Abstract
BACKGROUND AND OBJECTIVES: Understanding the immunologic changes induced by immune reconstitution therapies (IRTs) is key to optimizing multiple sclerosis (MS) treatment. We evaluate lymphocyte dynamics and their association with secondary autoimmune disease (SAD) and its recurrence after treatment with alemtuzumab (ALZ), autologous hematopoietic stem cell transplantation (AHSCT), and cladribine tablets (CladT). METHODS: People with MS (pwMS) initiating treatment with ALZ, AHSCT, and CladT were included in this cohort study. Blood samples were collected at baseline (BL) and at months (M) 6, 12, and 24 for flow cytometry analysis of lymphocyte subpopulation. RESULTS: A total of 130 pwMS (ALZ: n = 51; AHSCT: n = 20; CladT: n = 59) were included, with a mean (SD) age of 35.5 (±8.2) years. The median (IQR) Expanded Disability Status Scale (EDSS) score was 1.5 (1.0-2.5) at BL. The median follow-up duration was 4.7 (ALZ: 5.0; AHSCT: 4.2; CladT: 3.7) years. During follow-up, 29.2% (38/130; ALZ n = 29; AHSCT n = 3; CladT n = 6) received a SAD diagnosis and 43.1% (56/130; ALZ n = 15; AHSCT n = 13; CladT n = 28) showed no disease activity. The SAD cohort (n = 38) showed lower median BL ratios of CD4(+) T-cell recent thymic emigrant (Trte):CD4 (0.26 [0.12-0.34], p = 0.04) and CD4(+) Trte:CD8+ terminally differentiated effector memory (Temra) (1.73 [0.76-4.39], p = 0.02) compared with the non-SAD cohort (CD4(+) Trte:CD4 = 0.31 [0.23-0.42]; CD4(+) Trte:CD8+ Temra = 3.61 [1.47-7.24]). During follow-up, the SAD cohort exhibited a greater relative increase in CD4(+) Trte:CD4, CD4(+) Trte:CD8+ Temra, and CD4(+) T regulatory cell (Treg):CD8+ Temra ratios at M12 and M24, compared with BL, relative to the non-SAD group. The difference at M24 was most pronounced for the CD4(+) Trte:CD8+ Temra ratio (SAD: +100% vs non-SAD: -23%, p < 0.001), with this difference being confirmed in the ALZ cohort (SAD: +123% vs non-SAD: -21%, p = 0.03), but not in the CladT cohort (SAD: -62% vs non-SAD: -38%, p = 0.39). In a multivariable Cox analysis, BL CD8(+) T-cell count (aHR 0.34, 95% CI 0.15-0.80, p = 0.01) was associated with a reduced hazard of evidence of disease activity. DISCUSSION: A low BL CD4(+) Trte:CD8(+) Temra ratio, accompanied by a sharp relative increase during follow-up, was associated with SAD development. While no definitive associations were found between BL lymphocyte subpopulations and disease activity, a lower CD8(+) T-cell count may suggest an increased risk.