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 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.

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The peroxydatic activity of haemoglobin in the presence of hydrogen peroxide catalyses the oxidation of TMB to a coloured product. Haemoglobin peroxidase has been termed a 'pseudoperoxidase'7 because, unlike true peroxidases which exhibit specificity for phenols, erythrocytes contain a peroxidase (erythrocyte glutathione peroxidase) specific for oxidation of reduced glutathione. This causes the in vitro detoxification of hydrogen peroxide. Glutathione peroxidase activity has been found to be associated with a relatively stable, nondialysible, heat-labile, intracellular component which can be separated from haemoglobin by gel filtration and ammonium sulphate precipitation. The pH optimum of glutathione peroxidase has been shown to be pH 8-0 with negligible activities below pH 6.0.8 Pretreatment of the fixed slides with resorcinol before staining with TMB and hydrogen peroxide inhibits myeloperoxidase staining. This increases specificity of the stain and reduces error in enumeration of erythroid colonies. By omitting counter staining only erythroid colonies and precursors are stained.

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