Don’t wait to treat. That’s the bottom-line message for physicians caring for patients with multiple sclerosis. Demyelinating and possibly autoimmune in nature, MS swings patients through baffling cycles of remission, relapses and plateaus, and can produce a wide variety of pathologies, including optic neuritis.
Not yet curable, MS is definitely treatable. “There’s a further accumulation of evidence that the earlier the treatment is started, the better the outcome appears to be,” said Steven L. Galetta, MD, professor of neurology and ophthalmology at the University of Pennsylvania, Philadelphia.
“Evidence comes from the CHAMPIONS1 study, which suggests that there is a penalty in delaying treatment with beta-interferon therapy in those patients with high-risk clinically isolated syndromes. As an example, this would include a patient with optic neuritis and a brain MRI that shows white matter abnormalities typical of demyelination. This confirms what we’ve observed with the relapsing-remitting forms of the disease,” said Dr. Galetta, who is a member of the CHAMPIONS Study Group. In the study, “those patients initially randomized to placebo don’t seem to be faring as well as those randomized to interferon beta-1a [Avonex] over the long haul.”
The rationale to treat based on imaging may seem at odds with the patient’s appearances, Dr. Galetta said. “At every stage of the disease, those with new or active MRI lesions are usually best served by being on immunomodulatory therapy.” But there can be a “disconnect between how the MRI images look and how the patients look physically,” Dr. Galetta said. “There may be a time lag between what the MRI shows and what physically happens to the patient 10 years later.”
Lesion now = symptoms down the road. Supporting evidence for this hypothesis comes from a recently published study in which early activity in T2 lesions seemed to predict the clinical and MRI status of the patient 13 years later,2 Dr. Galetta noted. In particular, the researchers found that early T2 lesion activity correlated well with subsequent disability and brain atrophy.
“MRI just becomes a more and more important part of making treatment decisions,” Dr. Galetta said. “When we take all of this in clinical context, the apparent disconnect between MRI findings and physical disability may just be a time lag.”
It may be that, during the time when patients appear to be doing well clinically, they are actually accumulating “silent” brain lesions, Dr. Galetta said. “They eventually hit a threshold, where the whole process begins to unravel with relapses and disability progression becoming evident.”
While MRI imaging of the brain is essential to making the diagnosis of MS, “other evolving technologies are documenting early injury to the axons,” Dr. Galetta said. “We now understand that acute axonal injury may be greatest in the early phases of the disease, and that acute plaques have the greatest number of axons affected.”
OCT as understudy. In particular, optical coherence tomography is garnering attention for its ability to image axonal loss. “The beauty of OCT is that it’s noninvasive and noncontact. It gives a reproducible, accurate, living measurement of what’s going on with the axons,” said Robert C. Sergott, MD, professor of ophthalmology at Thomas Jefferson University and codirector of neuro-ophthalmology at Wills Eye Hospital in Philadelphia. To date, researchers have used OCT to examine the extent of axonal loss in the retinal nerve fiber layer of MS patients, subsequent decreases in RNFL thickness and any correlation between RNFL thinning and decreased vision. (For general tips on OCT, visit “OCT: Getting the Best Images”)
For instance, in a study published earlier this year, MS patients with a history of acute optic neuritis had the greatest amount of RNFL thinning. But even MS patients who hadn’t had optic neuritis demonstrated a decrease in RNFL thickness when compared with healthy subjects. This suggests a pattern of chronic axonal loss in MS, the researchers note.3
While conventional MRI can image some axonal anatomy, Dr. Sergott said, “It does not image the axons as well as OCT does.”
Moreover, he noted, using MRI for this purpose means that “testing time is long—the patient will spend a lot of time inside the magnet. OCT is much easier on patients.”
Tandem testing. Looking forward, Dr. Sergott said, “I envision OCT doing the same thing that MRI did about 10 years ago—providing a more accurate diagnosis more quickly.” He added, “Once we have ultrahigh-resolution OCT, that will also parallel what happened with MRI. When we had a one Tesla unit, we were amazed—then we had three Tesla and were even more amazed.” Within the next year, he said, OCT will enter new multicenter trials, with the North American Neuro-Ophthalmology Society heading up the largest.
OCT and other new technologies also are expected to be used in tandem with MRI imaging. “New measures can bring out more subtle defects and can correlate better with MRI changes,” Dr. Galetta said. For instance, his team has used low-contrast vision testing and compared those results with MRI findings.
About vision testing, he added, “We now recognize that an abnormal vision test may have meaning regarding a patient’s quality of life. This is not an insignificant parameter to look at— for instance, losing contrast sensitivity can have a severe impact on daily visual activities. Thus, if a medication can alter the progression of visual loss, we will have a significant opportunity to help the patient.”
Dr. Galetta expects that future trials will use OCT and low-contrast vision testing “as markers for drug effects in MS patients.”
Through the Pipeline, Slowly
The research pipeline of potential MS treatments is fairly full and includes monoclonal antibodies, statins and sodium channel blockers. Neuroprotection is one hot area of research; remyelination is another.
But it will be some time before physicians have newly approved MS drugs in hand. “We’re in a bit of a lull right now,” Dr. Galetta said. “A number of drugs are being tested, but I think it will be another two to three years before we see them hit the market. I’m looking at a 2009 time frame.”
The current roster. Drugs currently approved for MS are:
- natalizumab (Tysabri);
- the beta-interferons (Avonex, Betaseron and Rebif);
- glatiramer acetate (Copaxone); and
- mitoxantrone (Novantrone).
While these medications can’t reverse the damage already caused by the disease, they can help reduce the frequency of attacks and slow the rate of future disability.
Tysabri came back on the market this year. (It was withdrawn last year because of three cases of progressive multifocal leukoencephalopathy reported with its use.)
In discussing its reintroduction, Dr. Galetta said, “I think Tysabri will be used for more aggressive forms of relapsing-remitting disease. I suspect it will be a second-line drug that is used for those patients who either have failed the immunomodulating drugs or are intolerant of, or noncompliant with, those drugs. This may not be an insignificant number of patients; it’s hard to know at this point.”
Overall, he said, “I think we’ll see a slow uptake of Tysabri use because of the necessary caution regarding side effects.”
1 Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance. CHAMPIONS Study Group. Neurology 2006;66:678–684.
2 Rudick, R. A. et al. Ann Neurol 2006;60:236–242.
3 Fisher, J. B. et al. Ophthalmology 2006;113:324–332.
Dr. Galetta has received research grant support and speaking honoraria from Biogen. Dr. Sergott is a consultant for Centocor, Pfizer, Serono and Teva. He also has received independent medical grants and is on the speakers’ bureaus for Pfizer and Serono.