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Richard A Rudick

Publications and source records attributed to Richard A Rudick.

At least 19 recordsLinked to original sources
PubMed2006

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

Adolescent↗
PubMed2006

Significance of T2 lesions in multiple sclerosis: A 13-year longitudinal study.

OBJECTIVE: To evaluate the relation between T2 lesions and disease severity in relapsing-remitting multiple sclerosis (MS). METHODS: This article describes a 13-year longitudinal study in 30 patients. RESULTS: Patients were 36.3 +/- 6.0 years old, had MS for 6.1 +/- 5.8 years, Expanded Disability Status Scale was 2.2 +/- 0.8, and brain parenchymal fraction (BPF) was 0.825 +/- 0.015 at study entry. At last visit, Expanded Disability Status Scale was 4.4 +/- 1.95, Multiple Sclerosis Functional Composite was -0.34 +/- 1.7, and BPF was 0.774 +/- 0.037. Baseline T2 lesion volume correlated with the BPF of the last visit (r = -0.66; p < 0.0001), magnetization transfer ratio (MTR) in normal-appearing brain tissue (r = -0.52; p = 0.004), and lesion MTR (r = -0.76; p < 0.0001). Change in T2 lesion volume in the first 2 years correlated with BPF of the last visit (r = -0.40; p = 0.03), normal-appearing brain tissue MTR (r = -0.44; p = 0.015), lesion MTR (r = -0.46; p = 0.018), Multiple Sclerosis Functional Composite scores (r = -0.50; p = 0.005), and Paced Auditory Serial Addition Task scores (r = -0.52; p = 0.003). Age was a significant covariate for clinical but not magnetic resonance imaging outcomes. INTERPRETATION: T2 lesions in relapsing-remitting MS correlate strongly with brain tissue loss and brain tissue integrity 13 years later, and with clinical disease severity, though age significantly impacts the clinical correlation. The results provide direct evidence for the disability threshold hypothesis in MS and support monitoring T2 lesions in relapsing-remitting MS.

Adult↗
PubMed2006

Drug Insight: interferon treatment in multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Between 1987 and 1997, clinical trials of three preparations of recombinant interferon-beta were conducted in patients with MS, ushering in a new therapeutic era. These medications have demonstrable benefits and seem to be safe; they represent an important advance in MS treatment. All three formulations of interferon-beta had modest effects on relapses and short-term progression of disability, but the effects on MRI lesion parameters were more substantial. The benefits were greater in clinically isolated syndromes and relapsing-remitting MS than in secondary progressive MS. Although these drugs have been shown to be effective, however, their long-term impact on clinically relevant disability progression is uncertain, and there are many areas of controversy in the MS field regarding the use of these products. There is still a need for more effective treatments, which might include new agents or combination therapies.

Antibodies↗
PubMed2006

Chemokine receptors as biomarkers in multiple sclerosis.

Leukocyte infiltrates characterize tissue inflammation and are thought to be integral in the pathogenesis of multiple sclerosis (MS). This attribute underlines the importance of understanding mechanisms of leukocyte migration. Chemokines are secreted proteins which govern leukocyte trafficking into targeted organs. Chemokine receptors (CKR) are differentially expressed on leukocytes and their modulation is a potential target for MS disease modifying therapies. Chemokines and their receptors are also potential biomarkers of both disease activity and response to treatment. We describe the fluctuations in CKR expression on peripheral leukocytes in a group of MS patients followed longitudinally for up to 36 months. We observed little fluctuation in CKR expression within each patient over time, despite considerable variability in CKR expression between patients. These observations suggest that individual patients have a CKR set point, and this set point varies from one patient to another. Evaluation of chemokines or chemokine receptors as biomarkers in MS will need to account for this individual variability in CKR expression.

Adult↗
PubMed2005

Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity.

BACKGROUND: Gray matter magnetic resonance imaging T2 hypointensity, a marker of iron deposition, is associated with clinical impairment and brain atrophy in cross-sectional studies of multiple sclerosis. Treatment with intramuscular interferon beta-1a limits brain atrophy in the second year of treatment. OBJECTIVE: To test whether T2 hypointensity predicts brain atrophy and whether interferon affects this relationship. DESIGN: Post hoc analysis. SETTING: A multicenter treatment trial conducted at tertiary care comprehensive multiple sclerosis centers. Patients Patients with multiple sclerosis who took part in a 2-year clinical trial in which they received intramuscular interferon beta-1a (30 mug/wk) or placebo. MAIN OUTCOME MEASURES: Deep gray matter T2 hypointensity, brain parenchymal fraction (BPF), and total T2, gadolinium-enhancing, and T1 lesion volumes. RESULTS: T2 hypointensity in various gray matter areas correlated with baseline BPF (r = 0.19-0.39; P = .001-.03). In placebo-treated patients (n = 68), baseline T2 hypointensity predicted the change in BPF in the first year and throughout 2 years (r = 0.26-0.42; P<.001-.03). T2 hypointensity was chosen in regression modeling as the best predictor of BPF change at the 1-year (R(2) = 0.23; P = .002) and 2-year (R(2) = 0.33; P<.001) time points after accounting for all magnetic resonance imaging variables. In the interferon group (n = 65), no relationship existed between baseline T2 hypointensity and BPF change. CONCLUSIONS: Gray matter T2 hypointensity predicts the progression of brain atrophy in placebo- but not interferon beta-1a-treated patients. This predictive effect is seen as early as the first year. We hypothesize that interferon beta may exert its effect on brain atrophy in part by reducing a cascade of events that involve iron deposition as a mediator of neurotoxicity or as a disease epiphenomenon.

Adult↗
PubMed2005

Primary progressive multiple sclerosis as a phenotype of a PLP1 gene mutation.

We report a 49-year-old woman with a history of progressive gait disturbance, white matter disease, and cerebrospinal fluid immunoglobulin abnormalities who met criteria for primary progressive multiple sclerosis and whose son died at age 10 years of an unknown congenital neurodevelopmental disorder. Sequencing of the proteolipid protein 1 gene showed a novel mutation, Leu30Arg (c.89TG), in the mother and son. Pelizaeus-Merzbacher disease is the cause of death in the son and explains the mother's adult-onset neurological disorder. This case goes against dogma that mothers of severely affected sons are asymptomatic as adults and expands the differential diagnosis of primary progressive multiple sclerosis to include proteolipid protein 1 gene mutations.

Arginine↗
PubMed2005

Effects of sex hormones on costimulatory molecule expression in multiple sclerosis.

Sex hormones play a central role as modulators of immune responses and autoimmune diseases. We hypothesized that suppression of MS disease during pregnancy may be mediated by sex steroid hormones via regulation of costimulatory molecules such as CD40L or CD80/CD86 (B7-1/B7-2). We tested two sex hormones that are implicated in immune suppression during pregnancy: estriol and progesterone. We also examined whether this regulation is gender-specific or disease-related. PBMC from untreated relapsing remitting multiple sclerosis (RR MS) patients and controls were examined for expression of T cell and monocyte costimulatory molecules following mitogen stimulation in the presence or absence of sex hormones. In the absence of hormones, we confirmed that mitogen stimulation induced significantly more CD40L on the surface of CD4(+)T cells in MS patients compared to controls, and we extend these findings by showing there were no gender differences in induction of CD40L. Although supra-physiologic doses of hormones mildly suppressed CD40L expression on activated T cells, in vitro exposure to typical pregnancy-related physiologic doses of estriol or progesterone showed very little or no suppression of CD40L. On monocytes, neither estriol nor progesterone significantly altered the expression of CD80/CD86. These results suggest that physiologic doses of estriol or progesterone cannot alter CD40L on T cells or CD80/CD86 on monocytes sufficiently to explain the improvement observed in MS during pregnancy. Thus, although amelioration of MS and other autoimmune diseases during pregnancy is thought to be due to increased sex hormones, the present results do not support a role for suppression of costimulation via estriol or progesterone.

Adult↗
PubMed2005

Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications.

BACKGROUND: The short-term effect of corticosteroids on MRI measures of multiple sclerosis (MS) is not well understood and may have a significant impact when using these quantitative measures to evaluate disease activity and changes following other therapeutic interventions. OBJECTIVE: To determine the impact of a course of intravenous methylprednisolone (IVMP) on quantitative measures of disease activity and tissue injury in MS patients. METHODS: We prospectively measured brain parenchymal fraction (BPF), magnetization transfer ratio (MTR, lesional and whole brain), and lesion volumes on nine weekly brain MRI studies in ten MS patients receiving a course of IVMP. A group of nine MS patients not receiving IVMP served as controls. RESULTS: In comparison to untreated controls, BPF declined over the eight weeks following IVMP treatment (P <0.02). BPF decline was most prominent in patients with secondary progressive MS (SPMS, P <0.03), and was not seen in relapsing-remitting (RR) MS patients. Short-term change in BPF correlated with baseline BPF (r =0.62, P =0.05) and short-term change in lesional MTR (r = -0.55, P =0.03), but not with change in enhancing lesion volume. Short-term change in lesional MTR inversely correlated with baseline lesional and whole brain MTR (r = -0.79, P =0.04 for both). There was no significant difference between treated and control patients in measures of MTR or T2, T1 or enhancing lesion volumes. CONCLUSIONS: Patients with SPMS showed a greater decline in BPF following IVMP than RRMS patients. A correlation between changes in BPF and MTR suggest that these changes are secondary to altered water content within MS lesions. Differential response to a standardized therapeutic intervention in RRMS and SPMS suggests that responses to therapy may differ due to a fundamental pathologic difference between early and late stage MS.

Adult↗
PubMed2005

Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment in patients with multiple sclerosis.

An open-label extension study of the phase III trial of intramuscular interferon beta-1a (IFNbeta-1a-Avonex) was conducted to evaluate the immunogenicity and safety of IFNbeta-1a-Avonex over six years in patients with relapsing multiple sclerosis (MS). Patients who participated in the pivotal phase III study were offered enrolment; entry was also open to patients who had not participated. All patients received IFNbeta-1a-Avonex 30 microg intramuscularly once weekly for six years, for a treatment duration of up to eight years in patients who received IFNbeta-1a-Avonex in the phase III trial. Serum levels of IFNbeta antibodies were measured every six months using a screening enzyme-linked immunosorbent assay (ELISA) followed by an antiviral cytopathic effect assay to detect neutralizing antibodies (NAbs) in serum samples positive on ELISA. The incidence of adverse events and laboratory test results assessed safety. Of 382 total patients, 218 had participated in the phase III study (103 placebo, 115 IFNbeta-1a-Avonex) and 164 had not participated; 24 of the 164 were IFNbeta-naïve. At baseline, 281 patients were negative for IFNbeta antibodies (NAb-). NAbs (titre > or = 20) developed at any time over six years in 5% of these patients. Of 140 patients who had been on IFNbeta-1b-Betaseron, 49 were positive for NAbs (NAb+) at baseline; 11 of 115 who had been on IFNbeta-1a-Avonex were NAb+ at baseline. Thirty-nine of 49 patients who had been on Betaseron and were NAb+ had titres < 100; 36 of these 39 seroconverted to NAb- while on IFNbeta-1a-Avonex, with a median time of approximately six months. Ten patients who had been on Betaseron had NAb titres > or = 100; five remained NAb+ during six years on IFNbeta-1a-Avonex and five seroconverted to NAb-, but only after at least two years. Five patients who had been on IFNbeta-1a-Avonex during the clinical trial were NAb+ with titres < 100 at baseline; four seroconverted to NAb-, with a median time of two to three years. Six patients who had been on IFNbeta-1a-Avonex had NAb titres > or = 100; five of these remained NAb+ at six years. No patient with a NAb titre > 1000 seroconverted to NAb-, whether initially treated with IFNbeta-1a-Avonex or -Betaseron. Adverse events were similar to those observed in the pivotal phase III trial. Results from this trial indicated that IFNbeta-1a-Avonex was associated with a low incidence of NAbs and was well tolerated for up to eight years. Further, the results indicate that persistence of NAbs is dependent on titre and IFNbeta product.

Activities of Daily Living↗
PubMed2004

Association of fatigue and brain atrophy in multiple sclerosis.

Functional imaging studies have demonstrated a relationship between fatigue and altered cerebral activation patterns in multiple sclerosis patients, but no relationship between fatigue and brain atrophy has been demonstrated. We hypothesized that the subjective complaint of fatigue would predict the severity of destructive brain pathology. We assessed the relationship between fatigue and brain atrophy longitudinally in a cohort of 134 patients previously enrolled in a 2-year clinical trial of interferon beta-1a and re-evaluated 8 years after randomization into the trial. Brain atrophy was measured using the brain parenchymal fraction (BPF), and disability was measured using the Multiple Sclerosis Functional Composite at baseline, year 2 and year 8. Fatigue was measured using the Sickness Impact Profile's Sleep and Rest Scale (SIPSR) at baseline, year 2 and year 8. Linear regression analyses were used to assess the relationship between changes in fatigue and atrophy progression. Worsening fatigue on the SIPSR during the initial 2 years was significantly associated with progressive brain atrophy over the subsequent 6 years. The relationships between fatigue and brain atrophy were independent of changes in disability, mood, or other MRI characteristics. This suggests that the subjective complaint of fatigue is linked to destructive pathologic processes in RRMS patients.

Atrophy↗
PubMed2004

Defining interferon beta response status in multiple sclerosis patients.

IFN-beta is effective in reducing relapses and magnetic resonance imaging (MRI) lesions in multiple sclerosis (MS). It is assumed that individual therapeutic responses vary, but methods to identify IFN-beta responsiveness have not been validated. Our objective was to evaluate methods to classify IFN-beta responder status using relapses and MRI lesions. Data was analyzed from 172 patients who were followed up in a placebo-controlled clinical trial of IFN-beta1a for 2 years. Patients were classified as responders or nonresponders using (1) the number of relapses during the 2-year trial; (2) the number of new T2 lesions after 2 years; and (3) the number of gadolinium-enhancing lesions at year 1 and year 2 on study. Outcomes included 2-year change in the Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, and brain parenchymal fraction. We found that subgroups with high on-study relapse numbers had more disease progression, differences between responder subgroups were similar in the IFN-beta1a and placebo arms. In contrast, subgroups with high numbers of new MRI lesions had significantly more disease progression only in the IFN-beta1a arm. Baseline characteristics failed to account for differential outcome. New MRI lesion activity during IFN-beta1a treatment correlates with poor response to IFN-beta1a. MRI classification may facilitate rational therapeutic decisions, better clinical trial designs, and studies correlating biomarkers with therapeutic response.

Adult↗
PubMed2004

Impact of disease-modifying therapies on brain and spinal cord atrophy in multiple sclerosis.

Brain and spinal cord atrophy occur early in the course of multiple sclerosis (MS) and continue throughout this lifelong illness, resulting in substantial parenchymal tissue loss at later disease stages. Treatments that slow or prevent atrophy may reduce disability progression in the long term. Disease-modifying agents (DMAs) such as interferon beta-1b (IFNbeta-1b), IFNbeta-1a, and glatiramer acetate inhibit inflammatory events believed to initiate and perpetuate the disease process. DMAs have been shown to inhibit aspects of MS related to brain inflammation such as relapses and gadolinium-enhanced lesions. Because brain inflammation has been linked to irreversible brain tissue injury, DMAs should be effective in reducing the rate of brain atrophy progression. Weekly IFNbeta-1a (Avonex or Rebif) has been shown to slow the rate of brain atrophy; a large study of a frequent injection regimen with IFNbeta-1a (Rebif) showed continued atrophy progression despite IFNbeta-1a at a rate similar to placebo-treated patients. It is not clear why weekly treatment regimens with lower total doses of IFNbeta-1a would show beneficial effects on brain atrophy compared with frequent injections with larger weekly doses. This article reviews results of clinical trials that have examined the effects of DMAs on brain and spinal cord atrophy in patients with MS. Some of these agents have demonstrated positive effects in well-controlled studies, suggesting that anti-inflammatory therapy can delay or prevent the emergence of irreversible central nervous system pathology.

Adjuvants, Immunologic↗
PubMed2004

Natalizumab: alpha 4-integrin antagonist selective adhesion molecule inhibitors for MS.

Natalizumab (Antegren, Elan Corp. plc.; Biogen Idec.) is the first alpha4-integrin antagonist in the class of selective adhesion molecule inhibitors and is in Phase III clinical trials for the treatment of multiple sclerosis. After a 300 mg intravenous infusion, natalizumab has an elimination half-life of 6 to 9 days, but alpha4-integrin receptors expressed on the surface of peripheral blood leukocytes are more than 80% saturated approximately 1 month postinfusion. Therefore, natalizumab is given as a 300 mg dose administered monthly. Preliminary efficacy results showed a marked reduction (approximately 90%) in the formation of new gadolinium-enhancing lesions and reduced the number of patients with relapse by 50% in patients with relapsing-remitting or secondary progressive multiple sclerosis receiving natalizumab versus those receiving placebo over a 6-month period. In clinical studies, natalizumab has demonstrated a favorable safety profile. Pivotal Phase III studies of natalizumab as monotherapy and in combination with intramuscular interferon-beta-1a are underway in patients with relapsing-remitting multiple sclerosis. Natalizumab may be an important addition to the therapeutic armamentarium for multiple sclerosis.

Antibodies, Monoclonal↗
PubMed2003

Biologic impact of interferon antibodies, and complexities in assessing their clinical significance.

The relevance of neutralizing antibodies (NAb) to interferon-beta (IFNbeta) for patients with MS treated with IFNbeta injections has been controversial. Published data from several double-blind, randomized clinical trials demonstrate that disease activity in IFNbeta-treated patients with MS is similar to placebo-treated patients within the same study. This observation is easily understood by other studies that demonstrate attenuation of the biologic response to IFNbeta injections in patients who are NAb positive. Because of the period over which antibodies develop, however, studies will demonstrate an impact of IFNbeta NAb only after the initial 18 months of therapy. Further, because the effects of IFNbeta on MS disease activity and progression are partial, large sample sizes are required to demonstrate clinical correlates of NAb. Therapeutic decisions related to disease management for patients with MS must consider IFNbeta NAb.

Antibodies↗
PubMed2003

Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis.

BACKGROUND: Atrophy is recognized as a measure of destructive changes in multiple sclerosis (MS). The time course and pathologic mechanisms of atrophy development are not well understood. Significant atrophy was reported to occur within 9 to 12 months in relapsing remitting MS. OBJECTIVES: To test whether atrophy can be detected over short time intervals, and to evaluate its relationship to inflammation. DESIGN AND METHODS: Prior to randomization to a treatment trial, 138 untreated patients with relapsing remitting MS had 3 magnetic resonance imaging scans within a mean +/- SD follow-up of 76 +/- 20.2 days. Brain parenchymal fraction (BPF), a normalized measure of whole brain volume, the proportion of active (gadolinium-enhancing) scans, and the volume of T1-weighted gadolinium-enhancing and T2-weighted hyperintense lesions were determined at all time points. An annualized atrophy rate was estimated by calculating a regression slope. RESULTS: The median Expanded Disability Status Scale score was 3.5, the mean disease duration was 7.6, and the mean age was 38.5 years. The BPF decreased significantly by -0.229% from scan 1 to scan 3, while the proportion of active scans remained high (65%, 63%, and 67%). The BPF change was only weakly correlated to the volume of T1-weighted gadolinium-enhancing lesions in scan 1 (r = -0.185). The estimated annualized atrophy rate was -1.06% (95% confidence interval, -1.50% to -0.62%). CONCLUSIONS: The annualized atrophy rate found in this study is comparable with rates reported previously. Measurements of BPF allow detection of atrophy over short time intervals in active disease. The short-term relationship of inflammation to atrophy development was weak. Brain parenchymal fraction might be a promising measure in future phase 2 studies of agents, with an expected effect on tissue-destructive pathologic mechanisms of MS.

Adult↗