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Treatment of primary progressive multiple sclerosis in adults

Treatment of primary progressive multiple sclerosis in adults
Literature review current through: Sep 2023.
This topic last updated: Aug 22, 2022.

INTRODUCTION — This topic will discuss the treatment of primary progressive multiple sclerosis (PPMS). The treatment of secondary progressive multiple sclerosis (SPMS) and relapsing-remitting multiple sclerosis (RRMS) are discussed separately. (See "Treatment of secondary progressive multiple sclerosis in adults" and "Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults".)

Other aspects of multiple sclerosis are reviewed elsewhere:

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

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

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

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

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

PATTERN AND COURSE OF MS

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

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, with or without superimposed attacks. Secondary progressive disease is the single largest category of MS. Typically, when the secondary progressive stage is reached, the relapse rate is also reduced. This type of MS, which ultimately develops in as many as 90 percent of patients with RRMS after 25 years, causes the greatest amount of neurologic disability attributable to MS.

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

Determining the onset of PPMS — PPMS usually presents with insidious neurologic progression, most often as a gradually worsening myelopathy with gait difficulty [1].

The McDonald criteria require evidence of one year of disease progression (retrospectively or prospectively determined), independent of clinical relapse, plus two of the three following criteria [2]:

One or more hyperintense T2 lesions characteristic of MS in one or more of the periventricular, cortical or juxtacortical, or infratentorial areas on brain magnetic resonance imaging (MRI)

Two or more hyperintense T2 lesions in the spinal cord on MRI

Presence of cerebrospinal fluid-specific oligoclonal bands

The diagnosis of the different clinical subtypes of MS is reviewed in detail elsewhere. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'Diagnosis'.)

Disease activity and progression — The MS subtypes 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 [3]:

Active and with progression

Active but without progression

Not active but with progression

Not active and without progression (stable disease)

TREATMENT

Disease-modifying therapy (DMT) for PPMS — For patients with PPMS who are younger (age ≤55 years) and/or have active disease on MRI, we suggest treatment with ocrelizumab (see 'Ocrelizumab' below). For patients with PPMS who are older and without disease activity, symptomatic therapy may be most appropriate. We have offered ocrelizumab treatment to patients with PPMS who are older (eg, age >55 years) and have inactive disease, but patients with these characteristics may be less likely to benefit and more likely to experience adverse effects if treated with ocrelizumab. For each patient, we carefully evaluate the potential risks and benefits of DMT at the time treatment is to be started, noting the modest effect sizes established in clinical trials and the associated risks that may ensue over longer-term use.

Ocrelizumab — Ocrelizumab is a recombinant human anti-CD20 monoclonal antibody designed to optimize B cell depletion. The US 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 [4,5]. The indications were later expanded to include active SPMS.

Efficacy – The double-blind, multicenter, placebo-controlled ORATORIO trial randomly assigned 732 adult patients (patients above 55 excluded) with PPMS to treatment in a 2:1 ratio with intravenous (IV) ocrelizumab 600 mg (given as two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks [6]. All patients were pretreated with one dose of IV methylprednisolone (100 mg) before each infusion.

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 also 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. In an open-label extension trial that enrolled 86 percent of participants from the randomized trial, benefit for reduction of disease progression persisted for up to 6.5 years [7].

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 [6]. 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 [5].

Dosing and administration – The initial dose of ocrelizumab is a 300 mg IV infusion, followed two weeks later by a second 300 mg IV infusion [8]. 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 or 125 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.

Adverse effects – The most common adverse events with ocrelizumab treatment are infusion reactions, upper and lower respiratory tract infections, and skin infections [6,8]. In the ORATORIO trial, neoplasms were more frequent with ocrelizumab compared with placebo (2.3 versus 0.8 percent) [6]. Postmarketing reports have described rare cases of herpes simplex virus and varicella-zoster virus infections, hepatitis B reactivation, progressive multifocal leukoencephalopathy (PML), and immune-mediated colitis [8]. More data are needed to assess the long-term risks of serious adverse events such as infections and neoplasms. Age-appropriate routine cancer screening, particularly for breast cancer in women, is recommended. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Ocrelizumab'.)

Ocrelizumab is contraindicated in patients with active hepatitis B virus infection [8]. Therefore, patients must be screened for hepatitis B virus before starting ocrelizumab (see "Hepatitis B virus: Screening and diagnosis in adults"). We also screen at baseline for hepatitis C, tuberculosis, HIV, and obtain a complete blood count, lymphocyte subsets, levels of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin M (IgM), and a metabolic panel. In addition, patients should ideally receive all necessary immunizations at least six weeks prior to starting ocrelizumab; 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 [8].

Suboptimal response to ocrelizumab — It is not clear whether there is a time period after which lack of response to ocrelizumab, as determined by the rate of disability progression, should be considered an indication of treatment failure. However, patients and clinicians should carefully evaluate the ongoing utility and goals of ocrelizumab treatment at least annually (see 'Monitoring' below), given the high rate of serious infections observed after prolonged use of rituximab [9], which is a nearly identical therapy to ocrelizumab. Because of their older average age, people with PPMS may be especially prone to the risk of these infectious complications. Some clinicians advise reducing the frequency or the dose of ocrelizumab therapy over time, but there are no high-quality data to determine if this strategy has merit.

Other than ocrelizumab, trials of DMTs used for patients with RRMS have failed to show evidence of benefit in patients with PPMS:

Fingolimod – In the multicenter, double-blind INFORMS trial, which enrolled 970 patients with PPMS, oral fingolimod compared with placebo failed to slow disease progression [10].

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 [11]. An unexpected low rate of disability progression among study participants may have contributed to the negative results of the study.

Interferons – A 2009 systematic review identified only two randomized controlled trials of interferon beta for the treatment of PPMS [12]. One evaluated interferon beta-1a [13], and the other interferon beta-1b [14]. In the pooled analysis, with a total of 123 patients, interferon beta treatment did not reduce disability progression [12].

Rituximab – In the randomized placebo-controlled OLYMPUS trial of 439 adults with PPMS, rituximab was not beneficial for prolonging time to confirmed disease progression [15]. 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. Of note, the mechanisms of action of ocrelizumab and rituximab are very similar, though not identical.

Other treatments for PPMS — All other treatments that have been used for PPMS are empiric, as they lack convincing clinical trial evidence of effectiveness; most MS experts do not use these medications for PPMS on a routine basis.

Glucocorticoids – Bolus intravenous glucocorticoids, typically 1000 mg of methylprednisolone, have been used for treatment of PPMS or SPMS alone or in combination with other immunomodulatory or immunosuppressive medications.

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

Methotrexate – Oral or subcutaneous methotrexate, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses, has been used to treat patients with progressive forms of MS, based on limited and ambiguous evidence from a single trial [16]. The only high-quality randomized controlled trial evaluating oral methotrexate for progressive MS found only a trend toward improvement in symptoms and radiographic findings [16,17]. In that trial, 60 patients with chronic progressive MS were randomized to receive either weekly low-dose oral methotrexate (7.5 mg) or placebo [16]. 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 [18].

Intravenous immune globulin (IVIG) – Few randomized trials have studied IVIG in progressive forms of MS, and these have shown little or no benefit [19]. In one 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); while the difference was statistically significant, it was not necessarily clinically meaningful [20].

Mitoxantrone – It is possible that mitoxantrone has a beneficial effect on disease progression in MS [21], but the drug is seldom used because of its toxicity and the somewhat limited evidence of benefit [1].

MONITORING — Most patients with PPMS should be followed at least annually with clinical and imaging assessments, although the follow-up period should be based upon individual patient circumstances [3]. Clinical follow-up, including the response to DMT, should focus on possible manifestations of MS disease activity and progression of disability [22,23].

Evaluation for activity – Manifestations of MS disease activity including attacks (relapses) and/or the development of new MS lesions on brain MRI, including gadolinium-enhancing lesions or new or enlarging T2 lesions [3,22]. Along with brain MRI, spinal cord MRI should be obtained periodically, particularly if there are clinical findings attributable to the spinal cord. Attacks (relapses) are defined by acute or subacute onset of new or worsening neurologic dysfunction that is followed by recovery, either partial or full, in the absence of infection or fever [3].

Evaluation for progression – Disease progression, a measure of disability, is characterized by steady, insidious deterioration of neurologic function that occurs independently of relapses [2,3]. Progression can be determined from patient history and/or objective measures, such as a worsening of the Expanded Disability Status Scale (EDSS) (table 1) that persists for more than three to six months. Some experts define disability progression as a one-point drop in the EDSS over one year for patients with PPMS on DMT. Ambulatory disability progression is particularly important in progressive forms of multiple sclerosis; progression in most patients resembles a worsening myelopathy and can be assessed by evaluating motor strength and gait speed. The 25 foot timed walk, used by most centers, is a good yet simple measure for determining ambulatory changes. It can be difficult, given within-person fluctuations in the examination and variation between examiners, to be certain of progression or stability, particularly in the short term. Therefore, it is important to evaluate progression or regression of competence in activities of daily living (eg, ability to transfer, self-care, etc) as obtained from the patient, particularly in non-ambulatory patients. Note that the EDSS and assessments for progression are best administered by MS experts or other clinicians with experience in these measures.

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

Additionally, there is a growing recognition that medical comorbidities, such as cardiovascular problems caused by diabetes, hypertension, and smoking, may play a role in the progression of MS [24]. The initial management of obesity involves a comprehensive lifestyle intervention with a combination of diet, exercise, and behavioral modification. Referral to obesity specialists should be considered. The role of behavioral therapy, diet, and exercise in the treatment of obesity are reviewed in detail separately. (See "Obesity in adults: Overview of management" and "Obesity in adults: Role of physical activity and exercise" and "Obesity in adults: Dietary therapy" and "Obesity in adults: Behavioral therapy".)

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

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

SUMMARY AND RECOMMENDATIONS

Primary progressive multiple sclerosis (PPMS) represents approximately 10 percent of multiple sclerosis (MS) cases and is characterized by disease progression from onset, although occasional plateaus, temporary minor improvements, and, less likely, acute relapses may occur. PPMS usually presents with insidious neurologic progression, most often as a gradually worsening myelopathy with gait difficulty. (See 'Pattern and course of MS' above.)

The MS subtypes 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 secondary progressive multiple sclerosis (SPMS). (See 'Disease activity and progression' above.)

For patients with PPMS who are younger (eg, age ≤55 years) or have active disease on MRI, we suggest treatment with ocrelizumab (Grade 2B). We offer ocrelizumab treatment to patients with PPMS who are older and have inactive disease, but patients with these characteristics may be less likely to benefit and more likely to experience adverse effects if treated with ocrelizumab. Other than ocrelizumab, trials of disease-modifying therapies (DMTs) used for patients with relapsing remitting multiple sclerosis (RRMS) have failed to show evidence of benefit in patients with PPMS. (See 'Disease-modifying therapy (DMT) for PPMS' above and 'Ocrelizumab' above and 'Suboptimal response to ocrelizumab' above.)

Other treatments that have been tried for PPMS (eg, glucocorticoid pulses, methotrexate, intravenous immune globulin, mitoxantrone) lack convincing clinical trial evidence of effectiveness; most MS experts do not use these medications for PPMS on a routine basis. (See 'Other treatments for PPMS' above.)

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