Download IS an OCCURENCE of NAbs the PERMANENT MARKER of the

DO EXIST EVIDENCES
CONCERNING RELATIONSHIP
BETWEEN AN OCCURENCE
OF NAbs AND EFFICACY OF
INTERFERON´S THERAPY IN
MS?
Bartko D., Čombor I., Bošelová M.
Institute of Medical Sciences, Neurosciences and
Military Health, Central Military University Hospital,
Faculty of Health Sciences,
Ružomberok, Slovak Republic,
NAbs occur with all current
immunomodulatory therapies
BUT
it is difficult to compare the influence
of NAb on drug effectiveness
(Oger, Cantillon 2006)
Many analyses showed that NAb to
some INFs are transient, e.g.
the incidence of NAb to Betaseron
peaks until approx 12 - 18 months
of treatment
AND THEN
NAb disappear over time
The transient nature of NAb to INF has
been reported by many authors, recently
by Sorensen et al. (2006), and most
recently also
by Oger and Cantillon (2007).
The median NAb titer peaked
at months 18.
The highest median titer was 48,
which is not considered as high
(Oger, Cantillon 2006)
Median (Q1–Q3) NAb Titre at Each
Timepoint
The number of patients tested is given under the x-axis
Generally, the recent data on NAb to INF
suggest that treatment decision
(when NAbs occure)
„TO STOP OR TO CONTINUE
WITH INF TREATMENT“
should be based on the patient´s
CLINICAL COURSE
AND NOT
on the NAb status
Neutralizing antibodies (NAbs) arising
during IFN therapy
CAN AFFECT
bioavailability and production of
interferon-induced biological markers.
This may impact on clinical and MRI
outcomes, although this hypothesis is
CONTROVERSIAL.
In one long-term evaluation of NAbs in pts
treated with INF-beta
NAb ferquency was associated with
an EARLIER REVERSION
to NAb - negative status and
DID NOT AFFECT
clinical response to treatment
(Ricci et al.2006)
How can we explain this?
It can be explain
• by induction or by reflection of
increased immunological
tolerance (B cell tolerance) or
• by induction so-called habituation
Three different INF products
are registered for the treatment of RRMS.
Recently (2004), selective monoclonal
antibody adhesion molecule inhibitor
was registered for the treatment of
MS (Natalizumab)
Their efficacy has been proven in
many multicenter, controlled trials
(IFNb MS Study GROUP 1993, PRISMS 1998
INCOMIN 2002 and others)
Recombinant INFs beta are produced
by different cell systems, which
result in some differences in their
aminoacide structure, molecular weight,
degree of glycosylation and specific
activity
Each drug has been registered for use in
different doses (30 μg, 22 and
44 μg and 250 and 375 μg) and
different administration schedules
(IM once a week, SC 3-times a week,
SC every other day or IV once a month)
Results of pharmaclogical and
clinical
studies suggest
• a dose-response effect for beta
interferon
• for better effect when the drug is
administered several times a week
rather than only once a week
(Deisenhammer et al.2000)
• the effect of treatment on both CLINICAL
AND MRI outcomes increased
proportionally to the administered weekly
doses (OWIMS Study, INCOMIN Study 2002)
Effect of NAbs on Disability
Mean change in EDSS
NAb+ Patients Have Greater Disability Progression
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
NAb+
P=0.01
NAb-
0
6
12
18
24
30
36
42
48
Month
NAb+ n=
26
26
26
26
25
26
26
20
14
NAb- n=
732
722
698
670
649
621
605
420
286
Kappos et al. Neurology. 2005;65:40.
NAbs occur frequently in pts receiving
IFN-beta for MS differently
in different IFNs-beta
BUT
It is unclear whether occurrence of NAbs is
PREDICTIVE
for the persistence of NAbs during
continued IFN-beta therapy.
Some authors have shown that NAbs
REDUCE
the effect on relaps rates and MRI
measures of disease activity
(Rudick et al., 1998, Sorensen et al., 2003)
The another studies have shown that
NAbs
MAY DISAPPEAR
in a large proportion of NAb-positive pts
after several months or years of continous
therapy with high-dose IFN-beta-1b
(Sorensen et al., 2003, Petkau et al., 2004)
Reversion to NAb-negative Status
or Decrease in NAb titer Over 4 years
NAb titer changes
(%, n/N)
250μg
375μg
p
Titer unchanged or
81 (21/26) 29 (2/7)
increased
Titer decreased or
reverted to
negative status
19 (5/26)
71 (5/7)
0.02
(Ricci et al., 2006)
Reversion to NAb-negativity
occurs
• 28 NAb –positive pts were studied,
• after 2 years, 43
negative,
• Characteristics:
% were NAb-
– NAbs developed earlier,
– lower titer of NAbs
– more likely to have been treated
with IFN-beta-1b than
with IFN-beta -1a
(Gneiss et al., 2004)
In the most recent study
(Goodin et al., 2006)
it was shown that
NAbs to IFN-beta-1b have
no impact on clinical
response in MS
Cumulative probality of remaining NAb-negative.
Significantly high proportion of pts treated with IFN-beta- 1b
(Betaseron), and IFN-beta -1a (Rebif) and Avonex reverted
NAb-negative status
to
Probability of NAB development
(2 consecutive positive titers)
•Avonex vs
•Rebif and Betaferon: p<0.01
•NEUROLOGY 2005;65:
It is important to stress
that pts who have remained
NAb - negative
during the first 6 - 24 months
of IFN-beta therapy
only rarely
develop NAbs
(Soelberg Sorensen et al., 2005)
The prevalence of NABs seems
to vary widely among present
three products and between studies
On the contrary, the majority of pts,
who had been NAb - positive from
12 through 30 months after start therapy,
remaind NAb - positive
THEREFORE
NAbs should be measured in all
pts treated with IFN-beta
at least during the first 24 months
of therapy
If pts have been persistently NAb-negative
for 24 months,
measurments can be discontinued.
Risk of becoming NAB-positive
is negligible
WHY SUCH
CONTROVERSIAL
RESULTS CAN BE
FOUND?
Because data from previous trials
cannot be compared.
The antibody titers were achieved with
different assays
and therefore the definitions of
NAb-positive were different
(PRISMS1998, PRISMS 2001)
There is no
internationally
agreed standard method
to test for NABs.
Neutralizing assay are cell-based
bioassays with inherent variability and
THEREFORE
assay interpretations are variable among
different laboratories
Of the available methods
the antiviral cytopathic effect (CPE)
is widely used and is
recommended by the WHO
BUT
this method is time-consuming and
relatively complicated
The myxovirus resistance
protein A (MxA) induction assay
is an alternative method
which is less time-consuming
Three months ago very
interesting data were published
(Sominand at al 2007).
The authors differentiate
between
* prevalence of NAb, and
* immunogenicity of Nab
* titer
Duration of therapy 40 months
PREVALENCE
* Avonex: 13%
* Betaferon: 43%
* Rebif 22ug: 39 %
* Rebif 44ug: 30%
Austrian NAB project
Preparation
Patients tested for NAb
NAb positive
N (%)
High titer
N (%)
IFNb-1b
239
74 (31 %)
43 (18 %)
IFNb-1a i. m.
202
11 (5 %)
9 (4 %)
IFNb-1a s. c.
405
118 (29 %)
83 (20 %)
Total
846
203 (24 %)
135 (16 %)
c2: p < 0.0001
Multiple Sclerosis 2006; 12: 731 - 737
IMMUNOGENICITY
* Avonex
* Betaferon
induced LOW NAb titers
* Rebif
induced the highest titers
i.e. it showed HIGHEST
IMMUNOGENICITY
(Sominanda et al., 2007)
POSITIVITY was only moderatly
increased
in those showing WORSENING
in comparison with other pts
(without worsening).
NAb TITER is less studied, despite
it is MORE IMPORTANT marker
than NAb prevalence
From this point of view,
I would like to stress that many of us
have tendency to remain in –not always
confirmed-DOGMAS, e.g.
•
•
•
•
LP in MS can worsen the disease
pregnancy can lead to worsening of MS
MS belongs to demyelinizing disease
at present: demyelinization
axon and oligodendrocytes are
involved
intensive infammation
etc.
In 1980 in „Foreword“ of one monograph
I have written:
„It is dedicated to everyone who is
looking for what is unexpected,
to everyone who doesn’t suffer from
common belief that whatever exists
is all right, and to everyone who respects
facts and mistrusts dogmas.”
(Bartko, 1980)
I have no reason to change this philosophy.
Disbelief into dogmas
is the basis of progress,
belief into dogmas
is the basis of stagnation
CONCLUSIONS
EFNS-AAN guidelines agreement
1. EFNS + AAN: Treatment of MS
with IFNb is associated with the
production of NAbs to the IFN
molecule (Level A).
2. NAbs are not necessarilly the same.
„NAbs differ“,
3. AAN: It is probable that the
presence of NAbs, especially in
persistently high titers, is
associated with a reduction in
the radiographic and clinical
effectiveness of IFN treatment (Level B).
4. Controversy: for some IFN pts NAbs
do not impact on clinical
outcomes
5. If pts on IFN do get NAbs, they are
transient
6. AAN: .......it seems clear that IFN-1a
(as it is currently formulated for IM
injection) is less
immunogenic
than the current IFN preparations
7. EFNS: There is general agreement
that the IFN-b-1a (Avonex)
is
the least immunogenic.
EFNS-AAN guidelines disagreement
8. AAN: insufficient information
on NAb testing regarding
* when to test,
* which test to use,
* how many tests are necessary,
* and which cutoff titer to apply.
EFNS-AAN guidelines
9. The answers (by EFNS):
* when to test?
12 - 24 month!
* which test to use?
bioassay!
* how many tests are necessary?
at least two
* and which cutoff titer to apply?
minimum >20, for prognosis >100
10. The induction of NAbs against IFNs
could be only relevant if they affect
patient outcome
11. In almost 7000 pts across three
continents,
it was not found correlation
between NAb status at any prevalence
and treatment outcome
(Real world data 2006)
12. In the majority of pts (92 %) who
were not doing well on treatment,
NAbs were not primary
cause of treatment failure
(Hurwitz, Pulmon, Real world data, 2006)
13. Therefore, the treatment decision
should be based on clinical course
and not on NAb status
14.
No question about the negative
effects of NAB is generally
accepted
15.
The immunogenicity is still
the most important issue and
needs to be considered when
chosing a IFNb preparation
To all my friends and
participants:
I am
grateful...