Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers.

BACKGROUND: Ocrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. METHODS: We have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann-Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. RESULTS: After initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. CONCLUSIONS: Our real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Ocrelizumab-related neutropenia: Effects of age, sex and bodyweight using the FDA Adverse Event Reporting System (FAERS).

OBJECTIVE: Neutropenia is a rare complication of anti-CD20 treatment, such as Ocrelizumab (OCR) in Multiple Sclerosis (MS). Using FDA´s Adverse Event Reporting System (FAERS), a post-marketing, open access pharmacovigilance database, we aimed to identify risk factors of neutropenia in OCR-treated patients. METHODS: Data were retrieved from FAERS identifying OCR-treated patients with and without neutropenia. Only data with OCR as the single suspected product were considered. Multivariable logistic regression (MLR) analysis was run to study if MS disease course, age, sex and bodyweight were associated with the risk of neutropenia. RESULTS: Of 15,313 initial hits, 3177 complete datasets were included in the analysis. MLR demonstrated that MS disease course was not associated, whereas sex (female sex (reference male sex) 0.356, 95%CI 0.145-0.875, p = 0.0124), age (years, 0.909, 95%CI 0.875-0.944, p = 7.4105 × 10-7) and bodyweight (kilogram, 0.961, 95%CI 0.935-0.988, p = 0.005) were factors associated with OCR-related neutropenia (Nagelkerkes R2=0.17, n = 3177). No deaths were reported for identified neutropenia cases. CONCLUSION: Using FAERS, we identified male sex, younger age and lower bodyweight as factors associated with OCR-related neutropenia. With the limitations inherent to this open data source, our data need prospective validation, but elucidate potential factors for a personalized side effect profiling.

Hypogammaglobulinemia: A contributing factor to multiple sclerosis fatigue?

OBJECTIVE: Fatigue is one of the most disabling and difficult to treat symptoms of autoimmune diseases and frequently presents in people with multiple sclerosis (PwMS). Hypogammaglobulinemia for immunoglobulin G (IgG) affects approximately 8-25% of PwMS. We performed a retrospective analysis to investigate the association of MS-fatigue and IgG hypogammaglobulinemia. METHODS: PwMS, treated at Eginition University Hospital Athens or at the University Hospital Bern, were included (n = 134 patients (Bern n = 99; Athens n = 35)). Mann Whitney U-test (MWT), ANOVA test, Chi2 test and multivariable linear regression models were run. RESULTS: 97/134 (72.4%) PwMS reported fatigue. In the multivariable linear regression analysis, IgG serum concentration (-1.6, 95%CI -2.7 - -0.5, p = 0.006), daytime sleepiness (0.8, 95%CI 0.2-1.4, p = 0.009), and a depressive mood (1.1, 95%CI 0.8-1.4, p < 0.001) were significantly associated with fatigue. The impact of IgG serum concentration (-2.9 95%CI -4.7 - -1.1, p = 0.002) remained significant also in the subcohort of PwMS without depressive symptoms or daytime sleepiness. CONCLUSIONS: We found an association between IgG hypogammaglobulinemia and fatigue in PwMS (Level of Evidence IV), which might be translated to other autoimmune diseases. It bears a potential therapeutic consequence considering IgG supplementation strategies, if our finding can be validated prospectively.

Natalizumab induced blood eosinophilia: A retrospective pharmacovigilance cohort study and review of the literature.

OBJECTIVE: To describe frequency of natalizumab related eosinophilia and clinical symptoms of eosinophilic disease in our monocentric cohort. METHODS: Comparison of clinical characteristics of 115 natalizumab treated and 116 untreated RRMS patients and review of literature. RESULTS: 38% of natalizumab treated patients had eosinophilia, which occurred significantly more frequently compared to untreated MS patients (3%, p-value<0.001). In symptomatic patients, mean eosinophil counts were significantly higher than in asymptomatic patients and symptoms developed within one year. DISCUSSION: Eosinophilia is a side effect of natalizumab and mostly asymptomatic. However, few patients develop within one year after start of natalizumab an eosinophilic disease as severe side effect.

Factors affecting the oxygen balance in the awake cerebral cortex exposed to spreading depression.

Oxygen balance was evaluated in the cerebral cortex, using the surface fluorometry technique of the intramitochondrial NADH redox state, exposed to various physiological and pathological situations. Using flexible fiber optic light guide, connected to the brain surface via a cemented holder, the measurements were done continuously from the awake rat and gerbil. In few experiments the NADH redox state was correlated with the electrical and ionic activity (measured by surface K+ and DC electrodes). Three different animal models were used in the study: the adult rat, the very young rat (20 g) and the adult gerbil. Those 3 models were used in studying the effect of hypoxia, partial ischemia, and anesthesia on the metabolic and ionic activities measured from the awake brain. Spreading cortical depression (elicited by topical KCl solution) was used as a standard stimulation of the ionic and metabolic activities of the cerebral cortex. Two typical metabolic responses to spreading depression (SD) were recorded, namely 'oxidation cycle' and 'reduction cycle' depending upon the ability of the tissue to compensate for the extra amount of oxygen needed for the higher mitochondrial activity. It was found that the adult rat brain showed oxidation cycles in most conditions (besides partial ischemia), while the young rat and the gerbil brains were much more sensitive to the various perturbations of the brain and exhibited reduction cycle ( as a response to SD) under all pathological situations tested. We conclude from our detailed studies that the type of response to SD, as measured by NADH surface fluorometry, represents the oxygen balance which exists in the tissue under various conditions.

Comparative measurements of in vitro thermogenesis of brown adipose tissue from control and cold adapted rats.

Heat output and oxygen uptake rates as well as caloric equivalents of O2 were measured in brown fat fragments from cold-adapted and control rats. Resting metabolic rate per unit wet weight was the same in both groups. Submaximal responses to noradrenaline were significantly lower in the cold-adapted than in the control group. Apparent maximal responses were the same for both groups. Caloric equivalents of O2 gave no evidence for anaerobic glycolysis even under conditions of oxygen limitation.

Metabolic, ionic, and electrical responses of gerbil brain to ischemia.

The effects of short- or long-term complete cerebral ischemia were studied in the gerbil brain using a multi-parameter monitoring system. Metabolic (NADH redox state) and hemodynamic responses were monitored by surface fluorometry-reflectometry. Ionic activities (K+ and pH) were measured by surface macroelectrodes. Electrical activity was evaluated by monitoring the general electrocorticogram (ECoG) as well as local DC steady potential (two sites). Two groups of gerbils were studied to compare the effects of 4-5 min occlusions with those of 30 min complete ischemia. During bilateral carotid artery occlusion the cortex is exposed to complete ischemia resulting in the complete depletion of O2 with attendant maximal reduction of NADH. Extracellular K+ began to increase as soon as energy reserves were decreased with a time course suggesting two different kinetic areas. Surface pH decreased very shortly after the occlusion. During the recovery phase, NADH was reoxidized soon after recirculation, whereas the pH and K+ recovery showed a short delay. ECoG did not recover even when all other parameters reached base-line levels. The recovery of all the measured parameters was correlated to the duration of the ischemic insult; i.e., the recovery from 30 min of ischemia took significantly longer than after 5 min of ischemia. We conclude that pH recovery depends on recirculation and adequate O2 supply to the tissue, whereas K+ recovery required not only an adequate O2 supply but also the integrity of the adenosine triphosphatase system.

Does cytoplasmic alkalinization trigger mitochondrial energy dissipation in the brown adipocyte?

Indirect calorimetry measurements showed that brown fat thermogenesis was very sensitive to modifications of intra-cellular pH induced by extracellular acid-base perturbations. Specific blockage of active Na-K transport by ouabain inhibited the thermogenic response only in acidosis and more efficiently when the glycoside was administered before the catecholamine stimulus than when it was added after the full calorigenic response had developed. It is suggested that the catecholamine stimulus might initiate a positive feed-back alkalinization of the cytoplasm, concomitant with activation of Na-K transport.

Multiprobe monitoring of ionic, metabolic, and electrical activities in the awake brain.

A new approach for studying brain metabolic, ionic, and electrical activities in the awake animal is described. We developed a multiprobe assembly holding electrodes for extracellular K+, pH, DC potential, electrocorticogram, and temperature as well as a light guide for monitoring intramitochondrial NADH oxidation-reduction state. The assembly was designed so that because of the type of electrodes used and the protection system around them, the same system could be used in many experiments. The results presented here are typical and show the potential use of the multiprobe approach for studying the effects of hypoxia, anoxia, spreading depression, and ischemia on the awake brain. From the results obtained the following conclusions can be drawn. 1) The DC correction for the K+ and H+ measurements is necessary, although it was not as good for the H+ as for the K+ signals. 2) During ischemia (complete or partial) a clear acidification of the brain was found in correlation with the decrease in oxygen availability as evaluated by the NADH fluorescence signal. 3) During brain activation (induced by spreading depression) extracellular K+ was elevated and then actively pumped back into the cells. The NADH showed an oxidation response, and the pH response started with an alkalinization followed by a short acidification.