Flipping the pyramid

Was the concept of flipping the pyramid as a treatment strategy explained to you when you were started on a DMT?

For several years I have been arguing for adopting the concept of flipping the pyramid as a treatment strategy for MS. This is a treatment strategy developed by rheumatologists for treating rheumatoid arthritis with great success. In short, flipping the pyramid is using very high efficacy treatments first line. The other treatment strategies are watchful waiting, slow escalation or rapid escalation.

I kid you not that watchful waiting is still alive and kicking, but is less common now than it was a decade or so ago. The message is finally getting through that ‘active MS’ is a modifiable disease and should be treated. Please note my emphasis on ‘active MS’, we are unable to offer people with inactive MS DMTs nor should we, therefore, watchful waiting is entirely appropriate in this situation. The debate, however, is about how to define inactive MS and how hard should we interrogate patients to exclude smouldering MS?

The slow escalation strategy uses clinical monitoring to make a decision to change treatments or not and is probably still the norm in the UK. The main reason is a lack of resources, i.e. staff and MRI scanners to implement annual MRI monitoring. Rapid escalation is probably the most common option chosen by patients and neurologists in other high-income countries, however, frequent MRI monitoring which is costly remains a barrier in many parts of the world.

By maintenance-escalation, we mean starting low and escalating up a treatment ladder using MRI monitoring to assist decision making. We know from several real-life data sets and clinical trials that on average you do better if you start on either natalizumab, fingolimod, alemtuzumab, daclizumab or more recently ocrelizumab, compared to the lower efficacy platform therapies.

It is very reassuring to see the latest real-life data set from Wales showing how much better pwMS do when they have started an ‘early intensive therapy’ compared to a ‘moderate efficacy maintenance-escalation’ approach. The evidence is now overwhelmingly in favour of the former treatment approach.

The question is whether or not neurologists and HCPs will at least register these observations and start to offer their patients a choice between these two treatment approaches?

When we designed our treat-2-target NEDA trial to compare these two approaches, several years ago, these concepts were quite new. When the trials finally got funded we at Barts-MS declined to participate because we don’t think there is clinical equipoise anymore; in other words, we don’t think it is ethical to randomise patients to a maintenance-escalation arm of a study given the emerging evidence-base.

At Barts-MS we feel strongly that our patients are educated about the above issues and actively participate in the decisions about which treatments they are started on or switched to. This does not mean that we the neurologists are not involved. In some situations, we make the decisions for our patients or limit the choices available because of extenuating factors. We also offer patients the choice of allowing us to choose or recommend a specific treatment for them. Interestingly, with the rising complexity of treatment options many more patients are opting for the latter.

Paternalistic medicine, i.e when the doctor makes the decisions, is making a comeback but only this time as an informed choice

Many of the relevant issues I discuss above were covered in my ‘Hot Topics’ talk at ECTRIMS. I am going to suggest I do a Hangout on this topic to go through these in more detail and to allow you to ask questions. In particular, I need you to understand about the cognitive bias I refer to as the Gambler’s dilemma and how you need to try and overcome it when making decisions about your treatment.

For those of you reading this post and have been started on DMTs in the last 5 years was the concept of flipping the pyramid ever explained to you and the potential consequences, to you and your brain, if you chose the slower maintenance-escalation approach?

Harding et al. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.

IMPORTANCE: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.

OBJECTIVE: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.

DESIGN, SETTING AND PARTICIPANTS: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in the analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).

EXPOSURES: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

MAIN OUTCOMES AND MEASURES: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.

RESULTS: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

CONCLUSIONS AND RELEVANCE: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

CoI: multiple