Interferons in relapsing remitting multiple sclerosis: a systematic review

doi:10.1016/S0140-6736(03)12512-3

The Lancet

Volume 361, Issue 9357, 15 February 2003, Pages 545-552

https://doi.org/10.1016/S0140-6736(03)12512-3 Get rights and content

Summary

Background

Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs.

Methods

With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo.

Findings

The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0·73, 95% CI 0·54–0·99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0·81, 0·74–0·89) or progressed (0·70, 0·55–0·88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1·11, 0·73–1·68) and disease progression (1·31, 0·60–2·89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life.

Interpretation

Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.

Introduction

Use of interferons in multiple sclerosis has been studied for more than 20 years. Interferons exert effects of potential relevance to multiple sclerosis: their antiviral action, and their pleiotropic effects on the immune system and blood-brain barrier, could benefit patients with multiple sclerosis.¹

Results of some early pilot trials showed fewer exacerbations in multiple sclerosis patients given human interferon than in those on placebo.2, 3 Recombinant interferons were approved by many national regulatory agencies for the treatment of relapsing remitting multiple sclerosis, after clinical trials established that interferon beta preparations reduced disease activity.4, 5, 6, 7, 8 Interferon beta-1b is now also licensed for secondary progressive multiple sclerosis⁹ and interferon beta-1a for the treatment of patients who have had a sole demyelinating event.¹⁰ Interferons have been used for the treatment of multiple sclerosis for almost a decade, and are available for this use free of charge from many national health services. However, doubts remain as to their effectiveness, in particular whether they can really prevent progression of the disease and whether the effect is sustained over time.¹¹ Furthermore, the beneficial effects might be small or non-existent in relation to untoward side-effects and high cost.¹²

We therefore undertook an assessment of the methodological quality of interferon trials, and did a meta-analysis of the results. Our primary question was: are recombinant interferons more effective than placebo in reduction of the number of patients with relapsing remitting multiple sclerosis who have clinical exacerbations and disease progression? Our secondary objectives were to assess the effectiveness of recombinant interferons in reduction of the need for treatment with corticosteroids and hospital admission, the incidence and severity of side-effects, and the effect of interferons on cerebral lesions as measured by serial MRI.

Section snippets

Methods

For our systematic review we applied the Cochrane Collaboration methodology (www.cochrane.org) and followed our predefined protocol.¹³ We assessed only randomised, double-blind, placebo-controlled trials that compared alfa or beta recombinant interferons with placebo in patients diagnosed with relapsing remitting multiple sclerosis according to accepted criteria.¹⁴ Trials in which the comparisons of interest were confounded by other treatments, such as immunosuppressive drugs, were excluded.

Results

We identified 227 abstracts (144 in MEDLINE, 23 in EMBASE, 46 by hand-searching, and 14 in the Cochrane controlled trials register). 24 studies were identified as potentially fulfilling inclusion criteria. We excluded 17 studies after reading the full published papers: a randomised controlled trial of ingested interferon alfa-2a;¹⁹ two controlled clinical trials;20, 21 two open-label trials;22, 23 four studies of natural interferon alfa;24, 25, 26, 27 two in which only immunological, not

Discussion

Our results show a modest protective effect of interferon against recurrence of exacerbations during the first year of treatment. This effect could not be confirmed during the second year since the results were highly dependent on what happened to the dropouts. We analysed all the randomised controlled trials undertaken so far on the use of interferon in patients with the relapsing-remitting form of multiple sclerosis. Most trials had major weaknesses. The commonest flaws were high dropout

References (46)

DerSimonianR et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986)
RudgeP et al.
Does interferon beta cause initial exacerbation of multiple sclerosis?
Lancet
(1995)
HohlfeldR
Biotechnological agents for the immunotherapy of multiple sclerosis: principles, problems and perspectives
Brain
(1997)
JacobsL et al.
Intrathecal interferon reduces exacerbations of multiple sclerosis
Science
(1981)
KnoblerRL et al.
Systemic alpha-interferon therapy of multiple sclerosis
Neurology
(1984)
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial
Neurology
(1993)
Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial
Neurology
(1995)
PatyDW et al.
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: II MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial
Neurology
(1993)
JacobsLD et al.
A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients
Mult Scler
(1995)
JacobsLD et al.
Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis
Ann Neurol
(1996)

Committee for Proprietary Medicinal Products European Public Assessment Report (EPAR): Betaferon

(2002)

Committee for Proprietary Medicinal Products European Public Assessment Report (EPAR): Avonex

(2002)

NoseworthyJH et al.

Multiple Sclerosis

N Engl J Med

(2000)

ForbesRB et al.

Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis

BMJ

(1999)

Interferon in relapsing-remitting multiple sclerosis (Cochrane protocol)

PoserCM et al.

New diagnostic criteria for multiple sclerosis: guidelines for research protocols

Ann Neurol

(1983)

KurtzkeJF

Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS)

Neurology

(1983)

JüniP et al.

Assessing the quality of randomised controlled trials

EbrahimS

Numbers needed to treat derived from meta-analyses: pitfalls and cautions

BrodSA et al.

Ingested IFN-alpha: results of a pilot study in relapsing-remitting MS

Neurology

(2001)

TilberyCP et al.

Interferon beta 1-a in multiple sclerosis: 1-year experience in 62 patients

Arq Neuropsiquiatr

(2000)

NarayananS et al.

Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b

J Neurol

(2001)

HerndonRM et al.

Results of an ongoing, open-label, safety-extension study of interferon beta-1a (Avonex) treatment in multiple sclerosis

Int J MS Care

(1999)

Cited by (290)

The combined treatment of NAD<sup>+</sup> and atorvastatin ameliorates the development of experimental autoimmune encephalomyelitis in C57BL/6 mice
2021, Journal of Neuroimmunology
Citation Excerpt :
However, not all MS patients have perfect responses to these drugs (Guo et al., 2008; Kala et al., 2010; Van Kaer, 2011; Podbielska et al., 2012). Additionally, these drugs may be associated with inevitable side effects and undesirable toxicities (Filippini et al., 2003; Munari and Filippini, 2004; Yousry et al., 2006). Therefore, it is of importance to explore existing or novel agents that can complement one another in combination to exhibit synergistic effect on MS patients for a better treatment.
Multiple sclerosis (MS) is a demyelinating and degenerating disorder of the central nervous system impacting many patients worldwide. Due to the complex pathogenesis of MS, drugs to treat MS often show partial effectiveness. Earlier experiments have demonstrated that both atorvastatin and nicotinamide adenine dinucleotide (NAD⁺⁾ may ameliorate experimental autoimmune encephalomyelitis (EAE), which is known as a classical model of MS, via different protective mechanisms. Since combination therapy can exhibit more beneficial effects than monotherapy, we observed the protective effects of combined treatment of atorvastatin and NAD⁺ in EAE mice. Our results showed that the combined treatment of these two drugs at half of their optimal dosages had synergistic effect to alleviate the severity of EAE in mice than treatment with each alone. The combined treatment of EAE mice with atorvastatin plus NAD⁺ relieved the clinical signs and histologic changes, increased the proportion of Treg cells, attenuated IL-17 production, reduced proinflammatory cytokine secretion of Th17 cells, and increased cytokine secretion of Treg cells. In addition, the combined treatment also diminished phosphorylation of both P38 MAPK and ERK, while elevated SIRT1 expression. Taken together, these data suggested that combined treatment with NAD⁺ and atorvastatin could attenuate the progression of EAE by synergistic immune regulation.
Prediction of long-term disability in Chinese patients with multiple sclerosis: A prospective cohort study
2020, Multiple Sclerosis and Related Disorders
Much information about outcomes of multiple sclerosis (MS) has been studied in Caucasian cohorts. However, little is known about the predictors of long-term disability in Chinese patients with MS. The aim of this prospective, observational study is to identify the prognostic factors associated with long-term disability progression (expanded disability status scale, EDSS=6.0) in Chinese patients with relapsing-onset MS.
Based on data from the MSNMOBase registry within the neurology department of Peking Union Medical College Hospital (PUMCH) in China, this hospital-based cohort study was conducted to estimate the median time of attaining disability endpoint (EDSS = 6.0) by Kaplan-Meier curves, and identify factors that associated with disability progression by Cox proportional regression analysis.
A total of 415 consecutive, eligible patients with MS were registered in the MSNMOBase of PUMCH and prospectively followed from 2011 to 2019. Of these patients, 365 patients with relapsing-onset MS were analyzed. The median time to reach an EDSS of 6.0 was 22.0 (95% CI 16.5-27.5) years. Age at disease onset greater than 50 years (HR 3.846, 95% CI 1.240–11.932, P=0.020), incomplete recovery from first attack (HR 2.107, 95% CI 1.168–3.800, P=0.013), and ≥2 relapses during the first 2 years after onset (HR 2.217, 95% CI 1.148–4.281, P=0.018) significantly associated with a higher hazard ratio to reach an EDSS of 6.0.
Our results confirm the importance of age at onset, recovery from the first attack, and number of relapses during the first 2 years after disease onset as predictors of disability progression in Chinese patients with relapsing-onset MS.
Physical Activity and the Mosaic of Autoimmunity
2019, Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases
Physical activity is any skeletal activity that results in energy expenditure. Physical activity has been demonstrated to decrease all risk mortality and cardiovascular disease. Autoimmune diseases result from loss of tolerance to self-tissue. The etiopathogenesis of autoimmune diseases remains a controversial topic. Nonetheless, recent research highlighted the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. In this chapter, the clinical efficacy and the impact of physical activity on autoimmune diseases is further elucidated.
Headache characteristics in multiple sclerosis
2019, Multiple Sclerosis and Related Disorders
The aims of this study were to study the prevalence and characteristics of headache in patients with multiple sclerosis and to clarify the relationship between headache and multiple sclerosis therapies.
782 MS patients were consecutively admitted. All patients filled out a detailed headache questionnaire and 754 patients were included.
Of 754 patients, 515 (68%) reported having headache. According to the International Headache Society criteria, we detected 202 (39%) suffering from migraine, 103 (20%) suffering from tension-type headache and 198 (38%) with medication overuse headache. Twelve patients (2%) had unclassified headache. Three hundred and seventy seven patients (73%) were treated with interferon beta, 81 (16%) with fingolimod, 35 (7%) with teriflunamide and 22 (4%) with natalizumab, respectively.
One hundred and one (20%) reported that onset of headache occured prior to onset of multiple sclerosis therapies, while 414 (80%) had headaches occured after therapy. A higher incidence of headache was found in patients treated with interferon beta. We found a significant association between migraine and the age of onset of multiple sclerosis therapies. The age of onset of headache was the earliest in the patients with migraine. In migraine patients, the duration of medication use until the headache onset was the shortest when compared to other headache groups. Four hundred and fifty nine patients (89%) have sought help from a physician because of the severity and frequency of headache.
In our study, the prevalence of headache among all multiple sclerosis patients was 68%. The results of this study indicate a possible relationship may exist between headache and multiple sclerosis therapies since 80% of patients described headaches after the onset of treatments. The younger start and the shorter duration of interferon beta use caused the higher incidence of headache, but this correlation was not observed in other drugs. Interestingly, medication overuse headache was far more prevalent in multiple sclerosis patients than in previously reported community populations.
Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review
2018, Multiple Sclerosis and Related Disorders
Psychiatric comorbidity is prevalent in persons with multiple sclerosis (MS). Few studies have assessed whether second-generation disease-modifying therapies (DMT) are associated with adverse psychiatric effects.
We aimed to systematically review the literature regarding the APEs associated with natalizumab, fingolimod, dimethyl fumarate, teriflunomide and alemtuzumab in MS. As a secondary objective, we evaluated changes in anxiety or depression scores following treatment with the aforementioned DMTs.
We searched MEDLINE, EMBASE, International Pharmaceutical Abstracts, PsychINFO, Central Register of Controlled Trials & Cochrane database of systematic reviews for published studies, and clinicaltrials.gov and regulatory documents from the US and Canada for unpublished studies. Data sources were searched from inception to September 2017. Studies reporting adverse psychiatric effects involving any DMT of interest were included. We report the incidence proportions of the adverse psychiatric effects and, where applicable, risk differences between DMT-exposed and unexposed individuals along with the corresponding 95% confidence intervals. We calculated the standardized mean differences (SMD) of changes in anxiety and depression scores if reported as study outcomes, and pooled the data using random effects meta-analysis.
Of 4389 abstracts screened, 78 met the inclusion criteria, including 48 clinical trials, 28 observational studies and 2 case reports. Depression was the most commonly reported adverse psychiatric effect. Incidence proportions for all adverse psychiatric effects ranged from 0 to 24.7%. None of the DMT studied were associated with a statistically significant increased risk of any adverse psychiatric effect (range of risk difference: -7.69% [95%CI: -16.06%, 5.56%] to 6.67 [-8.56, 15.59]). Eighteen studies examined changes in depression or anxiety following fingolimod, natalizumab or dimethyl fumarate treatment; depression symptoms improved in fingolimod-treated groups (SMD [95%CI]: 1.18 [0.17, 2.19]). We did not identify studies examining changes in these outcomes following treatment with any of the other DMTs.
The DMTs reviewed were not associated with an increased risk of adverse psychiatric effect in MS, and some may reduce the incidence of depressive symptoms. This may reflect either a positive direct effect (e.g. immune modulation) or an indirect effect arising due to a positive impact on disease activity or course.
Physical activity and autoimmune diseases: Get moving and manage the disease
2018, Autoimmunity Reviews
Physical activity, by definition, is any skeletal muscle body movement that results in energy expenditure. In the last few decades, a plethora of scientific evidences have accumulated and confirmed the beneficial role of physical activity as a modifiable risk factor for a wide variety of chronic diseases including cardiovascular diseases (CVDs), diabetes mellitus and cancer, among others. Autoimmune diseases are a heterogeneous group of chronic diseases, which occur secondary to loss of self-antigen tolerance. With the advent of biological therapies, better outcomes have recently been noted in the management of autoimmune diseases. Nonetheless, recent research highlights the salient role of modifiable behaviors such as physical inactivity on various aspects of the immune system and autoimmune diseases. Physical activity leads to a significant elevation in T-regulatory cells, decreased immunoglobulin secretion and produces a shift in the Th1/Th2 balance to a decreased Th1 cell production. Moreover, physical activity has been proven to promote the release of IL-6 from muscles. IL-6 released from muscles functions as a myokine and has been shown to induce an anti-inflammatory response through IL-10 secretion and IL-1β inhibition. Physical activity has been shown to be safe in most of autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel diseases (IBD), as well as others. Additionally, the incidence of RA, MS, IBD and psoriasis has been found to be higher in patients less engaged in physical activity. As a general trend, patients with autoimmune diseases tend to be less physically active as compared to the general population. Physically active RA patients were found to have a milder disease course, better cardiovascular disease (CVD) profile, and improved joint mobility. Physical activity decreases fatigue, enhances mood, cognitive abilities and mobility in patients with MS. In SLE patients, enhanced quality of life and better CVD profile were documented in more physically active patients. Physically active patients with type 1 diabetes mellitus have a decreased risk of autonomic neuropathy and CVD. Both fibromyalgia and systemic sclerosis patients report decreased disease severity, pain, as well as better quality of life with more physical activity. Further, SSc patients improve their grip strength, finger stretching and mouth opening with increased level of exercise. The purpose of this paper is to review the clinical evidence regarding the safety, barriers to engagement, and impact of physical activity on autoimmune diseases.

View all citing articles on Scopus

View full text

ArticlesInterferons in relapsing remitting multiple sclerosis: a systematic review

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

Control Clin Trials

Lancet

Biotechnological agents for the immunotherapy of multiple sclerosis: principles, problems and perspectives

Brain

Intrathecal interferon reduces exacerbations of multiple sclerosis

Science

Systemic alpha-interferon therapy of multiple sclerosis

Neurology

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: I Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology

Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial

Neurology

Interferon beta-1b is effective in relapsing-remitting multiple sclerosis: II MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology

A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating-remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

Mult Scler

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

Ann Neurol

Committee for Proprietary Medicinal Products European Public Assessment Report (EPAR): Betaferon

Committee for Proprietary Medicinal Products European Public Assessment Report (EPAR): Avonex

Multiple Sclerosis

N Engl J Med

Population based cost utility study of interferon beta-1b in secondary progressive multiple sclerosis

BMJ

Interferon in relapsing-remitting multiple sclerosis (Cochrane protocol)

New diagnostic criteria for multiple sclerosis: guidelines for research protocols

Ann Neurol

Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS)

Neurology

Assessing the quality of randomised controlled trials

Numbers needed to treat derived from meta-analyses: pitfalls and cautions

Ingested IFN-alpha: results of a pilot study in relapsing-remitting MS

Neurology

Interferon beta 1-a in multiple sclerosis: 1-year experience in 62 patients

Arq Neuropsiquiatr

Axonal metabolic recovery in multiple sclerosis patients treated with interferon beta-1b

J Neurol

Results of an ongoing, open-label, safety-extension study of interferon beta-1a (Avonex) treatment in multiple sclerosis

Int J MS Care

Articles
Interferons in relapsing remitting multiple sclerosis: a systematic review