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MS TREATMENTS - BETASERON/BETAFERON/EXTAVIA

 
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agate
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PostPosted: Sat Jul 15, 2006 6:26 pm    Post subject: MS TREATMENTS - BETASERON/BETAFERON/EXTAVIA Reply with quote

Here's a place for people who are on Betaseron or who are thinking about trying it, or who have been on it in the past.

Last edited by agate on Sat Mar 02, 2013 2:36 pm; edited 1 time in total
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agate
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PostPosted: Tue Nov 28, 2006 4:30 pm    Post subject: (Abstract) [Betaseron sometimes exacerbates MS] Reply with quote

From PubMed, November 28, 2006:

Quote:
J Neurol Sci. 2006 Nov 22

Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination

Warabi Y, Matsumoto Y, Hayashi H.
Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan; Department of Molecular Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan.

To evaluate the effect of interferon beta-1b (IFNB-1b) on multiple sclerosis (MS) with severe optic nerve and spinal cord demyelination, we examined the relationship between IFNB-1b treatment outcome and the clinical and genetic characteristics of three types of demyelinating diseases of the central nervous system, i.e., neuromyelitis optica (NMO), MS and MS with severe optic-spinal demyelination.

Japanese MS frequently carried HLA DPB1()0501, which is associated with NMO. MS with DPB1()0501 showed severe optic-spinal demyelination represented by longitudinally extensive spinal cord lesion, blindness and CSF pleocytosis. IFNB-1b treatment did not succeed in these patients because of the increase of optic nerve and spinal cord relapse and other severe side effects.

IFNB-1b should not be administered to demyelinating patients with genetic and clinical characteristics mimicking NMO such as HLA DPB1()0501 allele, longitudinally extensive spinal cord lesion, blindness and CSF pleocytosis even if they have symptomatic cerebral lesions as typically seen in MS. The present study strongly suggests that these patients should be diagnosed as having NMO.

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Matt



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PostPosted: Tue Nov 28, 2006 4:36 pm    Post subject: Reply with quote

Thanks for posting that!
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Snoopy



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PostPosted: Tue Nov 28, 2006 7:08 pm    Post subject: Reply with quote

Apparently MS is different in Japanese patients versus white patients.....


Interferon beta-1b is effective in Japanese RRMS patients: a randomized, multicenter study.Saida T, Tashiro K, Itoyama Y, Sato T, Ohashi Y, Zhao Z; Interferon Beta-1b Multiple Sclerosis Study Group of Japan.
Department of Neurology, Utano National Hospital, Kyoto, Japan. saida@unh.hosp.go.jp

OBJECTIVE: To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS). BACKGROUND: The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations--classic MS (C-MS) and optic-spinal MS (OS-MS)--and chronic progressive forms are infrequent. METHODS: A total of 205 Japanese patients with RRMS were randomized to receive 50 microg or 250 microg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS. RESULTS: Annual relapse rates were 0.763 in the 250 microg group and 1.069 in the 50 microg group, a relative reduction of 28.6% (p = 0.047). Results for all secondary endpoints favored 250 microg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size. CONCLUSIONS: Interferon beta-1b (IFNB-1b) 250 microg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.

PMID: 15728282 [PubMed - indexed for MEDLINE]
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Matt



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PostPosted: Tue Nov 28, 2006 7:23 pm    Post subject: Reply with quote

Hmmm...two totally contradictory abstracts.
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agate
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PostPosted: Tue Nov 28, 2006 8:29 pm    Post subject: Reply with quote

Matt, I've been wondering about that too. I'm trying to find out more about the date on the second one.
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Matt



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PostPosted: Tue Nov 28, 2006 10:22 pm    Post subject: Reply with quote

I found it.

Neurology. 2005 Feb 22;64(4):621-30

I can try to access the full article for either or both if you want me too. If I test positive, then I am sure I will read those articles. You have had pretty severe optic nerve and spinal involvement, so maybe you want the articles too. Just let me know.
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agate
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PostPosted: Tue Nov 28, 2006 11:09 pm    Post subject: Reply with quote

Thanks! I would be interested in reading them. Maybe you could post them here--if/when it's convenient for you?

It looks as if there's been a lot of speculation about a possible variant of MS, observed among the Japanese, which they're calling opticospinal MS.
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Snoopy



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PostPosted: Wed Nov 29, 2006 5:39 am    Post subject: Reply with quote

Sorry about the confusion - getting the abstracts on here as nicely as everyone else is not my strong point.
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Matt



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PostPosted: Wed Nov 29, 2006 11:28 am    Post subject: Reply with quote

Here's the one posted by LeAnn
Quote:

Interferon beta-1b is effective in Japanese RRMS patients: A randomized, multicenter study
[Articles]
Saida, T MD, PhD; Tashiro, K MD, PhD; Itoyama, Y MD, PhD; Sato, T MD, PhD; Ohashi, Y PhD; Zhao, Z MD; the Interferon Beta-1b Multiple Sclerosis Study Group of Japan

From the Department of Neurology (Drs. Saida and Zhao), Utano National Hospital, Kyoto; Department of Neurology (Dr. Tashiro), Hokkaido University, Sapporo; Department of Neurology (Dr. Itoyama), Tohoku University, Sendai; Department of Neurology (Dr. Sato), Konodai Hospital, NCNP, Ichikawa; and Department of Epidemiology and Biostatistics (Dr. Ohashi), University of Tokyo, Japan.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the February 22 issue to find the title link for this article.
See also page 594
*See the Appendix on page 628 for a listing of members of The Interferon Beta-1b Multiple Sclerosis Study Group.
Supported by Nihon Schering K.K., which provided funding and study medication.
Some of the authors have received honoraria from Nihon Schering K.K. for consultancy and delivering lectures at scientific meetings; in addition, the departments of the authors have received financial support for participation in research on interferon beta in multiple sclerosis.
Received May 27, 2004. Accepted in final form October 22, 2004.
Address correspondence and reprint requests to Professor Takahiko Saida, Department of Neurology, Center for Neurologic Diseases, Utano National Hospital, Narutaki, Ukyo-ku, Kyoto 616-8255, Japan; e-mail: saida@unh.hosp.go.jp
Abstract—
Objective: To assess the efficacy of interferon beta-1b (IFNB-1b) in Japanese patients with relapsing-remitting multiple sclerosis (RRMS).

Background: The effects of IFNB in RRMS have been assessed in study populations comprised predominantly of white patients. MS in Japanese patients is different from that in white patients in that there are two different presentations—classic MS (C-MS) and optic-spinal MS (OS-MS)—and chronic progressive forms are infrequent.

Methods: A total of 205 Japanese patients with RRMS were randomized to receive 50 µg or 250 µg (1.6 or 8.0 MIU) IFNB-1b administered SC every other day for up to 2 years. The primary endpoint was annual relapse rate. Secondary endpoints included further relapse-related and MRI outcome measures, as well as changes in Expanded Disability Status Scale and Neurologic Rating Scale. Efficacy was assessed in 188 patients, and safety was assessed in 192 patients. Supplemental ad hoc subgroup analyses were also performed for patients with OS-MS and those with C-MS.

Results: Annual relapse rates were 0.763 in the 250 µg group and 1.069 in the 50 µg group, a relative reduction of 28.6% (p = 0.047). Results for all secondary endpoints favored 250 µg IFNB-1b. Subgroup analyses suggested that the magnitude and direction of treatment effect in patients with OS-MS and C-MS was similar, albeit not significant due to small sample size.

Conclusions: Interferon beta-1b (IFNB-1b) 250 µg significantly reduced relapse rates and change in MRI lesion area in Japanese patients with relapsing-remitting multiple sclerosis, and seemed to be comparably effective in optic-spinal multiple sclerosis (MS) and classic MS. The response to treatment with IFNB-1b in Japanese patients with MS suggests that a common pathogenesis and underlying genetic characteristics are shared with white patients.


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Multiple sclerosis (MS) is the most common disabling neurologic disorder in young adults in northern Europe, continental North America, Australia, and New Zealand, with a prevalence of >70 per 100,000 depending on geographic area.

In Asian populations, however, the overall prevalence of MS is much lower. Estimates of the prevalence of MS in Japan range from 1.0 to 4.0 per 100,000.1,2 In addition, the relative frequencies of primary and secondary chronic progressive forms are much lower than in white MS patients, even in those patients with a long disease duration.3

MS in Asian populations is also often characterized by selective involvement of the optic nerve and spinal cord. This optic-spinal MS (OS-MS) is characterized by lesions that are predominantly confined to the optic nerve and spinal cord, with few or no lesions observed in the cerebrum or cerebellum. This is in marked contrast to classic MS (C-MS), where frequent lesions are observed in the cerebrum, cerebellum, or brainstem, as well as in the optic nerve and spinal cord.3–7 For example, one study showed significantly lower cerebellar involvement in Japanese MS patients relative to British MS patients (38% vs 71%) and a substantially higher occurrence of clinical OS presentation (13% vs 6%).4 A comparative pathologic study of MS in Japanese and North Americans also found that the frequency of OS-MS was significantly higher (47%) in Japanese, although that of North Americans was not negligible (13%).8,9

Studies on the immunology, pathology, and immunogenetics of OS-MS show significant differences between patients with OS-MS and C-MS,8,9 although no clear-cut clinically differentiating marker has yet been established. In Japanese MS patients, oligoclonal IgG bands were found in the CSF of only 56% of C-MS patients, a much lower frequency compared with white MS patients, and rarely among OS-MS patients.10,11 OS-MS is also characterized by a higher age at onset, a higher female to male ratio compared to C-MS, and a higher degree of CSF pleocytosis, sometimes with neutrophil predominance.7 Although the classic perivascular inflammatory demyelinative lesions seen in C-MS are also the predominant pathologic feature in OS-MS, severe lesions of OS-MS are often characterized by necrotic changes and sometimes by cavity formation,9,12,13 which are rarely seen in C-MS.

Whether OS-MS in Asians is the same disease entity as neuromyelitis optica (NMO) in white subjects remains inconclusive. However, the clinical definition of OS-MS is almost identical to that of relapsing NMO and the majority of Japanese OS-MS cases share common neurologic, MRI, and laboratory characteristics with relapsing NMO, although proportion of patients with positive conventional autoantibodies seems to be much higher in white NMO than in Japanese OS-MS.7 In fact, recent preliminary reports have described that 58% of Japanese OS-MS patients and 54% of patients with NMO from North America were positive for a characteristic immunostaining pattern in which IgG from human subjects bind selectively to an element associated with cerebellar capillaries, pia, subpia, and white matter of mice. The specificity of this antibody is very high but even its absence does not exclude the diagnosis and its pathogenetic role, if any, has not been explored.14,15

Interferon beta-1b (IFNB-1b, Betaseron/Betaferon) was the first effective treatment for relapsing-remitting MS (RRMS), with a recommended dose of 250 µg (8.0 million international units [MIU]) injected subcutaneously (SC) every other day (EOD). The pivotal North American Phase III study of IFNB-1b (North American study) provided compelling evidence for the efficacy of IFNB-1b in RRMS.16 More recently, IFNB-1b has also been shown to be effective in secondary progressive MS (SPMS).17 Since the publication of the North American study in RRMS, IFNB-1a (Avonex, Rebif) has also shown efficacy in the treatment of RRMS.18,19

Previous controlled clinical studies demonstrating the efficacy and safety of IFNB in RRMS have for the most part been conducted in cohorts with a vast majority (>90%) of white patients.16,18,19 We evaluated the efficacy and safety of two doses of IFNB-1b (50 µg and 250 µg) SC EOD in a Japanese RRMS population. The results from the final analysis of this 2-year study are presented here.

Methods.
Patients, treatment, and schedule.
Japanese patients aged 16 to 59 years with clinically definite RRMS according to the Poser criteria 20 were considered for enrollment in the study. Other inclusion criteria were an Expanded Disability Status Scale (EDSS) score of <=7.0 (ideally <=5.5), at least one relapse in the past year or at least two relapses in the 2 years prior to enrollment, and a stable neurologic state for at least 1 month. The main exclusion criteria were pregnancy, pretreatment with IFNB, radiotherapy, immunosuppressants, or plasmapheresis 1 to 3 months prior to initiation of treatment with IFNB-1b, other serious complications, psychiatric disease, hypersensitivity or allergy to biologic drugs, and use of any other experimental treatment within 30 days of initiation of IFNB-1b treatment.

The study was performed according to Good Clinical Practice guidelines, and was approved by the institutional review boards of the participating centers prior to initiation. Patients provided informed written consent prior to study entry. Patients with OS-MS and C-MS were differentiated on the basis of lesion location, over the entire disease course estimated from the results of clinical observations before treatment initiation. Patients exhibiting selective involvement of the spinal cord and optic nerves, or spinal cord alone, with no clinical signs associated with cerebrum, cerebellum, or brainstem involvement were defined as OS-MS, while those with estimated lesions in cerebrum, cerebellum, or brainstem were defined as C-MS.

After an initial dose titration period where patients received half their allocated dose for the first 2 weeks (seven injections), patients received either 50 µg or 250 µg IFNB-1b administered SC EOD for 2 years. After a suitable training period, patients were expected to self-administer the study medication, although injections could also be performed with the help of a caregiver if necessary. Treatment was discontinued in cases of intolerable adverse events, clinically relevant laboratory abnormalities, pregnancy, or poor compliance.

Study medications were supplied by Chiron Corporation (Emeryville, CA) and were of identical appearance. The coordinating statistician, who took no part in the conduct of the study, was responsible for randomization of patients to treatment group, and the randomization code was held centrally. Study medications were supplied to investigators and patients, who were blinded to the IFNB-1b content (60 µg or 300 µg as product), every 6 months. All clinical and MRI assessments were performed by blinded investigators, while the lack of a placebo group ensured that patients could also be blinded to treatment allocation. To compensate for the large number of study centers involved, and to ensure comparability of the baseline characteristics of the two treatment groups, a dynamic balancing technique was used for the randomization process, where the balancing factors were disability, MRI brain lesion area, number of relapses in the past year, and clinical site.

Weekly visits were scheduled for the first month after initiation of treatment, and monthly thereafter. Patients were hospitalized for the first 2 weeks of treatment. A complete medical examination, including chest X-ray and ECG, was performed at baseline and at the end of study. Adverse events were recorded and laboratory tests were performed at every visit. Vital signs (blood pressure, pulse rate, body weight) were taken at baseline and every 3 months. Sera for antibody determination were collected at baseline and 4 weeks after the end of treatment and assayed by a cytopathic effect (CPE) method.21

Complete neurologic examination was performed at baseline and in case of relapse. Disability was evaluated using the EDSS 22 and the Neurologic Rating Scale (NRS)23 at baseline, every 3 months, and in case of relapse. Neurologic examinations were performed by the same investigator throughout the trial.

Relapses were defined according to the criteria of Schumacher et al.,24 and the definition of both relapse and remission were consistent with those used in the North American study in RRMS. When a relapse occurred, the date of occurrence and duration (time to remission), the peak EDSS and NRS scores, and corresponding neurologic changes were recorded. Patients were treated for relapse with one or two courses of IV methylprednisolone at a dose of 0.5 g per day for 3 to 5 days or 1.0 g per day for 3 days, if necessary.

T1- and T2-weighted axial cranial MRI scans were performed at baseline and every 6 months. MRI was performed using 0.5 to 1.5 tesla scanners imaging contiguous slices of uniform thickness (5 mm) of the entire brain. A single neuroradiologist, who took no part in conduct of the study, assessed the MRI data. The areas of the MS lesions in T2-weighted images were summed slice by slice for a total lesion area and were recorded as mm2.

Primary endpoint.
The primary endpoint was annual relapse rate, calculated as follows:



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[Email Jumpstart To Image] Figure 1. Patient disposition (number of patients).

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This method differs from that of the North American pivotal study in that relapse rate is calculated using only the time a patient is free from relapses, rather than the total on-study period. This allows for the relatively long duration of relapses in MS and assesses only the time a patient is at risk of a relapse, since a new relapse will not occur during an existing one.

Other endpoints.
Secondary endpoints were change in lesion area based on brain MRI, time to the first and second relapse, proportion of relapse-free patients, relapse severity based on NRS scores as defined by change in NRS score from the peak value before the relapse (0 to 7: mild, 8 to 14: moderate, 15+: severe), relapse duration, and changes in EDSS and NRS scores.

Statistical methods.
For the primary endpoint, annual relapse rate, treatment group differences were tested using a one-sided permutation test for the relative rate ratios. Statistical tests for secondary endpoints were as follows: change in the EDSS and NRS scores, duration of annual relapse, and change in MRI lesion area: Wilcoxon test; time to the first and second relapse: Kaplan-Meier survival analysis and log-rank test; proportion of relapse-free patients: Fisher’s exact test.

The intention-to-treat (ITT) population comprising all patients receiving at least one injection of IFNB-1b (i.e., at least one injection at 50% of allocated dose during dose escalation) was analyzed for safety, and the modified ITT population including all patients receiving at least eight injections of IFNB-1b (i.e., at least one injection at the allocated dose after dose escalation) was analyzed for efficacy. Group comparisons were made using one-sided significant tests at the level of [alpha] = 0.05, thus providing for superiority of 250 µg over 50 µg IFNB-1b. Statistical analyses were performed using SAS software (version 6.1.2).

Results.
Patients.
Enrollment of patients began in July 1995 and the study completed with the observation of the last patient in November 1999. A total of 205 patients were randomized, of whom 192 were included in the ITT population for safety analyses (n = 96 in each treatment group), and 188 were in the modified ITT population for efficacy analyses (50 µg: n = 93; 250 µg: n = 95) (figure 1). Treatment groups in the modified ITT population were well balanced for all baseline demographic and disease characteristics, although patients in the 50 µg dose group had a longer mean disease duration prior to enrollment (8.0 ± 6.6 years vs 6.3 ± 5.3 years) (table 1). The majority of patients (70.7%) were women, and most patients (approximately 75%) in both treatment groups had a baseline EDSS score of <=3.5. A total of 40/188 (21.3%) patients had OS-MS (18 in the 50 µg and 22 in the 250 µg group). The baseline characteristics of these patients were also comparable between treatment groups, but differed from patients with C-MS in that the proportion of women was higher, the age at onset was higher, and patients with OS-MS had higher EDSS scores than those with C-MS (table 2). The number of relapses in the year prior to the study was comparable between patients with OS-MS and C-MS.



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[Email Jumpstart To Image] Table 1 Patients’ baseline characteristics

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[Email Jumpstart To Image] Table 2 Baseline characteristics of patients with optic-spinal MS and classic MS

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[Email Jumpstart To Image] Table 3 Summary of efficacy results

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A total of 53 patients withdrew from the study prematurely (50 µg: n = 25; 250 µg: n = 28). A greater proportion of patients on 50 µg IFNB-1b discontinued due to worsening of MS (in the opinion of the investigator) or withdrawal of consent (15/25 patients, 60%) than those on 250 µg IFNB-1b (10/28, 35.7%), and a greater proportion of patients on 250 µg discontinued due to adverse events (15/28, 53.6%) compared to those on 50 µg (5/25, 20%).

Efficacy.
The mean (median) observation period on treatment for patients in the modified ITT population was 19.6 (23.9) months in the 250 µg group and 21.1 (23.9) months in the 50 µg group. The results for the primary and secondary efficacy endpoints are summarized in table 3.



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[Email Jumpstart To Image] Equation (Uncited)

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Primary efficacy endpoint: Annual relapse rate.
The annual relapse rates were 0.763 (95% CI: 0.628 to 0.919) in the 250 µg group and 1.069 (95% CI: 0.909 to 1.248) in the 50 µg group, a relative reduction of 28.6% in the 250 µg group (p = 0.047) (see figure E-1 on the Neurology Web site at www.neurology.org ).

Other endpoints.
The mean change in MRI lesion area in the 50 µg group was +53.9 mm2 compared to -338.6 mm2 in the 250 µg group (p = 0.390), corresponding to changes of +2.4% and -16.3%, a difference between groups (p = 0.035, see figure E-2).

Treatment with 250 µg IFNB-1b increased the median time to first relapse by 66 days compared to the 50 µg treatment group (426 vs 360 days). However, this difference did not reach significance (p = 0.143, see figure E-3). The time to second relapse for the 25th percentile was increased by 160 days in the 250 µg group relative to the 50 µg group (541 vs 382 days)—a group difference (p = 0.009, see figure E-3).

The median duration of relapse was reduced in the 250 µg group relative to the 50 µg group (7.11 days vs 16.43 days, p = 0.030).

A total of 42/95 (44.2%) in the 250 µg group and 32/93 (34.4%) in the 50 µg group were relapse-free at the end of the study; the group difference showed a strong trend in favor of 250 µg IFNB-1b, but did not reach significance (p = 0.110).

Other secondary efficacy endpoints (severity of relapse, change in EDSS and NRS) are listed in table 3, and showed no significant between-group differences.

Neutralizing activity was assessed using the CPE antiviral assay in only 71 patients in the 50 µg group and 67 patients in the 250 µg group. Of these, neutralizing activity could not be assessed in 26 patients (36.6%) from the 50 µg group and 23 patients (34.3%) from the 250 µg group, due to an unknown component in their serum samples that led to cytotoxicity in the cell lines used in the bioassay. Data were therefore only available in 45 and 44 patients in the respective groups. A greater proportion of patients in the 50 µg group (13/45; 29%) were NAB-positive relative to the 250 µg group (7/44; 16%).

Subgroup analyses of OS-MS patients.
Patients with OS-MS and C-MS were also analyzed as separate subgroups. The number of OS-MS cases was 18 (19.4%) in the 50 µg group and 22 (23.2%) in the 250 µg group. Relapses in patients with OS-MS involved the spinal cord or optic nerves only, with two exceptions: one involving the cerebrum and cerebellum in one patient in the 50 µg group, and another involving the brainstem in one patient in the 250 µg group.

The ratio of the annual relapse rate in the 250 µg group to that in the 50 µg group was 0.608 (-39.2%) in the OS-MS patients and 0.746 (-25.4%) in the C-MS patients, i.e., showing comparable treatment effects of IFNB-1b in patients with OS-MS and C-MS (p = 0.093 in OS-MS and p = 0.106 in C-MS, see figure 2).



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[Email Jumpstart To Image] Figure 2. Annual relapse rate in optic-spinal multiple sclerosis (OS-MS) vs classic MS (C-MS) in Japanese patients. Annual relapse rates were calculated as follows:

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[Email Jumpstart To Image]

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The proportion of relapse-free patients was 28% (5/18) in the 50 µg group and 27% (6/22) in the 250 µg group in patients with OS-MS (p = 0.653), compared to 36% (27/75) in the 50 µg group and 49% (36/73) in the 250 µg group in patients with C-MS (p = 0.067).

There were 50 patients in the 50 µg group and 43 patients in the 250 µg group with a diagnosis of C-MS, and lesions involving the spinal cord prior to the start of the study. Of these, 29 (58%) in the 50 µg group and 18 (42%) in the 250 µg group had relapses involving the spinal cord during the study, compared with 13/18 (72%) in the 50 µg group and 12/22 (55%) in the 250 µg group for patients diagnosed with OS-MS. Of the remaining C-MS patients, i.e., those with no lesions involving the spinal cord prior to study entry, 3/25 (12%) in the 50 µg group and 3/30 (10%) in the 250 µg group experienced relapses involving the spinal cord. The ratio of the annual relapse rate between the 250 µg and 50 µg treatment groups in patients with spinal cord lesions was 0.542 in patients with OS-MS and 0.571 in patients with C-MS, demonstrating a comparable reduction in relapses involving the spinal cord in both patient groups (figure 3).



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[Email Jumpstart To Image] Figure 3. Annual rate of relapses with spinal cord involvement in patients with optic-spinal multiple sclerosis (OS-MS) and classic MS (C-MS) with lesion involving the spinal cord from disease onset to study entry. Annual relapse rates were calculated as shown in the legend to figure 2.

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Safety.
In the 192 patients included in the ITT safety population (n = 96 in each treatment group), the mean (median) observation period on treatment was 19.4 (23.9) months in the 250 µg group and 20.4 (23.9) months in the 50 µg group.

Adverse events were observed in 91/96 (94.8%) patients in the 50 µg group and 93/96 (96.9%) patients in the 250 µg group. The most frequent adverse events were suggestive of flu-like symptoms and injection site reactions (see table E-1 on the Neurology Web site at www.neurology.org ). On the first day of administration, fever was observed in 32 (33.3%) patients in the 50 µg group and 61 (63.5%) in the 250 µg group. After 6 months of treatment, the incidence of fever fluctuated between 10 and 20% of patients in both groups. During the entire study period, serious injection site reactions (necrosis or ulceration) were reported in 6/96 (6.3%) patients in the 50 µg group and 13/96 (13.5%) in the 250 µg group, and was assessed as severe in 2 cases (2.1%) in the 50 µg group and 6 cases (6.3%) in the 250 µg group. Withdrawals due to adverse events are displayed in figure 1. No deaths were reported during the study.

Abnormal changes in laboratory parameters occurred in 90.6% (87 cases) in the 50 µg group and 86.5% (83 cases) in the 250 µg group during the study period. Severe laboratory events were rare, transient, and did not lead to discontinuation of treatment in any of the patients except three in the 250 µg group and one in the 50 µg IFNB-1b group who discontinued treatment due to elevated GOT and GPT.

Discussion.
This randomized, double-blind clinical study of IFNB-1b performed in Asia comprised solely Japanese patients with RRMS. The study design was largely based on the preceding Phase III North American study of IFNB-1b in patients with RRMS.16

In light of the known treatment effects of IFNB-1b in RRMS,16,25 the use of a placebo control arm was considered inappropriate from an ethical viewpoint. Therefore, 50 µg IFNB-1b, which has been shown to be significantly superior to placebo in the North American study in RRMS, was used as an active treatment control. Although possible underestimation of the efficacy of the standard dose of 250 µg cannot be ruled out, two active treatment arms (50 µg and 250 µg IFNB-1b) were deemed adequate to demonstrate relative efficacy and provide further information on the dose-response relationship and safety of IFNB-1b. Moreover, adequate blinding was guaranteed by the absence of placebo arm, as some side effects of IFNB-1b such as flu-like symptoms and injection site reactions are well known.

Due to the much lower prevalence of MS in Japan,4,26–28 a substantially higher number of centers were required compared to the Phase III North American study in RRMS (85 vs 11). For this reason also, the range of age for inclusion was expanded.

The primary outcome measure in this study was annual relapse rate. Even though the efficacy of IFNB-1b 250 µg may be underestimated as a result of using IFNB-1b 50 µg as an active treatment control rather than placebo, a reduction in relapse rate was observed in the 250 µg treatment group, relative to the 50 µg treatment group over the 2-year study period (p = 0.047). Calculating these relapse rates using the method employed in the North American study in RRMS in order to compare the two studies (table 4) showed that the annual relapse rates for each dose group observed were nearly identical in the two studies,16 and were significantly lower in the 250 µg group compared to the 50 µg group. In the Japanese study, a reduction of 27% was observed in the 250 µg group relative to the 50 µg group, compared with 28% in the North American study in RRMS. Similarly, both studies demonstrated a reduction in the annual rate of moderate or severe relapses in patients receiving 250 µg IFNB-1b, although only a trend was observed in the present study.



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[Email Jumpstart To Image] Table 4 Comparison of efficacy in the Japanese and North American studies

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The time to first relapse was similar to that reported in the respective treatment groups of the North American study in RRMS, but did not reach statistical significance, possibly because of the smaller sample size. Irrespective of the smaller number of patients, however, the difference between the groups in the time to second relapse was statistically significant in Japanese patients. The median relapse duration in the 250 µg group was 7.1 days, which was shorter than 16.4 days in the 50 µg group (p = 0.030).

The MRI results corroborated the clinical results in terms of change in lesion area: changes of +2.4% and -16.3% (p = 0.035), consistent with the results of the North American study in RRMS (see table 4). Reproducibility assessment of MRI lesion area evaluations showed a very low mean variation coefficient (2.5%).

No significant changes in EDSS and NRS scores were seen, but this trial was not powered to detect any differences. In addition, the observation period of 2 years was too short to detect a difference between the two active treatment groups.

The data from this study indicate that the clinical and MRI effects of IFNB-1b are dependent on the dose administered, with greater benefit being seen at the higher dose, an observation consistent with that from other studies of IFNB. The original IFNB-1b dose finding study provided evidence for a dose-dependent biologic and clinical effect,29 while the pivotal North American study in RRMS of IFNB-1b provided evidence for dose effects on both clinical and MRI measures.16 There is also evidence for a dose-dependent effect for IFNB-1a therapy,19 and two recent comparative studies have provided further support for the importance of higher dose IFNB therapy. INCOMIN 30 and EVIDENCE 31 compared once weekly IFNB-1a with IFNB-1b EOD and IFNB-1a three times weekly, and demonstrated that the frequent, high dose therapy produced significant improvements in clinical and MRI outcomes compared to the lower dose, once weekly IFNB-1a.30,31 Furthermore, recent guidelines from the American Academy of Neurology for the treatment of MS 32 have also suggested that there is a dose-response curve associated with IFNB therapy, though whether this is due solely to dose, administration frequency, or a combination of both is currently not clear. Given that these observations in Japanese patients, whether they have C-MS or OS-MS, are consistent with those for white patients, it is reasonable to conclude that higher dose therapies are more effective in Japanese, as well as white, patients.

NAB positivity was observed in 29% of evaluable patients in the 50 µg group (13/45) and 16% of evaluable patients in the 250 µg group during treatment (7/44). Unfortunately, technical difficulties with the CPE assay, and the small number of patients evaluated, make it difficult to draw any conclusions from these observations. The CPE assay, which was also used in the North American study of IFNB-1b,16 is now deprecated in favor of the more rigorous MxA assay. Nevertheless, even sophisticated analyses using the MxA assay have failed to show consistent effects of NAB in other studies.31,33,34 NAB, which tends to develop early in treatment, are reported to have disappeared in almost all patients during the long-term treatment.35 The clinical relevance of NAB is therefore not well defined, and the broad consensus is that individual treatment decisions should be based on clinical measures of loss of efficacy, such as relapses or progression of disability.36

In this study the definitions of subtypes of MS were based solely on the neurologic findings. Brain MRI was not included, since objective MRI criteria have not yet been proposed for OS-MS. The majority of Japanese OS-MS patients show small subclinical brain MRI lesions during the disease course and some C-MS patients have no brain MRI lesions at the time of examination. After the initiation of this study, the presence of longitudinal spinal MRI lesions extending three or more segments was proposed as being diagnostic for NMO.37 However, this needs to be confirmed in Japanese OS-MS and was therefore not included in this study.

MS is a heterogeneous disease with a variety of subtypes and transitional cases.12,38 The questions of whether OS-MS represents a variant of MS common in Asians or is identical to relapsing NMO or represents an independent disease entity, separate from MS, are still subjects of debate. Japanese MS researchers and their Western collaborators have considered OS-MS as a variant of MS for years: the universal presence of the core findings of MS, relapsing remitting clinical course and perivascular inflammatory demyelinative lesions in the CNS, in OS-MS makes it unnatural to exclude this entity from MS.8,9,12,13,38,39 Most of the reported cases of relapsing NMO in white patients correspond well to severe cases but not to milder cases of OS-MS in Japanese. Various autoantibodies are reported to be frequently found in white NMO but occasionally in Japanese OS-MS.7

Given the current state of uncertainty, it was important to investigate the safety and efficacy of IFNB-1b in the subgroup of patients presenting with OS-MS in this cohort. The proportion of patients presenting with OS-MS (ca. 20%) was in line with previous studies (21 to 31%).11,40 Due to the relatively small numbers of patients with OS-MS the present study was not expected to be adequately powered to provide definitive comparison of treatment effects in OS-MS and C-MS. Differences in baseline characteristics between the OS-MS and C-MS patients were consistent with previous findings.

A comparative assessment of the efficacy and safety of IFNB-1b in patients with OS-MS and C-MS suggested that IFNB-1b treatment was equally effective in both MS presentations. In both the C-MS and OS-MS groups dose-dependent reductions in relapse rate were observed, with the larger reduction observed in the OS-MS group (39% vs 25%). Efficacy was seen irrespective of the possibly different pathogeneses and underlying genetic characteristics of patients with OS-MS. This study raises questions about the presumption, which is unsupported by any clinical trial evidence, that IFNB is ineffective in NMO variant. Further study of patients with this form of MS with better power will be necessary for a definitive conclusion about efficacy.

The range and occurrence of adverse events in this study did not differ from those reported in the North American study in RRMS 16 or those reported in other studies performed in Europe with IFNB-1b, in RRMS (e.g., INCOMIN 30) and secondary progressive MS.17 They are also consistent with those reported from studies with other commercially available beta interferons.18,19

Flu-like symptoms were one of the more frequently occurring adverse events in both treatment groups, with a higher frequency of occurrence in the 250 µg group.16 The incidence of flu-like symptoms was not higher in Japanese patients in this study (mean body weight: 55 kg) compared to the overwhelmingly white cohort of the North American study in RRMS (mean body weight: 69 to 70 kg). There were no significant group differences for injection site events during the whole study period of 2 years, which were reported less frequently in the present study, i.e., in 51 (53.1%) patients in the 50 µg group and 52 (54.2%) patients in the 250 µg group, compared to approximately 80% of patients in both active treatment arms of the North American study in RRMS. Headache was also reported considerably less frequently in Japanese patients (72/192, 37.5%) than in the North American study in RRMS (approximately 80%).

Clinically significant laboratory abnormalities were rare: only three patients in the 250 µg and one patient in the 50 µg IFNB-1b group discontinued treatment due to elevated GOT and GPT.

Treatment with 250 µg IFNB-1b administered SC significantly reduces the relapse rate and change in MRI lesion area in Japanese RRMS patients. The annual relapse rates in Japanese and white patients were nearly identical during treatment. IFNB-1b is safe and well tolerated in this Japanese population, again with results comparable to those reported in white patients. It was also suggested that IFNB-1b is effective in the treatment of OS-MS as well as C-MS. The similar responses to treatment with IFNB-1b indicate that Japanese MS patients may have a common pathogenesis and underlying genetic characteristics shared with white patients. This study demonstrates the benefits of IFNB in a different race, which is likely to have different genetic influences on the development and course of MS.

Acknowledgment
The authors thank the clinical staff personnel at the participating institutions, the clinical/statistical departments of Nihon Schering K.K., and the MS patients for their participation.

Appendix
Investigators: Hokkaido University, School of Medicine—Tashiro K, MD. Moriwaka F, MD. Kikuchi S, MD. Miyagishi R, MD. Fukaura H, MD. Hokuyukai Neurology Hospital—Hamada T, MD. Fukazawa T, MD. Sapporo Medical University—Matsumoto H, MD. Chiba S, MD. Imai T, MD. Kobayashi N, MD. Sapporo Minami National Hospital—Shima K, MD. Doi S, MD. Minami N, MD. Oikawa O, MD. Suzuki K, MD. Nogoshi S, MD. Hakodate Municipal Hospital—Maruo Y, MD. Hirosaki University, School of Medicine—Matsunaga M, MD. Aomori Prefectural Central Hospital—Kurahashi K, MD. Akita Red Cross Hospital—Hirota K, MD. Ishiguro H, MD. Makino K, MD. Shimohata T, MD. Terashima K, MD. Research Institute for Brain and Blood Vessels–AKITA—Hirata Y, MD. Watahiki Y, MD. Yamagata University, School of Medicine—Sasaki H, MD. Yamatani K, MD. Kato T, MD. Kurita K, MD. Tohoku University, School of Medicine—Itoyama Y, MD. Fujihara K, MD. Sekizawa T, MD. Kohnan Hospital—Takase S, MD. Nomura H, MD. Okita N, MD. Konno H, MD. Seki H, MD. National Miyagi Hospital—Mochizuki H, MD. Hisanaga K, MD. Tobita M, MD. Fujii R, MD. Fukushima Medical University—Yamamoto T, MD. Tsukamoto T, MD. Shimizu S, MD. Honma M, MD. Muroi A, MD. Ogata M, MD. Gunma University School of Medicine—Hirai S, MD. Okamoto K, MD. Tanaka M, MD. Shoji M, MD. Nippon Medical School—Terashi A, MD. Kitamura S, MD. Katayama Y, MD. Toho University School of Medicine—Kinoshita M, MD. Segawa F, MD. Ikeda K, MD. Toranomon Hospital—Takagi A, MD. Nakase H, MD. Ida M, MD. Uesaka Y, MD. Toranomon Branch Hospital—Nakase H, MD. Watanabe T, MD. Faculty of Medicine, University of Tokyo—Kanazawa I, MD. Sakurai M, MD. Goto J, MD. Okazawa H, MD. Kaku S, MD. Jikei University School of Medicine—Inoue K, MD. Mochio S, MD. Honda H, MD. Oka H, MD. Hasegawa S, MD. Sato H, MD. Matsui K, MD. School of Medicine, Keio University—Fukuuchi Y, MD. Koto A, MD. Tokyo Medical College—Utsumi H, MD. Harukawa H, MD. Masuda M, MD. Kobayashi T, MD. Juntendo University, School of Medicine—Mizuno Y, MD. Miwa H, MD. Mori H, MD. Hirabayashi K, MD. Urabe T, MD. Tokyo Medical and Dental University, School of Medicine—Kobayashi T, MD. Mizusawa H, MD. Yamada M, MD. Wada Y, MD. Yokota T, MD. Kanto Teishin Hospital—Tamaki M, MD. Arasaki K, MD. Tokyo Women’s Medical University, School of Medicine—Iwata M, MD. Ota K, MD. Musashino Red Cross Hospital—Watabiki S, MD. Shimokawa M, MD. National Center Hospital of Neurology and Psychiatry Musashino Hospital—Sunohara N, MD. Ogawa M, MD. Showa General Hospital—Uchigata M, MD. Sano M, MD. Tokyo Metropolitan Neurological Hospital—Tanabe H, MD. Yagi K, MD. Tokyo Metropolitan Hospital of Fuchu—Yagi K, MD. University of Tsukuba, School of Medicine—Shoji S, MD. Tamaoka A, MD. Ohkoshi N, MD. Dokkyo University School of Medicine—Katayama S, MD. Hirata K, MD. Miyamoto M, MD. Jichi Medical School—Nishizawa M, MD. School of Medicine, Chiba University—Yamada T, MD. Hattori T, MD. Yoshiyama Y, MD. Kawaguchi N, MD. Matsudo Municipal Hospital—Kojima S, MD. Kameda General Hospital—Maki T, MD. Shibayama H, MD. Kameda Clinic—Maki T, MD. Shibayama H, MD. Kohnodai Hospital, National Center of Neurology and Psychiatry—Sato T, MD. Yoshino H, MD. Juntendo University, Urayasu Hospital—Tanaka S, MD. Omiya Red Cross Hospital—Okayama K, MD. Hoshino M, MD. Kubo H, MD. Saitama Medical School—Hamaguchi K, MD. Ohno R, MD. Nomura K, MD. Tomioka R, MD. Yokohama Rosai Hospital—Inoue K, MD. Kunimoto M, MD. St. Marianna University School of Medicine—Kawakami M, MD. Sato T, MD. Arai Y, MD. Tochigi S, MD. Maebara S, MD. School of Medicine, Kitasato University—Kowa H, MD. Saito T, MD. Ito H, MD. Okamiya S, MD. School of Medicine, Tokai University—Shinohara Y, MD. Yoshii F, MD. Takahashi W, MD. Juntendo University, Izunagaoka Hospital—Yamamoto T, MD. Shinshu University, School of Medicine—Yanagisawa N, MD. Koh CS, MD. Yamazaki M, Inoue A, MD. Fushimi T, MD. Niigata University, School of Medicine—Tsuji S, MD. Inuzuka T, MD. Hozumi I, MD. Tanno Y, MD. Sato M, MD. Ishikawa M, MD. Niigata City General Hospital—Onishi Y, MD. Yamazaki M, MD. Kawachi I, MD. National Sanatorium Nishi-Niigata Chuo Hospital—Tanaka M, MD. Tsubame Rosai Hospital—Motegi T, MD. Watanabe H, MD. National Saigata Hospital—Fukuhara N, Nakajima T, MD. Ozawa T, MD. Furui E, MD. Hayashi T, MD. Nagaoka Red Cross Hospital—Suzuki M, MD. Fujita N, MD. Nagai H, MD. Tabe H, MD. Kimura T, MD. Endo K, MD. National Shizuoka Hospital—Nishimura Y, MD. Mizoguchi K, MD. Obi T, MD. Serizawa M, MD. Kurita R, MD. Sugimoto M, MD. Hamamatsu Rosai Hospital—Aii H, MD. Tokonami F, MD. Ohtuka K, MD. Nakamizo T, MD. Takaoka Koseiren Hospital—Takado M, MD. School of Medicine, Kanazawa University—Takamori M, MD. Nitta E, MD. Yamaguchi K, MD. Kanazawa Medical University—Hirose G, MD. Sakai K, MD. Yoshioka A, MD. Kawada J, MD. Shirakawa T, MD. Nagoya University, School of Medicine—Sobue G, MD. Nagamatsu M, MD. Niwa H, MD. Kawai K, MD. Wakai M, MD. Medical School, Nagoya City University—Ojika K, MD. Ueda R, MD. Mitake S, MD. Tsugu Y, MD. Nagoya National Hospital—Takegami T, MD. Mukai E, MD. Hasegawa Y, MD. Kato C, MD. Hasegawa S, MD. Kawata T, MD. Mori K, MD. Aichi Medical University—Mitsuma T, MD. Terao S, MD. Fujita Health University School of Medicine—Yamamoto H, MD. Koga H, MD. Nomura M, MD. Chubu National Hospital—Kachi T, MD. Yamada T, MD. Mie University, School of Medicine—Kuzuhara S, MD. Narita Y, MD. Masuzugawa S, MD. Murai K, MD. Niwa A, MD. Sato M, MD. Kokubo Y, MD. Matsusaka Chuo Hospital—Watanabe Y, MD. Komada S, MD. Kondo M, MD. Kyoto University, Faculty of Medicine—Kimura J, MD. Nakamura S, MD. Kinoshita M, MD. Utano National Hospital—Saida T, MD. Ozawa K, MD. Nishimura M, MD. Saida K, MD. Tenri Hospital—Hashimoto S, MD. Suenaga T, MD. Takahashi K, MD. Kanki R, MD. Asahara (Nakano) H, MD. Matsuhashi M, MD. Nara Medical University—Takayanagi T, MD. Suzumura A, MD. Tazuke-Kofukai Kitano Hospital—Imai T, MD. Matsumoto S, MD. Shiomi K, MD. Kusaka H, MD. Osaka University Faculty of Medicine—Yanagihara T, MD. Abe K, MD. Sakota S, MD. Fujimura H, MD. Osaka Medical Center for Cancer and Cardiovascular Diseases—Matsubara T, MD. Azuma T, MD. Funauchi M, MD. Nagai Y, MD. Osaka Prefectural General Hospital—Nakata T, MD. Naka T, MD. Hazama T, MD. Hattori N, MD. Okuno T, MD. The Kansai Electric Power Company Incorporated Hospital—Kawanishi T, MD. Doi T, MD. Labor Welfare Corporation Wakayama Rosai Hospital—Ishimoto S, MD. Shimoya K, MD. Kobe University School of Medicine—Chihara K, MD. Kanda F, MD. Kobe City General Hospital—Kawamura J, MD. Yoshikawa N, MD. Takatsuka K, MD. Ohga T, MD. Kawamoto M, MD. Araki M, MD. Takano M, MD. Hyogo Prefectural Amagasaki Hospital—Ichikawa K, MD. Kageyama Y, MD. Hoshino M, MD. Okayama University, Medical School—Shomori T, MD. Kohira I, MD. Kashihara K, MD. National Sanatorium Minami-Okayama Hospital—Namba R, MD. Nobukuni K, MD. Takada H, MD. Kawasaki Medical School—Terao A, MD. Funakawa I, MD. Hiroshima University School of Medicine—Nakamura S, MD. Kohriyama T, MD. Hiroshima City Hospital—Yoshinaga J, MD. Nakamura Y, MD. Miyata S, MD. Endo S, MD. Kikumoto O, MD. Hiroshima Red Cross and Atomic-Bomb Survival Hospital—Ohta M, MD. Ohori N, MD. Tottori University, Faculty of Medicine—Nakashima K, MD. Araga S, MD. Kishimoto M, MD. Takai H, MD. Doi S, MD. Yamaguchi University, School of Medicine—Morimatsu M, MD. Nogaki H, MD. Negoro K, MD. Nishimura Y, MD. Kagawa Prefectural Central Hospital—Yamamoto M, MD. Faculty of Medicine, Kyushu University—Kobayashi T, MD. Kira J, MD. Labor Welfare Corporation Kyushu Rosai Hospital—Miyoshi T, MD. Tamura K, MD. Motomura S, MD. Kikuchi H, MD. Saga Medical School—Kuroda Y, MD. Matsui M, MD. Sato J, MD. National Sanatorium Chikugo Hospital—Iwashita H, MD. Koike F, MD. Iizuka Hospital—Fujii N, MD. Nagasaki University, School of Medicine—Nagataki S, MD. Nakamura T, MD. Furuya T, MD. Nagasaki-Chuo National Hospital—Mori M, MD. Kawatana National Hospital—Shibuya N, MD. Fujishita S, MD. Ichinose K, MD. Matsuo H, MD. Ohtsuru I, MD. Tsushima Izuhara Hospital—Makise T, MD. Oita Medical University—Tsuda T, MD. Kumamato T, MD. Ueyama H, MD. Oita Prefectural Hospital—Nagamatsu K, MD. Hokezu Y, MD. Miyazaki Medical College—Matsukura S, MD. Ohi T, MD. Sugimoto S, MD. Miyauchi K, MD. Faculty of Medicine, Kagoshima University—Osame M, MD. Usuku K, MD. Arimura K, MD.

Chief Advisor: Aichi Pref. Foundation for Promotion of Healthy Life—Igata A, MD.

External Evaluation Committee: Aichi Pref. Foundation for Promotion of Healthy Life—Igata A, MD.

Neurological Score Evaluation Committee: Hokkaido University, School of Medicine—Tashiro K, MD. Fukaura H, MD. Miyagishi R, MD. Hokuyukai Neurology Hospital—Fukazawa T, MD. [Context Link]

References
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3. Shibasaki H, Kubo N, Nishitani H, et al. Nationwide survey of multiple sclerosis in Japan: reappraisal of clinical features. J Tropical Geographical Neurol 1992;2:73–82. [Context Link]

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5. Kira J, Kanai T, Nishimura Y, et al. Western versus Asian types of multiple sclerosis: immunogenetically and clinically distinct disorders. Ann Neurol 1996;40:569–574. Bibliographic Links [Context Link]

6. Kira J, Yamasaki K, Horiuchi I, Ohyagi Y, Taniwaki T, Kawano Y. Changes in the clinical phenotypes of multiple sclerosis during the past 50 years in Japan. J Neurol Sci 1999;166:53–57. Full Text Bibliographic Links [Context Link]

7. Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol 2003;2:117–127. Full Text Bibliographic Links [Context Link]

9. Ikuta F, Koga M, Takeda S, et al. Comparison of MS pathology between 70 American and 75 Japanese autopsy cases. In: Kuriowa Y, Kurland LT, eds. Multiple sclerosis East and West. Fukuoka: Kyusyu University Press, 1982;298–306. [Context Link]

11. Nakashima I, Fujihara K, Itoyama Y. Oligoclonal IgG bands in Japanese multiple sclerosis patients. J Neuroimmunol 1999;101:205–206. Full Text Bibliographic Links [Context Link]

13. Seitelberger F. Comparative neuropathology of Oriental and Western multiple sclerosis cases. In: Kroiwa Y, Kurland LT, eds. Multiple sclerosis East and West. Fukuoka: Kyusyu University Press, 1982;273–295. [Context Link]

15. Weinshenker BG, Fujihara K, Pittock SJ, et al. The Asian optic-spinal form of multiple sclerosis is the same entity as neuromyelitis optica in Caucasians: insights from a novel serum marker. Neurology 2004;62(suppl 5):A480–A481. [Context Link]

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19. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352:1498–1504. Full Text [Context Link]

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25. IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 1995;45:1277–1285. Bibliographic Links [Context Link]

27. Kurtzke JF. A reassessment of the distribution of multiple sclerosis. Part one. Acta Neurol Scand 1975;51:110–136. Bibliographic Links [Context Link]

29. Knobler RL, Greenstein JI, Johnson KP, et al. Systemic recombinant human interferon-beta treatment of relapsing-remitting multiple sclerosis: pilot study analysis and six-year follow-up. J Interferon Res 1993;13:333–340. Bibliographic Links [Context Link]

31. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002;59:1496–1506. Ovid Full Text Bibliographic Links [Context Link]

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Matt



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PostPosted: Wed Nov 29, 2006 11:39 am    Post subject: Reply with quote

I can't seem to find agate's article. Is this an abstract ahead of print? The Journal of neurological sciences is out of Turkey, so it might even be in Turkish. But, I will try again at a later date.
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agate
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PostPosted: Wed Nov 29, 2006 3:38 pm    Post subject: Reply with quote

Matt, here's the link to the PubMed listing:

http://tinyurl.com/yedukq

It says "Epub ahead of print," and so I assume that it isn't in print yet.

Thanks for posting the article!

LeeAnn
, you're doing just fine. It's very easy to omit details from these postings of abstracts!
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PostPosted: Wed Jan 31, 2007 3:13 pm    Post subject: NEW ASSISTANCE PROGRAM FOR THOSE ON BETASERON Reply with quote

From the MS Foundation newsletter, 1/31/07:

Quote:
NEW ASSISTANCE PROGRAM FOR THOSE ON BETASERON

Berlex has launched a new Patient Assistance Program to help ensure that Betaseron® (interferon beta-1b) is available to people with MS who, after exhausting all other avenues of coverage and assistance, cannot otherwise afford it.

The Betaseron Patient Assistance Program replaces the Betaseron Foundation, which ceased operations at the end of 2006. All participants who were active in the Betaseron Foundation at the end of 2006 who continue to meet the eligibility criteria will be transitioned into the new program. Enrollment is also available to new participants.

Similar to the Betaseron Foundation, participants in the new Betaseron Patient Assistance Program will:

* Receive assistance in the form of medication
* Pay a participation fee for the program
* Meet eligibility based on financial and other relevant criteria
* Reapply for assistance every year

Participants will also receive medication training, access to live nursing support (24/7), reimbursement counseling, and other services offered through the MS Pathways program.

To learn more, please contact the Betaseron Patient Assistance Program at
877-836-5724.
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agate
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PostPosted: Sun Mar 11, 2007 6:14 pm    Post subject: (Abstract) Effects of immediate vs. early onset of Betaseron Reply with quote

Scheduled for the upcoming AAN conference in May:

Quote:
Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT): Effects of Immediate vs. Early Onset of Interferon Beta-1b Treatment

Mark S. Freedman, Ottawa, Canada, Chris Polman, Ludwig Kappos, Basel, Switzerland, Gilles Edan, Rennes, France, Hans-Peter Hartung, Duesseldorf, Germany, David Miller, London, United Kingdom, Xavier Montalban, Barcelona, Spain, Frederik Barkhof, Amsterdam, Netherlands, Lars Bauer, Susanne Dahms, Christoph Pohl, Rupert Sandbrink, Berlin, Germany

OBJECTIVE: To evaluate the impact of immediate vs. delayed initiation of interferon beta (IFNB) therapy for the first event suggestive of MS.

BACKGROUND: The BENEFIT follow-up study is the first prospectively planned, controlled, multicenter trial to address the impact of randomly assigned immediate vs. later initiation of interferon beta (IFNB) therapy at the time of a CIS[clinically isolated syndrome] on further evolution of MS.

DESIGN/METHODS: In the double-blind BENEFIT study, 468 CIS patients with magnetic resonance imaging (MRI) findings suggestive of MS were treated with IFNB-1b 250 mcg (n=292) or placebo (n=176) sc eod until either a diagnosis of clinically definite MS (CDMS) was attained or they reached two years of evaluation. At this point they were eligible to enter a pre-planned, open-label, follow-up study and were offered IFNB-1b for up to five years after start of the double-blind treatment.

RESULTS: A total of 437 patients were eligible for the follow-up study and 418 (96%) have been enrolled, comprising 261 (96%) formerly IFNB-1b-treated and 157 (94%) placebo-treated patients. In the follow-up study, 95% of patients agreed to receive IFNB-1b; the remainder agreed to be monitored but not receive IFNB-1b. All patients have recently completed a three-year observation period after start of the double-blind study. An interim analysis of the follow-up study will evaluate the effects of immediate (patients originally assigned to IFNB-1b) vs. later (patients originally assigned to placebo) IFNB-1b treatment after a total study duration of three years. Effects on clinical (e.g. time to CDMS) and paraclinical endpoints (e.g. cumulative number of newly active lesions on brain MRI over time) will be presented.

CONCLUSIONS/RELEVANCE: The results will provide valuable data on the impact of immediate vs. delayed treatment with IFNB-1b treatment on disease evolution in patients with a CIS suggestive of MS.

Supported by: Schering AG, Germany.

Tuesday, May 1, 2007 2:45 PM
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PostPosted: Fri Mar 16, 2007 2:40 pm    Post subject: (Abstract) Interferon beta in SPMS... Reply with quote

From PubMed, 3/16/07:

Quote:
J Neurol. 2007 Mar 14

Interferon beta in secondary progressive multiple sclerosis : Daily clinical practice

Rio J, Tintore M, Nos C, Tellez N, Galan I, Pelayo R, Montalban X.
2 feminine planta EUI, Unitat de Neuroimmunologia Clinica, Hospital Universitario Vall d'Hebron, Psg Vall d'Hebron 119-120, 08035, Barcelona, Spain, jrio@vhebron.net.

BACKGROUND AND OBJECTIVE: Observational studies may provide additional information about the behaviour of different drugs in the post-marketing period. We present the data from a cohort of secondary progressive multiple sclerosis (SPMS) patients treated with interferon beta (IFNss-1b) at our MS clinic.

METHODS: This was an independent, open-label, non-randomised, observational study. Within the period 1998 to 2005, all patients with SPMS who started therapy with IFNss-1b at our centre were studied. Each patient was included in a follow-up protocol collecting demographic and baseline clinical data.

RESULTS: We studied 146 SPMS patients with a median follow-up of 60 months. Over the total study period, 62.2% of patients had confirmed progression. The analysis of the time to confirmed progression showed that patients with two or more relapses in the 2 years before IFNbeta initiation, had a higher risk of disability increase than those patients with less than two relapses (p = 0.002). Multiple regression analysis showed disease activity in terms of relapses as the only factor to predict increase of disability during the follow-up period. A significant proportion of patients (36%) stopped treatment during the follow-up period. IFNbeta was safe, although some unexpected adverse events were observed.

CONCLUSIONS: A higher disease activity before the beginning of treatment with IFNbeta in SPMS patients with a given EDSS rank could identify those with faster disability progression after treatment initiation.

PMID: 17361342
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PostPosted: Tue May 08, 2007 2:32 pm    Post subject: (Abstract) Panniculitis & IFN-beta vascular toxicity Reply with quote

From PubMed, May 8, 2007:

Quote:
Ann Dermatol Venereol. 2007 Apr;134(4):374-7

[Panniculitis induced by interferon beta vascular toxicity]

[Article in French]

Soria A, Maubec E, Henry-Feugeas MC, Marinho E, Le Bozec P, Huisse MG, Pocidalo MA, Descamps V, Crickx B.
Service de Dermatologie, Hopital Bichat, Assistance Publique Hopitaux de Paris, Universite Paris 7-Denis-Diderot.

BACKGROUND: Interferon-beta-1b is a valuable first-line therapy for patients with relapsing-remitting multiple sclerosis. Many non-severe cutaneous reactions to recombinant interferon beta are described at injection sites. Panniculitis after subcutaneous injection of beta interferon is a rare adverse event; we describe two such cases at beta interferon injection sites.

CASE-REPORTS:
Two women aged 22 years and 45 years with severe multiple sclerosis receiving immunotherapy with beta interferon were admitted to an emergency department following the appearance of extremely painful induration at injection sites rendering walking impossible after several months of interferon injections. One of the patients had fever. Histology tests showed vasculitis and capillary thrombosis in one-woman and dermal oedema in the other. MRI scanners showed extensive avascular necrosis of soft tissue without fasciitis in both patients. Interferon withdrawal and surgical debridement was carried out in one case and beta interferon was successfully reintroduced in both cases.

DISCUSSION: Only two cases of panniculitis induced by subcutaneous beta interferon injection have been reported. Clinically, such cases may mimic infectious processes. The present cases show that MRI may be useful in diagnosis and that the vascular toxicity of interferon beta probably plays a role in panniculitis. Temporary withdrawal of treatment, rotation of several injection sites and alternative routes of administration may all be proposed.

PMID: 17483759
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PostPosted: Thu Aug 02, 2007 5:25 pm    Post subject: (Abstract) NABs to Betaseron in MS patients over 3 years Reply with quote

Quote:
From PubMed, August 2, 2007:

Quote:
Clin Exp Immunol. 2007 Jul 30

A case study of the effect of neutralizing antibodies to interferon beta 1b in multiple sclerosis patients followed for 3 years with monthly imaging

Chiu AW, Ehrmantraut M, Richert ND, Ikonomidou VN, Pellegrini S, McFarland HF, Frank JA, Bagnato F.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

Interferon beta (IFN-beta) is among the first-line treatment options for patients with multiple sclerosis (MS). A potential caveat of therapy, however, is the development of neutralizing antibodies (NAb) and/or neutralizing activity (NA) non-antibody mediated, although debate is still ongoing as to whether NAb significantly hampers the efficacy of the drug or rather represents an immunologically irrelevant epiphenomenon.

In the present study, we describe the effect of NAb on IFN-beta-1b through clinical and magnetic resonance imaging (MRI) outcome measures of five relapsing-remitting multiple sclerosis (RRMS) patients who were treated with 250 mug of subcutaneously administered IFN-beta-1b every other day and developed NAb at varying titres and times during the course of therapy. Despite the small number of NAb(+) patients, heterogeneity in MRI/clinical response to IFN-beta-1b was identified. Response to IFN-beta-1b therapy was observed in the absence or presence of NAb.

Also observed was failure to IFN-beta-1b coincident with high and sustained NAb titres, but also before NAb development or in the presence of low NAb titres. Multiple MRI and NAb measurements performed within the same individual allow for a better description of the complex heterogeneous response to IFN-beta-1b with respect to NAb occurrence.

PMID: 17666095
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PostPosted: Fri Aug 03, 2007 2:21 pm    Post subject: (Abstract) Lupus panniculitis induced by Betaseron... Reply with quote

From PubMed, August 3, 2007:

Quote:
J Clin Neurosci. 2007 Jul 30

Lupus erythematosus profundus (lupus panniculitis) induced by interferon-beta in a multiple sclerosis patient

Gono T, Matsuda M, Shimojima Y, Kaneko K, Murata H, Ikeda SI.
Department of Internal Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

We report a patient with multiple sclerosis (MS) who developed subcutaneous nodules on the face, shoulders and extremities while being treated with interferon (IFN)-beta-1b. These nodules fluctuated in parallel with myelopathy, and were diagnosed as lupus erythematosus profundus (LEP) based on histopathological findings. The patient showed no relapse of either neurological symptoms or subcutaneous nodules after cessation of IFN-beta-1b.

This agent can cause induration and necrosis in the sites of injection but also systemic skin lesions such as LEP ascribable to its immunomodulatory effects.

PMID: 17669654
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PostPosted: Tue Aug 07, 2007 1:40 pm    Post subject: (Abstract) Early vs. delayed Betaseron treatment... Reply with quote

From PubMed, August 7, 2007:

Quote:
Lancet. 2007 Aug 4;370(9585):389-97

Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study

Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü EW, Bauer L, Dahms S, Lanius V, Pohl C, Sandbrink R; for the BENEFIT Study Group.
University Hospital, Basel, Switzerland.

BACKGROUND: Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS.

METHODS
: In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 mug (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study.

The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI).

This trial is registered with ClinicalTrials.gov, number NCT00185211.

FINDINGS: Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31).

INTERPRETATION
: Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

PMID: 17679016
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PostPosted: Mon Sep 03, 2007 2:21 pm    Post subject: (Article) Caution urged in early MS treatment Reply with quote

More about the BENEFIT study, from WebMD, September 3, 2007:

Quote:
Caution Urged in Early MS Treatment

Too Soon for 'Treat-All' Approach to Multiple Sclerosis?


By Daniel J. DeNoon
WebMD Medical News

Reviewed by Louise Chang, MD

Aug. 2, 2007 -- A new study shows that early treatment for multiple sclerosis cuts the risk of disability. But some experts say it's too soon to take a "treat-all approach" to MS.

The international BENEFIT study tested a current trend -- giving MS treatments to patients at the first sign of what might be MS. The study showed that early treatment with Betaseron, one of three forms of beta-interferon approved for MS, cut the three-year risk of disability by 41% compared with delayed treatment.

However, patients who got early treatment only reduced their overall three-year risk of disability by 14%. The final report on the study appears in the Aug. 4 issue of The Lancet. Accompanying the study is an editorial by Mayo Clinic MS expert Sean J. Pittock, MD.

The benefits seen in the BENEFIT study were "modest," Pittock writes. He notes that 12 patients would have to be treated with Betaseron -- beginning at the first sign of MS -- to protect one patient from worsening disability.

Pittock notes that the BENEFIT trial does show, for the first time, that early beta-interferon treatment has a "beneficial effect on accumulation of confirmed disability in patients with a first event suggestive of multiple sclerosis."

But he warns against over-optimistic interpretation of the findings.

"The results should be interpreted with care because the magnitude of benefit, although statistically significant, is clinically small," Pittock writes. The study findings "should not be misconstrued as evidence for a treat-all approach."

In a 2004 study, Pittock and colleagues found that some patients have "benign MS" that does not progress to ever greater levels of disability. Pittock and colleagues suggested that this argues against aggressive early treatment for all MS patients.

Pittock and colleagues, however, may be bucking a trend. The new findings mean it's time to start treatment when you've had a single MS-like event, says BENEFIT researcher Mark S. Freedman, MD, FRCPC, director of the MS research center at the University of Ottawa, Ontario, Canada.

"The first paradigm shift came at the end of the '90s, when we learned that waiting for an MS relapse is too late and we started treating MS at the time of diagnosis," Freedman told WebMD in May. "Now we see you have to start when you think you have MS. This is the new paradigm shift in MS treatment."

Robert Fox, MD, medical director of Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research, agrees with Freedman.

"We have finally shown that treating MS super early can have a significant impact on the development of disability, which is what patients are most worried about," Fox told WebMD in May.



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PostPosted: Mon Sep 10, 2007 2:14 pm    Post subject: (Abstract) MRI effects of Betaseron in BENEFIT study Reply with quote

From Archives of Neurology, September 9, 2007:

Quote:
Vol. 64 No. 9, September 2007


Magnetic Resonance Imaging Effects of Interferon Beta-1b in the BENEFIT Study

Integrated 2-Year Results

Frederik Barkhof, MD, PhD; Chris H. Polman, MD, PhD; Ernst-Wilhelm Radue, MD; Ludwig Kappos, MD; Mark S. Freedman, MD; Gilles Edan, MD; Hans-Peter Hartung, MD; David H. Miller, MD; Xavier Montalbán, MD; Peter Poppe, MD; Marlieke de Vos, MSc; Fatiha Lasri, MD; Lars Bauer, MD; Susanne Dahms, PhD; Klaus Wagner, MD; Christoph Pohl, MD; Rupert Sandbrink, MD, PhD


Arch Neurol. 2007;64:1292-1298.

Background

In the Betaseron/Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, interferon beta-1b delayed conversion to multiple sclerosis in patients with a first clinical event and at least 2 clinically silent brain magnetic resonance imaging (MRI) lesions.

Objective


To examine detailed MRI findings from the first 2 years of this trial.

Design

Double-blind, placebo-controlled, randomized, parallel-group, multicenter, phase 3 study.

Setting

Ninety-eight centers worldwide.

Patients

A total of 404 individuals with a first demyelinating event suggestive of multiple sclerosis.

Interventions

Patients were randomized to receive interferon beta-1b, 250 µg subcutaneously every other day, or placebo. After 24 months of treatment or on conversion to clinically definite multiple sclerosis, open-label interferon beta-1b treatment was offered.

Main Outcome Measures

Reported MRI data from patients completing 2 years of follow-up.

Results


Data were analyzed from 248 patients taking interferon beta-1b and 156 taking placebo. Across 2 years the cumulative number of newly active lesions was lower in patients receiving interferon beta-1b vs placebo (median, 2.0 vs 5.0 [reduction of 60%]; P < .001). This corresponded to lower cumulative numbers of new T2 lesions (median, 1.0 vs 3.0 [reduction of 66%]; P < .001) and new gadolinium-enhancing lesions (median, 0.0 vs 1.0; P < .001) in patients receiving interferon beta-1b vs placebo. From screening to month 24, T2 lesion volume decreased and was more pronounced in patients receiving interferon beta-1b (P = .02).

Conclusions

Interferon beta-1b treatment had a robust effect on MRI measures, supporting its value as an early intervention in this patient group. This effect was maintained despite including patients who switched from placebo to interferon beta-1b in the active treatment group.

Trial Registration clinicaltrials.gov Identifier: NCT00185211


Author Affiliations: Departments of Diagnostic Radiology (Drs Barkhof, Poppe, and Lasri and Ms de Vos) and Neurology (Dr Polman), Vrije Universiteit Medical Center, Amsterdam, the Netherlands; Department of Neurology and Neurosurgery, University Hospital Basel, Basel, Switzerland (Drs Radue and Kappos); Multiple Sclerosis Research Unit, The Ottawa Hospital, Ottawa, Ontario, Canada (Dr Freedman); Department of Neurology, Centre Hospitalier Universitaire, Rennes, France (Dr Edan); Department of Neurology, Heinrich-Heine-Universität, Düsseldorf, Germany (Dr Hartung); Institute of Neurology, University College London, London, England (Dr Miller); Unit of Clinical Neuroimmunology, Hospital Vall d'Hebron, Barcelona, Spain (Dr Montalbán); Bayer Schering Pharma AG, Berlin, Germany (Drs Bauer, Dahms, Wagner, Pohl, and Sandbrink); and Department of Neurology, University Hospital, Bonn, Germany (Dr Pohl).




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PostPosted: Thu Oct 18, 2007 2:47 pm    Post subject: (Abstract) Slowing cerebral atrophy in Betaseron SPMS trial Reply with quote

From the ECTRIMS conference in Prague, October 11-14, 2007:

Quote:
Immunomodulation 1

Friday, October 12, 2007, 15:30 - 17:00

Slowing of cerebral atrophy after year 1 in a placebo-controlled trial of interferon beta 1b in secondary progressive multiple sclerosis

D.H. Miller, D. MacManus, A.J. Thompson, L. Kappos, F Barkhof, C.H. Polman, K. Wagner, R. Sandbrink, K. Beckmann, C. Pozzilli, V. Santana, G.J. Barker (London, UK; Basel, CH; Amsterdam, NL; Berlin, D; Rome, I)

Background:

The European placebo-controlled trial of interferon beta-1b (IFNB-1b) in secondary progressive MS (EUSPMS) reported beneficial effects on relapse rate and disability1. There was no significant slowing of cerebral atrophy in a substudy of a minority of subjects who had T1-weighted scans2. The cohort may have been too small to detect a significant effect on the cerebral volume measure.

Aim:

To investigate brain atrophy changes in the EUSPMS trial in a larger cohort using dual-echo images.

Method:

All 718 study subjects were scheduled to have annual dual-echo T2-weighted brain MRI. “Pseudo-T1” weighted images (with dark CSF, and good brain/CSF contrast) were created by subtracting the longer from the shorter echo scan. An automated MIDAS segmentation procedure was applied to 4 contiguous 5mm thick slices from the velum interpositum rostrally. A trained analyst defined the slice levels chosen and edited minor segmentation errors. The MRI analysis was blinded to subject study arm.

Results:

Satisfactory images and segmentations were achieved at baseline and on at least one follow-up scan in 198 placebo- and 195 IFNB-1b treated patients. Significant atrophy was seen over 3 years in both study arms (p<0.0001 in both arms). In year 1, there was greater atrophy in IFNB-1b treated patients (median -0.80% vs -1.20%,.,p=0.005, non-parametric ANCOVA, adjusted for baseline volume). From year 1 to year 3, there was significantly more atrophy in placebo-treated patients (median -2.00% vs. -1.35%, p=0.032). The difference in favour of IFNB-1b was significant between years 1 and 2 (median -1.20% vs. -0.70%, p=0.023) but not between years 2 and 3 (medians -0.80% in both groups).

Conclusion:

Quantitative cerebral volumes can be measured from conventional dual-echo T2-weighted images. The increased loss of brain volume after year 1 in placebo patients indicates a favourable effect of interferon beta-1b treatment on the rate of atrophy development in MS patients. Increased loss of cerebral volume in year 1 in IFNB-1b-treated patients may reflect resolution of pre-existing inflammation accompanied by a reduction in new inflammatory lesions3. The decrease in new inflammatory lesions also might reduce axonal transaction and loss, which in turn may contribute to the decreased atrophy seen after year 1 in IFNB-1b treated patients.

1.EUSPMS Study Group. Lancet 1998;352:14917.
2.Molyneux PD, et al. Brain 2001;123:2256-63.
3.Miller DH, et al Ann Neurol 1999;46 :850-59.

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PostPosted: Thu Oct 18, 2007 6:32 pm    Post subject: (Abstract) Betaseron therapy over 3 yrs. ... Reply with quote

From the ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) conference in Prague, October 11-14, 2007:

Quote:
Adherence, tolerability and quality of life: Betaferon® therapy over 3 years in patients with a first event suggestive of multiple sclerosis

G. Edan, M.S. Freedman, H-P. Hartung, L. Kappos, D.H. Miller, X. Montalbán, C.H. Polman, L. Bauer, V. Lanius, C. Pohl, R. Sandbrink for the BENEFIT Study Group

Objective:

To assess adherence to treatment with interferon beta-1b (IFNB-1b; Betaferon®), its tolerability, and the quality of life (QoL) of patients with a first event suggestive of multiple sclerosis (MS).

Background:


The BENEFIT (BEtaferon in Newly Emerging multiple sclerosis For Initial Treatment) studies are investigating the impact of early versus delayed treatment with IFNB-1b on the course of MS over a period of 5 years.

Methods:

In the randomised phase of BENEFIT, patients with a first demyelinating event and MRI findings suggestive of MS were treated with IFNB-1b 250 mcg or placebo, subcutaneously every other day, for 2 years or until diagnosed with clinically definite MS (if earlier). Patients were then asked to participate in the follow-up phase with the option of receiving IFNB-1b for a total period of up to 5 years after the initial randomisation. Patients and physicians remain blinded to the original treatment allocation. At the clinical visits adverse events were documented and health-related QoL assessed with the Functional Assessment of MS-Trial Outcome Index (FAMS-TOI) and the EuroQol 5-Dimensional (EQ-5D) questionnaire.

Results:

Of the 468 patients randomised to treatment with IFNB-1b (n=292) or placebo (n=176), 437 (93.4%) completed the double-blind phase, and 418 (89.3%) were enrolled for follow-up. 378 (80.8%) of these patients opted for treatment with IFNB-1b. 343 (73.3%) patients were still on treatment with IFNB-1b at 3 years. Adverse events were within the ranges as expected for IFNB-1b treatment, with no new safety signal arising. FAMS-TOI scores remained high and stable throughout the study. EQ-5D scores at 3 years were in favour for the early treatment group (p=0.016).

Conclusions:

IFNB-1b is well tolerated in patients with a first event suggestive of MS. The high proportion of patients opting for IFNB-1b in the follow-up study and the high adherence rate after 3 years show that patients accepted this treatment. High and stable QoL ratings underline the tolerability of IFNB-1b treatment.
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PostPosted: Thu Oct 18, 2007 6:42 pm    Post subject: (Abstract) Early vs delayed Betaseron treament... Reply with quote

From the ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis) conference in Prague, October 11-14, 2007:

Quote:
Early versus delayed interferon beta-1b treatment in patients with a first event suggestive of MS: the impact on progression of disability

L. Kappos, M.S. Freedman, C.H. Polman, G. Edan, H-P. Hartung, D. Miller, X. Montalbán, F. Barkhof, E-W. Radue, L. Bauer, V. Lanius, S. Dahms, C. Pohl, R. Sandbrink for the BENEFIT Study Group

The BENEFIT (BEtaferon® in Newly Emerging multiple sclerosis For Initial Treatment) project aims to evaluate the impact of early versus delayed initiation of interferon beta-1b (IFNB-1b; Betaferon®) treatment on disease evolution in patients with a first event suggestive of MS.

In the placebo-controlled phase of BENEFIT, patients were randomised to IFNB-1b 250 mcg (n=292) or placebo (n=176) subcutaneously every other day for 2 years or until clinically definite MS (CDMS) was diagnosed. Patients were then enrolled in a follow-up phase and were offered IFNB-1b treatment for up to 5 years after the first event. In the follow-up phase, patients and physicians remain blinded to the original treatment allocation.

In a prospectively planned analysis of data obtained up to 3 years after the first event, the effects of early IFNB-1b treatment (i.e. patients initially randomised to IFNB-1b) were compared to delayed IFNB-1b treatment started after diagnosis of CDMS or after two years on study (i.e. patients initially randomised to placebo). Primary outcome measures in the follow-up study include time to CDMS and time to 6 month-confirmed disability progression as measured by the expanded disability status scale (EDSS).
Of the 468 patients originally randomised, 418 (89.3%) entered, and 392 (83.8%) completed the 3 year follow-up. Over the 3-year period, early treatment reduced the risk for confirmed progression of disability by 40% versus delayed treatment (hazard ratio with 95% confidence interval: 0.60, 0.39–0.92; log-rank test: p=0.022). Sensitivity analyses were carried out and yielded very similar results, e.g. when including unscheduled visits the risk reduction was 39% (hazard ratio with 95% confidence interval: 0.61, 0.40–0.93; log-rank test: p=0.024). Thus, the robustness of these findings could be demonstrated. The risk for CDMS remained 41% lower (hazard ratio with 95% confidence interval: 0.59, 0.44–0.80; p=0.0011). Over the 3 year period, a significant reduction of the annualised relapse rate was found, which was also seen in year 1 but not in the 2nd or 3rd year on study.

This is the first study in patients with a first event suggestive of MS showing that early initiation of IFNB-1b treatment prevents accumulation of sustained disability. This finding supports the value of IFNB-1b treatment in the very early phase of MS and has implications for treatment decisions.
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PostPosted: Thu Dec 06, 2007 5:56 pm    Post subject: (Abstract) Lupus-like reaction to interferon... Reply with quote

From PubMed, December 6, 2007:

Quote:
J Cutan Pathol. 2007 Dec;34 Suppl 1:18-21

Lupus-like reaction to interferon at the injection site: report of five cases

Arrue I, Saiz A, Ortiz-Romero PL, Rodríguez-Peralto JL.
Department of Dermatology, University Hospital, Madrid, Spain.

Background:

Interferon therapy at the injection sites has been related to different cutaneous lesions including erythema and induration as the most frequent ones. While the glycoprotein induces fatigue, fever and is even believed to precipitate autoimmune disorders such as type I diabetes, thyroid disease and systemic lupus erythematosus, a lupus erythematosus-like histologic reaction at the interferon injection site has never been reported. To our knowledge, a microscopic self-resolving lesion mimicking lupus erythematosus at the injection site of interferon has not been described.

Results:

We report five cases of cutaneous lesions at the inoculation site of interferon with a histopathologic lupus erythematosus-like pattern. Three of them were receiving interferon alfa therapy because of a malignant melanoma, and the other two patients were receiving interferon beta-1b for multiple sclerosis.

Biopsy specimens taken from different lesions showed similar microscopic findings consisting of dermal mucin deposits and dense lymphocytic infiltrates along hair follicles with hydropic degeneration of follicular basal layer.

Conclusions:

Multiple cutaneous lesions related to interferon at the injection site have been reported, but none of them with a histologic lupus-like presentation. In this study we describe five cases in which interferon therapy has induced a resolutive cutaneous lesion mimicking lupus erythematous. This peculiar microscopic pattern has been previously described once before, but interpreted as cutaneous mucinosis.

PMID: 17997732
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PostPosted: Sat May 31, 2008 7:19 pm    Post subject: (Abstract) Neutralizing antibodies & effect of IFN-beta Reply with quote

From PubMed, May 29, 2008:


Quote:
Mult Scler. 2008 May 27

Is the treatment effect of IFN-{beta} restored after the disappearance of neutralizing antibodies?

Sorensen PS, Koch-Henriksen N, Flachs EM, Bendtzen K.
Danish Multiple Sclerosis Research Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Objective

To establish whether multiple sclerosis (MS) patients, who have lost the therapeutic effect of interferon-beta (IFN-beta) owing to neutralizing antibodies (NAbs) and subsequently revert from a NAb-positive to a NAb-negative state under continued IFN-beta-1b therapy, regain clinical effect after reversion.

Background

Several studies have shown that a significant proportion of patients treated with IFN-beta develop NAbs that hamper or abolish the therapeutic effect of IFN-beta. However, some patients, who become NAb-positive under treatment with IFN-beta-1b, may revert to a NAb-negative state under continuous treatment.

Methods

We identified 40 patients from the Danish IFN protocol, who fulfilled the criteria: NAb-positive status for at least 12 months followed by reversion to NAb-negative state for at least 12 months. For comparison, we included 64 matching cases that had remained NAb-negative during an observation time of at least 36 months. The two groups were clinically and demographically alike.

We measured NAb-neutralizing capacity using a clinically validated cytopathic effect assay. A blood sample with a neutralizing capacity of 20% or more was considered as NAb-positive. A patient was defined as NAb-positive after two consecutive blood tests separated by at least 6 months. Reversion to a NAb-negative state required at least two consecutive negative tests. To allow for the confounding effect of time we employed a mixed Poisson model.

Results

Patients who had been NAb-positive and reverted to a NAb-negative state regained treatment effect with the relapse rate as before the NAb-positive period adjusting for the effect of time, and the relapse rate was the same as in the permanently NAb-negative patients in corresponding time periods. The relapse rate ratio comparing the NAb-positive with the NAb-negative periods was 1.98 (95% confidence interval: 1.32-2.97).

Conclusion

Under NAb-positive periods, the clinical effect of IFN-beta was abolished. When NAbs disappeared spontaneously under continued treatment, patients regained the full effect of INF-beta-1b therapy with no negative carry-over effect from the previous NAb-positive period.

PMID: 18505772
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PostPosted: Fri Jun 13, 2008 5:54 pm    Post subject: (Abstract) IFN-beta1b induces gene expression in RRMS... Reply with quote

From PubMed, June 13, 2008:

Quote:
J Interferon Cytokine Res. 2008 May;28(5):317-31.

IFN-beta1b Induces Transient and Variable Gene Expression in Relapsing-Remitting Multiple Sclerosis Patients Independent of Neutralizing Antibodies or Changes in IFN Receptor RNA Expression

Reder AT, Velichko S, Yamaguchi KD, Hamamcioglu K, Ku K, Beekman J, Wagner TC, Perez HD, Salamon H, Croze E.
Department of Neurology, University of Chicago, Chicago, IL 60687.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Interferon-beta (IFN-beta) therapy for MS is hypothesized to cause short-term and long-term changes in gene expression that shift the inflammation from Th1 to Th2. In vivo gene induction to define kinetics of response to IFN-beta therapy in a large cohort of MS patients is described. Differential gene expression in peripheral blood mononuclear cells (PBMCs) obtained from relapsing-remitting MS patients (RRMS) was assessed using high content microarrays. Rapid onset of gene expression appeared within 4 h of subcutaneous IFN-beta administration, returning to baseline levels at 42 h in clinically stable RRMS.

IFN-beta therapy in vivo rapidly but transiently induced strong upregulation of genes mediating immune modulation, IFN signaling, and antiviral responses. RT-PCR showed significant patient-to-patient variation in the magnitude of expression of multiple genes, especially for IFN-beta-inducible genes, such as MxA, IRF7, and CCL8, a Th1 product.

Variation among patients in IFN-beta-induced RNA transcription was not explained by neutralizing antibodies or IFN receptor expression. Surprisingly, genes regulated in vivo by IFN-beta therapy do not support a simple Th1 to Th2 shift. A complex interplay between both proinflammatory and anti-inflammatory immune regulatory genes is likely to act in concert in the treatment of RRMS.

PMID: 18547162
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PostPosted: Wed Jul 02, 2008 4:30 pm    Post subject: (Abstract) MS risk & treatment effect of IFN-1b Reply with quote

From PubMed, July 2, 2008:

Quote:
J Neurol. 2008 Apr;255(4):480-7

Subgroups of the BENEFIT study: risk of developing MS and treatment effect of interferon beta-1b

Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Selmaj K, Uitdehaag BM, Dahms S, Bauer L, Pohl C, Sandbrink R; BENEFIT investigators.

Collaborators (98)


Vrije Universiteit Medical Centre, Amsterdam, The Netherlands. ch.polman@vumc.nl

BACKGROUND :

The BENEFIT study examined interferon beta (IFNB)-1b treatment in patients with clinically isolated syndrome (CIS) and > or = 2 clinically silent brain MRI lesions.

METHODS:

Subgroups of 468 patients (IFNB-1b: n = 292; placebo: n = 176) were created for demographics, clinical, laboratory, and MRI findings at onset. The 'natural' risk of clinically definite MS (CDMS) over 2 years was estimated by Kaplan Meier statistics in placebo-treated patients; the IFNB-1b treatment effect was analysed by Cox proportional hazards regression.

RESULTS:

The risk of CDMS was increased in placebo-treated patients (overall 45 %) if they were younger (< 30 years: 60%), were cerebrospinal fluid (CSF)-positive (49 %), or had received steroid treatment (48 %). MRI parameters implied a higher risk in placebo-treated patients with > or = 9 T2-lesions (48%) or > or = 1 gadolinium (Gd)-enhancing lesions (52 %). The CDMS risk was highest (75 %) in placebo-treated patients with monofocal disease onset displaying MRI disease activity (> or = 1 Gd-lesion) and dissemination (> or = 9 T2-lesions).

Treatment effects were significant across almost all subgroups including patients with less disease dissemination/activity at onset (monofocal: 55%; < 9 T2-lesions: 60%; no Gd-lesions: 57%) and patients without steroid treatment for the CIS (62 %). Monofocal patients had greater treatment effects if they had > or = 9 T2-lesions (61 %), Gd-lesions (58 %), or both (65 %).

CONCLUSIONS:

This study confirms the impact of age of onset, CSF and MRI findings on risk of conversion from CIS to CDMS. IFNB-1b treatment effect was robust across the study population including patients without MRI disease activity and less clinical or MRI disease dissemination at onset and patients not receiving steroids for the CIS.

PMID: 18004635
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PostPosted: Sat Jul 26, 2008 6:45 pm    Post subject: (Article) Air bubble helps PwMS adhere to injectable drugs Reply with quote

From NeuraNet, July 26, 2008:

Quote:
Nurse Network > MS Scan > Issue 18 (2008) >


Library [7/26/2008]


Air Bubble Helps Patients With MS Adhere to Injectable Therapies

Moore LA, Kaufman MD, Algozzine R, et al. Adherence to therapy: using an evidence-based protocol. Rehab Nurs. 2007;32;227-232. [PubMed]

Injections are not pleasant experiences; all the more so when they need to be administered on an ongoing basis, every day or several times a week. Adherence to such a regimen can be a serious problem, especially if the medication involved may cause tissue reactions at injection sites.

Unfortunately, patients with chronic illnesses are prone to discontinue such therapies. It is important therefore for clinicians to be able to demonstrate methods that help patients adhere to injectable therapy regimens. This is especially important in MS, for despite evidence that early initiation and long-term maintenance of disease-modifying therapy significantly reduces relapses and CNS lesions, half the patients in the US discontinue their injectable therapy by the end of the first year.

Moore and colleagues suggest that injection site reactions, which may vary from minor redness to tissue necrosis, are a major barrier to continuing MS therapy. Citing as an example their experience with SC interferon β-1b (Betaseron) taken every other day, they assert that “patients discontinue or reduce the number of injections [because of] injection site reactions, especially those associated with skin necrosis.” They note that previous research had suggested that low body mass, female sex, and areas of the body with less subcutaneous fat, such as arms and thighs (as opposed to buttocks and abdomen) correlate with injection site reactions. They point out that poor injection techniques are also risk factors for adverse skin reactions. These include
    ~cold injection solutions, ~repeated use of the same injection site,
    ~exposure of recent injection sites to sunlight,
    ~medication penetration into the dermis because needles are too short to reach deep subcutaneous tissue


Although the recommendations of the manufacturer of SC interferon β-1b were designed to minimize skin site reactions (eg, room temperature warming of injection solutions, rotating injection sites, changing needle length, using ice before and after injection), the authors were concerned because patients nevertheless continued to report skin reactions. They therefore undertook a study of a modified injection protocol for SC interferon β-1b based on an air bubble technique described in Kozier et al, Fundamentals of Nursing: Concepts, Process, and Practice, 6th edition, Upper Saddle River, NJ: Prentice Hall Health, 2000:

    ~All the manufacturer’s recommendations are followed
    ~A bubble (0.1 mL) of air is added to the syringe before injection, making sure it accumulates beneath the plunger
    ~After subcutaneous injection, the air bubble is the last to enter the needle
    ~The air-filled (and therefore dry) needle is withdrawn
    ~The dry needle prevents a siphoning effect, which would have occurred if an unbroken column of liquid had remained in the needle as it was withdrawn
    ~This prevents leakage into the skin and surrounding tissue


The researchers randomized 44 subjects (33 experimentals and 11 controls) with MS who were using SC interferon β-1b but had had injection site reactions, including 7 who had had necrotic reactions; the subjects ranged in age from 24 to 57 years. At baseline, there were no significant differences between experimentals and controls in redness size (cm) at injection sites (ie, before the bubble injection technique was taught to the experimentals.) It should be noted that use of the bubble technique was the only difference between the 2 groups. Autoinjectors were not permitted. After 4 weeks the experimentals ended their involvement, whereas the controls crossed over to the experimental protocol.

The results showed that there was a significant difference (P=0.001) in mean injection site redness size between experimentals and controls (0.87 cm vs 3.43 cm, respectively). Similarly, after the controls (n=10) crossed over to the experimental protocol, mean redness size was significantly reduced to 1.22 cm from the previous control size of 3.67 cm (P=0.002).

The authors note that at baseline, the participants had complained of previous deep-red (“very angry-looking”) skin reactions with a mean size of 3.3 cm that could last for 1-2 weeks, but with the bubble technique the reactions were a light pink and lasted 2-3 days. Ice made no difference in degree of redness. There were no necrotic reactions after starting the bubble technique. Before the bubble technique was initiated, several subjects would omit as many as 4-6 injections per month because of skin reactions, and without even informing their health care provider; now they were consistently adhering to the treatment regimen. Although autoinjectors were barred during the experiment, it may be possible to employ the bubble technique with these devices as well. Some prepackaged syringes now include an air bubble (which should be positioned under the plunger during injection). Finally, the authors point out that the bubble technique is amenable to use in other chronic conditions that require injectable medications.

Clinical Insight:



~Adherence to the frequent injection regimens used in RRMS can be a serious problem if the medication causes tissue reactions at injection sites

~Poor injection techniques are risk factors for adverse skin reactions. The air bubble technique minimizes these reactions

~The resulting dry needle avoids a siphoning effect; this prevents leakage into the skin and surrounding tissue largely responsible for adverse reactions

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PostPosted: Fri Oct 03, 2008 2:46 pm    Post subject: (Article) Betaseron introduces thinner needle Reply with quote

From MSFYi, the MS Foundation's monthly Internet newsletter for October 2008:

Quote:
Betaseron Introduces Thinner Needle

Bayer Healthcare Pharmaceuticals, maker of Betaseron, has announced plans for a 30-gauge needle, the thinnest offered for an injectable disease-modifying drug.

A recent survey found that of 220 people in the U.S. and Canada polled, 33 percent said that the length of the needle used for MS injections made them nervous, and 31 percent were concerned by the needle’s thickness.

According to Bayer, the new Betaseron needle is comparable to those used for insulin and pediatric injections.

The new needle will be introduced with an optional auto injector, called BETAJECT. ®

For more information, visit www.betaseron.com/thinner.


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PostPosted: Sat Nov 08, 2008 7:47 pm    Post subject: (Abstract) Betaseron's effect on lesion size... Reply with quote

From PubMed, November 8, 2008:

Quote:
Expert Opin Biol Ther. 2008 Dec;8(12):1823-9.

The effect of interferon beta-1b on size of short-lived enhancing lesions in patients with multiple sclerosis

Gaindh D, Jeffries N, Ohayon J, Richert ND, Pellicano C, Frank JA, McFarland H, Bagnato F.
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive, Bethesda, Maryland 20892, USA.

BACKGROUND:

Contrast-enhancing lesions (CELs) in MRI represent inflammatory events in multiple sclerosis (MS). IFN-beta-1b decreases the formation of CELs. However, the ability of IFN-beta-1b to reduce the size of CELs arising during therapy has not been extensively investigated.

METHODS:

Thirty patients with relapsing-remitting (RR) MS were followed for a 3-month pre-therapy phase, then for a 6-month therapy phase during which treatment with IFN-beta-1b at a dosage of 250 microg subcutaneously injected every other day was employed. Each patient underwent monthly clinical and MRI examinations. For all patients, CELs were identified on postcontrast T1-weighted MRIs. CEL number, size, and volume were computed using Medx software.

RESULTS:

The average number and total lesion volume of CELs visible during the therapy phase were significantly lower than the number and total lesion volume of CELs observed in the pre-therapy phase. However, there was no significant reduction between pre-therapy and therapy phases in the mean size of individual lesions arising during the respective phases.

CONCLUSIONS:


Since size of CELs has been related to severity of tissue damage, the lack of size decrease during therapy suggested a limited therapeutic effect of IFN-beta-1b if a blood-brain barrier breakdown has occurred.

PMID: 18990070
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PostPosted: Sun Nov 09, 2008 11:22 am    Post subject: Reply with quote

Good thing controlling "enhancing lesions" doesn't seem to mean much to long term disability/progression. cheers

Cherie
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PostPosted: Sun Nov 09, 2008 12:38 pm    Post subject: Reply with quote

You don't often see articles or abstracts that have negative results for one of the DMDs.
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PostPosted: Mon Nov 10, 2008 3:34 pm    Post subject: (Abstract) Heterogeneity in response to IFN-Beta in MS... Reply with quote

From Archives of Neurology Early Releases, November 10, 2008:


Quote:
Heterogeneity in Response to Interferon Beta in Patients With Multiple Sclerosis:
A 3-Year Monthly Imaging Study


Annie W. Chiu, BS; Nancy Richert, MD, PhD; Mary Ehrmantraut, MS; Joan Ohayon, MSN; Shiva Gupta, MD; Giuseppe Bomboi, MD; Deeya Gaindh, AB; Fredric K. Cantor, MD; Joseph A. Frank, MS, MD; Henry F. McFarland, MD; Francesca Bagnato, MD, PhD


Arch Neurol. 2009;66(1):(doi:10.1001/archneur.66.1.noc80047).

Objectives

To investigate the heterogeneity in magnetic resonance image (MRI) patterns of response to interferon beta across patients with multiple sclerosis or within an individual patient over time.

Design, Setting, and Patients

Fifteen patients with relapsing-remitting multiple sclerosis underwent monthly MRIs and clinical examinations (6-month pretherapy phase and 36-month therapy phase) and bimonthly neutralizing antibody tests. On each MRI, the total number of contrast-enhancing lesions was noted. Therapy MRI responders were defined as those with a reduction of 60% or more in the total number of contrast-enhancing lesions during each semester of therapy.

Intervention

Subcutaneous administration of interferon beta-1b, 250 µg, every other day for 3 years.

Main Outcome Measure

Reduction in the number of contrast-enhancing lesions.

Results


Eight patients (53.3%) were MRI responders and 7 (46.7%) were nonresponders. Of those 7, 3 (20.0%) had only an initial optimal reduction of the total number of contrast-enhancing lesions, 2 (13.3%) never reached an optimal response, and 2 (13.3%) had a delayed optimal response. No clear association between neutralizing antibody profile and MRI response was evident.

Conclusions

Multiple MRI evaluations disclose that approximately only half of the patients treated with interferon beta achieve and maintain a full response to the drug over time, although an additional small number of individuals may still restore an optimal response to the drug after an initial failure.



Author Affiliations:

Neuroimmunology Branch (Mss Chiu, Ehrmantraut, Ohayon, and Gaindh and Drs Richert, Gupta, Bomboi, Cantor, McFarland, and Bagnato) and Laboratory of Diagnostic Radiology and Research (Dr Frank), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.








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PostPosted: Sat Nov 15, 2008 3:35 pm    Post subject: Different account of the study above Reply with quote

From MedPage Today, November 10, 2008:

Quote:
Half of Multiple Sclerosis Patients Fail Interferon Therapy

By Judith Groch, Contributing Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

BETHESDA, Md., Nov. 10 -- Only eight of 15 relapsing-remitting multiple sclerosis patients treated with interferon achieved and maintained a full response over three years, a small retrospective imaging study found.


Two of the seven non-responders went on to achieve an optimal response after initial failure, Francesca Bagnato, M.D., Ph.D., of the National Institute of Neurological Disorders and Stroke, and colleagues reported online in Archives of Neurology.

This delayed response, the researchers said, suggests that frequent MRI monitoring is warranted during the first year of therapy.


Another reason for frequent monitoring: a small number of patients designated as responders nevertheless experienced a clinical exacerbation during the first six months of therapy.


MRI visualizes inflammatory plaques, namely contrast-enhancing lesions (CELs), in patients with multiple sclerosis. These lesions precede clinical relapses, which in turn are presumed to lead to disease progression, the researchers said.


Although clinical studies have shown that interferon beta can reduce these lesions, little is known about the heterogeneity of the MRI response profiles between patients or within an individual patient over time, the researchers wrote.


To get that sort of data, this open-label study at the National Institutes of Health, analyzed and described in detail the MRI responses to interferon beta in a cohort of 15 patients with relapsing-remitting MS.


No patients were treated with immunomodulatory or immunosuppressive drugs, except for steroids given for acute relapse before the first MRI.


The patients were given MRIs monthly for three years once therapy started, clinical examinations (six months prior to therapy and during 36 months of therapy), and bimonthly neutralizing antibody tests.


On each MRI, the total number of contrast-enhancing lesions was noted. MRI responders to therapy were defined as those with a reduction of 60% or more in the total number of lesions during each six-month semester of therapy.


Patients were given subcutaneous interferon beta-1b, 250 μg, every other day for three years.


MRIs were done with a 1.5-T magnet using a standard head coil.


Eight patients (53.3%) were MRI responders, showing a reduction of 60% or more in activity of the total number of lesions.


However, three of the MRI responders had clinical relapses during the first six months of therapy, and two of these had a sustained progression in the Expanded Disability Status Scale (EDSS).


Of the seven non-responders (46.7%), three (20.0% of the original study group) had only an initial optimal reduction in the total number of lesions, but no further change. Two (13.3%) never reached an optimal response.


However, two of the seven non-responders (13.3% of the total group) did reach and maintain a response of 60% or more after the first six months on therapy.


All seven of the non-responders experienced at least one clinical exacerbation during the treatment phase.


No clear association between neutralizing antibody profile and MRI response was evident, the researchers said.


Neither MRI nor clinical parameters at the beginning of the study predicted which of the patients would be not respond to therapy. However, because the number of patients was small, a definitive conclusion is not possible, the researchers said.


One could argue, they said, that changes with treatment might be more easily identified in patients with a higher total number of lesions. However, on close inspection of the data, overall the total number of lesions among different responder types was heterogeneous.


Possible limitations of this study, in addition to its small size, included the fact that the study was open-label and lacked a systematic analysis of potential effects of steroids given for acute relapses.


Also because a small number of patients achieved a response after initial failure and some patients classified as responders had clinical relapses during the first six months of therapy, frequent radiological monitoring is advised during the first year of therapy, the researchers said.


The novel aspect of this study is the unique number of monthly MRIs done for each patient, potentially disclosing information masked by approaches using less frequent measurements, the investigators said.


This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health.
No financial conflicts were reported.




Primary source: Archives of Neurology
Source reference:
Chiu AW, et al "Heterogeneity in Response to Interferon Beta in Patients With Multiple Sclerosis: A 3-Year Monthly Imaging Study" Arch Neurol 2009; 66: DOI: 10.1001/archneur.66.1.noc80047.

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PostPosted: Tue Jan 27, 2009 3:09 pm    Post subject: (Abstr.) IFN-beta-1b for CIS--economic evaluation Reply with quote

Another study coping with how PwMS can drain the economy--from PubMed, January 27, 2009:

Quote:
Neurol Sci. 2009 Jan 24

Economic evaluation of treating clinically isolated syndrome and subsequent multiple sclerosis with interferon beta-1b

Lazzaro C, Bianchi C, Peracino L, Zacchetti P, Uccelli A.
Studio di Economia Sanitaria, Via Stefanardo da Vimercate, 19, 20128, Milan, Italy, carlo.lazzaro@tin.it.

New therapeutic options have modified the natural history and health care costs of multiple sclerosis (MS). An epidemiological 25 years-long model-based cost-utility analysis was performed following the Italian National Health Service (INHS) and societal perspectives to compare costs and quality-adjusted life years of treatment with interferon beta-1b (IFNB-1b) from diagnosis of clinically isolated syndrome (CIS) versus treating at subsequent conversion to clinically definite MS (CDMS).

Among patients treated (untreated) with IFNB-1b from CIS diagnosis, 40,420 (43,700) converted to CDMS after 25 years; the estimated cumulative probability of converting to CDMS during the first 3 years was 72.90% (84.94%) (P < 0.0001).

Early treatment with IFNB-1b is highly cost-effective for the INHS (incremental cost-effectiveness ratio: Euros 2,574.94) and dominant from the societal viewpoint. Sensitivity analyses confirmed the base case findings. Early treatment with IFNB-1b delays conversion to CDMS in CIS patients and might be a "good value for money" health care programme.

PMID: 19169625


http://tinyurl.com/cydlct
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PostPosted: Wed Aug 19, 2009 9:01 am    Post subject: Enter Novartis with Extavia Reply with quote

Betaseron will now also be available as Extavia through Novartis. From Medical News Today, August 19, 2009:

Quote:
US FDA Approves Extavia(R) - The First In A New Portfolio Of Planned MS Therapies From Novartis To Help Patients With This Devastating Disease

The US Food and Drug Administration (FDA) has approved Extavia(R) (interferon beta-1b), the first in a new planned portfolio of multiple sclerosis (MS) medicines from Novartis to help patients manage this devastating disease.

Extavia is approved by the FDA for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbations. The therapy is also indicated for patients who have experienced a first clinical episode of MS and have features consistent with the disease as shown by magnetic resonance imaging (MRI)(4).

The same medicinal product as Betaseron(R)*, Extavia offers patients and physicians a new branded version of interferon beta-1b, a first-line disease-modifying therapy that has been a standard-of-care for MS in the US for more than 16 years(1). Extavia will be marketed by the Pharmaceuticals Division of Novartis.

"Interferon is a mainstay of treatment in MS," said Doug Jeffery, MD, Associate Professor at Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, USA. "With the approval of Extavia, patients have another option with a well-established safety and efficacy profile to help manage this disease."

MS is estimated to affect approximately 400,000 patients in the US, of whom more than 80% have relapsing-remitting MS(5). MS is one of the most common causes of neurological disability in young adults. It is a chronic autoimmune disease in which the body's immune system attacks the myelin sheath, or protective tissue surrounding the nerve fibers that carry electrical signals in the brain(6). The destruction of myelin causes problems with muscle control and strength, vision, balance, sensation and mental function(7).

"Novartis has been a leader in neuroscience for more than 50 years, having pioneered a number of breakthrough therapies which remain important treatments to this day," said Joe Jimenez, CEO of the Novartis Pharmaceuticals Division. "We are committed to providing new approaches to MS care, and the FDA approval of Extavia marks the beginning of our long-term commitment to the MS community in the US."

Extavia will be available to patients in the US this fall. Along with their prescription for Extavia, patients will be given access to a support program including a nurse helpline, one-on-one injection training and reimbursement support services. Extavia patients will have an autoinjector available to them from Novartis.

"MS is unpredictable and can be difficult to manage," said Aaron Miller, MD, Professor of Neurology at Mount Sinai School of Medicine in New York, USA. "Support programs are an essential element to help patients and physicians effectively manage this complicated disease."

MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (known as exacerbations or relapses), followed by complete or partial restoration of function(6).

Interferon beta-1b has been shown to reduce annualized relapse rates by 34% (p=0.0001)(8), with patients nearly twice as likely to remain relapse-free for more than two years compared to those receiving placebo (31% vs. 16%, p=0.007)(8). In addition, treatment with interferon beta-1b may slow disease progression(9). After two years, almost three-quarters of patients who experienced a single episode of neurological disease lasting 24 hours or more did not progress to clinically definite MS(10).

In the European Union Extavia is available in 12 countries and is approved for relapsing-remitting MS as well as early MS (defined as a single demyelinating event with an active inflammatory process) and a steadily worsening form of the disease known as secondary progressive MS with relapses.

Extavia should be used with caution in patients with depression. Injection site necrosis has been reported in 4% of patients in controlled trials. Typically, injection site necrosis occurs within the first four months of therapy. Necrosis may occur at a single injection site or multiple injection sites. Patient understanding and use of aseptic self-injection techniques and procedures should be periodically reevaluated, particularly if injection site necrosis has occurred. Anaphylaxis has been reported as a rare complication of interferon use. Other allergic reactions have included dyspnea, bronchospasm, tongue edema, skin rash, and urticaria.

The rate of flu-like symptom complex was approximately 57% in the four controlled clinical trials. The incidence decreased over time, with only 10% of patients reporting flu-like symptom complex at the end of the studies. Monitoring of complete blood and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, are recommended at regular intervals.

The most commonly reported adverse reactions are lymphopenia, injection site reaction, asthenia, flu-like symptom complex, headache and pain. Based on all the available evidence, the relationship between antibody formation and clinical safety and efficacy is not known. Female patients should be warned about the potential risk to pregnancy. The mechanism of action of interferon beta-1b in patients with multiple sclerosis is unknown. Gradual dose titration and use of analgesics during treatment initiation may help reduce flu-like symptoms. Patients should be advised of the importance of rotating injection sites.

Novartis gained the rights to seek approval for its own branded version of interferon beta-1b through agreements with Bayer Schering, the company that markets Betaseron.

Betaseron is marketed under the name of Betaferon(R) outside the US. Betaseron and Betaferon are registered trademarks of Bayer Schering Pharma AG.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "planned," "may," "committed," "long-term commitment," "will," "can," "likely," or similar expressions, or by express or implied discussions regarding potential future multiple sclerosis products or regarding potential future revenues from Extavia or other multiple sclerosis products. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that any additional Novartis multiple sclerosis products will be approved for sale in any market. Nor can there be any guarantee that Extavia or such other products will achieve any particular levels of revenue in the future. In particular, management's expectations regarding such products could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

....

References
1. FDA approves Betaseron(R) for use after the first event suggestive of multiple sclerosis [press release]. Wayne, NJ: Berlex: 23 October 2006.

2. National Multiple Sclerosis Society website: http://www.nationalmssociety.org/about-multiple-sclerosis/who-gets-ms/index.aspx. Accessed August 12, 2009.

3. Multiple Sclerosis International Federation website. http://www.msif.org/en/about_ms/what_is_ms.html. Accessed August 12, 2009.

4. Extavia Prescribing Information, August 14, 2009.

5. Habermann, T. and Amit K. Ghosh, ed. Mayo Clinic Internal Medicine Concise Textbook. Florence, KY: Informa HealthCare, 2007.

6. National Multiple Sclerosis Society website.

7. Multiple Sclerosis International Federation website.

8. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Neurology. 1993;43:655-661.

9. Betaseron (interferon beta-1b) Prescribing Information.

10. Kappos L, Freedman MS, Polman CH, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology. 2006;67:1242-1249.

Source: Novartis Pharmaceuticals Corporation


The article can be seen here.
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PostPosted: Sat Oct 03, 2009 1:08 pm    Post subject: (Abstract) Betaseron & PPMS & transitional MS Reply with quote

From PubMed, October 3, 2009:

Quote:
Mult Scler. 2009 Sep 29.

A single-centre, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary progressive and transitional multiple sclerosis

Montalban X, Sastre-Garriga J, Tintoré M, Brieva L, Aymerich FX, Río J, Porcel J, Borrŕs C, Nos C, Rovira A.
Unitat de Neuroimmunologia Clínica, Multiple Sclerosis Centre of Catalonia.

Inflammation and neurodegeneration may have differential impacts on disease evolution in the different forms of multiple sclerosis. However, a beneficial effect of immunomodulatory drugs should not be ruled out in primary progressive multiple sclerosis.

Our aim is to investigate the safety and efficacy of interferon beta-1b in primary progressive multiple sclerosis. We conducted a double-blind, stratified, randomized, parallel group, phase II pilot study where patients with primary progressive multiple sclerosis or 'transitional' forms of multiple sclerosis received interferon beta-1b at doses of 8 MIU or placebo for 24 months.

The main objective of the study was to investigate the safety and tolerability of interferon beta-1b. The primary efficacy variable was the time to neurological deterioration (Expanded Disability Status Scale) confirmed at 3 months. Seventy-three patients were included and three dropped out the study. More patients in the treatment arm had at least one related adverse event (94.4% versus 45.9%; p < 0.001); no other significant differences in safety endpoints were observed.

Time to neurological deterioration was not different between trial arms (log-rank test, p = 0.3135). Statistically significant differences favoring treatment were observed for the Multiple Sclerosis Functional Composite score at several timepoints, T1 and T2 lesion volume changes at 12 and 24 months, mean number of active lesions and proportion of patients with active lesions at 24 months.

We conclude that interferon beta-1b is safe and well tolerated in patients with primary progressive multiple sclerosis and transitional multiple sclerosis. Positive effects of interferon beta on secondary clinical and magnetic resonance imaging outcomes were observed, but a beneficial effect on Expanded Disability Status Scale progression was not demonstrated.

PMID: 19797261


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PostPosted: Thu Jun 10, 2010 10:50 am    Post subject: (Abstract) Cross-sectional study of long-term safety...RRMS Reply with quote

From PubMed, June 10, 2010:

Quote:


Neurology. 2010 Jun 8;74(23):1877-1885.

Cross-sectional study assessing long-term safety of interferon-{beta}-1b for relapsing-remitting MS

Reder AT, Ebers GC, Traboulsee A, Li D, Langdon D, Goodin DS, Bogumil T, Beckmann K, Konieczny A; For the Investigators of the 16-Year Long-Term Follow-Up Study.

Department of Neurology, University of Chicago, 5841 South Maryland Avenue, MC2030 Chicago, IL 60637 areder@neurology.bsd.uchicago.edu.


OBJECTIVE:

The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments.

METHODS:

In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 mug (n = 125), or IFNbeta-1b 250 mug (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive.

RESULTS:

In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established.

Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes.

There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 mug (9/108 [8.3%]) or IFNbeta-1b 250 mug (6/111 [5.4%]).

CONCLUSION:

The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis.

Classification of evidence: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 mug or 250 mug subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

PMID: 20530324


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PostPosted: Thu Oct 14, 2010 5:09 pm    Post subject: (Abstr.) Betaseron-induced psychosis in a patient w/MS Reply with quote

From PubMed, October 14, 2010:

Quote:

Psychiatry Clin Neurosci. 2010 Oct;64(5):584-6.

Persistent interferon-ß-1b-induced psychosis in a patient with multiple sclerosis

Manfredi G, Kotzalidis GD, Sani G, Koukopoulos AE, Savoja V, Lazanio S, Girardi N, Tatarelli R.

Psychiatric Unit, Department of Neurosciences, Mental Health and Sensory Functions (NESMOS), Sapienza University, 2nd Medical School, Sant' Andrea Hospital, Rome, Italy. giovanni.manfredi@uniroma1.it

Interferon-ß is used in patients with multiple sclerosis to reduce autoimmunity; although other psychiatric side-effects are common, in contrast to interferon-alpha, psychosis has been reported only once. A patient with multiple sclerosis developed auditory hallucinations, paranoid delusions, and increased aggressiveness after 16 months of treatment with interferon-ß-1b, 250 mg every other day. He responded after about one month to antipsychotic treatment, but tended to relapse upon dose reduction, and after 2 years still needs antipsychotics to control his symptoms.

Because there was no change in his magnetic resonance imaging between pre- and post-treatment with interferon, we concluded that psychosis was more related to interferon treatment than to the underlying disease.

PMID: 20939157


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PostPosted: Fri Feb 11, 2011 6:58 pm    Post subject: (Abstr.) Predictive factors of NABs in RRMS on IFN-beta1b Reply with quote

From PubMed, February 11, 2011:

Quote:
Neurol Sci. 2011 Feb 10.

Predictive factors of neutralizing antibodies development in relapsing-remitting multiple sclerosis patients on interferon Beta-1b therapy

Lanzillo R, Orefice G, Prinster A, Ventrella G, Liuzzi R, Scarano V, Florio C, Vacca G, Brunetti A, Alfano B, Brescia Morra V, Bonavita V.

Department of Neurological Sciences, Federico II University, Via Pansini 5, Naples, Italy, robertalanzillo@libero.it.

The identification of predictive factors of NAbs development might have a relevant impact on clinical practice. Our objective is to look after predictive factors of NAbs development in MS IFN Beta-1b-treated patients. Database was screened for patients on IFN Beta-1b treatment with an Expanded Disability Status Scale (EDSS) at a baseline between 1 and 3.5, disease duration shorter than 15 years, and NAbs analysis performed every 6 months. The NAbs positive status was analysed in relation to baseline clinical, neuropsychological and brain imaging measures. Forty-nine patients were included. Sixteen patients had become NAbs positive at some point on IFN therapy (35%). NAbs producers differed from non- producers [in] higher incidence of cognitive deficit and higher lesion load (OR = 5.0 and 5.6, respectively).

Our study suggests that NAbs development might be a marker of a more aggressive disease and that worse outcome in NAbs producers might be biased by baseline condition.

PMID: 21308385


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PostPosted: Sat Jun 04, 2011 8:28 am    Post subject: (Abstr.) Improving adherence to Betaseron... Reply with quote

From PubMed, June 4, 2011:

Quote:
J Neurol Sci. 2011 May 31.

Supportive strategies to improve adherence to IFN beta-1b in Multiple Sclerosis - Results of the BetaPlus observational cohort study

Pozzilli C, Schweikert B, Ecari U, Oentrich W; for the BetaPlus Study group.

Source

University Rome, Department of Neurological Sciences, 'La Sapienza' University, S. Andrea Hospital, Multiple Sclerosis Centre, Viale dell'Universitŕ 30, 00185 Rome, Italy.

BACKGROUND:

Low adherence to treatment in Multiple Sclerosis (MS) has been shown to lead to poor health outcomes. Various strategies to improve adherence have been suggested including educative programs, injection devices and dedicated nurse assistance.

OBJECTIVE:

To assess the impact of elements of the patient support program on adherence; to explore disease factors affecting adherence; and to determine whether these factors influence the choices of supportive elements.

METHODS:

A prospective, observational cohort study was conducted. MS patients were eligible if they had switched to Interferon beta-1b (IFNB-1b) between 1 and 3months prior to inclusion. Data were collected at months 6, 12, 18 and 24 after inclusion. Adherence was defined as completion of both study protocol and medication at 24months. Patients underwent evaluations of disability, quality of life, depression, and coping styles.

RESULTS:

A total of 1077 patients from 15 countries were included, of which 61.8% were adherent to IFNB-1b after 24-months. Depression, quality of life and autoinjector devices were baseline predictors of adherence at 24-months. Coping styles did not show to have substantial impact on adherence. Lower quality of life increased the probability of choosing supportive elements.

CONCLUSION:

The study showed that the usage of autoinjector devices chosen during the study was the strongest predictor of drug adherence of all the supportive elements tested in this study.

PMID:21636099





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PostPosted: Fri Sep 30, 2011 5:32 pm    Post subject: (Abstr.) Neutralizing antibodies to Betaseron in MS... Reply with quote

From Multiple Sclerosis Journal, Septebmer 30, 2011:

Quote:
Neutralizing antibodies to interferon beta-1b [in] multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial

Douglas S Goodin
douglas.goodin@ucsf.edu
University of California at San Francisco, San Francisco, CA, USA

Hans-Peter Hartung
Heinrich-Heine Universität, Düsseldorf, Germany

Paul O'Connor
St. Michael’s Hospital, Toronto, ON, Canada

Massimo Filippi
Neuroimaging Research Unit, Scientific Institute and University, Ospedale San Raffaele, Milan, Italy

Barry Arnason
Surgery Brain Research Institutes, Chicago, IL, USA

Giancarlo Comi
Department of Neurology and Clinical Neurophysiology, Vita-Salute University, Milan, Italy

Stuart Cook
UMD New Jersey Medical School, Newark, NJ, USA

Douglas Jeffery
UMD New Jersey Medical School, Newark, NJ, USA

Ludwig Kappos
University Hospital Basel, Basel, Switzerland

Timon Bogumil
Bayer HealthCare Pharmaceuticals, Montville, NJ, USA

Volker Knappertz
Heinrich-Heine Universität, Düsseldorf, Germany/Bayer HealthCare Pharmaceuticals, Montville, NJ, USA

Rupert Sandbrink
Heinrich-Heine Universität, Düsseldorf/Bayer Schering Pharma AG, Berlin, Germany

Karola Beckmann
Bayer Schering Pharma AG, Berlin, Germany

Rick White
University of British Columbia, Vancouver, Canada

John Petkau
University of British Columbia, Vancouver, Canada

Christoph Pohl
Bayer Schering Pharma AG, Berlin/University Hospital of Bonn, Germany for the BEYOND Study Group

Background:

The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNβ-1b) on clinical and radiographic outcomes is controversial.

Objective:

To assess NAb impact in the BEYOND study.

Methods:

2244 patients were randomized (2:2:1) to receive IFNβ-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2–3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors.

Results:

In the IFNβ-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNβ-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNβ groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNβ groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes.

Conclusion:

There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNβ-1b is complex.

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PostPosted: Mon Nov 14, 2011 11:48 pm    Post subject: (Abstr.) IFN-beta-1b for PPMS: 5-yr. clinical trial followup Reply with quote

From Archives of Neurology, November 14, 2011:

Quote:
Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis

Five-Year Clinical Trial Follow-up

Carmen Tur, MD; Xavier Montalban, PhD; Mar Tintoré, PhD; Carlos Nos, MD; Jordi Río, PhD; Francesc Xavier Aymerich, MSc; Luis Brieva, PhD; Nieves Téllez, PhD; Héctor Perkal, MD; Manuel Comabella, MD; Ingrid Galán, MD; David Calle, BSc; Jaume Sastre-Garriga, MD; Alex Rovira, PhD


Arch Neurol. 2011;68(11):1421-1427.

Objectives

To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution.

Design

Five-year clinical trial follow-up.

Setting

Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Autonomous University of Barcelona, Spain.

Patients

Seventy-three patients received interferon beta-1b or placebo during the trial.

Main Outcome Measures

After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 patients, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 patients, respectively.

Results

After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (P = .02) and Word List Generation Test (P < .001) scores, and their magnetization transfer ratio measures in the normal-appearing white matter were significantly higher (P = .02, P = .009, and P = .03 for the mean, peak location, and peak height magnetic transfer ratios, respectively). During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain parenchymal fraction (P = .004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (P = .004).

Conclusions

Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.


Author Affiliations:

Clinical Neuroimmunology Unit, Multiple Sclerosis Centre of Catalonia, Department of Medicine, Autonomous University of Barcelona, and Centre d’Anŕlisi i Recerca en Neuroimatge i Esclerosi Můltiple (Drs Tur, Montalban, Tintoré, Nos, Río, Brieva, Téllez, Perkal, Comabella, Galán, and Sastre-Garriga), and Magnetic Resonance Unit (Mr Aymerich and Dr Rovira), Vall d’Hebron University Hospital, Barcelona; and Nuvisan Clinical Development Solutions, Madrid (Mr Calle), Spain.



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PostPosted: Sat Dec 24, 2011 7:04 pm    Post subject: Betaseron maker agrees to reimburse insurers for relapses Reply with quote

From MedPage Today, December 10, 2011:

Quote:
Interferon Maker to Repay Insurer for MS Relapse Costs

By John Gever, Senior Editor, MedPage Today


The manufacturer of a major drug for multiple sclerosis has given what appears to be a money-back guarantee that its product will prevent severe relapses when used as directed.

Bayer HealthCare, maker of the Betaseron brand of interferon-beta-1b, has entered into a contract with Illinois-based Health Alliance Medical Plans (HAMP) agreeing to reimburse the insurer for hospitalization costs incurred by member patients who experience severe relapses while taking the drug according to prescribed directions.

"This agreement reinforces our commitment to people taking Betaseron and demonstrates our belief that when patients are adherent to their treatment plan, there may be a greater chance for positive outcomes by reducing clinical exacerbations," said Alex Santini, Bayer's vice president of managed markets, in a statement.

Another Bayer spokesperson said the average cost of hospitalization for severe MS relapses is about $12,000.

Details of the agreement, including the exact amount of compensation that Bayer would pay HAMP for relapses, how adherence would be measured, and whether patients' out-of-pocket costs would also be reimbursed, were not released.

HAMP has about 335,000 members in Illinois and Iowa, according to its website. The insurer did not respond to a request for comment.

Kim Calder, a spokeswoman for the National Multiple Sclerosis Society, told MedPage Today that the agreement was interesting and innovative, but "time will tell" whether it benefits patients significantly.

"We have not seen anything like this before," she said. "It's a little too soon to know the impact [on patients]."

However, she added, the NMSS supports anything that will genuinely promote treatment adherence and relapse prevention in MS patients.

Bayer said it has a patient support program called Betaplus that provides 24-hour access to specialists who can answer questions about insurance coverage and other issues related to starting and staying on treatment.

Calder charged that insurers themselves have created one of the most important barriers to treatment adherence in MS -- the classification of interferon drugs as specialty pharmaceuticals subject to high patient copayments, often 25% to 33% of the retail price.

Such cost sharing "doesn't serve anyone's interest," Calder said.








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PostPosted: Wed Apr 04, 2012 10:23 pm    Post subject: (Abstr.) Effects of Betaseron on cognitive performance... Reply with quote

From Multiple Sclerosis Journal, April 4, 2012:

Quote:
Effects of interferon beta-1b on cognitive performance in patients with a first event suggestive of multiple sclerosis

Iris-Katharina Penner1,2,#
Brigitte Stemper3,10,#
Pasquale Calabrese1
Mark S Freedman4
Chris H Polman5
Gilles Edan6
Hans-Peter Hartung7
David H Miller8
Xavier Montalbán9
Frederik Barkhof5
Dirk Pleimes3
Vivian Lanius3
Christoph Pohl3,11
Ludwig Kappos2,+
Rupert Sandbrink3,7,+

1University of Basel, Switzerland.
2University Hospital Basel, Switzerland.
3Bayer HealthCare Pharmaceuticals, Berlin, Germany.
4Ottawa Hospital, Canada.
5Vrije Universiteit Medical Center, The Netherlands.
6Clinique Neurologique, Rennes, France.
7Department of Neurology, Heinrich Heine Universität, Germany.
8National Hospital for Neurology and Neurosurgery, UK.
9Hospital Vall d’Hebron, Spain.
10Department of Neurology, University of Erlangen-Nürnberg, Germany.
11Department of Neurology, University of Bonn, Germany.
Iris-Katharina Penner, Department of Cognitive Psychology and Methodology, University of Basel, Missionsstr. 60/62, CH-4055 Basel, Switzerland. Email: ik.penner@unibas.ch

Background:

Cognitive dysfunction occurs at the earliest stages of multiple sclerosis (MS), including the stage of clinically isolated syndrome (CIS).

Methods:

We evaluated the impact of interferon beta-1b (IFNβ-1b) 250 µg on cognitive performance during the CIS stage in the BENEFITstudy. Cognition was assessed by Paced Auditory Serial Addition Test-3” (PASAT-3”) scores.

Results:

Improvement in PASAT-3” score from baseline to year two was greater for IFNβ-1b treatment than placebo in patients not reaching clinically definite MS (CDMS) by year two. The treatment effect was maintained at year five and was statistically significant.

Conclusions:

To conclude, early IFNβ-1b treatment had a sustained positive effect on PASAT-3” score over the 5-year BENEFIT study.
------------------
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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PostPosted: Fri Apr 13, 2012 9:09 am    Post subject: Survival in MS: Randomized cohort study... Reply with quote

From PubMed, April 13, 2012:

Quote:
Neurology. 2012 Apr 11.

Survival in MS: A randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial

Goodin DS, Reder AT, Ebers GC, Cutter G, Kremenchutzky M, Oger J, Langdon D, Rametta M, Beckmann K, Desimone TM, Knappertz V.

From the Department of Neurology (D.S.G.), University of California, San Francisco; Department of Neurology (A.T.R.), University of Chicago, IL; University Department of Clinical Neurology (G.C.E.), John Radcliffe Hospital, Oxford, UK; Department of Biostatistics (G.C.), University of Alabama School of Public Health, Birmingham; London Health Sciences Center (M.K.), London, Canada; Neuroimmunology Laboratories and Multiple Sclerosis Clinic (J.O.), University of British Columbia, Vancouver, Canada; Department of Psychology (D.L.), Royal Holloway, University of London, Surrey, UK; Bayer HealthCare Pharmaceuticals (M.R.), Wayne, NJ; Bayer HealthCare Pharmaceuticals (K.B.), Berlin, Germany; PAREXEL (T.M.D.), Hackensack, NJ; Bayer HealthCare Pharmaceuticals (V.K.), Montville, NJ; and Heinrich-Heine-Universität (V.K.), Düsseldorf, Germany.

OBJECTIVE:

To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments.

METHODS:

For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.

RESULTS:

After a median of 21.1 years from RCT enrollment, 98.4% (366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.

CONCLUSIONS:

There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality.Classification of Evidence:This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

PMID:22496198


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PostPosted: Mon Jul 09, 2012 8:11 pm    Post subject: Betaseron + melilot supplement-->liver dysfunction Reply with quote

From PubMed via NTK Watch, July 9, 2012:

Quote:
J Clin Pharm Ther. 2012 May 30.

Severe liver dysfunction possibly caused by the combination of interferon beta-1b therapy and melilot (sweet clover) supplement

Tamura S, Warabi Y, Matsubara S.

Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan.

What is known and objective: 

We report a case of severe liver dysfunction exacerbated after interferon beta (IFNB)-1b injection in a patient with multiple sclerosis (MS) who had been taking a melilot (sweet clover) supplement. Although IFNB-1b therapy for MS can cause mild liver dysfunction, severe hepatotoxicity attributable to supplement use has been reported.

Case summary: 

A 23-year-old Japanese woman taking a melilot supplement containing coumarin at 10 mg/day for 3 years was admitted to our hospital to receive IFNB-1b therapy for MS. Fourteen days after subcutaneous injection of IFNB-1b every other day, her aspartate transaminase (AST) and alanine aminotransferase (ALT) levels were elevated at 235 and 681 IU/L, respectively.

After the discontinuation of IFNB-1b therapy and supplement intake, AST and ALT returned to normal levels. Later, she started receiving an intramuscular injection of IFNB-1a weekly without supplement intake. She was able to continue IFNB-1a therapy this time, showing a slight elevation of AST level at 61 IU/L.

What is new and conclusion:

The combination of IFNB-1b therapy and melilot supplement intake may cause severe liver dysfunction in patients with MS. Given the doubtful value of the supplement, we suggest that it should be avoided by patients receiving interferon therapy.


PMID:22642738


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PostPosted: Wed Aug 22, 2012 11:06 pm    Post subject: Long-term cost effectiveness model of IFN beta-1b... Reply with quote

From PubMed, August 22, 2012:

Quote:
Clin Ther. 2012 Aug 17.

Long-Term Cost-Effectiveness Model of Interferon Beta-1b in the Early Treatment of Multiple Sclerosis in the United States

Pan F, Goh JW, Cutter G, Su W, Pleimes D, Wang C.

Source:
United BioSource Corporation, Bethesda, Maryland.

BACKGROUND:

Multiple sclerosis (MS) is a potentially debilitating autoimmune disease that affects the brain and spinal cord. Disease-modifying therapies have been shown to slow disease progression but were not believed to prolong the survival of patients with MS. The recent 21-Year Long-Term Follow-Up (21Y-LTF) study found a significant survival advantage for patients receiving early treatment with interferon beta (IFNβ)-1b compared with placebo (no early treatment).

OBJECTIVES:

The aim of this study was to conduct cost-effectiveness analyses estimating the long-term benefit of early treatment with IFNβ-1b among MS patients from a US societal perspective.

METHODS:

A Markov model was developed to simulate the experience of patients with MS from the 21Y-LTF study over a lifetime. Patients were randomized to receive either IFNβ-1b or placebo for up to 5 years and then receive a variety of MS treatments (including no treatment) thereafter. Survival data reported from the 21Y-LTF study were incorporated into the model. The model assumes that patients' MS was managed in similar ways for both groups during the uncontrolled phase of the 21Y-LTF study (ie, survival difference between the 2 groups is the result of early use of IFNβ-1b). Health outcomes were life-years and quality-adjusted life-years (QALYs). Costs included treatments, direct disease management, informal care, and lost productivities and were reported in 2011 US dollars.

RESULTS:

In the modeled placebo group, the median age at death was predicted to be 63.7 years, and the median survival time from disease onset was 36.7 years. Early treatment with IFNβ-1b reduced the lost health benefits by 2.8 life-years and 1.9 QALYs, respectively, after discounting. Total discounted cost for IFNβ-1b-treated patients was $86,223 higher than that of patients receiving placebo. The incremental cost-effectiveness ratio was $46,357 per QALY gained and $30,967 per life-year gained. Sensitivity analyses indicate the robustness of the model's results.

CONCLUSIONS:

Treatment with IFNβ-1b during the earlier disease phase of patients with MS significantly increased patient life-years and QALYs. IFNβ-1b is likely to be a cost-effective intervention for MS.



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PostPosted: Wed Sep 12, 2012 6:33 pm    Post subject: Tysabri de-escalation to Betaseron in MS patients Reply with quote

From Science Direct Message Center, September 8, 2012:

Quote:
Natalizumab de-escalation to interferon beta-1b in multiple sclerosis patients

C. Zeccaa, D.S. Meierb, U. Candriana, F. Cottonc, d, N. Nadarajaha, M. Sintzele, C.R.G. Guttmannb, C. Gobbia

a Neurocentre of Southern Switzerland, Ospedale Regionale di Lugano, Lugano, Switzerland

b Center for Neurological Imaging, Departments of Radiology and Neurology, Brigham and Women’s Hospital, Harvard Medical SchoolBoston, MA, USA

c Université de Lyon, Université Lyon 1, Laboratoire d’Anatomie de Rockefeller, Lyon et Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service de Radiologie , Pierre Bénite Cedex, France

d Université de Lyon, Université Lyon 1, Villeurbanne Cedex, France

e Medical Communication Services (MCS), Küsnacht, Switzerland

Background

Natalizumab (NAT) discontinuation leads to multiple sclerosis reactivation.

Objective

To explore the concept of natalizumab de-escalation to interferon beta-1b (IFNB-1b) compared to continued treatment with NAT.

Methods

One year, randomized, rater-blinded, parallel-group, pilot study. RRMS patients on NAT for >12 months and clinically stable (free from relapses and disability progression for >6 months, without enhancing lesions [CEL] at baseline MRI) were randomized to NAT or IFNB-1b. Primary endpoint was time to first on-study relapse. Secondary endpoints were frequency of relapse free patients, number of relapses per patient, number of new/enlarging T2 (NT2) lesions and CEL at months 3, 6, 9 and 12 vs baseline (BL). Analyses are based on the intention to treat population.

Results

Nineteen patients were included (NAT n = 10; IFNB-1b n = 9) having comparable baseline characteristics. Time to first on study relapse
showed a trend favouring NAT without reaching significance (p = 0.125, log-rank test). Among secondary clinical and radiological outcomes, the majority showed a trend favouring NAT without reaching significance except for number of NT2 lesions at month 6 being significantly higher in the IFNB-1b group (p = 0.043, U-Mann Whitney). Adverse events were within the expected range.

Conclusions

Our results suggest no pronounced inflammatory activity after de-escalation of NAT to IFNB-1b and indicate that the concept should be evaluated further.


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PostPosted: Sat Jan 19, 2013 9:13 am    Post subject: Nephrotic syndrome in MS patients on interferon beta-1b Reply with quote

From PubMed, January 19, 2013:

Quote:
Rinsho Shinkeigaku. 2013;53(1):19-23.

Nephrotic syndrome in multiple sclerosis patients who had undergone long-term interferon β-1b therapy

Ikeda K, Okamoto T, Yamamura T, Ohsawa I, Furutera R, Murata M.

Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry.

A 59-year-old man (case 1) with multiple sclerosis (MS) presented with shortness of breath and general fatigue. He had been treated using interferon β-1b (IFNβ-1b) since he was 51 years of age. Laboratory test results showed hypoproteinemia and hypoalbuminemia, proteinuria, and absence of hematuria. He was diagnosed with nephrotic syndrome, and the administration of IFNβ-1b was stopped. Percutaneous renal biopsy was performed, and the histology revealed membranous nephropathy.

A 33-year-old woman (case 2) with MS, who had been treated using IFNβ-1b for 7 years, was diagnosed with proteinuria during a medical checkup. She was referred to a nephrologist and was found to have hypoalbuminemia and proteinuria. A diagnosis of nephrotic syndrome was made, and IFNβ-1b therapy was stopped. The patient underwent percutaneous renal biopsy, and the histology revealed membranous nephropathy.

Both patients were treated using intravenous methylprednisolone followed by oral prednisolone.

Case 1 was administered ciclosporin orally, and his clinical symptoms and laboratory test results improved at first, but his laboratory test results subsequently showed recurrence of proteinuria. Case 2 was administered mizoribine orally, resulting in improvement in clinical symptoms and laboratory test results.

Case 2 showed relapse of multiple sclerosis, but the symptoms were mild and were alleviated after steroid therapy. IFNβ therapy has several complications including nephropathy.

Previously, several cases of nephrotic syndrome associated with IFNβ within 2 years of therapy were reported, but drug-induced nephropathy could appear after several years of the therapy as our cases. We should pay attention to nephrotic syndrome under using long-term IFNβ.

PMID:23328061


The abstract can be seen here.
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PostPosted: Fri Feb 08, 2013 9:33 pm    Post subject: (Abst.) Nephrotic syndrom in an MS patient on Betaseron Reply with quote

From NTK Institute Today in General Medicine, February 8, 2013:

Quote:

Am J Kidney Dis. 2013 Jan 31.

Nephrotic Syndrome in a Multiple Sclerosis Patient Receiving Long-term Interferon Beta Therapy.

Wallbach M, Gröne HJ, Kitze B, Müller GA, Koziolek MJ.

Department of Nephrology and Rheumatology, Georg-August-University, Goettingen, Germany.

Recombinant interferon α (IFN-α) and interferon β (IFN-β) are efficient drugs for clinical use in multiple sclerosis, hepatitis C virus infection, and malignant diseases.

We report a case of a 40-year-old woman with relapsing-remitting multiple sclerosis who was treated with interferon beta-1b for several years before being admitted to our department with nephrotic-range proteinuria (protein excretion, 8.3 g/d) and serum albumin level of 2.9 g/dL without any clinical and laboratory change typical for a systemic autoimmune disease.

The kidney biopsy led to the diagnosis of immune complex-mediated membranoproliferative glomerulonephritis with immunoglobulin and complement deposits visible by immunohistology, as well as subendothelial deposits and tubuloreticular inclusions evident by electron microscopy.

Subsequently replacing interferon beta-1b with glatiramer acetate resulted in partial remission, with proteinuria decreasing to protein excretion of 1.0 g/d 2 months thereafter. The association of a focal mesangiocapillary glomerular change and immunoglobulin-complement deposits with tubuloreticular inclusions suggests lupus nephritis.

To our knowledge, this is the first report of an interferon beta-1b-induced immune complex glomerulonephritis characterized by histologic, immunohistologic, and ultrastructural features that resembled lupus nephritis, but that occurred in a patient without evidence of systemic lupus erythematosus. Our review of experimental data and earlier case reports suggests a pathogenic role of recombinant IFN in some autoimmune diseases, especially those with the potency to induce systemic lupus erythematosus-like syndromes.

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PostPosted: Thu May 16, 2013 1:53 pm    Post subject: (Abst.) Limited effect of IFN-beta for SPMS--Cochrane review Reply with quote

From PubMed, May 15, 2013:

Quote:
Ugeskr Laeger. 2013 May 6;175(19):1342-1344.

[Limited effect of interferon-beta for the treatment of secondary progressive multiple sclerosis.]

[Article in Danish]

Schreiber K, Voldsgaard A, Sřrensen PS.

Source:

Dansk Multipel Sclerose Center, Afsnit 2082 N5, Rigshospitalet, Blegdamsvej 9, 2100 Křbenhavn Ř. karen.schreiber@rh.dk.

Interferon (IFN)-beta 1b is approved for the treatment of secondary progressive multiple sclerosis (SPMS) with relapses in the EU.

This Cochrane review analysed all double- or single-blinded randomised placebo controlled studies that had evaluated the efficacy of IFN-beta versus placebo in SPMS. The meta-analysis included five studies with 3,122 patients in all; 1,829 of these received IFN-beta.

The study concluded that IFN-beta did not prevent the development of permanent physical disability in patients with SPMS, but significantly reduced the risk of relapse and of short-term relapse-related disability.

In accordance with these findings, the Danish national guidelines recommend IFN-beta 1b treatment only for relapsing or rapidly progressing SPMS. Evaluation of the beneficial effect must be done every 6-12 months and the treatment should be discontinued if progression continues.

PMID: 23663372


The abstract can be seen here.
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PostPosted: Mon Jun 03, 2013 6:37 pm    Post subject: (Abst.) IL 17F & IFN-beta response in PwMS Reply with quote

From JAMA Neurology, June 3, 2013:

Quote:
Interleukin 17F Level and Interferon Beta Response in Patients With Multiple Sclerosis

Hans-Peter Hartung, MD; Lawrence Steinman, MD; Douglas S. Goodin, MD; Giancarlo Comi, MD; Stuart Cook, MD; Massimo Filippi, MD; Paul O’Connor, MD; Douglas R. Jeffery, MD; Ludwig Kappos, MD; Robert Axtell, MS, PhD; Volker Knappertz, MD; Timon Bogumil, MD; Susanne Schwenke, PhD; Ed Croze, PhD; Rupert Sandbrink, MD, PhD; Christopher Pohl, MD


Importance

High serum levels of interleukin 17F (IL-17F) at baseline have been associated with suboptimal response to interferon beta in patients with relapsing-remitting multiple sclerosis.

Objective

To further investigate the role of IL-17F in predicting treatment response to interferon beta-1b in patients with relapsing-remitting multiple sclerosis using the Singulex Erenna IL-17F immunoassay.

Design, Setting, and Patients

Serum samples were analyzed from 239 randomly selected patients treated with interferon beta-1b, 250 μg, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study.

Exposure

Treatment with interferon beta-1b, 250 μg, for at least 2 years.

Main Outcome Measures

Levels of IL-17F at baseline and month 6 as well as the difference between the IL-17F levels at month 6 and baseline were compared between the following: (1) patients with less disease activity vs more disease activity; (2) patients with no disease activity vs some disease activity; and (3) responders vs nonresponders.

Results

Levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging criteria. Relapses and new lesions on magnetic resonance imaging were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change. All patients with levels of IL-17F greater than 200 pg/mL were associated with poor response with some clinical or radiological activity.

Conclusions and Relevance

An increase of IL-17F before and early after treatment with interferon beta-1b was not associated with poor response. These data do not support the value of IL-17F as a treatment response indicator for therapy of patients with multiple sclerosis with interferon beta, although high levels of IL-17F greater than 200 pg/mL may predict nonresponsiveness.
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PostPosted: Fri Jul 12, 2013 5:35 pm    Post subject: (Abst.) IFN beta-1b reduces black holes... Reply with quote

From Multiple Sclerosis Journal, July 10, 2013:

Quote:
Interferon beta-1b reduces black holes in a randomised trial of clinically isolated syndrome

Gijsbert JA Nagtegaal1
Christoph Pohl2,3
Mike P Wattjes1
Hanneke E Hulst1
Mark S Freedman4
Hans-Peter Hartung5
David Miller6
Xavier Montalban7
Ludwig Kappos8
Gilles Edan9
Dirk Pleimes10
Karola Beckman2
Brigitte Stemper2
Christoph H Polman1
Rupert Sandbrink2,5
Frederik Barkhof1

1Department of Radiology and Nuclear Medicine, VU University Medical Centre, The Netherlands
2Global Clinical Development, Bayer Pharma AG, Germany
3Department of Neurology, University Hospital of Bonn, Germany
4Department of Medicine, Ottawa Hospital Research Institute, Canada
5Neurology Clinic, Heinrich-Heine-Universität, Germany
6Institute of Neurology, National Hospital for Neurology and Neurosurgery, UK
7MS Centre of Catalonia, Hospital Vall d’Hebron, Spain
8Department of Neurology, University of Basel and University Hospital, Switzerland
9Service de Neurologie, Université of Rennes, France
10Global Medical Affairs, Bayer HealthCare Pharmaceuticals, USA
Frederik Barkhof, VU University Medical Centre, Room PK 0 X 116, PO Box 7057; 1007 MB Amsterdam, The Netherlands. Email: f.barkhof@vumc.nl


Background:

Multiple sclerosis (MS) is characterised by inflammatory lesions of the central nervous system. Interferon beta-1b (IFNB-1b) has been shown to improve clinical and magnetic resonance imaging (MRI) measures for patients with MS.

Objective:

To evaluate whether IFNB-1b in patients presenting with clinically isolated syndromes (CIS) prevented persisting T1 hypointensities on MRI (persistent black holes (PBHs)).
Methods: In the placebo-controlled phase, patients (n = 468) were initially randomised to IFNB-1b (n = 292) or placebo (n = 176) for two years or clinically definite MS (CDMS). In the open-label phase (n = 418), both groups were offered IFNB-1b for up to five years. Lesions were classified as PBHs if T1 hypointensity persisted throughout the last available scan (minimum time one year).

Results:

A total of 435 patients were evaluable for analysis. The number of PBHs/patient was lower in the early rather than the delayed treatment arm during both phases (.42 vs .71, p = .0102 and .70 vs 1.17, p = .0121). Exploratory analyses identified baseline characteristics that affected rate of conversion.

Conclusions:

Although the rate of lesions that converted to PBH showed no significant differences between groups, the numbers of PBHs per patient out of new lesions was significantly lower in IFNB-1b patients compared to patients on placebo. Trial registration number: NCT00544037.
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