Is interferon-beta dead, or not? #ResearchSpeak #MSBlog #MSResearch
"On our last Barts-MS Preceptorship one of the delegates asked if I thought there was still a place for interferon-beta in the treatment of MS? I answered yes. Firstly, if you are on an interferon and you are NEDA, and are tolerating the therapy well, why would you want to change? Maybe NEDA is not sufficient and you would want to know if you had smouldering MS or not. If we had done serial MRI studies on you, and were able to show that over a 3-4 year period your rate of brain volume loss was within the normal range, and your spinal fluid analysis showed normal neurofilament levels, would you be satisfied? You need to remember that interferon-beta is a safe drug and is not associated with any major long-term risks so if you happen to be in the 20-40% of pwMS who respond why change? Remember that being a responder to interferon-beta does not necessarily mean you will respond to another class of DMT."
"What about naive patients, would I ever start interferon-beta in someone who has active MS? Yes, I would if that is what they choose when given the choice the available 1st-line therapies available on the NHS. In addition to interferon beta the other options are glatiramer acetate, terflunomide, dimethyl fumarate, alemtuzumab and shortly daclizumab. In price sensitive markets interferon-beta is still being widely prescribed; local guidelines state that you have to fail an injectable DMT first to be able to access one of the newer DMTs. Another factor is the emergence of cheaper biosimilars; these are forcing payers to demand that they be used first-line."
"Another factor that may drive the ongoing use of interferon-beta may be the re-emergence of the so-called induction-maintenance paradigm. This is when interferon-beta is used after an induction therapy; orginally interferon-beta was used in this way after mitoxantrone. May be using interferon-beta after an initial course of alemtuzumab, cladribine or HSCT may re-emerge as a viable and safe long-term treatment option. However, we would need data to support this."
"Finally, we are in discussion with one of the interferon-beta manufacturers of making their product available in resource-poor settings, on humanitarian grounds, to help treat pwMS who can't afford to pay for commercial product. We hope to start by running a pilot scheme so as to address all the local regulatory and logistical issues about making this happen. I was surprised at how difficult it is to provide a biological therapy in resource poor settings. However, I am confident we will be able to make this happen; where there is a will there is a way."
"Please note the study below showing that relapses and MRI activity on interferon-beta predicted failure in terms of disease progression on the EDSS. I note they set their threshold on 3 or more new T2 lesions for predicting failure on treatment. I don't buy into the concept of MEDA (minimal evident disease activity). Why would you allow some inflammation (MEDA) in your brain when you could have none (NEDA as measured using MRI)? I will need to analyse this paper in more detail to see if the investigators had enough power to assess whether or not patients with zero new T2 lesions did better than patients with one, or more, new T2 lesions. In the past when I attempted this I calculated that thousands of study participants would be needed to address this question."
"One final point. If you have been reading this blog for some time you will be aware that relapses and MRI activity in natural history studies, or on placebo drug, don't predict long-term disease outcome in MS. In contrast, relapse and MRI activity on a DMT do predict disease outcome. These observations tell us that relapses and MRI activity are not the disease. If they were the disease they would predict disease outcome regardless of whether you were on a treatment or not! Please think about these observations carefully. These observations challenge the current dogma about what is causing MS. Based on these insights alone it is important to find-out how interferon-beta changes the natural history of MS. Therefore there is another reason why we need to continue to use interferon-beta to treat MS, to pin down the cause of the disease."
Epub: Sormani et al. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology. 2016. pii: 10.1212/WNL.0000000000002830.
OBJECTIVE: To provide new insights into the role of markers of response to interferon-β therapy in multiple sclerosis (MS) in a multicenter setting, focusing on the relevance of MRI lesions in combination with clinical variables.
METHODS: A large multicenter clinical dataset was collected within the Magnetic Resonance Imaging in MS (MAGNIMS) network. This included a large cohort of patients with relapsing-remitting MS on interferon-β treatment, MRI and clinical assessments during the first year of treatment, and clinical follow-up of at least 2 additional years. Heterogeneity among centers was assessed before pooling the data. The association of 1-year MRI or clinical relapses with the risk of treatment failure (defined as Expanded Disability Status Scale [EDSS] worsening or treatment switch for inefficacy) and of EDSS worsening alone was evaluated using multivariate Cox models.
RESULTS: A pooled dataset of 1,280 patients with relapsing-remitting MS from 9 MAGNIMS centers was analyzed. The risk of failure had a relevant increase with 1 relapse (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.39-2.44, p < 0.001) and ≥3 new T2 lesions (HR 1.55, 95% CI 0.92-2.60, p = 0.09). In patients without relapses and less than 3 new T2 lesions, the 3-year risk of failure and EDSS worsening were 17% and 15%; in patients with 1 relapse or ≥3 new T2 lesions, the risks were 27% and 22%; in patients with both conditions or more than 1 relapse, the risks were 48% (p < 0.001) and 29% (p < 0.001).
CONCLUSIONS: Substantial MRI activity, particularly if in combination with clinical relapses, during the first year of treatment with interferon-β indicates significant risk of treatment failure and EDSS worsening in the short term.