PracticeUpdate Neurology June 2019

EDITOR’S PICKS 16

Association of Initial Disease- Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis The Journal of the American Medical Association Take-home message • The authors of this cohort study sought to evaluate the association between disease-modifying treatments (DMTs) and conversion to secondary progressive multiple sclerosis (MS) among untreated patients with relapsing-remitting MS. The authors found that initial treatment with fingolimod, alemtuzumab, or natalizumab provided a reduced risk of conversion to secondary progressive MS relative to initial treatment with either glatiramer acetate or interferon beta. • The study authors conclude that these findings may help inform treatment decisions for patients with MS considering DMT therapy.

Abstract IMPORTANCE Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed second- ary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.

" These data strongly suggest that long-term outcomes are substantially improved when effective therapy is instituted for MS during its earliest stages. "

OBJECTIVE To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. DESIGN, SETTING, AND PARTICIPANTS Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with

COMMENT By Erin Longbrake MD, PhD

I n the past, many neurologists prescribed immunomodulatory therapies for multiple sclerosis (MS) based on the principle of “do no harm.” This led to the habit of “step therapy,” where patients were started on older, less-effective medications at disease onset due to the perception of increased drug safety. More effective therapies were reserved for those with evidence of ongoing disease despite initial treatments. Insurers adopted step therapy as standard practice, and, often, companies insti- tuted specific step requirements based on preferred medications before allowing access to more highly effective treatments. With increasing availability of highly effective medications for MS, including ocrelizumab, fingolimod, natalizumab, and alemtu- zumab, many neurologists have called the appropriateness of step therapy into question, instead suggesting that MS ought to be immediately treated with highly effective therapies. Debate has been driven in large part by expert opinions rather than data, as the novelty of many highly effective medications precluded long-term follow-up data. Brown and colleagues utilize a large database of prospec- tively collected observational data to evaluate the hypothesis that treating with highly effective medications at disease onset leads to better disease control over time. Using propensity score matching, they compare patients initiating newer/more-effective medications (fingolimod, alemtuzumab, and natalizumab) to those initiating older, injectable medications (interferons and glatiramer

acetate). Patients whose initial MS therapy was highly effective were less likely to develop secondary progressive MS (SPMS) than those prescribed interferons or glatiramer, and patients switched from injectable to highly effective medications within 5 years of disease onset were also less likely to develop SPMS. These data strongly suggest that long-term outcomes are substantially improved when effective therapy is instituted for MS during its earliest stages. Although the reported data are observational and propensity score matching cannot control for unmeasured clinical variables, the study includes a large number of patients and is well controlled. Although more data will continue to clarify this important clinical question, this study represents substantial progress and supports early, highly effec- tive immunotherapy for patients with MS. It is to be hoped that insurers will take note of these data and move toward abolish- ing the frequently arbitrary requirements for step therapy, which continue to inhibit patient care.

Dr. Longbrake is an Assistant Professor in the Departments of Neurology and Immunobiology at Yale School of Medicine in New Haven, Connecticut.

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