Primum non nocere
A guest post from Dr James Stankiewicz, Boston.
One of the fundamental tenants of medicine is “Primum non nocere”—First, Do No Harm. In theory this sounds quite easy to accomplish. And at times it can be. A surgeon should not, for example, amputate the left foot when the right foot is problematic one. But at other times it can become quite complicated to know what to do when employing this principle. It is interesting to consider how this cardinal rule applies to MS. I have spoken with respected MS clinicians who tell me about how they are avoiding harming their patients with toxic MS drugs. They might cite an increased death rate seen with ocrelizumab. Inevitably there would come the mention of PML in the context of ocrelizumab or natalizumab. And they would divulge that most of their patients are doing well on glatiramer acetate or teriflunomide. And they would discuss the idea of shared decision making and that their patients most often prefer to start with “cleaner agents.”
But frankly these conversations leave me frustrated and saddened. Because I believe they are getting it wrong and influencing their patients to get it wrong. By not employing more effective but safe medications like ocrelizumab or natalizumab early in the disease they are actually harming the people with MS they treat rather than sparing them some terrible side effect. But I can see how they fall into the trap. Because most of their patients will appear to do well as measured by clinical relapses or MRI in the first years of being on a weak agent. But when many of these patients enter into their forties and fifties they’ll gradually worsen. And these clinicians become frustrated when they then switch to the stronger agents and their patients continue to worsen. They don’t draw the connection between the undertreatment their patients have experienced in their earlier age and the loss of ambulation, fatigue, and cognitive/bowel/bladder/mood/sexual dysfunction the patient is experiencing years later. It is hard to associate actions taken 20 years earlier with consequences in the present. And I don’t think many patients will blame their neurologist if they fight this chronic neurologic condition and have some signs to show for it over the long term. Many will accept this and view it as the way of things. But a neurologist may certainly experience blame if that neurologist puts them on natalizumab and they develop PML. So you can see how the incentive structure is misaligned with achieving the best possible long term outcomes. Take this perverse incentive structure and add to the mix that neurologists tend to be a conservative lot in general and you can understand how as a field we are undertreating patients. And this doesn’t even factor in limited availability of MS drugs in developing countries or ill-advised restrictions put in place by insurers throughout the world.
There are some fundamental points about MS that I think both patients and clinicians should keep front and center as they have important implications for treatment approach. These are traced in the bullet points below but further definition and references can be found at an open access article I recently co-wrote: https://nn.neurology.org/content/7/1/e636
A) We are not particularly good at predicting at onset who will have a worse or better clinical course—a careful look at the published literature indicates that we cannot predict course as well as we’d like to think
B) There is a critical period early in the disease where we can have the most impact—research shows that the first year or two have outsized impacts on disease course. We know from clinical trials that younger patients experience better reductions in disease (relapse rate, MRI activity) than older patients. It may even be that many patients above roughly 50 years old don’t experience much benefit from treatment
C) MS damage may be ongoing but not detected by conventional MRI or overt immediate clinical change. We see more damage on MRI at higher magnet resolution/magnet strength (eg, 3T vs 7T). Novel imaging techniques such as diffusion tensor imaging or magnetization transfer show damage that cannot be found with traditional FLAIR sequences. At autopsy we can find areas that look normal on MRI but are in fact damaged and have inflammatory cells. This underappreciation of damage may lead us to see MS as more contained than it actually is. Evidence for this can be found in an interesting recent study that switched patients who were “stable” on injectable agents to ocrelizumab and found that they did better over time on the ocrelizumab.
D) MS rarely leaves patients unscathed over the long term–A study in the US found that at 55 years old about half of MS patients were receiving disability benefits. Another study found that 80% are walking with a walker at 65 years old. A recent study by Tallantyre and others found that only 3% of patients had “benign” disease when carefully examined.
E) Some MS drugs are better than others—Head to head trials show a clear superiority of efficacy for some drugs. And side effect profile looks no worse for some of these drugs than the less effective comparator. Ocrelizumab and natalizumab (if JCV negative) are quite effective and data shows good tolerability and rare serious safety concerns. Patients on natalizumab who are JCV negative can expect a 1/10,000 risk of PML which might be reduced even further with extended dosing. Indeed, patients on natalizumab are at more risk of a fatal motor vehicle accident than developing PML. The safety profile of ocrelizumab is excellent when one examines the data available rather than relies on hearsay and speculation or worry about future not yet materialized side effects.
Some argue that we do not actually know that more effective therapies should be started up front. That you could start a less effective medication and then switch quickly if overt new damage occurs. And there are trials ongoing to look at this question. I could list off in detail my concerns over trial methodology but will instead take a 10,000 foot (3000 meter!) view. Ultimately if side effect profile is essentially similar between two medicines and one is probably going to work better for you which would you take? And I think this currently is the true equation. As a field we need to stop overcomplicating things, tying ourselves up into cognitive knots. We should use the best medicines available and not harm our patients. It’s that simple. Primum non nocere.
An argument for broad use of high efficacy treatments in early multiple sclerosis
(Open access please read)
Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS.
Biography: Dr. Stankiewicz is an Assistant Professor of Neurology at Harvard Medical School. He is Clinical Director of the Partners Multiple Sclerosis Center. He is neurology clerkship director at Brigham and Women’s Hospital, holding ultimate responsibility for the education of Harvard Medical Students in their core and advanced neurology rotation. He also co-directs the multiple sclerosis fellowship program at the Partners MS center.
Dr. Stankiewicz received his AB from the University of Chicago in 1993 in the Biological Sciences with a specialization in Neurosciences, graduating Phi Beta Kappa. He earned his MD at Loyola University. He completed medical internship at Mt. Auburn hospital and neurology residency at Tufts. He was a post-doctoral research fellow in the neuroimaging of multiple sclerosis under the guidance of Rohit Bakshi, MD.
He is a topic co-chair American Academy of Neurology’s annual meeting scientific program for MS and CNS Inflammatory Disease. He serves on the medical advisory board of The Assistance Fund and co-edits Multiple Sclerosis: Principles of Diagnosis and Treatment. He has published over thirty peer reviewed papers, with a general focus on treatment of multiple sclerosis. He has been recurrently named a Top Doctor by Castle-Connolly and Boston Magazine.
Disclosures: Dr. Stankiewicz has consulted for Novartis, Biogen, EMD Serono, Genentech, Genzyme, Bayer and Teva.