A major dilemma facing clinicians is whether to continue treatment with disease-modifying drugs, effective in relapsing-remitting multiple sclerosis (RRMS), as the disease progresses to secondary progressive MS (SPMS). In SPMS, these treatments seem to lose their benefits and — as they are often associated with severe side effects and high costs — clinicians are faced with deciding if disease-modifying therapies should be stopped.
At the 10th World Congress on Controversies in Neurology (CONy) in Lisbon, Portugal (March 17-20, 2016), Abhijit Chaudhuri, a consultant neurologist at Queens Hospital, London, U.K., and Jacek Losy from the Poznan University of Medical Science, Poland, discussed this important issue in a debate titled “Should disease-modifying therapies be stopped in patients who have developed secondary progressive MS?”
According to Dr. Chaudhuri, the lack of progress in SPMS treatment stems from the fact that the pathology of this disease form is inherently different from earlier disease stages. The progression to PPMS is mainly driven by neurodegenerative changes, in contrast to the principal inflammatory processes in RRMS. The cause of this neurodegeneration is not well explored, but it is likely dependent on several factors heavily influenced by metabolic brain changes.
“Neurodegeneration in SPMS is considered to be multi-factorial, diffuse, and significantly influenced by metabolic neuroaxonal changes,” Dr. Chaudhuri said in the debate. “Accumulation of disability in SPMS is driven by a neurodegenerative process which is independent of focal inflammatory changes.”
Since the underlying causes are different in the two MS stages, it is not surprising to find that current RRMS disease-modifying treatments have little effect on SPMS — and there is plenty of evidence that they do not, Dr. Chaudhuri said, citing several important studies.
Several clinical trials from 1988 onward, enrolling more than 6,000 patients and testing a multitude of both immunosuppressive and first-line disease-modifying drugs, have failed to show beneficial effects in SPMS patients. Together, these trials have investigated the efficiency of immune-suppressive drug therapies (ISDT) such as Azathioprine, Ciclosporin, Cyclophosphamide, Sulfasalazine, Linomide, Mitoxantrone and Cladribine; first-line disease modifying therapies like Interferon beta 1-a, Interferon 1-b and Glatiramer Acetate; and human intravenous immunoglobulin (IVIg), antiCD20 monoclonal antibody (Rituximab), Myelin Basic Protein (MBP), and cannabinoid (Dronabinol) for SPMS treatment.
Dr. Chaudhuri also mentioned a small trial investigating alemtuzumab (Lemtrada) in SPMS, which found no benefit in terms of Expanded Disability Status Scale (EDSS, a measure of disability) progression or rate of brain atrophy in MRI. Fingolimod (Gilenya) also failed to show efficacy in a trial for primary progressive MS, a disease form that likely shares underlying causes with SPMS.
“Success of DMT [disease-modifying therapies] is established for relapse prevention,” Dr. Chaudhuri said. “Anti-inflammatory therapy does not arrest the disease progression in SPMS.”
Dr. Losy countered that clinical trials assessing Interferon beta 1b therapy for SPMS came to different conclusions. A European study found favorable treatment effects on disease progression, the number of relapses, and several MRI parameters, while a North American study found no impact on such parameters. An analysis of the trials showed that the European study included more patients with active MS.
The “Interferon beta-1b in secondary progressive MS [yielded] very different results in trials, because populations were not comparable,” he said.
Therefore, according to Dr. Losy, the question of whether to continue treatment or not depends on whether the patient has active or non-active SPMS, and what type of disease-modifying treatment was used early in the disease. To further support this argument, he cited a subgroups analysis from the SPECTRIMS study — investigating Interferon beta 1a in SPMS — which showed that the treatment slowed disease progression only in individuals with active disease, namely in terms of relapses and MRI findings.
He also mentioned the MIMS study, a trial testing the drug mitoxantrone in patients with progressive relapsing or secondary progressive MS, which suggested that the drug had a positive impact on some MRI parameters.
Dr. Chaudhuri agreed that a small proportion of relapsing-progressive patients with MRI evidence of lesion expansion could, in theory, benefit from continued treatment, but he warned against generalizing data from these patients to the SPMS group as a whole.
While there is an enormous unmet need for effective treatment in SPMS, Dr. Chaudhuri said the problem remains our inability to understand the disease. He noted that despite the use of disease-modifying treatment, much of the pathology remains untouched, evidenced by the fact that patients progress from RRMS to SPMS even when relapses are kept at bay.
Based on the very thin evidence of favorable outcomes and the high cost of maintaining treatment, the option of continuing treatment is not feasible, he said. Instead, he argued that clinicians should focus on offering patients an optimal treatment withdrawal process. He stated that many patients feel apprehensive when faced with the prospect of stopping treatment, and patients should be offered counseling and a slow withdrawal process.
“Loss of brain volume and spinal cord atrophy are hallmarks of progressive MS, and few licensed DMT can reverse these changes” Dr. Chaudhuri concluded. “Patient education and pre-counseling [is the] key to successful DMT withdrawal, carried out over two–three months instead of abrupt withdrawal.”
These patients should then be offered opportunities to enroll in new SPMS trials, Dr. Chaudhuri said. These trials are focusing on other mechanisms than current immune and inflammatory therapies, investigating neuroprotection, mitochondrial function, neuraxonal metabolism, and ion transport. Early positive results have been reported from studies investigating Simvastatin and Biotin, he said, and added that in the future, such drugs could be introduced at an earlier disease stage to stop the progression of RRMS to SPMS.
In the end, the two researchers seemed to reach some understanding, as Dr. Losy agreed that existing data only supported the continuation of disease-modifying treatment in patients with the active, relapsing form of SPMS.