Skip to main content
PMC home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 Aug;73(2):148–153. doi: 10.1136/jnnp.73.2.148

Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory

A Bertolotto 1, S Malucchi 1, A Sala 1, G Orefice 1, P Carrieri 1, M Capobianco 1, E Milano 1, F Melis 1, M Giordana 1
PMCID: PMC1737963  PMID: 12122172

Abstract

Objective: To evaluate the incidence and the prevalence of neutralising antibodies (NABs) to three interferon beta (IFNß) products in patients with multiple sclerosis (MS).

Methods: Sera were tested from 125 patients with relapsing-remitting MS. Patients were treated with IFNß-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFNß-1a (Avonex, n = 44) 30 µg intramuscularly once weekly, or IFNß-1a (Rebif, n = 36) 22 µg subcutaneously three times weekly for 6 to 18 months. An additional 16 patients were treated with Rebif 22 µg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment. Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+).

Results: At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18. Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04). In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07). At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif.

Conclusion: The three IFNß preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest. These differences should be considered by neurologists when selecting treatment for their patients with MS because NABs can reduce both bioavailability and clinical efficacy of IFNß.

Full Text

The Full Text of this article is available as a PDF (181.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abdul-Ahad A. K., Galazka A. R., Revel M., Biffoni M., Borden E. C. Incidence of antibodies to interferon-beta in patients treated with recombinant human interferon-beta 1a from mammalian cells. Cytokines Cell Mol Ther. 1997 Mar;3(1):27–32. [PubMed] [Google Scholar]
  2. Antonelli G., Bagnato F., Pozzilli C., Simeoni E., Bastianelli S., Currenti M., De Pisa F., Fieschi C., Gasperini C., Salvetti M. Development of neutralizing antibodies in patients with relapsing-remitting multiple sclerosis treated with IFN-beta1a. J Interferon Cytokine Res. 1998 May;18(5):345–350. doi: 10.1089/jir.1998.18.345. [DOI] [PubMed] [Google Scholar]
  3. Antonelli G., Simeoni E., Bagnato F., Pozzilli C., Turriziani O., Tesoro R., Di Marco P., Gasperini C., Fieschi C., Dianzani F. Further study on the specificity and incidence of neutralizing antibodies to interferon (IFN) in relapsing remitting multiple sclerosis patients treated with IFN beta-1a or IFN beta-1b. J Neurol Sci. 1999 Oct 15;168(2):131–136. doi: 10.1016/s0022-510x(99)00185-9. [DOI] [PubMed] [Google Scholar]
  4. Arnason B. G., Dianzani F. Correlation of the appearance of anti-interferon antibodies during treatment and dimunition of efficacy: summary of an International Workshop on Anti-Interferon Antibodies. J Interferon Cytokine Res. 1998 Aug;18(8):639–644. doi: 10.1089/jir.1998.18.639. [DOI] [PubMed] [Google Scholar]
  5. Bertolotto A., Malucchi S., Milano E., Castello A., Capobianco M., Mutani R. Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations. Immunopharmacology. 2000 Jul 20;48(2):95–100. doi: 10.1016/s0162-3109(00)00182-x. [DOI] [PubMed] [Google Scholar]
  6. Deisenhammer F., Reindl M., Harvey J., Gasse T., Dilitz E., Berger T. Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology. 1999 Apr 12;52(6):1239–1243. doi: 10.1212/wnl.52.6.1239. [DOI] [PubMed] [Google Scholar]
  7. Jacobs L. D., Beck R. W., Simon J. H., Kinkel R. P., Brownscheidle C. M., Murray T. J., Simonian N. A., Slasor P. J., Sandrock A. W. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000 Sep 28;343(13):898–904. doi: 10.1056/NEJM200009283431301. [DOI] [PubMed] [Google Scholar]
  8. Jacobs L. D., Cookfair D. L., Rudick R. A., Herndon R. M., Richert J. R., Salazar A. M., Fischer J. S., Goodkin D. E., Granger C. V., Simon J. H. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG) Ann Neurol. 1996 Mar;39(3):285–294. doi: 10.1002/ana.410390304. [DOI] [PubMed] [Google Scholar]
  9. Kawade Y. Quantitation of neutralization of interferon by antibody. Methods Enzymol. 1986;119:558–573. doi: 10.1016/0076-6879(86)19076-8. [DOI] [PubMed] [Google Scholar]
  10. Khan O. A., Xia Q., Bever C. T., Jr, Johnson K. P., Panitch H. S., Dhib-Jalbut S. S. Interferon beta-1b serum levels in multiple sclerosis patients following subcutaneous administration. Neurology. 1996 Jun;46(6):1639–1643. doi: 10.1212/wnl.46.6.1639. [DOI] [PubMed] [Google Scholar]
  11. Kivisäkk P., Alm G. V., Fredrikson S., Link H. Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis. Eur J Neurol. 2000 Jan;7(1):27–34. doi: 10.1046/j.1468-1331.2000.00002.x. [DOI] [PubMed] [Google Scholar]
  12. Knobler R. L., Greenstein J. I., Johnson K. P., Lublin F. D., Panitch H. S., Conway K., Grant-Gorsen S. V., Muldoon J., Marcus S. G., Wallenberg J. C. Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up. J Interferon Res. 1993 Oct;13(5):333–340. doi: 10.1089/jir.1993.13.333. [DOI] [PubMed] [Google Scholar]
  13. Kurtzke J. F. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983 Nov;33(11):1444–1452. doi: 10.1212/wnl.33.11.1444. [DOI] [PubMed] [Google Scholar]
  14. Lublin F. D., Reingold S. C. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907–911. doi: 10.1212/wnl.46.4.907. [DOI] [PubMed] [Google Scholar]
  15. Myhr K. M., Ross C., Nyland H. I., Bendtzen K., Vedeler C. A. Neutralizing antibodies to interferon (IFN) alpha-2a and IFN beta-1a or IFN beta-1b in MS are not cross-reactive. Neurology. 2000 Nov 28;55(10):1569–1572. doi: 10.1212/wnl.55.10.1569. [DOI] [PubMed] [Google Scholar]
  16. Pachner A. R. Anticytokine antibodies in beta interferon-treated MS patients and the need for testing: plight of the practicing neurologist. Neurology. 1997 Sep;49(3):647–650. doi: 10.1212/wnl.49.3.647. [DOI] [PubMed] [Google Scholar]
  17. Poser C. M., Paty D. W., Scheinberg L., McDonald W. I., Davis F. A., Ebers G. C., Johnson K. P., Sibley W. A., Silberberg D. H., Tourtellotte W. W. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol. 1983 Mar;13(3):227–231. doi: 10.1002/ana.410130302. [DOI] [PubMed] [Google Scholar]
  18. Ross C., Clemmesen K. M., Svenson M., Sørensen P. S., Koch-Henriksen N., Skovgaard G. L., Bendtzen K. Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurol. 2000 Nov;48(5):706–712. [PubMed] [Google Scholar]
  19. Rudick R. A., Simonian N. A., Alam J. A., Campion M., Scaramucci J. O., Jones W., Coats M. E., Goodkin D. E., Weinstock-Guttman B., Herndon R. M. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG) Neurology. 1998 May;50(5):1266–1272. doi: 10.1212/wnl.50.5.1266. [DOI] [PubMed] [Google Scholar]
  20. Runkel L., Meier W., Pepinsky R. B., Karpusas M., Whitty A., Kimball K., Brickelmaier M., Muldowney C., Jones W., Goelz S. E. Structural and functional differences between glycosylated and non-glycosylated forms of human interferon-beta (IFN-beta). Pharm Res. 1998 Apr;15(4):641–649. doi: 10.1023/a:1011974512425. [DOI] [PubMed] [Google Scholar]
  21. Trojano M., Avolio C., Liuzzi G. M., Ruggieri M., Defazio G., Liguori M., Santacroce M. P., Paolicelli D., Giuliani F., Riccio P. Changes of serum sICAM-1 and MMP-9 induced by rIFNbeta-1b treatment in relapsing-remitting MS. Neurology. 1999 Oct 22;53(7):1402–1408. doi: 10.1212/wnl.53.7.1402. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES