ImportanceProgression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS).ObjectiveTo investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA.Design, Setting, and ParticipantsThis cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments.ExposuresExposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA).Main Outcomes and MeasuresExpanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0.ResultsOf the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009).Conclusions and RelevanceResults of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.

Intrathecal production of kappa free light chains (KFLC) occurs in multiple sclerosis and can be measured using the KFLC index. KFLC index values can be determined more easily than oligoclonal bands (OB) detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of OB, KFLC index cut-offs 5.9, 6.6, and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome (CIS) inception cohort. We selected patients with sufficient data to determine OB positivity, MRI dissemination in space (DIS) and time (DIT), IgG index, and sufficient quantities of paired CSF and blood samples to determine KFLC indexes (n = 214). We used Kendall´s Tau coefficient to estimate concordance; calculated the number of additional diagnoses when adding each positive index to DIS and positive OB; performed survival analyses for OB and each index with the outcomes second attack and 2017 MRI DIS and DIT; and estimated the diagnostic properties of OB and the different indexes for the abovementioned outcomes at five years. OB were positive in 138 patients (64.5%), KFLC-5.9 in 136 (63.6%), KFLC-6.6 in 135 (63.1%), KFLC-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between OB and KFLC-6.6 (τ=0.727) followed by OB and KFLC-5.9 (τ=0.716). Combining DIS plus OB or KFLC-5.9 increased the number of diagnosed patients by 11 (5.1%), with KFLC-6.6 by 10 (4.7%), with KFLC-10.61 by 9 (4.2%), and with IgG index by 3 (1.4%). Patients with positive OB or indexes reached second attack and MRI DIS and DIT faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [aHR (95% CI)], the risk for second attack was very similar between KFLC-5.9 [2.0 (0.9-4.3), P = 0.068] and KFLC-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI DIS and DIT was demonstrated with KFLC-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by KFLC-6.6 [3.4 (1.9-6.3), P < 0.0001]. KFLC-5.9 and KFLC-6.6 had a slightly higher diagnostic accuracy than OB for second attack (70.5, 71.1, and 67.8) and MRI DIS and DIT (85.7, 85.1, and 81.0). KFLC indexes 5.9 and 6.6 performed slightly better than OB to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between OB and these indexes, we suggest using DIS plus positive OB or positive KFLC index as a modified criterion to diagnose multiple sclerosis.

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