Treatment of progressive multiple sclerosis in adults
Author:
Michael J Olek, DO
Section Editor:
Francisco González-Scarano, MD
Deputy Editor:
John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Mar 23, 2018.

INTRODUCTION — Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) that is a leading cause of disability in young adults. 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.

This topic will discuss treatment of progressive forms of MS. The treatment of relapsing forms of MS is discussed separately. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults".)

Other aspects of MS are reviewed elsewhere:

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

(See "Clinical course and classification of multiple sclerosis".)

(See "Clinical features of multiple sclerosis in adults".)

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

(See "Diagnosis of multiple sclerosis in adults".)

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

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 result in severe residual disability.  

SPMS begins as relapsing-remitting disease, hence the designation of "secondary," but over time the disease enters a stage of steady deterioration in function, unrelated to acute attacks. Typically, when the secondary progressive stage is reached, the relapse rate is also reduced. This type of MS, which ultimately develops in approximately 90 percent of patients with RRMS after 25 years, causes the greatest amount of neurologic disability. 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.

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

These phenotypes are further modified by assessments of disease activity and disease progression. Disease activity is determined by clinical relapses or 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 PPMS and SPMS. Thus, the phenotype of progressive disease (PPMS and SPMS) can be characterized as one of the following [1]:

Active and with progression

Active but without progression

Not active but with progression

Not active and without progression (stable disease)

MANAGEMENT APPROACH — Treatment directed at the progressive phase of MS is typically more difficult than treatment of relapsing forms of MS, where a number of effective disease-modifying therapies are available (see "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults"). In contrast, ocrelizumab is the only disease-modifying treatment option with high-quality evidence of efficacy for patients with primary progressive MS (PPMS) (see 'Ocrelizumab' below). Therapeutic options for patients with secondary progressive MS (SPMS) are even more limited, though there are promising results from randomized controlled trials of siponimod for SPMS. Other clinical trials have generally found only limited or no effectiveness for the treatment of patients with SPMS and PPMS.

Most of the treatment options for progressive types of MS involve various immunosuppressive therapies (see 'Immune-modulating treatments' below). However, the nonspecific immunosuppressants suffer from the same basic defect; they may temporarily halt a rapidly progressive downhill course, but it is difficult or dangerous to employ them for more than a few months to a year or two. Since MS is an illness of decades, not months, immunosuppressive therapy is only a temporary solution at best.

Despite these obstacles, therapeutic decisions must be made. In the absence of effective 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, fatigue, gait impairment, heat intolerance, pain, sexual dysfunction, sleep disorders, spasticity, speech and swallowing dysfunction, tremor, vertigo, and visual disturbances. (See "Symptom management of multiple sclerosis in adults".)

Immune-modulating treatment should be individualized on the basis of disease activity and progression as well as patient and physician preference. 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 immune-modulating therapies in comparison with patients lacking these characteristics [2]. Although consensus is lacking, some experts believe there is no role for immune-modulating therapy in the absence of active inflammation [2].

Treatment recommendations differ between PPMS and SPMS.

Secondary progressive — Although in general the results of clinical trials have been negative, some study findings and clinical experience suggest that the treatments listed below have a modest benefit for patients with SPMS. For patients with relapsing-remitting MS (RRMS) who reach the stage of SPMS, particularly those with evidence of active disease by clinical or MRI measures, immune-modulating treatment options include:

Continuing the same disease-modifying therapy (DMT) used during the relapsing-remitting phase of MS, or switching to a different DMT. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults".)

Starting or switching to an interferon as DMT – Interferon beta treatment is an option for patients with SPMS who are still experiencing relapses [3]. The effectiveness of interferons in patients with SPMS but without relapses is uncertain. As noted below (see 'Interferons' below), pronounced disease progression may be a clinical feature that identifies patients with SPMS who are likely to be interferon responders.

Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone) – 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 'Glucocorticoids'). However, there does not appear to be any long-term effect in the degree of functional recovery from an attack following the use of glucocorticoids. However, it is possible that regular pulse glucocorticoids may be useful in the long-term management of patients with SPMS, particularly those who in addition to between-relapse progression, also experience acute attacks. (See 'Glucocorticoids' below.)

Intravenous cyclophosphamide and glucocorticoid treatment – There is limited evidence that younger patients (age ≤40 years) with 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 (PPMS and SPMS). (See 'Cyclophosphamide' below.)

Methotrexate oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses – Based on limited and somewhat ambiguous evidence from a single trial [4], it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS [3]. (See 'Methotrexate' below.)

Primary progressive — For patients with PPMS, we suggest treatment with ocrelizumab, the only drug to receive regulatory approval for use in adult patients with PPMS. The approval was based on the results of the ORATORIO trial, which showed that ocrelizumab reduced the risk of disability progression among patients with PPMS. (See 'Ocrelizumab' below.)

All other suggested treatments for PPMS are empiric, as they lack convincing clinical trial evidence of effectiveness.

Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone). (See 'Glucocorticoids' below.)

Methotrexate, oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses – Based on limited and somewhat ambiguous evidence from a single trial [4], it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS [3]. (See 'Methotrexate' below.)

Cladribine intravenous or subcutaneous – Cladribine reduces gadolinium enhancement on brain MRI scans in patients with both relapsing and progressive forms of MS [3]. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack-rate or disease progression. (See 'Cladribine' below.)

Intravenous immune globulin (IVIG). (See 'IVIG infusions' below.)

Mitoxantrone – It is possible that mitoxantrone has a beneficial effect on disease progression in MS [3], but the drug is seldom used because of its toxicity and the somewhat limited evidence of benefit [2]. (See 'Mitoxantrone' below.)

IMMUNE-MODULATING TREATMENTS — With the exception of ocrelizumab and siponimod, randomized controlled trials of immune-modulating treatments have failed to find consistent benefit for patients with primary and secondary MS [5].

Ocrelizumab — Ocrelizumab, a recombinant human anti-CD20 monoclonal antibody designed to optimize B cell depletion, is the first drug to significantly reduce the risk of disability progression among patients with primary progressive MS (PPMS) [6], as shown by the double-blind, multicenter, placebo-controlled ORATORIO trial [7]. In this trial, 732 adult patients (mean age approximately 45 years) with PPMS were randomly assigned to treatment in a 2:1 ratio with intravenous ocrelizumab 600 mg (given as two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks. All patients were pretreated with one dose of intravenous methylprednisolone (100 mg) before each infusion. The following observations were reported [7]:

Compared with placebo, ocrelizumab modestly reduced both 12-week confirmed disability progression (33 percent versus 39 percent, hazard ratio [HR] 0.76; 95% CI 0.59-0.98, absolute risk reduction [ARR] 6 percent) and 24-week confirmed disability progression (30 versus 36 percent, HR 0.75, 95% CI 0.58-0.98, ARR 6 percent).

Ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk (mean decline in performance 39 percent, versus 55 percent with placebo) and led to significant improvements on other endpoints, including change in MRI T2 lesion volume and whole brain volume loss.

The most common adverse events with ocrelizumab treatment were infusion reactions. Neoplasms were more frequent with ocrelizumab compared with placebo (2.3 versus 0.8 percent).

Based upon these positive results, the U.S. Food and Drug Administration (FDA) approved ocrelizumab for the treatment of adult patients with PPMS in March 2017, making it the first approved drug for PPMS [8]. More data are needed to assess the long-term risks of serious adverse events such as infections and neoplasms.

The mean age of subjects in the ORATORIO trial was approximately 45 years, and gadolinium-enhancing lesions on baseline MRI, a radiographic marker of inflammation, were present in approximately 27 percent of the enrolled patients [7]. Thus, one criticism of the trial is that it was enriched with younger patients and more active, early-stage PPMS, who might optimally respond to the anti-inflammatory effects of ocrelizumab [6].

Dosing of ocrelizumab — The initial dose of ocrelizumab is a 300 mg intravenous (IV) infusion, followed two weeks later by a second 300 mg IV infusion [9]. Subsequently, ocrelizumab is given as 600 mg IV infusion every six months. The drug should be given under close medical supervision with access to medical support to manage possible severe infusion reactions. Premedication is recommended with both methylprednisolone 100 mg IV (or equivalent glucocorticoid) approximately 30 minutes prior to each ocrelizumab infusion and with an antihistamine (eg, diphenhydramine) approximately 30 to 60 minutes prior to each ocrelizumab infusion to reduce the frequency and severity of infusion reactions; an antipyretic (eg, acetaminophen) can be added as well. Infusions should be delayed if there is active infection until the infection resolves.

Ocrelizumab is contraindicated in patients with active hepatitis B virus infection [9]. Therefore, patients must be screened for hepatitis B virus before starting ocrelizumab (see "Hepatitis B virus: Screening and diagnosis"). In addition, patients should receive all necessary immunizations at least six weeks prior to starting ocrelizumab; live-attenuated and live vaccines are not recommended during ocrelizumab treatment or after discontinuation until B-cell repletion occurs.

There are no data regarding the risk of fetal harm associated with ocrelizumab treatment for pregnant women, but animal data suggest harm with observations of increased perinatal mortality and renal, bone marrow, and testicular toxicity [9].

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 [10]. 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.

Cladribine — Cladribine, a potent immunosuppressive agent useful in the treatment of hairy cell leukemia, was reported to be of benefit in a study of patients with chronic progressive MS [11]. In this one-year, double-blind trial, 48 matched pairs received four monthly courses of cladribine or placebo through a central venous catheter over a seven-day period. Seven out of 23 evaluable patients receiving placebo experienced a one point or more worsening in their Expanded Disability Status Scale (EDSS) score at one year, while only 1 of 24 patients receiving cladribine had worsened. Treated patients had improvement on disability scores, no increase in brain MRI lesions, and decreased cerebrospinal fluid (CSF) oligoclonal bands, while the placebo group experienced the opposite in all of these categories. Side effects included two cases of herpes zoster, a fatal case of hepatitis (not clearly related to the treatment), and persistently lowered CD4 counts.

In a subsequent multi-center trial, 159 patients with progressive MS (30 percent of whom had primary progressive and the remainder secondary progressive disease) were randomly assigned to one of two doses of subcutaneous cladribine (0.07 mg/kg per day for five consecutive days every four weeks for either two or six cycles [total dose 0.7 mg/kg and 2.1 mg/kg, respectively]) or to placebo [12]. There was no significant difference between the groups in terms of EDSS score during the course of the study. However, the results of MRI studies were significantly different between the treatment and placebo groups. At baseline, approximately 35 percent of patients in each group had enhanced lesions on MRI; this remained unchanged in the placebo group, while decreasing to 10 and 6 percent in the low- and high-dose treatment groups, respectively. The cladribine groups also had a 90 percent reduction in the mean number of enhanced lesions at month six that persisted over 24 months of follow-up, while the placebo group had a 33 and 50 percent reduction at the sixth month and final evaluation, respectively.

Cladribine was generally well tolerated in this trial [12]. The high-dose group reported more cases of upper respiratory infection, pharyngitis, back pain, arthralgia, and skin disorder compared with the low-dose and placebo groups; no serious infections occurred. Dose-related decreases in the mean lymphocyte count occurred with cladribine therapy. A disadvantage of the subcutaneous method of administration is that the total lymphocyte and CD4 counts, as measures of effectiveness, do not fall for a number of months and may remain low for months after discontinuing therapy.

One explanation for the difference in outcome between these two studies in terms of the EDSS score is that the patients in the second study had relatively high EDSS scores at baseline (median score 6.0); the size and duration of the study were not powered to detect results in patients with this severity of disease [12]. In addition, a significant proportion had primary progressive disease, and this subgroup did not respond as favorably on MRI as the secondary progressive group.

A third study of 159 patients with progressive MS (70 percent secondary progressive, 30 percent primary progressive) found that treatment with cladribine did not prevent brain atrophy compared with placebo [13]. Furthermore, the change in brain volume did not correlate with other MRI measures of disease (eg, number and volume of enhancing lesions).

The use of cladribine for relapsing-remitting MS (RRMS) is discussed separately. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Cladribine'.)

Glucocorticoids — Bolus intravenous (IV) glucocorticoids, typically 1000 mg of methylprednisolone, are used at many institutions for treatment of PPMS or secondary progressive MS (SPMS) alone or in combination with other immunomodulatory or immunosuppressive medications. In a trial of bimonthly intravenous 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 [14]. Each intravenous 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.

Cyclophosphamide — Cyclophosphamide has been used for the treatment of MS since the early 1980s, even with inconsistent data supporting its use. In a systematic review of four trials that evaluated a total of 152 participants with progressive MS, treatment with cyclophosphamide (either alone or in combination with glucocorticoids) not only failed to prevent clinical disability progression in comparison with either placebo or no treatment, but the mean change in disability favored the control group at 24 months [15]. An early study compared an induction course of cyclophosphamide with glucocorticoid treatment and found impressive differences; in retrospect, however, the patients were all in a rapidly progressive phase of the illness [16]. By comparison, a Canadian study several years later found no effect from an induction course of cyclophosphamide; these patients and controls were more representative of the chronic progressive patients treated in other trials [17].

Results from a trial comparing different regimens of cyclophosphamide for patients with progressive MS suggested a modest benefit for booster therapy (cyclophosphamide every two months for two years) compared with no booster therapy [18]. A subgroup analysis, though not prespecified, suggested that cyclophosphamide pulse plus booster therapy was effective only in patients age ≤40 years, especially in those who had been in the progressive phase for less than one year.

Dosing of cyclophosphamide — A number of cyclophosphamide regimens have been employed. One such regimen involves pulse cyclophosphamide outpatient treatment that is repeated every four weeks in the first year of treatment, every six weeks in the second year, and every eight weeks in the third year. The duration of treatment is limited by the risk of bladder cancer, which appears to rise with time and may depend upon the total accumulated drug dose. Cyclophosphamide is generally tapered by going to an every 10 to 12 week schedule for the fourth year and then discontinuing.

Pulse therapy is initiated by giving methylprednisolone 1 g IV followed by cyclophosphamide 800 mg/m2 IV (rounded to the nearest 100 mg) over 30 minutes on the same day. The following cyclophosphamide dose is titrated to the white blood cell (WBC) count nadir that occurs between 8 and 14 days after treatment. The dose is increased by 200 mg/m2 each month until the subsequent WBC nadir is between 1500 to 2000 mm3, or by 100 mg/m2 if the cyclophosphamide dose has reached 1400 mg/m2 and the target WBC nadir has not been achieved. The maximum cyclophosphamide dose is 1600 mg/m2. The dose is reduced by 100 to 200 mg/m2 if the WBC nadir falls below 1500 mm3.

The cyclophosphamide dose is also modified by a WBC count drawn just prior to the schedule treatment. The established cyclophosphamide dose is given if the pretreatment WBC count is above 4000 mm3, but it is reduced to 75 percent of the established dose if the pretreatment WBC count is between 3000 and 4000 mm3, and it is reduced to 50 percent if the pretreatment WBC count is 2000 to 3000 mm3. No maintenance dose is given if the pretreatment WBC count is below 2000 mm3; a repeat WBC count one week later can be used to determine if the patient is eligible for another treatment.

Adverse effects of cyclophosphamide include nausea, vomiting, infection, scalp alopecia, gonadal suppression, menstrual irregularities, premature menopause, and hemorrhagic cystitis. Nausea and vomiting can usually be managed with antiemetics. Infection should be treated promptly with appropriate antibiotics, and urinalysis should be done with each treatment. Cyclophosphamide is teratogenic and is considered a category D drug regarding pregnancy (table 1). It is excreted in breast milk, and its use is contraindicated during breast feeding.

Cyclosporine — A large multicenter trial of cyclosporine in the United States [19] and a trial in London [20] found that cyclosporine (at a mean dose of 7.2 mg/kg per day) has a beneficial, though modest, effect in ameliorating clinical disease progression. However, its clinical utility is limited because of a narrow benefit-to-risk ratio [3].

Fingolimod — In the multicenter, double-blind INFORMS trial, which enrolled 970 patients with PPMS, oral fingolimod compared with placebo failed to slow disease progression [21].

Fingolimod is effective for reducing the relapse rate in patients with RRMS, as discussed elsewhere. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Fingolimod'.)

Glatiramer acetate — A phase 3 multicenter randomized controlled trial of glatiramer acetate for PPMS enrolled 943 patients but was prematurely halted after the second preplanned interim analysis because there was no discernible treatment effect on the primary outcome [22]. An unexpected low rate of disability progression among study participants may have contributed to the negative results of the study.

Interferons — The trial data described below 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. These data have major implications for the treatment of MS, since secondary progressive disease is the single largest category of MS. Pronounced disability progression or continuing superimposed relapses may be useful features to identify interferon treatment responders among patients with SPMS, although no prospective clinical trials have confirmed this hypothesis.

The efficacy of interferons has been well documented in patients with RRMS. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults".)

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 [23]. 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).

A 2009 systematic review identified only two randomized controlled trials of interferon beta for the treatment of PPMS [24]. One evaluated interferon beta-1a [25], and the other interferon beta-1b [26]. In the pooled analysis, with a total of 123 patients, interferon beta treatment did not reduce disability progression [24].

Results of the individual trials are reviewed in the sections that follow.

Interferon beta-1b — Interferon beta-1b treatment for SPMS has been studied in at least two major randomized, controlled trials.

In a European study conducted at 32 centers, 718 patients with SPMS were randomly assigned to receive placebo or interferon beta-1b every other day subcutaneously for up to three years [27]. There was a 22 percent relative reduction in the proportion of patients with progression in the interferon beta-1b group compared with placebo. The time to becoming wheelchair-bound was also significantly delayed in the treatment group, equivalent to 12 months (p<0.01). The placebo group had a mean eight percent increase in MRI lesion volume compared with a 5 percent decrease in the interferon beta-1b group. The authors asserted that the positive effect of treatment was due to a true effect on progression and not merely to a reduction in relapses leading to an indirect reduction in disability. Whether this effect was due to suppression of an inflammatory process could not be answered directly.

Side effects were manageable; 45 patients taking interferon beta-1b stopped because of adverse effects compared with 15 taking placebo, but twice as many stopped because of inefficacy of treatment in the placebo group (see "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Side effects of interferons'). Neutralizing antibodies were seen in 28 percent of patients (see "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Neutralizing antibodies and response markers').

A North American study of interferon beta-1b in SPMS found no effect on time to confirmed progression to disability, although significant benefit was shown on all other outcomes, including a reduction in clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2-weighted MRI [28].

The reason for the disparity for the primary outcome measure (progression to disability) in the European and North American trials of interferon beta-1b in SPMS was most likely due to differences in the baseline progression and ongoing disease activity in the two study populations. These differences were noted in a retrospective pooled analysis of data from the two trials [29]. Although the trials had similar (but not identical) entry criteria and study designs [30], the European study included patients in an earlier phase of SPMS who were younger and had a slightly shorter duration of disease. In addition, the European study had patients with more active disease both before and during the trial period. This suggests that MS progression in the European study population was more closely related to the acute inflammatory component of the disease, the component thought to be most responsive to interferon treatment, leading to a significant impact of interferon therapy on disease progression in the European but not the North American population.

The retrospective pooled overall risk reduction with interferon beta-1b treatment for EDSS progression confirmed at six months was 20 percent [29], showing a modest effect across the two studies, although this effect was driven largely by the European study. For patients with at least one relapse or change in EDSS by >1 in the two years prior to study entry, the pooled risk reduction was 30 to 40 percent. This suggests that interferon beta-1b treatment reduced the risk of disease progression in patients with active clinical disease.

Interferon beta-1a — Interferon beta-1a treatment for SPMS has been studied in several randomized controlled trials.

The Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon beta-1a in MS (SPECTRIMS), which enrolled 618 patients, found similar results to the North American study of interferon beta-1b, with no significant effect on disability progression but significant benefit for relapse-related outcomes [31]. Subgroup analysis suggested that the maximal benefit occurred in women and in patients who were still experiencing relapses when treatment started. In the latter subgroup only, treatment with interferon beta-1a was associated with benefit for disease progression [32]. In an MRI substudy, treatment with interferon beta-1a for three years resulted in significant improvements in all MRI measures, particularly in patients with relapses in the two years before the study [33].

The International MS Secondary Progressive Avonex Controlled Trial (IMPACT) used the Multiple Sclerosis Functional Composite (MSFC) as the primary endpoint, rather than the Expanded Disability Status Scale (EDSS) favored by most other large MS clinical trials [34]. Treatment with interferon beta-1a was associated with modest benefit on the MSFC but not the EDSS; treatment benefit was seen for reduction in relapses as with the earlier trials.

A trial employing low-dose interferon beta-1a compared with placebo found no benefit for disease progression or relapses [35].

IVIG infusions — Few clinical trials have studied intravenous immune globulin (IVIG) in progressive forms of MS, and these have shown little or no benefit [5].

A double-blind, placebo-controlled study of 67 patients with an apparently irreversible motor deficit found that IVIG (0.4 g/kg for five days, then single infusions every two weeks for three months) did not reverse established weakness in MS [36].

A larger trial randomly assigned 318 patients with clinically definite SPMS to monthly IVIG or placebo for 27 months [37]. There was no difference between the IVIG and placebo groups on any of the clinical outcome measures or in change in T2 lesion load on MRI scan over time.

In a placebo-controlled randomized trial of patients with PPMS (n = 34) and SPMS (n = 197), treatment with IVIG delayed the mean time to sustained disability progression (74 weeks, versus 62 weeks in the placebo group), and the difference was significant [38].

Studies of IVIG for RRMS are discussed elsewhere. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Intravenous immune globulin'.)

Methotrexate — Methotrexate is a well-known immunomodulator used for other conditions such as rheumatoid arthritis. The only high-quality randomized controlled trial evaluating oral methotrexate for progressive MS found a statistically nonsignificant trend toward improvement in symptoms and radiographic findings [4,39]. In that trial, 60 patients with chronic progressive MS were randomized to receive either weekly low-dose oral methotrexate (7.5 mg) or placebo [4]. 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 [40].

Mitoxantrone — Mitoxantrone is an anthracycline analogue that is used as a chemotherapeutic agent for some cancers. A few small randomized trials found that mitoxantrone is effective for patients with worsening RRMS or SPMS [41-44]. However, the risks of cardiotoxicity and potential for the development of leukemia with mitoxantrone limit its utility.

The largest trial of mitoxantrone in MS was a single multicenter, double-blind trial of 194 patients with worsening RRMS or SPMS [41]. Patients were randomly assigned to treatment with intravenous mitoxantrone (5 mg/m2 or 12 mg/m2) or placebo every three months for two years. Treatment with mitoxantrone was associated with significant clinical benefits compared with placebo on multivariate analysis, reducing progression of disability and clinical exacerbations.

A subsequent report from the same trial analyzed brain MRI data collected from a nonrandomized subgroup of 110 patients [45]. In contrast to the clinical benefits, mitoxantrone treatment did not significantly reduce the primary MRI outcome measure, the number of scans with positive gadolinium enhancement at 12 and 24 months, compared with placebo.

The risk of cardiotoxicity with mitoxantrone prevents prolonged usage. Mitoxantrone therapy also is associated with a risk of developing therapy-related acute leukemia [46-50]. In patients with MS treated with mitoxantrone, a systematic review published in 2010 estimated that the risks of developing systolic dysfunction, heart failure, and acute leukemia were 12, 0.4, and 0.8 percent, respectively [49]. In patients with cancer who were treated with mitoxantrone, the rate of heart failure was estimated to be approximately 3 percent.

The usual dose of mitoxantrone is 12 mg/m2 by intravenous administration every three months up to a maximum cumulative lifetime dose of 140 mg/m2 [49]. The left ventricular ejection fraction (LVEF) should be evaluated before initiating mitoxantrone and prior to each subsequent dose. Mitoxantrone should be discontinued if there is a clinically significant reduction in the LVEF or if the LVEF is <50 percent. In addition, annual cardiac testing should continue after completion of mitoxantrone therapy because of concern for delayed cardiotoxicity.

Because of its toxicity and the somewhat limited evidence of benefit, mitoxantrone is reserved for patients with rapidly advancing disease who have failed other therapies [51]. Patients older than age 50 years, those with long-standing disability, and those with substantial spinal cord atrophy may be less likely to respond to intense immunosuppression with agents such as mitoxantrone than patients without these characteristics [52].

Natalizumab — The effectiveness of natalizumab for progressive forms of MS is unproven [53], and preliminary data from one placebo-controlled trial suggest that natalizumab did not slow disability progression in patients with SPMS [54].

The utility of natalizumab treatment for relapsing forms of MS is discussed separately. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults".)

Plasma exchange — Several trials have shown no benefit of plasma exchange for progressive forms of MS [17,55-57].

Rituximab — In the randomized placebo-controlled OLYMPUS trial of 439 adults with primary progressive MS, rituximab was not beneficial for prolonging time to confirmed disease progression, the primary outcome measure [58]. The rituximab group had a significantly lower increase in T2 lesion volume on brain MRI than those assigned to placebo, but brain volume loss was similar.

Siponimod — Siponimod, an investigational agent, is a sphingosine 1-phosphate receptor modulator that is similar to but more selective than fingolimod. In the double-blind, randomized EXPAND trial of 1651 subjects with SPMS, oral siponimod compared with placebo reduced the risk of confirmed disability progression at three and six months, and reduced disability progression in a predefined subgroup of patients who did not have relapses [59]. In addition, siponimod treatment reduced 12- and 24-month annualized relapse rates and reduced the volume of brain lesions identified by T2-weighted MRI. Siponimod was generally well-tolerated but infections were more common in subjects who received the drug.

Stem cell transplantation — Hematopoietic stem cell transplantation (HSCT) has shown promise in patients with progressive forms of MS [60-63] and in those with refractory RRMS [61,62,64]. In addition, mesenchymal stem cell therapy for MS is being explored [65-67].

In a 2011 systematic review of autologous HSCT in patients with progressive MS refractory to conventional medical treatment, the following observations were reported [68]:

In eight case series with 161 patients (most with SPMS), progression-free survival at median follow-up times of 24 to 42 months ranged from 33 to 95 percent. There was substantial heterogeneity among these studies, which appeared to be due mainly to the intensity of the immunoablative conditioning regimen employed prior to HSCT.

In a meta-analysis, the estimated rate of progression-free survival for 102 patients receiving intermediate-intensity conditioning regimens (five studies with a median followup of 39 months) was 79 percent (95% CI 70-87 percent).

In contrast, the estimated rate of progression-free survival for 61 patients receiving high-intensity regimens (three studies with a median followup of 24 months) was 45 percent (95% CI 27-65 percent).

Among 15 studies that reported adverse events, the most frequent complications occurring within six months of autologous HSCT were fever, engraftment syndrome, enteritis, and transient neurologic deterioration.

Among 13 case series with post-treatment follow-up, seven patients died from treatment-related causes, mainly infection, and six patients died from nontreatment-related causes, mainly disease progression. Overall mortality was approximately 3 percent.

Transplant-related mortality was as high as 8 percent in older studies [69,70], but appears to be lower since the year 2000 [60,68].

Larger controlled trials are awaited to evaluate the risk/benefit ratio of autologous HSCT for the treatment of MS.

OTHER TREATMENTS — Limited data suggest that high-dose biotin and simvastatin are beneficial for select patients with progressive forms of MS, but more data are needed to confirm these findings.

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 [71]. A small, open label study found that high-dose biotin treatment of patients with progressive forms of MS was associated with a reduced disability and disease progression [72]. A subsequent double-blind trial enrolled 154 subjects with primary progressive MS (PPMS) or secondary progressive MS (SPMS), excluding those with clinical or radiologic evidence of inflammatory activity within the previous year, and assigned them in a 2:1 ratio to high-dose biotin (100 mg three times daily) or placebo [73]. The proportion of patients with disability reversal at 9 months, confirmed at 12 months, was significantly higher for the high-dose biotin group compared with the placebo group (13 versus 0 percent). The degree of disability reversal was modest. New MS lesions on brain MRI were more frequent in the biotin group (23 percent, versus 13 percent for placebo) but the difference was not statistically significant.

While these reports are promising, additional trials are needed to confirm the safety and efficacy of high-dose biotin.

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 [74]. 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.

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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 MS (SPMS) begins as relapsing-remitting disease but over time enters a stage of steady deterioration in function, unrelated to acute attacks. Primary progressive MS (PPMS) represents only about 10 percent of MS cases and is characterized by disease progression from onset. These phenotypes are further modified by assessments of disease activity and disease progression (see 'Pattern and course of MS' above):

Active and with progression

Active but without progression

Not active but with progression

Not active and without progression (stable disease)

With few effective treatment options for the SPMS and PPMS, multidisciplinary management for the common complications and symptoms of MS is critical. (See 'Management approach' above.)

For patients with relapsing-remitting MS (RRMS) who reach the stage of SPMS, particularly those with evidence of active disease by clinical or MRI measures, immune-modulating treatment options include (see 'Secondary progressive' above):

Continuing the disease-modifying therapy (DMT) used during the relapsing-remitting phase of MS, or switching to an alternate DMT

Starting or switching DMT to interferon beta treatment

Intravenous glucocorticoid pulses

Intravenous cyclophosphamide and glucocorticoid pulse plus booster therapy

Oral or subcutaneous methotrexate

For patients with PPMS, we suggest treatment with ocrelizumab (Grade 2B). (See 'Ocrelizumab' above.)

For patients with PPMS who cannot take or tolerate ocrelizumab, and for those who are unresponsive to ocrelizumab, other interventions are unproven. However, particularly for patients with evidence of active disease by clinical or MRI measures, immune-modulating treatment options for PPMS include (see 'Primary progressive' above):

Intravenous glucocorticoid pulses

Oral or subcutaneous methotrexate

Intravenous or subcutaneous cladribine

Intravenous immune globulin infusions

Intravenous mitoxantrone

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REFERENCES

  1. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83:278.
  2. Willis MA, Fox RJ. Progressive Multiple Sclerosis. Continuum (Minneap Minn) 2016; 22:785.
  3. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 2002; 58:169.
  4. Goodkin DE, Rudick RA, VanderBrug Medendorp S, et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 1995; 37:30.
  5. Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev 2013; :CD008933.
  6. Calabresi PA. B-Cell Depletion - A Frontier in Monoclonal Antibodies for Multiple Sclerosis. N Engl J Med 2017; 376:280.
  7. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376:209.
  8. FDA approves new drug to treat multiple sclerosis. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm549325.htm (Accessed on March 30, 2017).
  9. Ocrevus - Highlights of prescribing information. https://www.gene.com/download/pdf/ocrevus_prescribing.pdf (Accessed on March 30, 2017).
  10. Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database Syst Rev 2007; :CD003982.
  11. Sipe JC, Romine JS, Koziol JA, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994; 344:9.
  12. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000; 54:1145.
  13. Filippi M, Rovaris M, Iannucci G, et al. Whole brain volume changes in patients with progressive MS treated with cladribine. Neurology 2000; 55:1714.
  14. Goodkin DE, Kinkel RP, Weinstock-Guttman B, et al. A phase II study of i.v. methylprednisolone in secondary-progressive multiple sclerosis. Neurology 1998; 51:239.
  15. La Mantia L, Milanese C, Mascoli N, et al. Cyclophosphamide for multiple sclerosis. Cochrane Database Syst Rev 2007; :CD002819.
  16. Hauser SL, Dawson DM, Lehrich JR, et al. Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH. N Engl J Med 1983; 308:173.
  17. The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group. Lancet 1991; 337:441.
  18. Weiner HL, Mackin GA, Orav EJ, et al. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northeast Cooperative Multiple Sclerosis Treatment Group. Neurology 1993; 43:910.
  19. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. The Multiple Sclerosis Study Group. Ann Neurol 1990; 27:591.
  20. Rudge P, Koetsier JC, Mertin J, et al. Randomised double blind controlled trial of cyclosporin in multiple sclerosis. J Neurol Neurosurg Psychiatry 1989; 52:559.
  21. Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387:1075.
  22. Wolinsky JS, Narayana PA, O'Connor P, et al. Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol 2007; 61:14.
  23. La Mantia L, Vacchi L, Di Pietrantonj C, et al. Interferon beta for secondary progressive multiple sclerosis. Cochrane Database Syst Rev 2012; 1:CD005181.
  24. Rojas JI, Romano M, Ciapponi A, et al. Interferon beta for primary progressive multiple sclerosis. Cochrane Database Syst Rev 2009; :CD006643.
  25. Leary SM, Miller DH, Stevenson VL, et al. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003; 60:44.
  26. Montalban X. Overview of European pilot study of interferon beta-Ib in primary progressive multiple sclerosis. Mult Scler 2004; 10 Suppl 1:S62; discussion 62.
  27. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet 1998; 352:1491.
  28. Panitch H, Miller A, Paty D, et al. Interferon beta-1b in secondary progressive MS: results from a 3-year controlled study. Neurology 2004; 63:1788.
  29. Kappos L, Weinshenker B, Pozzilli C, et al. Interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004; 63:1779.
  30. Cohen JA, Antel JP. Does interferon beta help in secondary progressive MS? Neurology 2004; 63:1768.
  31. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group. Randomized controlled trial of interferon- beta-1a in secondary progressive MS: Clinical results. Neurology 2001; 56:1496.
  32. Hughes RA. Interferon beta 1a for secondary progressive multiple sclerosis. J Neurol Sci 2003; 206:199.
  33. Li DK, Zhao GJ, Paty DW, University of British Columbia MS/MRI Analysis Research Group. The SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 2001; 56:1505.
  34. Cohen JA, Cutter GR, Fischer JS, et al. Benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002; 59:679.
  35. Andersen O, Elovaara I, Färkkilä M, et al. Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2004; 75:706.
  36. Noseworthy JH, O'Brien PC, Weinshenker BG, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000; 55:1135.
  37. Hommes OR, Sørensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet 2004; 364:1149.
  38. Pöhlau D, Przuntek H, Sailer M, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Mult Scler 2007; 13:1107.
  39. Gray OM, McDonnell GV, Forbes RB. A systematic review of oral methotrexate for multiple sclerosis. Mult Scler 2006; 12:507.
  40. Olek MJ, Hohol MJ, Weiner HL. Methotrexate in the treatment of multiple sclerosis. Ann Neurol 1996; 39:684.
  41. Hartung HP, Gonsette R, König N, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002; 360:2018.
  42. Edan G, Miller D, Clanet M, et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997; 62:112.
  43. Millefiorini E, Gasperini C, Pozzilli C, et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol 1997; 244:153.
  44. Martinelli Boneschi F, Vacchi L, Rovaris M, et al. Mitoxantrone for multiple sclerosis. Cochrane Database Syst Rev 2013; :CD002127.
  45. Krapf H, Morrissey SP, Zenker O, et al. Effect of mitoxantrone on MRI in progressive MS: results of the MIMS trial. Neurology 2005; 65:690.
  46. Ramkumar B, Chadha MK, Barcos M, et al. Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis. Cancer Genet Cytogenet 2008; 182:126.
  47. Bosca I, Pascual AM, Casanova B, et al. Four new cases of therapy-related acute promyelocytic leukemia after mitoxantrone. Neurology 2008; 71:457.
  48. Martinelli V, Cocco E, Capra R, et al. Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone. Neurology 2011; 77:1887.
  49. Marriott JJ, Miyasaki JM, Gronseth G, et al. Evidence Report: The efficacy and safety of mitoxantrone (Novantrone) in the treatment of multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010; 74:1463.
  50. Chan A, Lo-Coco F. Mitoxantrone-related acute leukemia in MS: an open or closed book? Neurology 2013; 80:1529.
  51. Goodin DS, Arnason BG, Coyle PK, et al. The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2003; 61:1332.
  52. Boster A, Edan G, Frohman E, et al. Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol 2008; 7:173.
  53. Goodin DS, Cohen BA, O'Connor P, et al. Assessment: the use of natalizumab (Tysabri) for the treatment of multiple sclerosis (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008; 71:766.
  54. Biogen reports top-line results from phase 3 study evaluating natalizumab in secondary progressive MS. http://media.biogen.com/press-release/corporate/biogen-reports-top-line-results-phase-3-study-evaluating-natalizumab-seconda (Accessed on March 21, 2016).
  55. Gordon PA, Carroll DJ, Etches WS, et al. A double-blind controlled pilot study of plasma exchange versus sham apheresis in chronic progressive multiple sclerosis. Can J Neurol Sci 1985; 12:39.
  56. Khatri BO, McQuillen MP, Harrington GJ, et al. Chronic progressive multiple sclerosis: double-blind controlled study of plasmapheresis in patients taking immunosuppressive drugs. Neurology 1985; 35:312.
  57. Cortese I, Chaudhry V, So YT, et al. Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2011; 76:294.
  58. Hawker K, O'Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009; 66:460.
  59. Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018.
  60. Mancardi G, Saccardi R. Autologous haematopoietic stem-cell transplantation in multiple sclerosis. Lancet Neurol 2008; 7:626.
  61. Fassas A, Kimiskidis VK, Sakellari I, et al. Long-term results of stem cell transplantation for MS: a single-center experience. Neurology 2011; 76:1066.
  62. Mancardi GL, Sormani MP, Di Gioia M, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler 2012; 18:835.
  63. Sullivan KM, Muraro P, Tyndall A. Hematopoietic cell transplantation for autoimmune disease: updates from Europe and the United States. Biol Blood Marrow Transplant 2010; 16:S48.
  64. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol 2009; 8:244.
  65. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol 2011; 10:649.
  66. Connick P, Kolappan M, Crawley C, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 2012; 11:150.
  67. Rice CM, Kemp K, Wilkins A, Scolding NJ. Cell therapy for multiple sclerosis: an evolving concept with implications for other neurodegenerative diseases. Lancet 2013; 382:1204.
  68. Reston JT, Uhl S, Treadwell JR, et al. Autologous hematopoietic cell transplantation for multiple sclerosis: a systematic review. Mult Scler 2011; 17:204.
  69. Popat U, Krance R. Haematopoietic stem cell transplantation for autoimmune disorders: the American perspective. Br J Haematol 2004; 126:637.
  70. Hough RE, Snowden JA, Wulffraat NM. Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective. Br J Haematol 2005; 128:432.
  71. Sedel F, Bernard D, Mock DM, Tourbah A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology 2016; 110:644.
  72. Sedel F, Papeix C, Bellanger A, et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat Disord 2015; 4:159.
  73. Tourbah A, Lebrun-Frenay C, Edan G, et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult Scler 2016; 22:1719.
  74. Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383:2213.
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