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Home > News from MSAA > Primary-Progressive Multiple Sclerosis Update

Primary-Progressive Multiple Sclerosis Update

March 30, 2007

Please Note: This article appeared in the Research News section of the Winter/Spring 2007 issue of MSAA's quarterly magazine, The Motivator .

The Less Talked-About Form of MS

Historically, primary-progressive multiple sclerosis (PPMS) has seemingly taken a back seat to other types of multiple sclerosis (MS). By far, the largest amount of information published about research and treatments for multiple sclerosis (MS) has been in reference to relapsing-remitting and secondary-progressive forms of MS (RRMS and SPMS respectively).

The emphasis has been on RRMS and SPMS for a number of reasons. First, 85 percent of individuals diagnosed with MS begin with the RRMS form, and after many years, RRMS usually advances to SPMS - so clearly the vast majority of patients fall under these categories. Second, RRMS, with its trademark flare-ups and remissions, is the easiest to identify, measure, and observe changes - both in terms of symptoms and diagnostic/ evaluative testing. And third, unlike PPMS (and eventually SPMS), constant flare-ups of inflammation play a vital role in RRMS.

This inflammation in RRMS occurs within the brain and spinal cord (components of the central nervous system [CNS]), and gives researchers a specific target for potential drug and treatment therapies. Disease flare-ups as well as ongoing subclinical disease activity (referring to changes occurring inside the body without any new or worsening symptoms) are frequently observed and measured through the use of magnetic resonance imaging (MRI) technology.

In contrast to RRMS, only 10 percent of individuals with MS are diagnosed with PPMS, and only five percent have a form known as progressive-relapsing MS (PRMS). These types of MS often begin (or present to the doctor) with a very gradual accumulation of walking difficulties. At the same time, PPMS (and early PRMS) patients do not experience any type of exacerbation, or flare-up of symptoms.

Equally confounding for the treating physician is the fact that little or no abnormalities will be visible on the gadolinium-enhanced MRI scan - which is a standard diagnostic tool for identifying lesions (areas of inflammation) in RRMS. Gadolinium is a chemical agent used to highlight areas of inflammation. It is administered to a patient prior to having an MRI scan performed. Since PPMS patients have little or no known inflammation, these types of scans can often appear normal, with little or no evidence of active MS.

The reason for a normal-appearing MRI of the brain as well as the presenting symptom of gradual walking difficulties, is the fact that most of the disease's effects are thought to take place in the spinal cord for individuals with PPMS. An MRI of the spinal cord shows a slowly worsening spinal cord syndrome, also known as progressive myelopathy, in at least 60 percent of those diagnosed with this type of MS. Atrophy (cell death) is often apparent in the spinal cord, along with loss of tissue, largely caused by the degeneration of nerve fibers.

Two features are necessary for a doctor to diagnose PPMS. First, the patient must be experiencing a slow and gradual worsening in his or her symptom(s), and second, she or he must have never had a flare-up of symptoms (also known as a clinical relapse, exacerbation, or attack). Some individuals who are initially diagnosed with PPMS, unexpectedly begin experiencing acute flare-ups of their symptoms. This is what distinguishes a person as having PRMS, and the diagnosis at that time is changed from PPMS to PRMS. As mentioned earlier, approximately five percent of individuals with MS are eventually diagnosed with PRMS - but these patients always begin as having PPMS.

Not everyone with PPMS experiences walking difficulties and has disease activity largely limited to the spinal cord. A portion of individuals with PPMS are found to have progressive cerebellar syndrome. People who are diagnosed with this type of PPMS show significant changes on their brain MRI, often similar to someone with SPMS. And rather than presenting with problems walking (in terms of strength), someone with progressive cerebellar syndrome will typically have difficulties with balance as well as a disabling tremor.

Do the Various Forms of MS Differ Biologically?

Obvious differences exist in the demographics of who is initially diagnosed. Twice as many women are diagnosed with RRMS than men, whereas PPMS is divided equally between the genders, and some sources report a slight tendency toward more men than women being diagnosed with this form of MS. Individuals are typically diagnosed or experience initial symptoms of RRMS as a young adult, often in one's teens or 20s. The onset of PPMS is generally after age 35, with many people being diagnosed in their 40s or 50s.

For several years, experts in the field of MS have suggested that at least two different types of disease pathologies are involved with MS. One mode of action is inflammation, as seen as gadolinium-enhanced active lesions on an MRI scan and as a flare-up of symptoms. This is believed to occur as myelin (protective nerve covering) and axons (nerve fibers) are attacked by one's own immune-system.

Certain types of immune-system cells and chemical responses promote inflammation and damage to the CNS, with resultant flare-ups of symptoms. To a certain extent the myelin may be repaired (remyelination) and function returned (remission). Over time, however, eventual accumulation of deficits usually occurs. The flare-ups and remissions are the defining disease behaviors for RRMS. Inflammation is thought to also be involved to a certain extent with the other types of MS that may exhibit flare-ups and remissions (PRMS and SPMS).

The second mode of action is degeneration, which may be defined as the deterioration of specific cells. As with inflammation, degeneration is thought to be caused by one's own immune system. This process does not promote extensive inflammation, but rather is thought to pre-program healthy cells for an early death. And as the myelin and axons die off, deficits relating to these areas of damage slowly progress. This appears to be the type of disease activity with PPMS, PRMS, and SPMS, although the latter two may have more inflammatory component because PRMS patients and some SPMS patients experience flare-ups.

These two modes of action - inflammation and degeneration - help to differentiate RRMS from PPMS. Finding treatments for these different types of MS may well involve different approaches.

So far, inflammation has been the easier mode of action to treat. All six of the FDA-approved disease-modifying therapies (Avonex® [interferon beta-1a], Betaseron® [interferon beta-1b], Copaxone® [glatiramer acetate], Novantrone® [mitoxantrone], Rebif® [interferon beta-1a], and Tysabri® [natalizumab]) take action using various methods to reduce the inflammation caused by the immune system's attack on the CNS. They are most effective for individuals with RRMS, with limited effectiveness for some individuals with SPMS. Since the primary mode of action in PPMS is degeneration, these drugs that treat inflammation do not appear to have much effect on this type of MS - although studies are still being conducted with PPMS and some of these drugs.

PPMS Research Is Ongoing Around the World

Simply because more people have the RRMS form of MS, which has proven to be easier to study, evaluate, and treat, does not mean that progress is not being made with research into PPMS and other progressive types of the disease. In fact, research is ongoing around the world to discover better diagnosis criteria, more specific evaluation methods, and possible treatment options.

To follow are a few examples of PPMS research around the world. Researchers are dedicated to learning more about PPMS and possible treatments.

  • Internationally, a trial was conducted with PPMS patients using Copaxone, showing no effectiveness other than a possible effect for men with quickly progressing disease.
  • In the United States ( Texas ), another study looked at the cellular changes in PPMS patients when treated with Rituxan® (rituximab), a drug presently in clinical trials for PPMS.
  • In the United States ( Ohio ), researchers suggest that a subset of PPMS patients (with active lesions) may potentially respond to Novantrone, although an improved understanding of the drug and disease activity is needed.
  • In Canada , researchers looked to better understand patient characteristics, disease progression, and associated risk factors with PPMS.
  • In London , researchers used magnetization transfer imaging (MTI) to identify abnormalities in the brain (not seen on conventional MRI) occurring in patients with early PPMS. Another study (using triple-dose gadolinium) found that gadolinium-enhancing lesions were on MRI scans of the brain in almost half of the individuals with very early clinical stages of PPMS, suggesting an early inflammatory phase in PPMS (this was also associated with a greater disease impact).
  • In the Netherlands , a course of high-dose corticosteroids showed an initial improvement in progressive MS patients, followed by a subsequent deterioration within days after the treatment was stopped, resulting in more disability than before treatment began.
  • In Italy , MRI techniques are being researched for more reliable prognostic markers of PPMS, which may help to select and evaluate PPMS patients in future studies. Another trial found stem-cell transplantation (from bone marrow) to be a promising procedure to slow down progression in a subset of patients affected by severe, progressive MS.
  • In France , a study found that a monthly IV pulse of cyclophosphamide with methylprednisolone led to significant improvement in cognition in progressive MS patients (10 with PPMS and 18 with SPMS), although the mechanisms of action remain unclear. [ Editor's note: this treatment is still considered experimental and larger, long-term studies have not been conducted to fully investigate any possible negative effects of the treatment .]
  • In Spain , researchers discuss new findings in MRI studies that demonstrate damage in normal-appearing brain tissue of patients with PPMS, noting that the findings indicate that disease activity in PPMS patients may now be better evaluated and suggest that this patient population should no longer be excluded from therapeutic trials.
  • In Australia, researchers explain how PPMS differs from the more common types of MS, noting that lesions in PPMS tend to be more diffuse (more scattered and/or less defined), less inflammatory, and less likely to remyelinate; they also recognize rituximab as a potential new therapy for PPMS.

Examples of drugs and therapies that have been studied in recent years or are presently in clinical trails with PPMS include: all of the FDA-approved disease-modifying drugs for MS (listed earlier); riluzole (an oral medication used to slow the progression of ALS), Imuran® (azathioprine), methotrexate, cladribine, intravenous immunoglobulin (IVIg) and cyclophosphamide, stem-cell transplantation (also referred to as bone-marrow transplant), total lymphoid irradiation (TLI), pirfenidone (unapproved drug tested in idiopathic pulmonary fibrosis), and Rituxan® (rituximab), among others.

Future Research with PPMS

As noted earlier, one of the drugs showing potential for the treatment of PPMS is Rituxan® (rituximab), which is currently in phase II/III clinical trials for this type of MS. It is presently approved for the treatment of certain cancers and rheumatoid arthritis, and is in trials for other conditions, including lupus. Rituxan is a monoclonal antibody which binds to the surface of antibody-producing B-cells in the immune system.

Looking to future treatments, researchers point out that the next line of MS drugs and therapies may be aimed at repairing and regenerating lost myelin and nerve fibers (axons). This would have the potential for a return of function, which is a vital goal in MS research. Some agents are showing this type of action in animal studies, but making the leap from animal studies to human trials can be a long and difficult transition.

Neuroprotection is another area of great interest for the treatment of all types of MS. If successful, this type of treatment would potentially protect the central nervous system from damage caused by an attack from the body's immune-system cells. Theoretically, nerves and myelin would remain more intact, and patients would have fewer symptoms.

While scientists may need several years to accomplish such mighty goals, today's approved drugs for MS are effective in slowing down disease activity for individuals with relapsing forms of the disease. This has been a dramatic step toward a cure, and with studies now being directed to PPMS as well, researchers believe it will only be a matter of time before individuals with PPMS may also have access to several effective disease-modifying treatments.

List of References

Bieniek M, et al, " Cord atrophy separates early primary progressive and relapsing remitting multiple sclerosis." Journal of neurology, neurosurgery, and psychiatry , 2006 Sep;77(9):1036-9.

Coyle PK , Halper J, Meeting the Challenge of Progressive Multiple Sclerosis , Demos Medical Publishing, Inc., New York , 2001.

Cree B, " Emerging monoclonal antibody therapies for multiple sclerosis." Neurologist , 2006 Jul;12(4):171-8. (Review)

Ingle GT, et al, "Is inflammation important in early PPMS? A longitudinal MRI study." Journal of Neurology, Neurosurgery, and Psychiatry , 2005 Sep;76(9):1255-8.

Koch M, De Keyser J, "Irreversible neurological worsening following high-dose corticosteroids in advanced progressive multiple sclerosis." Clinical Neuropharmacology , 2006 Jan-Feb;29(1):18-9.

Leary SM, Thompson AJ, " Primary progressive multiple sclerosis: current and future treatment options." CNS Drugs , 2005;19(5):369-76 .

Monson NL, et al, "Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis." Archives of Neurology , 2005 Feb;62(2):258-64.

Montalban X, "Primary progressive multiple sclerosis." Current Opinion in Neurology , 2005 Jun;18(3):261-6.

Pelfrey CM, et al, "Immunological studies of mitoxantrone in primary progressive MS." Journal of Neuroimmunology , 2006 Jun;175(1-2):192-9, Epub 2006 Apr 27.

Pender MP, "The pathogenesis of primary progressive multiple sclerosis: antibody-mediated attack and no repair?" Journal of Clinical Neuroscience , 2004 Sep;11(7):689-92.

Ramio-Torrenta L, et al, "Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetization transfer study." Journal of Neurology, Neurosurgery, and Psychiatry , 2006 Jan;77(1):40-5.

Rovaris M, et al, "Grey matter damage predicts the evolution of primary progressive multiple sclerosis at 5 years." Brain , 2006 Oct;129(pt 10):2628-34, Epub 2006 Aug 18.

Saccardi R, et al, " Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database." Multiple Sclerosis , 2006 Dec:12(6):814-23.

Tremlett H, et al, "The natural history of primary progressive MS in British Columbia , Canada ." Neurology , 2005 Dec 27;65(12):1919-23.

Wolinsky, JS, et al, "Glatiramer acetate in primary progressive multiple sclerosis: results of a multinational, multicenter, double-blind, placebo-controlled trial." Annals of Neurology , 2007 Jan;61(1):14-24.

Zephir H, et al, "One-year cyclophosphamide treatment combined with methylprednisolone improves cognitive dysfunction in progressive forms of multiple sclerosis." Multiple Sclerosis , 2005 Jun;11(3):360-3.

Rituxan® (rituximab) from Genentech; information found at: www.gene.com/gene/pipeline/status/immunology/rituxan/index.jsp

By Susan Wells Courtney, MSAA Senior Writer
Reviewed by Dr. Jack Burks,MSAA Chief Medical Officer
Multiple Sclerosis Association of America
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(800) 532-7667



Last Updated on Wednesday, 17 October 2012 11:39