Multiple Sclerosis: Ross C

Sørensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C, Anonymous00318. · Danish Multiple Sclerosis Research Centre, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #16241970 No free full text.

Abstract: Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Sellebjerg F, Ross C, Koch-Henriksen N, Sørensen PS, Frederiksen JL, Bendtzen K, Sørensen TL. · The MS Clinic, Copenhagen University Hospital, Glostrup, Denmark. · Mult Scler. · Pubmed #16320722 No free full text.

Abstract: Biomarkers that allow the identification of patients with multiple sclerosis (MS) with an insufficient response to immunomodulatory treatment would be desirable, as currently available treatments are only incompletely efficacious. Previous studies have shown that the expression of CD25, CD26 and CCR5 on T cells is altered in patients with active MS. We studied the expression of these molecules by flow cytometry in patients followed for six months during immunomodulatory treatment. In interferon (IFN)-beta-treated patients, we found that the hazard ratio for developing an attack was 28 in patients with CD26 + CD4 + T cell counts above median, and this risk was independent of the risk conferred by neutralizing anti-IFN-beta antibodies. CD26 + CD4 + T cell counts may identify patients with MS at increased risk of attack during treatment with IFN-beta.

Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N, Anonymous00193, Anonymous00194. · Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Neurology. · Pubmed #14610108 No free full text.

This publication has no abstract.

Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnborg M, Stenager E, Koch-Henriksen N, Anonymous00129. · Department of Neurology, Institute for Inflammation Research, Rigshospitalet, Copenhagen, Denmark. · Lancet. · Pubmed #14568740 No free full text.

Abstract: BACKGROUND: Interferon beta is the first-line treatment for relapsing-remitting multiple sclerosis, but the drug can induce neutralising antibodies against itself, which might reduce effectiveness. We aimed to assess the clinical effect of neutralising antibodies. METHODS: We measured neutralising antibodies every 12 months for up to 60 months in 541 patients with multiple sclerosis, randomly selected from all patients who started treatment with interferon beta between 1996 and 1999. Patients left the study if they changed or discontinued therapy. Antibodies were measured blindly, using antiviral neutralisation bioassays with high, medium, and low sensitivity, and with different neutralising capacities as cutoff value for definition of a neutralising-antibody-positive result. FINDINGS: Patients developed neutralising antibodies independent of age, sex, disease duration, and progression index at start of treatment. Relapse rates were significantly higher during antibody-positive periods (0.64-0.70) than they were during antibody-negative periods (0.43-0.46; p<0.03). When comparing the number of relapses in the neutralising-antibody-positive and neutralising-antibody-negative periods we found odds ratios in the range 1.51 to 1.58 (p<0.03). Time to first relapse was significantly increased by 244 days in patients who were antibody-negative at 12 months (log rank test 6.83, p=0.009). During this short-term study, presence of neutralising antibodies did not affect disease progression measured with the expanded disability status scale. INTERPRETATION: Our findings suggest that the presence of neutralising antibodies against interferon beta reduces the clinical effect of the drug. In patients who are not doing well on interferon beta, the presence of such antibodies should prompt consideration about change of treatment.

Sorensen PS, Tscherning T, Mathiesen HK, Langkilde AR, Ross C, Ravnborg M, Bendtzen K. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. · Neurology. · Pubmed #17101906 No free full text.

Abstract: We measured neutralizing antibodies (NABs) and the in vivo biologic response to interferon-beta on neopterin and beta(2)-microglobulin blood levels. All NAB-negative patients had an in vivo biologic response (full or partial), whereas all high-level positive patients had no response. High-level NAB patients had more MRI activity than NAB-negative patients (p = 0.031). Patients with a full response had less MRI activity than patients without biologic response (p = 0.032).

Petersen B, Bendtzen K, Koch-Henriksen N, Ravnborg M, Ross C, Sorensen PS, Anonymous00374. · Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Mult Scler. · Pubmed #16764336 No free full text.

Abstract: OBJECTIVE: The main objective was to follow serum levels of neutralizing antibodies (NABs) against interferon-beta (IFNbeta) after discontinuation of IFNbeta therapy. BACKGROUND: A large proportion of patients treated with recombinant IFNbeta for multiple sclerosis (MS) develop therapy-induced NABs. Knowledge of persistence of NABs after discontinuation of therapy is limited. Design/patients: A retrospective follow-up study of patients treated in Denmark for relapsing remitting (RR) MS with IFNbeta for at least 12 months. NAB-positive patients, who discontinued therapy, were followed up with measurements of NABs. METHODS: We measured NAB-neutralizing capacity and NAB titres a.m. Kawade using a clinically validated cytopathic effect assay. RESULTS: Thirty-seven patients were included. Mean follow-up time was 22 months. Of the 29 patients with a NAB titre at or above 25 prior to termination of therapy, only three patients reverted to a titre below 25. Of these, two had a titre below 200 and one patient a titre of 600 at the last examination before treatment stop. The longest post-treatment follow-up during which a patient maintained NAB positivity was 59 months. CONCLUSION: NABs against IFNbeta, especially with high titres, tend to persist for a long time after discontinuation of IFNbeta therapy. NABs should always be measured before reinstitution of IFNbeta treatment in NAB-positive patients.

Ross C, Clemmesen KM, Sørensen PS, Koch-Henriksen N, Bendtzen K. · Institute for Inflammation Research, Rigshospitalet University Hospital, Copenhagen, Denmark. · Mult Scler. · Pubmed #16459718 No free full text.

Abstract: Administration of interferons (IFNs) may induce antibodies that interfere with therapeutic efficacy. We have optimized and validated methods for large-scale economic screening. Sera from patients with relapsing-remitting multiple sclerosis (MS) were investigated for binding antibody (BAb) by protein-G affinity-chromatography radioimmunoassay and a commercially available enzyme immunoassay (EIA). Neutralizing antibody (NAb) was investigated by cytopathic effect assays (CEA) using both fixed amount and serially diluted sera. BAb correlated with log10-transformed titres obtained by EIA (r=0.70, P<0.0001); the latter, however, failed to demonstrate low-level BAb. Comparison of clinical significance of NAb-positivity measured by biological assays with different sensitivities demonstrated an optimal odds ratio for relapse rate using 10 laboratory units (LU)/mL. Purification of IgG prior to CEA removed toxicity from toxic sera. The neutralizing capacity data correlated linearly with logl0-transformed titres obtained by a Kawade 10-to-1 LU/mL CEA (r=0.77, P<0.0001). In conclusion, neutralizing capacity CEA utilizing a fixed amount of serum predicts differences in relapse rates in IFNbeta-treated MS patients and correlates with NAb titres of the 10-to-1 LU/mL CEA. Neutralizing capacity CEA is less laborious and more economical than titre-based NAb assays and suitable for large-scale screenings of MS patients.

Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K, Anonymous00296. · Copenhagen MS Center, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark. · Neurology. · Pubmed #15888603 No free full text.

Abstract: BACKGROUND: Neutralizing antibodies (NABs) occur frequently in patients receiving interferon (IFN)-beta for multiple sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-beta therapy. METHODS: The authors used an antiviral neutralization bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-beta. Patients were classified into three groups: 1) persistently NAB-negative patients, defined as patients without any positive samples at any time; 2) definitely NAB-positive patients, defined as patients who had at least two consecutive positive samples; and 3) patients with fluctuating NAB-positive and NAB-negative samples. RESULTS: A total of 455 patients were included in the study. Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating. More patients treated with IFN-beta-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-beta-1b (Betaferon) and IFN-beta-1a (Rebif). Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive. CONCLUSIONS: NABs should be measured in all patients treated with IFN-beta. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued. Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.

Myhr KM, Ross C, Nyland HI, Bendtzen K, Vedeler CA. · Department of Neurology, Haukeland University Hospital, University of Bergen, Norway. · Neurology. · Pubmed #11094118 No free full text.

Abstract: Sera from patients with MS treated with recombinant interferon (rIFN) alpha-2a, rIFNbeta-1a, or rIFNbeta-1b were analyzed for cross-reacting neutralizing antibodies (NAB). Because cross-reactivity was not found, switching treatment from rIFNbeta-1a or rIFNbeta-1b to rIFNalpha-2a might provide a secondary treatment response in patients with NAB to rIFNbeta-1a or rIFNbeta-1b. A positive treatment response also might be achieved by switching NAB rIFNalpha-2a-positive patients to rIFNbeta-1a or rIFNbeta-1b.

Ross C, Clemmesen KM, Svenson M, Sørensen PS, Koch-Henriksen N, Skovgaard GL, Bendtzen K. · Laboratory for Clinical Interferon Research, Institute for Inflammation Research, Rigshospitalet University Hospital, Copenhagen, Denmark. · Ann Neurol. · Pubmed #11079533 No free full text.

Abstract: A total of 754 consecutive patients with relapsing-remitting multiple sclerosis were investigated for interferon-beta (IFNbeta) antibodies by protein-G affinity chromatography and antiviral neutralization bioassay during 24 months on 6 MIU (22 microg) of subcutaneous IFNbeta-1a once weekly (n = 143) or three times weekly (n = 160), 6 MIU (30 microg) of intramuscular IFNbeta-1a once weekly (n = 140), or 8 MIU every other day of IFNbeta-1b (n = 311). The proportion of binding antibodies was higher in those receiving IFNbeta-1b compared with 6 MIU of IFNbeta-1a three times weekly (97 vs 89% at 12 months), and fewer became positive if 6 MIU of IFNbeta-1a was administered once weekly (58 vs 89%). Fewer patients on intramuscular than subcutaneous IFNbeta-1a became positive (33 vs 58%). The binding and neutralizing capacities were higher in the IFNbeta-1b group than in the IFNbeta-1a groups; these differences, however, were not significant after 12 months. The number of positive patients varied considerably and depended on the amount of IFN added to the bioassay; adding 10 LU/ml or more masked antibody detection. Antibodies induced by either preparation neutralized both IFNbeta species but not IFNalpha. In conclusion, IFNbeta-induced antibodies are frequently found in multiple sclerosis patients, and IFNbeta-1b is more immunogenic than IFNbeta-1a. The immunogenicity of IFNbeta-1a increases with the frequency of administration and if it is given subcutaneously.