Impact of Oral Cladribine on TSPO-PET-Measurable Immune Cell Activation in Multiple Sclerosis

Introduction Oral cladribine reduces focal inflammatory activity in relapsing–remitting multiple sclerosis (RRMS). Preclinical studies suggest it may also modulate microglial activation. In this prospective, single-arm pilot study, we investigated the effect of oral cladribine on glial activation using 18 kDa translocator protein (TSPO) positron emission tomography (PET) in a real-world, longitudinal RRMS cohort. Methods People with RRMS initiating oral cladribine underwent TSPO-PET with [11C]PK11195, 3-T brain magnetic resonance imaging (MRI), serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) measurements, and clinical assessments at baseline and 18 months. Age- and sex-matched healthy controls underwent a single PET and MRI. The primary outcome was change in TSPO availability quantified as a percentage of TSPO-active voxels and distribution volume ratio. Secondary outcomes included brain volumetrics, paramagnetic rim lesions, serum biomarkers, clinical measures, and patient-reported outcomes. Results Fourteen people with RRMS and 14 healthy controls were enrolled. Baseline TSPO availability did not differ between groups. Over 18 months, TSPO availability quantified as percentage of TSPO-active voxels increased 21% in normal-appearing white matter (NAWM) (mean [95% CI] change 1.2 [0.2–2.3]; p = 0.026) and 16% in the whole brain (mean [95% CI] change 0.9 [0.01–1.8]; p = 0.047). Both the median (1st to 3rd quartile) annualized relapse rate (from 0.67 [0.17–0.67] to 0.00 [0.00–0.00]; p = 0.033) and the age- and BMI-adjusted sNfL Z-score (from 0.69 [0.16–1.22] to − 0.03 [− 0.39 to 0.21]; p = 0.038) decreased significantly. Conclusion TSPO-binding in the NAWM increased during oral cladribine treatment despite suppressed relapses and decreased sNfL Z-score. These exploratory findings raise the possibility that cladribine may have limited ability to control smoldering pathology. This possibility warrants further investigation in larger prospective studies. Trial Registration This study was registered on ClinicalTrials.gov (NCT04239820) on January 21, 2020.