Barts-MS rose-tinted-odometer: zero-★s
I saw her in the clinic last year for a second opinion. She has secondary progressive MS and had been on fingolimod for just shy of 4 years with an EDSS of at least 5.5. She was using a walking stick intermittently, particularly when mobilising outdoors and her EDSS was probably 6.0 or even 6.5 because on her own admission she was unable to walk 100m. She was told by her treating neurologist that according to NHS England guidelines he was going to have to stop her fingolimod because she had secondary progressive MS. He told her she must not worry because in 12 months time she could be eligible for the high-dose simvastatin or STAT-2 trial. Despite being anxious she stopped her fingolimod and two months later she had a rebound relapse with a brainstem syndrome. Repeat MRI after the relapse showed she had at least 8 new lesions. When I saw her she had an EDSS 7.0, which was during the recovery phase of her relapse. We restarted her on fingolimod. She has managed to claw back some function and her EDSS is between 6.5 and 7.0.
This case is not unique. Several times a year one of my colleagues will discuss a patient who has advanced MS (wheelchair-user) who after stopping their DMT have recurrent inflammatory activity and relapse. Please note that we have to stop DMTs when patients become wheelchair users or reach an EDSS of 7.0; this is what the NHS England’s stopping criteria mandate (black and white?).
NHS England Stopping Criteria 2019
The current DMT should be stopped if any of the following criteria are met:
1. No reduction in frequency or severity of relapses compared with the pre-treatment phase following adequate exposure to the DMTs (which varies for each DMT, but should be a minimum of 6 months)
2. Intolerable adverse effects of the drug
3. Development of inability to walk (EDSS 7.0), persistent for more than 6 months due to MS
4. Confirmed secondary progressive disease with an observable increase in disability for more than a 12 month period, in the absence of relapse activity. Secondary progressive disease would usually only be diagnosed in patients with an EDSS of 6.0 or greater. (Except for the rare phenotype of “relapsing-progressive multiple sclerosis” detailed in section 13).
Criteria 1 and 2 might lead to switching to alternative DMTs.
Criteria 3 and 4 will lead to stopping all DMTs.
Past criteria have included pregnancy, breastfeeding or attempting conception, but increasing evidence shows that some DMTs may be considered safe in these situations.
Stopping DMTs should lead to continued care within the MS team or transfer of care to services which can provide appropriate support, such as neuro-rehabilitation. If a drug is stopped for a reason other than intolerance or lack of efficacy, then it may be restarted at a later date, even though the patient may not have “requalified” through new lesions. This may apply, for instance, to people who come off a drug during pregnancy or to take an experimental drug in a trial.
Rebound MS disease activity is particularly problematic with anti-trafficking therapies such as natalizumab, fingolimod and potentially with the other newer-generation S1P modulators (siponimod, ozanimod, ponesimod). This is why I feel so uncomfortable about applying the NHS England’s stopping criteria to patients on these therapies. Another thing to remember is that the NHS England treatment guidelines are only based on evidence in terms of starting DMTs. In comparison the stopping criteria are not evidence-based, which is why I proposed we do a national trial to see how appropriate they are.
I suggested a few years ago that we, the MS community, do a randomised controlled trial to assess the efficacy of generic cladribine in patients with advanced MS. Patients having to stop their existing DMT because they have developed SPMS or reached EDSS 7.0 are randomised to treatment with generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function. The trial will be an event driven study and if someone reaches study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo or a further course of treatment or another off-label salvage therapy if they had been randomised to cladribine.
The SALVAGE-MS study would become part of our suite of #ThinkHand trials; i.e. to salvage upper limb function in people with 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 really question NHS England’s stopping criteria. Do you agree?
Another practice that is emerging is the stopping of DMTs in patients with so-called ‘inactive SPMS’ in the hope they become active and hence are eligible for siponimod treatment. Please note this practice puts patients like the one above at risk of rebound disease activity, which may come at a cost to the individual.
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.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.