Sunday, 8 April 2018

Guest post: Stopping therapy - is it worth the risk?



Some MSers ask if they can stop taking DMTs after being stable for a long time, especially older pwMS and people with advanced MS. This is a two-sided discussion: There are those who are for it and those who are against it. Let’s take a closer look at the arguments of those on each side of this fence:


Discontinuing DMTs?
Yes
No
·       Inflammatory features of MS decrease over years and other mechanisms drive disease progression.
·       Relapses become less frequent with age, especially in patients who are 60 or older.
·       The immune system also ages and does not work as well, making immune modulation less necessary.
·       Older patients may be at greater risk from infectious and neoplastic complications associated with immunosuppressive medications.
·       DMTs mostly have not proven beneficial in progressive non-active stages of MS.
·       Many patients with advanced MS still have upper limb (arm & hand) and bulbar (swallowing and speech) function that should be preserved as much as possible.
·       We are fully aware of the MS rebound that occurs when some DMTs are withdrawn.
·       Some patients do not recover fully from a relapse. That is why severe relapses after discontinuation of DMTs can lead to substantial worsening of disability, especially in older patients.
·       Robust evidence is lacking to support therapy withdrawal at any time point and premature discontinuation may lead to worse outcomes.


Disease activity in MS is extremely variable, so predicting how it will progress in each person is very difficult. Despite discontinuation studies in younger stable patients have reported mixed results, more recent research has shown that older patients who discontinued DMT, remained off DMT and relapse-free. Age, therefore, appeared to be one of the most important predictive factors of future outcome after therapy discontinuation. Although a prospective randomized controlled trial on DMT discontinuation will hopefully provide more definitive guidance, we have previously considered how unethical it would be for us to stop a DMT in someone and randomise them to a placebo: http://multiple-sclerosis-research.blogspot.com/2017/08/clinicspeak-thinkhand-stopping-dmts-are.html.

While most data is true at the population level, I am an enthusiastic supporter of an individualized approach to each case in terms of treatment strategies. In this post, I would like to emphasize the importance of close medical follow-up of MSers, even those with a chronic non-active disease. Proactive monitoring and shared decision-making are key. To give you an idea of how important this is, consider that MSers who stopped DMT on the advice of providers do better than those stopped on their own.

The article below presents two female MS patients, aged 61 and 67 years, who experienced unexpected acute clinical MS exacerbations after decades of chronic non-active disease.
What do you think? What else would you like to add to the table above? 

Haupts MR, Spill-Askeridis P, Humpert M, Seidel D, Hartung HP. Acute exacerbations after decades of non-active chronic multiple sclerosis. Mult Scler. 2018 Jan 1:1352458518754365.

CASE 1 had been diagnosed with RRMS 41 years ago. She had not been on DMD therapy before admission. After three decades of a “chronic progressive, non- active” course, she presented with an increase in her paraparesis, marked fatigue and abrupt cognitive deterioration. Her Expanded Disability Status Scale (EDSS) was 7.5. Cranial MRI showed four active gadolinium-enhancing lesions in the parietal deep white matter bilaterally. She was treated with high- dose intravenous corticosteroid therapy and improved.

CASE 2 had been diagnosed with MS 42 years before. She had been on interferon beta 1 a (IFN beta-1a) 22mcg sc tiw during the last 13years. IFN had been stopped 3 months before admission as neutralizing antibodies (NAbs) against IFN were demonstrated and confirmed. She presented an acute exacerbation with a pronounced left-sided spastic tetraparesis and severe fatigue. Spinal MRI showed gadolinium- enhancing T1 lesions in her cervical cord. EDSS was 6.5. She received an intravenous corticosteroid pulse and experienced walking improvement.

**In both cases, no additional trigger factors (viral infec- tions, comorbidities, etc.) except withdrawal of DMD treatment in the presence of neutralizing anti-drug antibodies in the second case were found.

by Saúl Reyes


14 comments:

  1. I have a couple of questions
    1. I completely agree with your arguments as to why people with progressive MS should continue their DMT but I thought that with NHS England's new blueteqthat someone with advanced MS who cannot walk should have there DMT withdrawn. Can GG please clarify that.
    2. What do you do if you have had alemtuzumab your Ms continues to worsen but you are in a chair so you do now not qualify for other treatments?

    ReplyDelete
    Replies
    1. Yes, NHS England guidelines state that we should stop DMTs once a patient becomes secondary progressive and/or if they reach EDSS 7.0. At present this is not policed, but will be soon when we have to submit annual EDSS scores on all patients on DMTs via blueteq.

      Delete
    2. Do EDSS scores fluctuate during the day? Even a small amount.

      Do factors such as time of the month for women (internal body heat increasing symptoms), time of day and recent exercise impact on EDSS scores.
      I know exercise before a neurological examination might improve things very temporarily such as exercise can give relief of a tremor for a few hours (from my own experiences).

      In other words, if I had my neurological examination in the morning when I'm at my best, not the time of the month and after some exercise would my EDSS score be better?

      Delete
    3. Anon 11:31, good point. EDSS is just a snapshot of the patient’s condition and with a disease such as MS, that is not static, it is not very accurate.

      Delete
  2. Even stable MS patients exhibit low level or smoldering inflammation. Also, since we do not know the cause of this disease or the source of the neuroinflammation it would be unwise to discontinue DMTs.

    ReplyDelete
  3. "High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only
    for patients younger than 40.5 years."

    progressive MS is simply a later
    stage of the MS disease process and that age is an essential modifier of a drug efficacy.
    Higher efficacy treatments exert their benefit over lower efficacy treatments only during
    early stages of MS, and, after age 53, the model suggests that there is no predicted
    benefit to receiving immunomodulatory DMTs for the average MS patient.

    Meta-analysis of the age-Dependent
    efficacy of Multiple sclerosis
    Treatments

    doi: 10.3389/fneur.2017.00577

    "There are now over a dozen disease modifying therapies (DMTs) approved for MS since 1993, and these have significant impacts on development of new relapses and MRI changes, but much less effect on slow progression. Almost all clinical trials identifying benefit of MS DMTs have had a maximum age of 55, and subgroup analyses by age of many different MS clinical trials reveal that response to presently available DMTs is greatest in younger patients, especially those under age 40. These observations suggest it may be reasonable to consider a trial off of DMTs, especially for older patients who have been clinically quiescent, but in practice many patients simply start using a DMT at clinical onset and continue indefinitel"

    "The relative futility of presently available DMTs in aging MS patients, especially those with progressing symptoms, argues strongly for development of approaches that diminish neurodegeneration and enhance CNS recovery and/or regeneration."

    https://onlinelibrary.ectrims-congress.eu/ectrims/2017/ACTRIMS-ECTRIMS2017/202618/john.corboy.disease.modifying.therapy.in.the.aging.multiple.sclerosis.patient.html?f=media=3

    Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS – Commentary

    For treatable, chronic conditions such as multiple sclerosis (MS), it is often unclear whether deliberate treatment discontinuation due to presumed lack of necessity or overall benefit is reasonable and safe. In this issue of Multiple Sclerosis Journal, Kister1 and Tobin and Weinshenker2 argue different sides of this debate, but come to a similar conclusion—maybe

    "Finally, the apparent reduction in efficacy of the presently available DMTs in the aging MS patient, at a time when many are experiencing progressive disability, should be a reminder that there remains a critical need to develop therapies directed toward this patient population. These might be focused on the meningeal infiltrates, cortical abnormalities, and microglial activation seen more prominently in progressive MS, but also should include neuroprotective and regenerative approaches focused on repair."

    http://journals.sagepub.com/doi/10.1177/1352458517717809

    Obrigado

    ReplyDelete
    Replies
    1. All these analyses are based on the EDSS that is really not fit for purpose. When you start using upper limb function in more advanced MS you get a different answer. The exception being with the S1P modulators.

      Delete
  4. I would ask the author of this post the following question: the risk of relapse in someone over 55 who has entered progressive phase of MS is estimated to be about 5% (see http://n.neurology.org/content/84/1/81.short). Assuming that platform therapies (injectables) work in older patients the same as in younger patients - an unproven assumption - we would the estimate that risk of relapse in the older progressive patient is decreased to 3.5% if they continue on DMT. Even if this is a true reduction in relapse risk, is it worth continuing platform therapy for decades on end for such 1.5% reduction risk??
    At the same time we need to remember that even 'benign' therapy like IFNb is not risk free; a recent study suggested 1.8 increase in risk of stroke (http://n.neurology.org/content/neurology/early/2017/05/12/WNL.0000000000004037.full.pdf).
    Bottom line: I do not think we can learn much from these cases about discontinuing DMT. All we can say is that MS pts can supersize us and sometimes have relapses when 'they are not supposed to'. I could present patients from my own practice with chronic progressive MS who had unexpected bad relapses at advanced age despite being on DMT.

    ReplyDelete
    Replies
    1. Most experienced MSologists have anecdotes of older MSers coming off DMTs and going on to have catastrophic relapses. It is very difficult to stop a maintenance therapy with any confidence. The evidence-base in this space is very weak.

      Delete
    2. I do not dispute that such cases exist, however preponderance of evidence (some of it cited in the response chain above)) suggests that there is no uptick in relapses upon stopping DMT. Here is another very recent article that suggests that older pts who stop DMT overwhelmingly do not need to restart it -

      Send to
      Mult Scler. 2018 Mar 1:1352458518765656. doi: 10.1177/1352458518765656. [Epub ahead of print]
      Discontinuation of disease-modifying therapy in patients with multiple sclerosis over age 60.
      Hua LH1, Fan TH2, Conway D3, Thompson N4, Kinzy TG4.
      Author information
      Abstract
      BACKGROUND:
      The risk-benefit ratio of continuing immunomodulating disease-modifying therapy (DMT) in older multiple sclerosis (MS) patients is unknown.

      OBJECTIVE:
      To evaluate clinical and patient-reported outcomes after stopping DMT in older MS patients.

      METHODS:
      Retrospective, observational study identifying patients from our MS clinics who were aged over 60 and on DMT > 2 years. Cause-specific Cox proportional hazards regression modeled time to discontinuation and time to reinitiation of therapy. Pre- and post-discontinuation comparisons of Performance Scales (PS), Timed 25-Foot Walk, and Patient Health Questionnaire-9 (PHQ9) were analyzed using linear mixed models.

      RESULTS:
      A total of 600 patients were included, with 178 (29.7%) discontinuing. Discontinuers were 2.2 years older, had 3.2 years longer disease duration, and 1.6 years lesser treatment exposure. Providers initiated discontinuation more than patients (68.0%). Only one clinical relapse occurred in discontinuers. A proportion (10.7%) reinitiated DMT. Provider-initiated discontinuers restarted less often (hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.12-0.9). In discontinuers, relapsing-remitting patients had lower PS on average than primary progressive. Provider-initiated discontinuation was associated with lower PS than patient- initiated discontinuation. PHQ9 scores appeared higher in those stopping intravenous (IV) therapies than interferons. Lower PS and PHQ9 indicate better outcomes.

      CONCLUSION:
      Most patients over age 60, who discontinued DMT, remained off DMT. This study provides real-world data that may guide clinicians considering discontinuing DMT.

      Delete
  5. Meanwhile, there is compelling evidence of the potential benefits of non-pharmacological interventions https://www.linkedin.com/pulse/meeting-ms-patients-point-unmet-health-needs-dr-mario-weiss/?published=t

    ReplyDelete
    Replies
    1. Couldn't agree more; exercise, diet, sleep, con meds, comorbidities, mental health, wellness, etc. all have a major role to play. This is why we talk about the holistic management of MS. These are in my opinion complementary and not alternative to DMTs.

      Delete
  6. Its all a bit of a vicious circle. As MS becomes more advanced so issues like fatigue, sleep, diet and mental health wellness become more of an issue. So the MS sufferer takes less care of him/her self and their social life shrinks (social capital). As their social capital shrinks so the MS advances even more rapidly.

    I think people with any advanced Long Term Condition need help to look after and preserve their mental & physical well being as well as medical treatment if it exists. There needs to be some serious thought and education given to this problem.

    ReplyDelete
  7. Can you comment on the decision to initiate or not maintenance therapy after a patient has received two cycles of treatment with alemtuzumab? At what point does waiting for a return of disease activity to initiate a DMT after an induction treatment become similar to being "off treatment"? Phrased differently, how do you decide whether or not to start a maintenance therapy after an induction treatment?

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.