Treatment of secondary progressive multiple sclerosis in adults

INTRODUCTION — Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. The course of MS is variable. For some, MS is a disease with one or two acute neurologic episodes and no further evidence of disease activity. In others, it is a chronic relapsing or progressive disease, with an unpredictable clinical course that may span 10 to 20 years, during which time neurologic disability accumulates. Most experts view MS as occurring on a spectrum, in which episodic, immune-mediated events (relapses and the accumulation of new lesions on magnetic resonance imaging [MRI]) occur more typical at younger ages and wane in frequency as a person with MS ages; at the same time, accumulating neurodegeneration gives rise in many patients to gradually worsening disability, known as progressive disease.

This topic will discuss treatment of secondary progressive MS. The treatment of primary progressive MS and relapsing-remitting MS is discussed separately. (See "Treatment of primary progressive multiple sclerosis in adults" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Other aspects of MS are reviewed elsewhere:

●(See "Overview of disease-modifying therapies for multiple sclerosis".)

●(See "Pathogenesis and epidemiology of multiple sclerosis".)

●(See "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)

●(See "Manifestations of multiple sclerosis in adults".)

●(See "Symptom management of multiple sclerosis in adults".)

●(See "Evaluation and diagnosis of multiple sclerosis in adults".)

PATTERN AND COURSE OF MS

Clinical subtypes — MS is categorized into several clinical subtypes, including relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), and primary progressive multiple sclerosis (PPMS), as reviewed here briefly and discussed in detail separately. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Disease onset and pattern'.)

Relapses are characterized by clearly defined acute to subacute attacks (also known as flares or exacerbations) with full or incomplete recovery in the absence of fever. In MS clinical trials, these symptoms are required to last at least 24 hours. Progressive disease is characterized by the slow, chronic accumulation of disability, which may be accompanied by occasional plateaus, temporary minor improvements, and/or superimposed acute relapses.

●RRMS is characterized by clearly defined relapses with either full recovery, or with sequelae and residual deficit upon recovery. There is no or minimal disease progression during the periods between disease relapses, though individual relapses themselves may occasionally result in severe residual disability.

●SPMS evolves from relapsing-remitting disease, hence the designation of "secondary," as over time the disease enters a stage of steady deterioration in function, with or without superimposed attacks. When the secondary progressive stage is reached, the relapse rate is typically reduced. This may be a phenomenon of immunosenescence, as relapses and new MS lesions are less common as people age, while progressive MS is more likely as age increases. SPMS, which ultimately develops in up to 90 percent of patients with RRMS after 25 years, causes the greatest amount of neurologic disability attributable to MS.

●PPMS represents approximately 10 percent of MS cases and is characterized by disease progression from onset, although occasional plateaus, temporary minor improvements, and acute relapses may occur.

Determining the onset of SPMS — A diagnosis of SPMS is made only by taking a careful history, as there are no physical exam findings, laboratory markers, or radiographic features that separate it from RRMS. The change from RRMS to SPMS is a gradual process rather than an abrupt transition [1]. Often, the diagnosis is made retrospectively. Although a clear consensus is lacking, one definition of SPMS requires that a patient with MS and a history of at least one clinical relapse (ie, RRMS) has a period of continuous disability progression of at least 6 to 12 months that is independent of clinical relapses [2]. (See "Clinical presentation, course, and prognosis of multiple sclerosis in adults", section on 'Secondary progressive MS'.)

Disease activity and progression — The MS subtypes (RRMS, SPMS, and PPMS) are further modified by assessments of disease activity and disease progression. Disease activity is determined by clinical relapses or magnetic resonance imaging (MRI) evidence of contrast-enhancing lesions and/or new or unequivocally enlarging T2 lesions. Disease progression is a measure of disability, and it is independently quantified from relapses, even for RRMS; it is characteristic of PPMS and SPMS. Thus, the phenotype of progressive disease (PPMS and SPMS) can be characterized as one of the following [3]:

●Active and with progression (new lesions and progressive disability)

●Active but without progression (new lesions, with recovery)

●Not active but with progression (no new lesions, but progressive disability)

●Not active and without progression (stable disease)

DISEASE-MODIFYING THERAPY FOR SPMS

Approach to choosing disease-modifying therapy — For most patients with relapsing-remitting multiple sclerosis (RRMS) with who reach the stage of secondary progressive multiple sclerosis (SPMS) and have active disease with ongoing clinical relapses and/or new MS lesions on magnetic resonance imaging (MRI), we suggest using a MS disease-modifying therapy (DMT). The choice of DMT should be individualized based upon disease activity and progression, adverse effect profile, and patient preference. Potential therapeutic options for patients with active SPMS, at least in the United States, include all DMTs approved for relapsing forms of MS.

While there is evidence from a placebo-controlled randomized trial that oral siponimod was effective for reducing disability progression at three and six months for patients with SPMS, there is not a strong rationale for its exclusive use in this MS subtype, particularly when other DMTs may suppress relapses or lesions just as well (see 'DMTs used for active SPMS' below). Observational data from a MS registry also suggest DMTs are associated with a reduced rate of disability progression in patients with active SPMS [4]. Some of our expert contributors treat active SPMS with an approach similar to how they treat RRMS, believing that none of the approved DMTs really prevents neurodegeneration. In their view, the treatment target is still inflammatory activity (ie, relapses and new MS lesions), and continuing or switching DMT is unlikely to alter the course of disease progression.

Thus, for patients who reach the stage of SPMS and have a relatively low level of active disease while on a DMT, it is reasonable to continue the same DMT used during the relapsing-remitting phase of MS. For patients with a higher level of active disease, it may also be reasonable to switch to another DMT that is selected based upon the individual risk/benefit profile, but no randomized clinical trials have addressed this issue. (See 'Suboptimal response to DMT' below.)

Although definitive data are lacking, subgroups of patients with progressive MS characterized by younger age, recent relapses, recent MRI disease activity, or recent disability progression may be more likely to benefit from DMT in comparison with patients lacking these characteristics [2]. Those who are older or more disabled may also be at greater risk of infectious adverse events related to DMT.

For patients with inactive SPMS (ie, no ongoing relapses or gadolinium-enhancing lesions on MRI of the brain and spinal cord) who have been nonambulatory for at least two years, it is reasonable to discuss stopping DMT. (See 'Inactive SPMS' below.)

DMTs used for active SPMS — Therapeutic options for patients with active SPMS, at least in the United States, include all DMTs approved for relapsing forms of MS. (See "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Among the DMTs, only siponimod has shown efficacy for reducing the risk of disability progression in a large randomized trial of patients with SPMS. However, there have not been large randomized trials evaluating other DMTs approved for relapsing forms of MS in patients with SPMS, and differences in the included patient populations may account for some of the discrepancies in outcomes among the smaller trials that have been conducted.

Ocrelizumab and rituximab are used most often by our expert contributors to treat patients with active SPMS.

●Monoclonal antibody DMTs – The dosing, monitoring, and adverse effects of the monoclonal antibody DMTs listed below are reviewed in detail separately. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis".)

•Ocrelizumab – Ocrelizumab is a humanized anti-CD20 (a B-cell marker) monoclonal antibody that binds to a different, but overlapping, CD20 epitope than rituximab. It is more humanized than rituximab and was designed to optimize B cell depletion by modification of the Fc region, which enhances antibody-dependent cell-mediated cytotoxicity and reduces complement-dependent cytotoxicity compared with rituximab. The FDA approved ocrelizumab for the treatment of adult patients with primary progressive multiple sclerosis (PPMS) in 2017; the indications were later expanded to include active SPMS. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Ocrelizumab'.)

•Rituximab – Rituximab is a recombinant chimeric monoclonal antibody that also targets CD20 and is thought to act primarily by depleting CD20-positive B cells. Rituximab has been widely used off-label to treat patients with active forms of MS. A retrospective cohort study of patients with SPMS, using propensity-matched scoring and with varying doses of rituximab, found that patients treated with rituximab had lower Expanded Disability Status Scale (EDSS) scores during a mean follow-up of 3.5 years and delayed time to confirmed disability progression compared with control patients never treated with rituximab (hazard ratio 0.49, 95% CI 0.26-0.93) [5]. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Rituximab'.)

•Ofatumumab – Ofatumumab is a human monoclonal antibody that targets CD20 and causes selective B cell depletion. Ofatumumab was approved in August 2020 for relapsing forms of MS, including active SPMS. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Ofatumumab'.)

•Ublituximab – Ublituximab is a recombinant mouse-human chimeric monoclonal antibody that binds to a CD20 epitope distinct from those targeted by ocrelizumab, rituximab, and ofatumumab. Ublituximab was glycoengineered with a low sugar content in its Fc segment to achieve a high affinity for Fc gamma RIIIa (CD16) receptor. This enhances its ability to activate natural killer cell-mediated antibody-dependent cellular cytotoxicity, leading to B cell depletion. Ublituximab was approved by the FDA in December 2022 for the treatment of adults with relapsing forms of MS, including active SPMS. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Ublituximab'.)

•Natalizumab – Natalizumab is a humanized recombinant monoclonal antibody directed against the alpha-4 subunit of integrin molecules, thereby blocking integrin association with vascular receptors and limiting adhesion and transmigration of leukocytes. Natalizumab is approved for the treatment of active SPMS. However, the effectiveness of natalizumab for progressive forms of MS is remains to be established [6], and data from one placebo-controlled trial suggest that natalizumab does not slow disability progression in patients with SPMS [7]. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Natalizumab'.)

•Alemtuzumab – Alemtuzumab is a humanized monoclonal antibody that causes depletion of CD52-expressing T cells, B cells, natural killer cells, and monocytes. Alemtuzumab is approved for the treatment of relapsing forms of MS, including RRMS and active SPMS. Because of its adverse effect profile, alemtuzumab is generally reserved for patients with highly active RRMS who have had an inadequate response to two or more DMTs, or where other DMTs cannot be used. (See "Clinical use of monoclonal antibody disease-modifying therapies for multiple sclerosis", section on 'Alemtuzumab'.)

●Oral DMTs – The dosing, monitoring, and adverse effects of the oral DMTs discussed below are reviewed in detail separately. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Introduction'.)

•Siponimod – Siponimod is a sphingosine 1-phosphate receptor (S1PR) modulator that is similar to, yet more selective than, fingolimod. Siponimod was approved in the United States by the US Food and Drug Administration (FDA) in 2019 for the treatment of adults with active SPMS, RRMS, and clinically isolated syndromes [8]. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Siponimod'.)

In the double-blind, randomized EXPAND trial of 1651 subjects with SPMS (average age 48 years), oral siponimod compared with placebo reduced the risk of confirmed disability progression at three months (26 versus 32 percent, HR 0.79, 95% CI 0.65-0.95; absolute risk reduction 6 percent) and at six months [9]. In addition, siponimod treatment reduced 12- and 24-month annualized relapse rates and reduced the volume of brain lesions identified by T2-weighted MRI. However, siponimod treatment did not show any effect on the timed 25-foot walk test, a commonly used outcome measure in MS trials that has practical relevance for assessing gait speed and clinically meaningful change in ambulation [10]. Siponimod was generally well tolerated, but infections were more common in subjects who received the drug.

•Other S1PR modulators – Besides siponimod, other S1PR modulators approved for the treatment of active SPMS are fingolimod, ozanimod, and ponesimod. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'S1PR modulators'.)

•Fumarates – Oral fumarates approved for the treatment of active SPMS are dimethyl fumarate, diroximel fumarate, and monomethyl fumarate. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Fumarates'.)

•Teriflunomide – Teriflunomide is the active metabolite of leflunomide that inhibits pyrimidine biosynthesis and disrupts the interaction of T cells with antigen presenting cells; it is approved for the treatment of active SPMS. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Teriflunomide'.)

•Cladribine – Cladribine, a purine antimetabolite agent that targets lymphocyte subtypes, is approved for the treatment of active SPMS. While cladribine is beneficial for patients with relapsing forms of MS, controlled trials of cladribine have demonstrated only an inconsistent benefit specifically for patients with progressive forms of MS [11-13]. Its adverse effect profile includes a risk of life-threatening infection and, potentially, tumor development. Because of this, cladribine is generally reserved for patients who do not tolerate or have inadequate response to other DMTs for MS [14]. Efficacy, dosing, and adverse effects of cladribine are reviewed in greater detail elsewhere. (See "Clinical use of oral disease-modifying therapies for multiple sclerosis", section on 'Cladribine'.)

●Older injection (platform) DMTs – The dosing, monitoring, and adverse effects of the injectable DMTs discussed below are reviewed in detail separately. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Injection therapies'.)

•Interferons – The clinical trial data for interferon beta-1a and particularly interferon beta-1b suggest but do not establish that patients with SPMS who have an acute inflammatory component can benefit from treatment with interferons [15-20]. A 2012 systematic review identified five randomized placebo-controlled trials that evaluated either interferon beta-1a or interferon beta 1-b in over 3100 patients with SPMS [21]. In the pooled analysis of three trials with outcome data assessed at three years, interferon beta treatment did not significantly decrease the risk of sustained disability progression (relative risk [RR] 0.98, 95% CI 0.82-1.16). However, data from four trials with three-year outcome data showed that interferon treatment reduced the risk of having at least one relapse (RR 0.91, 95% CI 0.84-0.97).

Suboptimal response to DMT — For patients with active SPMS who have a suboptimal response to DMT, as determined by evidence of ongoing disease activity with attacks (relapses) and/or the development of new MS lesions (see 'Monitoring' below), switching to a different DMT is a reasonable option. Continued progression independent of relapses generally is not a reason to change DMT. Ultimately, the decision is based upon clinical experience and individual patient characteristics, as no randomized clinical trials have addressed this issue. Careful discussion surrounding such decisions is important, particularly considering the potential for overlapping immune suppression surrounding treatment switches.

The frequency and severity of clinical relapses and MRI lesion activity on therapy are the crucial factors in determining a suboptimal response to DMT. Fewer data are available, however, to determine the appropriate threshold for recommending a treatment switch after breakthrough disease in patients with SPMS, and it is less clear than in RRMS whether breakthrough disease has as great an association with long-term disability as it does when it occurs early in the RRMS period. Thus, a single relapse of mild severity or a single new MRI lesion within six months of starting DMT is usually insufficient to demand a change in therapy. However, any serious relapse, multiple relapses regardless of severity, or a pronounced increase in MRI activity with multiple contrast-enhancing lesions, particularly after more than a few months on therapy, should prompt a review of treatment options with a predisposition to change the DMT.

In discussing with a given patient, it is important to review that, with the possible exception of siponimod, none of the currently available DMTs are definitively proven to reduce disability progression for patients who appear to have SPMS (although our expert contributors generally think it is unlikely that siponimod has unique disability prevention capacity). This factor must be considered when deciding whether to switch to another DMT and, in general, to establish the overall goals of DMT for a given patient. These goals include the need to balance the risks posed by the medications with the risks posed by the disease, though prognosticating long-term outcomes in MS is difficult. The contribution of medication adherence and other factors to inadequate treatment response is also important.

Other treatments — Other treatments that are sometimes used for SPMS lack convincing evidence of effectiveness or have risks of serious toxicity that limit their utility; most MS experts do not use these interventions for SPMS on a routine basis. These include:

●Mitoxantrone – A few small, randomized trials found that mitoxantrone is effective for patients with worsening RRMS or SPMS [22-25]. However, the drug is seldom used because of potential for serious complications (particularly cardiotoxicity and leukemia) and the availability of alternatives.

In a single multicenter, double-blind trial of 194 patients with worsening RRMS or SPMS, treatment with mitoxantrone was associated with significant clinical benefits compared with placebo on multivariate analysis, reducing progression of disability and clinical exacerbations [22]. However, in a subset of patients with MRI data, mitoxantrone treatment did not reduce the number of scans with positive gadolinium enhancement at 12 and 24 months, compared with placebo [26]. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Mitoxantrone'.)

●Glucocorticoids – Bolus IV glucocorticoids, typically 1000 mg of methylprednisolone, have been used for treatment of PPMS or SPMS alone or in combination with other immunomodulatory or immunosuppressive medications. While there does not appear to be any long-term effect in the degree of functional recovery from an attack following the use of glucocorticoids, it is possible that regular pulse glucocorticoids may be useful in the long-term management of patients with SPMS, particularly those who continue to have acute attacks in addition to progression between relapses. In a trial of bimonthly IV methylprednisolone in SPMS, 108 patients were randomly assigned to receive either high-dose (500 mg) or low-dose (10 mg) methylprednisolone once daily for three consecutive days every eight weeks for two years [27]. Each IV bimonthly pulse was followed by an oral methylprednisolone taper beginning on day 4 and finishing on day 14. Although there was no difference in the proportions of patients in each treatment group who experienced sustained progression of disability, the time to onset of sustained treatment failure was delayed in the high-dose group.

Glucocorticoid treatment has a short-term benefit on the speed of functional recovery in patients with acute relapses, as reviewed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids'.)

●Cyclophosphamide – There is limited evidence that younger patients (age ≤40 years) with seemingly progressive MS may derive some benefit from pulse plus booster cyclophosphamide treatment. However, the bulk of evidence suggests that cyclophosphamide treatment does not alter the course of progressive MS [28-30]. Adverse effects of cyclophosphamide include nausea, vomiting, infection, scalp alopecia, gonadal suppression, menstrual irregularities, premature menopause, infertility in females and males, and hemorrhagic cystitis.

●Methotrexate – Oral or subcutaneous methotrexate, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses, has been used to treat patients with progressive forms of MS, based on limited and ambiguous evidence from a single trial [31]. The only high-quality randomized controlled trial evaluating oral methotrexate for progressive MS found only a trend toward improvement in symptoms and radiographic findings [31,32]. In that trial, 60 patients with chronic progressive MS were randomized to receive either weekly low-dose oral methotrexate (7.5 mg) or placebo [31]. Methotrexate positively affected measures of upper extremity function such as the 9-Hole Peg Test and a Block-in Box Test; these tests are a sensitive measure of repeated use of digits. However, lower extremity function, as measured by ambulation and disability scales, was not affected. There was no clinically significant toxicity. The relatively low dose of oral methotrexate (7.5 mg weekly) studied in this trial is a potential explanation for the lack of clear benefit. Whether higher doses given intravenously or intrathecally would be more effective in MS is unclear. The safety of methotrexate has been established in patients receiving 20 mg subcutaneously weekly [33].

●Azathioprine – Azathioprine (titrated up to a dose of 2 mg/kg per day) has been studied in both relapsing-remitting and chronic progressing MS since 1971. A systematic review of five randomized, controlled trials of azathioprine versus placebo for MS (including patients with relapsing-remitting and progressive types of MS) found that azathioprine treatment significantly reduced the number of patients who had relapses; data from three trials with a total of 87 patients suggested that azathioprine also reduced disability progression during the first two to three years of treatment [34]. The validity of this finding is uncertain given the obvious limitation of small patient numbers. The most common side effect of azathioprine is an idiosyncratic flu-like illness with fever, nausea, vomiting, and malaise, which affects approximately 10 percent of treated patients and typically develops in the first few weeks of treatment. Less common, but serious, potential adverse effects include hepatotoxicity, suppression of the white blood count, and pancreatitis. In addition, the risk of malignancy may be increased with long-term use of azathioprine.

●Stem cell transplantation – Stem cell transplantation has shown promise for the treatment of patients with progressive forms of MS. These data are reviewed separately. (See "Overview of disease-modifying therapies for multiple sclerosis", section on 'Stem cell transplantation'.)

●Biotin – Biotin is a cofactor for several carboxylases involved in fatty acid synthesis and energy production; speculative mechanisms of action in MS include axonal remyelination via augmented myelin production and reduced axonal hypoxia via increased energy production [35]. Studies have found no consistent benefit, despite early promise [36]. A small randomized controlled trial (MS-SPI) found that the proportion of patients with disability reversal at 9 and 12 months was greater for the high-dose biotin group compared with the placebo group, although the degree of disability reversal was modest [37]. However, a larger phase 3 placebo-controlled randomized trial (SPI2) found that biotin was not beneficial for improving disability or walking speed in patients with inactive SPMS or PPMS [38].

●Simvastatin – A controlled trial of 140 adults with SPMS found that the group assigned to simvastatin (80 mg daily) had a significant reduction in the mean annualized rate of whole-brain atrophy (0.29 percent versus 0.58 percent for the placebo group) and a significant reduction in some secondary measures of disability [39]. There was no significant difference between groups in the rate of new and enlarging brain lesions or in the relapse rate. Further trials are needed to establish whether simvastatin reduces progression of disability in patients with SPMS.

Inactive SPMS — For patients who transition from RRMS to SPMS while on DMT and enter a stage of inactive disease (ie, no ongoing relapses or gadolinium-enhancing lesions on MRI of the brain and spinal cord) and who have been nonambulatory for at least two years, it is reasonable to discuss discontinuing DMT [40]. Many patients with progressive MS are older and less likely to have active disease, and therefore less likely to respond to DMT. Furthermore, since progressive MS is an illness of decades, a patient with inactive but progressing MS may be more likely to develop infectious and other complications of immunosuppressive therapy due to long exposure and older age. However, clinical experience suggests that severe rebound of MS activity may sometimes occur after stopping some DMTs, even in patients with progressive MS, though this is not common. These are highly individualized decisions without clear data to drive them. The evidence for patients with MS who stop DMTs is inconsistent. One study identified 426 patients (median age 45 years) with stable MS (ie, no relapses for five or more years) who stopped DMT; relapses during follow-up were reported by 36 percent of patients and DMT was restarted by 46 percent [41]. By contrast, another study tracked 178 patients age 60 and older who stopped their DMT; only one patient experienced a relapse, and only 11 percent restarted DMT [42]. The DISCOMS trial should help determine whether it is safe to stop DMT in older, stable patients [43,44]. (See "Indications for switching or stopping disease-modifying therapy for multiple sclerosis", section on 'Reasons for stopping DMT'.)

DMT is generally continued indefinitely for patients with previously active MS who transition to inactive SPMS while still ambulatory, with the rationale that the preserved ability to walk has been safeguarded by DMT. There is no clear indication for starting DMT or other immune-modulating therapy anew for patients with SPMS in the absence of active disease [2]. However, since there are no markers that predict any future reactivation, many clinicians opt to treat these patients as well with DMT as previously discussed.

MONITORING — Most patients with secondary progressive multiple sclerosis (SPMS) should be followed at least annually with clinical and imaging assessments, although the follow-up period should be based upon individual patient circumstances [3]. Clinical follow-up, including the response to disease-modifying therapy (DMT), should focus on possible manifestations of MS disease activity and progression of disability [40,45].

●Evaluation for activity – Manifestations of MS disease activity consist of attacks (relapses) and/or the development of new MS lesions on brain magnetic resonance imaging (MRI), including gadolinium-enhancing lesions or new or enlarging T2 lesions [3,40]. Spinal cord MRI should be obtained if there are clinical findings attributable to the spinal cord. Attacks (relapses) are defined by acute or subacute onset of new or worsening neurologic dysfunction that is followed by recovery, either partial or full, in the absence of infection or fever [3].

●Evaluation for progression – Disease progression, a measure of disability, is characterized by steady, insidious deterioration of neurologic function that occurs independently of relapses [3,46]. Progression can be determined from patient history and/or objective measures, such as a worsening of the Expanded Disability Status Scale (EDSS) (table 1) that persists for a number of months. Ambulatory disability progression is particularly important, and the 25-foot timed walk, used by most centers, is a good yet simple measure for determining ambulatory changes. However, given fluctuations in the examination of individual patients and variation between examiners, it can be difficult to be certain of progression or stability, especially in the short-term. Therefore, progression or regression of activities of daily living (ADL) competence as obtained from the patient is also important to evaluate, particularly in non-ambulatory patients (eg, ability to transfer, self-care, etc). Note that the EDSS and assessments for progression are best administered by MS experts or other clinicians with experience in these measures.

SYMPTOM MANAGEMENT — Beyond immune-modulating or disease-modifying therapy, multidisciplinary management for the common complications and symptoms of MS is critical. These complications include bladder and bowel dysfunction, cognitive impairment, depression and anxiety, fatigue, gait impairment, heat intolerance, pain, sexual dysfunction, sleep disorders, spasticity, speech and swallowing dysfunction, tremor, vertigo, and visual disturbances, as reviewed separately. (See "Symptom management of multiple sclerosis in adults".)

ACUTE ATTACKS — Acute attacks of MS are often treated with glucocorticoids. Indications for treatment of a relapse include functionally disabling symptoms with objective evidence of neurologic impairment. This is reviewed in detail separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Multiple sclerosis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Secondary progressive multiple sclerosis (SPMS) – This subtype of multiple sclerosis (MS) evolves from relapsing-remitting multiple sclerosis (RRMS) as the disease over time enters a stage of steady deterioration in function, unrelated to acute attacks. The change from RRMS to SPMS is a gradual process rather than an abrupt transition. Although a clear consensus is lacking, one definition of SPMS requires that a patient with multiple sclerosis and a history of at least one clinical relapse (ie, RRMS) has a period of continuous disability progression of at least 6 to 12 months that is independent of clinical relapses. (See 'Clinical subtypes' above and 'Determining the onset of SPMS' above.)

●Disease activity and progression – The subtypes of MS are further modified by assessments of disease activity and disease progression. Disease activity is determined by clinical relapses or magnetic resonance imaging (MRI) evidence of contrast-enhancing lesions and/or new or unequivocally enlarging T2 lesions. Disease progression is a measure of disability, and it is independently quantified from relapses; it is characteristic of both primary progressive multiple sclerosis (PPMS) and SPMS. (See 'Disease activity and progression' above.)

●Who should be treated with DMT? – For most patients who reach the stage of SPMS and have active disease, as determined by ongoing clinical relapses and/or new MS lesions on MRI, we suggest starting or continuing MS disease-modifying therapy (DMT) (Grade 2C). (See 'Approach to choosing disease-modifying therapy' above.)

●Choosing DMT – Therapeutic options for patients with active SPMS, at least in the United States, include all DMTs approved for relapsing forms of MS. Despite evidence that siponimod was modestly effective for reducing disability progression at six months in patients with SPMS, there is not a strong rationale for its exclusive use in SPMS, particularly when other DMTs may suppress relapses or lesions just as well. (See 'Approach to choosing disease-modifying therapy' above.)

•Some of our expert contributors treat active SPMS with an approach similar to that for RRMS. For patients with a relatively low level of active disease, continuing the same DMT used during the relapsing-remitting phase of MS is often the best option.

•Other experts favor switching to siponimod for patients previously on a different DMT (eg, while being treated for RRMS).

●Suboptimal response to treatment – For patients with active SPMS who have a suboptimal response to DMT, as determined by evidence of ongoing disease activity with attacks (relapses) and/or the development of new MS lesions, switching to a different DMT is a reasonable option. However, the decision is based upon clinical experience and individual patient characteristics, as no randomized clinical trials have addressed this issue. (See 'Suboptimal response to DMT' above and 'Monitoring' above.)

●Inactive disease and stopping DMT – For patients with inactive disease (ie, no ongoing relapses or gadolinium-enhancing lesions on MRI of the brain and spinal cord) who have been nonambulatory for at least two years, it is reasonable to discuss stopping DMT. (See 'Inactive SPMS' above.)

●Symptom management – Multidisciplinary management for the common complications and symptoms of MS is critical. These complications include bladder and bowel dysfunction, cognitive impairment, depression, fatigue, gait impairment, heat intolerance, pain, sexual dysfunction, sleep disorders, spasticity, speech and swallowing dysfunction, tremor, vertigo, and visual disturbances, as reviewed separately. (See "Symptom management of multiple sclerosis in adults".)