6 Megan H. Hyland1 and Jeffrey A. Cohen2 1 Neuroimmunology Unit, Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA 2 Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA Progressive forms of multiple sclerosis (MS) differ from relapsing–remitting MS (RRMS) in their clinical course, imaging characteristics, and response to disease-modifying therapy, making it important to have distinct treatment approaches. Secondary progressive MS (SPMS) is defined by an initial relapsing–remitting (RR) course followed by gradual worsening with or without superimposed relapses or minor remissions. Primary progressive MS (PPMS) is characterized by gradual disease progression from the outset without distinct relapses. Approximately 50% of RRMS patients transition to SPMS after 10 years, and nearly 90% convert to SPMS after 25 years. Factors that contribute to a more rapid onset to progressive disease from a RR course include male gender, older age of disease onset, early motor symptoms, and a shorter time to second relapse. However, these factors have relatively modest predictive ability, and the absence of such factors does not guarantee a good prognosis. A primary progressive (PP) course is the initial presentation of 10–15% of all MS patients. PPMS affects a relatively higher percentage of men and has an older age of onset compared to RRMS, with a median age of onset similar to that of the typical transition from RRMS to SPMS. Although the time from disease onset to progression is variable in SPMS, the time from the start of progression until attainment of distinct levels of disability is more uniform. Using the Disability Status Scale (DSS) to measure disability, a natural history cohort study demonstrated a median time from onset of progression to DSS score of 3 of 1.4 years; median times from onset of progression to DSS scores of 6 and 8 were 4.5 and 24.1 years, respectively. A comparable rate of disease progression is observed in PPMS, supporting the concept that the two forms of progression have similar underlying pathogenic mechanisms. Clinical manifestations of progressive MS typically include worsening motor symptoms and spasticity with significant contribution to gait impairment and largely irreversible disability. Magnetic resonance imaging (MRI) studies demonstrate an overall greater T2 white matter lesion burden in SPMS patients compared to RRMS, but the development of new white matter lesions and gadolinium (Gd)-enhancing lesions generally occurs with decreasing frequency over time. PPMS shares some of the MRI characteristics seen in SPMS (fewer new or Gd-enhancing lesions) but typically has fewer focal lesions and an overall smaller lesion burden than SPMS. These MRI findings along with the relative paucity of relapses support the suggestion that decreased or more isolated inflammatory changes occur during the progressive disease phase. The mechanisms for disease progression are still not fully understood. Wallerian degeneration and axonal injury resulting from chronic demyelination following relapses are one component of the proposed mechanism, but axonal loss has been seen in early disease, and white matter lesion burden and atrophy do not correlate strongly with disease progression. However, the concept of MS as a neurodegenerative disease with progression that may occur longitudinally is also becoming more widely recognized. MRI has become increasingly sensitive, and different techniques now allow measurement of gray matter demyelination and atrophy. Cortical lesions have been shown to increase at a greater rate in actively progressive disease, and gray matter atrophy also has a greater rate of increase during SPMS. The identification of different factors contributing to relapsing and progressive disease mechanisms aids in the understanding why medications effective in RRMS do not seem to work as well in progressive forms of MS. It also supports the notion that progressive forms with relapses or MRI lesion activity can be treated more like RRMS, while alternative strategies may be needed for progression without relapses. The data on efficacy of disease therapies in progressive forms of MS are limited. Some of this is the result of specific challenges to clinical trials in progressive disease. One challenge is to accurately categorize patients as they transition from RRMS to SPMS when they tend to have features of both forms of the disease. An additional challenge is the rather slow, insidious progression of disease, which often may be difficult to quantify. The Expanded Disability Status Scale (EDSS), a commonly used clinical trial metric, has several recognized limitations. These limitations may have less impact on trials in RRMS because additional informative metrics are available, such as relapse rate and MRI lesion activity. However, the far fewer relapses and MRI lesion changes seen in progressive MS require that trials depend much more heavily on the EDSS. Known EDSS issues include the inequality between score changes of the same magnitude at different points along the scale (i.e., an increase in 1 point from 1.0 to 2.0 has less clinical significance than an increase from 6.0 to 7.0) and insensitivity to detect important sources of disability (e.g., cognitive impairment, upper extremity dysfunction). Additionally, the optimal duration of time over which worsening of disability should be confirmed is unclear; a 3-month confirmation is often the standard but has been shown to revert on occasion and alter clinical trial results. A 6-month confirmation is more likely to detect sustained changes but results in fewer events. Finally, the slow progression of disability that may occur in progressive forms of MS and the relative insensitivity of the EDSS also are problematic because it may take several years to accrue detectable change in disability, and this may not be captured in the typical clinical trial duration of 2–3 years. This may be particularly difficult in PPMS in which relapses do not occur. However, one advantage with clinical trials in progressive MS is that they generally can be performed without an active comparator. Placebo-controlled trials do not raise the same ethical and practical concerns as in RRMS due to the lack of therapy with proven efficacy in progressive MS. The disease-modifying therapies used to treat RRMS tend to be more effective in treating the inflammatory aspect of the disease. Of the eight medications that have been approved for treatment of RRMS by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA), only one form of interferon (IFN)-beta is approved by the EMA for SPMS in patients who have demonstrated recent relapses. Mitoxantrone is the only medication specifically approved by the FDA for SPMS (or worsening RRMS), and its approval for SPMS varies from country to country within the region of the EMA. Glatiramer acetate is approved for RRMS. Natalizumab and fingolimod are approved for relapsing forms of MS by the FDA, allowing for use in SPMS with relapses, while approval is restricted to RRMS by the EMA. There are currently no medications approved for usage in PPMS. Clinical trial data are summarized later and in Table 6.1. Table 6.1 Summary of Disease-Modifying Therapy Clinical Trials EDSS, Expanded Disability Status Scale; Gd, gadolinium. Of the four randomized placebo-controlled clinical trials of IFN-beta in SPMS, three failed to show significant benefit on time to confirm EDSS worsening. The trials did show benefit on reduction of relapse rate, new T2 lesions, and Gd-enhancing lesions. This finding supports the concept that IFN-beta may be beneficial in early SPMS or in SPMS with relapses where relapses and MRI lesion activity would have greater impact. The one trial that showed a positive effect of IFN-beta-1b on EDSS progression (European Study Group) generally had a younger study population with shorter disease duration and more recent baseline relapses, again supporting the use of IFN-beta for relapsing forms of MS rather than purely progressive disease. The intramuscular (IM) form of IFN-beta-1a was investigated in 50 PPMS patients who received either placebo or one of two IFN-beta-1a doses (30 or 60 µg weekly). The study demonstrated greater side effects with the higher IFN-beta-1a dose but no benefit on the primary endpoint, sustained EDSS progression. IFN-beta-1b was compared with placebo in 49 PPMS patients but showed no treatment effect on sustained EDSS progression over 2 years. There was a treatment effect observed on MS Functional Composite, but the study population was too small to demonstrate clinically meaningful outcomes. Though not studied in SPMS, there was an investigation in a PPMS population of the effect of glatiramer acetate versus placebo on the time to a 3-month sustained disability progression using the EDSS. This large study enrolling 943 patients had the goal of 3-year follow-up but was terminated early due to projected lack of efficacy. In addition to IFN-beta, another medication that has been tested more extensively in SPMS is the chemotherapeutic agent mitoxantrone. A study of 194 patients with worsening RRMS or SPMS compared mitoxantrone (5 and 12 mg/m2 doses) to placebo administered once every 3 months for 24 months. Patients receiving 12 mg/m2 of mitoxantrone compared with placebo demonstrated statistically significant improvement in the primary outcome, a global analysis of five clinical measures that included EDSS change, number of relapses, time to first relapse, standardized neurological status change, and change in Ambulation Index. Similar to some of the IFN-beta trials, the patients involved in the study described previously were generally younger than typical SPMS patients with disease durations <10 years and average baseline EDSS <5.0. Rare but serious adverse events have been observed with mitoxantrone, most notably cardiotoxicity and acute myeloid leukemia (AML). Because of these concerns, mitoxantrone has a cumulative dose limit of 140 mg/m2, and its use has decreased recently. Another chemotherapeutic agent, cyclophosphamide, whose mechanism of action involves CD4+ T-cell depletion and a reduction in Th1 response, has been studied in several trials in progressive MS. Early individual and small group treatment success led to an initial randomized trial comparing adrenocorticotropic hormone (ACTH) alone with either ACTH combined with plasma exchange and oral cyclophosphamide or ACTH and intravenous (IV) cyclophosphamide in a total of 58 patients with progressive MS. The study was unblinded but showed improvement or stabilization in 80% of the IV cyclophosphamide group as compared with 20% of the ACTH group, and the effect was shown to last for an average of 18 months. These results prompted an additional single-blind trial, the Northeast Cooperative Treatment Group, which studied 261 progressive MS patients for possible prolonged disease stabilization with addition of booster treatments following initial induction. Different induction protocols were used without significant differences identified, but there was a relatively small but significant effect of booster dosing. It was also shown that younger patients, those with shorter duration of progression, and those with SPMS were more likely to benefit from booster therapy. Although there have also been negative single-blind studies of cyclophosphamide in progressive MS, there has been debate about whether the results negate the positive findings because the studies were conducted in older patient populations with different treatment administration protocols. In general, the recommended cyclophosphamide protocol treats patients with monthly pulses and allows for dose adjustment to attain a goal white blood cell (WBC) count nadir between 1500 and 2000/mm3. The common side effects seen with cyclophosphamide include alopecia, nausea, infertility, leukopenia, bladder toxicity, and malignancy (most commonly bladder). Aggressive hydration is recommended along with drug administration to prevent some of the urologic complications. There is a lifetime maximum dose of 80–100 g. Monitoring should include midmonthly WBC counts and yearly cystoscopy after 3 years of treatment. The immunosuppressant methotrexate inhibits dihydrofolate reductase and has also been studied as treatment of progressive MS. A study of 60 patients (30% PPMS, 70% SPMS) compared oral methotrexate 7.5 mg weekly to placebo over 36 months and showed a benefit of methotrexate on the primary endpoint, a composite outcome measure consisting of EDSS, Ambulation Index, 9-Hole Peg Test, and Box and Block Test. However, there was no difference between treatment and placebo groups for sustained EDSS progression. Overall, low-dose methotrexate is generally safe with the most common side effects including nausea, diarrhea, and infection. Complete blood counts and comprehensive metabolic profiles should be monitored at 1, 2, and 4 weeks and then every 1–3 months. Another medication studied in the treatment of progressive MS is IV methylprednisolone (MP), which was studied at high and low doses (500 and 10 mg/day) administered for three consecutive days in bimonthly pulses over 2 years in SPMS patients. The study of 108 patients showed no significant difference between the two treatment groups in the proportion of patients experiencing sustained disability progression as measured by a composite outcome. However, a planned secondary analysis demonstrated a significant increase in time to onset of disability in the high-dose IVMP group compared with the low-dose group. This suggests that there may be a role for the use of intermittent pulse-dose IVMP in SPMS patients, although the optimal dose and frequency are not well defined. The baseline patient and disease characteristics from the aforementioned study were not described in detail, so it is also difficult to know whether the IVMP treatment effect is more likely attributable to early SPMS patients and patients with more frequent baseline relapses. The potential utility of intermittent IVMP must be weighed against potential adverse effects. For example, effects of high-dose steroids on blood sugar levels may complicate use in patients with diabetes. The effects on bone density should be considered in patients with severe osteoporosis with high fall risks. Several other immunosuppressive medications have been evaluated in progressive MS patients in small groups with some anecdotal success. In addition to those studies, PPMS patients (n = 439) were evaluated in a double-blind, placebo-controlled trial of rituximab over 96 weeks. Confirmed disease progression measured by EDSS showed a trend toward being delayed in the treated group, but statistically significant delay was only seen in subgroup analyses of patients who were younger and had baseline inflammatory lesions. Many of the other medications typically used in RRMS have not been adequately studied in progressive MS. Both natalizumab and fingolimod are FDA approved for relapsing forms of MS, but their effect on progressive disease has not been fully investigated. A randomized placebo-controlled clinical trial is currently underway to examine the effect of natalizumab on disability progression in SPMS patients (as measured by the EDSS and timed 25-Foot Walk) over 2 years. A placebo-controlled trial of fingolimod is being conducted in PPMS patients. RRMS patients are generally monitored clinically through history and physical exam for assessment of relapses; radiological monitoring with periodic brain MRI is also relatively straightforward and high yield for identifying new T2 or Gd-enhancing lesions. As noted previously, these are not particularly effective means of monitoring progressive MS due to the infrequency of relapses and new MRI lesions. Accumulation of disability is the primary clinical measure of progressive MS, but the most accepted standard of grading disability, the EDSS, is not widely used in practice due to limited time constraints for patient follow-up visits. An increasingly used measure of progressive MS through imaging is quantification of brain atrophy, but this is not yet a widespread or easily reproducible measure across different sites. Therefore, the typical way to monitor patients tends to encompass clinical history (i.e., patient descriptions of new difficulties with ambulation or activities of daily living). Additionally, shorter standardized physical exam measures, such as components of the MS Functional Composite, may be used. A common measure is the timed 25-Foot Walk, which can be tracked over time to indicate persistent disease progression. Another important aspect of monitoring progressive MS patients is verification that disability progression is due to MS. For example, when RRMS patients first appear to be transitioning to progressive disease, MRI studies of the brain and/or cervical spine should be considered to rule out a structural abnormality, such as spondylotic myelopathy. Additionally, the same MS mimics that are investigated during the initial diagnosis of MS should be reconsidered as possible contributing factors to disease progression. Based on the clinical history, it may be reasonable to check TSH, vitamin B12, and other blood work to rule out other possible etiologies for clinical disease progression.
Progressive MS Treatment Algorithms
Background
Challenges to clinical trials in progressive MS
Clinical trials in progressive MS
Treatment
Secondary Progressive Multiple Sclerosis
Primary Progressive Multiple Sclerosis
IFN-beta
No effect on sustained EDSS progression
No effect on sustained EDSS progression
Statistically significant benefit on relapse rate, new T2 MRI lesions, Gd-enhancing lesions
Glatiramer acetate
Limited trial evidence
Trend toward decrease in sustained EDSS progression
Natalizumab
Ongoing placebo-controlled trial
No trial evidence
Fingolimod
Limited trial evidence
Ongoing placebo-controlled trial
Mitoxantrone
Improvement in composite outcome that included sustained EDSS progression and relapses
Limited trial evidence
MP
No effect on sustained disability measured by composite outcome. Secondary analysis showed high-dose benefit on time to sustained disability
Methotrexate
No significant improvement in sustained EDSS progression. Statistically significant improvement in composite outcome including EDSS, Ambulation Index, 9-Hole Peg Test
Cyclophosphamide
Variable evidence—overall showed disease stabilization in patients who were younger, had shorter disease duration, had secondary progressive disease
Interferon-beta
Glatiramer acetate
Mitoxantrone
Cyclophosphamide
Methotrexate
Methylprednisolone
Other disease-modifying therapies
Monitoring progressive MS in clinical practice
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