Emotional state of patients with relapsing-remitting MS treated with interferon beta-1b.

BACKGROUND: Depression has been cited as a possible side effect of interferon beta-1b (IFNbeta-1b) therapy in patients with MS. This association remains unproven because of a lack of longitudinal studies. OBJECTIVE: To determine the changes in emotional state in relapsing-remitting (RR) MS patients during the first 2 years of treatment with IFNbeta-1b. METHODS: Emotional state was evaluated in a sample of 90 patients at the onset of IFNbeta-1b treatment during an inclusion period of 2.5 years. Seventy-five patients were evaluated at their 12th month of treatment and 56 patients at their 24th month. We assessed their emotional state with the following psychological tests: Hamilton Depression Rating Scale, Beck Depression Inventory, and State-Trait Anxiety Inventory. RESULTS: We found significant improvement in emotional state after the first and second years of treatment. CONCLUSIONS: Our findings show that IFNbeta-1b does not increase depression or anxiety in RR MS patients during the first and second years of IFNbeta-1b treatment. In fact, slight but significant improvement in depression and anxiety symptoms was observed during this period.     

Relationship between serum levels of IL-10, MRI activity and interferon beta-1a therapy in patients with relapsing remitting MS

BACKGROUND: The purposes of this study were to: (1) compare monthly serum IL-10 in patients with relapsing remitting (RR) multiple sclerosis (MS) and healthy controls, (2) determine the relationship between IL-10 and MRI activity and (3) determine the effect of interferon beta-1a (IFNB-1a) treatment on IL-10 levels. RESULTS: Median serum IL-10 levels were lower in untreated RRMS (185.5 pg/ml) compared to controls (438.5 pg/ml) (P=0.19). Serum levels of IL-10 did not appear to predict the appearance of new gadolinium-enhancing (Gd+) lesions concurrently or 1 month thereafter. However, IL-10 levels were more likely to be elevated the month during which Gd+ lesions resolved (OR=3.14, P=0.01). Median IL-10 levels were lower during IFNB-1a treatment (P=0.01). CONCLUSIONS: These observations suggest a relationship between serum IL-10 levels and resolution of abnormal vascular permeability in new lesions.     

Benefit of interferon beta-1a on MSFC progression in secondary progressive MS

BACKGROUND: Interferon beta-1a (IFNbeta-1a, Avonex) is efficacious in relapsing forms of MS. Studies of other IFNbeta preparations in secondary progressive MS (SPMS) yielded conflicting results. This study was undertaken to determine whether IFNbeta-1a slowed disease progression in SP-MS. METHODS: A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFNbeta-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years. The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of ambulation (Timed 25-Foot Walk), arm function (Nine-Hole Peg Test [9HPT]), and cognition (Paced Auditory Serial Addition Test [PASAT]). RESULTS: Median MSFC Z-score change was reduced 40.4% in IFNbeta-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT. There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFNbeta-1a subjects had 33% fewer relapses (p = 0.008). There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-hyperintense brain MRI lesions and gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001). IFNbeta-1a was well tolerated by the majority of subjects. Neutralizing antibodies developed in 3.3% of IFNbeta-1a-treated subjects. CONCLUSIONS: IFNbeta-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.     

Ibuprofen treatment versus gradual introduction of interferon beta-1b in patients with MS.

Flu-like symptoms and injection site reactions are adverse effects of treatment with interferon beta-1b in patients with MS. We compared gradual dose escalation, ibuprofen treatment, or their combination in an open-label study. The combination reduced the incidence of flu-like symptoms to rates comparable with the placebo group in the pivotal trial but increased the frequency of injection site reactions, albeit modestly and transiently.     

Longitudinal MRI study: the effects of azathioprine in MS patients refractory to interferon beta-1b

An open-label study was performed to assess the effectiveness of oral azathioprine (AZA) on augmenting the response to interferon beta-1b (IFNbeta-1b) in patients with treatment-refractory relapsing-remitting MS. Six IFNbeta-1b-treated MS patients with continued disease activity were studied on IFNbeta-1b and AZA therapy for a median period of 15 months. A 69% reduction in the number of contrast-enhancing lesions was observed during the combination therapy (p = 0.002).     

MRI and clinical activity in MS patients after terminating treatment with interferon beta-1b

Monthly MRI activity and clinical disability were evaluated in two relapsing-remitting multiple sclerosis (RRMS) patients for 4 years during a cross-over treatment trial with IFNbeta-1b, and for a mean of 21 months after terminating treatment with IFNbeta-1b. Post-treatment MRI activity was compared to baseline activity in these patients. Although contrast enhancing lesions (CEL) and the bulk white matter lesion load (BWMLL) on T2-weighted images eventually returned to baseline values, there was a refractory period of 6 - 10 months after terminating treatment, before baseline MRI activity was restored. Although the mechanism for a sustained effect of IFNbeta-1b is unclear at this time, these results have important implications for enrollment of such patients into new treatment protocols that rely on contrast enhancing lesion frequency as an outcome measure.     

Mx proteins in blood leukocytes for monitoring interferon beta-1b therapy in patients with MS

OBJECTIVE: To correlate Mx protein (Mx) levels in lysed blood leukocytes with the clinical response to interferon (IFN) beta-1b (IFNbeta-1b) in relapsing-remitting MS (RR-MS) patients for monitoring treatment. BACKGROUND: Intracellular Mx expression is exclusively induced by the type I IFNs (IFN-alpha, -beta, and -omega) or by viruses and is strongly increased under IFN treatment. Quantitative determination of Mx allows objective assessment of biological effects of IFN. METHODS: Mx protein levels were measured in blood leukocyte lysates from IFNbeta-1b-treated RR-MS patients by ELISA and correlated to clinical parameters, including relapse rate and clinical deterioration. RESULTS: In stable IFNbeta-1b-treated MS patients, Mx levels were significantly increased compared to patients with or without immunosuppressive treatment. In IFN-1b-treated MS patients during relapse, Mx levels were significantly lower than during stable phases of the disease. Mean values of Mx (MVMx) over time of treatment in patients with a reduction of relapse rate were significantly higher than in patients without response. CONCLUSION: Mx levels in lysed blood cells may represent a useful surrogate marker for IFNbeta-1b activity corresponding to the clinical response during treatment of MS.     

Immunomodulatory effects of interferon beta-1a in multiple sclerosis

Several studies have established a role for interferon beta (IFNbeta) as a treatment for relapsing-remitting multiple sclerosis (MS). IFNbeta 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 IFNbeta may underlie its clinical efficacy. We used intracellular cytokine flow cytometry to analyze the effects of IFNbeta-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 IFNbeta-1a. The primary cellular sources of IL-10 were monocytes and CD4(+) T lymphocytes. IL-10 production in response to IFNbeta-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 IFNbeta-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 IFNbeta-1a treatment of MS patients. IFNbeta-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 IFNbeta-1a treatment. These data suggest that co-stimulatory molecules are modulated by IFNbeta, providing a possible mechanism for its in vivo immune regulatory effects.     

Clinical benefits of interferon beta-1a in relapsing-remitting MS: a phase IV study

OBJECTIVE: To evaluate the efficacy and safety of IFNbeta-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with relapsing-remitting multiple sclerosis (MS). METHODS: In this multicenter, open-label, prospective clinical trial, 96 patients with relapsing-remitting MS received IFNbeta-1a 30 mcg intramuscularly once weekly for 2 years. Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2. RESULTS: IFNbeta-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2. Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFNbeta-1a treatment was well tolerated. CONCLUSION: This study confirms and extends the beneficial clinical profile for IFNbeta-1a in relapsing MS.     

Time-dependent cytokine deviation toward the Th2 side in Japanese multiple sclerosis patients with interferon beta-1b

To address the immune mechanism sustaining interferon beta (IFNbeta) efficacy in multiple sclerosis (MS), we longitudinally analyzed expressions of IFN-gamma, IL-4, IL-5 and IL-13 in CD4+ T cells and CD8+ T cells in 22 Japanese MS patients (16 patients with conventional MS and 6 with opticospinal MS) undergoing IFNbeta using flow cytometry. During the 48-week observation period, five opticospinal MS patients (83%) relapsed compared to only four conventional MS patients (25%); the frequency of relapsed patients was significantly higher in the former (p=0.046). The effects of IFNbeta on individual cytokines were time-dependent and altered cytokine productions were particularly evident in CD4+ rather than CD8+ T cells. A decreased intracellular IFN-gamma/IL-4 ratio in CD4+ T cells was thus evident soon after the initiation of therapy, and persisted for the entire 1 year follow-up period, regardless of whether or not the patient relapsed (p<0.01). IFNbeta treatment resulted in a rapid increase in the percentage of IFN-gamma- IL-4+ and IL-13+ CD4+ T cells 1 week after the initiation of therapy and high values were sustained for 6 months but declined to the baseline over 1 year. Later, the percentage of IFN-gamma+ IL-4- CD4+ T cells decreased significantly from weeks 24 through 48 of therapy (p<0.01). When comparisons with the pretreatment values were made for each subtype of MS, a significant reduction of IFN-gamma+ IL-4- CD4+ T cell percentages was shown in conventional MS (p<0.0001), but not in opticospinal MS. Moreover, when such a comparison was made by the presence or absence of relapse during therapy, a significant reduction of IFN-gamma+ IL-4- CD4+ T cell percentages was observed in MS patients without relapse (p<0.01). Thus, a reduction of IFN-gamma+ IL-4- CD4+ T cell percentages in the late phase of therapy is considered important for reducing relapse in conventional MS. When the expression patterns of IFN-gamma, IL-4, IL-5 and IL-13 in CD4+ T cells and CD8+ T cells were compared between patients with and without relapse during therapy, the only significant difference was an increase in the IL-13+ CD4+ T cell percentages in patients with relapse compared to those without (p<0.05). The results indicate that in CD4+ T cells IL-4 was preferentially up-regulated in the early course and IFN-gamma was down-regulated in the late phase of IFNbeta therapy. The net effect of IFNbeta on the immune balance was entirely toward type 2 immune deviation, possibly contributing to its beneficial effects on MS.     

An open-label trial of combination therapy with interferon beta-1a and oral methotrexate in MS.

An open-label study was performed to evaluate the safety and efficacy of combination therapy with weekly oral methotrexate (20 mg) and interferon beta-1a (IFN beta-1a) in 15 patients with MS who had experienced exacerbations while receiving IFN beta monotherapy. Nausea was the only major side effect. A 44% reduction in the number of gadolinium-enhanced lesions seen on MRI scan was observed during combination therapy (p = 0.02). There was a trend toward fewer exacerbations. This combination therapy appears to be safe and well tolerated, and should be studied in a controlled trial.     

Physiological measures of therapeutic response to interferon beta-1a treatment in remitting-relapsing MS.

OBJECTIVE: This pilot study was designed to determine the effects of interferon beta-1a (IFNB) therapy (Avonex) on cortically evoked motor potentials (MEPs) during resting and fatigued states in individuals with multiple sclerosis (MS). METHODS: Eight women with relapsing-remitting MS (mean age 36) and mean Expanded Disability Status Scale (EDSS) score of 3.1 were evaluated before and after 3, 6, and 12 months of IFNB therapy. At each test period, MEPs were recorded at rest and following a fatigue paradigm (3 min maximal contraction). Effects of IFNB on neurological and functional (7.7 m walk and 10 s finger tapping) status and fatigue were also examined. RESULTS: Recovery from post-exercise depression of MEP amplitudes (PED) was 41, 43, and 43.5% faster at 3, 6, and 12 months, respectively, compared to baseline (P < 0.05). Percent reduction of MEP amplitude was significantly less at 6 months (P < 0.05) The majority of subjects (5/8 at 3 months; 6/8 at 6 and 12 months) reported decreased physical fatigue. Functional improvements were observed for walk and finger tapping scores after 3 months of IFNB treatment. MEP latencies were unchanged over the course of the intervention. CONCLUSIONS: Results indicate that IFNB therapy may improve the rate of recovery from central fatigue. SIGNIFICANCE: Transcranial magnetic stimulation (TMS) may have promise as an objective physiological tool to evaluate disease activity and treatment responses in MS.