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Impact of Oral Cladribine on TSPO-PET-Measurable Immune Cell Activation in Multiple Sclerosis
Olli Rajalehto1,2,3, Markus Matilainen1,2,3,4, Jussi Lehto2,3,4
1Clinical Neurosciences, University of Turku, Turku, Finland.
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.
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