"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
About 10-15% of patients with the demyelinating disorder multiple sclerosis (MS) have the primary progressive (PP) form of the disease, which is characterized by a phenotype of gradual progression from onset.
PPMS typically includes a steady loss of function from the onset of symptoms. The vast majority of people with MS receive an initial diagnosis of the relapsing-remitting (RR) form of the disease characterized by subacute episodes of new neurologic symptoms which last more than 24 hours and occur in the absence of fever or infection. Of those, some people will go on to develop secondary progressive (SP) MS over time in which they have a gradual worsening separate from relapses.
Although there has been significant focus on the distinct phenotypes of MS since their initial descriptions, some experts believe that MS may all be one disease with varied underlying biology throughout its course and that individuals manifest different phenotypes.
Experts suspect that focusing treatment and research on the underlying biology of an individual's course of the disease may be more effective than trying to identify a specific phenotype such as PP, RR, or SP. The limitation to this, however, is that monitoring the disease focuses mainly on MRI findings and clinical evaluation of symptoms indicative of relapse. Advanced diagnostics will be needed to focus on the underlying biology, which may evolve throughout the course of the disease.
Applying the McDonald Criteria
According to the , which are used to determine if someone has MS, the disease process must be disseminated in "space and time," meaning that more than one location in the central nervous system (CNS) must be affected. Additionally, the effects must change or evolve over time.
Primary progressive MS can be diagnosed in patients in whom other disease mimics have been ruled out with:
- 1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse
Plus, two of the following criteria:
- One or more T2-hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
- Two or more T2-hyperintense lesions in the spinal cord
- Presence of cerebrospinal fluid-specific oligoclonal bands
This last requirement makes the use of lumbar puncture during diagnosis especially important, noted Stephen Hauser, MD, and Bruce Cree, MD, PhD, both of the University of California San Francisco Weill Institute for Neurosciences, writing in .
"Oligoclonal bands reflect the products of a highly focused immune response by activated B cells in the CNS. The abnormal intrathecal synthesis of gamma globulins, measured by an elevated IgG [immunoglobulin G] index or two or more discrete oligoclonal bands not present in a paired serum sample, is present in >90% of MS patients," the team said.
Differentiating Between Progressive & Relapsing MS
Given that disability progression is essential for a diagnosis of PPMS, physicians seek telltale signs that help them differentiate among the different forms of MS. In a 2019 review in , Gabrielle Macaron, MD, and Daniel Ontaneda, MD, PhD, both of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic Foundation, noted that actively demyelinating plaques are common in relapsing/remitting MS, the most widespread form of the disease.
"However, active lesions are rare in progressive MS, and axonal transection is not seen as frequently within inactive lesions compared to highly inflammatory recently developed lesions," the authors wrote. "Whole brain atrophy, smoldering and enlarging lesions, cortical demyelination (specifically subpial lesions), and diffuse axonal injury and microglial activation in normal appearing grey and white matter are prominent in patients with progressive MS compared to patients with early RRMS."
Disability in Progressive MS
According to Macaron and Ontaneda, disability in progressive MS is related to secondary neurodegeneration of chronically demyelinating axons. This process may be in response to various factors, including:
- Inflammation and lesion accumulation, with subsequent retrograde and anterograde degeneration
- Mitochondrial damage and subsequent virtual hypoxia and oxidative stress
- Iron accumulation in myelin sheath and oligodendrocytes with subsequent amplification of oxidative stress
- Lymphoid follicle-like structures that might contribute to sustaining cortical pathology
- Age-related neurodegeneration and reduced neuronal reserve
Early aggressive treatment appears to make more of a difference in RRMS than it does in PPMS. "Early use of DMTs [disease-modifying treatments], specifically highly effective DMTs, decreases the odds of conversion to SPMS, which supports the role of early disease activity in the development of long-term disability progression," the team said.
Ocrelizumab for Progressive MS
There is currently only one FDA-approved DMT to treat PPMS: ocrelizumab, a humanized anti-CD20 monoclonal antibody. The ocrelizumab for PPMS in 2017 based on results from the clinical trial.
In that study, 732 patients with PPMS were randomized 2:1 to receive intravenous ocrelizumab or placebo every 24 weeks for at least 120 weeks. In the ocrelizumab group, 32.9% of patients experienced the primary outcome of 12-week confirmed disability progression, compared with 39.3% in the placebo group. The differences between the two groups continued over time: the 24-week confirmed disability progression was 29.6% in the ocrelizumab group versus 35.7% in the placebo group.
"By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02)," the ORATORIO authors wrote.
Ocrelizumab is given by infusion every 6 months and is contraindicated for patients with hepatitis B infections. Ocrelizumab also has FDA approval for use in patients with relapsing forms of MS including active SPMS.
In a 2022 of their 2019 Cochrane Review of ocrelizumab, the authors concluded that, for people with PPMS, "ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate‐certainty evidence). Ocrelizumab may result in a reduction in disability progression and may result in little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low‐certainty evidence)."
The authors noted that ocrelizumab was well tolerated clinically, with infusion‐related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections being the most common adverse events. "Based on these results, clinicians may consider ocrelizumab as an effective and safe treatment to be offered to people with RRMS and PPMS," the team wrote.
DMTs for Secondary Progressive MS
Prior to the advent of today's era of effective DMTs, researchers believed that approximately half of patients with RRMS progressed to SPMS within a decade of disease onset. That estimate rose to about 90% within 25 years of the initial RRMS diagnosis without MS treatment. However, found that fewer than 10% of patients with RRMS will develop SPMS over a median of three decades, thanks to available treatments.
Unlike patients with PPMS, those who have SPMS have options besides just ocrelizumab. These include:
- Cladribine
- Ofatumumab
- Siponimod
- Ublituximab-xiiy
A in Frontiers in Neurology sought to tease out differences in the efficacy and safety of DMTs for progressive MS. The authors evaluated pooled evidence from multiple clinical trials involving agents such as ocrelizumab and siponimod. Other DMTs evaluated included:
- Laquinimod
- Mitoxantrone
- Natalizumab
- Rituximab
Among the authors' findings: "Mitoxantrone, siponimod, and ocrelizumab are superior to other drug options in delaying disease progression (high certainty). Mitoxantrone was the best (with high certainty) for mitigating deterioration (progression of disability)," the team wrote.
With low certainty, ocrelizumab performed best on the pre- and post-treatment timed 25-foot walk test, while natalizumab performed the best in the 9-hole peg test (high certainty).
Additionally, rituximab (not yet FDA approved, but sometimes used off label) and natalizumab were less effective in controlling disease progression and, although mitoxantrone effectively alleviated disease progression, its use came with more serious adverse reactions including cardiotoxicity, therapy-related acute leukemia, and liver toxicity. As a result, mitoxantrone has fallen out of use for the treatment of MS.
Rituximab is a chimeric anti-CD20 monoclonal antibody, while ocrelizumab is a humanized anti-CD20 monoclonal antibody. Rituximab's results may be due to the small number of patients in two of the three studies included in the study, which affected the overall results, the authors wrote.
Read previous installments in this series:
Part 1: Early Diagnosis Can Mean Better Outcomes in Multiple Sclerosis
Part 2: How Does Multiple Sclerosis Start?
Part 3: The Deep and Multidimensional Connection Between Multiple Sclerosis and Depression
Part 4: Case Study: Sudden Blurred Vision in a Young Woman
Part 5: Early Aggressive Treatment May Work Best in Newly Diagnosed Multiple Sclerosis