Immunoglobulin levels are higher at multiple sclerosis onset - a part of natural history?

BACKGROUND: Changes in immunoglobulin (Ig) levels may occur in association with various drugs targeting immunity, including disease-modifying drugs (DMD) and corticosteroids (CS) used to treat multiple sclerosis (MS). However, kinetics of Ig levels during the natural history of MS is poorly described. OBJECTIVE: To describe the natural history of the Ig levels in MS. METHODS: Monocentric retrospective study examining changes in Ig levels in relation with CS intake in a series of 304 consecutive MS patients (and 1204 samples) followed or hospitalized for 7 years in a single centre. Ig levels are routinely collected in MS patients followed in our centre. RESULTS: IgG levels were higher in samples taken at diagnosis than in those taken after the onset of MS symptoms. This effect was also observed in patients remaining free of DMD or CS since onset. On the other hand, overall Ig levels remained stable across fixed time points ranging from 1 to 20 years after onset CONCLUSION: An unanticipated finding of this study was the transient higher IgG levels in samples taken at onset, which suggests that strong inflammatory processes may occur early.

Corticosteroid-induced low immunoglobulin levels in multiple sclerosis - A confounding factor.

BACKGROUND: Changes in immunoglobulin (Ig) levels may occur in association with various drugs targeting immunity, including those used to treat multiple sclerosis (MS). However, influence of high-dose corticosteroids (CS) is poorly described. OBJECTIVE: To describe influence of disease-modifying drugs (DMD) and CS on the Ig levels. METHODS: Monocentric retrospective study examining changes in Ig levels in relation with CS intake in a series of 304 consecutive MS patients (and 1204 samples) followed or hospitalized for 7 years in a single centre. Ig levels are routinely collected in MS patients followed in our centre. RESULTS: IgG levels were significantly lower in MS patients exposed to CS infusion during the last 24 months. IgG levels were also lower in DMD-treated patients exposed to CS. DMD-specific decrease of IgM levels was confirmed in interaction with CS. CONCLUSION: Stratification by CS exposure suggested that a decrease in Ig levels occurring during DMD treatment was strongly associated with CS infusion. The strong and persistent effect of CS on Ig levels could be a hidden variable and should be considered in further studies targeting Ig levels.

No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial).

BACKGROUND: The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. METHODS: We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. RESULTS: Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 (p = 0.02). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. CONCLUSION: Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed.

Estimation of intrathecal IgG synthesis: simulation of the risk of underestimation.

OBJECTIVE: The low level of passively diffused IgG through the blood-brain barrier is sufficient to blur the estimation of intrathecal IgG synthesis (ITS). Therefore, this estimation requires a mathematical calculation derived from empirical laws, but the range of normal values in healthy controls is wide enough to prevent a precise calculation. This study investigated the precision of various methods of ITS estimations and their application to two clinical situations: plasma exchange and immune suppression targeting ITS. METHODS: Based on a mathematical model of ITS, we constructed a population of healthy controls and applied a tunable ITS. RESULTS: We demonstrate the following results: underestimation of ITS is common at individual level but true ITS is well fitted by cohorts; Q IgG increases after plasma exchange; IgG Loc calculation based on Qlim falsely increases when Q Alb decreases; the sample size required to demonstrate a decrease in ITS increases exponentially with larger Q Alb. INTERPRETATION: Studies evaluating changes in ITS level should be adjusted to Q Alb. Low amounts of ITS could be largely underestimated.