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#ClinicSpeak & #ThinkHand: stopping DMTs - are you salvageable?


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Could the SALVAGE trial be something the NIHR and/or MS Society would fund? #ClinicSpeak #ThinkHand

At least once a month Barts-MS have a MDT (multidisciplinary team) meeting to discuss difficult cases. One of my colleagues presented a patient who was had advanced MS (EDSS 7.5 = wheelchair bound) who was still on interferon-beta. So in keeping with NHS England guidelines she stopped the interferon-beta. Three months later this patient presented with double-vision due a brain-stem relapse. An MRI with contrast showed multiple Gd-enhancing lesions indicative of reactivation of MS disease activity, or possibly rebound, post-interferon-beta. As this patient was not eligible to be restarted on a licensed DMT, we at the MDT recommended that the patient be offered off-label treatment with generic subcutaneous cladribine. Our position was that although the patient may be wheelchair-bound with advanced MS, she still had upper limb (arm & hand) and bulbar (swallowing and speech) function to try and preserve. This patient is not unique and almost every MSologist I know working in the NHS has similar cases. 

Since Thursday I have been thinking about this case and as NHS England get more militant with implementing their DMT stopping criteria we as a community need to do some proactive about this. I am therefore suggesting we do a randomised controlled trial to assess the efficacy of generic cladribine in patients with advanced MS? In essence as someone stops their existing DMT they are randomised to treatment with generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function. We can make this an event driven trial and if someone reaches study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo. If they had broken through on cladribine they could be offered a further course of treatment or another off-label salvage therapy. 


Should we at least try and salvage upper limb function in more advanced MS?

The real question is do we have equipoise to do this study? Please note that in a small French study below, of stopping DMTs in pwSPMS, 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). Similarly, in the MS-BASE study below, of 485 DMT-stoppers vs. 854 DMT-stayers followed for at least 3-years, time to confirmed disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should ignore NHS England, because their stopping criteria are not evidence-based and give the patient the option of stopping their DMT or continuing with it. What do you think? 


<iframe allowfullscreen="true" frameborder="0" height="530" mozallowfullscreen="true" src="https://docs.google.com/presentation/d/1YCB36mV6bhkR_bncsNle5_aAgHlaQF-HHl3FX-6idWs/embed?start=false&loop=false&delayms=3000" webkitallowfullscreen="true" width="680"></iframe>

FRENCH STUDY

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.

MS-BASE STUDY

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.

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