancy. Of the remaining 38 articles comprising 27 unique studies, only 16 studies contained complete information to allow for full analysis. All 38 articles were reviewed for information on reported reasons for discontinuation. For KQ2, 30 articles comprising 27 unique studies were included. Detailed tables and synthesis can be found in the full report.

KQ1a. Benefits of Continuing Versus Discontinuing DMT

The key points for KQ1a are as follows:

• No studies directly assessed the consequences of continuing versus discontinuing DMT in comparable populations.
• Low-strength evidence from one study with moderate risk of bias suggests that, for RRMS patients, long-term all-cause survival is higher for treatment-naïve patients who did not delay starting IFNbeta-1b by 2 years and used DMT for a longer duration than those who started later.
• Low-strength evidence from one study with moderate risk of bias suggests that IFN use did not change disability progression for RRMS patients.
• Insufficient evidence was available to assess long-term benefits of DMT for SPMS patients and most outcomes for RRMS patients. Except for those noted above, studies were high risk of bias and had small sample sizes, and reported effects were small in magnitude.

Results are summarized in Table A.

Table A

Outcomes reported from unique studies included in the analytic set for long-term DMT use.

No studies directly assessed continuing versus discontinuing DMT in comparable populations. We therefore turned to literature examining benefits for continuing DMT long term. Variation among the included studies on long-term benefits of DMT for patient populations, interventions, outcome measurements, and timeframes precluded meaningful pooling. Only two studies provide a low strength of evidence for two benefit outcomes measured long term for IFNs.

One study with moderate risk of bias examined all-cause mortality over a 21-year period for 366 patients who had enrolled in an RCT (98.4% of the original RCT participants) testing IFNbeta-1b for treatment-naïve RRMS patients in 11 clinics in North America.¹⁸ The study's strength lies in the nearly complete followup of patients and the objective outcome measure. Participants in the two treatment arms (50 mg and 250 mg) showed lower all-cause mortality compared with the placebo arm. The survival rate for the placebo arm was consistent with survival rates reported in MS natural history studies. Median treatment duration for the three groups ranged from 7 years for the placebo group to 14 years for the 50 mg arm and 12 years for the 250 mg arm. Patients assigned to placebo had both later starts and shorter exposure to DMTs. Thus, the study cannot distinguish between the effects of early use and the effects of long-term use.

One study with moderate risk of bias examined the association between IFNbeta use and progression to a sustained Expanded Disability Status Scale (EDSS) score of 6 for 2,656 RRMS patients in Canada.²⁰ Three arms were used: a treatment cohort followed for 5.1 years, a contemporary cohort followed 4 years, and a historical cohort (drawn from the pre-IFN period) followed 10.8 years. The strength of this study lies in the almost complete capture of MS patients, since patients were unable to obtain DMTs other than from the participating clinic, and the multiple statistical approaches used to test for association, including use of comorbidities (Charlson score) and socioeconomic status along with age, sex, disease duration, and EDSS. Propensity score adjustments did not substantially change the results. The study did not find statistically significant differences in hazard ratios for reaching a sustained EDSS score of 6 for either contemporary or historical cohort comparisons.

Insufficient evidence exists to address long-term benefits for glatiramer acetate, teriflunomide, and natalizumab for either RRMS or SPMS, as well as important MS outcomes for IFNbeta for RRMS beyond all-cause mortality or 5-year disability progression.

KQ1b. Evidence for Harms

The key points for KQ1b are as follows:

• Limited low-strength evidence suggests that harms for injectable DMTs do not differ between short term (2-3 years) and long term (up to 16 years for IFN, 22 years for glatiramer acetate, and 8.5 years for teriflunomide).
• The majority of discontinuation tends to occur in the short term (2-3 years from start).
• Broad variation in harms reporting precludes informative aggregation and summary.
• Because of high risk of bias and small sample sizes, evidence is insufficient for whether rebound after discontinuing natalizumab exists.
• Because of high risk of bias and small sample sizes, evidence is insufficient to address the risks of fetal exposure to DMT during pregnancy in women with MS or the risks to the mother from the drug holiday.

Results are summarized in Table B.

Table B

Harms reported from unique studies included in the analytic set.

Eleven of the 16 unique studies reported harms in enough detail for abstraction.^{9,18,19,21-36} Only one of the studies was moderate risk of bias;¹⁸ all others were rated as high risk of bias.

The included studies used a wide range of reporting methods and adverse event categories that precluded simple aggregation over the studies. The most commonly reported adverse events were injection site reactions, flulike symptoms, depression, and headache. Serious adverse events were generally not reported, although two studies gave rates of about 25 percent to 30 percent of participants. Discontinuations tended to occur during the first or second year of the study. When reported, discontinuation rates during long-term followup were low, about 3 to 4 percent, but rates due to adverse events were not separate from total discontinuation rates, which would also include perceived lack of efficacy and other reasons not necessarily related to adverse events or side effects. Further, all studies lost participants to attrition. Dropouts from observational studies are more likely to bias reporting toward lack of adverse events. Patients on long-term treatment are self-selected for positive outcomes, even though this may be due to any combination of treatment effects and benign disease course. The studies also did not use large enough patient populations to adequately detect rare events.

Eight observational studies (all high risk of bias) addressed the risks of rebound disease activity with natalizumab treatment interruption. Determining whether rebound exists requires comparing disease activity prior to receiving natalizumab and disease activity after interrupting treatment. None of the studies used appropriate comparison groups. All but one study used a subjective definition for rebound.

Twelve observational studies (all high risk of bias) addressed the benefits and risks to mothers and fetuses of IFN, glatiramer acetate, or natalizumab treatment discontinuation due to pregnancy or intended pregnancy. Women who discontinue DMT with the intention of becoming pregnant risk increased relapses between discontinuation and pregnancy, as well as postpartum. Given that the studied populations are those who became pregnant, none of the studies capture what happens to women who discontinue DMT but do not become pregnant. Therefore, no research has observed whether such women are at increased risk of relapse.

KQ1c. Reasons for Discontinuing DMT

The key points for KQ1c are as follows:

• The broad variation in discontinuation reporting prevented useful aggregation of studies.
• All studies reported one or more adverse events and inefficacy or progression of disability as reasons to discontinue.
• Patient reasons for discontinuing DMT were not explored.

Results are summarized in Table C.

Table C

Studies reporting reasons for discontinuing medication.

Twenty articles of the full reporting set reported reasons for discontinuing treatment. The wide range of reporting methods and discontinuation categories prohibited detailed quantitative aggregation over the studies. Most articles reported numerous reasons for discontinuations. Unfortunately, the reason for the patient's decision to discontinue remained largely unexplored. Minimal text in this category generally used phrases such as “by own will,”^25,37 “withdrew consent,”^22,28 or “voluntary withdrawal.”^34,38,39

Discussion

Effective health care relies on the three legs of physicians' clinical experience, patients' knowledge of their specific health situations and preferences, and an evidence base. Together, these three components provide the input for medical decisions. In the absence of a clear unambiguous path to follow, patients are best served by shared decisionmaking, which requires clinicians to provide the best available information against which patients can weigh their preferences and risk tolerance.

The decisions around discontinuation of DMT are extremely personal and individual. It is hard to envision ever having enough information to cover all contingencies. Providers and MS patients who have followed a prolonged DMT treatment plan have little information to guide decisions regarding discontinuing DMT. Thus, personal preferences about risks take on more weight.

No literature directly compared continuing versus discontinuing DMT in comparable populations. Only sparse information was available to address one part of the decisionmaking picture faced by providers and patients: long-term benefits and harms. As summarized in Table D, low-strength evidence showed increased all-cause mortality for patients who started IFNbeta-1b 2 years earlier than the comparators, but no differences between treated and comparator groups in time to progression to SPMS (as measured by a sustained EDSS score of 6). Similarly, overall long-term harms were found to be no different from short-term harms. Low-strength evidence implies low confidence in the findings and the expectation that future research could change the findings. Evidence is insufficient to assess long-term benefits and harms for any other patient population, type of DMT, or outcome.

Table D

Summary of KQ1 findings with sufficient evidence.

The current literature did not examine whether long-term benefits for DMTs remain after a patient converts to SPMS. For the special cases of natalizumab and discontinuation for planned pregnancy, evidence was insufficient to answer whether discontinuation is problem free.

In the absence of evidence, providers and patients are left with little to inform their preferences and guide their decisions regarding when to discontinue treatments. The majority of included studies reported reasons for patients discontinuing treatments, but the information provided was without detail. Adverse events and inefficacy or progression of disability were two expected categories. Other possible reasons for discontinuation, such as a patient's desire to try alternative medicine approaches, perceived risk of long-term use, or financial concerns such as out-of-pocket costs or loss of insurance, are not noted. The “patient decision” category for discontinuing was consistently unexplored.

Harms from long-term DMT use, as is true for many treatments and medical conditions, is poorly reported in the literature. The low-strength evidence showing long-term harms to be generally similar to short-term harms may very well be upset by improved tracking and reporting. For example, a November 2014 FDA Drug Safety Communication reported the first confirmed fatal case of PML for an MS patient using dimethyl fumarate (Tecfidera^®).⁶⁸ The patient had used dimethyl fumarate for 4 years.

KQ2 aimed to delve into what is known about patient and provider preferences. While the literature was sparse, with only 28 studies available to populate the conceptual map provided in Figure A, each of the three major conceptual areas was at least partially represented. No study directly asked why people are reluctant to discontinue when treatment seems no longer effective, but taken as a whole, the literature set provides some insight.

Overall, one can weave together the general themes found in the KQ2 literature. Admittedly, physicians cannot reliably predict patient preferences for shared decisionmaking, and often physicians and patients perceive the relative importance of health status or acceptable risks differently. However, when it comes to the decision to discontinue DMT, the patient drives the decision, and this preference and role are generally unchallenged by the physician. In some DMT discontinuations, the balance of shared decisionmaking may shift to discordance between the physician and patient, with the physician deferring to patient preferences for continuing treatment or not. The quantified preferences work by Prosser and colleagues⁴⁷ illustrates a paradox—patients are less likely to prefer DMT during the early course of the disease, when disease symptoms are lower than the side effects of the DMT, and more likely to use it at later stages of the disease, when the side effects are less than disease symptoms. This behavior is counter to the hypothesis under which DMTs are assumed to work, which is by using DMTs to reduce relapses early in the disease course to prevent or delay disease progression. Without more solid evidence for the long-term net benefits or the thresholds at which treatment is no longer effective in preventing disease progression, the decision to discontinue treatment remains preference sensitive.

The preferences literature underscores the complexity of the topic and the processes underlying decisionmaking. Both rational and nonrational (such as heuristic) processes came into play, and neither had primacy over the other. Cost was a factor in both self-report and through observation of purchasing behavior. Cognitive deficits impairing decisional capacity may be overcome with adequate cuing. Information is a necessary component of decisionmaking, yet nonrational factors can influence what information is sought at what time.

Preferences, values, and beliefs are highly variable, may change over time, and are linked to the nature of the patients' relationships with their doctors. There may well be differences based on age, sex, race, class, and other factors. A patient's preference position between “treat my MS at any cost/comfort from knowledge of receiving treatment” and “need strong evidence that the medication will help and be worth the cost/side effects” may change over time and as the disease changes.

Changing perceptions regarding health states were common across different parts of the intrapersonal literature. Risk perceptions and quantified preferences (which are risk based as well) both suggested that people with longer MS experience assigned higher values to disabled states or viewed them as less serious than people with shorter MS experience did. This is a finding consistent with other research into how people value different health states. Many people overestimate their aversion to hypothetical states of disability and hence eliminate treatment options that might lead to such disability, especially if it could be long term.^69-72 The hypothetical disutilities for these states are consistently higher than the actual disutilities for those experiencing the state.

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