Time, how much does your brain have?
How early is early when it comes to treating MS? Is watchful waiting appropriate considering what we now know about multiple sclerosis?
Is your MS treated-2-target? In other words, do you have ongoing MS disease activity that needs to be suppressed to prevent ongoing damage to your brain and spinal cord?
In the last 2-3 years I have been talking about the need for the MS community to treat-2-target beyond NEIDA (no evident inflammatory 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).
You may not know that my father had an autoimmune disease of the kidney that caused his kidneys to fail. When I was 12 he started dialysis and he waited a further 10 years before agreeing to have a kidney transplant. The tragedy was that when he was a teenager he had a few episodes of blood in his urine or haematuria, that was precipitated by exertion. Although it was brought to the attention of his GP it was never taken seriously by his general practitioner (family doctor), nor himself, so the problem was never investigated. By the time he presented with headaches and nose bleeds due to severe secondary hypertension and problems with blood clotting he was in chronic renal failure. The inflammation in his kidneys had caused irreparable end-organ damage. His kidneys were small and scarred. The nephrologist who saw him said ‘if only I had got to you sooner with immune therapies I would have had a chance of saving your kidneys’. If only; two small seemingly trivial words that mean so much and at a personal level resulted in so much suffering, reduced quality of life and cost my family and society so much money.
Fortunately, my father lived in an era when salvage kidney therapy was possible; he had peritoneal dialysis, haemodialysis and subsequently a kidney transplant. All three of these innovations are modern miracles and are now part of routine clinical practice. In a previous era, he would have died a young man. The lessons I learnt from my father’s case were (1) get a good doctor who takes things seriously and (2) early diagnosis and treatment are better than salvage therapy. These lessons are as pertinent to MS today as they were in my father’s case 40 years ago. Unfortunately for pwMS, we don’t have salvage therapy; we can’t repair or transplant the brain or spinal cord. Therefore, your best chance of avoiding end-organ damage is an early effective therapy and getting yourself a good neurologist who takes treating your disease seriously. We have to start viewing DMTs as preventive therapies, i.e. to prevent irreparable end-organ damage.
In almost every MS clinic I do I see the difference between pwMS who have either had a delay in getting a diagnosis, or a delay in getting access to effective therapy, compared to those pwMS with early access to optimal therapies with no evident inflammatory disease activity (NEIDA). A large number of the latter pwMS are leading near-normal lives, whereas the former have to live with the consequences of end-organ damage. Bladder, bowel and sexual dysfunction, cognitive problems, anxiety, depression, fatigue, and all the rest that goes with a failing nervous system. I am stressing the hidden problems because they are invisible to others but cause so many problems for individuals with MS. For those who need reminding, the blue or symptomatic line in my MS tube map is the consequence of end-organ damage; maybe I should change it to the end-organ damage line?
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 clinically isolated syndrome studies disability at 14 years and beyond correlates with the lesion volume on MRI at 5 years and the increase in lesion volume over the first 5 years (Brex et al. N Engl J Med. 2002 Jan 17;346(3):158-64.). In natural history studies, it is the number of relapses in the first two years that predicted poor outcomes. PwMS who only had 1 relapse in the first 2 years compared to those who had 3 or more relapses take 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 (Scalfari et al. Brain. 2010 Jul;133(Pt 7):1914-29). 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 a 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 an immune reconstitution therapy or IRT? I would argue the latter but instead of using alemtuzumab or HSCT, I would probably recommend something with a better safety profile such as cladribine. However, this is not possible at present in the NHS as cladribine is not licensed for CIS and the current NHS England treatment algorithm is quite clear that we shouldn’t treat CIS.
NHS England Treatment Algorithm: ‘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.’ (Treatment Algorithm for Multiple Sclerosis Disease-Modifying Therapies (NHS England Reference: 170079ALG, Date Published: 4 September 2018, Updated: 8 March 2019 Gateway reference: 07603)
Fortunately, the number of patients presenting with a clinical event who have CIS is now very small and most of them have MS if they have 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, yes and yes, please.
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?
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
I first developed nerve pain in my hands in 2009, misdiagnosed as carpal tunnel. When surgery failed I saw a neurologist in 2010 who said I did not have MS, but did have a patch of inflammation on my spinal chord. After a relapse in November 2018 which affected my balance- misdiagnosed as vertigo - I eventually saw a neurologist at the hospital I worked at, only arranged by a medic friend with a mother with MS who recognised the symptoms, and was finally diagnosed with MS in April 2019. He told me I should have been diagnosed in 2009. Started on Tecfidera immediately, no relapses since but have since had to medically retire. Disappointing that I was not diagnosed in 2010, when I might have started treatment earlier.
This article was so enthralling and moving to read. I have had MS since 1992 with a few relapses early on and nothing really to note since. I have been off beta interferon for about 15 yrs. I have secondary MS with minimal disability. I walk slowly with a stick and suffer from Fatigue. My neurologist says there are no drugs or nothing for inactive disease? It feels a bit like you life in their hands.