Introduction

Physicians and patients face many challenges in the use of disease-modifying agents for the treatment of multiple sclerosis (MS). Although a large number of patients with MS have benefited from recent advances in the treatment options, many others remain inadequately managed due to low response rates, or intolerable adverse events resulting in low adherence to therapy. Many of these challenges were addressed in clinical studies presented at the Thirteenth Meeting of the European Neurological Society (ENS), held June 14-18, 2003 in Istanbul, Turkey. A number of practical management strategies were explored and options offered that might effectively alleviate or even prevent restrictive adverse events and enhance patient adherence.

This Multiple Sclerosis Forum Report reviews many of these studies-discussions on the long-term efficacy of current MS treatment strategies, combination therapy regimens, neutralizing antibodies and their clinical impact on treatment, quality of life issues, and updates on investigational agents in development.

Long-term Efficacy of Interferon Betas

Long-term clinical experience with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis patients.
Brescia Morra V, Florio C, Coppola G, et al. Universitа Federico II, Ospedale Cardarelli, Naples, Italy.

Intramuscular Avonex 30 mcg once weekly has proven efficacy to reduce disability progression and relapse rates in the treatment of relapsing-remitting MS patients. However, extensive data on long-term follow-up and outcomes in large cohorts of patients are still limited. To identify possible predictors of therapeutic response, Italian investigators monitored the long-term efficacy and tolerability of Avonex in 225 patients with relapsing-remitting MS.¹ Patients received Avonex 30 mcg intramuscularly once weekly for up to 66 months (mean duration of therapy 27.6 months).

Baseline characteristics included Expanded Disability Status Scale (EDSS) basal score and prior annual relapse rate. Clinical outcomes included assessment of EDSS, relapse rate and relapse-free proportion of patients reaching a 2-year follow-up. Time to EDSS 1-point progression and time to first relapse were evaluated by means of survival analysis. At baseline, median EDSS was 2.5, mean prior annual relapse rate was 1.0 and the mean interval between the onset of disease and initiation of therapy was 7.5 years.

Among the 119 patients who completed the first 2 years of therapy, 66% did not show any worsening of EDSS (disability progression-free) and 50% remained relapse-free. Mean annual relapse rate in the 2-year period was 0.4 (P<0.01). Thirty-seven patients (24%) dropped-out, due to disease activity (relapses and disability progression), voluntary decision and side effects.

Patients with baseline EDSS ≤2 (55%) showed significantly longer estimated time to both EDSS progression and first relapse. Survival analysis showed that an estimated 75% of patients were EDSS-stable and 50% relapse-free. Therefore, lower baseline EDSS scores appeared to predict a better prognosis for those with EDSS 2 and below.

The EVIDENCE study: 16 months' data.
Goodin, D. Multiple Sclerosis Center, University of California, San Francisco, California.

Douglas S. Goodin, MD, of the Multiple Sclerosis Center, University of California, San Francisco, California presented an analysis of the 16-month data of the EVIDENCE Study.² The EVIDENCE Study was a randomized, multicenter, assessor-blinded study that compared subcutaneous Rebif 44 mcg three times weekly to intramuscular Avonex 30 mcg once weekly.³ The study enrolled 677 patients with relapsing-remitting MS from 56 multi-national centers and was conducted in two 24-week phases.

The primary outcome measure was the proportion of relapse-free patients. Secondary outcome measures included relapse rate and change in T2 lesion activity on magnetic resonance imaging (MRI). Tertiary outcomes included percentage of T2 active scans, proportion of patients with no T2 active scans, and time to first relapse, relapse severity and steroid use. Baseline patient characteristics of both treatment arms were well matched. Baseline MRI characteristics were also similar; however, the Avonex treatment arm had 20% more combined unique lesions at baseline.

Of the 339 patients randomized to subcutaneous Rebif 44 mcg three times weekly, 315 (93%) continued in the study and 299 (88%) continued on treatment until study completion; 319 of 338 patients (94%) randomized to intramuscular Avonex 30 mcg once weekly continued in the study and 306 (91%) completed treatment. Discontinuation due to adverse events was noted in 19 and 18 patients in the Rebif and Avonex treatment arms, respectively.

The proportion of relapse-free patients treated with Rebif 44 mcg was 56% compared with 48% for Avonex-treated patients (adjusted odds ratio 1.5; 95% Confidence Interval (CI), 1.1-2.0; P = 0.023) an absolute difference of 8% (Table 1). This difference appears to be lessening over time as the absolute difference at 24 weeks was 12% and at 48 weeks was 10%. As was seen in the annualized relapse rate, the results suggest that the beneficial treatment effect seen with Rebif compared to Avonex is demonstrated most clearly in Months 0 to 6 and declines over time.

The annualized relapse rate for Rebif-treated patients was lower than Avonex-treated patients, 0.54 versus 0.65, respectively (P = 0.033), although there was not a significant difference at 48 weeks (Table 2). Time to first relapse was 13.5 months for Rebif-treated patients compared to 6.7 months in Avonex-treated patients (hazard ratio 0.70; 95% CI, 0.56-0.88; P = 0.002). Mean T2 active lesion count was 0.9 for Rebif-treated patients and 1.4 for Avonex-treated patients (P<0.001); mean proportion of active scans per patient was 27% and 44%, respectively (P<0.001); and proportion of patients with no active scans was 58% and 38%, respectively (P<0.001).

Persistent neutralizing antibody titers (defined as at least 2 consecutive positive tests of titers ≥20) were observed in 21% of Rebif-treated patients compared to 3% of Avonex-treated patients (Table 3). This incidence is consistent with previously reported results and it remains low for Avonex. The long-term effects of neutralizing antibodies during EVIDENCE cannot be rigorously assessed because the study was not of sufficient duration (>2 years) and no effort was made to assess the balance of relative benefits reported and the negative impact of emergence of neutralizing antibodies on clinical outcomes cannot be determined. For example, data from PRISMS-4 indicate that neutralizing antibody-positive patients receiving Rebif experience relapse rates similar to placebo recipients 3 to 4 years after initiating therapy.⁴ This question is important to those faced with the decision of starting therapy with a more or less immunogenic interferon beta.

Injection-site reactions were significantly higher with Rebif administration (84.7% vs 33.2%; P<0.001) (Table 4). The incidence of inflammation and rash was 34.8% and 17.7% in Rebif-treated patients versus 8.6% and 2.7% in Avonex-treated patients, respectively (both P<0.001). Liver function abnormalities occurred in 18% and 9.8% of Rebif- and Avonex-treated patients, respectively (P = 0.003). White blood cell (WBC) abnormalities were significantly higher with Rebif than with Avonex (13.6% vs 5.3%; P<0.001).

The majority of the advantage observed with Rebif is found in the first 24 weeks of treatment. Subsequently, the benefit diminishes (percent relapse free and relapse rate). During the second 24 weeks of the study, the relapse rate was not significantly different between Avonex and Rebif.

An additional complication in interpreting the data is the open-label aspect of the study design. Patients may have been influenced by the extensive media promotion of the 24-week results suggesting that Rebif was more effective than Avonex. In an open-label trial, this may bias a patient's reporting of relapses.

The impact of change in interferon beta-1a dose regimen (30 mcg once weekly to 44 mcg 3 times weekly) in patients with relapsing MS--cross-over results from the EVIDENCE study.
Sharief, MK for the EVIDENCE Study Group. Guy's Hospital, London, England.

At the conclusion of EVIDENCE, consenting patients being treated with Avonex 30 mcg once weekly crossed over to Rebif 44 mcg 3 times weekly and were evaluated post-crossover for an average of 34 weeks. The post-crossover period analysis included the change in relapse counts and change in T2 active lesion counts. Dr. Mohammad K. Sharief of Guy's Hospital, London, England reported the results of that evaluation.⁵

A total of 223 patients switched from Avonex to Rebif treatment while 272 patients continued on Rebif (Table 5). During the post-crossover phase, 33 patients (15%) withdrew from higher-dose Rebif therapy while 190 patients completed treatment. For patients switching from Avonex to Rebif, relapse count decreased from 0.32 (pre-crossover) to 0.21 (post-crossover) (P = 0.015). The mean annualized relapse rate decreased from 0.65 to 0.32 (P<0.001). The number of T2 active lesions and proportion of active scans per patient decreased by 22% (P = 0.022) and 30% (P<0.001), respectively. At the end of the post-crossover phase, the incidence in binding and neutralizing antibodies had increased from 15% and 1.4% to 30% and 7%, respectively in Rebif-treated patients originally treated with Avonex, which represented a 5-fold increase in neutralizing antibodies after therapy transition.

With the crossover to Rebif, the incidence of injection site reactions, liver dysfunction and white blood cell dysfunction increased from 33%, 10%, and 5% to 51%, 14%, and 10%, respectively.

Complicating the interpretation of these results are several issues. Avonex-treated patients were allowed to switch to Rebif while those opting to remain on Avonex therapy were dropped from the study. Additionally, there had been much publicity surrounding the release of the 24-week results which could have biased the patient selection of therapy. Because there is no longer a comparative treatment arm, it is difficult to assess the implications of this data. A treatment arm with patients continuing on Avonex therapy would have been useful in an analysis.

Neutralizing antibodies--factors in the long-term success of disease management.
Hans-Peter Hartung, MD from the Department of Neurology, Heinrich-Heine-University, Dьsseldorf, Germany.

The issue of patient management, specifically, patients who become neutralizing antibody-positive was extensively addressed by Hans-Peter Hartung, MD from the Department of Neurology, Heinrich-Heine-University, Dьsseldorf, Germany.⁶ The concept of developing neutralizing antibodies to an immunogenic medication is not a recent phenomena and not limited to MS. Dr. Hartung first elaborated on the clinical impact of neutralizing antibodies in other diseases.

Development of neutralizing antibodies has been reported in patients treated with interferon alpha-2a for hairy cell leukemia and renal cell carcinoma, and with interferon alpha-2b for chronic myeloid leukemia with a resultant decline in efficacy. This decline in interferon alpha efficacy in neutralizing antibody-positive patients⁷ is consistent with observations of decreased clinical efficacy of interferon beta in neutralizing antibody-positive patients with MS.

The key consideration according to Dr. Hartung in the development of neutralizing antibodies is to consider the implication of neutralizing antibody development at initiation of therapy and options for neutralizing antibody-positive patients. For example, Factor VIII is used to treat Hemophilia A. Neutralizing antibodies inactivate Factor VIII by increasing proteolysis requiring costly and cumbersome alternative therapies. Alternative treatment options include induction of immune tolerance, Bonn protocol (high dose Factor VIII), Malmo protocol (Factor VIII, cyclophosphamide, intravenous IgG), Factor hrVIIa, and activated prothrombin complex concentrates (FEIBA).

Data illustrates that Avonex has the lowest frequency of neutralizing antibody development in clinical trials of interferon beta in the treatment of MS (Table 6).

To illustrate the clinical consequences of neutralizing antibodies, Dr. Hartung reviewed the results from the phase III trial of Betaseron⁸ from the IFNB MS Study Group. After three years of treatment with Betaseron, it was demonstrated that although neutralizing antibodies began to appear early in the treatment (3 to 6 months), the clinical effects were apparent only after 24 months. An examination of the relapse rates from Months 13 to 36 of treatment for placebo-treated, neutralizing antibody-positive and neutralizing antibody-negative patients, respectively, revealed an annual relapse rate of 1.06, 1.08, and 0.56 (P = 0.001). A similar association was demonstrated for mean number of enlarging T2 lesions between neutralizing antibody-positive and neutralizing antibody-negative patients.

A phase III study evaluating the clinical impact of neutralizing antibodies on MRI measures in patients receiving Avonex,⁹ showed an increase in mean gadolinium-enhancing lesions in neutralizing antibody-positive patients (1.7, n = 18) compared to neutralizing antibody-negative patients (0.6, n = 63) but this difference did not reach statistical significance (P = 0.062). An analysis of annualized relapse rates in neutralizing antibody-positive and neutralizing antibody-negative patients receiving Avonex 30 mcg, annualized relapse rates were higher in neutralizing antibody-positive patients in Years 1, 2, and 3 of treatment. Clearly, neutralizing antibody-positive patients do not realize the same therapeutic benefits from receiving interferon beta therapy, as do neutralizing antibody-negative patients after 2 years.

Similar findings were observed in patients receiving Rebif 44 mcg in PRISMS-4.¹⁰ The annualized relapse rate (Years 3 and 4) for neutralizing antibody-positive patients was 0.81 compared to 0.5 in neutralizing antibody-negative patients (P = 0.002). Furthermore, neutralizing antibody-positive patients showed a greater median burden of disease on T2 active lesions on MRI measures compared with neutralizing antibody-negative patients (1.4 vs 0.3, respectively; P<0.001).

In assessing the clinical impact of neutralizing antibodies on immunomodulatory agents, Dr. Hartung made an important observation: short-term clinical trials of MS treatments are incapable of detecting the clinical impact of neutralizing antibodies (Figure 1).

Consequently, Dr. Hartung strongly recommended to practicing neurologists that, when making treatment decisions, physicians should consider the long-term impact of neutralizing antibodies and choose a therapy with a sustained and proven long-term benefit.

In conclusion of his presentation, Dr. Hartung indicated the known incidence of neutralizing antibody formation is greatest with Betaseron, followed by Rebif, and lastly Avonex. High-titer neutralizing antibodies are recognized to weaken the efficacy of the interferons and this effect may be missed in short-term studies. Thus, cautioned Dr. Hartung, neutralizing antibody-positive patients may no longer gain therapeutic benefit from interferon beta therapy.

Combination Therapy in Treating Multiple Sclerosis

Safety profile of different doses of interferon beta in association with azathioprine in relapsing-remitting multiple sclerosis.
Repice A, Barilaro A, Parigi A, Catapano A, Tragni E, Massacesi L. University of Florence, Florence, Italy.

According to the results of a study presented here, the combination of azathioprine and Rebif 22 mcg 3 times weekly was poorly tolerated and results in lymphocytopenia or relapsing infections in a majority of patients.¹¹ The study was designed to evaluate optimal doses of Rebif to be used in combination with immunosuppressive doses of azathioprine in treating patients with relapsing-remitting MS.

Fourteen patients (EDDS ≤5.5) were randomized to 4 treatment groups: 3 patients received Rebif 11 mcg 3 times weekly, 4 patients received Rebif 22 mcg 3 times weekly, 4 patients received Rebif 11 mcg 3 times weekly in combination with azathioprine 3 mg/kg/day, and 3 patients received Rebif 22 mcg 3 times weekly in combination with azathioprine 3 mg/kg/day. The patients were followed clinically for 9 months.

For those patients who received Rebif alone, adverse events were consistent with Rebif administration (fever, flu-like syndrome). Patients who received Rebif 11 mcg in combination with azathioprine showed evidence of lymphocytopenia but dosage adjustment of azathioprine (2.5-3.0 mg/kg/day) prevented further worsening. However, 2 of 3 patients who received Rebif 22 mcg in combination with azathioprine interrupted treatment after 4 and 6 months for >grade 3 lymphocytopenia. The remaining patient showed neutropenia, photosensitization, and a relapsing candida infection.

On the basis of these findings, investigators reported a randomized controlled trial is in progress evaluating the combination of Rebif 11 mcg 3 times weekly and azathioprine (2.5 mg/kg/day) against Rebif 22 mcg 3 times weekly.

Interferon beta-azathioprine association activity on immunological marker in vitro and in multiple sclerosis.
Biagioli T, Mazzanti B, Aldinucci A, Ballerini C, Vergelli M, Massacesi L. University of Florence, Florence, Italy.

According to investigators, the immunomodulatory effects of interferon beta are not reduced, and are sometimes enhanced, by concurrent administration of azathioprine.¹² Since interferon beta and azathioprine both act on T-cell functions, the 2 agents may counteract their effects. To test this hypothesis, a study was designed on the premise that 6-mercaptopurine (the active metabolite of azathioprine) is believed to inhibit nucleic acid synthesis, whereas, the immunomodulatory effects of interferon beta modulate de novo protein synthesis. The immunomodulatory effects of interferon beta, azathioprine and the combination were also investigated in 18 patients with relapsing-remitting MS.

Researchers presented data on the combined activities of interferon beta and 6-mercaptopurine on mitogen and antigen-specific T-cell proliferation, and cytokine production. The results demonstrated antigen specific T-cell stimulation, mitogen driven T-cell proliferation, and significantly reduced tumor necrosis factor (TNF)-α production. Interferon gamma levels declined and interleukin-10 production increased.

Treatment with azathioprine significantly decreased the frequency of positive T-cell proliferation in response to recall antigens (P = 0.027). This pattern of reactivity was maintained in the patients who underwent combined therapy of interferon beta and azathioprine (P = 0.04). These results indicate that, in vivo, azathioprine activity on the immune system is selective and may be tolerated by the patients. Azathioprine activity on gene expression does not affect the interferon beta activity based on protein synthesis activity; therefore the immunomodulatory functions of interferon beta in treating MS are not affected by azathioprine. However, further studies are needed to conclusively establish this therapeutic advantage in patients with MS.

Binding and Neutralizing Antibodies: Clinical Impact on Treatment Success

Patient management--treatment solutions for neutralizing antibody-positive patients. Riachi N. Head of the Division of Neurology, Lebanese University in Beirut, Beirut, Lebanon.

Employing a case study, Dr. Naji Riachi, Head of the Division of Neurology, Lebanese University in Beirut, Beirut, Lebanon presented practical solutions for the treatment of neutralizing antibody-positive patients.¹³ The 6-year time course of disease progression in a 28-year-old Argentinean woman with unremarkable past medical and neurological history who had been treated with Betaseron was detailed.

Within 3 years of initial presentation, the patient's disease had progressed from "probable optic neuritis" to sensory disturbance, followed by lower limb weakness. The diagnosis of relapsing-remitting MS was confirmed by MRI scanning (EDSS 3.0). The patient responded favorably to corticosteroid therapy. Immunomodulating therapy with Betaseron 8 MIU subcutaneously every other day was initiated. The patient developed neutralizing antibodies after 12 months of Betaseron therapy. After 2 years of clinical stability, new exacerbation with cerebellar signs and diplopia developed. Complete remission of symptoms was achieved with methylprednisolone administration (1000 mg daily for 5 days). However, MRI scans revealed new disease activity with gadolinium uptake (EDSS increased to 4.5). Immunomodulating therapy was maintained and corticosteroid therapy was repeated as the patient remained persistently neutralizing antibody-positive. Dr. Riachi noted that the case illustrated that inadequate immunomodulating treatment was continued in treating the patient, and that a new therapeutic intervention had to be selected.

Dr. Riachi asked those in attendance to consider the most appropriate therapeutic interventions and when on to offer several possible interventional strategies. In the neutralizing antibody-positive, Betaseron non-responder, continuation of Betaseron therapy may have clinical consequences, including, reduced or abolished interferon beta bioavailability^[14] or reduced clinical efficacy.^[15] One option is to discontinue all treatments for 3 months and initiate Avonex 30 mcg once weekly. This may increase clinical and MRI markers of disease activity, furthermore, the immune memory may persist and the patient may not tolerate the new therapy (or other interferon betas). An alternative regimen could be administration of methylprednisolone 1000 mg monthly for 3 months, because there is clinical evidence to support that monthly corticosteroid administration decreases the incidence of Betaseron-induced neutralizing antibodies,^[16] and then initiate Avonex 30 mcg once weekly. Another treatment strategy is adding azathioprine, methotrexate or cyclophosphamide to the Betaseron therapy to reduce the incidence of neutralizing antibodies, although continuing Betaseron may cause the neutralizing antibody levels to increase. Switching to mitoxantrone or glatiramer acetate are less than desirable options because of the known adverse effects of mitoxantrone and new evidence that demonstrates glatiramer acetate can also induce the development of antibodies in MS patients. Moreover, antibodies can block the effects of glatiramer acetate in vitro; therefore, antibodies may neutralize the in vivo effect of glatiramer acetate on serum cytokine concentration.^[17]

Concluding his presentation, Dr. Riachi cited two quotations from recent publications, "The immunogenicity of the different interferon beta preparations should be one of the factors that we need to consider when starting treatment" and "It would be reasonable to substitute treatment, even if the patients are doing well, when two positive neutralizing antibody titers are identified." Further studies, with the use of standardized clinical protocols and well-validated assays, are required to resolve whether or not interferon beta therapy should be stopped in all neutralizing antibody-positive patients responding poorly to treatment. "Neutralizing antibodies are not the only determining factor that discerns responders from non-responders, natural progression of disease may also have an effect", said Dr. Riachi.

Neutralizing antibodies during treatment of relapsing multiple sclerosis patients with three interferon betas: correlation with clinical outcomes.
Paolicelli D, Avolio C, Lavolpe V, Ruggieri M, Livrea P, Trojano M, University of Bari, University of Foggia, Italy.

The results of a new study confirm that Betaseron induces the highest incidence of neutralizing antibodies in MS patients receiving interferon beta, followed by Rebif, and lastly by Avonex.¹⁸ The purpose of the study was to compare the incidence of neutralizing antibodies to Betaseron, Rebif and Avonex and investigate the relationships between neutralizing antibodies, and clinical and demographic outcomes in a follow-up study population.

Five hundred and seventy-five patients with relapsing MS were treated with standard doses of Betaseron (n = 160), Avonex (n = 203), and Rebif (n = 212). Sera were longitudinally obtained from all patients at baseline and every 3 months during treatment for up to 24 months. The presence of neutralizing antibodies was determined by cytopathic effect (CPE) assay. Patients with 2 or more consecutive positive samples 3 months apart (positivity = titer ≥20) were considered neutralizing antibody-positive.

Forty-six patients were determined to be neutralizing antibody-positive. Betaseron induced the highest incidence of neutralizing antibodies (16.2%, P<0.00001), followed by Rebif (8%), and Avonex (2%). At baseline, neutralizing antibody-positive patients showed a longer pre-treatment disease duration (P = 0.02) and a lower progression index (EDSS/disease duration) (P = 0.01) than neutralizing antibody-negative patients. Moreover, neutralizing antibody-positive patients showed a significantly greater increase in the mean number of relapses (P = 0.002) after seroconversion in comparison with that observed before seroconversion. The reduction in relapse rate was significantly higher (P<0.05) in neutralizing antibody-negative patients (56%) than in neutralizing antibody-positive patients (50%).

These results confirm previous findings showing the highest incidence of neutralizing antibodies is associated with Betaseron administration, followed by Rebif, and then Avonex. In addition to demonstrating the clinical impact of neutralizing antibodies on interferon beta efficacy, the results suggest a possible association between longer pre-treatment disease duration and the development of neutralizing antibodies, thus, supporting recommendations to initiate early treatment for patients with MS.

The clinical impact of interferon beta neutralizing and binding antibodies in relapsing-remitting multiple sclerosis.
Gallo P, Perini P, Calbrese M, Biasi G. Multiple Sclerosis Centre, Department of Experimental Pathology, Padua, Ancona, Italy.

According to the results of a study presented at ENS 2003, high titers of both binding and neutralizing antibodies reduce the clinical efficacy of interferon beta in patients with relapsing-remitting MS.¹⁹ Although treatment with interferon beta has been associated with the development of binding and neutralizing antibodies, their clinical significance has been the subject of much debate.

In order to analyze the kinetics and clinical impact of binding and neutralizing antibodies on interferon beta, a total of 90 patients received 1 of 3 treatment regimens for up to 4 years: Betaseron 250 mcg subcutaneously every other day, Avonex 30 mcg intramuscularly once weekly or Rebif 22 mcg subcutaneously 3 times weekly. The impact of binding and neutralizing antibodies on relapse rate and EDSS was also evaluated.

Eighty-three percent of patients developed binding antibodies to Betaseron, 47% to Rebif, and 13% to Avonex. Forty percent of patients developed neutralizing antibodies to Betaseron, 26.7% to Rebif, and 6.7% to Avonex. Of 22 neutralizing antibody-positive patients, 10 patients (45.5%) demonstrated high titers of both neutralizing antibodies (defined as >1:100) and binding antibodies (defined as >1:500). There was a significant positive correlation between high neutralizing antibody titers and relapse rate (>2 relapses after evidence of neutralizing antibodies, P = 0.03), and an even higher significance level for the correlation between high titers of both neutralizing antibodies and binding antibodies and relapse rate (P<0.001). In 10 patients with high titers of both neutralizing antibodies and binding antibodies, an increase in mean EDSS score from 2.2 at baseline to 3.6 at Year 2 was observed (P<0.01), while neutralizing antibody-negative patients showed no significant change in EDSS score at Year 2.

The results of this study demonstrate that high titers of both binding and neutralizing antibodies reduce the clinical efficacy of interferon beta in patients with relapsing-remitting MS. The observed incidence of neutralizing antibodies with Betaseron, Rebif, and Avonex continue to confirm previously established results.

Neutralizing antibodies to interferon beta in multiple sclerosis: impact of dosage on therapeutic strategy.
Giannesini C, Heinzlef O, Pez D, Lebon P, Roullet E. Hфpital Tenon, Hфpital Saint-Vincent de Paul, Paris, France.

While interferon beta has proven its efficacy on relapse rate reduction and MRI activity in treating MS, it is impossible to determine prior to treatment whether a patient will respond to therapy. Further, the development of neutralizing antibodies may reduce the clinical and MRI efficacy of interferon beta. The present study was designed to evaluate the influence of neutralizing antibody-positivity on treatment strategy for non-responders.²⁰

A total of 29 patients (considered by their respective neurologists as non-responders) were evaluated for the presence of neutralizing antibodies through CPE assay. Twenty-three patients had relapsing-remitting MS (mean age 34.6 years, mean disease duration 8 years) and 6 patients had secondary-progressive MS (mean age 50.7 years, mean disease duration 11 years).

Eight patients (35%) with relapsing-remitting MS and one patient (17%) with secondary-progressive MS tested positive for neutralizing antibodies. In the 23 patients with relapsing-remitting MS, treatment was modified in 7 of 8 neutralizing antibody-positive patients and in 5 of 15 neutralizing antibody-negative patients (P<0.05). The presence of neutralizing antibodies was significantly associated with treatment modification. Because of possible cross-reactivity of neutralizing antibodies between the three different interferon betas, another drug class was chosen for neutralizing antibody-positive patients. Five neutralizing antibody-negative patients stopped interferon beta therapy because of adverse drug reactions. In the 6 patients with secondary-progressive MS, the single neutralizing antibody-positive patient stopped treatment with interferon beta and 2 of 5 neutralizing antibody-negative patients received immunosuppressant agents due to significant disability progression.

Investigators concluded that the presence of neutralizing antibodies when the patient is suspected to be a non-responder has a significant impact on treatment strategy. Therefore, testing for neutralizing antibodies should be performed systematically for non-responders to interferon beta therapy.

Quality of Life Issues in Multiple Sclerosis

MusiQoL: a unique quality of life questionnaire for patients with multiple sclerosis.
Auquier P, Blumhardt L, Fernandez O, et al for MusiQol Study Group.

"Life expectancy has increased dramatically in the last century. As life is prolonged, it is becoming clear that it is not only the duration of life that is important, but how this life is lived," stated Oscar Fernandez, MD, PhD, of Hospital Regional Universitario Carlos Haya, Malaga, Spain. "One of the most important factors in quality of life is health," noted Dr. Fernandez. Measurement of health-related quality of life is now possible through the Multiple Sclerosis International Quality of Life (MusiQoL) scale--a unique quality of life questionnaire for patients with multiple sclerosis.²¹

A total of 107 patients with MS were interviewed in 5 countries. A list of patients' common concerns was compiled that resulted in the generation of a preliminary questionnaire. The questionnaire was further tested among an additional 178 patients (mean age 42 years, 60% female, 38% secondary-progressive MS) of differing nationalities. After careful analysis of the interviews, a definitive list of 73 questions was created. These questions related to 7 aspects of patients' lives: social relationships, psychological health, physical health and activities, autonomy, financial issues and treatment. The questionnaire is currently being validated in a study involving 200 patients in 20 countries.

"Patients are very happy to collaborate", concludes Dr. Fernandez, "and no major cultural differences were identified among patients from different countries". Dr. Fernandez believes MusiQoL may be the future gold standard by which quality of life in MS patients is to be measured. The MusiQoL questionnaire will allow physicians, patients and policy makers to further understand the clinical significance of health-related quality of life issues and thus, improve the quality of life for patients with MS.

New Treatments in Development

New potential target antigens involved in the pathogenesis of multiple sclerosis.
Cepok S, Zhou D, Stei S, Nessler S, Buessow K, Sommer N, Hemmer B. Philipps-University Marburg, Max-Planck-Institute for Molecular Genetics, Marburg, Berlin, Germany.

The etiology of MS is still unknown; the putative target antigens, auto-antigens or infectious agents, which may be involved in the pathogenesis of the disease, remain elusive. Dr. S. Cepok and colleagues presented preliminary results on employing a novel protein expression array technology to investigate the antigen specificity of the local antibody response in MS patients.²²

Serum samples and cerebral spinal fluid (CSF) from 15 MS patients and 5 controls were searched against protein arrays, comprising 35,000 cDNA inserts from a human fetal brain library. Immune responses to 25 novel proteins were specifically recognized in MS patients that were not seen in the controls. Supplementary analyses revealed a higher immunreactivity to 4 of these potential antigens in the CSF of MS patients compared with controls. Interestingly, they also discovered intrathecal antibody production and binding of the oligoclonal IgG bands to the proteins.

Utilizing substitutional analyses for epitope mapping, in two of the proteins, researchers unveiled the peptide sequence of the humoral immune response; with complete epitope matches to two proteins derived from the same neurotropic pathogen [two related Epstein-Barr virus proteins]. Additional testing in 150 MS patients and 190 controls confirmed a significantly higher immunreactivity to these microbial peptides in MS patients. To identify the role of these antigens in the pathogenesis of MS, the investigators are producing monoclonal antibodies that will be used for future research to investigate their expression in lesions of MS patients.

Clinical and MRI outcome 3 years after autologous hematopoietic stem cell transplantation (AHSCT) in MS.
Blanco Y, Saiz A, Carreras E, et al. Hospital Clнnic de Barcelona, Barcelona, Spain.

Autologous hematopoietic stem cell transplantation (AHSCT) is a potential treatment for severe cases of MS. Dr. Y. Blanco of the Hospital Clinic de Barcelona, Barcelona, Spain presented clinical and MRI outcome data of 15 patients treated with AHSCT after a median follow-up of 3 years.²³ Baseline patient characteristics included a median age of 30 years (range, 22 to 45 years), median EDSS of 6.0 (range, 4.5 to 6.5), median annual relapses of 3 (range, 1 to 7), and median worsening of EDSS in the previous year to AHSCT of 1.0 (range, 0.5 to 4.5).

After a median follow-up of 35 months (range, 12 to 53), the EDSS remained stable in 8 patients, improved in 4, and worsened in 2 patients. The 3-year progression-free survival and disease activity-free survival in this uncontrolled study were 86% (95% CI, 60-90%), and 46% (95% CI, 24-76%), respectively. No enhanced T1 lesions have been detected since one month after AHSCT. Moreover, at 3 years, the mean percentage reductions of T2 lesion volume and corpus callosum area were 20.2% and 12.7%, respectively, compared with baseline. Similar reductions were observed for brain atrophy as measured by brain volume technique.

The protocol of AHSCT was generally well tolerated. Stem cell mobilization failed in one patient and there was no major toxicity in the 14 remaining patients. Neurological deterioration related to the AHSCT procedure was observed in 3 patients (2 transient and one persistent).

Dr. Blanco proposed that in view of their findings, AHSCT deserves further evaluation in multicenter randomized controlled trial setting.

References

1. Brescia Morra V, Florio C, Coppola G, et al. Long-term clinical experience with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis patients. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 318.
2. Goodin D. The EVIDENCE study: 16 months' data. Presented during the Satellite Symposium "Quality quantitative indicators in multiple sclerosis". Presented during the 13th Meeting of the European Neurological Society (ENS), June 16, 2003, Istanbul, Turkey.
3. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimen in MS: the EVIDENCE trial. EVIDENCE Study Group. Evidence of Interferon Dose-response: European North American Comparative Efficacy; University of British Columbia MS/MRI Research Group. Neurology. 2002;59:1496-1506.
4. Palace J. Long-term efficacy of interferon beta - do neutralizing antibodies matter? 12th Meeting of the European Neurological Society, June 22-26, 2002, Berlin, Germany. Satellite Symposium: Make a difference - the importance of efficacy in RRMS. Presented June 25, 2002.
5. Sharief MK for the EVIDENCE Study Group. The impact of change in interferon beta-1a dose regimen (30 mcg qw to 44 mcg tiw) in patients with relapsing MS- cross-over results from the EVIDENCE study. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Abstract 194.
6. Hartung HP. Neutralizing antibodies - factors in the long-term success of disease management. Presented during the Satellite Symposium "Multiple Sclerosis: Treatment Goals and Long-Term Success Factors". Presented during the 13th Meeting of the European Neurological Society (ENS), June 16, 2003, Istanbul, Turkey.
7. Oberg and McKenna. In: Reder, ed. Interferon Therapy of Multiple Sclerosis. 1997:509.
8. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. IFNB MS Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45:1277-1285.
9. Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group. Neurology. 1998;50:1266-1272.
10. PRISMS-4: long-term efficacy of interferon beta-1a in relapsing MS. PRISMS Study Group, University of British Columbia MS/MRI Analysis Group. Neurology. 2001;56:1628-1636.
11. Repice A, Barilaro A, Parigi A, Catapano A, Tragni E, Massacesi L. Safety profile of different doses of interferon beta in association with azathioprine in relapsing-remitting multiple sclerosis. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 777.
12. Biagioli T, Mazzanti B, Aldinucci A, Ballerini C, Vergelli M, Massacesi L. Interferon beta-azathioprine association on immunological marker in vitro and in multiple slcerosis. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 184.
13. Riachi N. Patient management - treatment solutions for neutralizing antibody-positive patients. Presented during the Satellite Symposium "Multiple Sclerosis: Treatment Goals and Long-term Success Factors". Presented during the 13th Meeting of the European Neurological Society (ENS), June 16, 2003, Istanbul, Turkey.
14. Bertolotto A, Gilli F, Sala A, et al. Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients. Neurology. 2003;60:634-369.
15. Bertolotto A, Malucchi S, Sala A, et al. Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry. 2002;73:148-153.
16. Pozzilli C, Antonini G, Bagnato F, et al. Monthly corticosteroids decrease neutralizing antibodies to IFN beta-1b: a randomized trial in multiple slcerosis. J Neurol. 2002;249:50-56.
17. Zang YCQ, Salama HH, El-Mongui A. Blocking effects of serum-reactive antibodies induced by glatiramer acetate treatment in patients with multiple sclerosis. Neurology. 2003; 60(Suppl 1):A396.P05.132.
18. Paolicelli D, Avolio C. Lavolpe V, Ruggieri M, Livrea P, Trojano M. Neutralizing antibodies during treatment of relapsing multiple sclerosis patients with three interferon betas: correlation with clinical outcomes. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 406.
19. Gallo P, Perini P, Calabrese M, Biasi G. The clinical impact of interferon beta neutralizing and binding antibodies in relapsing-remitting multiple sclerosis. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 188.
20. Giannesini C, Heinzlef O, Pez D, Lebon P, Roullet E. Neutralizing antibodies to interferon beta in multiple sclerosis: impact of dosage on therapeutic strategy. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Poster 659.
21. Auquier P, Blumhardt L, Fernandez O, et al. MusiQol: a unique quality of life questionnaire for patients with multiple sclerosis: MuSIQoL. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Abstract 41.
22. Cepok S, Zhou D, Stei S, et al. New potential target antigens involved in the pathogenesis of multiple sclerosis. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Abstract 43.
23. Blanco Y, Saiz A, Carreras E, et al. Clinical and MRI outcome 3 years after autologous hematopoietic stem cell transplantation (AHSCT) in MS. 13th Meeting of the European Neurological Society (ENS), June 14-18, 2003, Istanbul, Turkey. Abstract 183.