Friday, 21 October 2016

ClinicSpeak & ResearchSpeak: to stop, or not to stop, DMTs in SPMS that is the question

Stop DMTs and do the right thing; save the NHS money! #ClinicSpeak #MSResearch #MSBlog #ResearchSpeak

The small French study below concludes that in pwSPMS on DMTs it is safe to stop DMTs because the relapse rate stays relatively constant off, or on, treatment. Please note that 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). What they don't tell you is how massively under-powered their study is (they only had 100 participants in this study) and the study was uncontrolled (no comparator group). When we want to show that a DMT works in progressive MS we take a large number of pwMS and randomise them to active treatment or placebo. The PPMS-ocrelizumab study randomised 732 subjects and the SPMS-siponimod study 1651 subjects; do we really expect 100 pwSPMS to answer the reverse question? 

What we really need is a randomised double-blind study where we randomise pwSPMS on DMT to remain on their active treatment or to placebo and then we wait see what happens in terms of long-term outcomes. A non-blinded study like this is being planned in the US. The best we have is the MS-BASE data below using real-life data and matching of subjects at baseline (propensity scoring). This study included 485 DMT-stoppers and 854 DMT-stayers followed for at least 3-years. Unsurprisingly, time to confirmed disability progression was significantly shorter among DMT stoppers than stayers, implying that the stayers were still deriving benefit from their DMT. Some would argue that this study took all-comers and not just pwSPMS. I would counteract that argument that the progressive pathology that drives both SPMS, and PPMS, is there from the beginning of the disease and that our clinical definition of when SPMS begins is arbitrary. 

Stopping DMTs in pwMS who have transitioned from the relapsing to the clinically-apparent SPMS phase is at present is non-evidence based and flies in the face of recent data showing that DMTs, in particular high-efficacy therapies, are still having an effect on protecting upper limb, and possibly bulbar (speech and swallowing), function in pwMS with more advanced disease. This is why I find it hard to stop DMTs in people who have SPMS. 

Despite the lack of evidence to help us we have strict NHS guidance to stopping DMTs in pwSPMS. The latter is mainly driven by costs; the NHS is on its knees financially and any cost savings are welcomed. Another solution would be to ask the NIHR to fund a randomised DMT stopping trial to see if we can generate the much needed evidence to guide clinical practice?

SAVE THE NHS MONEY!

Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181

BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.


METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.

RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).

CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.


Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.

BACKGROUND:  Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.


OBJECTIVES: (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.

METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.


RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.

CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.

CoI: multiple

7 comments:

  1. I find this post to be somewhat biased in favor of the aggressive use of pharmaceuticals in patients where there is questionable or unproven benefit. Anyone with any reasonable clinical experience is skeptical of the use of DMTs in progressive MS because they have seen so many patients progress on treatment. The problem with these studies is that they include people who still have relapses and still make new T2 or gad+ MRI lesions. Obviously, these are markers of inflammatory activity, and we should offer DMTs to such patients. The real question is, "are you hot or are you not?" In other words, "Do you have objective signs of active inflammation in your disease as evidence by clinical relapses or MRI change?" I think there is overwhelming evidence that progressive multiple sclerosis includes a component of degenerative disease marked by neuronal death, brain atrophy, and mitochondrial failure which is distinct from inflammation and does not respond to disease modifying therapy-even highly potent treatments including hematopoietic stem cell transplant. Do you really think that natalizumab magically protects the upper extremities and not the lower extremities? This is nonsense. The only reason that this trial has a hint of positivity is because it includes patients who clearly have active inflammation. If you repeat the trial with 60+ year olds with no superimposed relapses and stable MRI scans for many years, do you really think natalizumab is going to magically prevent gradual worsening of the upper extremities? Just looks in your waiting room. These treatments are not working. We need a revolution in our treatment strategy. Let us admit our shortcomings and continue the search.

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    1. Re: "I find this post to be somewhat biased in favor of the aggressive use of pharmaceuticals in patients where there is questionable or unproven benefit."

      The patients being studied here were on DMTs presumably from when they had relapsing disease. They have now become SP clinically. We all have large numbers of these patients in our clinics. What do we do with them? The evidence of what to do with them is not available, which is why we need trials. Stopping treatment is an option, but as you can see from even these studies the ones in whom you stop the treatment reactivate and progress more quickly compared to those who stay on treatment.

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    2. Re: "The only reason that this trial has a hint of positivity is because it includes patients who clearly have active inflammation. If you repeat the trial with 60+ year olds with no superimposed relapses and stable MRI scans for many years, do you really think natalizumab is going to magically prevent gradual worsening of the upper extremities?"

      The ASCEND population where chosen not to be active, no relapses and very few had Gd+ve MRIs. Over 60% of them were EDSS 6.0 & 6.5. This was a very different population to the EXPAND (Siponimod) and ORATORIO (ocrelizumab) who were both more active; lower EDSS scores and more activity on scans. So yes I think natalizumab must be having an effect on inflammation, probably microscopic foci below the detection level of the MRI scans.

      You can be sceptical and write-off the results, but then you are probably not someone who has MS and wants to maintain their arm and hand function.

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    3. Re: "We need a revolution in our treatment strategy. Let us admit our shortcomings and continue the search."

      We still need an potent anti-inflammatory at the base of the pyramid. We then need to add-on neuroprotective and neurorestortative therapies. The idea that you can hope to have a big impact on progressive MS whilst leaving inflammation untouched is one of the reasons why we have failed with several neuroprotective trials; lamotrigine, THC, etc.

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    4. Please could you explain when you consider a pwMS to be "SP clinically". In your view, can a person still have inflammatory activity and be SP?

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  2. 100% agree with anonymous 11:24 PM. I do really appreciate your Bart's posts but they do seem quite unbalanced in terms of your treatment pyramid. Much of the focus in the MS world of research, in general, is solely on inflammation but not on progression, remyelination or neuro-restoration. Progression is thought to be due to loss of gray matter or atrophy and there is almost a complete paucity of B and T-cells in this gray matter on autopsy/pathology results. I believe your hope is that if you catch the inflammation early enough that your will prevent a move in to progressive state and I hope you are right for the new and next generation of MS patients. This line of thinking has proven to be an economic and health disaster with CRAB drugs, which show no signs of stopping RRMS to converting to SPMS (or progression). I hope I am wrong and that the newer potent immunosuppressants work better and stop progression but I will believe when I see it, as I firmly believe something else other than B and T-cells are causing progression of this miserable disease.

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    1. "as I firmly believe something else other than B and T-cells are causing progression of this miserable disease."

      I agree. They are clearly involved in MS - more heavily in some than others - but progression as I have experienced it seems a process in itself. This PPMS began in my 20s. I do not believe that a potent anti-inflammatory would do much for me at all.

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