Clinical characteristics of late and early onset neuromyelitis optica spectrum disorders [Abstract]
(2023)
Objective: This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD.
Methods: This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes.
Results: Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81–3.84).
Interpretation: LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved.
Background: Glatiramer acetate (GA) is a well-tolerated treatment for multiple sclerosis (MS) and comparable in its efficacy to high-dose interferon beta (IFN). As a lack of validated treatment response biomarkers for MS hampers progress in personalised treatment, the study goal was to search for biomarkers of a successful treatment response utilising the known observation of T-cell expansions after GA treatment.
Methods: T-cell receptor beta chain (TRB) sequencing was performed in 3021 patients with MS: a discovery cohort of 1627 patients with MS, 204 of whom had previously been treated with GA, and then validated in 1394 patients with MS, 424 of whom had previously been treated with GA. Clinical data from 1987 patients with MS treated with GA or IFN and available HLA information from the NationMS, ACP, EPIC, BIONAT, and CombiRx trial cohorts were used for a subsequent analysis.
Findings: Common GA-associated TRB expansions were exclusively detected in HLA-A∗03:01 or in HLA-DRB1∗15:01 backgrounds, within CD8+ effector- or CD4+ central-memory T cells. Both sets of common sequences clonally expanded after GA treatment in a first validation cohort and predicted GA exposure in two further validation cohorts. To evaluate whether restriction of public TRBs to only two HLA alleles is also associated with GA's clinical efficacy, we analysed five cohorts of patients with MS for a potential benefit of the two HLAs concerning the GA response compared to IFN. We consistently found positive interactions with HLA-A∗03:01. This included a relative reduction in relapse risk compared to IFN in HLA-A∗03:01 carriers of 33% (CombiRx: GA + IFN arm: HR 0.67 [95% CI: 0.47-0.96], p = 0.0269) and 34% (CombiRx: GA arm: HR 0.66 [95% CI: 0.45-0.98], p = 0.0377), and in risk to first relapse of 63% (NationMS: HR 0.37 [95% CI: 0.16-0.88], p = 0.0246), but no positive association with DRB1∗15:01.
Interpretation: HLA-A∗03:01 carrying patients with MS specifically benefit from GA treatment and GA significantly outperforms IFN in these patients. Therefore, determining HLA-A∗03:01 status before choosing a platform treatment for MS, would allow for a personalised treatment decision between GA and IFN.
