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“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)