Mirela Cerghet

Measuring adherence and persistence to disease-modifying agents among patients with relapsing remitting multiple sclerosis

OBJECTIVES To measure disease-modifying agent adherence and persistence among patients with multiple sclerosis (MS). DESIGN Retrospective cohort study. SETTING Multispecialty, salaried group practice in southeast Michigan, between June 1, 2004, and June 30, 2006. PATIENTS 224 insured adult patients with relapsing remitting MS with an outpatient visit. MAIN OUTCOME MEASURES Medical record-documented receipt of medication recommendation and prescription. Pharmacy claims data-derived measures of dispensing and among patients with two or more dispensings, medication possession ratios (MPRs), and proportion of gap days were estimated. Among those initiating agent use, persistence was estimated. RESULTS Mean cohort age was 47.6 years, while 77% of participants were women and 39% were black. Of patients, 81.8% had a recommendation for a disease-modifying agent, 75.0% had a prescription, and 66.5% had two or more dispensings. Among those with two or more dispensings, mean MPR between the first and last dispensing date was 83.8% (95% CI 80.8-86.8), while mean MPR for the entire 24-month period was 68.0% (64.4-71.7). MPR for the 24-month period decreased with increasing drug copayments and was lower among black patients, while MPR between the first and last dispensing date increased with increasing age. Among those initiating therapy, 43% were nonpersistent with medications within 14 months. CONCLUSION Medication adherence and persistence among patients with relapsing remitting MS is far from monolithic. Measuring medication adherence and persistence among defined populations is useful for understanding the relationship between medication use and outcomes in practice and for targeting patients and programs to improve medication adherence.

The use of migraine preventive medications among patients with and without migraine headaches

The aim was to describe the use of and adherence to migraine preventives among insured patients meeting the International Classification of Headache Disorders, 2nd edn (ICHD-II) criteria for migraine headaches. A retrospective, case–control study was conducted using data from a telephone interview linked with health insurance claims data. Subjects were health plan enrollees aged 18–55 years who had incurred at least one encounter between June 2000 and November 2001. Interview responses were used to identify cases meeting the ICHD-II criteria for strict and probable migraine and a random sample of controls. Pharmacy claims data were used to construct measures of use and adherence. Differences in outcomes by adherence status were evaluated using generalized linear models. We identified 2517 cases and 941 controls. Among cases, the prevalence of antidepressant use was 4%, anticonvulsant use was 1.9%, antihypertensive use was 8.9%. Combined use was 13.4% among cases and did not differ significantly from that observed among controls (12.4%). Mean adherence rate between the first and last dispensing during the year was high (88%) and did not differ by migraine status. When the entire 12-month period is considered, adherence was substantially lower (56%). Patients who were adherent between dispensings reported significantly less migraine-related disability and incurred higher prescription drug costs, but did not differ in their total medical care costs. Patients with migraine are unlikely to be users of preventive medications. Among users, few are taking preventive medications continuously. Patients with migraine—especially those without a medical diagnosis for migraine or headaches—are not receiving the benefits available from existing pharmacotherapy options.

Untargeted plasma metabolomics identifies endogenous metabolite with drug-like properties in chronic animal model of multiple sclerosis

We performed untargeted metabolomics in plasma of B6 mice with experimental autoimmune encephalitis (EAE) at the chronic phase of the disease in search of an altered metabolic pathway(s). Of 324 metabolites measured, 100 metabolites that mapped to various pathways (mainly lipids) linked to mitochondrial function, inflammation, and membrane stability were observed to be significantly altered between EAE and control (p < 0.05, false discovery rate <0.10). Bioinformatics analysis revealed six metabolic pathways being impacted and altered in EAE, including α-linolenic acid and linoleic acid metabolism (PUFA). The metabolites of PUFAs, including ω-3 and ω-6 fatty acids, are commonly decreased in mouse models of multiple sclerosis (MS) and in patients with MS. Daily oral administration of resolvin D1, a downstream metabolite of ω-3, decreased disease progression by suppressing autoreactive T cells and inducing an M2 phenotype of monocytes/macrophages and resident brain microglial cells. This study provides a proof of principle for the application of metabolomics to identify an endogenous metabolite(s) possessing drug-like properties, which is assessed for therapy in preclinical mouse models of MS.

Adherence to Disease-Modifying Agents and Association with Quality of Life Among Patients with Relapsing-Remitting Multiple Sclerosis

This study was conducted to evaluate the association of adherence to disease-modifying agents (DMAs) and outcomes among multiple sclerosis (MS) patients in a practice setting. The study had a cross-sectional design. A survey was administered to 214 patients with relapsing-remitting multiple sclerosis (RRMS) to measure quality of life, health status, disability, and employment. Measures of health-care costs and adherence to DMAs were constructed using claims data. The relationship between DMA adherence and outcomes was evaluated using generalized estimating equation methods, adjusting for patient sociodemographic characteristics, comorbidities, medication on hand at the time of the survey, insurance status, prescription copay, and duration of disease. A total of 163 patients (76%) responded to the survey, of whom 111 had been dispensed a DMA. Mean adherence in the 12-month period preceding the survey was 78.1%. Patients with higher adherence had better mental health and pain interference scores. Increasing...

Perfusion and Diffusion Abnormalities of Multiple Sclerosis Lesions and Relevance of Classified Lesions to Disease Status

Objective Hemodynamic abnormality and disruption of white matter (WM) integrity are significant components in the pathophysiology of multiple sclerosis (MS) lesions. However, the roles of stratified lesions with distinct degrees of hemodynamic and structural injury in disease states remain to be explored. We tested the hypothesis that hemodynamic and structural impairment, as assessed by cerebral blood volume (CBV) and fractional anisotropy (FA), respectively, characterizes the extent of tissue injury, and the load of lesion with substantial tissue destruction would reflect the disease status and therefore, would be related to clinical disability. Methods Seven relapsing-remitting MS patients and seven healthy controls underwent perfusion, diffusion and conventional MRI scans. Based on T2-FLAIR and T1-weighted image, WM plaques were classified. After image coregistration, values of CBV and FA were estimated in three distinct lesion types (active, T1-hypointense and T1-isointense lesion) and compared with those obtained in WM from controls. A total of 1135 lesions were evaluated. Brain volumetric measurement and correlative analysis between brain atrophy, lesion volume and clinical disability were also performed. Results Compared with normal WM, significantly reduced CBV and FA were present in the T1-hypointense lesion, while insignificant changes in both parameters were exhibited in the T1-isointense lesion. However, increased CBV but significantly decreased FA was detected in the active lesion. A close spatial relationship between active and T1-hypointense lesion was observed. Lesion load represented by T1-hypointense plus active lesion volume significantly correlated with brain atrophy, which, in turn, significantly correlated with the severity of clinical disability. Conclusion A distinct combination of CBV and FA characterizes the status of a specific lesion type. A severe structural impairment does not solely occur in the T1-hypointense lesion, but is also associated with the active lesion. The burden of the lesion with extensive structural damage provides an image index, indicative of disease status.

Urinary and Plasma Metabolomics Identify the Distinct Metabolic Profile of Disease State in Chronic Mouse Model of Multiple Sclerosis

AbstractIdentification of non-invasive biomarkers of disease progression in multiple sclerosis (MS) is critically needed for monitoring the disease progression and for effective therapeutic interventions. Urine is an attractive source for non-invasive biomarkers because it is easily obtained in the clinic. In search of a urine metabolite signature of progression in chronic experimental autoimmune encephalomyelitis (EAE), we profiled urine at the chronic stage of the disease (day 45 post immunization) by global untargeted metabolomics. Using a combination of high-throughput liquid-and-gas chromatography with mass spectrometry, we found 105 metabolites (P < 0.05) significantly altered at the chronic stage, indicating a robust alteration in the urine metabolite profile during disease. Assessment of altered metabolites against the Kyoto Encyclopedia of Genes and Genomes revealed distinct non-overlapping metabolic pathways and revealed phenylalanine-tyrosine and associated metabolism being the most impacted. Combined with previously performed plasma profiling, eight common metabolites were significantly altered in both of the biofluids. Metaboanalyst analysis of these common metabolites revealed that phenylalanine metabolism and Valine, leucine, and isoleucine biosynthetic pathways are central metabolic pathways in both bio-fluids and could be analyzed further, either for the discovery of therapeutics or biomarker development. Overall, our study suggests that urine and plasma metabolomics may contribute to the identification of a distinct metabolic fingerprint of EAE disease discriminating from the healthy control which may aid in the development of an objective non-invasive monitoring method for progressive autoimmune diseases like MS. Graphical AbstractUntargeted urinary metabolomics of a chronic mouse model of multiple sclerosis identified Phenylalanine, tyrosine & tryptophan metabolism as the significantly altered metabolic pathway. Eight common metabolites were identified when we combined urinary and plasma metabolic signature, which revealed a perturbation of Phenylalanine metabolism and valine, leucine & isoleucine metabolic pathways, involved in CNS dysfunction during diseases. The identified eight metabolic signature of urine and plasma may be of clinical relevance as potential biomarkers and guide towards the identification of specific metabolic pathways as novel drug targets.