Early Initiation of Disease-Modifying Therapy to Delay Disability Progression in Multiple Sclerosis
By Clinical Content Hub
- Even prior to diagnosis, patients with multiple sclerosis (MS) begin to experience brain atrophy, and the gray matter of the central nervous system (CNS) exhibits volume loss in early stages of disease, indicating that early treatment is critical to preserve movement, memory, and other important functions.
- There is no cure for MS, and damage to the CNS cannot be reversed. Treatment should therefore begin as soon as a patient meets diagnostic criteria for MS or related conditions.
- Beginning disease-modifying therapy (DMT) within a year after MS diagnosis can delay disability accrual and postpone the onset of secondary progressive disease.
- Early initiation of DMT for MS can lead to less disability over time; however, DMT offers value regardless of time of initiation.
- Improved insurance coverage and affordability of treatment can make it easier to implement therapy at the ideal times.
Amos Katz, MD, is a board-certified neurologist and medical director of the Linda E. Cardinale Multiple Sclerosis Center at CentraState Medical Center, in Freehold, New Jersey. He has more than 40 years of medical experience, and his clinical focus is on managing patients with MS. He regularly participates in clinical MS research and consults for pharmaceutical firms on treatments for MS.
When do brain atrophy and volume loss begin for patients with MS?
Brain atrophy begins prior to the diagnosis of MS. Tissue loss from white matter inflammation, leading to gliosis, is a contributing factor, along with damage to axons in normal-appearing white matter. Volume loss is seen in deep gray-matter structures in early stages of MS, with subsequent cortical atrophy and ventricular enlargement appearing in progressive forms of MS.1
What is the initial treatment strategy for patients with newly diagnosed MS?
I start DMT as soon as the patient meets the latest McDonald criteria for clinically isolated syndrome or active MS.2 As the saying goes: “An ounce of prevention is worth a pound of cure.” Because there is no cure for MS currently, starting treatment as early as possible can prevent further CNS damage and subsequent progressive disability that cannot be reversed.
How has development of DMT changed the long-term prognosis for patients with MS, particularly in regard to accrual of disability?
Several studies have concluded that an early start (within 1 year of diagnosis) of DMT for relapsing-remitting MS can delay accrual of disability and postpone onset of secondary progressive MS.3 We’re not entirely sure yet if secondary progressive MS can be entirely avoided as these medications have not been available long enough.4
Are DMTs as effective when used later in disease progression?
DMTs are most effective if used early in relapsing-remitting MS, when inflammation predominates. They are much less effective later in the course of disease, when neurodegeneration is most evident. When you examine graphs of MS disability plotted against time, they always show much less disability, at any time point, when a DMT is started early, rather than later, after a diagnosis of MS. However, a late start is still better than no treatment.5
Can early treatment with DMT delay disability progression for patients with MS?
Several studies have shown that early treatment with DMT delays disability progression. More intriguing, new data suggest that initial treatment with highly effective DMTs — sometimes called “induction therapy” — yields better clinical outcomes at 4 years than the usual escalation strategy, which is used most often for MS.6
For which patients and phases of disease should induction therapy be considered, and what is the safety profile of drugs used for induction therapy?
Induction therapy for MS is a strategy to immediately introduce a DMT of higher efficacy, although with potentially more serious adverse effects. Treatment usually involves an immunosuppressive drug, followed by long-term use of an immunomodulatory agent that has a lower adverse effect profile. This has been done successfully for many years in oncology and rheumatology.7
The choice of induction therapy is individualized for patients in whom it is likely that MS would be more severe, as determined at time of diagnosis. Prognostic factors include brainstem or multiple spinal cord plaques, or both; multiple enhancing lesions; large disease burden seen on T2-weighted magnetic resonance imaging at diagnosis; and multiple relapses during the first year after diagnosis.
In my opinion, induction modalities include hematopoietic stem cell transplantation; anti-CD20 and anti-CD52 DMT agents; cladribine; and older medications, such as methotrexate, mitoxantrone, and cyclophosphamide.8 The safety profile of induction therapy can be more problematic with an increased occurrence of infection and cancer and reduced effectiveness of vaccines.
Some factors associated with delayed initiation of DMT in patients with newly diagnosed MS have been identified in recent studies,9 including younger age, absence of musculoskeletal diagnoses, a diagnosis of a balance disorder, numbness, and optic neuritis. How can healthcare providers better address earlier diagnosis and treatment initiation?
This retrospective study looked at a database of US patients with newly diagnosed MS from 2007 to 2013. It is disappointing to see that only 37.4% of patients started DMT within 2 years after diagnosis, with a mean starting date of 112.6 days. In my practice, several factors come to mind as important causes of delayed MS treatment, including:
- Patients’ skepticism about their diagnosis;
- Patients’ refusal to start DMT because they expressly want to be treated “holistically”;
- Lack of health insurance;
- Uncooperative health insurer policies;
- Lack of timely availability of neurologists who treat MS; and
- A long wait for an initial appointment.
Patients also complain that health care professional do not spend enough time with them after their shock of receiving an MS diagnosis. Also, I often hear from patients that their provider did not explain the need for DMT, possible adverse effects of DMTs, and the prognosis when MS goes untreated. These concerns should be discussed at length with the patient before they are lost to follow-up.
Is the cost of treatment a concern when making decisions regarding time of treatment initiation?
All MS drugs that are part of DMT cost an incredible amount of money, at least in the United States. Cost is not an issue so much as insurance coverage of each DMT, copay affordability, the logistics of getting the patient on the prescribed DMT, and many other factors.
This Q&A was edited for clarity and length.
Amos Katz, MD, reported affiliations with Allergan, Biogen, Genentech/Roche, Bristol-Meyers Squibb, Sanofi, and Janssen Pharmaceuticals.
1. Cerqueira JJ, Compston DAS, Geraldes R, et al. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? J Neurol Neurosurg Psychiatry. 2018;89(8):844-850. doi:10.1136/jnnp-2017-317509
2. Mantero V, Abate L, Balgera R, La Mantia L, Salmaggi A. Clinical application of 2017 McDonald diagnostic criteria for multiple sclerosis. J Clin Neurol. 2018;14(3):387-392. doi:10.3988/jcn.2018.14.3.387
3. Hänninen K, Viitala M, Atula S, Laakso SM, Kuusisto H, Soilu-Hänninen M. Initial treatment strategy and clinical outcomes in Finnish MS patients: a propensity-matched study. J Neurol. Published online June 25, 2021. doi:10.1007/s00415-021-10673-9
4. Brown JWL, Coles A, Horakova D, et al; for the MSBase Study Group. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321(2):175-187. doi:10.1001/jama.2018.20588
5. University of California, San Francisco MS-EPIC Team; Cree BAC, Gourraud P-A, Oksenberg JR, et al. Long-term evolution of multiple sclerosis disability in the treatment era. Ann Neurol. 2016;80(4):499-510. doi:10.1002/ana.24747
6. Schmierer K, Sørensen PS, Baker D. Highly effective disease-modifying treatment as initial MS therapy. Curr Opin Neurol. 2021;34(3):286-294. doi:10.1097/WCO.0000000000000937
7. Verhoeven M, Welsing P, Bijlsma JW, et al. Effectiveness of remission-induction strategies for early rheumatoid arthritis (RA): a systematic literature review. Ann Rheum Dis. 2019;78(Suppl 2):377-378. doi:10.1136/annrheumdis-2019-eular.3310
8. Ruggieri S, Pontecorvo S, Tortorella C, Gasperini C. Induction treatment strategy in multiple sclerosis: a review of past experiences and future perspectives. Mult Scler Demyelinating Disord. 2018;3:58. doi:10.1186/s40893-018-0037-7
9. Edwards NC, Munsell M, Menzin J, Phillips AL. Factors associated with early initiation of disease-modifying drug treatment in newly-diagnosed patients with multiple sclerosis. Curr Med Res Opin. 2018;34(8):1389-1395. doi:10.1080/03007995.2018.1447452
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Neurology Advisor had no role in this content’s preparation.
Reviewed September 2021