Antibody
Content
Neurol Sci (2006) 27:S355–S357
DOI 10.1007/s10072-006-0693-9
N. Grigoriadis • G. Deretzi • N. Artemis • N. Tascos • I. Milonas
Is there or is there not a place for anti-interferon antibodies
in the decision making of multiple sclerosis treatment optimisation?
Received: 27 March 2006 / Accepted in revised form: 19 July 2006
Abstract Several factors contribute to the fact that not all
multiple sclerosis (MS) patients respond equally well to
long-term interferon beta (IFNβ) treatment, even if the initial response is adequate. Among these factors, anti-interferon neutralising antibodies (NAbs) may be included.
There is increasing evidence that these antibodies have a
clinical impact in MS treated patients, which is evident
some months following the initiation of treatment with
IFN?. Several efforts to reduce the concentration of NAbs,
especially when they are in high titres and clinically
active, have failed. However, the same efforts may be more
effective if applied following early detection of the antibodies, thus leading to a continuation of the initially
selected interferon treatment.
Key words Multiple sclerosis
Neutralising antibodies
•
Treatment optimisation
•
N. Grigoriadis () • G. Deretzi • N. Artemis • N. Tascos • I. Milonas
B’ Department of Neurology
AHEPA University Hospital
Aristotle University of Thessaloniki
GR-54636 Thessaloniki, Greece
e-mail: [email protected]
Introduction
Multiple sclerosis (MS) is a representative autoimmune disease of the central nervous system (CNS) with unique
immunopathology [1]. Immune attacks contribute to axonal
damage, which is a key component of the gradually
increased disability of patients [2]. During the last decade, a
number of new disease-modifying therapies (DMTs) for
treating patients who have MS have been developed. Among
them, the three interferon beta (IFNβ) products, one IFNβ1b and two IFNβ-1a, as well as glatiramer acetate (GA) are
considered to be the first line of the currently applied
immunomodulatory agents for relapsing-remitting MS treatment, although they are only partially effective [3].
Considering all the data derived from both experimental
and clinical studies, a treatment initiation as early as possible
may be the best choice for halting the disease progression.
Indeed, axonal injury takes place early in the disease process.
Nevertheless, although axonal dysfunction is initially
reversible, a separate and destructive sequence of calciumdependent excitotoxic events follows due to a more prolonged exposure to inflammatory mediators [4]. It is therefore reasonable to expect that early immunomodulation
would result in early neuronal and axonal rescue from an
inflammatory environment, therefore preventing a cascade of
events that could lead to loss of tissue integrity and the onset
of secondary progression. Once a patient has entered the secondary progressive phase of MS, immunotherapy seems to
be ineffective in halting axonal degeneration [5]. Under these
circumstances, any comprehensive management must
include the issue of neuroprotection [6].
The rationale for early treatment optimisation
Most patients with MS or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis
S356
N. Grigoriadis et al.: Anti-interferon antibodies in MS treatment optimisation
[7]. In accordance with this concept, a change toward
more effective treatment should be performed as early as
possible in cases where the currently applied IFNβ therapy is inadequate. For as long as the underlying
immunopathology in MS is not controlled, there will be
non-reversible uncontrolled axonal damage. Indeed, not
all patients respond equally to DMTs and clearly defined
criteria for responders versus non-responders are yet to be
validated. However, everyday clinical practice indicates
that dose, treatment schedule or drug changes, as well as
combination of treatments, or even interruption of the
ongoing treatment, may be imposed in cases where there
is no evidence of benefit. Recently, a consensus on criteria for identifying patients with a suboptimal response to
DMTs has been developed. These criteria are rather
empirical and include clinical course as measured by serial history and examination, subjective impressions of the
patient and physician concerning impairments in function
affecting daily activities although not necessarily evident
by changes on examination, and significant MRI changes
indicating persistent inflammatory disease. MRI scans of
the brain in particular may be obtained in suspected suboptimal responders to support decisions to change therapy
and should be obtained as a new baseline if therapy is
changed [8].
However, MS may be active and progress without any
clinical evidence. Alternatively, it is often difficult to
assess whether the treatment response is favourable, or if
the outcome is simply a reflection of the patient’s underlying disease process. Therefore, the ability to recognise
whether or not a treatment is optimal for an individual
patient and the need for treatment optimisation guidelines
have become increasingly apparent [9]. In addition, since
the initiation of treatment in MS at the time of diagnosis is
considered to be crucial [7], alternatively, it might be
equally important to optimise current treatment by the
time the patient is identified as a non-responder one.
However, it is a common experience that in active MS
there may be times during which underlying lesions
remain silent until a threshold is reached and become clinically evident. Therefore, a major problem might be the
recognition of non-responders as early as possible.
An analogue model has been introduced in order to
facilitate treatment optimisation [10]. According to this
model, changes in relapses, progression and MRI are classified in three ordinal grades as notable, worrisome and
actionable. Combinations of changes in the three diseasemonitoring components may support decision making in
changing the current treatment to an optimal one. Natural
history of the disease, clinical evolution and magnetic resonance imaging are the putative indicators to be considered with respect to treatment response, but neutralising
antibodies (NAbs), possible immunological markers and
pathological or genetic diversity may also represent future
additional indicators [11]. Among these potential indica-
tors of response to treatment, there is increasing evidence
that NAbs should be taken into serious consideration
whenever an individual patient does not respond to treatment with IFNβ, in particular.
NAbs against IFNβ
The development of NAbs has been reported following
IFNβ administration in patients suffering from MS. There
are two types of antibodies that may develop: (i) binding
antibodies (BAbs), which are all antibodies capable of
binding to the protein, and (ii) NAbs, which are a subset of
binding antibodies that bind to the protein-based therapy
and neutralise it [12]. NAbs reduce exposure of the protein-based therapy to its target receptor and block receptor
activation.
The percentage of patients developing NAbs differs
among the three types of interferons [13, 14]. Moreover,
there is no doubt that anti-IFNβ NAbs have a clinical and
MRI impact in MS [15–18]. Similarly, in the Danish study
[19] an up to 50% increase of the mean annual relapse rate
was reported among NAb-positive compared to NAb-negative MS patients. The percentage of relapse-free patients
during the study period was 27% and 39% for the two
groups of patients, respectively (p=0.0064). The mean
Expanded Disability Status Scale (EDSS) score was also
higher in NAb-positive patients, 42 (p=0.0049) and 48
(p=0.008) months following treatment initiation. However,
there is no way of predicting which of the patients will
develop NAbs. The possibility is higher for those patients
that develop BAbs. There is also a possibility that a number of patients that develop NAbs will become NAb-negative within the next few years, especially in cases where
the titre is low [20].
Antibody production is also relevant to biological
DMTs, other than IFNβ. GA-reactive antibodies occur in a
number of patients treated with this agent. However, any
neutralising effect of GA antibodies, was ruled out [21]. In
a 6-month study of a humanised anti-VLA4 monoclonal
antibody (natalizumab), BAbs development in almost 11%
of MS patients has been reported [22]. There may be a possibility that these antibodies will neutralise and consequently impact negatively on the clinical efficacy of the drug.
There are also indications that NAb-positive patients
progress more rapidly compared to NAb-negative patients
during a 2- and 4-year follow-up [23]. However, longterm follow-up of a large number of patients is needed in
order to have a clearer picture of the impact of NAbs on
EDSS and the overall disability progression. As it is well
known that NAbs need some time to present their clinical
impact after they are developed, their detection as early as
possible would predict a poor future response of the
patients to IFNβ.
N. Grigoriadis et al.: Anti-interferon antibodies in MS treatment optimisation
At present, there is no effective treatment (i.e., corticosteroids, plasmapheresis, etc.) for NAb reduction by the
time they have already developed [24], especially in high
titres, and are expressing their clinical impact. However,
the possibility that the same interventions might be more
effective if applied soon after BAb or Nab early detection
[25], needs to be studied. The selection of an immunomodulatory agent for MS treatment should only be based on its
evidence-based clinical and MRI efficacy. No definite recommendations for the preferential selection of any of the
three IFNβ formulations can be given on the basis of current evidence [24]. As NAbs are an inhibitory factor of the
drug efficacy in an individual patient, their early detection
and inhibition of their further development may be a reasonable strategy.
References
1. Grigoriadis N, Grigoriadis S, Polyzoidou E et al (2006)
Neuroinflammation in multiple sclerosis: evidence for
autoimmune dysregulation, not simple autoimmune reaction. Clin Neurol Neurosurg 108:241–244
2. Grigoriadis N, Ben-Hur T, Karussis D, Milonas I (2004)
Axonal damage in multiple sclerosis: a complex issue in a
complex disease. Clin Neurol Neurosurg 106:211–217
3. Grigoriadis N (2002) Interferon beta treatment in relapsingremitting multiple sclerosis. A review. Clin Neurol
Neurosurg 104:251–258
4. Smith KJ, Kapoor R, Hall SM, Davies M (2001)
Electrically active axons degenerate when exposed to nitric
oxide. Ann Neurol 49:470–476
5. Rice GP, Filippi M, Comi G (2000) Cladribine and progressive
MS: clinical and MRI outcomes of a multicenter controlled
trial. Cladribine MRI Study Group. Neurology 54:1145–1155
6. Karussis D, Grigoriadis S, Polyzoidou E et al (2006)
Neuroprotection in multiple sclerosis. Clin Neurol
Neurosurg 108:250–254
7. Frohman EM, Havrdova E, Lublin F et al (2006) Most
patients with multiple sclerosis or a clinically isolated
demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 63:614–619
8. Cohen BA, Khan O, Jeffery DR et al (2006) Identifying and
treating patients with suboptimal responses. Neurology
63[Suppl 6]:S33–S40
9. G. Comi (2005) Optimisation of immunomodulatory therapies. Neurol Sci 26:S15–S17
10. International Working Group for Treatment Optimization in
MS (2004) Treatment optimization in multiple sclerosis: report
of an international consensus meeting. Eur J Neurol 11:43–47
11. Zaffaroni M (2005) Treatment optimisation in multiple sclerosis. Neurol Sci 26:S187–S192
S357
12. Schellekens H (2002) Bioequivalence and the immunogenicity of biopharmaceuticals. Nature Rev Drug Discov 1:457–462
13. Bertolotto A, Malucchi S, Sala A et al (2002) Differential
effects of three interferon betas on neutralising antibodies in
patients with multiple sclerosis: a follow up study in an
independent laboratory. J Neurol Neurosurg Psychiatry
73:148–153
14. Panitch H, Goodin DS, Francis G et al, Evidence of Interferon
Dose-response: European North American Comparative
Efficacy) Study Group and the University of British
Columbia MS/MRI Research Group (2002) Randomized,
comparative study of interferon β-1a treatment regimens in
MS. The EVIDENCE Trial. Neurology 59:1496–1506
15. The IFNB Multiple Sclerosis Study Group and the
University of British Columbia MS/MRI Analysis Group
(1996) Neutralizing antibodies during treatment of multiple
sclerosis with interferon beta-1b: experience during the first
three years. Neurology 47:889–894
16. The PRISMS (Prevention of Relapses and Disability by
Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study
Group and the University of British Columbia MS/MRI
Analysis Group PRISMS-4 (2001) Long-term efficacy of
interferon-β-1a in relapsing MS. Neurology 56:1628–1636
17. Giovannoni G, Munschauer FE 3rd, Deisenhammer F
(2002) Neutralising antibodies to interferon beta during the
treatment of multiple sclerosis. J Neurol Neurosurg
Psychiatry 73:465–469
18. Polman C, Kappos L, White R et al (2003) Neutralizing
antibodies during treatment of secondary progressive MS
with interferon b-1b. Neurology 60:37–43
19. Sorensen PS, Ross C, Clemmesen KM et al (2003) Clinical
importance of neutralising antibodies against interferon
beta in patients with relapsing–remitting multiple sclerosis.
Lancet 362:1184–1191
20. Gneiss C, Reindl M, Lutterotti A et al (2004) Interferon
beta: the neutralizing antibody (NAb) titer predicts reversion to NAb negativity. Mult Scler 10:507–510
21. Teitelbaum D, Brenner T, Abramsky O et al (2003)
Antibodies to glatiramer acetate do not interfere with its
biological functions and therapeutic efficacy. Mult Scler
9:592–599
22. Miller DH, Khan OA, Sheremata WA et al (2003) A controlled trial of natalizumab for relapsing multiple sclerosis.
N Engl J Med 348:15–23
23. Malucchi S, Sala A, Gilli F et al (2004) Neutralizing antibodies reduce the efficacy of beta IFN during treatment of
multiple sclerosis. Neurology 62:2031–2037
24. Hemmer B, Stuve O, Kieseier B et al (2005) Immune
response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol 4:403–412
25. Sorensen PS, Deisenhammer F, Duda P et al (2005) Guidelines
on use of anti-IFN-beta antibody measurements in multiple
sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12:817–827
DOI 10.1007/s10072-006-0693-9
N. Grigoriadis • G. Deretzi • N. Artemis • N. Tascos • I. Milonas
Is there or is there not a place for anti-interferon antibodies
in the decision making of multiple sclerosis treatment optimisation?
Received: 27 March 2006 / Accepted in revised form: 19 July 2006
Abstract Several factors contribute to the fact that not all
multiple sclerosis (MS) patients respond equally well to
long-term interferon beta (IFNβ) treatment, even if the initial response is adequate. Among these factors, anti-interferon neutralising antibodies (NAbs) may be included.
There is increasing evidence that these antibodies have a
clinical impact in MS treated patients, which is evident
some months following the initiation of treatment with
IFN?. Several efforts to reduce the concentration of NAbs,
especially when they are in high titres and clinically
active, have failed. However, the same efforts may be more
effective if applied following early detection of the antibodies, thus leading to a continuation of the initially
selected interferon treatment.
Key words Multiple sclerosis
Neutralising antibodies
•
Treatment optimisation
•
N. Grigoriadis () • G. Deretzi • N. Artemis • N. Tascos • I. Milonas
B’ Department of Neurology
AHEPA University Hospital
Aristotle University of Thessaloniki
GR-54636 Thessaloniki, Greece
e-mail: [email protected]
Introduction
Multiple sclerosis (MS) is a representative autoimmune disease of the central nervous system (CNS) with unique
immunopathology [1]. Immune attacks contribute to axonal
damage, which is a key component of the gradually
increased disability of patients [2]. During the last decade, a
number of new disease-modifying therapies (DMTs) for
treating patients who have MS have been developed. Among
them, the three interferon beta (IFNβ) products, one IFNβ1b and two IFNβ-1a, as well as glatiramer acetate (GA) are
considered to be the first line of the currently applied
immunomodulatory agents for relapsing-remitting MS treatment, although they are only partially effective [3].
Considering all the data derived from both experimental
and clinical studies, a treatment initiation as early as possible
may be the best choice for halting the disease progression.
Indeed, axonal injury takes place early in the disease process.
Nevertheless, although axonal dysfunction is initially
reversible, a separate and destructive sequence of calciumdependent excitotoxic events follows due to a more prolonged exposure to inflammatory mediators [4]. It is therefore reasonable to expect that early immunomodulation
would result in early neuronal and axonal rescue from an
inflammatory environment, therefore preventing a cascade of
events that could lead to loss of tissue integrity and the onset
of secondary progression. Once a patient has entered the secondary progressive phase of MS, immunotherapy seems to
be ineffective in halting axonal degeneration [5]. Under these
circumstances, any comprehensive management must
include the issue of neuroprotection [6].
The rationale for early treatment optimisation
Most patients with MS or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis
S356
N. Grigoriadis et al.: Anti-interferon antibodies in MS treatment optimisation
[7]. In accordance with this concept, a change toward
more effective treatment should be performed as early as
possible in cases where the currently applied IFNβ therapy is inadequate. For as long as the underlying
immunopathology in MS is not controlled, there will be
non-reversible uncontrolled axonal damage. Indeed, not
all patients respond equally to DMTs and clearly defined
criteria for responders versus non-responders are yet to be
validated. However, everyday clinical practice indicates
that dose, treatment schedule or drug changes, as well as
combination of treatments, or even interruption of the
ongoing treatment, may be imposed in cases where there
is no evidence of benefit. Recently, a consensus on criteria for identifying patients with a suboptimal response to
DMTs has been developed. These criteria are rather
empirical and include clinical course as measured by serial history and examination, subjective impressions of the
patient and physician concerning impairments in function
affecting daily activities although not necessarily evident
by changes on examination, and significant MRI changes
indicating persistent inflammatory disease. MRI scans of
the brain in particular may be obtained in suspected suboptimal responders to support decisions to change therapy
and should be obtained as a new baseline if therapy is
changed [8].
However, MS may be active and progress without any
clinical evidence. Alternatively, it is often difficult to
assess whether the treatment response is favourable, or if
the outcome is simply a reflection of the patient’s underlying disease process. Therefore, the ability to recognise
whether or not a treatment is optimal for an individual
patient and the need for treatment optimisation guidelines
have become increasingly apparent [9]. In addition, since
the initiation of treatment in MS at the time of diagnosis is
considered to be crucial [7], alternatively, it might be
equally important to optimise current treatment by the
time the patient is identified as a non-responder one.
However, it is a common experience that in active MS
there may be times during which underlying lesions
remain silent until a threshold is reached and become clinically evident. Therefore, a major problem might be the
recognition of non-responders as early as possible.
An analogue model has been introduced in order to
facilitate treatment optimisation [10]. According to this
model, changes in relapses, progression and MRI are classified in three ordinal grades as notable, worrisome and
actionable. Combinations of changes in the three diseasemonitoring components may support decision making in
changing the current treatment to an optimal one. Natural
history of the disease, clinical evolution and magnetic resonance imaging are the putative indicators to be considered with respect to treatment response, but neutralising
antibodies (NAbs), possible immunological markers and
pathological or genetic diversity may also represent future
additional indicators [11]. Among these potential indica-
tors of response to treatment, there is increasing evidence
that NAbs should be taken into serious consideration
whenever an individual patient does not respond to treatment with IFNβ, in particular.
NAbs against IFNβ
The development of NAbs has been reported following
IFNβ administration in patients suffering from MS. There
are two types of antibodies that may develop: (i) binding
antibodies (BAbs), which are all antibodies capable of
binding to the protein, and (ii) NAbs, which are a subset of
binding antibodies that bind to the protein-based therapy
and neutralise it [12]. NAbs reduce exposure of the protein-based therapy to its target receptor and block receptor
activation.
The percentage of patients developing NAbs differs
among the three types of interferons [13, 14]. Moreover,
there is no doubt that anti-IFNβ NAbs have a clinical and
MRI impact in MS [15–18]. Similarly, in the Danish study
[19] an up to 50% increase of the mean annual relapse rate
was reported among NAb-positive compared to NAb-negative MS patients. The percentage of relapse-free patients
during the study period was 27% and 39% for the two
groups of patients, respectively (p=0.0064). The mean
Expanded Disability Status Scale (EDSS) score was also
higher in NAb-positive patients, 42 (p=0.0049) and 48
(p=0.008) months following treatment initiation. However,
there is no way of predicting which of the patients will
develop NAbs. The possibility is higher for those patients
that develop BAbs. There is also a possibility that a number of patients that develop NAbs will become NAb-negative within the next few years, especially in cases where
the titre is low [20].
Antibody production is also relevant to biological
DMTs, other than IFNβ. GA-reactive antibodies occur in a
number of patients treated with this agent. However, any
neutralising effect of GA antibodies, was ruled out [21]. In
a 6-month study of a humanised anti-VLA4 monoclonal
antibody (natalizumab), BAbs development in almost 11%
of MS patients has been reported [22]. There may be a possibility that these antibodies will neutralise and consequently impact negatively on the clinical efficacy of the drug.
There are also indications that NAb-positive patients
progress more rapidly compared to NAb-negative patients
during a 2- and 4-year follow-up [23]. However, longterm follow-up of a large number of patients is needed in
order to have a clearer picture of the impact of NAbs on
EDSS and the overall disability progression. As it is well
known that NAbs need some time to present their clinical
impact after they are developed, their detection as early as
possible would predict a poor future response of the
patients to IFNβ.
N. Grigoriadis et al.: Anti-interferon antibodies in MS treatment optimisation
At present, there is no effective treatment (i.e., corticosteroids, plasmapheresis, etc.) for NAb reduction by the
time they have already developed [24], especially in high
titres, and are expressing their clinical impact. However,
the possibility that the same interventions might be more
effective if applied soon after BAb or Nab early detection
[25], needs to be studied. The selection of an immunomodulatory agent for MS treatment should only be based on its
evidence-based clinical and MRI efficacy. No definite recommendations for the preferential selection of any of the
three IFNβ formulations can be given on the basis of current evidence [24]. As NAbs are an inhibitory factor of the
drug efficacy in an individual patient, their early detection
and inhibition of their further development may be a reasonable strategy.
References
1. Grigoriadis N, Grigoriadis S, Polyzoidou E et al (2006)
Neuroinflammation in multiple sclerosis: evidence for
autoimmune dysregulation, not simple autoimmune reaction. Clin Neurol Neurosurg 108:241–244
2. Grigoriadis N, Ben-Hur T, Karussis D, Milonas I (2004)
Axonal damage in multiple sclerosis: a complex issue in a
complex disease. Clin Neurol Neurosurg 106:211–217
3. Grigoriadis N (2002) Interferon beta treatment in relapsingremitting multiple sclerosis. A review. Clin Neurol
Neurosurg 104:251–258
4. Smith KJ, Kapoor R, Hall SM, Davies M (2001)
Electrically active axons degenerate when exposed to nitric
oxide. Ann Neurol 49:470–476
5. Rice GP, Filippi M, Comi G (2000) Cladribine and progressive
MS: clinical and MRI outcomes of a multicenter controlled
trial. Cladribine MRI Study Group. Neurology 54:1145–1155
6. Karussis D, Grigoriadis S, Polyzoidou E et al (2006)
Neuroprotection in multiple sclerosis. Clin Neurol
Neurosurg 108:250–254
7. Frohman EM, Havrdova E, Lublin F et al (2006) Most
patients with multiple sclerosis or a clinically isolated
demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol 63:614–619
8. Cohen BA, Khan O, Jeffery DR et al (2006) Identifying and
treating patients with suboptimal responses. Neurology
63[Suppl 6]:S33–S40
9. G. Comi (2005) Optimisation of immunomodulatory therapies. Neurol Sci 26:S15–S17
10. International Working Group for Treatment Optimization in
MS (2004) Treatment optimization in multiple sclerosis: report
of an international consensus meeting. Eur J Neurol 11:43–47
11. Zaffaroni M (2005) Treatment optimisation in multiple sclerosis. Neurol Sci 26:S187–S192
S357
12. Schellekens H (2002) Bioequivalence and the immunogenicity of biopharmaceuticals. Nature Rev Drug Discov 1:457–462
13. Bertolotto A, Malucchi S, Sala A et al (2002) Differential
effects of three interferon betas on neutralising antibodies in
patients with multiple sclerosis: a follow up study in an
independent laboratory. J Neurol Neurosurg Psychiatry
73:148–153
14. Panitch H, Goodin DS, Francis G et al, Evidence of Interferon
Dose-response: European North American Comparative
Efficacy) Study Group and the University of British
Columbia MS/MRI Research Group (2002) Randomized,
comparative study of interferon β-1a treatment regimens in
MS. The EVIDENCE Trial. Neurology 59:1496–1506
15. The IFNB Multiple Sclerosis Study Group and the
University of British Columbia MS/MRI Analysis Group
(1996) Neutralizing antibodies during treatment of multiple
sclerosis with interferon beta-1b: experience during the first
three years. Neurology 47:889–894
16. The PRISMS (Prevention of Relapses and Disability by
Interferon-β-1a Subcutaneously in Multiple Sclerosis) Study
Group and the University of British Columbia MS/MRI
Analysis Group PRISMS-4 (2001) Long-term efficacy of
interferon-β-1a in relapsing MS. Neurology 56:1628–1636
17. Giovannoni G, Munschauer FE 3rd, Deisenhammer F
(2002) Neutralising antibodies to interferon beta during the
treatment of multiple sclerosis. J Neurol Neurosurg
Psychiatry 73:465–469
18. Polman C, Kappos L, White R et al (2003) Neutralizing
antibodies during treatment of secondary progressive MS
with interferon b-1b. Neurology 60:37–43
19. Sorensen PS, Ross C, Clemmesen KM et al (2003) Clinical
importance of neutralising antibodies against interferon
beta in patients with relapsing–remitting multiple sclerosis.
Lancet 362:1184–1191
20. Gneiss C, Reindl M, Lutterotti A et al (2004) Interferon
beta: the neutralizing antibody (NAb) titer predicts reversion to NAb negativity. Mult Scler 10:507–510
21. Teitelbaum D, Brenner T, Abramsky O et al (2003)
Antibodies to glatiramer acetate do not interfere with its
biological functions and therapeutic efficacy. Mult Scler
9:592–599
22. Miller DH, Khan OA, Sheremata WA et al (2003) A controlled trial of natalizumab for relapsing multiple sclerosis.
N Engl J Med 348:15–23
23. Malucchi S, Sala A, Gilli F et al (2004) Neutralizing antibodies reduce the efficacy of beta IFN during treatment of
multiple sclerosis. Neurology 62:2031–2037
24. Hemmer B, Stuve O, Kieseier B et al (2005) Immune
response to immunotherapy: the role of neutralising antibodies to interferon beta in the treatment of multiple sclerosis. Lancet Neurol 4:403–412
25. Sorensen PS, Deisenhammer F, Duda P et al (2005) Guidelines
on use of anti-IFN-beta antibody measurements in multiple
sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12:817–827
