“The Scandinavian countries are blessed with data and the ability to collect it. Why? I suspect because it is cultural and happens at a national level. In Sweden virtually every MSer belongs to the national register and data is collected and added to this register annually. This substudy of the largest treating MS centre in Sweden demonstrates that early access to DMTs reduces your chances of a poor outcome; i.e. of reaching EDSS 4 or beyond. An EDSS of 4 or higher indicates walking difficulties and most in the field (but not me) think this is a good proxy for the onset of SPMS. This is just another data set confirming that early access to DMTs changes the long-term natural history of MS and delays you reaching certain disability milestones. As most of this data was from the injectable DMT era (interferon-beta and glatiramer acetate) it is likely to get better with time with the emergence of more effective treatments.”
“The problem with our clinical definitions is that they are so unreliable and are a moving target. In the pre-DMT era SPMS used to be diagnosed when MSers had EDSS scores of 2.0-2.5. Now that we have DMTs most people will only diagnose SPMS when MSers are more disabled with EDSS scores above 4.0. Why? Simply because funders will only pay for DMTs in MSers who have relapsing disease. As soon you label someone with SPMS it makes it difficult to prescribe DMTs. How can we rely on a clinical definition of SPMS, when we are continuously changing the definition?”
“I have sat on countless steering committees that have tried to operationalise time to onset of SPMS as a clinical outcome. It has not been possible to reach any consensus. The proposal to use an EDSS milestone instead, for example time to confirmed disability progression to EDSS 4.0, also has problems. Why 4.0? I agree that most natural history studies suggest that once MSers hit 4.0 the disease progresses relentlessly regardless of whether or not they have superimposed relapses, or not. I am not sure if this is correct when you are on a DMT. A lot of emerging data suggests that things are very different in the DMT era; we cannot rely on the natural history data to make decisions about the onset of SPMS. For one we need to consider the concept of the therapeutic lag; this based on the hypothesis that in MSers with reduced reserve capacity, disease progression occurring now has been primed by inflammation from one to two years ago. If you switch off inflammation now you need to wait three to five years to see an impact.”
“The other problem I have is that our definition of SPMS tends to be defined by lower limb motor activity. What about the other neurological systems? This is why I think we need to seriously rethink our definition of what is progressive MS.”
“There is little doubt in my mind that if DMTs reduce end-organ damage they will delay disability progression and delay the clinical onset of SPMS, however, you want to define it. Apart from the British Columbia register all the other data sets showed that DMTs delayed the onset of clinically-defined SPMS. The issue for purists is that this data is not collected in randomised trials and is therefore unacceptable. What do they want?”
“When I did my PhD I worked in Marc Feldmann’s and Tini Maini’s laboratory; this duo pioneered the clincal development of anti-TNF (tumour necrosis factor alpha) therapy in rheumatoid arthritis. Anti-TNF therapy switched off the inflammation and made RAers feel well. This triggered a debate whether or not this would prevent end-organ joint damage and the need for joint replacement therapy in the future. Marc Feldmann had no doubt about the longterm impact of these therapies. Why? He understood the biology of RA and knew that inflammation was the driver of end-organ damage; switch it off and you protect joints. Marc has now been proved correct; it is clear that the number of joint replacements required in RAers has plummeted. Maybe we should start counting walking sticks and wheelchair numbers? We already do; EDSS 6.0 and 7.0 are measured surrogates for sticks and chairs. If DMTs are reducing time to EDSS 6.0 and 7.0 they are reducing the needs for sticks and chairs. If the clinical onset of SPMS is linked to EDSS progression then DMTs are delaying the onset of SPMS.”
“Unfortunately, unlike joint replacement therapies in RA, or renal dialysis, or transplantation in other end-stage organ failures, we can’t replace the brain and spinal cord, nor can we restore their function when they fail. It is time to think of DMTs as preventive therapies; they are preventing the rate MSers acquire disability. We shouldn’t get too bogged down in how we define this; particularly clinically. We need to remember the iceberg analogy.”
Kavaliunas et al. The Influence of Immunomodulatory Treatment on the Clinical Course of Multiple Sclerosis. GeNeDis 2014 Advances in Experimental Medicine and Biology Volume 822, 2015, pp 19-24. Date: 30 Oct 2014
Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system. One of the major questions concerning the clinical progression of MS, still insufficiently elaborated or confirmed, is if it can be slowed down or augmented by external factors. Immunomodulatory treatment is a disease modifiable factor shown to influence disease progression of various medical conditions.
Objective: To investigate if treatment affects the long-term clinical progression of MS, measured as time from diagnosis to score of 4 or higher of Expanded Disability Status Scale (EDSS).
Methods: Longitudinal, prospective data concerning treatment status and EDSS were collected by health professionals in the Swedish MS Registry. Study cohort comprised new diagnosed MS patients at Karolinska Hospital between 2001 and 2005. Survival analysis adjusted for suspected confounders was used with the outcome variable time from diagnosis to EDSS ≥4.
Results: Early treatment was correlated with longer time from diagnosis to EDSS ≥4 (HR: 1.77; 95 % CI: 1.15–2.73; p = 0.01). Additionally, the influence of the covariates—age at onset and the baseline EDSS, which were statistically significant with hazard ratios of 1.03 and 2.1, respectively, was found.
Conclusion: Early treatment was associated with a better clinical outcome.