Hypersensitivity Reactions

SIAAIC Toscana 2014
Nuove opportunità diagnostiche
per la gestione clinica delle
reazioni avverse
a farmaci biologici
Alessandra Vultaggio
AOU Careggi
(Florence, Italy)
Department of Biomedicine
Immunoallergology Unit
[email protected]
Adverse Events
Adverse Events (AE):
Any untoward medical occurrence
Infusion
Reactions
associated with the use of a drug,
whether or not drug related
Infusion Reactions (IR):
Any AE caused by the drug
Hyper
sensitivity
reactions
Hypersensitivity Reactions:
Antibody- or cellular-mediated IR
Biological agents-related
hypersensitivity reaction:
a SUBMERGED and EMERGENT problem !!!
(2014, in press)
Clinical management of
hypersensitivity reactions
Patients with
previous reactions
Definition of pathogenic
mechanisms
Patients with no
previous reactions
Identify patients at risk
Prevention of further or
first time reactions
Infusion reactions to biologicals :
extension and timing of onset
LOCAL
SYSTEMIC
IMMEDIATE
DELAYED
OCCUR DURING OR
WITHIN 1 HOUR AFTER
INFUSION
OCCUR FROM 1 HOUR TO
14 DAYS AFTER INFUSION
OCCUR WITHIN A FEW
MINUTES AFTER
INJECTION
OCCUR AT LEAST 1 DAY
AFTER INJECTION
Pichler WJ, Allergy 2006
Maggi E et al, Exp Rev Clin Immunol 2011
Pathogenic mechanisms of
reactions to biological agents (BA)
IMMEDIATE systemic REACTIONS
•
Non antibody-mediated adverse reactions
 Complement-mediated
 Cytokine release syndrome (CRS)
•
Antibody-mediated adverse reactions
 IgE-mediated
 Non IgE-mediated
Antibody-mediated
= Hypersensitivity
Vultaggio A et al, Curr Opin Allergy Clin Immunol 2012
BA-induced cytokine release syndrome
FcγRI
Biological agent
n
t io
a
t iv
c
s
A
lysi
d
e
t
ia
med
’
C
Target
cell
Mø
MAC
Direc
ta
popto
sis
AD
CC
-m
ed
ia
te
d
ly
si s
NK cell
Vultaggio A, Maggi E, Matucci A
Curr Opin Allergy Clin Immunol 2011
C
Y
T
O
K
I
N
E
R
E
L
E
A
S
E
Flu-like
reactions
Anaphylaxis-like
reactions
Cytokine storm
Overlap between CRS and HYPERSENSITIVITY
Antibody-mediated
Hypersensitivity
CRS
Headache
Myalgias
Diarrhea
MOF
Fever
Angioedema
Rash
Dizziness
Hypotension
Bronchospasm
Dyspnea
Pruritus
Tachycardia
Nausea
Different mechanisms
Different approaches to avoid
future reactions
Which tools are available for the clinician
to manage the infusion reactions?
– In vitro tests for ADA
detection and
Isotyping
– In vivo tests to
• Skin testing for IgEmediated HRs
• Non isotype-specific
ADA assay
• IgE Isotyping
T cell assays:
their role to
be defined
Detection of ADAs:
current methods
Each of these methods has
benefits and limitations !!

Immunochemical methods


Biophysical methods


Binding assays (ELISAs, RIA, elettrochemiluminesce)
Surface plasmon resonance
Bioassays
• ELISA bridging
format is the
most used test
Comparison of different tecniques to
monitor anti-drug antibdies
• IFX-treated patients
• BID patients (CD)
• ELISA, RIA, EIA, RGA
Performances of assays are comparable.
However, anti-IFX Ab titers show systematic differences,
and in individual patients, only the same assay should be used.
Problems may arise when different assays
are used to manage therapies in the same patient.
(Vande Casteele N et al, Aliment Pharmacol Ther 2012 )
Immediate systemic reactions to IFX
are associated with ADA formation
100
0
17,9
17.6
% of patients
80
61,1
75
60
93,2
100
82,1
82.4
40
20
38,9
25
0
6,8
RESPONDER
(n=103)
ATI ATI +
96 (93.2%)
7 (6.8%)
Vultaggio A, Matucci A et al,
Allergy 2010 and unpublished data
PARTIALLY NON TOTALLY NON
RESPONDER
RESPONDER
(n=28)
(n=36)
21 (75%)
7 (25%)
22 (61.1%)
14(38.9%)
REACTIVE
(n=34)
REACTIVE/NON
RESPONDER
(n=9)
6 (17.6%)
28 (82.4%)
0 (0%)
9 (100%)
IgG ADAs Isotype
Antibodies towards biotherapeutics
are mainly of the IgG isotype (IgG1 subclass)
Monitoring patients treated with
anti-TNFa biopharmaceuticals:
assessing serum infliximab and
anti-infliximab antibodies
Svenson M et al, Rheumatology 2007
ADR towards biologics: a model
IgG pathway of anaphylaxis in mice
High amount of
antibody
Maggi E, Vultaggio A, Matucci A
Exp Rev Clin Immunol 2011
High amount of
antigen
IgE ADA isotype
IgE-mediated reactions have been described towards several
BAs
Maggi E, Vultaggio A, Matucci A
Exp Rev Clin Immunol 2011
Drug
In vivo
In vitro
Ref
Muromonab
No
Yes
Georgitis, 1991
Cetuximab
No
Yes
Chung, 2008
Tocilizumab
No
Yes
Stubenrauch, 2010
Basiliximab
No
Yes
Baudouin , 2003
Omalizumab
Yes
No
Price, 2007
Etanercept
Yes
No
Bavbek, 2011
Adalimumab
Yes
No
Paltiel, 2008
Rituximab
Yes
No
Brennan , 2009
Natalizumab
Yes
Yes
MunozCano, 2010
Infliximab
Yes
Yes
Vultaggio, 2010
Rituximab
Yes
Yes
Vultaggio, 2012
Vultaggio A et al, Allergy 2010
Matucci A et al, Clin Exp Allergy 2013
IgE-mediated IFX-related events:
Update of our experience
Infliximab-specific IgE ADAs
ADR+ patients n=34
ATI+ patients n=28 (82.4%)
IgE+ patients n=7 (25%)
Vultaggio A et al, Allergy 2010
Matucci A et al, Clin Exp Allergy 2013
And Unpublished data
The Relevance of IgE Isotyping:
Why not “Just do it”?
the analysis of specific IgE anti-drug antibodies
is challenging
•
The level of circulating specific IgE antibodies is usually
low (1 ng/ml)
•
The timeframe in which sIgE is detectable in serum is
quite short
1
Non-isotype-specific ADA
IgE ADA
•
Assays are sensitive to:
–
–
Circulating drug
Antidrug antibodies
of other isotypes
OD
0,8
0,6
0,4
0,2
0
BaselineDay of
reaction
+7
+14
+21
+28
Days post reaction
Serum detection of IgE anti-drug antibodies:
Type of assay
Drug
In vitro
Ref
Muromonab
Yes, ELISA
Georgitis, 1991
Cetuximab
Yes, ImmunoCAP
Chung, 2008
Tocilizumab
Yes, ImmunoCAP
Stubenrauch, 2010
Basiliximab
Yes, ELISA
Baudouin , 2003
Natalizumab
Yes, ImmunoCAP
MunozCano, 2010
Infliximab
Yes, ImmunoCAP
Vultaggio, 2010, Matucci 2013
Rituximab
Yes, ImmunoCAP
Vultaggio, 2012
Why to measure
BA-specific IgE?
Highest incidence of anti-drug IgE
in severe reactions
1. IgE-mediated reactions have peculiar clinical characteristics
100
p<0.02
Matucci A al, Clin Exp Allergy 2013
% of IgE+ patients
80
60
40
20
0
Hypereactivity
Tolerant
Severe
Hypereacitivy
Mariotte D et al, mAbs 2011
Timing of the development of reactions
2. IgE-mediated reactions usually occur earlier and
more frequently after a period of interrruption
ATI+ IgE+
N° of patients
ATI+ IgEATI-
(N° of infusions)
ATI+ IgE+
ATI+ IgE-
1° Cycle
2/7 (28.6%)
14/16 (87.5%)
Re-exposure
5/7 (71.4%)
2/16 (12.5%)
Matucci A et al, Clin Exp Allergy 2013
p<0.02
Can diagnostic tools predict
BA-induced infusion reactions?
A role for ADA assays in
the identification of patients at risk
(A.Vultaggio, A.Matucci et al Allergy 2010)
1
Non-isotype-specific ATI
IgE ATI
0,8
Hypersensitivity risk
can be detected prior to
clinical symptoms !!
OD
0,6
0,4
0,2
0
Baseline
Day of
reaction
+7
+14
+21
Days post reaction
+28
IgE-mediated reactions at first exposure
The Cetuximab case
Chung CH et al, NEJM 2008
Sensitization
to Gal-1-3Gal
M ea
t Al
lerg
IgE
G1-3G
y
First exposure to
Cetuximab
Cetuximab
(SP2)
Murine part
Gal-1-3-Gal
n
ctio
e
j
n
I
G
1-3
l
Ga
IgE
G1-3G
Hypersensitivity
Reaction
al
(Matucci A. et al. EAACI 2014
Anti-cetuximab IgE as a
valuable screening test
5 out of 6
resulted
6 patients with
meat allergy
but IFX-naive
Delayed anaphylaxis
to meat
Previous history
of tick bites
IFX
POSITIVE
IgE anti-IFX antibodies probably preexist
to the treatment
Are they specific for glycans?
What is their clinical significance?
Do 2 different pathway of sensitization
toward IFX exist?
Serum detection of IgE anti-drug antibodies:
Clinical studies
Method Pts
ELISA
CAP
Controls
14
78
unreactive
117 HD
30
20
untreated;
15
unreactive;
15 LOR
Culprit
Sens
drugs
CTX
INF
71.4
26
Spec
82.1
90
PPV
33.3
26
NPV
98.5
89
Author
Mariotte D
(2011)
Matucci A
(2013)
Preexisting
crossreactive
ADA
New
developed
non crossreactive
ADA
ADA-positive but IgE-negative reactive
patients: why?
TRUE IgE-NEGATIVE
Other isotypes of ADAs
involved in the induction of
hypersensitivity reactions
FALSE IgE-NEGATIVE
Interference by other
antibodies in the assay
OR
Very low circulating IgE levels
(bound on cells)
Can skin testing help clinicians
in the allergological work-up for
IgE-mediated hypersensitivity reactions ?
Skin testing for BA
In vivo tests
are not currently standardized and approved for BA
•
Limited data in literature
•
Positive skin testing has been reported mainly in patients with HRs
caused by:
– antiTNF agents
– Rituximab
– Trastuzumab
•
A Few studies (small case series) report results of skin testing confirmed
by in vitro assay
– Infliximab
– Rituximab
– Natalizumab
What is the appropriate drug
concentration?
Biological Agent
Concentration
Dilutions
Infliximab
10 mg/ml
Prick test
1:100-1:1
IDT (0,02 ml)
1:1000-1:10
Adalimumab
50 mg/ml
1:100-1:1
1:1000-1:10
Etanercept
25 mg/ml
1:100-1:1
1:1000-1:10
Rituximab
10 mg/ml
1:100-1:1
1:1000-1:10
Cetuximab
5 mg/ml
1:100-1:1
1:1000-1:10
Trastuzumab
21 mg/ml
1:100-1:1
1:1000-1:10
Natalizumab
20 mg/ml
1:100-1:1
1:1000-1:10
Skin testing
for infliximab: our experience
Skin testing
Positive
Negative
Total
Patients with
HRs (n=23)
7
16
23
Patients with 1
no HRs (n=30)
29
30
Healthy
Donors
(n=20)
0
20
20
Total
8
65
73
Sensitivity(%) Specificity(%) PPV(%)
NPV(%)
30.4
90
Matucci A et al, Clin Exp Allergy 2013
96.6
56
Timing to perfom skin testing for BA
REACT
ION
The time between
the reaction and the in vivo evaluation
is a crucial point
IN VIVO
ASSAY
• Temporary irresponsiveness due to the massive activation
during the reaction
• Decrease of specific IgE over time
The value of skin testing for BA in the
clinical practice
Symptom-driven manner
• To assess REACTIVE PATIENTS
– To define IgE-mediated pathogenesis
desensitization
Brennan P et al, JACI 2009
Matucci A et al, Clin Exp Allergy 2013
The value of skin testing for BA in the
clinical practice
Preventive manner ??
• To assess UNREACTIVE PATIENTS
– To identify the risk of IgE-mediated events
since……
……..NPV is very high
……..The presence of IgE deeply correlate with the development of
(severe) reactions
…….skin test are easy and safe
…….may be predictable of reactions (at least for some BA)
……BUT not all patients could be submitted to skin
testing in a preventive manner (time consuming!!!)
…..preventive skin testing could be useful
IgE develop early during
the treatment
IgE develop more
frequently
after interruption
Skin prick test using cetuximab to
diagnose meat allergy
Conclusions
o Biological agents are up-growing cause of drug-related
adverse effects, and the majority of these adverse effects
are due to antibody formation
o In vivo procedures offer a new tool for the diagnosis of at
least IgE-mediated HR
o IgE and non IgE-mediated mechanisms may be involved
o In vitro ADA assay in combination with in vivo assay can be
suggested to characterize reactive patients and to identify
potentially reactive patients
Aknowledgement
AOU Careggi
University of Florence
Immunoallergology Unit
Andrea Matucci
Daniele Cammelli
Dept of Internal Medicine
Francesca Nencini
Sara Pratesi
Giulia Petroni
Prof. Enrico Maggi
External Collaborators
Dermatology Unit (Florence)
Francesca Prignano
Gastroenterology Units
Monica Milla (Florence)
Marco Bertini (Pisa)
G.Luigi De’ Angelis (Parma)
Francesca Vincenzi (Parma)
Rheumatology Unit (Prato)
Fabrizio Cantini
Thermofisher (Uppsala)
Serum detection of IgE anti-drug antibodies:
Clinical studies
Method
IMMUNO
CAP
ELISA
IMMUNO
CAP
Patients
Controls
25
51
unreactive;
462 HD
14
78
unreactive;
117 HD
30
20
untreated;
15
unreactive;
15 LOR
Culprit
drugs
Cetuximab
Cetuximab
Infliximab
Sensitivity specificity PAPER
92%
(68%)°
90%
(92%)°
Chung CH
(2008)
71.4%
82.1%
Mariotte D
(2011)
26%
90%
Matucci A
(2013)
Preexisting
crossreactive
ADA
New
developed
non crossreactive
ADA
Diapo DHM6 berna
Aknowledgement
AOU Careggi
University of Florence
Immunoallergology Unit
Andrea Matucci
Daniele Cammelli
Dept of Internal Medicine
Francesca Nencini
Sara Pratesi
Giulia Petroni
Prof. Enrico Maggi
External Collaborators
Dermatology Unit (Florence)
Francesca Prignano
Gastroenterology Unit (Florence)
Monica Milla
Gastroenterology Unit (Pisa)
Marco Bertini
Giampaolo Bresci
Gastroenterology Unit (Parma)
G.Luigi De’ Angelis
Francesca Vincenzi
Rheumatology Unit (Prato)
Fabrizio Cantini
Thermofisher (Phadia)
In vitro ADAs assays
Stage 1:
ADA screening
& confirmation
ADA screening assay
(Bridging ELISA)
-
No further
testing
-
No further
testing
+
Confirmatory assay
(binding inhibition)
+
Stage 2:
ADA
characterization
Isotype
determination
Relative ADA
concentration
Neutralizing
activity
Skin testing: implications in
desensitization
• SELECTION of PATIENTS
– To define IgE-dependent reactions
– To perform risk stratification ??
• Does skin testing positivity correlate with a greater likelood of developing
reactions during the subsequent desensitization?
• SELECTION of PROCEDURE
– Skin test endpoint-titration to choose the starting dose
• ASSESSMENT OF DESENSITIZATION OUTCOME
– Does skin testing become negative after desensitization?
Skin testing
for infliximab
Skin testing
Positive
Negative
Total
Patients with
HRs (n=23)
7
16
23
Patients with 1
no HRs (n=30)
29
30
Healthy
Donors
(n=20)
0
20
20
Total
8
65
73
Sensitivity(%) Specificity(%) PPV(%)
NPV(%)
30.4
99
Matucci A et al, Clin Exp Allergy 2013
96.6
55
Still an unsolved question……
• The presence of IgE in a reactive patient does
not exclude the presence of IgG ADAs
• What is the role for IgG ADAs in IgE+ patients?
Khodoun MV et al, PNAS 2011
When do IgE-mediated
infusion reactions occur?
Hypersensitivity
reactions are
a clinical
concern about
biological agents
Mild
Moderate
Severe
Maggi E, Vultaggio A,
Matucci A
Exp Rev Clin Immunol 2011
N° of patients
Clinical characteristics of IFX-related
Immediate infusion reactions
Matucci A et al
Clin Exp Allergy 2013, in press
% of patients
Clinical characteristics of IFX-related
Immediate infusion reactions
itching urticaria AE
Matucci A et al
Clin Exp Allergy 2013, in press
nausea back throat flushing dyspnea hypo- LOC
vomiting pain costriction
tension
tachy- low O2
cardia
RTX-induced infusion reactions can be induced by
an IgE-mediated mechanism
April 2009
RTX (2x1000 mg)
2 weeks
February 2010
RTX (2x1000 mg)
December 2010
RTX (2x1000 mg)
+2 +3 +4 +5 +6 +10 +12 +36 weeks post ADR
ADR
ADR




 
       
Sample # 0
1
2
3
4
6
5
7
8
9
10
12 13
RTX-specific IgE (kUA/l)
IgE-CAP ADAs
Total IgE (kU/l)
Anti-RTX non-isotype-specific
antibodies (OD)
Non isotype-specific ADAs
11
Sample #
(Vultaggio A, Matucci A et al, Int Arch Allergy Immunol 2012)
Sample #
RTX-specific IgE antibodies
SKIN TESTING
RESULT
Prick test 1:1
negative
IDT 1:1000
negative
IDT 1:100
positive
IDT 1:10
positive
Saline solution
negative
% of inhibition
Rituximab
Mouse IgG
Cetuximab
Inhibitor added (µg/ml)
RTX 10 mg/ml
RTX 1 mg/ml
RTX 0,1 mg/ml
RTX 0,01 mg/ml
1:1 formulation
1:10
1:100
1:1000
The importance of T cells in the
development of anti-therapeutic
antibodies
• The presence of multiple non-IgM ADAs isotypes
Vultaggio A et al, Allergy 2010
Bartelds GM et al, Ann Rheum Dis 2010
Ehrenforth S et al, Lancet 1992
• T cell subset polarization in treated haemophilic
patients
Reding MT et al, Thromb Haemost 2002
• Many therapeutics proteins contain T cell epitope
Harding FA et al, Mabs 2010
van Schouwenburg PA et al, Nat Rew Rheumatol 2013
Circulating T-cell response
to rituximab is detectable
RTX-reactive patient
Healthy controls
Isotype control
Anti-MHC class II
RTX-unexposed patients
(Vultaggio A, Matucci A et al, Int Arch Allergy Immunol 2012)
T cell response for infliximab in treated patients
(Vultaggio A, Matucci A et al, in preparation)
N° of patients
(11)
(10)
(8)
(6)
RTX-specific T cell response
is more easily detectable
N° of patients showing proliferative
response to drug by using
Patients (N°)
_____________________________________________________
PBMNC
CD4+T/DC Two-step Atg stim
(%)
(%)
(%)
Biologic
8 (38)
14* (66)
7 (33)
0
1 (6)
1 (6)
(anti-inflammatory)
effects
0
0
0
on transmembrane TNF
IFX-treated
ADA+ (21)
ADA- (15)
HC (10)
Mitoma et al, 2008
RTX-treated
Horiuchi etNDal, 2010
ADA+ ( 1)
1
1
Vos etNDal, 2011
ADA- ( 7)
4 (57)
4 (57)
HC ( 10)
0
0
ND
___________________________________________________________
•11 out of 14 patients showed ADR or ADR plus LOR.
Only one patient with ADR resulted negative
Features of IFX-specific T cells after ADR:
a clonal analysis
Non specific TCC
188 TCC
Clonal Efficiency:
Total: 36.6%
Specific: 4,7%
Non proliferating
cytokine-producing
TCC
N° of clones
CLONING
IFX-specific TCC
High IL-10 production by
IFX-specific T cell clones
* p<0.002
IL-10-producing TCC
*
*
(Vultaggio A, Matucci A et al, in preparation)
Infliximab-specific regulatory T cell clones
Annexin V- Treg clones
CD73-PE
T eff clones + IFX
T eff clones + IFX + Treg clones
CD39-FITC
IFX-specific response (cpm)
T eff clones + IFX + no-Treg clones
ANNEXIN V-CD39+CD73+ TCC
(preliminary unpublished data))
CD39-CD73- TCC
Remarks
Remarks
• Circulating T cells specific to biological agents are
detectable in the blood of ADR+ patients and usually
parallel the kinetics of serum ADAs
• Different subsets of drug-specific Treg cells are
detectable in PBMC of ADR+ patients, which can, at least
in part, explain the variable T (and B) cell response to the
drug
• The identification of T cell response to some biologicals
(such as IFX) may prove particularly difficult
A role for ADA assays in the
identification of at risk patients
1
Non-isotype-specific ADA
IgE ADA
0,8
Hypersensitivity risk
can be detected
prior to
clinical symptoms !!
OD
0,6
0,4
0,2
0
Baseline
Day of
reaction
+7
+14
+21
+28
Days post reaction
(A.Vultaggio, A.Matucci et al Allergy 2010)
Can patients at risk
be identified by clinical features?
BID
patients
patients
p<0.025
(Vultaggio A, Matucci A et al, IJIP 2008)
(Steenholdt C et al, Aliment Pharmacol Ther 2011)
Timing of the development of reactions
ATI+ IgE+
N° of patients
ATI+ IgEATI-
(N° of infusions)
ATI+ IgE+
ATI+ IgE-
1° Cycle
2/7 (28.6%)
14/16 (87.5%)
Re-exposure
5/7 (71.4%)
2/16 (12.5%)
Matucci A et al, Clin Exp Allergy 2013, in press
p<0.02
When to monitor immunogenicity?
Table 1. Patients’ characteristics and monitoring of sensitization to infliximab
Patient
Prick
IDR
(age/sex/disease/atopy)
Non isotype-specific
ATI (OD)
IgE ATI
A
(kUA/l)
#1 (33/F/BD/no)
1st course of therapy
Baseline
Neg
Neg
0.142
0.00
3rd infusion (°)
Neg
Neg
0.112
0.00
T0
Neg
Neg
0.136
0.02
T1
Neg
Pos (1/100)
2.194
0.19
2nd course of therapy
B
#2 (42/M/RA/no)
1st course of therapy
Baseline
Neg
Neg
0.126
0.02
5th infusion (°)
Neg
Neg
0.149
0.01
T0
Neg
Neg
0.134
0.01
T1
Neg
Pos (1/10)
2.085
0.16
2nd course of therapy
IDR: intradermal tests; ATI: anti-infliximab antibodies; OD: optical density; BD: Behçet disease;
RA: rheumatoid arthritis. Non isotype-specific (cut-off value: 0.160) and IgE ATI (cut-off value: 0.10)
have been measured as reported in the text. (°): serum samples have been collected before the
reported infusion. T0: baseline before retreatment; T1: twelve days after the first infusion of the second
course.
(Vultaggio A, Matucci A, et al. Intern Emerg Medicine 2011)
Frequency of ADA formation in different
immune-mediated diseases
Infliximab-treated patients
RA
SpA
BID
Vas
ATI +
15 (40.5%)
12 (20.7%)
19 (30.6%)
7 (23.3%)
ATI -
22
46
43
23
personal unpublished data
% of IgE+ patients
Highest incidence of anti-cetuximab IgE in
severe reactions
Mariotte D et al, mAbs 2011
Do IgE-mediated events have
peculiar clinical features?
Clinical management of
hypersensitivity reactions
Patients with
previous reactions
Definition of pathogenic
mechanisms
Patients with no
previous reactions
Identify patients at risk
Prevention of further or
first time reactions
Symptom-driven and preventive manner
Da cambiare!!!
Symptom-driven and preventive manner
Da cambiare!!!
Serum detection of IgE anti-drug antibodies:
Clinical studies
Method
IMMUNOCAP
ASSAY
ELISA
IMMUNOCAP
ASSAY
Patients
13 grade 1-2*
12 grade 3-4*
Controls
51 tolerant
patients; 462
HD
3 urticaria/angioedema
3 pulmonary/GI/CV symphy
toms
6 severe hypotension
2 cardiac/respiratory arrest
78 tolerant
patients;
117 HD
10 mild
10 moderate
10 severe
20 untreated,
15 tolerant
and 15 non
responder
patients
Confirmed
diagnosis
5/8 IgE-neg
subjects were
rechallenged: 1/5
had HR
Histamine and
tryptase
measurements
SPT + IDT
Culprit
drugs
Cetuximab
Cetuximab
Infliximab
Drugs
tested
Cetuximab
Sensitivity
Specificity
Sensitivity
92% (68%)°
Specificity
90% (92%)°
Cetuximab
Sensitivity
71.4%
Specificity
82.1%
Infliximab
Sensitivity
26%
Specificity
90%
Comments
Retrospective
study;
Pre-existing IgE
that are shown
to be specific for
Gal1-3Gal
Retrospective
study;
Good potential
of developed
ELISA for
predicting high
grade HR at first
cetuximab
therapy
Correlation
between skin
testing and
serum IgE
antibodies
PAPER
Chung CH
(2008)
Mariotte D
(2011)
Matucci A
(2013)
Which tools are available for the clinician
to manage the infusion reactions?

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