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First World Congress on Controversies in Neurology

Berlin, Germany / September 6-9, 2007

Multiple sclerosis (MS) is a severe neurological disorder with 80% of patients entering the progressive phase within 20 to 25 years of disease onset. Hence, early treatment is in the patients’ best interest, argued Prof. Giancarlo Comi, Director, Multiple Sclerosis Centre, Vita-Salute San Raffaele University, Milan, Italy, beginning the debate on optimal treatment onset of patients with early MS. “It’s a view that was not supported by many initially but that is increasingly shared now, as new data have become available,” Prof. Comi confirmed. From a pathological angle, he cited studies showing how axonal damage occurs very early in the course of the disease and correlates with inflammation. That damage is irreversible, even though it may remain hidden for years, until the nervous system’s capacity for compensation becomes overwhelmed.

Inflammatory activity in relapsing-remitting MS (RRMS) is not restricted to episodes of clinical impairment but typically starts before an initial clinical relapse, Prof. Comi explained. He reminded the audience of the AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) clinical trial that showed that the reduction of inflammation can result in a decrease of progression to disability. However, “the immune-mediated processes that underlie MS become more difficult to control as the disease progresses,” cautioned Prof. Comi. “Drugs which may work in the early phase of the disease may fail in later stages, when there is already widespread damage to the grey matter.”

He cited data from the BENEFIT (Betaferon in Newly Emerging Multiple Sclerosis For Initial Treatment) trial, where findings have shown that 85% of patients on placebo developed MS (according to McDonald criteria) within two years.

Prof. Comi also drew listeners’ attention to a development common to three clinical trials in MS involving interferons, namely, BENEFIT, CHAMPS (Controlled High Risk Avonex Multiple Sclerosis Study) and ETOMS (Early Treatment of MS). He pointed out that in all three trials, findings from those patients with a first event suggestive of MS—also known as clinically isolated syndrome (CIS)—had shown that treatment with interferon beta (IFNbeta) formulations could slow the rate of and prolong the time to conversion to clinically definite MS (CDMS) and reduce MRI activity.

Clinically Isolated Syndrome

Yet as argued by Dr. Aksel Siva, Multiple Sclerosis Clinic, Department of Neurology, Istanbul University Cerrahpasa School of Medicine, Turkey, this may not necessarily apply to all patients with a first event suggestive of MS, and not every patient with MS should be treated at time of diagnosis. To reinforce his argument, he recounted the case of one of his own patients whose disease might have been subclinical for decades until MS was finally confirmed at age 72, after an acute episode had been documented by MRI. “Under the circumstances, had he been on drugs 20 or 30 years earlier, one would have thought that those drugs had worked,” Dr. Siva speculated. The increasing use of MRI scans may also reveal many cases of subclinical MS where refraining from immediate treatment might not have negative consequences, he added.

Citing various studies, Dr. Siva estimated that for every patient diagnosed with MS, there may be one or two patients whose disease remains unrecognized. While admitting that studies such as BENEFIT, ETOMS and CHAMPS have given “clear evidence” for significant delays in the conversion to CDMS through the use of disease-modifying agents, Dr. Siva maintained it was also clear that not all patients will progress and that it is important to identify this subgroup. In the meantime, he indicated that he would delay treatment of patients with early MS until the next clinical or imaging activity was detected.

Prof. Comi maintained his position. “We have the tools to change the history of the disease and we must use them,” he stated. “There is an urgent need to treat patients early rather than wait for further MS signs to develop.”

Further evidence in favour of this approach was presented by Dr. Xavier Montalban, Director, Clinical Neuroimmunology Unit, Vall d’Hebron University Hospital, and Professor of Neurology, Universidad Autónoma de Barcelona, Spain, who reported on another analysis from the BENEFIT trial carried out three years after the first clinical event. Confirmed progression of impairment as measured on the Expanded Disability Status Scale (EDSS) was reached by only 16% of patients treated early vs. 24% of patients who deferred treatment (P=0.0218); 37% of patients treated immediately and 51% of those treated later developed CDMS, a highly significant difference (P=0.0011), according to Dr. Montalban.

Debating the Role of Neutralizing Antibodies

The controversies presented here at the Berlin meeting went beyond the question of when to initiate treatment. The next debate dealt with neutralizing antibodies (NAbs) which can develop in the presence of interferon therapy, the treatment of choice for RRMS.

Dr. Joel Oger, Professor of Medicine, Division of Neurology, University of British Columbia (UBC), Vancouver, posited that the mere presence of NAbs would not be sufficient evidence to discontinue treatment with interferons.

He offered an example from his own experiences at UBC Hospital. He stated that patients who ended up having high NAb titres at the beginning of therapy in general had experienced greater improvement with interferons. The treating MS specialist might be torn between the rules of evidence-based medicine and the questions posed by the patient sitting before him, but according to Dr. Oger, the physician should not modify treatment while the patient is still doing well. “If a patient appears not to do well, do MRI with gadolinium and measure NAbs, then decide what should be done,” he advised the audience.

Dr. Per Soelberg Sorensen, Danish Multiple Sclerosis Research Centre, Department of Neurology, Copenhagen University Hospitals, Denmark, supported the opposing view. NAbs may develop in up to 40% of patients who are treated with IFNbeta formulations. Yet he explained that the frequency and titre of NAbs depends on preparation dose, frequency and route of administration of IFNbeta. “Patients with persistently high NAb titres need to switch treatment to another class of therapy in order to be protected against deleterious disease activity of MS,” Dr. Sorensen told delegates, reflecting the treatment guidelines followed in most European countries. Because of the unpredictable course of MS, he advised that a treatment switch should also be carried out in patients who appear to have stable disease.

Dr. Oger’s point of view corresponded with findings in a poster presentation by Dr. Hans-Peter Hartung, Professor and Chair, Department of Neurology, Düsseldorf University Hospital, Germany, and colleagues. The investigators reported the frequency and effects of NAbs in the BENEFIT trial from the study’s pre-planned three-year analysis in patients initially randomized to IFNbeta-1b. Here, NAb positivity (defined as greater than or equal to 1:20 NU/mL using the MxA assay) did not affect the efficacy of treatment in delaying conversion to CDMS. While NAbs had developed in 31.8% of patients offered early treatment, almost half of these individuals had reverted to negative status by year 3. This development led the investigators to conclude, “NAb status is not a determining factor in treatment decisions for patients with a first neurological event suggestive of MS.”