Elsevier

Biochimie

Volume 89, Issues 6–7, June–July 2007, Pages 899-902
Biochimie

Interferons in multiple sclerosis: Ten years' experience

https://doi.org/10.1016/j.biochi.2007.03.016Get rights and content

Abstract

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFNβ in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFNβ are now approved in Europe and North America: chronologically IFNβ-1b (Berlex/Schering), IFNβ-1a given intramuscularly (Biogen), and IFNβ-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.

Section snippets

Efficacy of interferons: a review

Interferons (IFNs) are made by recombinant DNA technology in tissue culture and are highly purified. IFNβ-1b is not glycosylated and is issued from recombinant bacterial cell product, with a serine substituting for cysteine at position 17. IFNβ-1a is glycosylated and produced by recombinant mammalian cells. Its amino acid sequence is identical to that of natural IFNβ.

IFNβ-1b was approved after the publication in 1993 of a first multicentre United States double-blind versus placebo controlled

Interferon-beta treatment is associated with side effects

Interferon-beta is usually well tolerated. Side effects partially depend on the route of administration and on the dosage used. In most studies, the percentage of patients discontinuing treatment because of side effects was low [1], [5], [7].

The most important and valuable side effects for all preparations are flu-like reactions (fever, myalgia, arthralgia, general discomfort) lasting for 24 to 48 h after injections, and decreasing over time. Treatment of these symptoms is based on preventive

Should all patients be treated with IFNs?

In the 1990s, based on class I evidence from controlled clinical trials, it was recommended to treat with IFNs ambulatory patients (EDSS 5.5 or lower), aged 18 to 50 years with a definite MS, a RR course, and active disease defined by at least two acute exacerbations during the previous two years [11]. After the publication of the results of intramuscularly injected IFN, the definition of active disease was extended to two attacks during the three previous years.

In the late 1990s, it was also

What about patients with no MRI risk? With a possible benign predictable course?

Two important unresolved questions concern patients with CDMS without clinical activity, and those with a first demyelinating event with poor or no MRI lesions. In other words, what is the predictable value of MRI for the individual patient in clinical practice? This question is important as more and more MRIs are prescribed for another reason and may exhibit lesions responding to spatial and even temporal dissemination as defined by MacDonald et al. in 2001 [18] and Polman et al. in 2005 [19].

Other unresolved issues

Beta-IFNs may stimulate the formation of neutralizing antibodies (NABs). Their frequency (up to 35%) is different from one IFN to another, and may depend on dosage and route of administration. It is as yet unclear if their appearance has a clinical individual interest. In some patients, high NAB titres associated with a reappearance of clinical activity after 2 to 3 years of treatment may indicate decreased IFN efficacy.

A second question concerns the selection of responders before initiating the

Concluding remarks

Introducing IFNs in the treatment of MS is the result of methodologically robust data indicating an efficacy in preventing exacerbations and limiting lesion accumulation on MRI. There may be a tendency to limit progressive worsening and possibly to improve quality of life. However, this remains more uncertain. IFN activity may depend on the course of the disease which influences trial organization: short duration, weak sensitivity for EDSS of 4 and higher, a longer steady phase for EDSS between

References (24)

  • P. Rudge et al.

    Does interferon beta cause initial exacerbation of MS?

    Lancet

    (1995)
  • G. Comi et al.

    Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study

    Lancet

    (2001)
  • The IFNB Multiple Sclerosis Study Group

    Interferon β-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results

    Neurology

    (1993)
  • The IFNB Multiple Sclerosis Study Group and the UBC MS/MRI Analysis Group

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

    Neurology

    (1995)
  • D.W. Paty et al.

    the IFNB Multiple Sclerosis Study Group. Interferon β-1b is effective in relapsing remitting multiple sclerosis. II. MRI analysis

    Neurology

    (1993)
  • European Study Group on interferon β-1b in secondary progressive MS

    Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis

    Lancet

    (1998)
  • L.D. Jacobs et al.

    Intramuscular Interferon β-1a for disease progression in relapsing multiple sclerosis

    Ann. Neurol.

    (1996)
  • J.H. Simon et al.

    Magnetic resonance studies of intramuscular interferon β-1a for relapsing multiple sclerosis

    Ann. Neurol.

    (1998)
  • PRISMS Study Group

    Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis

    Lancet

    (1998)
  • D.W. Paty et al.

    High-dose subcutaneous interferon β-1a is effcacious in transitional MS, a group at high risk for progression to disability

    Ann. Neurol.

    (1998)
  • P. Bramanti et al.

    Enhanced spasticity in primary progressive MS patients treated with interferon β-1b

    Neurology

    (1998)
  • Quality Standards Subcommittee of the American Academy of Neurology

    Practice advisory on selection of patients with multiple sclerosis for treatment with Betaseron

    Neurology

    (1994)
  • Cited by (17)

    • The interferon-dependent orchestration of innate and adaptive immunity after transplantation

      2012, Blood
      Citation Excerpt :

      Type I IFN promotes the maturation of DCs34 and enhances cross-presentation to CD8 T cells by CD8α+ DC and subsequent rejection of tumor.35 The mechanism by which IFN-β administration induces beneficial outcomes in multiple sclerosis patients has been investigated in experimental autoimmune encephalitis.36 These studies demonstrate that type I IFN signaling down-regulates the Th17-mediated inflammatory response by inhibiting osteopontin expression in DCs, resulting in derepression of the potent inhibitory cytokine IL-27.37,38

    • The prospects of minocycline in multiple sclerosis

      2011, Journal of Neuroimmunology
      Citation Excerpt :

      Many studies about minocycline combined with other drugs in EAE and MS have been reported (Tables 3 and 4). Three IFN-β preparations, IFNβ-1b subcutaneous (Betaseron®), IFNβ-1a intramuscular (Avonex®) and IFNβ-1a subcutaneous (Rebif®), have been approved as first-line immunomodulatory treatments of MS. It has been confirmed that the number of relapse rate and severity of exacerbations in MS patients were significantly decreased by IFN-β (reviewed by Tourbah and Lyon-Caen, 2007). But the interferons were thought to enter minimally into the central nervous system and were shown to be proteolytically cleaved by matrix metalloproteinases (MMPs), which were upregulated in MS. (reviewed by Antel and Miron, 2008; Yong et al., 2001).

    • New lessons about old molecules: How type I interferons shape Th1/Th17-mediated autoimmunity in the CNS

      2010, Trends in Molecular Medicine
      Citation Excerpt :

      Together, these recent investigations provide useful insights into disease-limiting mechanisms that might open possibilities for cell-type specific IFN-β-based therapies that minimize the severe adverse effects. Therapeutic intervention with IFN-β is a major treatment option for MS that has proven to be beneficial as demonstrated by decreased inflammatory lesions in the CNS, visualized by magnetic resonance imaging (MRI), prolonged remissions and lower relapse rates [6,52]. However, in up to a third of the cases, the efficacy of IFN-β therapy ceases after a year, in part because many patients develop autoantibodies against IFN-β [53] (Box 2).

    View all citing articles on Scopus
    View full text