Healthcare resource utilization and costs for extended interval dosing of natalizumab in multiple sclerosis.

Aims: Natalizumab is approved as an infusion every 4 weeks (standard-interval dosing [SID]) in relapsing-remitting multiple sclerosis (MS). Extended-interval dosing (EID) reduces risk of progressive multifocal leukoencephalopathy (PML) compared with SID, but the impact on healthcare resources and costs remains unknown. Methods: In this population-based study, we included 208 natalizumab-treated MS patients who were classified into EID (≤15 infusions in the previous 18 months; n = 51; age = 33.7 ± 11.1 years; female = 72.5%) and SID (>15 infusions in the previous 18 months; n = 157; age = 36.5 ± 10.8 years; female = 68.1%) groups. Results: Natalizumab EID had fewer MS outpatient visits (p = 0.01) and related costs (p = 0.03), and lower natalizumab costs (p < 0.01) compared with SID, without changes in other healthcare resources and costs. Conclusion: Natalizumab EID is associated with reduced direct treatment costs, apparently without additional healthcare burden.

Natalizumab is associated with early improvement of working ability in relapsing-remitting multiple sclerosis patients: WANT observational study results.

BACKGROUND: The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. METHODS: WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. RESULTS: At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (-4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (-7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). CONCLUSIONS: The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab's effects on patient-centric and health economics outcomes.

Progranulin expression in brain tissue and cerebrospinal fluid levels in multiple sclerosis.

BACKGROUND: Progranulin (PGRN) is a fundamental neurotrophic factor, and is also involved in inflammation and wound repair. PGRN may have pro- or anti-inflammatory properties, depending upon proteolysis of the anti-inflammatory parent PGRN protein and the generation of pro-inflammatory granulin peptides. OBJECTIVES: Our objectives were as follows: (1) to evaluate the presence and distribution of PGRN in multiple sclerosis (MS) brain tissue, correlating it with demyelination and inflammation; (2) to evaluate cerebrospinal fluid (CSF) PGRN concentrations in patients with MS and controls, in relationship to the clinical features of the disease. METHODS: Our study involved the following: (1) neuropathological study of PGRN on post-mortem tissue of 19 MS and six control brains; (2) evaluation of PGRN CSF concentration in 40 MS patients, 15 non-inflammatory controls and five inflammatory controls (viral encephalitis). RESULTS: In active demyelinating lesions, PGRN was expressed on macrophages/microglia. In the normal-appearing white matter (NAWM), expression of PGRN was observed on activated microglia. PGRN was expressed by neurons and microglia in cortical lesions and in normal-appearing cortex. No expression of PGRN was observed in controls, except on neurons. PGRN CSF concentrations were significantly higher in patients with relapsing-remitting MS during relapses and in progressive MS patients, compared with relapsing-remitting MS patients during remissions and with non-inflammatory controls. CONCLUSIONS: PGRN is strongly expressed in MS brains, by macrophages/microglia in active lesions, and by activated microglia in the NAWM; PGRN CSF concentrations in MS are correspondingly increased in conditions of enhanced macrophage/microglia activation, such as during relapses and in progressive MS.

Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter.

Gray matter (GM) lesions are recognized as important components of the pathology of multiple sclerosis (MS), and involvement of the deep gray matter (DGM) is suggested by magnetic resonance imaging. The aims of this study were to determine the frequency and distribution of lesions and characterize the inflammatory and neurodegenerative changes in DGM of MS patients. Histochemistry, immunohistochemistry, and morphometry were performed on whole coronal sections of 14 MS and 12 control (6 normal, 6 from amyotrophic lateral sclerosis patients) brains. Demyelinating lesions were frequent in MS DGM; most often in the thalamus and caudate, but they were also seen in the putamen, pallidum, claustrum, amygdala, hypothalamus, and substantia nigra. Most DGM lesions involved both GM and white matter. Inflammation in active DGM lesions was similar to that in lesions only in white matter but was less intense, and there was a preponderance of activated microglia, scarce myelin-laden macrophages, and a lesser extent of axonal damage. Neuronal loss was observed both in DGM lesions and nondemyelinated DGM with neuron atrophy in nondemyelinated DGM. In conclusion, demyelination and neurodegenerative changes are common in MS DGM and may contribute to clinical impairment. Inflammation in DGM lesions is intermediate between the destructive inflammation of white matter lesions and the minimal inflammation of cortical lesions. We hypothesize that alterations of glutamate reuptake mechanisms may contribute to these differences.

Hepatic recovery after damage produced by sub-chronic intoxication with the cyanotoxin microcystin LR.

The effect of sub-chronic exposure of intraperitoneal (i.p.) injections of microcystin-LR (MC-LR) on microscopic tissue architecture, hepatic function and lipid peroxidation has been studied in liver and kidney of mice. Mice were treated i.p. with 25 microg of pure MC-LR/kg body weight or saline solution for 1 month (every 2 days) with the aim of producing an inflictive stage with evident damage. Histopathological analysis of dissected livers of mice showed a disrupted lobar architecture and the development of cytoplasmatic vacuoles. According to this, a significant increase in hepatic lipid content and in lipid peroxidation levels in liver and kidney was found in MC-LR-treated animals when compared with controls. Moreover, serum alkaline phosphatase and aspartate aminotransferase activities showed a significant alteration in MC-LR-treated animals. After damage, progression or recovery was studied for 1 and 2 months of wash-out. The recovery from liver damage was evident at the cytological and physiological level, only the recovery of lobar architecture was incomplete along the period investigated. In conclusion, the present study demonstrates the ability of hepatic tissue to recover from damage produced by sub-chronic MC-LR administration. The dynamic interplay between damage and tissue-repairing response in determining the ultimate outcome of toxicity should be considered in risk-assessment studies.