Interferon in relapsing-remitting multiple sclerosis.
Topic: Immunotherapy

Recombinant interferons have been shown to suppress both the clinical and magnetic resonance imaging (MRI) measures of disease activity in patients with relapsing remitting multiple sclerosis (RRMS).

PICO
Population: Patients with relapsing-remitting multiple sclerosis
Intervention: Recombinant interferons
Comparison: Placebo or alternative treatment
Outcomes: Suppression of clinical and MRI measures of disease activity

Included studies:
title: Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group.
abstract: We performed yearly MRI analyses on 327 of the total 372 patients in a multicenter, randomized, double-blind, placebo-controlled trial of interferon beta-1b (IFNB). Clinical results are presented in the preceding companion paper. Baseline MRI characteristics were the same in all treatment groups. Fifty-two patients at one center formed a cohort for frequent MRIs (one every 6 weeks) for analysis of disease activity. The MRI results support the clinical results in showing a significant reduction in disease activity as measured by numbers of active scans (median 80% reduction, p = 0.0082) and appearance of new lesions. In addition, there was an equally significant reduction in MRI-detected burden of disease in the treatment as compared with placebo groups (mean group difference of 23%, p = 0.001). These results demonstrate that IFNB has made a significant impact on the natural history of MS in these patients.
title: Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH.
abstract: Fifty-eight patients with severe, progressive multiple sclerosis were prospectively randomized to one of three treatments: 20 received intravenous ACTH, 20 received high-dose intravenous cyclophosphamide plus ACTH, and 18 were placed on a regimen consisting of plasma exchange, low-dose oral cyclophosphamide, and ACTH. The three groups were similar in age, sex, duration and type of disease, and degree of disability. Before treatment and six months and one year after treatment, a disability-status score, ambulation index, and functional-status score were determined, and a quantitative neurologic examination was performed. In the ACTH group, the number of patients stabilized or improved was 8 of 20 at six months and 4 of 20 at one year; in the cyclophosphamide-ACTH group, 18 of 20 at six months and 16 of 20 at one year; and in the plasma exchange group, 11 of 18 at six months and 9 of 18 at one year. High-dose cyclophosphamide plus ACTH was most effective in halting progression of the disease at both 6 and 12 months (at 12 months, cyclophosphamide-ACTH vs. ACTH, P = 0.0004; cyclophosphamide-ACTH vs. plasma exchange, P = 0.087). Thus, progressive multiple sclerosis may be stabilized by short-term, intensive immunosuppression with cyclophosphamide plus ACTH.
title: Impact of interferon beta-1a on neurologic disability in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
abstract: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-1a (IFN beta-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance.
title: Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial.
abstract: The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional clinical outcome measure that includes quantitative tests of leg function/ambulation (Timed 25-Foot Walk), arm function (9-Hole Peg Test), and cognitive function (Paced Auditory Serial Addition Test). The MSFC is the primary outcome measure in the ongoing multinational phase 3 trial of interferon beta-1a (Avonex) in patients with secondary progressive MS.
title: Clinical relapses and disease activity on magnetic resonance imaging associated with viral upper respiratory tract infections in multiple sclerosis.
abstract: Although the risk of clinical attacks of multiple sclerosis seems to be significantly increased with viral upper respiratory tract infections (URTI), serological evidence for the reported association remains controversial. In addition, although MRI is six to 10 times more sensitive than clinical exacerbations in indexing disease activity, any possible association between URTI and MRI activity has yet to be investigated.
title: Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a short term study in relapsing-remitting multiple sclerosis.
abstract: To evaluate whether recombinant human interferon-beta-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI. The study also evaluated the effect on six-monthly T2 weighted abnormality and relapse frequency.
title: Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up.
abstract: A pilot study was undertaken to test the safety and establish the side effect profile of recombinant human interferon-beta 1b (Betaseron, Berlex Laboratories, Richmond, CA), in patients with relapsing-remitting multiple sclerosis (RRMS). During the initial dose finding period (24 weeks), five groups of 6 patients each were treated by subcutaneous injection three times each week with either 0.8, 4, 8, or 16 million units (mU) of Betaseron or placebo (WHO Standard). Although some side effects were noted in all groups, a dose-related trend in reduction of exacerbation frequency and side-effect profile was noted. Patients given 16 mU had no exacerbations during the initial dosing period, but associated side effects led to dose reduction or dropout. An 8 mU dose was selected for further study after 24 weeks, and continuous dosing at 8 mU in 15 patients has now exceeded 6 years. Side effects abated over time. Neutralizing antibody developed in most patients, but titers were variable, fluctuated independently of clinical course, and tended to fall with prolonged treatment. A dose-dependent rise in neopterin levels was observed during the initial dosing period. This pilot study has demonstrated responsiveness to Betaseron, shown a stable safety profile over time, and established guidelines for a dosing regimen to evaluate and optimize further the efficacy of Betaseron in RRMS.
title: The effects of long-term administration of recombinant alpha-2 interferon on lymphocyte subsets, proliferation, and suppressor cell function in multiple sclerosis.
abstract: The immunological effects of long-term treatment with recombinant alpha-2 interferon (rIFN-alpha 2) were investigated in multiple sclerosis (MS) patients treated with 2 X 10(6) units of IFN or a placebo three times per week for one year. A mild lymphopenia was observed in IFN patients who also showed a decrease in the absolute number of total T cells in the blood (OKT3 binding cells); however, the percentage of cells reacting with OKT3, OKT4, and OKT8 antibodies did not change significantly during the study. The percentage of cells reacting with the Leu-7 antibody, which recognizes NK cells, was unchanged. During MS exacerbations, placebo patients showed a tendency for decreased levels of OKT3 and OKT8 cells. In contrast, IFN patients did not demonstrate a decrease in either OKT3 or OKT8 cells during disease attacks. Concanavalin A (ConA)-induced suppressor cell activity was depressed in both IFN and placebo-treated patients during attacks. Lymphoproliferative responses to phytohemagglutinin, pokeweed mitogen, and ConA were unchanged. These studies demonstrate that long-term treatment with rIFN-alpha 2 induces a generalized T-cell lymphopenia, but at this dose does not significantly affect the profiles of T-cell subsets and suppressor cell function in MS patients.
title: Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group.
abstract: Episodic inflammation in the CNS during the early stages of MS results in progressive disability years later, presumably due to myelin and axonal injury. MRI demonstrates ongoing disease activity during the early disease stage, even in some patients who are stable clinically. The optimal MRI measure for the destructive pathologic process is uncertain, however.
title: Systemic high-dose recombinant-alpha-2a-interferon therapy modulates lymphokine production in multiple sclerosis.
abstract: Chronic systemic high-dose recombinant alpha 2a-interferon (rIFNA) therapy reduces exacerbation rate and MRI signs of disease activity in relapsing/remitting multiple sclerosis (RR MS) patients. In order to clarify the possible mechanisms underlying the clinical efficacy of rIFNA in MS, several immunologic studies were performed as a part of a pilot clinical trial. Twenty RR MS patients were treated with 9 x 10(6) IU of rIFNA (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Cytokine production by cultured lymphocytes, major histocompatibility complex class II (MHC-II) antigen expression on cultured macrophages, peripheral blood (PB) and cerebrospinal fluid (CSF) lymphocyte phenotype, and IgG and beta 2 microglobulin levels were studied before therapy, after 6 months of therapy, and 6 months after stopping therapy. rIFNA therapy was associated with reduction of interferon-gamma and tumor necrosis factor-alpha production by PB lymphocytes (p < 0.04), and with slight, not significant, increase of transforming growth factor-beta 2 or interleukin (IL)-10 production. IL-4 was undetectable in the culture supernatants both before and after therapy. rIFNA therapy had no effect on macrophage MHC-II molecule expression. An increased percentage of CD8+, CD8+ high CD11b+ low, and CD3- CD16+ CD56+ cells, and of CD4+ absolute cell number was observed in CSF after rIFNA therapy. After rIFNA administration, IgG level significantly increased both systemically (p < 0.02) and intrathecally (p < 0.001). Serum beta 2 microglobulin level increased (p < 0.01), as well. Only 1 out of the 12 rIFNA treated patients developed neutralizing antibodies against rIFNA during therapy. Six months after stopping therapy all the immunologic changes returned to baseline. These data suggest that the beneficial effect of rIFNA therapy on MS disease activity is probably mediated by a downregulation of proinflammatory cytokine synthesis by PB lymphocytes rather than by macrophage MHC-II antigen expression. The immunologic effects of high-dose systemic rIFNA therapy are temporary and restricted to the period of drug administration.
title: Intrathecal interferon reduces exacerbations of multiple sclerosis.
abstract: Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.
title: Double blind study of intrathecal beta-interferon in multiple sclerosis: clinical and laboratory results.
abstract: Sixteen patients with clinically definite MS admitted to a double blind randomised controlled trial of intrathecal natural beta-IFN were followed for a mean of 22 months including the six month treatment period. Clinical response, evaluated in terms of relapse frequency and of progression rate, showed an increase in relapse rate in treated patients during the six month treatment period and, overall, no benefit in treated versus placebo patients. Serial evaluations were made of cerebrospinal fluid (CSF) cells, IgG, myelin basic protein and CSF and blood T-cell subsets. A rise in CSF IgG Index, MBP and DR+ cells in IFN-treated patients suggested an activation of intrathecal immune response in treated patients.
title: The quality-of-life effects of interferon beta-1b in multiple sclerosis. An extended Q-TWiST analysis.
abstract: A recombinant form of interferon beta-1b (Betaseron) was given Food and Drug Administration approval for use in the treatment of relapsing-remitting multiple sclerosis in 1993 based on a documented reduction in exacerbation rate. However, its effect on disease progression is less clear. It costs $11,000 per year and has documented adverse effects such as fatigue, feverlike symptoms, and depression.
title: Interferon alpha-2a treatment of relapsing-remitting multiple sclerosis: disease activity resumes after stopping treatment.
abstract: We evaluated the long-lasting effects of systemic high-dose recombinant interferon alpha-2a (rIFNA) in relapsing-remitting (RR) MS after discontinuing treatment in a single-blind randomized placebo-controlled trial with 20 RR clinically definite MS patients using either nine million IU intramuscular rIFNA (n = 12) or placebo (n = 8) every other day for 6 months. Follow-up continued for a further 6 months without IFN treatment. In rIFNA-treated patients, main outcome measures, significantly different from placebo during treatment, returned, after discontinuing treatment, to values similar to placebo or baseline. Active MRI lesions per patient increased from 0.08 +/- 0.08 to 1.2 +/- 0.4 (p < 0.02), number of patients with clinical MRI signs of disease activity from 2 of 12 to 8 to 12 (P < 0.04), lymphocyte IFN gamma production from 3.0 +/- 0.7 to 12.4 +/- 2.2 IU/mL (p < 0.01), lymphocyte tumor necrosis factor alpha production from 5.8 +/- 0.9 to 18.9 +/- 6.3 pg/mL (p < 0.05). All side effects of rIFNA treatment disappeared after discontinuing the drug. The reduction of clinical MRI signs of disease activity and the immunologic effects were temporary and restricted to the period of rIFNA administration. The depression of many immunologic and clinical MRI responses during drug administration and their simultaneous return to baseline after discontinuing the drug strongly argue all observed changes were related to drug administration.
title: Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
abstract: The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.
title: Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG).
abstract: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment.
title: A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
abstract: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon beta-1a (Avonex).
title: The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta-1b.
abstract: The fate of the neutralizing antibody (NAB) in MS patients treated with interferons remains unclear. We conducted a follow-up survey of NAB titers in 59 long-term treated patients from the London and Vancouver cohorts of the pivotal trial of interferon alpha-1b. NAB were measured with the myxovirus protein A assay and an ELISA, at a mean follow-up that exceeded 8 years. NAB disappeared in the majority of patients.
title: Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.
abstract: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value.
title: Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis.
abstract: An intravenous rather than oral course of methylprednisolone is often prescribed for treating acute relapses in multiple sclerosis (MS) despite the lack of evidence to support this route of administration. Our double-blind placebo-controlled randomised trial was designed to compare the efficacy of commonly used intravenous and oral steroid regimens in promoting recovery from acute relapses in MS.
title: Chronic systemic high-dose recombinant interferon alfa-2a reduces exacerbation rate, MRI signs of disease activity, and lymphocyte interferon gamma production in relapsing-remitting multiple sclerosis.
abstract: We report a randomized, double-blind, placebo-controlled pilot trial of systemic high-dose recombinant interferon alfa-2a (rIFNA) in 20 patients with relapsing-remitting (RR) multiple sclerosis (MS). Patients received 9 million IU rIFNA (n = 12) or placebo (n = 8) intramuscularly every other day for 6 months. Clinical exacerbations or new or enlarging lesions on serial MRI occurred in two of 12 rIFNA-treated and in seven of eight placebo-treated patients (p < 0.005). There was only one enlarging MRI lesion in the rIFNA group, whereas 27 new or enlarging lesions were present in the placebo group (p < 0.01). Baseline lymphocyte interferon gamma production of 19.10 +/- 7.12 IU/ml significantly decreased to 3.03 +/- 0.66 IU/ml (p < 0.04) in the rIFNA group, whereas production was unchanged in the placebo group. The rIFNA was tolerated without dropouts or serious side effects, but fever, malaise, fatigue (interfering with daily activities in two patients), and leukopenia occurred frequently. Neuropsychological tests excluded neurotoxicity. High-dose systemic rIFNA might reduce clinical and MRI signs of disease activity in RR MS and should be investigated in larger trials.
title: Systemic alpha-interferon therapy of multiple sclerosis.
abstract: A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 X 10(6) IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.
title: Incidence of antibodies to interferon-beta in patients treated with recombinant human interferon-beta 1a from mammalian cells.
abstract: Patients receiving recombinant human interferon-beta 1a (IFN-beta 1a) produced in Chinese hamster ovary (CHO) cells were tested for the formation of neutralizing antibodies (NABs) to IFN-beta. Samples were tested in an enzyme-linked immunosorbent assay (ELISA), and if positive were then tested for neutralization of antiviral activity in an IFN-beta bioassay. A total of 793 patients with viral diseases, premalignant and malignant diseases, and multiple sclerosis received IFN-beta 1a in clinical studies. Long-term studies included 56 patients with cancer treated for 6 or 12 months and 334 patients with multiple sclerosis (MS) at the end of one year of treatment. All of the NAB-positive patients were found in the latter. Positivity in a single specimen was found in 14.4% of the MS patients. The incidence of sustained neutralizing antibody titres (i.e. positive in two tests at least 6 months apart) was 6.9% in this group. Comparison with results from other studies suggests that CHO-derived IFN-beta 1a induces less neutralizing antibody than IFN-beta 1b produced in E. coli.
title: Determinants of Gd-enhanced MRI response to IFN-beta-1a treatment in relapsing-remitting multiple sclerosis.
abstract: The decision to use interferon beta (IFN-beta) as a treatment for relapsing-remitting multiple sclerosis (RRMS) is based on both clinical characteristics and course of the disease. To better identify the profile of responders, the relationships between baseline clinical/MRI characteristics and therapeutical response was analyzed in 49 patients with RRMS randomly assigned to receive subcutaneously 3 or 9 MIU of IFN-beta-1a. The therapeutical response was evaluated as a per cent change in the mean number and volume of monthly Gd-enhancing lesions in both first (early response) and second (late response) 6-month period of treatment, compared to the 6-month pre-treatment period. A better early response was seen in patients with a lower number of relapses during the pre-treatment period, while the late response was favourably influenced by a lower baseline EDSS and the high dose. Our findings suggest that the effect of IFN-beta-1 a on disease MRI activity is dose-related and dependent on the relapse rate and the level of disability before treatment.
title: Beta blockade during and after myocardial infarction: an overview of the randomized trials.
abstract: Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value, and for many such patients mortality reductions of about 25% can be achieved. No important differences are clearly apparent among the benefits of different beta blockers, although some are more convenient than others (or have slightly fewer side effects), and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit. If monitored, the side effects of long-term therapy are not a major problem, as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment. By contrast, although very early IV short-term beta blockade can definitely limit infarct size, more reliable information about the effects of such treatment on mortality will not be available until a large trial (ISIS) reports later this year, with data on some thousands of patients entered within less than 4 hours of the onset of pain. Our aim has been not only to review the 65-odd randomized beta blocker trials but also to demonstrate that when many randomized trials have all applied one general approach to treatment, it is often not appropriate to base inference on individual trial results. Although there will usually be important differences from one trial to another (in eligibility, treatment, end-point assessment, and so on), physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related randomized trials and not just a few particular trial results. Although most trials are too small to be individually reliable, this defect of size may be rectified by an overview of many trials, as long as appropriate statistical methods are used. Fortunately, robust statistical methods exist--based on direct, unweighted summation of one O-E value from each trial--that are simple for physicians to use and understand yet provide full statistical sensitivity. These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another. (Moreover, they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust.) Their robustness, sensitivity, and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews.