Nuove opportunit diagnostiche per la gestione clinica delle - - PowerPoint PPT Presentation

AOU Careggi (Florence, Italy) Department of Biomedicine Immunoallergology Unit vultaggioa@aou-careggi.toscana.it

Nuove opportunità diagnostiche per la gestione clinica delle reazioni avverse a farmaci biologici

Alessandra Vultaggio

SIAAIC Toscana 2014

Adverse Events

Infusion Reactions Hyper sensitivity reactions

Adverse Events (AE):

Any untoward medical occurrence

associated with the use of a drug, whether or not drug related Infusion Reactions (IR):

Any AE caused by the drug

Hypersensitivity Reactions:

Antibody- or cellular-mediated IR

(2014, in press)

Biological agents-related hypersensitivity reaction: a SUBMERGED and EMERGENT problem !!!

Clinical management of hypersensitivity reactions Definition of pathogenic mechanisms Identify patients at risk

Patients with previous reactions Patients with no previous reactions

Prevention of further or first time reactions

IMMEDIATE IMMEDIATE DELAYED DELAYED

OCCUR DURING OR WITHIN 1 HOUR AFTER INFUSION OCCUR FROM 1 HOUR TO 14 DAYS AFTER INFUSION

Pichler WJ, Allergy 2006 Maggi E et al, Exp Rev Clin Immunol 2011

OCCUR WITHIN A FEW MINUTES AFTER INJECTION OCCUR AT LEAST 1 DAY AFTER INJECTION

Infusion reactions to biologicals : extension and timing of onset

SYSTEMIC SYSTEMIC LOCAL LOCAL

• Non antibody-mediated adverse reactions
• Complement-mediated
• Cytokine release syndrome (CRS)
• Antibody-mediated adverse reactions
• IgE-mediated
• Non IgE-mediated

Pathogenic mechanisms of reactions to biological agents (BA)

IMMEDIATE systemic REACTIONS IMMEDIATE systemic REACTIONS

Antibody-mediated = Hypersensitivity

Vultaggio A et al, Curr Opin Allergy Clin Immunol 2012

Target cell Activation NK cell C’-mediated lysis D i r e c t a p

• p

t

• s

i s ADCC-mediated lysis

C Y T O K I N E R E L E A S E Mø

FcγRI

Biological agent

MAC

Vultaggio A, Maggi E, Matucci A Curr Opin Allergy Clin Immunol 2011

BA-induced cytokine release syndrome

Flu-like reactions Anaphylaxis-like reactions Cytokine storm Flu-like reactions

Overlap between CRS and HYPERSENSITIVITY

Fever Rash Hypotension Dyspnea Tachycardia Nausea Angioedema Dizziness Bronchospasm Pruritus Headache Myalgias Diarrhea MOF

CRS

Antibody-mediated Hypersensitivity 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

• Non isotype-specific

ADA assay

• IgE Isotyping

T cell assays: their role to be defined – In vivo tests to

• Skin testing for IgE-

mediated HRs

 Immunochemical methods

 Binding assays (ELISAs, RIA, elettrochemiluminesce)

 Biophysical methods

 Surface plasmon resonance

 Bioassays

Each of these methods has benefits and limitations !!

Detection of ADAs: current methods

• ELISA bridging

format is the most used test

• 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 )

Comparison of different tecniques to monitor anti-drug antibdies

• IFX-treated patients
• BID patients (CD)
• ELISA, RIA, EIA, RGA

6,8 25 38,9 82,1 100 93,2 75 61,1 17,9

20 40 60 80 100

RESPONDER (n=103) PARTIALLY NON RESPONDER (n=28) TOTALLY NON RESPONDER (n=36) REACTIVE (n=34) REACTIVE/NON RESPONDER (n=9) ATI - 96 (93.2%) 21 (75%) 22 (61.1%) 6 (17.6%) 0 (0%) ATI + 7 (6.8%) 7 (25%) 14(38.9%) 28 (82.4%) 9 (100%)

Immediate systemic reactions to IFX are associated with ADA formation

% of patients

Vultaggio A, Matucci A et al, Allergy 2010 and unpublished data

82.4 17.6

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

IgG pathway of anaphylaxis in mice

ADR towards biologics: a model

High amount of antibody High amount of antigen

Maggi E, Vultaggio A, Matucci A Exp Rev Clin Immunol 2011

IgE ADA isotype

IgE-mediated reactions have been described towards several BAs

Vultaggio A et al, Allergy 2010 Matucci A et al, Clin Exp Allergy 2013 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 And Unpublished data

ADR+ patients n=34 ATI+ patients n=28 (82.4%) IgE+ patients n=7 (25%)

Infliximab-specific IgE ADAs

IgE-mediated IFX-related events: Update of our experience

• 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

• Assays are sensitive to:

– Circulating drug – Antidrug antibodies

• f other isotypes

the analysis of specific IgE anti-drug antibodies is challenging the analysis of specific IgE anti-drug antibodies is challenging

The Relevance of IgE Isotyping: Why not “Just do it”?

Non-isotype-specific ADA IgE ADA

OD

BaselineDay of reaction Days post reaction

0,2 0,4 0,6 0,8 1

+14 +7 +21 +28

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

Serum detection of IgE anti-drug antibodies: Type of assay

Why to measure BA-specific IgE?

p<0.02

20 40 60 80 100 Hypereactivity Tolerant Severe Hypereacitivy % of IgE+ patients

Highest incidence of anti-drug IgE in severe reactions

Mariotte D et al, mAbs 2011 Matucci A al, Clin Exp Allergy 2013

• 1. IgE-mediated reactions have peculiar clinical characteristics
• 1. IgE-mediated reactions have peculiar clinical characteristics

ATI+ IgE+ ATI+ IgE- 1° Cycle 2/7 (28.6%) 14/16 (87.5%) Re-exposure 5/7 (71.4%) 2/16 (12.5%)

N° of patients

ATI+ IgE+ ATI+ IgE- ATI- (N° of infusions)

Timing of the development of reactions

p<0.02

Matucci A et al, Clin Exp Allergy 2013

• 2. IgE-mediated reactions usually occur earlier and

more frequently after a period of interrruption

• 2. IgE-mediated reactions usually occur earlier and

more frequently after a period of interrruption

Can diagnostic tools predict BA-induced infusion reactions?

(A.Vultaggio, A.Matucci et al Allergy 2010)

Hypersensitivity risk can be detected prior to clinical symptoms !!

Non-isotype-specific ATI IgE ATI

OD

Baseline Day of reaction Days post reaction

0,2 0,4 0,6 0,8 1

+14 +7 +21 +28

A role for ADA assays in the identification of patients at risk

Chung CH et al, NEJM 2008

The Cetuximab case The Cetuximab case

IgE-mediated reactions at first exposure

M e a t A l l e r g y Injection Gal-1-3-Gal Sensitization to Gal-1-3Gal

IgE G1-3G

Cetuximab (SP2)

Gal-1-3-Gal Murine part

First exposure to Cetuximab

IgE G1-3G

Hypersensitivity Reaction

(Matucci A. et al. EAACI 2014

Anti-cetuximab IgE as a valuable screening test

6 patients with meat allergy but IFX-naive Delayed anaphylaxis to meat Previous history

• f tick bites

IFX

5 out of 6 resulted POSITIVE IgE anti-IFX antibodies probably pre-

exist to the treatment Are they specific for glycans? What is their clinical significance? Do 2 different pathway of sensitization toward IFX exist?

Method Pts Controls Culprit drugs Sens Spec PPV NPV Author ELISA 14 78 unreactive 117 HD CTX 71.4 82.1 33.3 98.5

Mariotte D (2011)

CAP 30 20 untreated; 15 unreactive; 15 LOR INF

26

90 26 89

Matucci A (2013)

Serum detection of IgE anti-drug antibodies: Clinical studies

Pre- existing cross- reactive ADA New developed non cross- reactive ADA

Other isotypes of ADAs involved in the induction of hypersensitivity reactions Interference by other antibodies in the assay OR Very low circulating IgE levels (bound on cells)

TRUE IgE-NEGATIVE FALSE IgE-NEGATIVE

ADA-positive but IgE-negative reactive patients: why?

Can skin testing help clinicians in the allergological work-up for IgE-mediated hypersensitivity reactions ?

Skin testing 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

In vivo tests are not currently standardized and approved for BA

What is the appropriate drug concentration?

Biological Agent Concentration Dilutions Prick test IDT (0,02 ml) Infliximab 10 mg/ml 1:100-1:1 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 Positive Negative Total Patients with HRs (n=23) 7 16 23 Patients with no HRs (n=30) 1 29 30 Healthy Donors (n=20) 20 20 Total 8 65 73 Sensitivity(%) Specificity(%) PPV(%) NPV(%) 30.4 96.6 56 90

Skin testing for infliximab: our experience

Matucci A et al, Clin Exp Allergy 2013

Timing to perfom skin testing for BA

• Temporary irresponsiveness due to the massive activation

during the reaction

• Decrease of specific IgE over time

The time between the reaction and the in vivo evaluation is a crucial point The time between the reaction and the in vivo evaluation is a crucial point

REACT ION

IN VIVO ASSAY

The value of skin testing for BA in the clinical practice

Matucci A et al, Clin Exp Allergy 2013

Symptom-driven manner Symptom-driven manner

• To assess REACTIVE PATIENTS

– To define IgE-mediated pathogenesis desensitization

Brennan P et al, JACI 2009

The value of skin testing for BA in the clinical practice

Preventive manner ?? 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

• Biological agents are up-growing cause of drug-related

adverse effects, and the majority of these adverse effects are due to antibody formation

• In vivo procedures offer a new tool for the diagnosis of at

least IgE-mediated HR

• IgE and non IgE-mediated mechanisms may be involved
• 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)

Method Patients Controls Culprit drugs Sensitivity specificity

PAPER

IMMUNO CAP 25 51 unreactive; 462 HD Cetuximab

92%

(68%)° 90% (92%)°

Chung CH (2008)

ELISA 14 78 unreactive; 117 HD Cetuximab 71.4% 82.1%

Mariotte D (2011)

IMMUNO CAP 30 20 untreated; 15 unreactive; 15 LOR Infliximab

26%

90%

Matucci A (2013)

Serum detection of IgE anti-drug antibodies: Clinical studies

Pre- existing cross- reactive ADA New developed non cross- reactive 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)

ADA screening assay (Bridging ELISA)

In vitro ADAs assays

Stage 1: ADA screening & confirmation

Confirmatory assay (binding inhibition) + +

Isotype determination

Stage 2: ADA characterization No further testing

• No further

testing

• Relative ADA

concentration Neutralizing activity

In vitro ADAs assays

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 Positive Negative Total Patients with HRs (n=23) 7 16 23 Patients with no HRs (n=30) 1 29 30 Healthy Donors (n=20) 20 20 Total 8 65 73 Sensitivity(%) Specificity(%) PPV(%) NPV(%) 30.4 96.6 55 99

Skin testing for infliximab

Matucci A et al, Clin Exp Allergy 2013

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?

Maggi E, Vultaggio A, Matucci A Exp Rev Clin Immunol 2011

Hypersensitivity reactions are a clinical concern about biological agents

Mild Moderate Severe

Clinical characteristics of IFX-related Immediate infusion reactions

Matucci A et al Clin Exp Allergy 2013, in press

N° of patients

itching urticaria AE nausea vomiting back pain throat costriction flushing dyspnea hypo- tension LOC tachy- cardia low O2

% of patients

Clinical characteristics of IFX-related Immediate infusion reactions

Matucci A et al Clin Exp Allergy 2013, in press

0 1 2 3 4 5 6 7 8 9 10 11 12 13

RTX (2x1000 mg) RTX (2x1000 mg) RTX (2x1000 mg) April 2009

+2 +3 +4 +5 +6 +10 +12 +36 ADR ADR

2 weeks

         

December 2010 February 2010

Sample #

   

weeks post ADR

RTX-induced infusion reactions can be induced by an IgE-mediated mechanism

(Vultaggio A, Matucci A et al, Int Arch Allergy Immunol 2012)

Sample # Anti-RTX non-isotype-specific antibodies (OD) RTX-specific IgE (kUA/l) Total IgE (kU/l) Sample #

Non isotype-specific ADAs Non isotype-specific ADAs IgE-CAP ADAs IgE-CAP ADAs

RTX-specific IgE antibodies

Inhibitor added (µg/ml) Rituximab Mouse IgG % of inhibition Cetuximab

RTX 10 mg/ml 1:1 formulation RTX 1 mg/ml 1:10 RTX 0,1 mg/ml 1:100 RTX 0,01 mg/ml 1:1000

SKIN TESTING RESULT Prick test 1:1 negative IDT 1:1000 negative IDT 1:100 positive IDT 1:10 positive Saline solution negative

The importance of T cells in the development of anti-therapeutic antibodies

• The presence of multiple non-IgM ADAs isotypes
• T cell subset polarization in treated haemophilic

patients

• Many therapeutics proteins contain T cell epitope

Vultaggio A et al, Allergy 2010 Bartelds GM et al, Ann Rheum Dis 2010 Ehrenforth S et al, Lancet 1992 Reding MT et al, Thromb Haemost 2002 Harding FA et al, Mabs 2010 van Schouwenburg PA et al, Nat Rew Rheumatol 2013

Circulating T-cell response to rituximab is detectable

Isotype control Anti-MHC class II

(Vultaggio A, Matucci A et al, Int Arch Allergy Immunol 2012)

RTX-reactive patient Healthy controls RTX-unexposed patients

T cell response for infliximab in treated patients

(Vultaggio A, Matucci A et al, in preparation)

N° of patients

(11) (6) (10) (8)

Patients (N°) N° of patients showing proliferative

response to drug by using

_____________________________________________________ PBMNC CD4+T/DC Two-step Atg stim

(%) (%) (%) IFX-treated ADA+ (21) 8 (38) 14* (66) 7 (33) ADA- (15) 0 1 (6) 1 (6) HC (10) 0 0 RTX-treated ADA+ ( 1) 1 1 ND ADA- ( 7) 4 (57) 4 (57) ND HC ( 10) 0 0 ND ___________________________________________________________

• 11 out of 14 patients showed ADR or ADR plus LOR.

Only one patient with ADR resulted negative

RTX-specific T cell response is more easily detectable

Biologic (anti-inflammatory) effects

• n transmembrane TNF

Mitoma et al, 2008 Horiuchi et al, 2010 Vos et al, 2011

Features of IFX-specific T cells after ADR: a clonal analysis

188 TCC

CLONING Clonal Efficiency: Total: 36.6% Specific: 4,7%

Non specific TCC Non proliferating cytokine-producing TCC IFX-specific TCC N° of clones

High IL-10 production by IFX-specific T cell clones

*

*

IL-10-producing TCC

* p<0.002

(Vultaggio A, Matucci A et al, in preparation)

Infliximab-specific regulatory T cell clones

ANNEXIN V-CD39+CD73+ TCC CD39-CD73- TCC CD39-FITC CD73-PE Annexin V- Treg clones

IFX-specific response (cpm) T eff clones + IFX T eff clones + IFX + Treg clones T eff clones + IFX + no-Treg clones

(preliminary unpublished data))

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

Remarks

(A.Vultaggio, A.Matucci et al Allergy 2010)

Hypersensitivity risk can be detected prior to clinical symptoms !!

Non-isotype-specific ADA IgE ADA

OD

Baseline Day of reaction Days post reaction

0,2 0,4 0,6 0,8 1

+14 +7 +21 +28

A role for ADA assays in the identification of at risk patients

patients

(Vultaggio A, Matucci A et al, IJIP 2008)

p<0.025

Can patients at risk be identified by clinical features?

(Steenholdt C et al, Aliment Pharmacol Ther 2011)

BID patients

ATI+ IgE+ ATI+ IgE- 1° Cycle 2/7 (28.6%) 14/16 (87.5%) Re-exposure 5/7 (71.4%) 2/16 (12.5%)

N° of patients

ATI+ IgE+ ATI+ IgE- ATI- (N° of infusions)

Timing of the development of reactions

p<0.02

Matucci A et al, Clin Exp Allergy 2013, in press

When to monitor immunogenicity?

Table 1. Patients’ characteristics and monitoring of sensitization to infliximab

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. Patient (age/sex/disease/atopy) Prick IDR Non isotype-specific ATI (OD) IgE ATI (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 2nd course of therapy T0 Neg Neg 0.136 0.02 T1 Neg Pos (1/100) 2.194 0.19 #2 (42/M/RA/no) 1st course of therapy Baseline Neg Neg 0.126 0.02 5th infusion (°) Neg Neg 0.149 0.01 2nd course of therapy T0 Neg Neg 0.134 0.01 T1 Neg Pos (1/10) 2.085 0.16

(Vultaggio A, Matucci A, et al. Intern Emerg Medicine 2011)

B A

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

Highest incidence of anti-cetuximab IgE in severe reactions

% of IgE+ patients

Mariotte D et al, mAbs 2011

Do IgE-mediated events have peculiar clinical features?

Clinical management of hypersensitivity reactions Definition of pathogenic mechanisms Identify patients at risk

Patients with previous reactions Patients with no previous reactions

Prevention of further or first time reactions

Symptom-driven and preventive manner

Da cambiare!!!

Symptom-driven and preventive manner

Da cambiare!!!

Method Patients Controls Confirmed diagnosis Culprit drugs Drugs tested Sensitivity Specificity Comments PAPER

IMMUNOCAP ASSAY 13 grade 1-2* 12 grade 3-4* 51 tolerant patients; 462 HD 5/8 IgE-neg subjects were rechallenged: 1/5 had HR Cetuximab Cetuximab Sensitivity 92% (68%)° Specificity 90% (92%)° Retrospective study; Pre-existing IgE that are shown to be specific for Gal1-3Gal Chung CH (2008) ELISA 3 urticaria/angioedema 3 pulmonary/GI/CV symphy toms 6 severe hypotension 2 cardiac/respiratory arrest 78 tolerant patients; 117 HD Histamine and tryptase measurements Cetuximab Cetuximab Sensitivity 71.4% Specificity 82.1% Retrospective study; Good potential

• f developed

ELISA for predicting high grade HR at first cetuximab therapy Mariotte D (2011) IMMUNOCAP ASSAY 10 mild 10 moderate 10 severe 20 untreated, 15 tolerant and 15 non responder patients SPT + IDT Infliximab Infliximab Sensitivity 26% Specificity 90% Correlation between skin testing and serum IgE antibodies Matucci A (2013)

Serum detection of IgE anti-drug antibodies: Clinical studies

Which tools are available for the clinician to manage the infusion reactions?