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.     

Interferon beta-1b (betaseron/betaferon) is well tolerated at a dose of 500 microg: interferon dose escalation assessment of safety (IDEAS)

The approved interferon beta-1b (Betaseron/Betaferon) dose is 250 microg (8 MIU) administered subcutaneously (sc) every other day (eod). Clinical trial data suggest a dose response effect for interferon beta in multiple sclerosis (MS) treatment and a maximum dose has yet to be established. The Interferon Dose Escalation Assessment of Safety (IDEAS) study evaluated the safety and tolerability of interferon beta-1b 500 microg (16 MIU) sc eod with structured dose escalation and adverse event (AE) management in 22 patients (20 interferon beta-1b-treated (SD) and two interferon beta-1b-na?ve (ND)) with relapsing-remitting (RR) MS, secondary-progressive (SP) MS, or progressive relapsing MS. IDEAS comprised an eight-week dose escalation period and a 12-week maintenance period, with modification as clinically warranted. Autoinjectors were used for all injections > or =0.4 mL. Clinical laboratory values were monitored monthly. Baseline and exit assessments included the MS Functional Composite score, EDSS, and neutralizing antibody MxA assay. AEs were recorded at every injection. Dose escalation ranged from two to 12 weeks. Some 91% of patients (20/22) achieved the 500-microg dose, and of these 90% (18/20) completed the maintenance phase. There were no differences in response between ND and SD patients. Most common AEs were decreased general well-being, insomnia, and injection site reactions (mostly mild). The 500-microg dose of interferon beta-1b was well tolerated in the short-term with escalation and premedication in these patients, most of whom had previously been receiving 250 microg interferon beta-1b.     

Combination therapy with interferon beta-1a and doxycycline in multiple sclerosis: an open-label trial

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of combination therapy with intramuscular interferon beta-1a and oral doxycycline, a potent inhibitor of matrix metalloproteinases, in patients with relapsing-remitting multiple sclerosis (RRMS) having breakthrough disease activity. DESIGN: Open-label, 7-month trial. SETTING: Louisiana State University Health Sciences Center, Shreveport. PATIENTS: Fifteen patients with RRMS taking interferon beta-1a with breakthrough disease activity took doxycycline for 4 months. Patients underwent monthly neurologic examination, magnetic resonance imaging of the brain using triple-dose gadolinium, and safety blood work. INTERVENTIONS: Ongoing treatment with intramuscular interferon beta-1a plus oral doxycycline, 100 mg daily, for 4 months. MAIN OUTCOME MEASURES: The primary end point was gadolinium-enhancing lesion number change, and the secondary end points were relapse rates, safety and tolerability of the combination of interferon beta-1a and doxycycline in patients with MS, Expanded Disability Status Scale score, serum matrix metalloproteinase-9 levels, and transendothelial migration of monocytes exposed to serum from patients with RRMS. RESULTS: Combination of doxycycline and interferon beta-1a treatment resulted in reductions in contrast-enhancing lesion numbers and posttreatment Expanded Disability Status Scale values (P < .001 for both). Only 1 patient relapsed. Multivariate analyses indicated correlations between decreased serum matrix metalloproteinase-9 levels and enhancing lesion activity reduction. Transendothelial migration of monocytes incubated with serum from patients with RRMS undergoing combination therapy was suppressed. Adverse effects were mild; no adverse synergistic effects of combination therapy or unexpected adverse events were reported. CONCLUSIONS: Combination of intramuscular interferon beta-1a and oral doxycycline treatment was effective, safe, and well tolerated. Controlled clinical trials in larger cohorts of patients with MS are needed to evaluate the efficacy and tolerability of this combination. Trial Registration clinicaltrials.gov Identifier: NCT00246324     

Long-term experience with interferon beta-1b (Betaferon)in multiple sclerosis

The interferon beta-1b (IFNbeta-1b, Betaferon/Betaseron) molecule was cloned some 20 years ago. In a pilot dose-finding trial involving 30 multiple sclerosis (MS) patients, the 10 MS patients receiving 250 microg (8 MIU) IFNbeta-1b every other day at 6 months showed a reduced attack frequency relative to 6 patients receiving placebo. Based on these extremely preliminary results a Phase III placebo-controlled trial was undertaken. Treatment with IFNbeta-1b was shown to reduce attack frequency and severity and to markedly reduce magnetic resonance imaging-(MRI) measured activity and disease burden. IFNbeta-1b therapy was subsequently shown to reduce MRI activity within 2 weeks of starting treatment. The benefits of treatment with IFNbeta-1b observed in the original pivotal study are maintained in the longer term, with consistent treatment effects seen after 5 years. IFNbeta-1b has subsequently been shown to reduce accumulation of disability in MS patients with early active secondary progressive disease, to increase cerebral metabolism, and to improve cognitive performance.IFNbeta-1b therapy is generally well tolerated. Classical systemic side effects related to all beta interferons can effectively be managed by dose escalation, and the use of an autoinjector minimises injection site reactions. About one-third of MS patients receiving IFNbeta-1b develop anti-interferon antibodies, typically within the first year of therapy. These antibodies have variable titres that fall with time and ultimately disappear in most patients. The clinical consequences of the presence of antibodies are presently unclear and inconsistent-some patients without antibodies respond poorly to treatment, whereas others with high-titre antibodies respond well to treatment. It is possible that immune complexes formed when anti-interferon antibodies encounter IFNbeta may enhance some of the immunomodulatory actions of the drug by improving CD8 cell-mediated suppressor function. Until the clinical relevance of antibodies is better understood, treatment decisions should be based on clinical grounds only.     

High-dose, frequently administered interferon beta therapy for relapsing-remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study

Long-term trials have demonstrated the continued efficacy of interferon (IFN) beta treatment in patients with relapsing-remitting (RR) multiple sclerosis (MS) during prolonged administration. The objective of the work was to evaluate the effects of reducing IFN beta administration frequency and total weekly dose in patients with RR MS who have achieved clinical and MRI disease activity stabilization during long-term IFN beta-1b treatment. Prospective 1-year follow-up of 27 RR MS patients on long-term 250 microg every other day (standard dose) IFN beta-1b treatment were randomized either to gradually reduce dose to 30 microg once-a-week IFN beta-1a (13 patients), or to continue on IFN beta-1b standard dose (14 patients). We found significant differences in the two group of patients. In the group of patients continuously treated with IFN beta-1b standard dose, 79% remained relapse free compared to 23% in the group receiving once-weekly IFN beta-1a (p=0.006). The number of patients without new PD/T2 lesions was higher in the group of patients continuously treated with IFN beta-1b standard dose (77%) compared to the once-weekly IFN beta-1a group (23%) (p=0.04). IFN beta is a long-term treatment for MS. The reduction of IFN beta-1b administration frequency and dose is not advisable even in patients free from clinical and MRI disease activity for many years.     

Multiple sclerosis,interferon beta-1b and depression A prospective investigation

The objectives were twofold: a) to explore a possible association between major depression and treatment with interferon beta-1b in patients with multiple sclerosis; and b) to investigate whether putative antecedent risk factors such as a previous psychiatric history and a family history of affective illness influence the prevalence of major depression post-treatment with interferon beta-1b. Forty-two patients with relapsing-remitting MS underwent neurological examination and were interviewed with the Structured Clinical Interview for Axis 1 DSM-IV Disorders prior to starting interferon beta-1b and thereafter at 3, 6 and 12 months. Ethical considerations dictated that patients diagnosed with major depression received anti-depressant medication. At index assessment, 21.4 % of the sample were diagnosed with a major depression, the figures falling to 17.5 %, 11.4 % and 6.3 % at 3, 6 and 12 months respectively. The majority of subjects with a major depression had a history of psychiatric illness prior to treatment with interferon beta-1b. A family history of affective disorder was not associated with a significantly increased rate of major depression either before or after treatment with interferon beta-1b. While the study's methodology did not address causality, the data demonstrate that major depression post-treatment with interferon beta-1b is linked to a history of psychiatric illness prior to starting treatment. The threefold decline in prevalence rates for major depression over the course of a year demonstrates a good response to anti-depressant medication and possible beneficial effects of interferon beta-1b on mood.     

Interferon causes no myasthenia in a seropositive patient with multiple sclerosis

We describe a successful outcome of long-term interferon beta-1b therapy in a patient who had multiple sclerosis (MS) with positive serum autoantibody to muscle acetylcholine receptor (AChR-Ab). Because of the reported possible causative linkage between interferon beta-1b and myasthenia gravis (MG), the presence of the pathogenic antibody complicated therapeutic strategies. We carefully observed the patient for further 6 months before the treatment, excluding symptomatic MG. The interferon beta-1b therapy then provided a clinical benefit. Hopefully this report will allow MS patients in similar situations to make more rapid, unprejudiced judgments than our patients.     

Lessons from 10 years of interferon beta-1b (Betaferon/Betaseron) treatment

In 1993, interferon beta-1b (IFN beta-1b, Betaferon/Betaseron) was the first interferon approved in the USA for relapsing-remitting multiple sclerosis (RRMS). Since then, dose-dependent effects of IFN beta in MS have been extensively discussed. Such effects had already been observed in the pivotal trial and were followed by dose comparison trials with IFN beta-1a. Later, the therapeutic efficacy of IFN beta-1b could also be demonstrated in secondary progressive (SP) MS patients. We learnt from further studies that benefit from IFN beta in SPMS seems to be most pronounced in those patients still having active disease with superimposed relapses or clear progression. The most common IFN beta-related adverse events, especially in the early treatment phase, have been flu-like symptoms and injection-site reactions. The consequent management of those as well as of other, less frequent, side-effects turned out to be of tremendous importance to ensure patients' compliance. Based on the experience of 10 years, IFN beta-1b belongs to the firstline therapeutics in RR and SPMS.     

Atorvastatin added to interferon beta for relapsing multiple sclerosis: a randomized controlled trial

Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects. The present study evaluated the effect of atorvastatin added to interferon beta-1b in multiple sclerosis (MS) in a multicenter, randomized, parallel-group, rater-blinded study performed in eight Swiss hospitals. Seventy-seven patients with relapsing-remitting MS started interferon beta-1b every other day. After 3?months, they were randomized 1:1 to receive atorvastatin 40?mg/day or not in addition to interferon beta-1b until month 15. The primary endpoint was the proportion of patients with new lesions on T2-weighted images at month 15 compared to baseline at month three. At study end, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.14; 95?% CI 0.36–3.56; p?=?0.81). All predefined secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of new Gd-enhancing lesions on T1-weighted images, total brain volume, volume of grey matter, volume of white matter, EDSS, MSFC, relapse rate, time to first relapse, number of relapse-free patients and neutralizing antibodies did not show any significant differences (all p values >0.1). Transient elevations of liver enzymes were more frequent with atorvastatin (p?=?0.02). In conclusion, atorvastatin 40?mg/day in addition to interferon beta-1b did not have a beneficial effect on relapsing-remitting MS compared to interferon beta-1b monotherapy over a 12-month period.     

Fluvoxamine treatment of major depression associated with multiple sclerosis

Fluvoxamine 200 mg was administered for 3 months to a group of 43 interferon beta-1b treated patients affected by major depression associated with multiple sclerosis. Despite a 16.3% attrition rate, 79% of patients achieved response. The drug was well tolerated.     

Overview of European pilot study of interferon beta-Ib in primary progressive multiple sclerosis

This short monograph describes a trial of interferon beta-1b in patients with primary progressive multiple sclerosis (PPMS) or transitional MS. Designed as a randomized, placebo-controlled pilot, the trial randomly placed 73 eligible patients into two groups, placebo or interferon beta-1b 8 MIU given subcutaneously every other day for two years. Significant differences favouring interferon beta-1b in the MSFC score, T2 lesion volume and TI lesion volume at 24 months were observed. Further study of interferon beta-Ib therapy in PPMS patients in warranted.     

A pilot trial of combination therapy with mitoxantrone and interferon beta-1b using monthly gadolinium-enhanced magnetic resonance imaging

OBJECTIVE: To examine the safety of combination therapy with mitoxantrone (MITX) and interferon beta-1b (IFNbeta-1b) in patients with multiple sclerosis (MS) and a high on-therapy relapse rate and enhancing lesions on baseline magnetic resonance imaging (MRI) scan. METHODS: Ten patients with worsening relapsing remitting or secondary progressive MS were studied using monthly MRI with triple-dose gadolinium contrast. All patients must have been on IFNbeta-1b for at least six months, have at least one enhancing lesion on a screening MRI, at least one relapse on IFNbeta-1b in the six months prior to study entry and be neutralizing antibody negative. Monthly MRI scans using triple dose contrast and a 30-minute delay between contrast administration and scanning were carried out three times over two months to obtain baseline numbers of enhancing lesions each month. At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 3), and 5 mg/m2 at months 4 and 5. Dosing was continued at 5 mg/m2 every third month. Monthly MRI scanning was continued throughout the duration of MITX dosing. The primary outcome measure was the frequency of new enhancing lesions. Secondary outcome measures included relapse rate, and T1 hypointense and T2 lesion burden. RESULTS: Following the addition of MITX to IFNbeta-1b mean enhancing lesion frequency decreased 90% at month 7 (P = 0.008) and enhancing lesion volume decreased by 96% (P = 0.01). Relapse rates decreased 64% (P = 0.004). T2 lesion burden and T1 hypointense lesion burden increased slightly during the baseline phase and decreased following MITX but the difference did not reach statistical significance. There were no serious adverse events on combination therapy and no drop-outs due to toxicity. Total white blood cell count was reduced at 14 days post-MITX infusion but returned to normal levels by day 21. There were no neutropenic fevers and there was no clinically significant elevation of liver function tests. CONCLUSIONS: While the number of patients in this study was small, the results suggest that the combination is safe and well tolerated. Disease activity was substantially reduced following the addition of MITX to IFNbeta-1b.     

Magnetic resonance imaging effects of interferon beta-1b in the BENEFIT study: integrated 2-year results

BACKGROUND: In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions. OBJECTIVE: To examine detailed MRI findings from the first 2 years of this trial. DESIGN: Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study. SETTING: Ninety-eight centers worldwide. PATIENTS: A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis. INTERVENTIONS: Patients were randomized to receive interferon beta-1b, 250 microg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered. MAIN OUTCOME MEASURES: Reported MRI data from patients completing 2 years of follow-up. RESULTS: Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P < .001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P < .001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P < .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P = .02). CONCLUSIONS: Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group. Trial Registration clinicaltrials.gov Identifier: NCT00185211.     

Chemokines MIP-1 and MCP-1 and patients with multiple sclerosis treated with interferon beta-1a]

Chemokines: MCP-1 and MIP-1 alpha may play an important role in the pathogenesis of multiple sclerosis, influencing migration of lymphocytes to the CNS. One of possible mechanisms of interferon beta action may be an effect on chemokines. We measured MCP-1 and MIP-1 alpha chemokines in sera of 24 patients with MS treated with interferon beta-1a before and after 3 months of therapy and in 15 control patients. There was a significant increase of MIP-1 alpha concentration in sera of MS patients in comparison with control group. After 3 months of therapy with interferon beta-1a, MIP-1 alpha and MCP-1 levels did not differ from the values before therapy. Investigations will be continued after longer time of treatment with interferon beta.     

Treatment of early onset multiple sclerosis with suboptimal dose of interferon beta-1a

BACKGROUND: Patients with early onset multiple sclerosis may develop disability at a younger age than adults. There are several reports about safety of beta interferons in childhood and juvenile MS with different doses. OBJECTIVES: To determine safety and efficacy of substandard dose of intramuscular interferon beta-1a in a prospective randomized trial in patients with multiple sclerosis under the age of 16. METHODS: Sixteen patients were divided into two groups randomly. The first group was treated with intramuscular interferon beta-1a 15 micrograms once a week and the second group received no disease-modifying therapy. RESULTS: The patients were followed for four years. There was no significant side effect and none of the treated patients discontinued the drug. There were significant differences between two groups regarding relapse rates (p = 0.04), disability progression (p = 0.01), and new T2 lesions (p = 0.006). CONCLUSION: Treatment with interferon beta-1a is well tolerated for a long period of time and may be effective in substandard doses in early onset multiple sclerosis.     

Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis

BACKGROUND: Treatment with interferon beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The expression of survivin, a cell cycle-regulated antiapoptosis protein, is up-regulated in mitogen-stimulated T lymphocytes from patients with MS, and this expression correlates with MS disease activity. OBJECTIVE: To evaluate the effect of interferon beta on the expression of survivin and other apoptosis regulatory molecules in peripheral T lymphocytes from patients with MS. PATIENTS AND METHODS: In a prospective, combined clinical and immunologic study, we evaluated the expression of survivin, Bcl-2 protein, and the death receptor Fas in mitogen-stimulated T lymphocytes from 26 patients with MS, before and serially after treatment with interferon beta-1a. We also investigated the long-term effects of interferon beta-1a on cellular expression of these proteins and T-lymphocyte apoptosis in a cross-sectional study of 19 patients with MS receiving long-term interferon beta-1a therapy. RESULTS: Treatment with interferon beta-1a reduced the expression of survivin in in vitro stimulated T lymphocytes. This reduced expression correlated with augmented T-cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon beta-1a therapy did not significantly alter cellular expression of Bcl-2 protein or Fas. This down-regulatory effect of interferon beta-1a on cellular expression of survivin was maintained after long-term therapy. CONCLUSIONS: Our observations suggest that interferon beta exerts a regulatory effect on peripheral T lymphocytes through an antiapoptosis mechanism that involves the down-regulation of cellular survivin expression.     

Comparison of injection site pain and injection site reactions in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a or 1b

This prospective, multicentre, international, observational, cohort study compared injection site pain (ISP) and injection site reactions (ISRS) between interferon beta-1b (IFNB-1b; Betaferon) 250 microg subcutaneously every other day and interferon beta-1a (IFNB-1a; Rebif) 44 microg subcutaneously three times weekly in patients with relapsing-remitting MS. Patients started treatment within 3 months before recruitment and were on full dose of therapy at inclusion. Patients self-injected IFNB and self-assessed ISP for 15 consecutive injections immediately, 30 and 60 min after injection, using a visual analogue scale diary. Study staff assessed ISRS. Of 445 patients (valid cases), approximately 90% used autoinjectors. More patients were pain-free at all timepoints with IFNB-1b than with IFNB-1a (eg, 30 min: 42.6% versus 19.7%; P<0.0001). The mean proportion of pain-free injections was greater for IFNB-1b (eg, 30 min: 79.0%) than for IFNB-1a (53.3%; P<0.0001). The proportion of patients without ISRS was greater for IFNB-1b (second visit 51.8% versus 33.8%; P<0.0001). Compared with IFNB-1a, more IFNB-1b patients either had no pain or their ISP had no influence on treatment satisfaction (76.9% versus 64.1%; P=0.006). The impact on tolerability and patient acceptability of any new IFNB product formulations would, however, have to be evaluated in comparative studies.     

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.     

A retrospective, observational study comparing the four available immunomodulatory treatments for relapsing–remitting multiple sclerosis

We performed an observational, retrospective analysis of outcome in a sequential cohort of patients with relapsing-remitting multiple sclerosis (RRMS) in Argentina. Patients treated for 16 months with interferon beta-1a (Avonex; 30 micrograms intramuscularly, once a week), interferon beta-1a (Rebif); 44 micrograms subcutaneously, thrice weekly), interferon beta-1b (Betaferon; 250 micrograms subcutaneously, every other day) or glatiramer acetate (Copaxone; 20 mg subcutaneously daily) were compared with a non-treated group of patients. The different treatment groups were similar in baseline demographic and clinical variables. A significant fall in the annual relapse rate was observed for all four treatments, with the largest effect observed with glatiramer acetate (81% reduction in relapse rate, compared with pre-treatment values). The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 37% in untreated patients to 83% in the glatiramer acetate treated group. No statistically significant changes in disability scores were observed over the treatment period. This first such comparative study in Latin America shows that treatment of multiple sclerosis patients with immunomodulatory therapies in the context of current standards of care in Argentina provides clinically important benefit, and suggest that some of these therapies may be better than others.     

Advancing treatment with interferon beta-1b (Betaferon/Betaseron) in the next decade--thinking beyond the standard dose

Early therapeutic intervention with disease modifying agents in multiple sclerosis (MS) is recommended in an attempt to minimise damage to the central nervous system and improve clinical outcome. Interferon betas (IFN betas) are the most widely used approved therapies for MS at the present time. While optimal dosage and frequency of IFN administration is not fully known, evidence is growing that high-dose, high-frequency IFN beta may be the most effective regimen for controlling clinical activity and minimizing MRI lesion development for at least 1-2 years. Past experience demonstrates that commonly observed side-effects associated with IFN beta injections, such as flu-like symptoms and injection-site reactions, can be markedly reduced through a number of measures. Moreover, the incidence of these side-effects decreases with time. Taking these observations into account, it seems reasonable to consider increasing the maximum approved therapeutic dose of IFN beta-1b (Betaferon/Betaseron) in MS. It has recently been demonstrated that dose escalation of IFN beta-1b combined with pre-medication with ibuprofen enables doses as high as 500 microg every other day to be well tolerated. Further administration of IFN beta-1b (500 microg) in patients with hepatitis C revealed no safety or tolerability concerns, no unexpected or unusual symptoms and no relevant laboratory abnormalities during the 24-week treatment period. It is also noteworthy that the 500 microg dose produced a more marked increase in biological response markers (Mx protein) than that induced by the standard dose of IFN beta-1b, and that other studies have demonstrated similar effects on other such markers. Taken together, the available evidence provides a rationale for using an increased dose of IFN beta-1b in the treatment of MS. This will be investigated further in a new Phase III clinical trial (BEYOND).