Development Of New Brain Lesions Research Articles

Safety and Dose-Response of Vidofludimus Calcium in Relapsing Multiple Sclerosis: Extended Results of a Placebo-Controlled Phase 2 Trial.

Vidofludimus calcium suppressed MRI disease activity compared with placebo in patients with relapsing-remitting multiple sclerosis (RRMS) in the first cohort of the phase 2 EMPhASIS study. Because 30 mg and 45 mg showed comparable activity on multiple end points, the study enrolled an additional low-dose cohort to further investigate a dose-response relationship. In a randomized, placebo-controlled, phase 2 trial, patients with RRMS, aged 18-55 years, and with ≥2 relapses in the last 2 years or ≥1 relapse in the last year, and ≥1 gadolinium-enhancing brain lesion in the last 6 months. Patients were randomly assigned (1:1:1) vidofludimus calcium (30 or 45 mg) or placebo in cohort 1 and vidofludimus calcium (10 mg) or placebo (4:1) in cohort 2 for 24 weeks. The primary end point was the cumulative number of combined unique active (CUA) lesions at week 24. Secondary end points were clinical outcomes and safety. Across cohorts 1 and 2, 268 patients were randomized to placebo (n = 81), 10 mg (n = 47) vidofludimus calcium, 30 mg (n = 71) vidofludimus calcium, or 45 mg (n = 69) vidofludimus calcium. The mean cumulative CUA lesions over 24 weeks was 5.8 (95% CI 4.1-8.2) for placebo, 5.9 (95% CI 3.9-9.0) for 10 mg treatment group, 1.4 (95% CI 0.9-2.1) for 30 mg treatment group, and 1.7 (95% CI 1.1-2.5) for 45 mg treatment group. Serum neurofilament light chain decreased in a dose-dependent manner. The number of patients with confirmed disability worsening after 24 weeks was 3 (3.7%) patients receiving placebo and 3 (1.6%) patients receiving any dose of vidofludimus calcium. Treatment-emergent adverse events occurred in 35 (43%) placebo patients compared with 11 (23%) and 71 (37%) patients in the 10 mg or any dose of vidofludimus calcium groups, respectively. The incidence of liver enzyme elevations and infections were similar between placebo and any dose of vidofludimus calcium. No new safety signals were observed. Compared with placebo, vidofludimus calcium suppressed the development of new brain lesions with daily doses of 30 mg and 45 mg, but not 10 mg, establishing the lowest efficacious dose is 30 mg. This study provides Class II evidence that among adults with active RRMS and≥1 Gd+ brain lesion in the past 6 months, the cumulative number of active lesions decreased with vidofludimus calcium. ClinicalTrials.gov (NCT03846219) and EudraCT (2018-001896-19).

Body mass index as a predictor of MS activity and progression among participants in BENEFIT

Background: There is a lack of studies on the association between obesity and conversion from a clinically isolated syndrome (CIS) to multiple sclerosis (MS). Objective: The aim of this study was to determine whether obesity predicts disease activity and prognosis in patients with CIS. Methods: Body mass index (BMI) at baseline was available for 464 patients with CIS in BENEFIT. Obesity was defined as BMI ⩾ 30 kg/m2 and normal weight as 18.5 ⩽ BMI < 25. Patients were followed up for 5 years clinically and by magnetic resonance imaging. Hazard of conversion to clinically definite (CDMS) or to 2001 McDonald criteria (MDMS) MS, annual rate of relapse, sustained progression on Expanded Disability Status Scale (EDSS), change in brain and lesion volume, and development of new brain lesions were evaluated. Results: Obese individuals were 39% more likely to convert to MDMS (95% CI: 1.02–1.91, p = 0.04) and had a 59% (95% CI: 1.01–2.31, p = 0.03) higher rate of relapse than individuals with normal weight. No associations were observed between obesity and conversion to CDMS, sustained progression on EDSS or magnetic resonance imaging (MRI) outcomes, except for a larger reduction of brain volume in obese smokers as compared to normal weight smokers (−0.82%; 95% CI: −1.51 to −0.12, p = 0.02). Conclusion: Obesity was associated with faster conversion to MS (MDMS) and a higher relapse rate.

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain

IntroductionFinal overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP). MethodsOverall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients. ResultsAt data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31–1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38–1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45–1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57–1.74; previous TKI: HR = 1.22; 95% CI: 0.68–2.22) or liver metastases (HR = 1.01; 95% CI: 0.68–1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39–1.19). ConclusionsThis final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.

IMpower150: Exploratory analysis of brain metastases development.

9587 Background: In the global phase III IMpower150 study (NCT02366143), atezolizumab (atezo) + bevacizumab (bev) + chemo (carboplatin + paclitaxel [CP] (ABCP) showed significant improvements in PFS and OS vs BCP in patients with chemotherapy-naive metastatic NSCLC (Socinski et al. N Engl J Med 2018). Because bev has been shown to delay or prevent brain metastases progression in NSCLC (Fu et al. J Chemother 2016; Ilhan-Mutlu et al. Mol Can Ther 2016), exploratory analyses were conducted to assess the development of brain metastases in patients treated with ABCP, BCP and atezo + CP (ACP) in IMpower150. Methods: A total of 1202 patients (intention-to-treat [ITT] population) were randomized 1:1:1 to receive ABCP, ACP or BCP. Doses were given every 3 weeks: atezo 1200 mg, bev 15 mg/kg, carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2. Co-primary endpoints were investigator-assessed PFS and OS in ITT–wild-type (no EGFR or ALK alterations) patients. Exploratory analyses included the rate and time to development (TTD) of new brain metastases in the ITT population, regardless of the presence of baseline brain metastases, as well as safety. Brain scans were performed as clinically indicated, and analyses were based on investigator assessments. Results: With a minimum follow-up of 32.4 months in the ITT population (data cutoff: September 13, 2019), 100 patients had developed brain metastases, with the highest rate of new brain lesions seen in the ACP (11.9%) vs the ABCP (7.0%) and BCP (6.0%) arms (table). Median TTD was not reached in any arm; a trend toward delayed TTD was seen in the ABCP vs BCP arm (HR, 0.68 [95% CI: 0.39, 1.19]). Among patients with and without brain metastases, 17 (35.4%) and 155 (44.0%) in the ACP arm, 18 (64.3%) and 207 (56.7%) in the ABCP arm and 10 (41.7%) and 183 (49.5%) in the BCP arm had Grade 3-4 treatment-related adverse events, respectively. Conclusions: The ACP arm had the highest rate of new brain lesions, whereas the ABCP and BCP arms had similar, lower rates. Taken together with the trend toward delayed development of new brain lesions with ABCP, the data suggest that adding atezo to BCP may not reduce the rate of new brain lesion development but may delay the time to new lesion development. No new safety signals were observed in this exploratory analysis. Clinical trial information: NCT02366143 . [Table: see text]

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

BackgroundNatalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). ObjectiveTo evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. MethodsThis multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. ResultsNew active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. ConclusionsIn Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

Commentary on ‘Operative Factors Associated with the Development of New Brain Lesions During Awake Carotid Endarterectomy’

Commentary on ‘Operative Factors Associated with the Development of New Brain Lesions During Awake Carotid Endarterectomy’

Operative Factors Associated with the Development of New Brain Lesions During Awake Carotid Endarterectomy

The aim was to analyse a prospective, consecutive series of awake carotid endarterectomy (CEA) patients undergoing, when possible, pre- and postoperative diffusion-weighted magnetic resonance imaging brain scans (DWI). All CEA patients from June 23, 2006, to January 13, 2012, were prospectively entered in the study. CEA was performed under regional cervical block. Only patients demonstrating shunt dependence were shunted. Before August 7, 2008, all longitudinal endarterectomy had been performed with a vein patch. From that date all CEA were eversions without a patch, except shunted patients who were vein patched. DWI was performed 2 days before and 5 days after (3 Tesla). Scans were reported by MRI-trained radiologists. Logistic regression analysis (LRA) identified predictive variables for MRI changes using backward stepwise elimination of variables with p>.05. There was a total of 295 consecutive CEA. There were no deaths but four clinical strokes (1.4 %); 89 excluded from DWI leaving 206; of these 27 (13%) developed new DWI lesions including four of 57 (7%) in the asymptomatic group and 23 of 149 (15%) symptomatic patients. Nineteen of the 206 (9.2%) were shunted. LRA showed that shunt dependence was highly associated with new DWI lesions: odds ratio (OR) 6.43; 95% confidence interval (CI) 2.3-17.9; p<.001. Both the vein patched, non-shunted group (OR .25; CI 0.09-0.72; p=.010) and the eversion (all non-shunted and all non-patched) group (OR 0.05; CI 0.01-0.22; p<.001) were associated with a low risk of new lesions, with the eversion group a lower risk than the patched group. One in every eight CEA patients developed new DWI lesions (rate doubled in symptomatic patients). Shunt dependence in conscious CEA patients is highly associated with the development of new DWI lesions compared with non-shunted patients. For non-shunted patients the new lesion risk is low, and in those patients the risk in the eversion group is lower than in the patched group.

Systemic Lupus Erythematosus: Prediction by MRI of the Subsequent Development of Brain Lesions

Many patients with systemic lupus erythematosus (SLE) manifest the recurrence of new brain lesions on follow-up magnetic resonance imaging (MRI) scans. We assessed whether the initial MRI findings help to predict the subsequent development of brain lesions in patients with SLE. We enrolled 64 patients with SLE who had undergone initial and follow-up MRI studies. Two radiologists reviewed and categorized the initial MRI findings and divided the patients into those with no lesions on the initial and follow-up MRI scans (group A, n = 18), those with lesions on the initial scans only (group B, n = 32), and those with lesions on the first and new lesions on the follow-up MRI scans (group C, n = 14). We then looked for independent predictors of the subsequent development of brain lesions, such as antiphospholipid syndrome (APS) and findings on the initial MRI studies. The incidence of lacunar and localized cortical infarcts was significantly greater in group C than group B (50% vs. 0%, P < .001 and 50% vs. 9%, P < .05, respectively). Multivariate logistic regression analysis indicated that lacunar or localized cortical infarcts on the initial MRI scans were independent predictors of the subsequent development of brain lesions (odds ratio [OR]: 5.412, 95% confidence interval [CI]: 1.18-24.85, P = .03), whereas the presence of APS was not (OR: 0.621, 95% CI: 0.18-2.19). The presence of lacunar and/or localized cortical infarcts on initial MRI scans may predict the development of new brain lesions in patients with SLE.

Radio-induced brain lesions

Abstract Introduction : Radiotherapy, an important tool in multimodal oncologic treatment, can cause radio-induced brain lesion development after a long period of time following irradiation. Material and method : We report 4 cases with radio-induced brain lesions, admitted into the Fourth Department of Neurosurgery, Emergency Clinical Hospital Bagdasar-Arseni, during a 4 years period of time. Results : Two patients had meningiomas and two had unruptured cavernomas. Other side effects of radiotherapy, such as diffuse brain atrophy, leukoencephalopathy, optic atrophy, panhypopituitarism were also noted. The two patients with large meningiomas underwent surgery, with good outcome. Observation was the choice for the two asymptomatic cavernomas. Panhypopituitarism needed synthetic hormonal replacement therapy. Conclusions : Radiotherapy can cause long-term complications and can induce development of new brain lesions into previous radiation area. Meningiomas and cavernomas can be radio-induced brain lesions. Meningiomas can grow to large size, requiring surgery. Unruptured asymptomatic cavernomas can be left in place and patients are followed clinical and with serial imaging. Other findings after radiotherapy are diffuse brain atrophy, leukoencephalopathy, optic atrophy and panhypopituitarism.

Do positive or negative stressful events predict the development of new brain lesions in people with multiple sclerosis?

Stressful life events have long been suspected to contribute to multiple sclerosis (MS) disease activity. The few studies examining the relationship between stressful events and neuroimaging markers have been small and inconsistent. This study examined whether different types of stressful events and perceived stress could predict the development of brain lesions. This was a secondary analysis of 121 patients with MS followed for 48 weeks during a randomized controlled trial comparing stress management therapy for MS (SMT-MS) to a waitlist control (WLC). Patients underwent magnetic resonance imaging (MRI) scans every 8 weeks. Every month, patients completed an interview measure assessing stressful life events and self-report measures of perceived stress, anxiety and depressive symptoms, which were used to predict the presence of gadolinium-enhancing (Gd+) and T2 lesions on MRI scans 29-62 days later. Participants classified stressful events as positive or negative. Negative events were considered 'major' if they involved physical threat or threat to the patient's family structure, and 'moderate' otherwise. Positive stressful events predicted decreased risk for subsequent Gd+ lesions in the control group [odds ratio (OR) 0.53 for each additional positive stressful event, 95% confidence interval (CI) 0.30-0.91] and less risk for new or enlarging T2 lesions regardless of group assignment (OR 0.74, 95% CI 0.55-0.99). Across groups, major negative stressful events predicted Gd+ lesions (OR 1.77, 95% CI 1.18-2.64) and new or enlarging T2 lesions (OR 1.57, 95% CI 1.11-2.23) whereas moderate negative stressful events, perceived stress, anxiety and depressive symptoms did not. Major negative stressful events predict increased risk for Gd+ and T2 lesions whereas positive stressful events predict decreased risk.

Benefits of glatiramer acetate in the treatment of relapsing–remitting multiple sclerosis

Relapsing–remitting multiple sclerosis is a chronic, progressive disorder marked by repeated exacerbations that lead to increases in neurological disability. Glatiramer acetate and the IFN-βs are recommended as first-line agents for relapsing–remitting multiple sclerosis owing to their potential to reduce frequency and severity of relapses, decrease development of new brain lesions and delay permanent disability. After three decades of study, the preponderance of the evidence suggests that the efficacy of glatiramer acetate is similar to the IFN-βs and new data collected in more naturalistic settings suggest that it may provide improved quality of life, increased productivity and cost–effectiveness. This article will review this evidence including data from very recent head-to-head clinical trials and pharmacoeconomic analyses of cost–effectiveness.

A phase II trial of stereotactic radiosurgery boost following surgical resection for solitary brain metastases

1552 Background: At present there is no standard of care for adjuvant therapy following resection of solitary brain metastases. The objective of this study was to determine the local control, survival, patterns of relapse and the incidence of brain injury following a surgery-stereotactic radiosurgery (SRS) combined therapy approach while avoiding upfront whole brain radiation therapy (WBRT). Methods: The eligibility criteria included radiologically proven solitary brain metastases, KPS≥70 and a neurologic function score of 0–2. Following the surgical resection, SRS was delivered to the surgical cavity 4–8 weeks later to a dose of 15–22 Gy in a single fraction using the BrainLAB linear accelerator system. Patients were followed with neurological examination and serial MRI images done every 3 months following the procedure. Results: 25 out of 50 patients needed for the study have been accrued since it opened in August 2004. Four patients have failed locally, with a median time to local failure of 9.5 months. The one year local control at the site of original disease was 35%. Two of the four patients who had local recurrence at the time of relapse also had evidence of leptomeningeal disease. Six additional patients developed new brain metastases, resulting in a 1 year brain relapse free survival of 38% following the combined approach. The median overall survival was 12 months. One patient (4%) developed radiation necrosis that required surgical intervention 6 months following the procedure. Six patients (24%) needed WBRT, two patients (8%) needed further SRS and one patient (4%) needed surgery as salvage following development of new brain lesions with this approach. Conclusions: The preliminary results of surgery-SRS approach appear inferior to surgery-WBRT data for solitary brain metastases in terms of local control and development of new brain metastases. However, relapses can be subsequently managed with WBRT without adversely affecting the overall survival and the morbidity. No significant financial relationships to disclose.

Moderating Effects of Coping on the Relationship Between Stress and the Development of New Brain Lesions in Multiple Sclerosis

Objective Many patients with multiple sclerosis (MS) report that stress can trigger disease exacerbations. Considerable research has supported a relationship between stress and both clinical exacerbation and the development of new brain lesions. However, these relationships are not always consistent either within patients or across patients, suggesting the presence of moderators. This study examined the hypothesis that coping moderates the subsequent relationship between stress and the development of new brain lesions in MS. Methods Thirty-six patients (mean age = 44.4; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28–100 weeks. New brain lesions were identified using monthly Gd+ MRI. Stress was measured within 24 hours before MRI using a modified version of the Social Readjustment Rating Scale that assessed Conflict and Disruption in Routine. Coping was measured at baseline using the Coping with Health Injuries and Problems questionnaire, which produces four scales: distraction, instrumental, palliative, and emotional preoccupation. Data were analyzed using mixed effects logistic regression to account for within-subject correlations. Analyses were lagged such that stress assessments predicted new Gd+ MRI brain lesions 8 weeks later. Results As reported previously, stress was significantly related to the development of new Gd+ brain lesions 8 weeks later (OR = 1.62, p = .009). Greater use of distraction was found to be a significant moderator of the relationship between stress and new Gd+ lesions (OR = 0.69, p = .037) such that greater use of distraction was associated with a decreased relationship between stress and new Gd+ lesions. Increased instrumental coping was marginally associated with a decreased relationship between stress and new Gd+ lesions (OR = 0.77, p = .081), while increased emotional preoccupation was marginally associated with an increased relationship between stress and new Gd+ lesions (OR = 1.46, p = .088). There was no significant moderating effect for palliative coping (p = .27) and no significant main effects for any coping variables and the subsequent development of new Gd+ brain lesions (p values > .21). Conclusions These findings provide modest support for the hypothesis that coping can moderate the relationship between stress and the MS disease activity. Several limitations in this study are discussed. While these findings suggest areas of potentially fruitful research, readers are cautioned that these are preliminary results; inferences regarding the clinical importance of these findings are premature.

Moderating effects of coping on the relationship between stress and the development of new brain lesions in multiple sclerosis.

Many patients with multiple sclerosis (MS) report that stress can trigger disease exacerbations. Considerable research has supported a relationship between stress and both clinical exacerbation and the development of new brain lesions. However, these relationships are not always consistent either within patients or across patients, suggesting the presence of moderators. This study examined the hypothesis that coping moderates the subsequent relationship between stress and the development of new brain lesions in MS. Thirty-six patients (mean age = 44.4; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28-100 weeks. New brain lesions were identified using monthly Gd+ MRI. Stress was measured within 24 hours before MRI using a modified version of the Social Readjustment Rating Scale that assessed Conflict and Disruption in Routine. Coping was measured at baseline using the Coping with Health Injuries and Problems questionnaire, which produces four scales: distraction, instrumental, palliative, and emotional preoccupation. Data were analyzed using mixed effects logistic regression to account for within-subject correlations. Analyses were lagged such that stress assessments predicted new Gd+ MRI brain lesions 8 weeks later. As reported previously, stress was significantly related to the development of new Gd+ brain lesions 8 weeks later (OR = 1.62, p =.009). Greater use of distraction was found to be a significant moderator of the relationship between stress and new Gd+ lesions (OR = 0.69, p =.037) such that greater use of distraction was associated with a decreased relationship between stress and new Gd+ lesions. Increased instrumental coping was marginally associated with a decreased relationship between stress and new Gd+ lesions (OR = 0.77, p =.081), while increased emotional preoccupation was marginally associated with an increased relationship between stress and new Gd+ lesions (OR = 1.46, p =.088). There was no significant moderating effect for palliative coping (p =.27) and no significant main effects for any coping variables and the subsequent development of new Gd+ brain lesions (p values >.21). These findings provide modest support for the hypothesis that coping can moderate the relationship between stress and the MS disease activity. Several limitations in this study are discussed. While these findings suggest areas of potentially fruitful research, readers are cautioned that these are preliminary results; inferences regarding the clinical importance of these findings are premature.

Immunomodulatory effects of interferon beta-1a in multiple sclerosis

Several studies have established a role for interferon beta (IFNβ) as a treatment for relapsing–remitting multiple sclerosis (MS). IFNβ has been reported to decrease the relapse rate, relapse severity, progression of disability and development of new brain lesions. Its mechanisms of action, however, remain unclear. We hypothesize that immunomodulatory effects of IFNβ may underlie its clinical efficacy. We used intracellular cytokine flow cytometry to analyze the effects of IFNβ-1a on expression of the anti-inflammatory cytokine, IL-10, and its effects on major co-stimulatory molecules in MS patients. We found that peripheral blood mononuclear cells (PBMC) produced more IL-10 following in vitro or in vivo treatment with IFNβ-1a. The primary cellular sources of IL-10 were monocytes and CD4 + T lymphocytes. IL-10 production in response to IFNβ-1a was increased in unseparated PBMC compared to purified lymphocyte cultures, indicating that interaction between monocytes and lymphocytes may influence IL-10 production in response to IFNβ-1a. Using flow cytometry, we monitored the ex vivo expression of two major co-stimulatory pairs-B7/CD28 and CD40/CD40L-before and after intramuscular IFNβ-1a treatment of MS patients. IFNβ-1a lowered the expression of B7.1 on circulating B cells and increased B7.2 expression on monocytes. CD40 expression on B cells was down-regulated, but CD40 on monocytes was up-regulated by IFNβ-1a treatment. These data suggest that co-stimulatory molecules are modulated by IFNβ, providing a possible mechanism for its in vivo immune regulatory effects.

Interferon beta induces interleukin-10 expression: relevance to multiple sclerosis.

Interferon-beta decreases the relapse rate, relapse severity, progression of neurological disability, and development of new brain lesions observed with brain magnetic resonance imaging in relapsing-remitting multiple sclerosis patients. The mechanism of action of this effect is presently unknown. This study was based on the hypothesis that immunoregulatory effects of interferon-beta may underlie its demonstrated clinical efficacy. The objective of the study was to determine the effect of interferon-beta-1a on the expression of interleukin-10, a cytokine that strongly inhibits cell-mediated immune responses. Interferon-beta-1a induced accumulation of interleukin-10 messenger RNA and protein secretion by cultured peripheral blood mononuclear cells. The observed in vitro effects were similar for healthy control subjects and multiple sclerosis patients. Intramuscular injections of interferon-beta-1a increased serum levels of interleukin-10 at 12 and 24 hours following the injection. Greater increases were induced with 12 x 10(6)-IU than 6 x 10(6)-IU injections. The effect of interferon-beta-1a was relatively specific for interleukin-10, as treatment with interferon-beta-1a did not result in accumulation of transforming growth factor-beta messenger RNA. Upregulation of interleukin-10 represents a possible mechanism of action of interferon-beta's therapeutic effect in relapsing-remitting multiple sclerosis, and has implications for therapy of other autoimmune diseases.