Barts-MS rose-tinted-odometer: ★★
In the last 2-3 years I have been talking about the need for the MS community to treat-2-target beyond NEDA (no evident disease activity) to try and prevent end-organ damage. Yes, we need to protect the end-organ in MS just as the nephrologists try to protect the kidney in autoimmune kidney disease and the rheumatologists the joints in rheumatoid arthritis (RA).
However, in a very similar way to MS if you let too much damage accumulate in the kidney or RA joint self-perpetuating mechanisms are set up that lead to slow deterioration in kidney and joint junction and they eventually fail. Fortunately for nephrologists, you can put patients with kidney failure on renal dialysis (an artificial kidney) or offer a kidney transplant (substitute kidney) and in RA you can replace the joints. In comparison, in MS you can buy walking sticks, walkers, wheelchairs and exoskeletons, but you can’t repair and restore lost neurological function. This is why the ‘diagnose early, treat early, treat effectively’ message is so important. Yes, time really is brain.
There is a longstanding theory that the biology of MS changes with time. So with time as the inflammatory infiltrates within the central nervous system increase, B-cell follicle-like structures develop, plasma cells take up residence, oligoclonal IgG bands appear and increase in number, microglia become diffusely activated, slowly expanding lesions or SELs increase in number, astrocytes get activated and form glial scars, demyelination increases, remyelination fails, axonal and cortical plasticity decrease and synaptic pruning increase the die is set and the course of MS becomes unmodifiable with our current DMTs. In essence ‘smouldering MS’ becomes the real MS and we can’t modify it.
In the Queen Square longitudinal CIS study (see below) the EDSS score at 14 years correlated with the lesion volume on MRI at 5 years and the increase in lesion volume over the first 5 years. In the London Ontario natural history study it was the number of relapses in the first two years that predicted poor outcome. So pwMS who only had 1 relapse in the first 2 years compared to those who had 3 or more relapses took 7.6, 12.8 and 20.3 years longer to reach EDSS scores 6 (walking stick), 8 (bed) and 10 (death), respectively. Also, subjects who developed early disability, i.e. EDSS 3.0, become disabled quicker, i.e. they reached higher EDSS scores much quicker than those who don’t develop early disability. In other words, disability begets disability.
Therefore the clinical philosophy of watchful-waiting is hardly practised anymore even in patient’s who are diagnosed with clinically isolated syndrome (CIS). If patients with CIS have high-risk scans, i.e. lesions on the scan that look like demyelinating lesions, most neurologists now feel obliged to offer these patients treatment. A big debate now is how aggressively do you treat people with CIS. Do you simply start them on a safe platform therapy? Or do you hit their disease with a potent IRT? I would argue the latter but instead of using alemtuzumab or HSCT, I would recommend something like oral cladribine. However, this is not possible, cladribine is not licensed for CIS and the current NHS England treatment algorithm is quite clear that we shouldn’t treat CIS.
Treatment Algorithm for Multiple Sclerosis Disease-Modifying Therapies (NHS England Reference: 170079ALG, Date Published: 4 September 2018, Updated: 8 March 2019 Gateway reference: 07603)
‘Trials of first-line therapies in people with the original definition of Clinically Isolated Syndrome (CIS) at high risk of conversion have NOT shown a convincing long-term effect on the accumulation of disability. In 2018, NICE concluded that it was “unable to make recommendations for treating clinically isolated syndrome because the diagnostic criteria for multiple sclerosis and clinically isolated syndrome have changed and the treatment pathway has evolved”. These new diagnostic criteria are the 2010 and 2017 McDonald criteria.’
Fortunately, the number of patients presenting with a clinical event who have CIS is now very small and most of them have MS after underground a lumbar puncture and are shown to have CSF OCBs or convert to becoming MS very quickly. The question for pwCIS is how much damage will occur in the time window between presentation with CIS and conversion to MS and is this watchful waiting period of time long enough to allow the biology of MS to change, i.e. for smoulder MS pathology to take up residence in the CNS?
The question therefore remains is how early is early when it comes to treating MS? I would argue as early as possible, which is why when we were approached to be a trial centre to assess a very high efficacy DMT in RIS (radiologically isolated syndrome) or asymptomatic MS we said yes.
I would be interested to know how many of you who had been diagnosed with CIS were treated immediately, how many of you were asked to watchfully wait before being offered treatment and how many of you still have CIS?
Brex et al. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med. 2002 Jan 17;346(3):158-64. doi: 10.1056/NEJMoa011341.
Background: In patients with isolated syndromes that are clinically suggestive of multiple sclerosis, such as optic neuritis or brain-stem or spinal cord syndromes, the presence of lesions as determined by T2-weighted magnetic resonance imaging (MRI) of the brain increases the likelihood that multiple sclerosis will develop. We sought to determine the relation between early lesion volume, changes in volume, and long-term disability.
Methods: Seventy-one patients in a serial MRI study of patients with isolated syndromes were reassessed after a mean of 14.1 years. Disability was measured with the use of Kurtzke’s Expanded Disability Status Scale (EDSS; possible range, 0 to 10, with a higher score indicating a greater degree of disability).
Results: Clinically definite multiple sclerosis developed in 44 of the 50 patients (88 percent) with abnormal results on MRI at presentation and in 4 of 21 patients (19 percent) with normal results on MRI. The median EDSS score at follow-up for those with multiple sclerosis was 3.25 (range, 0 to 10); 31 percent had an EDSS score of 6 or more (including three patients whose deaths were due to multiple sclerosis). The EDSS score at 14 years correlated moderately with lesion volume on MRI at 5 years (r=0.60) and with the increase in lesion volume over the first 5 years (r=0.61).
Conclusions: In patients who first present with isolated syndromes suggestive of multiple sclerosis, the increases in the volume of the lesions seen on magnetic resonance imaging of the brain in the first five years correlate with the degree of long-term disability from multiple sclerosis. This relation is only moderate, so the volume of the lesions alone may not be an adequate basis for decisions about the use of disease-modifying treatment.
Scalfari et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010 Jul;133(Pt 7):1914-29.
The relationship of relapses to long-term disability in multiple sclerosis is uncertain. Relapse reduction is a common therapeutic target but clinical trials have shown dissociation between relapse suppression and disability accumulation. We investigated relationships between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10] by analysing 28 000 patient-years of evolution in 806-bout onset patients from the London Ontario natural history cohort. Having previously shown no effect of relapse frequency among progressive multiple sclerosis subtypes, here we examined these measures in the pre-progressive or relapsing-remitting phase. Survival was compared among groups stratified by (i) early relapses–number of attacks during the first 2 years of multiple sclerosis; (ii) length of first inter-attack interval; (iii) interval between onset and Disability Status Scale 3 (moderate disability); (iv) number of attacks from the third year of disease up to onset of progression; and (v) during the entire relapsing-remitting phase. Early clinical features can predict hard disability outcomes. Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints. Attack frequencies, in the first 2 years, of 1 versus >or=3, gave differences of 7.6, 12.8 and 20.3 years in times from disease onset to Disability Status Scale 6, 8 and 10, respectively. Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10. In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed a deleterious effect on times from disease onset, from progression onset and from Disability Status Scale 3 to these hard endpoints. The failure of a regulatory mechanism tied to neurodegeneration is suggested. Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to Disability Status Scale 6, 8 or 10, highlighting two distinct disease phases related to late outcome. These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression. They increase the probability of its occurrence, its latency and influence–to a lesser degree–its slope. The prevention or delay of the progressive phase of the disease is implicated as a key therapeutic target in relapsing-remitting patients.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.