Disability Progression In Patients Research Articles

Brain Hemodynamic Changes Associated with Chronic Cerebrospinal Venous Insufficiency Are Not Specific to Multiple Sclerosis and Do Not Increase Its Severity

To investigate the relationship between chronic cerebrospinal venous insufficiency (CCSVI) and cerebral hemodynamic parameters and to disclose any possible involvement in the pathophysiology of multiple sclerosis (MS). The study was approved by the institutional review board, and written informed consent was obtained from all participants. The diagnosis of CCSVI was assigned by using specific color Doppler ultrasonographic criteria. Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time were assessed with dynamic susceptibility contrast material-enhanced magnetic resonance imaging in normal-appearing white matter (NAWM) in 39 patients with MS. Of these, 25 had CCSVI and 14 did not. Twenty-six healthy control subjects were also evaluated, and of these, 14 had CCSVI and 12 did not. Two-way analysis of variance testing was used for statistical analysis, with Bonferroni correction for multiple comparisons. Correlation analysis was performed by calculating Spearman coefficients. Individuals with CCSVI showed cerebral hemodynamic anomalies, such as decreased CBF and CBV, as compared with individuals without CCSVI, without any delay in mean transit time. No significant interaction between MS and CCSVI was found for any hemodynamic parameters. Furthermore, no correlations were found between CBV and CBF values in NAWM or for severity of disability in patients with MS. The MS group showed prolonged mean transit time in the periventricular NAWM, as compared with the control group, and positive correlation was found between mean transit time values and disability scales in patients with MS. The data support a role of CCSVI in cerebral hemodynamic changes, such as a decrease of CBV and CBF, regardless of the presence of MS. CCSVI had no effect on neurologic function and disability progression in patients with MS.

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Impaired health‐related quality of life predicts progression of disability in multiple sclerosis

To determine the value of health-related quality of life (HRQOL) in predicting progression of disability in patients with multiple sclerosis (MS) over a period of 2years. Patients with MS were recruited in 13 outpatient clinics in Madrid, Spain. Baseline HRQOL was quantified using the Functional Assessment of MS (FAMS) and disability with Kurtzke Expanded Disability Status (EDSS). A clinical meaningful deterioration of disability was defined as an increased of ≥1 point in baseline EDSS scores of ≤5.5 and an increase of ≥0.5 point in baseline EDSS scores of ≥6.0. We dichotomized the change in disability according to clinical meaningful deterioration (dependent variable) and performed a logistic regression analysis with the tertiles of the FAMS scores (the upper tertile [high HRQOL] was the reference) as independent variable, adjusting by socio-demographic and clinical variables. Out of 371 enrolled patients, 61 patients with MS dropped out during the 2-year follow-up. Of the remaining 310, 94 (30.3%) had clinical meaningful deterioration of disability. The odds of clinical meaningful deterioration of disability were higher as HRQOL decreased with a significant dose-dependent effect. Adjusted odds ratios were 2.61 [95% confidence interval (CI) 95%=1.12-6.09], [middle tertile vs. upper tertile (reference)]; and 3.27 (95% CI=1.31-8.18), (lower tertile vs. upper tertile). The identification of those patients with MS with poor HRQOL may be important in assessing the risk of future disability progression. Clearly, impaired HRQOL should be one of the primary concerns amongst clinicians who provide treatment to patients affected by MS.

Patient assessment of an electronic device for subcutaneous self-injection of interferon β-1a for multiple sclerosis: an observational study in the UK and Ireland.

BackgroundInjectable disease-modifying drugs (DMDs) reduce the number of relapses and delay disability progression in patients with relapsing–remitting multiple sclerosis (RRMS). Regular self-injection can be stressful and impeded by MS symptoms. Auto-injection devices can simplify self-injection, overcome injection-related issues, and increase treatment satisfaction. This study investigated patient responses to an electronic auto-injection device.MethodsPatients with RRMS (n = 63), aged 18–65 years, naïve to subcutaneous (sc) interferon (IFN) β-1a therapy, were recruited to a Phase IV, observational, open-label, multicenter study (NCT01195870). Patients self-injected sc IFN β-1a using the RebiSmart™ (Merck Serono S.A. – Geneva, Switzerland) electronic auto-injector for 12 weeks, including an initial titration period if recommended by the prescribing physician. In week 12, patients completed a questionnaire comprising of a visual analog scale (VAS) to rate how much they liked using the device, a four-point response question on ease of use (‘very difficult’, ‘difficult’, ‘easy’, or ‘very easy’), and a list of ten device functions to rank, based upon their experiences.ResultsSix patients (9.5%) discontinued the study: one switched to manual injection; two discontinued all treatment; three changed therapy. In total, 59 out of 63 patients (93.7%) completed the VAS; 54 out of 59 (91.5%; 95% confidence interval: 81.3%–97.2%) ‘liked’ using the electronic auto-injector (score ≥6), whereas 57 out of 59 (96.6%) rated the device overall as ‘easy’ or ‘very easy’ to use. Device features rated as most useful were the hidden needle (mean [standard deviation] score: 3.3 [3.01]; n = 56), confirmation sound (3.9 [2.45]), and multidose cartridge (4.6 [2.32]). The least useful functions were the dose history list (8.0 [2.57]) and dose history calendar (7.5 [2.30]).ConclusionsThese findings suggest that the electronic auto-injector may be suitable for patients who are new to injectable DMD therapy. Devices that simplify the injection process may help to ensure that patients receive the full benefits of treatment.

Influence of age and sex on functional outcome over time in a cohort of patients with recent‐onset inflammatory polyarthritis: Results from the Norfolk arthritis register

It has been found that women with rheumatoid arthritis (RA) have a poorer prognosis than men. However, the impact of age at symptom onset is unclear. We investigated the relationship between these factors and functional disability in patients with recent-onset inflammatory polyarthritis (IP). A total of 3,666 patients (66% women) were registered with the Norfolk Arthritis Register between 1990 and 2008. Functional disability was assessed using the Health Assessment Questionnaire (HAQ), adjusted for age at HAQ completion. Linear random-effects models were used to examine HAQ score over time, by sex and age at symptom onset (early = age <55 years, late = age 55-74 years, very late = age ≥75 years). Women had higher HAQ scores over time than men (mean difference 0.29; 95% confidence interval [95% CI] 0.25, 0.34). Men with late-onset IP had lower baseline HAQ scores than men with early onset (mean difference -0.14; 95% CI -0.29, -0.001). Women had comparable baseline HAQ scores at all ages of onset. Both sexes showed the greatest rate of disability progression in patients with very late onset. Those with early onset had a steady level of disability over time. Adjustment for treatment received, comorbidities, and RA subgroup analysis produced results that were largely similar to the initial analysis. Female patients have higher HAQ scores than male patients; patients with early symptom onset show the smallest sex difference. Older age at symptom onset is associated with an increasingly steep trajectory of disability progression. The impact of sex on outcome is evident at baseline, whereas the impact of age at symptom onset becomes apparent during long-term followup.

PND7 Disability Progression in Patients with Relapsing Remitting Multiple Sclerosis (RRMS) Who Experience Disease Activity Despite Previous Disease Modifying Therapy

PND7 Disability Progression in Patients with Relapsing Remitting Multiple Sclerosis (RRMS) Who Experience Disease Activity Despite Previous Disease Modifying Therapy

Delayed fingolimod-associated asystole

Oral fingolimod (Gilenya) is a sphingosine-1-phosphate-receptor modulator that prevents the egress of lymphocytes from lymph nodes. Fingolimod reduces relapses and delays disability progression in patients with relapsing forms of multiple sclerosis (MS). We report a patient with MS who developed asystole and sustained bradycardia 21 hours after the first dose of fingolimod.

Long-term outcomes in patients with multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease of the CNS associated with axonal damage and neuronal loss, which leads to permanent neurologic disability. With an average age at MS onset of around 30 years1 and an average lifespan to 65 years,2 MS is a long-term disease that affects patients for decades. Immunomodulatory therapies have been shown to reduce the incidence of relapse and progression of disability in patients with relapsing-remitting MS (RRMS).3,4 Although guidelines recommend ongoing immunomodulatory therapy, it is currently uncertain how long therapy must be maintained to achieve maximum benefit, as the period of clinical studies tends to be shorter than the period of clinical use. In fact, the majority of MS disease-modifying therapy (DMT) clinical …

Mechanisms of disability accumulation in multiple sclerosis

Natural history studies have identified numerous features of disability progression in patients with multiple sclerosis (MS), and have provided valuable insight into the underlying pathology of the disease that could assist the development of new treatment strategies. A new study indicates that disability progression occurs in two stages in patients with MS.

POI09 Trends in BK and JC polyomavirus and relationship to CD4+/CD8+ ratio in patients with relapsing remitting multiple sclerosis on natalizumab therapy

Natalizumab reduces clinical relapses and the risk of sustained progression of disability in patients with relapsing remitting multiple sclerosis (RR MS). It has been associated with the development of progressive...

Oral drug approved for relapsing multiple sclerosis

Novartis and FDA on September 22 announced the approval of fingolimod, or Gilenya, for the treatment of patients with relapsing forms of multiple sclerosis. The drug, FDA said, is the first oral medication that can delay the progression of disability in patients with multiple sclerosis and reduce

3 T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing–remitting multiple sclerosis: A 3-year pilot study

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3 T in 8 stable relapsing–remitting (RR) MS patients treated with minocycline over 3 years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36 months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r = − 0.94, P = 0.02). This correlation was strongest in the head of caudate (r = − 0.95, P = 0.01) and putamen (r = − 0.89, P = 0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r = − 0.72, P = 0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study

Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Apolipoprotein E polymorphism interacts with cigarette smoking in progression of multiple sclerosis

The influence of apolipoprotein E (ApoE) polymorphism on clinical severity of multiple sclerosis (MS) is still controversial. Cigarette smoking has been suggested to influence the progression of disability in these patients. In this study, we aimed to investigate whether an interaction of smoking with the ApoE polymorphism influences the progression of disability in MS patients. Smoking history from 205 female patients with MS was obtained. Clinical data collected include age at onset, disease duration, annual relapse rate, the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS). ApoE polymorphism was examined in all patients and stratified according to smoking status and associations with the clinical data investigated. There were no significant associations between cigarette smoking and any of the clinical characteristics in the whole group of patients. In women carrying the ApoE E4 isoform, smokers had a lower EDSS (P = 0.033) and MSSS (P = 0.023) in comparison with non-smokers. Our data suggest that in women with MS carrying the ApoE E4 isoform, cigarette smoking may have a protective influence on disease progression and accumulation of disability. These findings need to be confirmed by future large longitudinal studies.

Gray matter atrophy and disability progression in patients with early relapsing–remitting multiple sclerosis: A 5-year longitudinal study

We assessed the relationship between gray matter (GM) and white matter (WM) atrophy and clinical status in early relapsing–remitting multiple sclerosis (MS) patients over 5 years. A group of 181 patients who participated in the ASA (Avonex–Steroid–Azathioprine) study and had complete clinical and MRI assessments over 2 and 5 years was investigated. One hundred seventy (170) patients completed the 12-month follow-up, 147 the 24-month, 98 the 36-month, 65 the 48-month and 47 the 60-month. Changes in GM (GMV), WM (WMV) and peripheral GM (PGV) volumes, whole brain volume (percentage brain volume change PBVC), lateral ventricle volume (LVV), third ventricle width (3VW) and T2-lesion volume (T2-LV) were measured. Patients were assigned according to their clinical status to one of two groups: the Stable group, and the Reached Confirmed Sustained Progression (RCSP) group (24-week interval). At 0–6 months PBVC and GMV, at 0–12 months PBVC, GMV and T2–LV, at 0–24 months PBVC and GMV, at 0–36 months PBVC, GMV and T2-LV, and at 0–48 PBVC predicted the differences between the RCSP and Stable groups. PBVC and LVV showed the strongest ability to differentiate patients who presented 0 or ≥ 3 relapses in the Stable group. Decline in PBVC and GMV were predictive markers of disability deterioration. Correlation of T2-LV with clinical status was weaker and decreased over time. Higher number of relapses was associated with faster decline in whole brain volume.

Corticosteroids and plasma exchange in multiple sclerosis

Corticosteroids (CS) remain a mainstay of treatment for relapses in multiple sclerosis (MS) and optic neuritis. Currently, there is not enough evidence that long-term corticosteroid treatment delays progression of long-term disability in patients with MS. Likewise, it is unclear whether there are, in fact, true differences among the various CS agents, doses, and their applications in specific pulse and tapering regimens.In some patients suffering from severe steroid-resistant relapses, the clinical response to CS treatment may be insufficient. Such patients may obtain clinical benefit from subsequent plasma exchange (PE). PE is increasingly considered as an individual treatment decision in patients with severe relapses not properly responding to CS. Because of the lack of appropriate studies, PE is not recommended as a permanent disease-modifying strategy in MS patients.

Interferon-β1b in Multiple Sclerosis: Effect on Progression of Disability and Clinical Markers of Treatment Response

There is limited long-term data on the effect of interferon-β_1b (IFN-β_1b) on disability progression in patients with multiple sclerosis (MS). There is also no reliable way of predicting individual responses to IFN-β_1b treatment. This prospective study investigated early clinical prognostic markers of disease activity and progression in 115 patients with relapsing-remitting MS (RRMS) treated with IFN-β_1b for almost 5 years. The study also compared progression of disability in IFN-β_1b-treated patients with a historic untreated cohort of MS patients (n = 44). The number of relapses in the first 2 years of MS and in the 2 years before treatment predicted an early relapse after IFN-β_1b treatment. The IFN-β_1b-treated group experienced a slower progression of disability than the untreated cohort, suggesting that IFN-β_1b treatment delays progression of disability in RRMS.

Editorial: Challenges in developing new multiple sclerosis therapies

Editorial: Challenges in developing new multiple sclerosis therapies

HOW EFFECTIVE ARE DISEASE-MODIFYING DRUGS IN DELAYING PROGRESSION IN RELAPSING-ONSET MS?

I read the article by Brown et al. who estimated delay of progression of disability in patients with multiple sclerosis (MS) treated with disease-modifying drugs (DMDs).1 Data indicating delay of progression utilizing patients treated with disease-modifying treatments as their own controls and comparing treated and untreated stages of the illness cannot provide the same significance as data from matched placebo-controlled studies of such medicines, which have only indicated trends toward significant effects on delay of progression of disability and not a robust effect of treatment. Matched placebo-controlled trials of disease-modifying medicines are more likely to determine the effect of disease-modifying treatment on progression of disability, although the authors have described their information as real-world effectiveness, based on their experiences in clinical practice. Reviewing their article, there was little effect of treatment on secondary progressive MS; however, table 1 indicated that such patients were much more disabled, Expanded Disability Status Scale (EDSS) scale of 4.64 at time of first injection, than the relapsing remitting patients, …

Corticosteroids for the long-term treatment in multiple sclerosis

Short term high dose corticosteroid treatment improves symptoms and short term disability after an acute exacerbation of multiple sclerosis (MS) but it is unknown whether its long-term use can reduce the accumulation of disability. To determine the efficacy and safety of long-term corticosteroid use in MS. We searched the following bibliographic databases: CENTRAL (Issue 1, 2007), MEDLINE (1966 to February 2007) and EMBASE (1980 to February 2007). In an effort to identify further published, unpublished and ongoing trials we searched reference lists and contacted trial authors and one pharmaceutical company. We considered controlled, randomised trials (RCTs), with or without blinding, of long term treatment (i.e. longer than 6 months) of any type of corticosteroid in MS, irrespective of disease course. Reviewers independently assessed trial quality and extracted data. Study authors were contacted for additional information. Three trials, all classified at high risk of bias, contributed to this review (Miller 1961; BPSM 1995; Zivadinov 2001) resulting in a total of 183 participants (91 treated). Corticosteroid therapy did not reduce the risk of being worse at the end of follow-up (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.26 to 1.02) but there was a substantial heterogeneity between studies (I(2): 78.4%). I. v. periodic high dose methylprednisolone (MP) was associated with a significant reduction in the risk of disability progression at 5 years in relapsing-remitting (RR) MS (OR 0.26, 95% CI 0.10 to 0.66), while oral continuous low dose prednisolone was not associated with any risk reduction in disability progression at 18 months (OR 1.23, 95% CI 0.43 to 3.56). Risk of experiencing at least one exacerbation at end of follow-up was not significantly reduced with corticosteroid treatment (OR 0.36; 95% CI 0.10 to 1.25). Only one study recorded adverse events: in one patient i. v. MP was discontinued after the fourth pulse when he developed acute glomerulonephritis; a second patient was removed from the study after the fifth i. v. MP pulse because of severe osteoporosis. There is no enough evidence that long-term corticosteroid treatment delays progression of long term disability in patients with MS. Since one study at high risk of bias showed that the administration of pulsed high dose i. v. MP is associated with a significant reduction in the risk of long term disability progression in patients with RR MS, an adequately powered, high quality RCT is needed to investigate this finding.