Early relapses

E

“Contrary to recent previous comments relapses do matter; particularly within the first 2 years.”

“Why do I say this?”

The following study investigated the relationship between relapses and disability progression for outcomes of requiring assistance to walk, being bedridden and dying from MS; i.e. EDSS 6, 8 or 10 respectively.

This group has previously shown no effect of relapse frequency among progressive MS subtypes (a post that caused many comments). 
In this study, however, the researchers examined these measures in the relapsing-remitting phase. 
Frequent relapses in the first 2 years and a shorter interval between early attacks predicted shorter times to reach disability endpoints. 
For example, MS’ers with one attack in the first 2 years took 7.6, 12.8 and 20.3 years longer to reach EDSS 6, 8 and 10, respectively, when compared to MS’ers with 3 or more attacks in the fist 2 years. 
Relapse frequency beyond year 2 did not predict the key outcome of secondary progression or times to EDSS 6, 8 or 10. 
Conclusion: This study suggests there are two distinct disease phases related to late disability outcomes and that theses phases appears to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset. 
“Therefore suppressing early relapses within the first two years of disease onset may be more effective in modifying later disease progression than suppressing relapses after the first two years from disease onset. This may explain the different efficacy results between the phase 2 and phase 3 Alemtuzumab trials; the phase 2 trial recruited subjects within 3 years of disease onset and the phase 3 trial within 5 years of disease onset.”

“It will be very interesting to see the sub-group analysis of the phase 3 Alemtuzumab trial comparing study subjects with a disease duration of less than 2 years with those with a disease duration of more than 2 years. Any bets on the results?”
Extra reading: EDSS, Alemtuzumab

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

21 comments

  • Please write something on how to count relapses

    If mild symptoms appear and go away in days or weeks without solumedrol treatment, is that a relapse?

    What about MRI results that show fresh activity without clinical change?

  • I've always felt that there is too much uhming and aahing about whether a relapse has actually occurred or not, particularly if symptoms have been "mild" in the first place. That's why I truly believe that MS'ers need access to routine MRI scans, as it would give a more definitive guide as to whether that "tingly feeling" or that "perceived loss of strength" or those "balance problems" are actually relapses or not and can, therefore, help target therapies accordingly to prevent further relapses in early-stage disease.

    As an MS patient it's highly frustrating and annoying when you present symptoms of what you think may be a relapse, are told it may be or may not be but then you're given no further help in determining for certain whether it is or not.

    Or maybe I look at things too simplistically?

  • Sorry boss, but I strongly disagree with your logic.

    You are inferring from an observation an unsubstantiated therapy action plan!

    and please, let's avoid the cheap populism with the "bets" routine… [Yeah, I wanna bet my life, my marriage, my mobility, and my children's college education. Which bet are you willing to place against mine?]

    Let's leave social journalism to unqualified party. You ought to focus on translating medical jargon into a simple layman's news feed. That's it!

    Otherwise, I have very few sources to rely on….

  • Fully agree with the very last comment.
    And to add to it, how are one's decision drivers influenced by the relapses in the first 2 years.

    Does that mean that the latter's risk/benefit analysis of all available treatment is dependant on his short term disease history?

    Will one take risks on 40+ years of disease progress on the back of a mere study, instead of choosing the most optimal therapy?

    This seems to me pure noise that will just add confusion to murky waters.

  • As someone who has not been diagnosed yet but has had two "relapses" in a one year period as shown in MRI scans, in my experience, I feel that general neurologists do not see urgency for diagnosis. For varying healthcare bureaucratic reasons, I've been waiting over four months for an LP and still no sign of an appointment date despite there being familial history of MS already. But all the pushing and chasing to get an LP done is being instigated by myself as I understand how important it is to get a diagnosis earlier rather than later – whether it is MS or not. In my experience, general neurology does not seem to think diagnosis of MS is urgent, as progression is over a period of time.

  • This study was for untreated patients. What is the graph or treated patients?
    A worrying thought: perhaps a DMT just suppresses relapses or reduces their severity without changing time to disability.

  • Re; "A worrying thought: perhaps a DMT just suppresses relapses or reduces their severity without changing time to disability."

    I agree. There is no serious proof that relapses and progression are the same pathological disease. That is why some people get progression from the outset and for others there is as period of relapses followed by full blown progression. By that stage the DMTs don't work anymore, and who knows, maybe they never really did other than dampening the relapse. If relapses lead to progression then why do some people not have any relapses and just become progressive? Likewise, why do DMTs stop working when a RRMS patient become SPMS?

    I'm not convinced by your argument Prof G.

  • Re "I'm not convinced by your argument."

    I can't win this argument either way, so I will sit this one out. The good news is that the experiment is running already. We need to sit back and wait 10 to 15 years to see what happens to MS'ers treated with with Alemtuzumab and other aggressive therapies. If it stops them becoming progressive, or delays the onset of SPMS, I win.

    The question is are you prepared to wait that long?

    The same questions arose in rheumatoid arthritis (RA) when the very active new biological therapies emerged about 15 years ago. These therapies are very effective at suppressing inflammation in the joints and preventing flare-ups of disease, but would they prevent long-term damage to joints; the RA equivalent of SPMS? What happened? Well orthopaedic surgeons rarely have to do joint replacements in RA'ers these days. These therapies prevent progressive RA.

    We have to take the same approach with MS; we can't replace the brain and spinal cord in the same way that we replace damaged joints. The brain and spinal cord are too precious! We need to work on the premise that by treating early and aggressively we will change the natural history of MS.

    If this blog is still running in 15 years time I suggest we revisit this debate.

  • I'm sure we are all hoping you win this argument, for the sake of the future patients who can get aggressive therapy in the first two years.
    You haven't said anything about interferons, early diagnosis & what counts for a relapse.

  • Re: "If mild symptoms appear and go away in days or weeks without solumedrol treatment, is that a relapse?"

    Yes, if they persist for 24 hours or more and did not occur in association with an infection or fever.

  • Re: "What about MRI results that show fresh activity without clinical change?"

    Most in the field view MRI activity without clinical symptoms, sub-clinical disease activity or a sub-clinical relapse. We know these lesions cause damage.

  • Re: "As an MS patient it's highly frustrating and annoying when you present symptoms of what you think may be a relapse, are told it may be or may not be but then you're given no further help in determining for certain whether it is or not."

    You are the one with the disease. I typically give the patient the benefit of the doubt.

  • Re: "Let's leave social journalism to unqualified party."

    Not sure I understand this one.

  • Re: "Does that mean that the latter's risk/benefit analysis of all available treatment is dependant on his short term disease history?"

    Yes, in the UK the Department of Health's risk sharing scheme under which we prescribe the first-line MS disease-modifying therapies, such as interferon-beta and glatiramer acetate, only looks at disease activity in the last 2 years.

    In comparison, the NICE guidance on Natalizumab only looks at disease activity in the last 12 months. MS'ers have to have two disabling attacks or relapses with the last 12 months with evidence of MRI activity to support the relapse activity.

  • Re: "As someone who has not been diagnosed yet but has had two "relapses" in a one year period as shown in MRI scans, in my experience, I feel that general neurologists do not see urgency for diagnosis."

    Why the delay? NICE guidelines on MS emphasise the need to make the diagnosis quickly and for a follow-up to occur within 4 weeks of the diagnostic tests. In England we have to get all this done within 18 weeks.

    I would suggest you discuss this with your neurologist.

  • RE: "You are the one with the disease. I typically give the patient the benefit of the doubt."

    That's why it's refreshing to come across a neurologist such as yourself, who seems to really listen and tries to see things from the patient's point of view!

  • Re: "Do we have a choice?"

    Yes, that's if you have RRMS. We have licensed "first-line" therapies and and two licensed therapies for highly active MS. There are also numerous other drugs that will come on line in the next few years.

    Unfortunately, the story is very different if you have non-relapsing progressive disease. But we are working on it.

  • "if you have RRMS. We have licensed "first-line" therapies and and two licensed therapies for highly active MS. There are also numerous other drugs that will come on line in the next few years."

    I really hope Alemtuzumab becomes available next year. As a recipient (with very active MS at the time), I haven't had a relapse since my first infusion (5 years ago) and my EDSS improved in the first year and has remained stable since. I work full time – colleagues don't know I have MS. I still have deficits (mainly sensory) from earlier relapses and I'm guessing these are now permanent.

    As Prof G says a number of therapies will be available in the next few years for RRMS.

    Hopefully, with the availability of highly effective therapies the focus of research teams and drugs companies will be on stopping progressive disease and encouraging some repair.

    Prof G – thanks for your RA analogy.

  • "Re: Why the delay?"

    A series of bureaucracy errors at the hospital. I understand mistakes can happen, but what I've found frustrating is that the onus has been put on me as a patient to sort it out when it wasn't even my fault. That's why I've had the impression from my neurologist that there is no hurry as I'd have assumed that if there was, he'd have taken an active role sorting this out rather than a passive one waiting for me to do it!? I don't mean to rant but my patience has been wearing thin in the past few weeks!?

  • Yes, the RA analogy was very helpful.

    '..haven't had a relapse since my first infusion (5 years ago) and my EDSS improved in the first year and has remained stable'- That is a dream treatment & I hope it becomes available to lots of people.

    Despite the latest results I still hope it will help people who have been diagnosed longer than two years.

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