Transcript Clinical pictures of hypersensitivity to biologicals

“Clinical pictures of hypersensitivity to
biologicals”
E. Maggi, MD
[email protected]
Center of Research, “DENOThe”,
University of Florence, Italy
HR to biologicals: Definition
All the infusion reactions recognising an antibodyor cellular-mediated mechanism
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
% of patients
Clinical features of IFX-related
Immediate infusion reactions
itching urticaria
AE
nausea back throat flushing dyspnea hypovomiting pain costriction
tension
Grading
mild
33,3%
moderate
33,3%
33,3%
severe
N° of patients
Matucci A et al
Clin Exp Allergy 2013,
LOC
tachy- low O2
cardia
Delayed
reactions
to biologicals
T-cell
involvement
in delayed
hypersensitivity
clinical pictures
and to
pathogenetic
mechanisms
reactions
anti-TNFα agents
•Biopsy
Disseminated
skin reactions
of maculopapular exanthema
after a drug provocation test with infliximab
– Maculopapular exanthema
– Steven-Johnson’s syndrome
– Acneiform eruptions
– Psoriasiform eruptions
• Serum-sickness syndrome
• Tromboembolism events
• Skin vasculitis
Torres MJ et al JACI , 2011
Likely sustained
by T cell response
Target-dependent event
Likely associated
with
ADA development
Local reactions to biologicals
• Unspecific irritative effect
IMMEDIATE
– Eccipient (e.g. sorbitol vs citric acid)
– Volume of injection (eg. 0,5 ml vs 1 ml)
• Antibody-mediated reaction
IMMEDIATE
– The development of ADA increases the risk of IRS
• T cell-mediated reaction
T-cell infiltration has been observed in
delayed ISR to etanercept (Zelster R, Arch Dermatol 2001)
DELAYED
Question
Can Immunogenicity explain the onset
of Hypersentivity Reactions to the drug?
The Immune response to Biologicals
VIRTUALLY ALL BIOLOGICALS ARE IMMUNOGENIC
• Large and complex proteins
• Different degree of glycosylation
• Presence of xenoantigens
• Partial or complete human sequence (allotypes)
• Neoantigens on junction-sites
• Repetitive Idiotype (mAbs)
• Cross-reactivity with recall epitopes
Chimeric
Humanized
Fully human
Fusion protein
IL-4; IL-13
ICC
IgG ADAs
V
Th
Y
TCR
APC
FcgR
IgE ADAs
B
MHC II
PRRs
Y
IgM ADAs
BCR
B
Aggregate
mAbs
Matucci A, Vultaggio A, et al. (IFIACI 2011)
ADA were prevalently detected in
non-responder or reactive patients
346 infliximab-treated patients:
34,6% ADA+
Tolerant n=200
Non responder n=93
Reactive n=53
% ATI+ patients
100
p<0.0001
The detection of ADA were performed
with validated commercial kits with
parallel evaluation of the drug levels.
A confirmatory assay and a speficic
inhibitory test was usually run in positive
assays
(Rup B et al & Abirisk Consortium, Clin
Exp Allergy, 2015)
p<0.005
75
The onset of ADA response as well as
the HR, develop within the 5-10 infusions
50
The ADA levels in patients with HR are
higher than in ADA+ patients who did
Not develop HR
25
0
tolerant
non responder
(Vultaggio A et al, submitted)
reactive
ADA of IgE isotype
IgE-mediated reactions have been
described towards several BAs
rug
In vivo
In vitro
Ref
Muromonab
No
Yes
Georgitis, 1991
Cetuximab
No
Yes
Chung, 2008
Tocilizumab
Infliximab-specific
IgE
ADAs 2010
Stubenrauch,
No
Yes
Baudouin , 2003
Yes
Drug
HR+ patients No
n=34 Price, 2007
Omalizumab Yes
Basiliximab
No
EtanerceptADA+
Yes patientsNo
IgE+Yespatients No
Adalimumab
Maggi E, Vultaggio A, Matucci A
Exp Rev Clin Immunol 2011
n=28 Bavbek,
(82,4%)
2011
p<0.02
n=7
(25%)
Paltiel, 2008
Rituximab
Yes
No
Brennan , 2009
Natalizumab
Yes
Yes
MunozCano, 2010
Infliximab
Yes
Yes
Vultaggio, 2010
Vultaggio A et al, Allergy 2010
Matucci A et al, Clin Exp Allergy 2013
Skin testing for infliximab
ADR
Skin testing
Patients with
ADA
pos
HRs (n=23)
Patients with
ADA
neg
no HRs(n=30)
Healthy
Donors(n=20)
Total
Skin
Total pos
Loss of Treated- Healthy
controls Total
donors
Positiveresponse
Negative
19
4
23
8
7
1
0
8
11
15
Sensitivity (%)
IgE pos
7
29
4
0
16
20
P<0.0001
Matucci A et al, Clin Exp Allergy 2013
11
15
65
0
Specificity (%)
0
30.4
4
23
30
20
0
34
20
39
20
73
0
0
73
PPV(%)
0
NPV(%)
0
96.6
55
Sensitivity Specificity PPV(%)
(%)
(%)
30.4
96.6
All
56
0
99
NPV(%)
90
Serum anti-Rituximab IgE Ab increased
during the two HRs of a RTX-treated patient
RTX-specific IgE
Total IgE
Total IgE (kU/l)
Skin Testing
Positivity
RTX-specific IgE (kUA/l)
HR
Sample #
1
2
3
4
5
6
7
8
9
10
(Vultaggio A et al, Int Archs Allergy Clin Immunol, 2012)
Dilution
Prick test
IDT (imm)
1:1000
Neg
Neg
1:100
Neg
Pos
1:10
Neg
Pos
SF
Neg
Neg
HR towards biologicals: a model
IgE anti-drug antibodies
IgG anti-drug antibodies
Remarks
The presence of high affinity ADA of
IgG/IgE isotypes and of IgG1/IgG4
subclasses in HR patients indicates that
the immune response to IFX is a T-cell
dependent phenomenon
(Baker MP et al, Slf nonself, 2010)
Rituximab-specific T cells derived from the
IgE ADA+ patient produce high type 2 cytokines
RTX-reactive patient
RTX-unexposed patients
Mitogenic Index
Healthy controls
Isotype control
18
Anti-MHC class II
12
6
0
RTX 100
RTX 10
mg/ml
RTX 1
(Vultaggio A, Matucci A et al,
Int Arch Allergy Immunol 2012)
Conclusions
• Local and systemic immediate and delayed HRs to biologicals
are due to the immunogenicity of the drug
• ADA positivity and levels correlate with the clinical outcomes
(LOR or HR).
•
IgE ADAs are detected in a proportion of reactive patients
and are pathogenetic since associated to positive skin tests
and drug-specific type2 response in vitro. Likely both IgE- and
non-IgE ADA are responsible for HRs.
• Anti-IFX T cella are likely induced in the majority of patients
during the first infusions, but they are inhibited by drugdriven regulatory mechanisms as IL-10-producing drugspecific T cells.
“Clinical pictures of Hypersensitivity
reactions to biologicals”
Internal
Lab. of Clin. Immunology
Francesca Nencini
Giulia Petroni
Sara Pratesi
Francesca Zanieri
Alessandra Vultaggio
DH Clinical Team
Andrea Matucci
AOU-Careggi
Unit of Gastroenterology
V. Annese
M. Milla
Unit of Rheumatology
M. Matucci Cèrinic
G. Fiore
Unit of Hematology
L. Rigacci
In/out-Patient Services
Fabio Almerigogna
Francesco Annunziato
Daniele Cammelli
Lorenzo Cosmi
Francesco Liotta
Paola Parronchi
Oliviero Rossi
IMI- EU Project “ABIRISK”
Chaired by M. Pallardy (Paris)