Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. (1) To compare time to first... more
Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. (1) To compare time to first relapse and disability progression among 'DMT stoppers' and propensity-score matched 'DMT stayers' in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers. Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a mar...
Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of... more
Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4(+) T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4(+)CD25(+)FoxP3(+) regulatory T-cells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.
The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested... more
The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the developm...
Complex pharmaceuticals are in demand of competent analytical methods able to analyze charge heterogeneity as a critical quality attribute (CQA), in compliance with current regulatory expectations. A notorious example is glatiramer... more
Complex pharmaceuticals are in demand of competent analytical methods able to analyze charge heterogeneity as a critical quality attribute (CQA), in compliance with current regulatory expectations. A notorious example is glatiramer acetate (GA), a complex polypeptide mixture useful for the treatment of relapsing-remitting multiple sclerosis. This pharmaceutical challenges the current state of analytical technology in terms of the capacity to study their constituent species. Thus, a strong cation exchange methodology was designed under the lifecycle approach to support the establishment of GA identity, trough the evaluation of its chromatographic profile, which acts as a charge heterogeneity fingerprint. In this regard, a maximum relative margin of error of 5% for relative retention time and symmetry factor were proposed for the analytical target profile. The methodology met the proposed requirements after precision and specificity tests results, the former comprised of sensitivity and selectivity. Subsequently, method validation was conducted and showed that the method is able to differentiate between intact GA and heterogeneity profiles coming from stressed, fractioned or process-modified samples. In summary, these results provide evidence that the method is adequate to assess charge heterogeneity as a CQA of this complex pharmaceutical.
This study evaluated the cost-effectiveness of first-line treatments of relapsing-remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily,... more
This study evaluated the cost-effectiveness of first-line treatments of relapsing-remitting multiple sclerosis (RRMS) (dimethyl fumarate [DMF] 240 mg PO BID, teriflunomide 14 mg once daily, glatiramer acetate 20 mg SC once daily, interferon [IFN]-β1a 44 µg TIW, IFN-β1b 250 µg EOD, and IFN-β1a 30 µg IM QW) and best supportive care (BSC) in the health care payer setting in Finland. The primary outcome was the modeled incremental cost-effectiveness ratio (ICER; €/quality-adjusted life-year [QALY] gained, 3%/y discounting). Markov cohort modeling with a 15-year time horizon was employed. During each 1-year modeling cycle, patients either maintained the Expanded Disability Status Scale (EDSS) score or experienced progression, developed secondary progressive MS (SPMS) or showed EDSS progression in SPMS, experienced relapse with/without hospitalization, experienced an adverse event (AE), or died. Patients׳ characteristics, RRMS progression probabilities, and standardized mortality ratios w...
Treatment with disease-modifying immunomodulators is recommended for patients with relapsing-remitting MS (RRMS). However, continuous adherence to treatment with these injected therapies can be challenging. The main objective was to... more
Treatment with disease-modifying immunomodulators is recommended for patients with relapsing-remitting MS (RRMS). However, continuous adherence to treatment with these injected therapies can be challenging. The main objective was to examine the predictors of adherence to glatiramer acetate using a study model derived from Prochaska's transtheoretical model of change. We conducted a 12-week, prospective, observational study. Potential predictors included readiness stage, MS self-efficacy, decisional balance (pros and cons of self-injection), and injection competence. Adults with RRMS, either treatment-naïve (TN) or treatment-experienced (TE), taking glatiramer acetate for the first time were studied. Interventions (including injection training) were implemented to promote adherence. The evaluable population included 146 TN patients and 88 TE patients who had previously discontinued beta-interferons. Adherence rates did not differ between TN and TE groups (86% for both at week 12); however, predictors of adherence did. For TN patients, greater functional self-efficacy, higher self-injection competence at baseline, and improvement in self-injection competence over the first month of therapy predicted adherence. For TE patients, lower body mass index and longer duration of MS predicted adherence. Interventions to improve self-efficacy and self-injection competence should be a priority when treating TN patients. Behavioral predictors of adherence in TE patients warrant further study.
Gait impairment represents one of the most common and disabling symptoms of multiple sclerosis (MS). To identify which temporal or spatial parameters of gait could be used as outcome measures in interventional studies of individuals with... more
Gait impairment represents one of the most common and disabling symptoms of multiple sclerosis (MS). To identify which temporal or spatial parameters of gait could be used as outcome measures in interventional studies of individuals with MS with different levels of disability, we evaluated characteristics of these parameters in a case study of 3 participants with MS, using 1 case as an exemplar and the other participants as validation. A case study of an exemplar participant was conducted with a 67-year-old woman with secondary progressive MS served as exemplar, with 2 other participants (52 and 55 years old) as validation. The primary outcome measures we used were stride time, stride length, gait velocity, and daily symptoms. Stride length and velocity of gait decreased with increasing pain and fatigue. The step time was significantly longer later in the day, whereas the step length remained the same. Stride length and velocity are associated with the level of fatigue and pain, as ...
CD45RO Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg... more
CD45RO Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age- matched early MS patients, whereas nTreg frequencies did
The main objective of this study is to evaluate the effect of immunomodulatory agents (IMAs) (Interferon-Beta, Glatiramer Acetate) in a large cohort of multiple sclerosis (MS) patients with disease onset in childhood or adolescence,... more
The main objective of this study is to evaluate the effect of immunomodulatory agents (IMAs) (Interferon-Beta, Glatiramer Acetate) in a large cohort of multiple sclerosis (MS) patients with disease onset in childhood or adolescence, treated before 16 years of age, after a long-term follow-up. A total of 130 patients were identified, 77 were treated with Avonex, 39 with Rebif/Betaferon, 14 with Copaxone. After a mean (SD) treatment duration of 53.6 +/- 27.0, 59.9 +/- 39.5 and 74.6 +/- 35.5 months, respectively, the relapse rate decreased significantly. The final EDSS score was unchanged with respect to the initial score. Similar results were also observed in subjects who continued a long-term follow-up after they were included in an observational study in 2004, and in subjects who were treated before 12 years of age. The frequency of clinical and laboratory adverse events was similar to that observed in adult patients. To conclude, IMAs were effective and well tolerated in paediatric patients with MS.
To identify predictors of ten year expanded disability status scale (EDSS) change after treatment initiation in patients with relapse-onset MS. Using data obtained from MSBase, we defined baseline as the date of first injectable therapy... more
To identify predictors of ten year expanded disability status scale (EDSS) change after treatment initiation in patients with relapse-onset MS. Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for one day and were monitored on any approved disease modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range 0-2) at 10 years post-baseline. Annualised relapse rate was highly predictive of increases in median EDSS over 10 years (coeff 1.14, p=1.9x10(-22) ). On therapy rel...
Copaxone modifies TH1 immune response in multiple sclerosis. As Crohn's disease shares TH1 predominance, this study came to investigate the anti-inflammatory response... more
Copaxone modifies TH1 immune response in multiple sclerosis. As Crohn's disease shares TH1 predominance, this study came to investigate the anti-inflammatory response of Copaxone in animal model of colitis. Colitis was induced by intra-rectal instillation of TNBS in 2 animal groups; one of them was daily treated intraperitoneally by 300 mug Copaxone starting 48 h post-colitis induction. Both colitis groups were compared to naive group. Eight male C57Bl6 mice were used in each group. At day 12, distal colon was excised for standard scoring, splenocytes were isolated for FACS and serum cytokines were assessed. Splenocytes were in-vitro-stimulated with colitis protein extracts in the presence or absence of Copaxone. Lymphocytes were blocked by either MHC anti-class I or anti-class II antibodies prior to Copaxone administration. Copaxone markedly alleviated macro/microscopic colitis scoring as they decreased from 2.9 +/- 1.1/2.6 +/- 0.8 in colitis group to 1.7 +/- 1/1.5 +/- 0.5 in Copaxone-treated mice (P = 0.03/P = 0.008, respectively) compared to 0 +/- 0/1 +/- 0 in naives (P < 0.001/P < 0.01, respectively). CD4 subsets significantly decreased following Copaxone administration as compared to naive mice (P = 0.05). Although Copaxone-treated mice manifested a block of both serum TH1/TH2 responses, only interferon gamma secreting CD4 cells significantly decreased. NK cells tend to increase following colitis induction (P = 0.08), however, they significantly decreased in Copaxone-treated animals (P = 0.006). NK-T followed NK pattern. Using in vitro studies, Copaxone showed amelioration of T-cell proliferation that was significantly blocked when cells were pre-incubated with anti-MHC class II but not class I antibodies. Copaxone had class-II-restricted anti-inflammatory effect in our animal colitis model associated with CD4/NK/NKT/TH1/TH2 suppression.
Objective: The pathological hallmarks of multiple sclerosis (MS) lesions are inflammation, demyelination, axon loss and gliosis. The aim of this study was to verify the relation of brain lesion load and volume of the cerebral hemisphere... more
Objective: The pathological hallmarks of multiple sclerosis (MS) lesions are inflammation, demyelination, axon loss and gliosis. The aim of this study was to verify the relation of brain lesion load and volume of the cerebral hemisphere determined by brain MRI with intrathecal antibody synthesis. Methods: A longitudinal study of 54 Brazilian patients with the relapsing-remitting form of MS was undertaken
Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term... more
Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were repo...
While CD8 subsets activate hepatic fibrosis, natural killer (NK) cells exhibit antifibrotic activity. Glatiramer acetate (GA) is an immune modulator for multiple sclerosis. We assessed the potential impact of GA on mouse hepatic... more
While CD8 subsets activate hepatic fibrosis, natural killer (NK) cells exhibit antifibrotic activity. Glatiramer acetate (GA) is an immune modulator for multiple sclerosis. We assessed the potential impact of GA on mouse hepatic fibrogenesis. Hepatic fibrosis was induced in C57BL/6 mice by intraperitoneal administration of carbon tetrachloride (CCl4) for 6 wk. During the last 2 wk, animals were also treated with either GA (200 μ/day ip) or medium and compared with naive and fibrotic mice (8 animals/group). GA markedly attenuated fibrosis without altering reactive oxygen species production. By morphometric measurement of Sirius red-stained tissue sections, the relative fibrosis area decreased from 5.28 ± 0.32% (mean ± SE) in the untreated CCl4 group to 2.01 ± 0.28% in CCl4+GA-treated animals, compared with 0.38 ± 0.07% in naive mice. α-Smooth muscle actin immunoblotting and mRNA expression revealed a similar pattern. Serum aminotransferase and Ishak-Knodell necroinflammatory score we...