Intrathecal interferon in the treatment of multiple sclerosis. Patient follow-up

Follow-up observations on patients with multiple sclerosis who were treated with human fibroblast interferon (interferon beta) administered intrathecally for six months revealed a persisting beneficial effect in terms of a reduction in exacerbation rates. At the time of our last report in 1982, ten interferon beta recipients had shown a reduction in their mean exacerbation rate from 1.8/yr before the study to 0.2/yr during the study while ten control patients with multiple sclerosis showed no change in their rates during the study (0.69/yr) compared with before it (0.68/yr). That report was based on observations made for means of 1.9 years in the recipients and 1.6 years in the controls. The recipient patients have now been followed up for 4.4 years (mean) and their exacerbation rates have continued to decrease to a current mean level of 0.16/yr. The control patients were "crossed over" and began receiving interferon beta intrathecally after they had been in the study for two years without showing any change in their rate. During the 2.0 years since crossover they also have shown a reduction in exacerbation rate to a mean of 0.30/yr. The toxic side effects of interferon beta administered intrathecally were acceptable in view of the benefit achieved. Interferon was identified in the cerebrospinal fluid (but not the serum) of two patients prior to treatment, which is probably a manifestation of de novo production of interferon by the central nervous system in response to the multiple sclerosis disease process.     

T-cell interferon gamma receptor binding in interferon beta-1b-treated patients with multiple sclerosis

OBJECTIVE: To investigate the effects of interferon beta treatment on T-cell interferon gamma binding (which is a possible marker for T-cell-dependent immune function) in patients with multiple sclerosis (MS). DESIGN: Assay interferon gamma binding on T lymphocytes from patients with stable relapsing-remitting MS before, 3 months after, and 6 months after initiating interferon beta-1b treatment. SETTING: The study was performed on ambulatory patients in a tertiary care center, where patients were diagnosed as having definite MS. PATIENTS: Eighteen patients with clinically definite, stable, relapsing-remitting MS (13 women and 5 men; mean age [+/-SD] 32.6+/-7.1 years) were selected consecutively. Clinical status was defined according to the Kurtzke Expanded Disability Status Scale. All patients were treated with 8 x 10(6) IU interferon beta-1b subcutaneously every other day. Eighteen age- and sex-matched healthy subjects with no family history of neuropsychiatric disorders formed the control group. RESULTS: T lymphocytes from untreated patients with MS had significantly smaller amounts of interferon gamma receptors than those from control subjects (638+/-7 [SE] vs 707+/-11 [SE] receptors per cell). After 3 months of interferon beta-1b treatment, they showed a significant increase in interferon gamma binding (681+/-9 [SE] receptors per cell). After 6 months, T-cell interferon gamma maximal receptor values were even higher (700+/-7 [SE] receptors per cell), only slightly lower than those of control subjects. CONCLUSION: Given that reduced interferon gamma binding might be related to lymphocyte activation, our data seem to demonstrate that the major effect of interferon beta-lb treatment is a decrease in T-cell activation.     

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.     

PHA-induced interferon in multiple sclerosis: association between gamma interferon and clinical and genetical variables

Gamma interferon (INF-gamma) production, after PHA stimulation of peripheral blood mononuclear cells, from multiple sclerosis (MS) patients with the acute remitting and chronic progressive forms, in attack and remission phases, and from normal controls, was studied by immunoradiometric assay. MS patients in all these 4 clinical states of disease produced less INF-gamma (log value range from 2.55 to 2.65). MNC from the total MS patients produced significantly low levels of INF-gamma compared to the control group (log values 2.60 vs. 2.82; P = 0.001). No association between the interferon production and antigens at any HLA locus (A, B, C, Dw and Bf) was found. There was no correlation between IFN-gamma production and age, sex, duration of disease, or disability index. However there was a slight tendency to negative correlation with the progression index of the disease. The results suggest that this lower IFN-gamma production in MS may be secondary to the disease, and the primary defect may be a severe reduction of the essential lymphocyte populations required for an effective lymphokine cascade to produce the normal immune response against infection.     

Anti-viral properties of interferon beta treatment in patients with multiple sclerosis

Viral infections are potentially associated with the etiology and pathogenesis of multiple sclerosis (MS). It has been speculated that the treatment efficacy of interferon beta (IFN beta) in MS may relate to its anti-viral properties. The study was undertaken to evaluate the in vivo anti-viral effects of IFN beta-1a in patients with MS. Human herpesvirus-6 (HHV-6) was studied as an example for being a latent neurotropic virus. IFN beta used at concentrations of approximately 0.5 microg/ml was shown to significantly reduce in vitro HHV-6 replication in a susceptible T-cell line. Sera derived from 23 MS patients treated with IFN beta-1a were examined for serum cell-free DNA of HHV-6 as an indicator for viral replication and the reactivity of IgM antibodies to a recombinant HHV-6 virion protein containing a known immunoreactive region. The results were compared with those of control sera obtained from untreated MS (n=29) and healthy individuals (n=21). The findings indicated that IFN beta treatment significantly reduced HHV-6 replication as evident by decreased cell-free DNA in treated MS specimens. The results correlated with decreased IgM reactivity to the HHV-6 antigen in treated MS patients compared to untreated controls, suggesting reduced exposure to HHV-6. The findings were confirmed in paired sera obtained from seven MS patients before and after the treatment The study provides new evidence indicating that IFN beta has potent in vivo anti-viral effects that may contribute to the treatment efficacy in MS.     

Response to interferon beta-1a treatment in African American multiple sclerosis patients

BACKGROUND: African Americans (AAs) with multiple sclerosis (MS) seem to have a more severe disease course than white Americans (WAs). To our knowledge, it is not known to what extent treatment with interferon beta-1a will effect the MS disease course within the AA population. OBJECTIVE: To compare the response to treatment with interferon beta-1a between AA and WA MS patients. DESIGN: This is an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study. SETTING: The EVIDENCE study is a randomized controlled trial that compared the efficacy of once weekly, intramuscular, 30-microg interferon beta-1a treatment with thrice weekly, subcutaneous, 44-microg interferon beta-1a therapy in treatment-na?ve MS subjects. PARTICIPANTS: Thirty-six AA subjects were compared with 616 WA subjects. MAIN OUTCOME MEASURES: The number of MS exacerbations, the proportion of exacerbation-free subjects, and the number of new MS lesions present on brain magnetic resonance imaging were compared between AA and WA subjects at 24 and 48 weeks after initiating treatment with interferon beta-1a. RESULTS: The AA subjects experienced more exacerbations and were less likely to remain exacerbation free (statistical trends). The AA subjects developed more new MS lesions on T2-weighted brain magnetic resonance imaging at 48 weeks (P = .04). CONCLUSIONS: Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients.     

Polyneuropathy associated with interferon beta treatment in patients with multiple sclerosis

Peripheral neuropathy has been reported as a side effect of interferon alpha, but not with interferon beta (IFNbeta) treatment. The authors assessed six patients with multiple sclerosis who developed polyneuropathy, or had exacerbation of previously subclinical neuropathy, during treatment with IFNbeta. In five patients the neuropathy improved after discontinuation of treatment and in two patients it relapsed upon rechallenge.     

Social support as a buffer in the relationship between treatment for depression and T-cell production of interferon gamma in patients with multiple sclerosis

OBJECTIVE: This study examined the buffering effects of social support on the relationship between depression and autoaggressive immune function in multiple sclerosis (MS). METHODS: Fourteen participants with comorbid diagnoses of MS and major depressive disorder received 16 weeks of psychotherapy or antidepressant medications. Depression and T-cell production of interferon-gamma (IFN-gamma), a lynchpin in MS pathogenesis, were assessed at baseline and posttreatment. Social support was assessed at baseline. RESULTS: Both depression and T-cell production of IFN-gamma were significantly reduced over the 16 weeks of treatment. There was a significant interaction between change in depression, change in IFN-gamma, and social support (R(2)=.26, P=.03) such that social support served as a buffer. CONCLUSION: These results support the hypothesis that social support buffers the effects of change in depression on IFN-gamma production. However, these findings should be viewed as preliminary due to the small sample size and the absence of a control condition.     

Electrophysiological, neuropsychological and clinical findings in multiple sclerosis patients receiving interferon beta-1b: a 1-year follow-up

We assessed serial event-related potentials (ERPs) as well as neuropsychological and clinical test findings in a group of multiple sclerosis (MS) patients (n = 14) treated with interferon beta-1b (INF-beta-1b) compared to normal controls (n = 14). All investigations were done within 1 week before INF-beta-1b therapy was started and 12 months later. An auditory oddball paradigm was employed. No significant differences in the N100, P200, N200 or P300 latencies between patients and control group were found, but 3 out of 14 MS patients developed abnormal P300 latencies (more than 2 standard errors from the mean) after 1 year of INF-beta-1b therapy. This was not reflected by the respective neurological impairment as assessed by the Expanded Disability Status Scale score. ERPs might be a useful tool in clinical studies in order to evaluate drug effects on cognition, but for a final statement, the analysis of ERPs in a larger group of patients is required.     

干扰素β-1b对多发性硬化患者生活质量影响的1年随访

目的观察干扰素β-1b(IFNβ-1b)治疗复发缓解型多发性硬化(MS)患者的疗效并进行生活质量评估,进一步探索生活质量的相关因素。方法选择接受IFNB-1b治疗的MS患者13例,并于治疗后第1个月、3个月、6个月、9个月、12个月对患者进行随访,评估包括扩展的功能缺损状况(EDSS)评分、多发性硬化患者生活质量量表(MSQOL-54)及汉密尔顿焦虑抑郁量表(HAMA、HAMD)评分。结果经IFNB1b治疗的MS患者在第1、3、6、9、12个月随访时生活质量、EDSS、HAMA、HAMD评分与治疗前比较均无明显变化(P0.05)。治疗前生活质量中躯体功能、性功能及对性生活满意度与EDSS评分呈负相关(P值均0.05);情绪致角色受限、疼痛与病程呈正相关(P值均0.05);躯体功能、情绪状况、社会功能、性功能及对性生活满意度与HAMA评分呈负相关(P值均0.05);认知、应激与HAMD评分均呈负相关(P值均0.05)。躯体致角色受限、精力、健康认知、总体生活质量及健康变化与病程、EDSS、HAMA、HAMD各项无相关性,年龄与MSQOL-54无关(P值均0.05)。结论 IFNB-1b短期内可能对MS患者生活质量无明显影响,生活质量与患者的EDSS评分、焦虑抑郁症状相关。     

Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up

Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m² every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 1/5 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended.     

Clinical follow-up of 304 patients with multiple sclerosis three years after mitoxantrone treatment

The objectives of this study were to assess the benefits of 1) mitoxantrone after three years of follow-up and 2) disease-modifying treatment (DMT) after stopping mitoxantrone. A retrospective analysis was performed on 304 patients with active relapsing-remitting (RR) or progressive multiple sclerosis (PMS) who were treated with mitoxantrone. After mitoxantrone therapy, some patients received DMT (interferon-beta or glatiramer acetate) while others did not. The disease course of the two groups was evaluated by the Expanded Disability Status Scale (EDSS) before and after mitoxantrone and then every year for three years. The mean EDSS score at starting mitoxantrone and three years after stopping mitoxantrone respectively, were: 3.3 (1.3) and 3.2 (1.7) for the RRMS patients and 5.9 (1.2) and 6.4 (1.4) for the PMS patients. Before starting mitoxantrone, demographic and clinical parameters of predictive disability were not significantly different between patients who received DMT or not. The variation of EDSS between time of stopping mitoxantrone and three years later was significantly different (+0.9 versus +0.3; P=0.03) for patients with RRMS. We found that mitoxantrone treatment induces stable disease up to two years after discontinuation of mitoxantrone therapy. In the third year, patients without DMT deteriorated.     

Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.     

Azathioprine and interferon beta(1a) in relapsing-remitting multiple sclerosis patients: increasing efficacy of combined treatment

Current treatments of relapsing-remitting multiple sclerosis (RRMS) with immunosuppressive or immunomodulatory drugs have been shown to modify the course of the disease in a significative number of patients. However, in many cases, the response to either interferon beta (IFN-beta) or azathioprine (AZA) treatments was not satisfactory and new therapeutic approaches are needed. We studied clinical and MRI efficacy, safety and tolerance of AZA and IFN-beta(1a) combined therapy in 23 patients with clinically definite RRMS, who had not previously been responsive to either monotherapies. Our cases were divided into three subgroups: 8 previously untreated patients (subgroup A) with at least 2 years of natural course of the disease, 8 patients (subgroup B) previously treated with AZA for 2 years and 7 patients (subgroup C) previously treated with IFN-beta(1a) for 2 years. The baseline Expanded Disability Status Scale (EDSS) ranged from 2 to 4 in all subgroups. All patients completed 2 years of combined treatment with a dose of AZA adjusted to reduce lymphocyte count down to 1,000 +/- 100/microl in association with IFN-beta(1a) at a dose of 6 MIU every other day. The mean number of relapses during the combined treatment period was significantly lower than that observed before combined therapy in all the three subgroups. Also, the mean Delta EDSS score was significantly lower during combined treatment than in monotherapy in subgroups B and C. Moreover, after 2 years of combined treatment, the number of new T(1) hypointense lesions, the number and volume of proton density/T(2) hyperintense lesions and the gadolinium enhancement of T(1) hypointense lesions were significantly lower than before combined treatment. After 2 years of treatment, this combination therapy appears to be safe and well tolerated and no serious side effects were reported. Despite some limitations of our study design, the information regarding efficacy, safety and tolerance of the association of AZA and IFN-beta is most encouraging.     

Quantitative brain volumetric analysis from patients with multiple sclerosis: a follow-up study

Using magnetic resonance imaging (MRI), we measured in patients with multiple sclerosis (MS) the brain volume changes over a one year period and correlated them with changes in disability. Three-dimensional T1-weighted magnetization prepared rapid acquisition gradient-echo (MP-RAGE) (with subsequent reconstruction of 1-mm thick axial slices) scans of the brain were obtained at baseline and after one year from 14 MS patients. The average percentage decrease of total brain volume was ten times higher for patients who had a deterioration in their expanded disability status scale (EDSS) scores than for those who had not (mean percentage changes were -4.7 and -0.4%, respectively). Over a short time follow-up period, the decrease of brain volume was higher in the MS patients with clinical evolution compared to those with unchanged disability.