Sandgren S, Novakova L, Axelsson M, Rosenstein I, Lycke JN, Malmeström C.Lymphocyte Dynamics and the Emergence of Secondary Autoimmunity Following Immune Reconstitution Therapies in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2025 Nov;12(6):e200497. doi: 10.1212/NXI.0000000000200497.
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. ……. Eh? Schtop…fast forward………Discussion: A low Baseline CD4+ recent thymic emigrants (cellsl eaving the thymus whih is an immune organ where T cells are educated to no cuase autoimmunity) :CD8+ T effector memory cells ratio, accompanied by a sharp relative increase during follow-up, was associated with SAD development. A lower CD8+ T-cell count may suggest an increased risk.
So straight on to AI and we ask:Does cladribine/HSCT/alemtuzumab cause secondary autoimmunity in MS?
No, cladribine is not associated with secondary autoimmunity in the same way as other treatments like alemtuzumab. Unlike therapies that cause a rebound effect, cladribine is thought to reboot the immune system without this risk because its mechanism of action does not involve a rebound of lymphocytes. While rare, isolated cases of other autoimmune events like glomerulonephritis have been reported, these do not appear to be a characteristic side effect of the drug.
Yes, hematopoietic stem cell transplantation (HSCT) can cause secondary autoimmunity in multiple sclerosis (MS), though it is a rare complication. This risk is higher with certain conditioning regimens, particularly those using alemtuzumab, which can lead to the development of new autoimmune conditions after the procedure. The secondary autoimmune diseases are often related to the conditioning regimen or the immune system’s reconstitution.
Yes, alemtuzumab can cause secondary autoimmune disorders in MS patients, most commonly affecting the thyroid and blood. This occurs because while the drug depletes the immune cells that cause MS, the subsequent regeneration of the immune system can lead to the development of new autoimmune responses.
However, do the individual maths and we have 29/51 (56.9%) alemtuzumab, 3/20 (15%) HSCT and 6/59 (10.2%) developed secondary autoimmunity. They looked at the cellular depletion which has been done numerous times before.
AHSCT leads to the fastest recovery, ALZ induces the most durable T-cell depletion, and CladT result in the slowest CD19+ B-cell repopulation They say “We found no definitive association between lymphocyte subpopulations and disease activity”. You can read the conclusions but I am not sure of the mechanism of action.
Source: multiple-sclerosis-research.org