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Sclerosis Journal
Systematic review of disease-modifying therapies to assess unmet needs in multiple sclerosis:
tolerability and adherence
G Giovannoni, E Southam and E Waubant
Mult Scler 2012 18: 932 originally published online 16 January 2012
DOI: 10.1177/1352458511433302
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33302
MSJ18710.1177/1352458511433302Giovannoni et al.Multiple Sclerosis Journal
MULTIPLE
SCLEROSIS MSJ
JOURNAL
Review
Systematic review of disease-modifying
therapies to assess unmet needs in
multiple sclerosis: tolerability and
adherence
Multiple Sclerosis Journal
18(7) 932­–946
© The Author(s) 2012
Reprints and permissions:
sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1352458511433302
msj.sagepub.com
G Giovannoni1, E Southam2 and E Waubant3
Abstract
Reviews of therapeutic drugs usually focus on the highly selected and closely monitored patient populations from
randomized controlled trials. The objective of this study was to review systematically the tolerability and adherence
of multiple sclerosis disease-modifying therapies, using data from both randomized controlled trials and observational
settings. Relevant literature was identified using predefined search terms, and adverse event and study discontinuation
data were extracted and categorized according to study type (randomized controlled trial or observational) and study
duration. A total of 151 papers were selected for analysis; 33% were classified as randomized controlled trials and 62% as
observational studies. Most of the papers concerned interferon preparations and glatiramer acetate; the limited available
information on mitoxantrone and natalizumab precluded extensive examination of these. The most common adverse
events were flu-like symptoms (interferon therapies only) and injection-site reactions. Mean discontinuation rates ranged
from 16% to 27%. There were no marked differences in tolerability or adherence data from randomized controlled trials
and observational studies, but the incidence of adverse events remained high in lengthy studies and discontinuations
accumulated with time. The present systematic review of randomized clinical trial and observational data highlights the
tolerability and adherence issues associated with commonly used first-line multiple sclerosis treatments.
Keywords
adherence, glatiramer acetate, interferon, multiple sclerosis, review, tolerability
Date received: 30th March 2011; revised: 5th November 2011; accepted: 7th November 2011
Introduction
Subcutaneous interferon β-1b (IFNβ-1b SC; Betaferon®),
the first approved disease-modifying therapy (DMT) for
multiple sclerosis (MS), was launched in 1993. Since then,
other IFNβ formulations for intramuscular (IFNβ-1a IM,
Avonex®) or subcutaneous (IFNβ-1a SC, Rebif®) administration, together with DMTs with different mechanisms of
action, including glatiramer acetate (GA SC, Copaxone®),
natalizumab (Tysabri®) and mitoxantrone (Novantrone®),
have been licensed for use in relapsing–remitting MS
(RRMS). Previous reviews of primary clinical data suggest
that the clinical impact of IFNβ therapy is modest and that
the benefits of long-term treatment are unclear.1–3
Comparisons of GA SC and IFNβ-1a SC suggest similar levels of efficacy.4–6 Comparisons of natalizumab and mitoxantrone with interferon and GA therapies are limited.7–9 All
current first-line DMTs require regular, long-term, parenteral
administration. As with other chronic conditions, long-term
adherence to treatment regimens involving self-injection
may affect adherence and hence reduce the likelihood of
achieving maximum treatment efficacy.
Systematic reviews tend to have narrow inclusion criteria and focus on placebo-controlled, randomized clinical
trials (RCTs) because these studies are considered to produce the highest quality of evidence supporting treatment
1Blizard
Institute of Cell and Molecular Science, Barts and The London
School of Medicine and Dentistry, Queen Mary University of London,
London, UK.
2Oxford PharmaGenesis Ltd TM, Oxford, UK.
3University of California San Francisco, Regional Pediatric Multiple
Sclerosis Center, 350 Parnassus Ave, Ste 908, San Francisco, CA, USA.
Corresponding author:
Gavin Giovannoni, Blizard Institute of Cell and Molecular Science,
Barts and The London School of Medicine and Dentistry, Queen Mary
University of London, London, UK.
Email: [email protected]
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933
Giovannoni et al.
benefits.1,2 However, such studies usually include highly
selected, closely monitored patient populations; in clinical
practice, patient populations receiving DMTs will be more
heterogeneous and may lack regular contact with healthcare professionals. Although RCTs are necessary to gain
regulatory approval and can inform clinical practice, realworld observations may reflect the experience of the majority of patients more accurately. In other therapeutic areas,
such as heart failure and digestive surgery,10,11 reviews of
observational studies have provided additional information
from clinical practice that complements information from
RCTs. This systematic review of the literature was intended
to be comprehensive, and therefore includes RCTs and
observational studies of patients receiving current MS
DMTs: IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC, GA SC,
natalizumab and mitoxantrone. The report examines DMTs
from the perspective of the patient and focuses on measures
of tolerability and adherence.
Methods
Literature search criteria
Literature to evaluate clinical impact and tolerability of
licensed DMTs for MS was identified by searching PubMed
using the following string: (multiple AND sclerosis) AND
(interferon OR Betaferon OR Avonex OR Rebif) OR
(Tysabri OR Antegren OR natalizumab) OR (glatiramer
acetate OR Copaxone OR copolymer 1) OR (mitoxantrone
OR Novantrone). The search was limited to: English language, clinical trials (to avoid inclusion of reviews),
humans, adults and papers published from January 1993 to
October 2008. The results were refined by manually examining the titles of all of the papers identified in the search
and discarding any that did not obviously fit the criteria.
Literature to evaluate the impact of therapies on adherence to treatment was identified by searching PubMed
using the following strings: (multiple AND sclerosis) AND
(interferon OR Betaferon OR Avonex OR Rebif OR glatiramer acetate OR Copaxone OR Tysabri OR Antegren OR
natalizumab OR mitoxantrone OR Novantrone) AND
(adherence OR compliance OR concordance OR withdrawal OR dropout OR satisfaction); (multiple AND sclerosis) AND (disease AND modifying AND therapy) AND
(adherence OR compliance OR concordance OR withdrawal OR dropout OR satisfaction).
The quality of life and adherence searches were limited
by the following criteria: publication from January 1993 to
October 2008, English language and human studies in
adults. Because information on quality of life, adherence
and patient satisfaction was limited, these searches were
not restricted to clinical studies, ensuring that potentially
relevant papers were not missed. The titles of the references
identified were examined manually to exclude those that
were clearly irrelevant to the review.
Identifying papers for inclusion
The results from the searches were combined, duplicate
citations were removed, and the abstracts examined to
exclude those papers that were clearly irrelevant to the
review. Papers with no abstract were rejected. Studies
involving 40 or more patients with RRMS given active
treatment with IFNβ, GA, natalizumab or mitoxantrone
were retained if the abstract reported either clinical outcomes (relapse rates, disability) and/or safety outcomes.
Owing to the limited available information, no patientnumber restrictions were applied if adherence or patient
satisfaction were reported, providing patients with RRMS
treated with a DMT were included. Papers with abstracts
reporting only MRI outcome measures, small clinical studies (< 40 patients) with abstracts that did not report adherence or quality of life outcomes, or studies that did not
include treatment of RRMS with a DMT were rejected.
Papers reporting treatment with natural (i.e. non-recombinant) or oral IFNβ, oral GA or studies in forms of MS that
did not include RRMS were excluded.
The full text of references selected on the basis of their
abstracts was examined to ensure that the above criteria
were all fulfilled. Papers that reviewed other information
without presenting new analyses were excluded. Although
adherence outcomes reported from studies involving fewer
than 40 patients treated with DMT were included, clinical
and tolerability outcomes from these studies were excluded
to ensure consistency in approach with the exclusion of
small studies (< 40 patients treated with DMT) reporting
only clinical and tolerability outcomes.
Analysis of the incidence of adverse events
and rates of discontinuation
A minimum of five or more published studies (each involving > 40 patients) was required for a DMT to be analysed in
depth. In considering tolerability issues from the perspective of the patient, this review excluded laboratory outcomes. To keep data to manageable levels, an initial adverse
event incidence rate threshold of 10% was set for each individual study for inclusion in ranking adverse events according to their incidence as a proportion of the overall patient
population in all studies. Ranking was based on the number
of patients reporting particular adverse events across all
included studies as a proportion of numbers of participants
in the studies. Based on the results of the ranking, further
analyses focused on the incidence of flu-like symptoms
(FLSs) and injection-site reactions (ISRs). The occurrence
of these adverse events was analysed by study type (RCT or
observational) and duration based on the incidence rates in
all those studies in which the adverse event was reported
(including those in which incidence rates of FLSs and ISRs
were below 10%). In longitudinal studies, when tolerability
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Multiple Sclerosis Journal 18(7)
data from the same patient population were reported more
than once, data from each time point were included when
analyses fell in different study duration categories.
Reasons for discontinuation were characterized as: lack
of efficacy (including disease progression, disease activity,
signs and symptoms, treatment failure, disability progression, need for > 3 courses of steroids, exacerbation, aggravation of MS, relapse), adverse events, patient decision
(including voluntary withdrawal, consent withdrawal,
rejected treatment, psychopathological reasons, doctor recommendation, cost, hassle, patient preference), lost to follow-up (including moved away from area, no longer a
patient of investigator, patient failed to return), pregnancy
(including the desire to become pregnant) and death.
Reasons for discontinuation of therapy were presented as
the percentage of total discontinuations for each DMT for
which reasons were reported. Discontinuation rates were
stratified by study duration (≤ 12 months, 13–24 months, or
> 24 months). Mean (SD) values were calculated when data
from five or more studies were available (IFNβ-1a IM,
IFNβ-1a SC, IFNβ-1b SC and GA SC). If the same patient
population featured in multiple published papers (e.g. longitudinal studies), only the latest dataset was used for the
analysis of overall discontinuation rates.
Results
Overview of studies included in the review
A total of 1152 papers that reported the clinical impact and
tolerability of current DMTs for MS were identified.
Searches for literature on adherence in MS identified 70 references. Combining the searches, removing duplicate references and checking the titles and abstracts resulted in 183
papers of potential interest. After checking the full papers,
151 references fulfilled the criteria for inclusion in the
review. The number of relevant publications increased with
each 5-year period (1993–1997: 10 papers; 1998–2002: 45
papers; 2003–2007: 84 papers; see the Online Supplementary
Appendix, Supplementary Figure 1).
Table 1 shows the numbers of papers included in the
review according to treatment and study type. A third of
papers (33%; 50/151) were classified as RCTs. The majority of papers in the review (62%; 93/151) reported openlabel treatment (including open-label follow-up to RCTs)
and were classified as observational studies. The remaining
papers, including those reporting results of surveys, models
or studies using historical comparator groups were classified as ‘other studies’.
A total of 91 papers (60% of those included in the
review) reported studies involving a single DMT. Almost
half of these (43/91, 47%) described RCTs of which 22
(51%) were placebo-controlled, and 8 (19%) investigated
the impact of analgesic, cognitive or other interventions on
injection tolerability. Papers reporting studies with licensed
IFNβ preparations made up 70% of the papers describing
Figure 1. Incidence of flu-like symptoms by (A) study type and
(B) duration of treatment.
Data are presented as the proportions of patients with FLSs in each
study (horizontal lines represent man values) for the disease-modifying
therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250 µg
SC e.o.d. Where publications reported different aspects of FLSs, the most
frequently reported symptom is presented; likewise. e.o.d., every other
day; FLSs, flu-like symptoms; IFN, interferon; IM, intramuscular; q.w., once
per week; SC subcutaneous; t.i.w., three times per week.
Sources of data panel A: IFNβ-1a IM q.w.;12,14,15,19–30 IFNβ-1a
SC t.i.w.;13,25,26,29,31–34 IFNβ-1b SC e.o.d.14,21,28,29,34–44
Sources of data panel B: IFNβ-1a 30 µg IM q.w.;12,14,15,19,20,22–30,45,46 IFNβ-1a
44 µg SC t.i.w.;13,16,25–27,29,31–34,47–49 IFNβ-1b 250 µg SC e.o.d.14,28,29,34,35,37–43,50
RCTs of a single DMT, with studies on GA contributing a
further 14% to the total.
Details of the papers included in the review that describe
studies of MS DMTs are summarized in the Online
Supplementary Appendix (Supplementary Tables 1–5).
A total of 60 papers (40% of included papers) were
­identified that reported studies of more than one DMT.
Observational studies comprise the majority of these papers
(48, 80%), with seven RCTs and five other studies (predominantly surveys) also included (Online Supplementary
Appendix, Supplementary Table 6). Studies involving various IFNβ preparations are reported by 60% of the papers on
multiple DMTs, with publications of IFNβ/GA studies
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935
Giovannoni et al.
Table 1. Numbers of papers (patient numbers) analysed in the review by therapy and study type.
DMT
RCT
Observational
Other
Total
One DMT only
IFNβ-1a IM
IFNβ-1a SC
IFNβ-1b SC
GA
Natalizumab
Mitoxantrone
Multiple DMTs
IFNβ-1a IM/IFNβ-1a SC
IFNβ-1a IM/IFNβ-1b SC
IFNβ-1a SC/IFNβ-1b SC
Any/all/unspecified IFNβ
IFNβ/GA
Other combinations
Total
43 (8261)
12 (2222)
9 (3566)
9 (1374)
6 (770)
5 (233)
2 (96)
7 (7739)
3 (4173)
1 (188)
0 (0)
1 (94)
0 (0)
2 (3284)
50 (16,000)
45 (9937)
13 (1630)
5 (2841)
12 (2360)
12 (2818)
0 (0)
3 (288)
48 (23,044)
2 (231)
5 (776)
4 (1010)
20 (16,185)
11 (4074)
6 (768)
93 (32981)
3 (133)
0 (0)
1 (1)
2 (132)
0 (0)
0 (0)
0 (0)
5 (3080)
0 (0)
0 (0)
0 (0)
0 (0)
2 (770)
3 (2310)
8 (3213)
91 (18,331)
25 (3852)
15 (6408)
23 (3866)
18 (3588)
5 (233)
5 (384)
60 (33,863)
5 (4404)
6 (964)
4 (1010)
21 (16,279)
13 (4844)
11 (6362)
151 (52,194)
DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; RCT, randomized controlled trial; SC, subcutaneous.
comprising a further 22% of these papers. Several studies
reported switching between different DMTs (Online
Supplementary Appendix, Supplementary Table 7).
Tolerability of treatments
All eligible papers were examined for information on tolerability. The incidence of all adverse events that occurred in
> 10% of patients in each individual study was extracted
from each paper and the overall incidence of adverse events
in the combined patient populations for IFNβ and GA treatments are ranked according to their designation in the source
papers in Table 2. Excluding laboratory outcomes, the most
commonly reported adverse events in patients receiving
IFNβ-1a IM, IFNβ-1a SC, IFNβ-1b SC and GA SC were
FLSs (interferon treatments only) and ISRs. The occurrence
of these adverse events is examined in more detail below.
The small number of studies did not permit an extensive
analysis of the tolerability profiles of mitoxantrone and
natalizumab in RCTs and observational studies.
Table 3 reports the results of the analysis of all reports of
FLSs and ISRs (including incidence rates of < 10%). FLSs
were reported in all interferon treatment groups with an
incidence of 57% of 3861 patients receiving IFNβ-1a IM,
40% of 1833 patients receiving IFNβ-1a SC and 32% of
3811 patients receiving IFNβ-1b SC. The proportion of
patients receiving interferon treatments reporting FLSs by
study type is summarized in Figure 1A.12–16,19–50 With the
caveat that inter-study variability in the reporting of FLSs
was high, there was no clear evidence of a consistent difference in incidence rates of FLSs between the two study
types for all three interferon treatments. In RCT and observational studies, respectively, the mean ± SD incidences of
FLSs in patients receiving interferon treatments were:
IFNβ-1a IM, 57 ± 23% versus 57 ± 26%; IFNβ-1a SC, 52 ±
17% versus 25 ± 27; IFNβ-1b SC, 44 ± 29% versus 34 ±
23%. The proportion of patients reporting FLSs over different durations of interferon treatment is shown in Figure 1B.
Although the number of studies in each study duration category is too small to permit firm conclusions, there appears
to be no evidence of the incidence of FLSs changing as a
result of the extended administration of IFNβ. In studies
exceeding 24 months duration, the mean incidence of FLSs
ranged from 22% (IFNβ-1a SC, 3 studies) to 55% (IFNβ-1a
IM, 4 studies).
ISRs were more commonly reported in patients receiving IFNβ-1a SC (65% of 2676 patients) and GA SC (61%
of 1997 patients) than in patients receiving IFNβ-1b SC
(33% of 3466 patients) or IFNβ-1a IM (22% of 2885
patients). A breakdown of patients who experienced ISRs
by study type is summarized in Figure 2A.14–22,24–27,29,31–42,
47–49,51–61 Again, with the caveat that inter-study variability
in the reporting of ISRs was high, there was no consistent
difference in the reporting rates of ISRs between the two
study types for all of the MS DMTs. In RCT and observational studies, respectively, the mean ± SD incidences of
ISRs in patients receiving interferon treatments were:
IFNβ-1a IM, 21 ± 12% versus 20 ± 11%; IFNβ-1a SC, 70 ±
8% versus 41 ± 30%; IFNβ-1b SC, 56 ± 31% versus 37 ±
21%; GA SC, 78 ± 12% versus 56 ± 29%. Figure 2B presents the occurrence of ISRs according to study duration.
Although the numbers of studies in each study duration category is too small to permit firm conclusions, there appears
to be no amelioration of the incidence of ISRs as a result of
the extended administration of these parenteral DMTs. In
studies exceeding 24 months duration, the mean incidence
of ISRs ranged from 22% (IFNβ-1a IM, 2 studies) to 60%
(IFNβ-1b SC, 2 studies).
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55.3
24.4
14.4
14.3
11.8
10.9
7.3
6.9
5.4
5.4
5.1
5.1
4.9
4.8
3.6
3.4
3.3
3.1
3.1
2.9
2.7
2.6
2.2
2.2
2.1
2.0
1.9
1.8
Flu-like symptoms
Headache
Myalgia/muscle ache
Depression
Injection-site reactions
Fatigue
Accidental injury
Fever
Nausea
Insomnia
Nasopharyngitis
Cold symptoms
Asthenia
Ill/distressed after injection
Chills
Sinusitis
Diarrhoea
Pain (unspecified)
Limb pain
Arthralgia
Injection-site pain
Paraesthesia
Loss of strength
Hypesthesia/numbness
Muscle weakness
Dizziness
Indigestion and dyspepsia
Loss of control of limbs/
hypertonia
injection-site redness
Malaise
Pharyngitis
Injection-site ecchymosis
Back pain
Injection-site reactions
Flu-like symptoms
Injection-site inflammation
Headache
Fatigue
Rhinitis
Myalgia/muscle ache
Injection-site pain
Fever
Depression
Other injection-site reactions
Rigors
Hepatic disorders
Injection-site erythema
Arthralgia
Menstrual disorders
Nasopharyngitis
IFNβ-1a SC (n = 2682)
56.4
27.6
19.2
18.2
10.6
8.7
7.0
5.7
5.3
4.8
4.4
2.0
1.3
0.7
0.6
0.4
0.4
%
Flu-like symptoms
Injection-site reactions
Cutaneous lesions
Systemic symptoms
Fever
Arthralgia
Asthenia
Fatigue
Injection-site inflammation
Depression
Headache
Myalgia/muscle ache
Feels ill/distressed
Injection-site erythema
Paraesthesia
Weakness
Rhinitis
Unspecified pain
Lymphadenopathy
IFNβ-1b SC (n = 3960)
30.0
18.3
14.3
7.6
5.7
4.4
3.6
2.3
2.3
1.9
1.7
1.7
1.1
1.0
1.0
0.9
0.6
0.4
0.2
%
Injection-site reactions
Systemic injection reaction
Immediate injection-site reaction
Local symptoms
Injection-site pain
Injection-site erythema
Injection-site pruritus
Injection-site mass
Chest tightening
Injection-site inflammation
Depression
Injection-site ecchymosis
Injection-site induration
Flushing
Injection-site burning
Paraesthesia
Muscle spasm
GA SC (n = 1997)
54.6
9.2
7.8
6.6
4.5
3.6
2.4
2.1
1.8
1.7
1.6
1.4
1.2
0.5
0.3
0.3
0.1
%
Adverse events were ranked in order of their incidence in the overall patient population. An adverse event incidence rate threshold of 10% was set for each individual study for inclusion in this analysis.
Laboratory outcomes were not included in this analysis. GA, glatiramer acetate; IFN, interferon; IM, intramuscular; SC, subcutaneous.
1.3
0.8
0.8
0.5
0.5
%
IFNβ-1a IM (n = 3921)
Table 2. Incidence (%) of reported adverse events in overall patient populations ranked in decreasing order.
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Multiple Sclerosis Journal 18(7)
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Giovannoni et al.
Table 3. Incidence of flu-like symptoms and injection-site reactions associated with MS disease-modifying therapies.
FLSs
IFNβ-1a 30 µg IM q.w.
IFNβ-1a 44 µg SC t.i.w.
IFNβ-1b 250 µg SC e.o.d.
ISRs
IFNβ-1a 30 µg IM q.w.
IFNβ-1a 44 µg SC t.i.w.
IFNβ-1b 250 µg SC e.o.d.
GA 20 mg SC o.d.
Total number
of patients
Number (%) reported
FLSs or ISRs
Maximum incidence
in single dataset
Mean (SD) incidence
across all datasets
3861
1833
3811
2198 (57%)
741 (40%)
1222 (32%)
92% [12]
71%[13]
77%[14]
54 (27)
38 (25)
39 (26)
2855
2676
3466
1997
626 (22%)
1744 (65%)
1153 (33%)
1226 (61%)
39%[15]
85%[16]
98%[17]
90%[18]
20 (11)
54 (26)
46 (27)
64 (26)
When individual publications report different flu-like or injection-related adverse events, the highest values were analysed. e.o.d., every other day;
FLSs, flu-like symptoms; GA, glatiramer acetate; IFN, interferon; IM, intramuscular; ISRs, injection-site reactions; q.w., once weekly; o.d., once daily; SC,
subcutaneous; t.i.w., three times per week.
Headache, fatigue and muscle aches/myalgia were commonly reported by patients receiving both IM and SC
IFNβ-1a preparations. Across the 19 analysed studies on
IFNβ-1a IM, the overall incidence of headache was 25%
(maximum 67%),19 fatigue was 13% (maximum 64%)15
and myalgia/muscle ache was 14% (maximum 85%).15
Across the 10 analysed studies on IFNβ-1a SC, the overall
incidence of headache was 27% (maximum 73%),47 fatigue
was 15% (maximum 44%)47 and muscle ache/myalgia was
10% (maximum 30%).47 In contrast, the mean reported
incidence of these symptoms was ≤5% in patients receiving
IFNβ-1b SC and GA SC although considerably higher rates
were reported in individual studies (e.g. headache in 51%
of patients receiving IFNβ-1b SC).35 Although possibly
confounded by its co-morbidity with MS, depression was
experienced by 11% of patients receiving IFNβ-1a IM
(maximum 40%)20 and 7% of patients receiving IFNβ-1a
SC (maximum 33%),47 but by < 2% of patients receiving
IFNβ-1b SC and GA SC.
Adverse event data was limited for mitoxantrone and
natalizumab, but commonly reported adverse events associated with the former were nausea (reported in ≤ 27% of
patients), alopecia/hair loss (≤ 33%) and amenorrhoea (≤
37%)62–64 and with the latter were headache (≤ 47%) and
infections (including nasopharyngitis and urinary tract
infections, ≤ 79%).65–67
Adherence to treatments
Overall (mean ± SD) discontinuation rates were: IFNβ-1a
IM, 20% of 5898 patients (20 ± 14%, 32 studies); IFNβ-1a
SC, 17% of 3446 patients (16% ± 11%, 17 studies); IFNβ-1b
SC, 23% of 3942 patients (22% ± 15%, 25 studies) and GA
SC, 36% of 2855 patients (27% ± 18%, 15 studies). Figure
3A summarizes the discontinuation rates for the IFNβ and
GA treatments according to study type (RCT and observational studies). The figure demonstrates that there was
­considerable variation between the studies in discontinuation
rates for each DMT and that there is no clear pattern emerging for data from RCTs compared with that from obser­
vational studies.13–17,19–25,27–32,34,35,37–40,42,44,45,48,49,54–61,68–94
Figure 3B presents discontinuation rates for the IFNβ therapies and GA according to duration of treatment. Mean ± SD
percentage discontinuation rates in long-term studies (> 24
months) were: IFNβ-1a IM, 30 ± 16%; IFNβ-1a SC, 22 ±
10%; IFNβ-1b SC, 34 ± 14%; and GA SC, 43 ± 14%. A
total of 12% of 343 patients (4 studies) discontinued mitoxantrone before the end of the planned regimen, and 11% of
755 patients (3 studies) discontinued natalizumab. Owing
to the limited data, discontinuation rates for mitoxantrone
and natalizumab were not analysed further.
The reasons for discontinuation were grouped according
to the following categories: lack of efficacy, adverse events,
patient decision, change in dose/therapy, lost to follow-up,
pregnancy, death and other. Figure 4 presents each of the
reported reasons for discontinuation as a proportion of the
total reasons for discontinuation for each therapy.13–17,19–25,
27–32,34,35,38–40,42,44,45,47,49,54–56,59–61,68–73,75–85,88–94
The occurrence of adverse events was the most common explanation for the discontinuation of IFNβ-1a SC
(64% of 256 reasons for discontinuation of the licensed
dose, 14 studies) and IFNβ-1b SC (44% of 730 reasons,
23 studies), and also accounted for 23% (of 851 reasons,
30 studies) and 19% (of 870 reasons, 12 studies) of the
discontinuations of IFNβ-1a IM and GA SC treatment,
respectively. Perceived lack of efficacy was the most frequently provided explanation for discontinuing IFNβ-1a
IM treatment (28%), and accounted for 26% of the reasons provided for ceasing IFNβ-1b SC treatment, but was
a minor cause of discontinuing IFNβ-1a SC (11%) and
GA SC (6%). Patient decision was recorded as the reason
for discontinuing treatment in 11–19% of cases across
therapy groups. Over a third (37%) of discontinuations of
GA SC therapy were reported as lost to follow-up (compared with < 5% for IFNβ-1a IM, IFNβ-1a SC and
IFNβ-1b SC).
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Figure 2. Incidence of injection-site reactions by (A) study
type and (B) duration of treatment.
Data are presented as the proportions of patients with ISRs in each
study (horizontal lines represent mean values) for the disease-modifying
therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250
µg SC e.o.d.; GA 20 mg SC o.d. Where papers reported different aspects
of ISRs, the most frequently reported symptom is presented. e.o.d., every other day; GA, glatiramer acetate; IFN, interferon; IM, intramuscular;
ISRs, injection-site reactions; o.d., once daily; q.w., once per week;
SC subcutaneous; t.i.w., three times per week.
Sources of data panel A: IFNβ-1a IM q.w.;14,15,19–22,24–27,29,51 IFNβ-1a
SC t.i.w.;13,16,25–27,29,31–34,47–49,52,53 IFNβ-1b SC e.o.d.;14,21,29,34–42,51
GA SC o.d.18,21,54–61
Source of data panel B: IFNβ-1a 30 µg IM q.w.;14,15,19,20,22,24–27,29,51
IFNβ-1a 44 µg SC t.i.w.;13,16,25–27,29,31–34,47–49 IFNβ-1b 250 µg
SC e.o.d.;14,17,29,34,35,37–42,51 GA 20 mg SC o.d.18,54–61
Discussion and conclusions
The data generated in this review highlight the tolerability
and adherence issues associated with current commonly
used MS DMTs. The majority of studies included in this
analysis concern treatment with IFNβ preparations and GA.
The limited number of studies reporting mitoxantrone and
natalizumab use precluded a detailed analysis of their tolerability issues. IFNβ therapies were associated with high
levels of FLSs and high levels of ISRs were observed in
Figure 3. Treatment discontinuation by (A) study type and (B)
duration of treatment.
Data are presented as the proportions of patients (horizontal lines
represent mean values) discontinuing from the the disease-modifying
therapies IFNβ-1a 30 µg IM q.w.; IFNβ-1a 44 µg SC t.i.w.; IFNβ-1b 250
µg SC e.o.d.; GA 20 mg SC o.d. e.o.d., every other day; GA, glatiramer
acetate; IFN, interferon; IM, intramuscular; o.d., once per day; q.w., once
per week; SC subcutaneous; t.i.w., three times per week.
Sources of data panel A: IFNβ-1a IM q.w.;14,15,19–25,28,29,45,68–86
IFNβ-1a SC t.i.w.;13,16,25,27,29,31,32,34,48,49,73,81–84,87 IFNβ-1b SC
e.o.d.;14,17,21,28,29,34,35,37–40,42,44,73,80–85,88–90 GA SC o.d.18,21,54–58,60,61,85,91–93
Sources of data panel B: IFNβ-1a 30 µg IM q.w.;14,15,19,20,22–25,28–30,45,68–72,74–
85 IFNβ-1a 44 µg SC t.i.w.;13,16,25,27,29,31,32,34,49,81–84,87 IFNβ-1b 250 µg SC
e.o.d.;14,17,28,29,34,35,38–40,42,44,80–85,88–90,94 GA 20 mg SC o.d.18,54–57,59–61,85,91–93
patients receiving parenteral DMTs. The incidence of
adverse events was highly variable between studies, but
there was no consistent evidence of differences between
RCTs and observational studies for all DMTs, or of attenuation in longer-term studies. Discontinuation of treatment
ranged from 17% (IFNβ-1a SC) to 36% (GA SC) with the
most common reasons for discontinuation reported to be
the occurrence of adverse events and lack of treatment
efficacy.
This survey identified FLSs and ISRs as the most common tolerability issues associated with these widely used
MS DMTs. FLSs frequently occur in patients treated with
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Giovannoni et al.
Figure 4. Reasons for discontinuation of therapy.
The proportions of discontinuations in each column include only those
discontinuations for which the reasons were reported. Total numbers
of reported reasons for discontinuation for each disease-modifying
therapies were: IFNβ-1a IM, 831; IFNβ-1a SC, 198; IFNβ-1b SC, 578; GA
SC, 870. Lack of efficacy includes: disease progression, disease activity, signs and symptoms, treatment failure, disability progression, need
for > 3 courses of steroids, exacerbation, aggravation of MS, relapse.
Adverse events include: allergic reaction, needle phobia, polyneuritis,
injections, positive needle prick test. Patient decision includes: voluntary
withdrawal, consent withdrawal, rejected treatment, psychopathological reasons, doctor recommendations, cost, hassle, patient preference.
Lost to follow-up includes: moved away from area, no longer a patient
of investigator, patient failed to return. Pregnancy includes the desire to
become pregnant. AE, adverse events; e.o.d., every other day; GA,
glatiramer acetate; IFN, interferon; IM, intramuscular; o.d., once per day;
q.w., once per week; SC subcutaneous; t.i.w., three times per week.
Data sources: IFNβ-1a 30 µg IM q.w.;14,15,19–25,28–30,45,68–73,75–85
IFNβ-1a 44 µg SC t.i.w.;13,16,25,27,29,31,32,34,47,49,73,81,83,84 IFNβ-1b 250 µg
SC e.o.d.;14,17,21,28,29,34,35,38–40,42,44,73,80–85,88–90,94 GA 20 mg
SC o.d.21,54–56,59–61,85,91–93
interferon preparations, although patients receiving
IFNβ-1a IM reported more FLSs (over half) than patients
receiving IFNβ-1a SC or IFNβ-1b SC. FLSs with interferon
preparations were observed despite the inclusion of studies
that used symptomatic treatments and dosage regimens
aimed at reducing their incidence.12,36,45,46,68 FLSs were not
reported in any GA SC or mitoxantrone studies, and were
reported only in a single study of natalizumab. The finding
of ISRs as a significant tolerability issue for all parenterally
administered MS DMTs was anticipated. SC administration
was associated with more frequent ISRs than IM administration, with only 22% of surveyed patients receiving
IFNβ-1a IM reporting ISRs compared with 65% and 61%
of patients, respectively, receiving IFNβ-1a SC and GA SC.
This review revealed rates of discontinuation from MS
DMTs ranging from 17% (IFNβ-1a SC) to 36% (GA SC).
The occurrence of adverse events was the most common
reason for the discontinuation of IFNβ-1a SC and IFNβ-1b
SC. ISRs lead directly to discontinuation and several studies also reported psychological factors associated with regular injections, including anxiety and injection phobia, that
may adversely impact adherence to current MS
DMTs.21,45,69,70,95–98 Patients receiving software-facilitated
telephone counselling or telephone-administered cognitive
behavioural therapy to support IFNβ administration were
more likely to adhere to therapy.71,72 The large proportion
of patients who discontinued GA SC therapy and were lost
to follow-up (37%) may have been influenced by the large
number of patients (159 of 247 reasons for discontinuation)
who were lost to follow-up in a single study.54 Perceived
lack of efficacy was identified as a key factor in poor patient
adherence,73 particularly to IFNβ-1a IM and IFNβ-1b SC,
although it was only a minor cause of discontinuing GA.
Adverse events may reduce patient perceptions of the benefits of treatment, such that some patients may prefer not to
be treated.100 Although efficacy outcomes have not been
reported here, other reviews indicate that the improvement
in relapse rates with commonly used DMTs is modest.1–5,99
It is, therefore, possible that a proportion of the patients
whose withdrawal from IFNβ and GA therapies was due to
‘patient decision’ and/or a ‘change in dose/therapy’ was
because of unidentified tolerability issues or the desire for
more effective treatment.
Patients who do not discontinue entirely from a DMT
may fail to take the medication according to the indicated
dosing schedule. In a study to assess MS DMT adherence,
14% of patients taking IFNβ or GA took fewer than 80% of
prescribed doses during the previous month.101 A survey of
681 patients found that 117 (17%) stopped taking their DMT
but restarted again within 4 months on at least one occasion.102 Other factors associated with poor adherence to
DMTs were investigated in studies included in the review. A
study of IFNβ-1a IM found that women were more likely to
discontinue than men, but discontinuations were not correlated with walking ability, time on medication or education.71 More years since MS diagnosis and low belief in
efficacy of treatment were associated with lower adherence101. In another study of patients prescribed GA, four
significant predictors of adherence were identified: high
levels of self-efficacy (measured using the MS Self-Efficacy
scale), hope (measured using the Herth Hope Index), belief
that physicians were supportive, and no previous use of
immunomodulators.103 In a prospective study, score on the
MS Self-Efficacy scale predicted adherence to GA.91
Study duration was not clearly shown to clearly affect
the reporting of tolerability issues, despite examples of the
incidence of FLSs declining within a single study.15,22 In
studies exceeding 24 months’ duration, the incidences of
FLSs and ISRs were not markedly different than with
shorter-term therapy. However, there was a trend for each
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Multiple Sclerosis Journal 18(7)
of the DMTs for discontinuations to accumulate with time.
These data suggest that tolerability issues persist during
extended treatment with DMTs.
Taken together, the observations on tolerability and
adherence suggest that there is patient dissatisfaction with
current DMTs. The high level of use of complementary
and alternative medicines (by an estimated 57–70% of
patients with MS) supports the view that conventional
therapies are not adequately meeting patient needs.104,105
There is, therefore, an impetus to enhance adherence to
MS DMTs in the future. The occurrence of FLSs is related
to the mechanism of action of IFNβ treatments and ISRs
are inherent to parenterally administered drugs. Ongoing
strategies to improve adherence include amelioration of
FLSs and ISRs through dose titration, a reduction in the
gauge of syringe needles, cognitive therapy and the prophylactic use of anti-inflammatory drugs, and the development of oral therapies with modes of action that differ
from current approved medications.106
Systematic reviews tend to concentrate on RCTs rather
than observational studies. This review is unique as it
encompasses 151 MS studies including both RCTs and
observational clinical surveys. A central objective of these
analyses was to investigate how well outcomes from RCTs
are reflected in observational studies that are conducted in
less rigorously controlled but more realistic clinical settings. Although the extent of inter-study variability may
have obscured subtle differences, no consistent differences
in the incidence of FLSs and ISRs were detected in RCTs
and observational studies of MS DMTs. Similarly, although
it has been previously reported that adherence rates of firstline MS DMTs are higher in clinical trials than in clinical
practice,107 the present review found no discernable differences between rates of discontinuation of MS DMTs in
RCT and observational studies. Based on this survey of
first-line MS DMTs therefore, it appears that it is appropriate to include observational studies in a systematic review
of MS DMTs, at least with regard to tolerability and adherence data. Moreover, this review indicates that tolerability
and adherence issues are associated with the use of firstline DMTs in uncontrolled, real-life environments as well
as RCT settings.
It is also important to recognize the limitations of the
present analyses. The synthesis of outcome measures with
different dosage regimens, assessed at a wide range of time
points, inevitably led to broad categorization of data (e.g.
use of time periods, rather than specific time points) and
precludes extensive statistical analysis. Some of the variability apparent in the figures presented here may be due to
these methodological considerations. The lack of standardization of adverse events and reasons for discontinuation
may have contributed to some of the inter-study variation
observed. By setting an initial incidence rate threshold of
10% for each study for adverse event data to be included in
the analysis, it is likely that the present review has
underestimated the overall incidence of adverse events,
particularly those that occur relatively infrequently.
Although such methodological considerations may have
obscured some subtle effects and resulted in infrequent
events being overlooked, the all-encompassing nature of
the present analyses suggest that the central conclusions
regarding the incidence of adverse events, particularly
FLSs and ISRs, and adherence rates are robust.
In conclusion, this review of 151 published studies
assessed both RCT and observational studies and found
that patients treated with commonly used MS DMTs experience high rates of adverse events, particularly FLSs and
ISRs. Furthermore, adherence to currents treatments is
poor. With several orally administered DMTs of various
modes of action under development, there is hope that
patient needs may be met better in the future.
Acknowledgement
Literature searching and editorial assistance was provided by
Oxford PharmaGenesis™ Ltd (Eric Southam PhD, Rowena
Hughes PhD and Diane Storey PhD).
Funding
This literature analysis was supported by Novartis Pharmaceuticals
Corporation.
References
1. Rice GP, Incorvaia B, Munari L, Ebers G, Polman C,
D’Amico R, et al. Interferon in relapsing–remitting multiple
sclerosis. Cochrane Database Syst Rev 2001; CD002002.
2. Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C,
D’Amico R, et al. Interferons in relapsing remitting multiple
sclerosis: a systematic review. Lancet 2003; 361: 545–552.
3. Bayas A and Gold R. Lessons from 10 years of interferon
beta-1b (Betaferon/Betaseron) treatment. J Neurol 2003; 250
(Suppl.4): IV3–8.
4. Wolinsky JS. Glatiramer acetate for the treatment of multiple
sclerosis. Expert Opin Pharmacother. 2004; 5: 875–891.
5. Wolinsky JS. The use of glatiramer acetate in the treatment
of multiple sclerosis. Adv Neurol 2006; 98: 273–292.
6. Mikol DD, Barkhof F, Chang P, Coyle PK, Jeffery DR, Schwid SR, et al. Comparison of subcutaneous interferon beta1a with glatiramer acetate in patients with relapsing multiple
sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS
Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008; 7: 903–914.
7. Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J
Med 2007; 356: 2622–2629.
8. Bartt RE. Multiple sclerosis, natalizumab therapy, and progressive multifocal leukoencephalopathy. Curr Opin Neurol
2006; 19: 341–349.
9. Scott LJ and Figgitt DP. Mitoxantrone: a review of its use in
multiple sclerosis. CNS Drugs 2004; 18: 379–396.
10. Dobre D, van Veldhuisen DJ, DeJongste MJ, van Sonderen
E, Klungel OH, Sanderman R, et al. The contribution of
observational studies to the knowledge of drug effectiveness
in heart failure. Br J Clin Pharmacol 2007; 64: 406–414.
Downloaded from msj.sagepub.com by guest on December 6, 2012
941
Giovannoni et al.
11. Shikata S, Nakayama T, Noguchi Y, Taji Y and Yamagishi H. Comparison of effects in randomized controlled trials with observational studies in digestive surgery. Ann Surg
2006; 244: 668–676.
12. Reess J, Haas J, Gabriel K, Fuhlrott A and Fiola M. Both
paracetamol and ibuprofen are equally effective in managing
flu-like symptoms in relapsing–remitting multiple sclerosis
patients during interferon beta-1a (AVONEX) therapy. Mult
Scler 2002; 8: 15–18.
13. Giovannoni G, Barbarash O, Casset-Semanaz F, Jaber A,
King J, Metz L, et al. Immunogenicity and tolerability of
an investigational formulation of interferon-beta1a: 24- and
48-week interim analyses of a 2-year, single-arm, historically
controlled, phase IIIb study in adults with multiple sclerosis.
Clin Ther 2007; 29: 1128–1145.
14. Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, et al. Every-other-day interferon beta-1b versus onceweekly interferon beta-1a for multiple sclerosis: results of
a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002; 359: 1453–1460.
15. Mohr DC, Likosky W, Boudewyn AC, Marietta P, Dwyer P,
Van der Wende J, et al. Side effect profile and adherence to
in the treatment of multiple sclerosis with interferon beta-1a.
Mult Scler 1998; 4: 487–489.
16. Mikol D, Lopez-Bresnahan M, Taraskiewicz S, Chang P
and Rangnow J. A randomized, multicentre, open-label,
parallel-group trial of the tolerability of interferon beta-1a
(Rebif) administered by autoinjection or manual injection in
relapsing–remitting multiple sclerosis. Mult Scler 2005; 11:
585–591.
17. Baum K. Safety and tolerability of a ‘refrigeration-free’ formulation of interferon beta-1b--results of a double-blind,
multicentre, comparative study in patients with relapsing–
remitting or secondary progressive multiple sclerosis. J Int
Med Res 2006; 34: 1–12.
18. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein
J, Lisak RP, et al. Copolymer 1 reduces relapse rate and
improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double-blind placebocontrolled trial. The Copolymer 1 Multiple Sclerosis Study
Group. Neurology 1995; 45: 1268–1276.
19. Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert
JR, Salazar AM, et al. Intramuscular interferon beta-1a for
disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
Ann Neurol 1996; 39: 285–294.
20. Herndon RM, Rudick RA, Munschauer FE, III, Mass MK,
Salazar AM, Coats ME, et al. Eight-year immunogenicity
and safety of interferon beta-1a-Avonex treatment in patients
with multiple sclerosis. Mult Scler 2005; 11: 409–419.
21. Minden S, Hoaglin D, Jureidini S, Hadden L, Frankel D,
Komatsuzaki Y, et al. Disease-modifying agents in the
Sonya Slifka Longitudinal Multiple Sclerosis Study. Mult
Scler 2008; 14: 640–655.
22. Fernandez O, Arbizu T, Izquierdo G, Martinez-Yelamos A,
Gata JM, Luque G, et al. Clinical benefits of interferon beta1a in relapsing–remitting MS: a phase IV study. Acta Neurol
Scand 2003; 107: 7–11.
23. Clanet M, Radue EW, Kappos L, Hartung HP, Hohlfeld R,
Sandberg-Wollheim M, et al. A randomized, double-blind,
dose-comparison study of weekly interferon beta-1a in
relapsing MS. Neurology 2002; 59: 1507–1517.
24. Phillips JT, Rice G, Frohman E, Vande Gaer L, Scott T,
Haas J, et al. A multicenter, open-label, phase II study of the
immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis. Clin Ther 2004; 26: 511–521.
25. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK,
O’Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE
Trial. Neurology 2002; 59: 1496–1506.
26. Minagara A and Murray TJ. Efficacy and tolerability of
intramuscular interferon beta-1a compared with subcutaneous interferon beta-1a in relapsing MS: results from PROOF.
Curr Med Res Opin 2008; 24: 1049–1055.
27. Schwid SR and Panitch HS. Full results of the Evidence of
Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly
versus high-dose, high-frequency interferon beta-1a for
relapsing multiple sclerosis. Clin Ther 2007; 29: 2031–2048.
28. Milanese C, La Mantia L and Palumbo R. Interferon beta
treatment in relapsing–remitting multiple sclerosis: a postmarketing study in Lombardia, Italy. Multiple Sclerosis Centers of Lombardia, Italy. Ital J Neurol Sci 1999; 20: 297–302.
29. Trojano M, Liguori M, Paolicelli D, Zimatore GB, De Robertis F, Avolio C, et al. Interferon beta in relapsing–remitting
multiple sclerosis: an independent postmarketing study in
southern Italy. Mult Scler 2003; 9: 451–457.
30. Rudick RA, Stuart WH, Calabresi PA, Confavreux C,
Galetta SL, Radue EW, et al. Natalizumab plus interferon
beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;
354: 911–923.
31. 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.
32. Oger J, Francis G and Chang P. Prospective assessment of
changing from placebo to IFN beta-1a in relapsing MS: the
PRISMS study. J Neurol Sci 2005; 237: 45–52.
33. Kappos L, Traboulsee A, Constantinescu C, Eralinna JP,
Forrestal F, Jongen P, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing–remitting
MS. Neurology 2006; 67: 944–953.
34. Baum K, O’Leary C, Coret Ferrer F, Klimova E, Prochazkova L and Bugge J. Comparison of injection site pain and
injection site reactions in relapsing–remitting multiple sclerosis patients treated with interferon beta-1a or 1b. Mult
Scler 2007; 13: 1153–1160.
35. Wroe SJ. Effects of dose titration on tolerability and efficacy
of interferon beta-1b in people with multiple sclerosis. J Int
Med Res 2005; 33: 309–318.
36. Rice GP, Ebers GC, Lublin FD and Knobler RL. Ibuprofen
treatment versus gradual introduction of interferon beta-1b in
patients with MS. Neurology 1999; 52: 1893–1895.
37. The IFNB Multiple Sclerosis Study Group. Interferon beta1b is effective in relapsing–remitting multiple sclerosis. I.
Clinical results of a multicenter, randomized, double-blind,
placebo-controlled trial. Neurology 1993; 43: 655–661.
Downloaded from msj.sagepub.com by guest on December 6, 2012
942
Multiple Sclerosis Journal 18(7)
38. Interferon beta-1b in the treatment of multiple sclerosis: final
outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British
Columbia MS/MRI Analysis Group. Neurology 1995; 45:
1277–1285.
39. Pozzilli C, Antonini G, Bagnato F, Mainero C, Tomassini
V, Onesti E, et al. Monthly corticosteroids decrease neutralizing antibodies to IFNbeta1 b: a randomized trial in multiple
sclerosis. J Neurol 2002; 249: 50–56.
40. Saida T, Tashiro K, Itoyama Y, Sato T, Ohashi Y and
Zhao Z. Interferon beta-1b is effective in Japanese RRMS
patients: a randomized, multicenter study. Neurology 2005;
64: 621–630.
41. Arbizu T, Alvarez-Cermeno JC, Decap G, Fernandez O, Uria
DF, Garcia Merino A, et al. Interferon beta-1b treatment in
patients with relapsing--remitting multiple sclerosis under
a standardized protocol in Spain. Acta Neurol Scand 2000;
102: 209–217.
42. Durelli L, Oggero A, Verdun E, Isoardo G, Ricci A, Barbero P, et al. Does high-dose interferon beta-1b improve
clinical response in more severely disabled multiple sclerosis
patients? J Neurol Sci 2000; 178: 37–41.
43. Verdun E, Isoardo G, Oggero A, Ferrero B, Ghezzi A, Montanari E, et al. Autoantibodies in multiple sclerosis patients
before and during IFN-beta 1b treatment: are they correlated
with the occurrence of autoimmune diseases? J Interferon
Cytokine Res 2002; 22: 245–255.
44. Koch-Henriksen N, Sorensen PS, Christensen T, Frederiksen
J, Ravnborg M, Jensen K, et al. A randomized study of two
interferon-beta treatments in relapsing–remitting multiple
sclerosis. Neurology 2006; 66: 1056–1060.
45. Brandes DW, Bigley K, Hornstein W, Cohen H, Au W and
Shubin R. Alleviating flu-like symptoms with dose titration
and analgesics in MS patients on intramuscular interferon
beta-1a therapy: a pilot study. Curr Med Res Opin 2007; 23:
1667–1672.
46. Rio J, Nos C, Bonaventura I, Arroyo R, Genis D, Sureda
B, et al. Corticosteroids, ibuprofen, and acetaminophen for
IFNbeta-1a flu symptoms in MS: a randomized trial. Neurology 2004; 63: 525–528.
47. Gold R, Rieckmann P, Chang P and Abdalla J. The longterm safety and tolerability of high-dose interferon beta-1a in
relapsing–remitting multiple sclerosis: 4-year data from the
PRISMS study. Eur J Neurol 2005; 12: 649–656.
48. PRISMS Study Group. PRISMS-4: Long-term efficacy of
interferon-beta-1a in relapsing MS. Neurology 2001; 56:
1628–1636.
49. Pozzilli C, Bastianello S, Koudriavtseva T, Gasperini C,
Bozzao A, Millefiorini E, et al. Magnetic resonance imaging changes with recombinant human interferon-beta-1a: a
short term study in relapsing–remitting multiple sclerosis.
J Neurol Neurosurg Psychiatry 1996; 61: 251–258.
50. Kivisakk P, Alm GV, Fredrikson S and Link H. Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A
comparison between IFN-beta-1a and IFN-beta-1b treatment
in multiple sclerosis. Eur J Neurol 2000; 7: 27–34.
51. Gottberg K, Gardulf A and Fredrikson S. Interferonbeta treatment for patients with multiple sclerosis: the
patients’ perceptions of the side-effects. Mult Scler 2000;
6: 349–354.
52. Freedman MS, Francis GS, Sanders EA, Rice GP, O’Connor
P, Comi G, et al. Randomized study of once-weekly interferon
beta-1la therapy in relapsing multiple sclerosis: three-year
data from the OWIMS study. Mult Scler 2005; 11: 41–45.
53. The Once Weekly Interferon for MS Study Group. Evidence
of interferon beta-1a dose response in relapsing–remitting
MS: the OWIMS Study. Neurology 1999; 53: 679–686.
54. Debouverie M, Moreau T, Lebrun C, Heinzlef O, Brudon F
and Msihid J. A longitudinal observational study of a cohort
of patients with relapsing–remitting multiple sclero­sis treated
with glatiramer acetate. Eur J Neurol 2007; 14: 1266–1274.
55. Cohen JA, Rovaris M, Goodman AD, Ladkani D, Wynn D
and Filippi M. Randomized, double-blind, dose-comparison
study of glatiramer acetate in relapsing–remitting MS. Neurology 2007; 68: 939–944.
56. Comi G, Filippi M and Wolinsky JS. European/Canadian multicenter, double-blind, randomized, placebo-controlled study
of the effects of glatiramer acetate on magnetic resonance
imaging--measured disease activity and burden in patients
with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 2001; 49: 290–297.
57. Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J,
Lisak RP, et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and maintains its clinical effect on
multiple sclerosis relapse rate and degree of disability. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1998;
50: 701–708.
58. Flechter S, Kott E, Steiner-Birmanns B, Nisipeanu P and
Korczyn AD. Copolymer 1 (glatiramer acetate) in relapsing forms of multiple sclerosis: open multicenter study of
alternate-day administration. Clin Neuropharmacol 2002;
25: 11–15.
59. Pollmann W, Erasmus LP, Feneberg W and Straube A. The
effect of glatiramer acetate treatment on pre-existing headaches in patients with MS. Neurology 2006; 66: 275–277.
60. Sindic CJ, Seeldrayers P, Vande Gaer L, De Smet E, Nagels
G, De Deyn PP, et al. Long-term follow up of glatiramer acetate compassionate use in Belgium. Acta Neurol Belg 2005;
105: 81–85.
61. Zwibel HL. Glatiramer acetate in treatment-naive and prior
interferon-beta-1b-treated multiple sclerosis patients. Acta
Neurol Scand 2006; 113: 378–386.
62. Hamzehloo A and Etemadifar M. Mitoxantrone reduced disability in Iranian patients with multiple sclerosis. Arch Iran
Med. 2007; 10: 59–64.
63. Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S and
Amato MP. Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an openlabel comparative study of efficacy and safety. J Neurol Sci.
2008; 266: 25–30.
64. Le Page E, Leray E, Taurin G, Coustans M, Chaperon J,
Morrissey SP, et al. Mitoxantrone as induction treatment in
aggressive relapsing remitting multiple sclerosis: treatment
response factors in a 5 year follow-up observational study
of 100 consecutive patients. J Neurol Neurosurg Psychiatry.
2008; 79: 52–56.
65. O’Connor PW, Goodman A, Willmer-Hulme AJ, Libonati
MA, Metz L, Murray RS, et al. Randomized multicenter
trial of natalizumab in acute MS relapses: clinical and MRI
effects. Neurology 2004; 62: 2038–2043.
Downloaded from msj.sagepub.com by guest on December 6, 2012
943
Giovannoni et al.
66. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice
GP, Libonati MA, et al. A controlled trial of natalizumab for
relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23.
67. Polman CH, O’Connor PW, Havrdova E, Hutchinson M,
Kappos L, Miller DH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.
N Engl J Med 2006; 354: 899–910.
68. Leuschen MP, Filipi M and Healey K. A randomized open
label study of pain medications (naproxen, acetaminophen
and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for
relapsing–remitting multiple sclerosis. Mult Scler 2004; 10:
636–642.
69. Mohr DC, Boudewyn AC, Likosky W, Levine E and Goodkin DE. Injectable medication for the treatment of multiple
sclerosis: the influence of self-efficacy expectations and
injection anxiety on adherence and ability to self-inject. Ann
Behav Med 2001; 23: 125–132.
70. Mohr DC, Cox D and Merluzzi N. Self-injection anxiety
training: a treatment for patients unable to self-inject injectable medications. Mult Scler 2005; 11: 182–185.
71. Berger BA, Liang H and Hudmon KS. Evaluation of software-based telephone counseling to enhance medication persistency among patients with multiple sclerosis. J Am Pharm
Assoc (2003) 2005; 45: 466–472.
72. Mohr DC, Likosky W, Bertagnolli A, Goodkin DE, Van Der
Wende J, Dwyer P, et al. Telephone-administered cognitivebehavioral therapy for the treatment of depressive symptoms
in multiple sclerosis. J Consult Clin Psychol 2000; 68: 356–
361.
73. Tremlett HL and Oger J. Interrupted therapy: stopping and
switching of the beta-interferons prescribed for MS. Neurology 2003; 61: 551–554.
74. Clanet M, Kappos L, Hartung HP and Hohlfeld R. Interferon
beta-1a in relapsing multiple sclerosis: four-year extension
of the European IFNbeta-1a Dose-Comparison Study. Mult
Scler 2004; 10: 139–144.
75. Granger CV, Wende K and Brownscheidle CM. Use of the
FIM instrument in a trial of intramuscular interferon beta-1a
for disease progression in relapsing–remitting multiple sclerosis. Am J Phys Med Rehabil 2003; 82: 427–436.
76. Coppola G, Lanzillo R, Florio C, Orefice G, Vivo P, Ascione
S, et al. Long-term clinical experience with weekly interferon beta-1a in relapsing multiple sclerosis. Eur J Neurol
2006; 13: 1014–1021.
77. Ruiz-Pena JL, Duque P and Izquierdo G. Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of
automatic system application criteria. BMC Neurol 2008; 8: 3.
78. Vermersch P, de Seze J, Delisse B, Lemaire S and Stojkovic T. Quality of life in multiple sclerosis: influence of
interferon-beta1 a (Avonex) treatment. Mult Scler 2002; 8:
377–381.
79. Vermersch P, de Seze J, Stojkovic T and Hautecoeur P. Interferon beta1a (Avonex) treatment in multiple sclerosis: similarity of effect on progression of disability in patients with
mild and moderate disability. J Neurol 2002; 249: 184–187.
80. Patti F, Pappalardo A, Florio C, Politi G, Fiorilla T, Reggio E, et al. Effects of interferon beta-1a and -1b over time:
6-year results of an observational head-to-head study. Acta
Neurol Scand 2006; 113: 241–247.
81. Portaccio E, Zipoli V, Siracusa G, Sorbi S and Amato MP.
Long-term adherence to interferon beta therapy in relapsing–
remitting multiple sclerosis. Eur Neurol 2008; 59: 131–135.
82. Rio J, Tintore M, Nos C, Tellez N, Galan I and Montalban
X. Interferon beta in relapsing–remitting multiple sclerosis.
An eight years experience in a specialist multiple sclerosis
centre. J Neurol 2005; 252: 795–800.
83. Ruggieri RM, Settipani N, Viviano L, Attanasio M, Giglia
L, Almasio P, et al. Long-term interferon-beta treatment for
multiple sclerosis. Neurol Sci 2003; 24: 361–364.
84. Trojano M, Paolicelli D, Zimatore GB, De Robertis F, Fuiani
A, Di Monte E, et al. The IFNbeta treatment of multiple sclerosis (MS) in clinical practice: the experience at the MS Center of Bari, Italy. Neurol Sci 2005; 26 (Suppl.4): S179–182.
85. Haas J and Firzlaff M. Twenty-four-month comparison of
immunomodulatory treatments - a retrospective open label
study in 308 RRMS patients treated with beta interferons
or glatiramer acetate (Copaxone). Eur J Neurol 2005; 12:
425–431.
86. Rudick RA, Miller D, Hass S, Hutchinson M, Calabresi PA,
Confavreux C, et al. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol 2007; 62:
335–346.
87. Colosimo C, Pozzilli C, Frontoni M, Farina D, Koudriavtseva
T, Gasperini C, et al. No increase of serum autoantibodies
during therapy with recombinant human interferon-beta1a
in relapsing–remitting multiple sclerosis. Acta Neurol Scand
1997; 96: 372–374.
88. Moore LA, Kaufman MD, Algozzine R, Irish N, Martin M
and Posey CR. Adherence to therapy: using an evidencebased protocol. Rehabil Nurs 2007; 32: 227–232.
89. Barak Y and Achiron A. Effect of interferon-beta-1b on cognitive functions in multiple sclerosis. Eur Neurol 2002; 47:
11–14.
90. Lanzillo R, Prinster A, Scarano V, Liuzzi R, Coppola G,
Florio C, et al. Neuropsychological assessment, quantitative MRI and ApoE gene polymorphisms in a series of MS
patients treated with IFN beta-1b. J Neurol Sci 2006; 245:
141–145.
91. Fraser C, Morgante L, Hadjimichael O and Vollmer T. A
prospective study of adherence to glatiramer acetate in individuals with multiple sclerosis. J Neurosci Nurs 2004; 36:
120–129.
92. Ford CC, Johnson KP, Lisak RP, Panitch HS, Shifronis G
and Wolinsky JS. A prospective open-label study of glatiramer acetate: over a decade of continuous use in multiple
sclerosis patients. Mult Scler 2006; 12: 309–320.
93. Johnson KP, Brooks BR, Ford CC, Goodman A, Guarnaccia
J, Lisak RP, et al. Sustained clinical benefits of glatiramer
acetate in relapsing multiple sclerosis patients observed for
6 years. Copolymer 1 Multiple Sclerosis Study Group. Mult
Scler 2000; 6: 255–266.
94. Rice GP, Oger J, Duquette P, Francis GS, Belanger M,
Laplante S, et al. Treatment with interferon beta-1b improves
quality of life in multiple sclerosis. Can J Neurol Sci 1999;
26: 276–282.
95. Koch-Henriksen N and Sorensen PS. The Danish National
Project of interferon-beta treatment in relapsing–remitting
multiple sclerosis. The Danish Multiple Sclerosis Group.
Mult Scler 2000; 6: 172–175.
Downloaded from msj.sagepub.com by guest on December 6, 2012
944
Multiple Sclerosis Journal 18(7)
96. Paolillo A, Pozzilli C, Giugni E, Tomassini V, Gasperini
C, Fiorelli M, et al. A 6-year clinical and MRI follow-up
study of patients with relapsing–remitting multiple sclerosis treated with Interferon-beta. Eur J Neurol 2002; 9:
645–655.
97. Sorensen PS, Ross C, Clemmesen KM, Bendtzen K,
Frederiksen JL, Jensen K, et al. Clinical importance of neutralising antibodies against interferon beta in patients with
relapsing–remitting multiple sclerosis. Lancet 2003; 362:
1184–1191.
98. Tomassini V, Paolillo A, Russo P, Giugni E, Prosperini L,
Gasperini C, et al. Predictors of long-term clinical response
to interferon beta therapy in relapsing multiple sclerosis. J
Neurol 2006; 253: 287–293.
99. Wolinsky JS, Narayana PA and Johnson KP. United States
open-label glatiramer acetate extension trial for relapsing
multiple sclerosis: MRI and clinical correlates. Multiple
Sclerosis Study Group and the MRI Analysis Center. Mult
Scler 2001; 7: 33–41.
100. Sadovnick AD. To treat or not to treat the person with clinical multiple sclerosis--a dilemma. Neurol Sci 2001; 22:
205–207.
101. Turner AP, Kivlahan DR, Sloan AP and Haselkorn JK. Predicting ongoing adherence to disease modifying therapies
in multiple sclerosis: utility of the health beliefs model.
Mult Scler 2007; 13: 1146–1152.
102. Twork S, Nippert I, Scherer P, Haas J, Pohlau D and
Kugler J. Immunomodulating drugs in multiple sclerosis:
compliance, satisfaction and adverse effects evaluation in a
German multiple sclerosis population. Curr Med Res Opin
2007; 23: 1209–1215.
103. Fraser C, Hadjimichael O and Vollmer T. Predictors of
adherence to Copaxone therapy in individuals with relapsing–remitting multiple sclerosis. J Neurosci Nurs 2001; 33:
231–239.
104. Page SA, Verhoef MJ, Stebbins RA, Metz LM and Levy
JC. The use of complementary and alternative therapies by
people with multiple sclerosis. Chronic Dis Can 2003; 24:
75–79.
105. Nayak S, Matheis RJ, Schoenberger NE and Shiflett SC.
Use of unconventional therapies by individuals with multiple sclerosis. Clin Rehabil 2003; 17: 181–191.
106. Linker RA, Kieseier BC and Gold R. Identification and
development of new therapeutics for multiple sclerosis.
Trends Pharmacol Sci 2008.
107. Munschauer F and Weinstock-Guttman B. Importance
of adherence to persistence with prescribed treatments in
patients with multiple sclerosis. US Neurology Review
2005; Touch Briefings, http://www.touchneurology.com/
files/article_pdfs/neuro_1891 (2005, accessed 13 December 2011).
108. Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW,
Hartung HP, Hohlfeld R, et al. Neutralizing antibodies and
efficacy of interferon beta-1a: a 4-year controlled study.
Neurology 2005; 65: 40–47.
109. Rudick RA, Goodkin DE, Jacobs LD, Cookfair DL, Herndon RM, Richert JR, et al. Impact of interferon beta-1a
on neurologic disability in relapsing multiple sclerosis.
The Multiple Sclerosis Collaborative Research Group
(MSCRG). Neurology 1997; 49: 358–363.
110. Rudick RA, Lee JC, Simon J, Ransohoff RM and Fisher E.
Defining interferon beta response status in multiple sclerosis patients. Ann Neurol 2004; 56: 548–555.
111. White AT and Petajan JH. Physiological measures of therapeutic response to interferon beta-1a treatment in remittingrelapsing MS. Clin Neurophysiol 2004; 115: 2364–2371.
112. Zivadinov R, Zorzon M, Tommasi MA, Nasuelli D, Bernardi M, Monti-Bragadin L, et al. A longitudinal study
of quality of life and side effects in patients with multiple
sclerosis treated with interferon beta-1a. J Neurol Sci 2003;
216: 113–118.
113. Patten SB and Metz LM. Interferon beta-1 a and depression in relapsing–remitting multiple sclerosis: an analysis
of depression data from the PRISMS clinical trial. Mult
Scler 2001; 7: 243–248.
114. Rieckmann P, O’Connor P, Francis GS, Wetherill G and
Alteri E. Haematological effects of interferon-beta-1a (Rebif)
therapy in multiple sclerosis. Drug Saf 2004; 27: 745–756.
115. Cramer JA, Cuffel BJ, Divan V, Al-Sabbagh A and Glassman M. Patient satisfaction with an injection device for
multiple sclerosis treatment. Acta Neurol Scand 2006; 113:
156–162.
116. Lana-Peixoto MA, Teixeira AL, Jr and Haase VG. Interferon beta-1a-induced depression and suicidal ideation in
multiple sclerosis. Arq Neuropsiquiatr 2002; 60: 721–724.
117. Rio J, Nos C, Marzo ME, Tintore M and Montalban X.
Low-dose steroids reduce flu-like symptoms at the initiation of IFNbeta-1b in relapsing–remitting MS. Neurology
1998; 50: 1910–1912.
118. Schwartz CE, Coulthard-Morris L, Cole B and Vollmer T.
The quality-of-life effects of interferon beta-1b in multiple
sclerosis. An extended Q-TWiST analysis. Arch Neurol
1997; 54: 1475–1480.
119. Bosca I, Coret F, Valero C, Pascual AM, Magraner MJ,
Landete L, et al. Effect of relapses over early progression
of disability in multiple sclerosis patients treated with betainterferon. Mult Scler 2008; 14: 636–639.
120. Durelli L, Ferrero B, Oggero A, Verdun E, Bongioanni
MR, Gentile E, et al. Autoimmune events during interferon
beta-1b treatment for multiple sclerosis. J Neurol Sci 1999;
162: 74–83.
121. Durelli L, Ferrero B, Oggero A, Verdun E, Ghezzi A, Montanari E, et al. Liver and thyroid function and autoimmunity during interferon-beta 1b treatment for MS. Neurology
2001; 57: 1363–1370.
122. Durelli L, Ferrero B, Oggero A, Verdun E, Ghezzi A, Montanari E, et al. Thyroid function and autoimmunity during
interferon beta-1b treatment: a multicenter prospective
study. J Clin Endocrinol Metab 2001; 86: 3525–3532.
123. Flechter S, Vardi J, Finkelstein Y and Pollak L. Cognitive
dysfunction evaluation in multiple sclerosis patients treated
with interferon beta-1b: an open-label prospective 1 year
study. Isr Med Assoc J 2007; 9: 457–459.
124. Keating MM and Ostby PL. Education and self-management of interferon beta-1b therapy for multiple sclerosis. J
Neurosci Nurs 1996; 28: 350–352, 357–358.
125. Parkin D, Jacoby A, McNamee P, Miller P, Thomas S and
Bates D. Treatment of multiple sclerosis with interferon
beta: an appraisal of cost-effectiveness and quality of life. J
Neurol Neurosurg Psychiatry 2000; 68: 144–149.
Downloaded from msj.sagepub.com by guest on December 6, 2012
945
Giovannoni et al.
126. Weinstein A, Schwid SR, Schiffer RB, McDermott MP,
Giang DW and Goodman AD. Neuropsychologic status
in multiple sclerosis after treatment with glatiramer. Arch
Neurol 1999; 56: 319–324.
127. Brenner T, Arnon R, Sela M, Abramsky O, Meiner Z,
Riven-Kreitman R, et al. Humoral and cellular immune
responses to Copolymer 1 in multiple sclerosis patients
treated with Copaxone. J Neuroimmunol 2001; 115: 152–
160.
128. De Stefano N, Filippi M and Hawkins C. Short-term combination of glatiramer acetate with i.v. steroid treatment
preceding treatment with GA alone assessed by MRI-disease activity in patients with relapsing–remitting multiple
sclerosis. J Neurol Sci 2008; 266: 44–50.
129. Schwid SR, Goodman AD, Weinstein A, McDermott MP
and Johnson KP. Cognitive function in relapsing multiple
sclerosis: minimal changes in a 10-year clinical trial. J
Neurol Sci 2007; 255: 57–63.
130. O’Connor P, Miller D, Riester K, Yang M, Panzara M,
Dalton C, et al. Relapse rates and enhancing lesions in a
phase II trial of natalizumab in multiple sclerosis. Mult
Scler 2005; 11: 568–572.
131. Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes
R, Hawkins CP, et al. The effect of anti-alpha4 integrin
antibody on brain lesion activity in MS. The UK Antegren
Study Group. Neurology 1999; 53: 466–472.
132. Edan G, Miller D, Clanet M, Confavreux C, Lyon-Caen
O, Lubetzki C, et al. Therapeutic effect of mitoxantrone
combined with methylprednisolone in multiple sclerosis: a
randomised multicentre study of active disease using MRI
and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;
62: 112–118.
133. Cocco E, Marchi P, Floris G, Mascia MG, Deriu M, Sirca
A, et al. Effect of dose and frequency of interferon beta-1a
administration on clinical and magnetic resonance imaging
parameters in relapsing–remitting multiple sclerosis. Funct
Neurol 2006; 21: 145–149.
134. Hamzehloo A and Etemadifar M. Mitoxantrone-induced
cardiotoxicity in patients with multiple sclerosis. Arch Iran
Med. 2006; 9: 111–114.
135. Francis GS, Grumser Y, Alteri E, Micaleff A, O’Brien F,
Alsop J, et al. Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance. Drug Saf 2003; 26: 815–827.
136. Speciale L, Saresella M, Caputo D, Ruzzante S, Mancuso
R, Calvo MG, et al. Serum auto antibodies presence in multiple sclerosis patients treated with beta-interferon 1a and
1b. J Neurovirol 2000; 6 (Suppl.2): S57–S61.
137. Dubois BD, Keenan E, Porter BE, Kapoor R, Rudge P,
Thompson AJ, et al. Interferon beta in multiple sclerosis:
experience in a British specialist multiple sclerosis centre.
J Neurol Neurosurg Psychiatry 2003; 74: 946–949.
138. Etemadifar M, Janghorbani M and Shaygannejad V. Comparison of interferon beta products and azathioprine in the
treatment of relapsing–remitting multiple sclerosis. J Neurol 2007; 254: 1723–1728.
139. Etemadifar M, Janghorbani M and Shaygannejad V. Comparison of Betaferon, Avonex, and Rebif in treatment of
relapsing–remitting multiple sclerosis. Acta Neurol Scand
2006; 113: 283–287.
140. Limmroth V, Malessa R, Zettl UK, Koehler J, Japp G,
Haller P, et al. Quality Assessment in Multiple Sclerosis
Therapy (QUASIMS): a comparison of interferon beta
therapies for relapsing–remitting multiple sclerosis. J Neurol 2007; 254: 67–77.
141. O’Rourke K, Walsh C, Antonelli G and Hutchinson M.
Predicting beta-interferon failure in relapsing–remitting
multiple sclerosis. Mult Scler 2007; 13: 336–342.
142. Pozzilli C, Prosperini L, Sbardella E, De Giglio L, Onesti
E and Tomassini V. Post-marketing survey on clinical
response to interferon beta in relapsing multiple sclerosis: the Roman experience. Neurol Sci 2005; 26 Suppl 4:
S174–178.
143. Rio J, Nos C, Tintore M, Borras C, Galan I, Comabella M,
et al. Assessment of different treatment failure criteria in
a cohort of relapsing–remitting multiple sclerosis patients
treated with interferon beta: implications for clinical trials.
Ann Neurol 2002; 52: 400–406.
144. Rio J, Nos C, Tintore M, Tellez N, Galan I, Pelayo R,
et al. Defining the response to interferon-beta in relapsing–
remitting multiple sclerosis patients. Ann Neurol 2006; 59:
344–352.
145. Russo P, Paolillo A, Caprino L, Bastianello S and Bramanti
P. Effectiveness of interferon beta treatment in relapsing–
remitting multiple sclerosis: an Italian cohort study. J Eval
Clin Pract 2004; 10: 511–518.
146. Simone IL, Ceccarelli A, Tortorella C, Bellacosa A, Pellegrini F, Plasmati I, et al. Influence of Interferon beta
treatment on quality of life in multiple sclerosis patients.
Health Qual Life Outcomes 2006; 4: 96.
147. Sorensen PS, Koch-Henriksen N and Bendtzen K. Are ex
vivo neutralising antibodies against IFN-beta always detrimental to therapeutic efficacy in multiple sclerosis? Mult
Scler 2007; 13: 616–621.
148. Trojano M, Pellegrini F, Fuiani A, Paolicelli D, Zipoli V,
Zimatore GB, et al. New natural history of interferon-betatreated relapsing multiple sclerosis. Ann Neurol 2007; 61:
300–306.
149. Trojano M, Russo P, Fuiani A, Paolicelli D, Di Monte E,
Granieri E, et al. The Italian Multiple Sclerosis Database
Network (MSDN): the risk of worsening according to IFNbeta exposure in multiple sclerosis. Mult Scler 2006; 12:
578–585.
150. Caon C, Din M, Ching W, Tselis A, Lisak R and Khan O.
Clinical course after change of immunomodulating therapy
in relapsing–remitting multiple sclerosis. Eur J Neurol
2006; 13: 471–474.
151. Guarnaccia JB, Aslan M, O’Connor TZ, Hope M, Kazis L,
Kashner CM, et al. Quality of life for veterans with multiple sclerosis on disease-modifying agents: Relationship to
disability. J Rehabil Res Dev 2006; 43: 35–44.
152. Khan OA, Tselis AC, Kamholz JA, Garbern JY, Lewis RA
and Lisak RP. A prospective, open-label treatment trial
to compare the effect of IFN beta-1a (Avonex), IFNbeta1b (Betaseron), and glatiramer acetate (Copaxone) on the
relapse rate in relapsing–remitting multiple sclerosis. Eur J
Neurol 2001; 8: 141–148.
153. Khan OA, Tselis AC, Kamholz JA, Garbern JY, Lewis RA
and Lisak RP. A prospective, open-label treatment trial to
compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b
Downloaded from msj.sagepub.com by guest on December 6, 2012
946
Multiple Sclerosis Journal 18(7)
(Betaseron), and glatiramer acetate (Copaxone) on the
relapse rate in relapsing--remitting multiple sclerosis: results
after 18 months of therapy. Mult Scler 2001; 7: 349–353.
154. Lily O, McFadden E, Hensor E, Johnson M and Ford H.
Disease-specific quality of life in multiple sclerosis: the
effect of disease modifying treatment. Mult Scler 2006; 12:
808–813.
155. Metz LM, Patten SB, Archibald CJ, Bakker JI, Harris CJ,
Patry DG, et al. The effect of immunomodulatory treatment
on multiple sclerosis fatigue. J Neurol Neurosurg Psychiatry 2004; 75: 1045–1047.
156. Pollmann W, Erasmus LP, Feneberg W, Then Bergh F
and Straube A. Interferon beta but not glatiramer acetate
therapy aggravates headaches in MS. Neurology 2002; 59:
636–639.
157. Tilbery CP, Mendes MF, Oliveira BE, Thomaz RB and
Kelian GR. Immunomodulatory treatment in multiple sclerosis: experience at a Brazilian center with 390 patients.
Arq Neuropsiquiatr 2006; 64: 51–54.
158. Ytterberg C, Johansson S, Andersson M, Olsson D,
Link H, Holmqvist LW, et al. Combination therapy with
interferon-beta and glatiramer acetate in multiple sclerosis. Acta Neurol Scand 2007; 116: 96–99.
159. Carra A, Onaha P, Luetic G, Burgos M, Crespo E, Deri
N, et al. Therapeutic outcome 3 years after switching of
immunomodulatory therapies in patients with relapsing–
remitting multiple sclerosis in Argentina. Eur J Neurol
2008; 15: 386–393.
160. Khan F, McPhail T, Brand C, Turner-Stokes L and Kilpatrick T. Multiple sclerosis: disability profile and quality of
life in an Australian community cohort. Int J Rehabil Res
2006; 29: 87–96.
161. Kobelt G, Berg J, Atherly D and Hadjimichael O. Costs and
quality of life in multiple sclerosis: a cross-sectional study
in the United States. Neurology 2006; 66: 1696–1702.
162. La Mantia L, D’Amico D, Rigamonti A, Mascoli N, Bussone G and Milanese C. Interferon treatment may trigger
primary headaches in multiple sclerosis patients. Mult
Scler 2006; 12: 476–480.
163. Rovaris M, Comi G, Rocca MA, Valsasina P, Ladkani D,
Pieri E, et al. Long-term follow-up of patients treated with
glatiramer acetate: a multicentre, multinational extension of the European/Canadian double-blind, placebo-­
controlled, MRI-monitored trial. Mult Scler 2007; 13:
502–508.
164. Thompson JP, Noyes K, Dorsey ER, Schwid SR and Holloway RG. Quantitative risk-benefit analysis of natalizumab.
Neurology 2008; 71: 357–364.
165. Villani V, Prosperini L, Ciuffoli A, Pizzolato R, Salvetti M,
Pozzilli C, et al. Primary headache and multiple sclerosis:
preliminary results of a prospective study. Neurol Sci 2008;
29(Suppl.1): S146–S148.
166. Vollmer T, Panitch H, Bar-Or A, Dunn J, Freedman MS,
Gazda SK, et al. Glatiramer acetate after induction therapy
with mitoxantrone in relapsing multiple sclerosis. Mult
Scler 2008; 14: 663–670.
Downloaded from msj.sagepub.com by guest on December 6, 2012