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.
Treatment directed at the progressive phase of MS is typically more difficult than treatment of relapsing forms of MS. Immunosuppressive therapies such as total lymphoid radiation, cyclosporine, methotrexate, 2-chlorodeoxyadenosine, cyclophosphamide, mitoxantrone, azathioprine, interferon, steroids, and intravenous immune globulin have shown at least some positive clinical effects in progressive disease. However, all of these 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. Thus, since MS is an illness of decades, not months, immunosuppressive therapy is only a temporary solution at best.
This topic will discuss treatment of progressive forms of MS. The treatment of relapsing forms of MS is discussed separately. (See "Treatment of relapsing-remitting multiple sclerosis in adults".) Management of comorbid symptoms is likewise discussed separately. (See "Comorbid problems associated with multiple sclerosis in adults".)
Measures of disease progression and prognosis are discussed in more detail separately. (See "Epidemiology and clinical features of multiple sclerosis in adults" and "Diagnosis of multiple sclerosis in adults".)
PROGRESSIVE MS TYPES
Secondary progressive — Secondary progressive MS (SPMS) begins as relapsing-remitting disease (RRMS), but it later changes so that the course becomes characterized by a steady deterioration in function, unrelated to acute attacks. Typically, the attack rate is also reduced when the secondary progressive stage is reached. This type of MS, which ultimately develops in approximately 80 percent of RRMS patients, causes the greatest amount of neurologic disability.
Primary progressive — Primary progressive MS (PPMS) represents only about 10 percent of cases at onset and is characterized by a steady decline in function from onset with no acute attacks.
Progressive relapsing — Progressive/relapsing MS (PRMS) begins with a progressive course, with occasional attacks superimposed upon the steadily progressive course.
PHARMACOLOGIC TREATMENTS
Azathioprine — Azathioprine (titrated up to a dose of 2 mg/kg per day) has been studied in both relapsing-remitting and chronic progressing multiple sclerosis (MS) since 1971. A meta-analysis of the results of five double-blind and two single-blind, randomized, controlled trials of azathioprine use in MS showed only a small difference after two years in favor of azathioprine [1]. The study concluded that the side-effect profile outweighs any small clinical gain.
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 [2]. 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 one 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 [3]. 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 T1 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 T1 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 [3]. 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 CD-4 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 [3]. 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 [4]. 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 is discussed separately. (See "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Cladribine'.)
Dalfampridine — Dalfampridine (4-aminopyridine; fampridine), a potassium channel blocker, may improve walking speed in some patients with MS. This issue is discussed separately. (See "Comorbid problems associated with multiple sclerosis in adults", section on 'Dalfampridine'.)
Glucocorticoids — Monthly bolus IV glucocorticoids, typically 1000 mg of methylprednisolone, are used at many institutions for treatment of primary or secondary progressive MS alone or in combination with other immunomodulatory or immunosuppressive medications. In a trial of methylprednisolone in secondary progressive MS, 108 patients received intravenous methylprednisolone (either 500 mg or 10 mg) every eight weeks for two years [5]. 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 in spite of conflicting data. An early study compared an induction course of cyclophosphamide with steroid treatment and found impressive differences; in retrospect, however, the patients were all in a rapidly progressive phase of the illness [6]. 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 [7].
Cyclophosphamide appears to be most effective in patients younger than age 40 years, especially in those who have been in the progressive phase for less than one year. The drug is ineffective for primary progressive MS.
Dosing — 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 [8] and a trial in London [9] 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.
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 [10]. An unexpected low rate of disability progression among study participants may have contributed to the negative results of the study.
These data do not exclude the possibility that glatiramer acetate may be used in PPMS, since at the present time there is no approved treatment for PPMS.
Interferons — The efficacy of interferons has been well documented in patients with relapsing-remitting disease. (See "Treatment of relapsing-remitting multiple sclerosis in adults".)
However, a 2009 systematic review identified only two randomized controlled trials of interferon beta for the treatment of primary progressive MS [11]. One evaluated interferon beta-1a [12], and the other interferon beta-1b [13]. In the pooled analysis, with a total of 123 patients, interferon beta treatment did not reduce disability progression [11].
Evidence is conflicting for the effectiveness of interferons in patients with secondary progressive MS (SPMS). 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 [14]. In the pooled analysis of three trials with outcome data assessed at three years, interferon treatment did not significantly decrease the risk of sustained disability progression (relative risk [RR] 0.98, 95% CI 0.82-1.16). In contrast, 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).
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 [15]. 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 "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Side effects of interferons'.) Neutralizing antibodies were seen in 28 percent of patients. (See "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Neutralizing antibodies'.) - 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 [16].
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 [17]. Although the trials had similar (but not identical) entry criteria and study designs [18], 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 [17], 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) 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 [19]. 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 [20].
- 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 [21]. 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 [22].
Additional hope for immunomodulatory therapy in patients with secondary progressive MS was provided by an MRI study, which found that compared with placebo, 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 [23].
Conclusions — The 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. These data have major implications for the treatment of MS, since secondary progressive disease is the single largest category of MS. The problem is finding clinical features that reliably identify patients who are likely to be treatment responders because of acute inflammatory disease, versus those who are likely to be nonresponders because of progressive disease occurring independent of overt inflammation [17]. 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. Additional data may further clarify the appropriate use of these agents.
Methotrexate — Methotrexate is a well-known immunomodulator used extensively in 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 [24,25]. In that trial, 60 patients with chronic-progressive MS were randomized to receive either weekly low-dose oral methotrexate (7.5 mg) or placebo [24]. 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 were 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 [26].
Mitoxantrone — Mitoxantrone is an anthracycline analogue that is used as a chemotherapeutic agent for some cancers. Although a small randomized trial found that mitoxantrone is effective for patients with worsening relapsing-remitting or secondary progressive MS, the risk of cardiotoxicity and potential for the development of leukemia with mitoxantrone limit its utility.
The efficacy of mitoxantrone in MS is supported by the results of a single multicenter, observer-blind trial of 194 patients with worsening relapsing-remitting or secondary progressive MS [27]. Patients were randomly assigned to treatment with IV mitoxantrone (5 mg/m^2 or 12 mg/m^2) 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 MRI data collected from a nonrandomized subgroup of 110 patients [28]. 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 [29-31]. 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 are 12, 0.4, and 0.8 percent, respectively [32]. In patients with cancer who were treated with mitoxantrone, the rate of heart failure is estimated to be approximately 3 percent.
The usual dose of mitoxantrone is 12 mg/m^2 by intravenous administration every three months up to a maximum cumulative lifetime dose of 140 mg/m^2 [32]. 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.
Guidelines from the American Academy of Neurology recommend that, because of its toxicity and the somewhat limited evidence of benefit, mitoxantrone should be reserved for patients with rapidly advancing disease who have failed other therapies [33]. Patients older than age 50, 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 [34].
Natalizumab — The effectiveness of natalizumab in the treatment of secondary progressive MS is unknown [35], and the drug has not been studied in patients with primary progressive MS. The utility of natalizumab treatment for relapsing forms of MS is discussed separately. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults".)
Rituximab — In the randomized placebo-controlled OLYMPUS trial of 439 adults with PPMS, rituximab was not beneficial for prolonging time to confirmed disease progression, the primary outcome measure [36]. 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.
OTHER IMMUNE MODULATING TREATMENTS
Stem cell transplantation — Hematopoietic stem cell transplantation (HSCT) has shown promise in patients with progressive forms of MS [37-40] and in those with refractory relapsing-remitting MS [40,41]. In addition, mesenchymal stem cell therapy for MS is being explored [42,43].
One of the larger HSCT studies involved 85 patients, almost all with progressive MS [44]. Improvement on the Expanded Disability Status Scale (EDSS) by one point or greater occurred in 18 patients (21 percent), and all 22 patients with MRI evidence of active central nervous system inflammation had complete radiologic resolution after HSCT. However, HSCT was associated with significant toxicity including neurologic deterioration during transplantation in 22 patients (associated with MS progression in six patients), and death in seven patients (8 percent).
In a study assessing safety, 26 patients with severe MS were treated with autologous HSCT; one patient had a flare of MS during treatment with granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization, one patient had a syndrome of fevers and progressive neurologic deterioration and died two years after high-dose immunosuppressive therapy, and there was a relatively high rate of bladder complications and engraftment syndrome (a noninfectious syndrome of fever, rash, and fatigue) [45].
A second uncontrolled study of HSCT in 21 patients with rapidly progressive MS also found a high rate of engraftment syndrome [46]. Patients with high pre-transplantation disability scores did not appear to benefit from HSCT; the study was unable to assess whether there was benefit in the subgroup of patients with lower baseline disability scores.
Transplant-related mortality is as high as 8 percent [37,38], but appears to be lower since 2000 [39]. As noted above, early neurologic deterioration due to fever, infection, or use of G-CSF is common.
Larger controlled trials are awaited to evaluate the risk/benefit ratio of this approach. One ongoing trial (ASTIMS) will compare autologous HSCT with monthly pulses of mitoxantrone followed by methylprednisolone in patients with MS who have increasing EDSS and and/or progressive MRI lesions in spite of immunomodulating therapy [39,47].
IVIG infusions — Few clinical trials have studied intravenous immune globulin (IVIG) in progressive forms of MS, and these have shown little or no benefit [48].
- 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 [49].
- A larger trial randomly assigned 318 patients with clinically definite secondary progressive MS to monthly IVIG or placebo for 27 months [50]. 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.
Based primarily on the latter study, treatment with IVIG for progressive MS cannot be recommended. IVIG has shown benefit for RRMS in clinical trials. (See "Treatment of relapsing-remitting multiple sclerosis in adults".)
Plasma exchange — Several trials have shown no benefit of plasma exchange for progressive forms of MS [7,51,52]. Therefore, guidelines from the American Academy of Neurology state that plasmapheresis should not be offered for chronic progressive or secondary progressive MS [53]. However, plasma exchange may have some benefit for patients with acute central nervous system inflammatory demyelinating disease who do not respond to steroid therapy. This is discussed separately. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Plasma exchange'.)
Total lymphoid irradiation — Total lymphoid irradiation (TLI) has potent immunosuppressive effects and has been found beneficial in patients with progressive MS [54]. The absolute lymphocyte count appears to be an indicator of therapeutic efficacy, with greater efficacy in patients with lower counts. Many patients developed recurrent disease progression after initial therapy, and a major limitation is that use of TLI may preclude the use of other treatments that affect the immune system at a later time if the patient reenters the progressive phase.
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RECOMMENDATIONS — Evidence supporting the efficacy of various treatments for multiple sclerosis (MS) is derived mainly from prospective clinical trials. However, clinical trials have generally found only limited or no effectiveness for the available treatments of patients with secondary and primary progressive MS. In addition, most trials did not last longer than two or three years and give only hints about long-term results of treatment. Furthermore, patients may differ markedly from those who have been treated in clinical trials.
Despite these obstacles, therapeutic decisions must be made. Treatment should be individualized on the basis of disease progression as well as patient and physician preference. The following treatment paradigm incorporates recommendations from the American Academy of Neurology (AAN) guidelines on disease modifying therapy for MS published in 2002 [55]. Updated and supplemental information for AAN guidelines may be found online (www.aan.com/go/practice/guidelines).
Treatment recommendations differ between primary progressive MS (PPMS) and secondary progressive MS (SPMS).
Secondary progressive — Clinical trials have found modest benefit for some treatments for patients with SPMS.
- Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone) — The AAN guidelines conclude that glucocorticoid treatment has a short-term benefit on the speed of functional recovery in patients with acute attacks of MS [55]. However, there does not appear to be any long-term improvement 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 RRMS. In my view, the same may be true for patients with SPMS who experience acute attacks. (See 'Glucocorticoids' above.)
- Intravenous cyclophosphamide and glucocorticoid monthly pulses — According to the AAN guidelines, it is possible that younger patients with progressive MS may derive some benefit from pulse plus booster cyclophosphamide treatment. However, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (PPMS and SPMS). (See 'Cyclophosphamide' above.)
- Methotrexate oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses — The AAN guidelines conclude that, based on limited and somewhat ambiguous evidence from a single trial [24], it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS [55]. (See 'Methotrexate' above.)
- Consider addition of an interferon, if not currently prescribed — The AAN guidelines state that it is appropriate to consider interferon treatment for patients with SPMS who are still experiencing relapses [55]. The effectiveness of interferons in patients with SPMS but without relapses is uncertain. As noted above (see 'Interferons' above), pronounced disease progression may be another clinical feature that identifies patients with SPMS who are likely to be interferon responders.
Primary progressive — All suggested treatments for PPMS are empiric, as no convincing clinical trial evidence of effectiveness has been found for disease modifying therapy.
- Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone). (See 'Glucocorticoids' above.)
- Methotrexate, oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses — The AAN guidelines conclude that, based on limited and somewhat ambiguous evidence from a single trial [24], it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS [55]. (See 'Methotrexate' above.)
- Cladribine intravenous or subcutaneous — The AAN guidelines conclude that cladribine reduces gadolinium enhancement on brain MRI scans in patients with both relapsing and progressive forms of MS [55]. 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' above.)
- Consider mitoxantrone — According to the AAN guidelines, it is possible that mitoxantrone has a beneficial effect on disease progression in MS [55]. (See 'Mitoxantrone' above.)
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