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Hypersensitivity and Immune-related Adverse Events in Biologic Therapy

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Abstract

Biologic medications are an expanding field of therapeutics for various medical conditions including cancer and inflammatory diseases. Due to their targeted approach to therapy, biologics can be less toxic than traditional systemic medications. However, as use becomes more widespread, adverse effects from biologic administration have also become apparent. Immune-related adverse events are a common mechanism by which biologics can cause on-target immune-related toxicities and both immediate and delayed-type hypersensitivity reactions. Immediate hypersensitivity reactions can be mediated by cytokine release or antibody mediated reactions, while delayed-type hypersensitivity is most often caused by serum sickness-like reactions. Additionally, biologics used for treatment of cancer using checkpoint blockade and rheumatologic disease using cytokine blockade can result in autoimmunity. Finally, when inflammatory cytokines are targeted for treatment of autoimmune or autoinflammatory disease, the host immune defense can be compromised predisposing to secondary immunodeficiency. This review will discuss the mechanisms of these reactions and discuss examples of biologics implicated in each of these adverse events.

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Fig. 1

Adapted from Picard et al. [12]

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References

  1. Corominas M, Gastaminza G, Lobera T (2014) Hypersensitivity reactions to biological drugs. J Investig Allergol Clin Immunol 24:212–25; quiz 1p following 25

  2. Purcell RT, Lockey RF (2008) Immunologic responses to therapeutic biologic agents. J Investig Allergol Clin Immunol 18:335–342

    CAS  PubMed  Google Scholar 

  3. Khan DA (2016) Hypersensitivity and immunologic reactions to biologics: opportunities for the allergist. Ann Allergy Asthma Immunol 117:115–120

    Article  CAS  PubMed  Google Scholar 

  4. Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497

    Article  CAS  PubMed  Google Scholar 

  5. Brennan PJ, Rodriguez Bouza T, Hsu FI, Sloane DE, Castells MC (2009) Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin Immunol 124:1259–1266

    Article  CAS  PubMed  Google Scholar 

  6. Pichler WJ (2019) Immune pathomechanism and classification of drug hypersensitivity. Allergy 74:1457–1471

    CAS  PubMed  Google Scholar 

  7. Pichler WJ (2006) Adverse side-effects to biological agents. Allergy 61:912–920

    Article  CAS  PubMed  Google Scholar 

  8. Mori F, Saretta F, Bianchi A, Crisafulli G, Caimmi S, Liotti L et al (2020) Hypersensitivity reactions to monoclonal antibodies in children. Medicina (Kaunas) 56

  9. Vultaggio A, Castells MC (2014) Hypersensitivity reactions to biologic agents. Immunol Allergy Clin North Am 34(615–32):ix

    Google Scholar 

  10. Isabwe GAC, Garcia Neuer M, de Las Vecillas Sanchez L, Lynch DM, Marquis K, Castells M (2018) Hypersensitivity reactions to therapeutic monoclonal antibodies: Phenotypes and endotypes. J Allergy Clin Immunol 142:159–70 e2

  11. Galvao VR, Castells MC (2015) Hypersensitivity to biological agents-updated diagnosis, management, and treatment. J Allergy Clin Immunol Pract 3:175–85; quiz 86

  12. Picard M, Galvao VR (2017) Current knowledge and management of hypersensitivity reactions to monoclonal antibodies. J Allergy Clin Immunol Pract 5:600–609

    Article  PubMed  Google Scholar 

  13. Bremmer M, Deng A, Gaspari AA (2009) A mechanism-based classification of dermatologic reactions to biologic agents used in the treatment of cutaneous disease: Part 2. Dermatitis 20:243–256

    Article  CAS  PubMed  Google Scholar 

  14. Bremmer M, Deng A, Gaspari AA (2009) A mechanism-based classification of dermatologic reactions to biologic agents used in the treatment of cutaneous disease: Part 1. Dermatitis 20:182–192

    Article  CAS  PubMed  Google Scholar 

  15. Puxeddu I, Giori L, Rocchi V, Bazzichi L, Bombardieri S, Tavoni A et al (2012) Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol 108:123–124

    Article  PubMed  Google Scholar 

  16. Broyles AD, Banerji A, Barmettler S, Biggs CM, Blumenthal K, Brennan PJ et al (2020) Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs. J Allergy Clin Immunol Pract 8:S16–S116

    Article  PubMed  Google Scholar 

  17. Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L et al (2003) The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 98:1315–1324

    Article  CAS  PubMed  Google Scholar 

  18. Akarsu A, Soyer O, Sekerel BE (2020) Hypersensitivity reactions to biologicals: from bench to bedside. Curr Treat Options Allergy 7:71–83

    Article  PubMed  PubMed Central  Google Scholar 

  19. Baldo BA (2013) Adverse events to monoclonal antibodies used for cancer therapy: Focus on hypersensitivity responses. Oncoimmunology 2:e26333

  20. Wong JT, Long A (2017) Rituximab hypersensitivity: evaluation, desensitization, and potential mechanisms. J Allergy Clin Immunol Pract 5:1564–1571

    Article  PubMed  Google Scholar 

  21. van Vollenhoven RF, Emery P, Bingham CO, 3rd, Keystone EC, Fleischmann RM, Furst DE et al (2013) Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis 72:1496–502

  22. Jung JW, Kang HR, Lee SH, Cho SH (2014) The incidence and risk factors of infusion-related reactions to rituximab for treating B cell malignancies in a single tertiary hospital. Oncology 86:127–134

    Article  CAS  PubMed  Google Scholar 

  23. Checkley LA, Kristofek L, Kile S, Bolgar W (2019) Incidence and Management of Infusion Reactions to Infliximab in an Alternate Care Setting. Dig Dis Sci 64:855–862

    Article  PubMed  Google Scholar 

  24. Choquette D, Faraawi R, Chow A, Rodrigues J, Bensen WJ, Nantel F (2015) Incidence and management of infusion reactions to infliximab in a prospective real-world community registry. J Rheumatol 42:1105–1111

    Article  CAS  PubMed  Google Scholar 

  25. Lichtenstein L, Ron Y, Kivity S, Ben-Horin S, Israeli E, Fraser GM et al (2015) Infliximab-Related Infusion Reactions: Systematic Review. J Crohns Colitis 9:806–815

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cook-Bruns N (2001) Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. Oncology 61(Suppl 2):58–66

    Article  CAS  PubMed  Google Scholar 

  27. Thompson LM, Eckmann K, Boster BL, Hess KR, Michaud LB, Esteva FJ et al (2014) Incidence, risk factors, and management of infusion-related reactions in breast cancer patients receiving trastuzumab. Oncologist 19:228–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pratt KP (2018) Anti-drug antibodies: emerging approaches to predict, reduce or reverse biotherapeutic immunogenicity. Antibodies (Basel) 7

  29. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M et al (2008) Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 358:1109–1117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lammerts van Bueren JJ, Rispens T, Verploegen S, van der Palen-Merkus T, Stapel S, Workman LJ et al (2011) Anti-galactose-alpha-1,3-galactose IgE from allergic patients does not bind alpha-galactosylated glycans on intact therapeutic antibody Fc domains. Nat Biotechnol 29:574-6

  31. Finkelman FD, Khodoun MV, Strait R (2016) Human IgE-independent systemic anaphylaxis. J Allergy Clin Immunol 137:1674–1680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Matucci A, Pratesi S, Petroni G, Nencini F, Virgili G, Milla M et al (2013) Allergological in vitro and in vivo evaluation of patients with hypersensitivity reactions to infliximab. Clin Exp Allergy 43:659–664

    CAS  PubMed  Google Scholar 

  33. Mourad AA, Boktor MN, Yilmaz-Demirdag Y, Bahna SL (2015) Adverse reactions to infliximab and the outcome of desensitization. Ann Allergy Asthma Immunol 115:143–146

    Article  CAS  PubMed  Google Scholar 

  34. Cox L, Platts-Mills TA, Finegold I, Schwartz LB, Simons FE, Wallace DV et al (2007) American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force Report on omalizumab-associated anaphylaxis. J Allergy Clin Immunol 120:1373–1377

    Article  CAS  PubMed  Google Scholar 

  35. Cox L, Lieberman P, Wallace D, Simons FE, Finegold I, Platts-Mills T et al (2011) American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Omalizumab-Associated Anaphylaxis Joint Task Force follow-up report. J Allergy Clin Immunol 128:210–212

    Article  PubMed  Google Scholar 

  36. Price KS, Hamilton RG (2007) Anaphylactoid reactions in two patients after omalizumab administration after successful long-term therapy. Allergy Asthma Proc 28:313–319

    Article  CAS  PubMed  Google Scholar 

  37. Owens G, Petrov A (2011) Successful desensitization of three patients with hypersensitivity reactions to omalizumab. Curr Drug Saf 6:339–342

    Article  CAS  PubMed  Google Scholar 

  38. Fouda GE, Bavbek S (2020) Rituximab hypersensitivity: from clinical presentation to management. Front Pharmacol 11:572863

  39. Sloane D, Govindarajulu U, Harrow-Mortelliti J, Barry W, Hsu FI, Hong D et al (2016) Safety, costs, and efficacy of rapid drug desensitizations to chemotherapy and monoclonal antibodies. J Allergy Clin Immunol Pract 4:497–504

    Article  PubMed  Google Scholar 

  40. Hong DI, Dioun AF (2014) Indications, protocols, and outcomes of drug desensitizations for chemotherapy and monoclonal antibodies in adults and children. J Allergy Clin Immunol Pract 2:13–9; quiz 20

  41. Dilley MA, Lee JP, Platt CD, Broyles AD (2016) Rituximab desensitization in pediatric patients: results of a case series. Pediatr Allergy Immunol Pulmonol 29:91–94

    Article  PubMed  PubMed Central  Google Scholar 

  42. Munoz-Cano R, Carnes J, Sanchez-Lopez J, Saiz A, Bartra J, Lopez-Matas MA et al (2010) Biological agents: new drugs, old problems. J Allergy Clin Immunol 126:394–395

    Article  PubMed  Google Scholar 

  43. Hellwig K, Schimrigk S, Fischer M, Haghikia A, Muller T, Chan A et al (2008) Allergic and nonallergic delayed infusion reactions during natalizumab therapy. Arch Neurol 65:656–658

    Article  PubMed  Google Scholar 

  44. Calabresi PA, Giovannoni G, Confavreux C, Galetta SL, Havrdova E, Hutchinson M et al (2007) The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 69:1391–1403

    Article  CAS  PubMed  Google Scholar 

  45. Camacho-Halili M, George R, Gottesman M, Davis-Lorton M (2011) An approach to natalizumab hypersensitivity: a case series of induction of tolerance. Mult Scler 17:250–253

    Article  CAS  PubMed  Google Scholar 

  46. Bignardi D, Ribizzi G, Voltolini S, Serrati C, Troise C (2012) Successful desensitization to natalizumab in a skin test–positive patient: a case report. Eur Ann Allergy Clin Immunol 44:26–29

    CAS  PubMed  Google Scholar 

  47. Ribizzi G, Bignardi D, Farinini D, Sassos D, Gentile R, Arecco D et al (2013) Desensitization to natalizumab: clinical and immunological observations. Mult Scler 19:376–377

    Article  PubMed  Google Scholar 

  48. Perez-Rodriguez E, Hernandez-Perez MA, Martinez-Tadeo JA (2017) Successful desensitization to natalizumab using a 1-solution protocol. Ann Allergy Asthma Immunol 118:113–114

    Article  CAS  PubMed  Google Scholar 

  49. Hansel K, Bianchi L, Tramontana M, Balato A, Scala E, Brozzi J et al (2019) Immediate local and systemic hypersensitivity due to etanercept and adalimumab. J Allergy Clin Immunol Pract 7:726–727

    Article  PubMed  Google Scholar 

  50. Baert F, Noman M, Vermeire S, Van Assche G, G DH, Carbonez A et al (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 348:601–8

  51. O’Meara S, Nanda KS, Moss AC (2014) Antibodies to infliximab and risk of infusion reactions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 20:1–6

    Article  PubMed  Google Scholar 

  52. Maneiro JR, Salgado E, Gomez-Reino JJ (2013) Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis. JAMA Intern Med 173:1416–1428

    Article  CAS  PubMed  Google Scholar 

  53. Bavbek S, Ataman S, Akinci A, Castells M (2015) Rapid subcutaneous desensitization for the management of local and systemic hypersensitivity reactions to etanercept and adalimumab in 12 patients. J Allergy Clin Immunol Pract 3:629–632

    Article  PubMed  Google Scholar 

  54. O’Neil BH, Allen R, Spigel DR, Stinchcombe TE, Moore DT, Berlin JD et al (2007) High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol 25:3644–3648

    Article  PubMed  Google Scholar 

  55. Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD et al (2009) Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol 123:426–433

    Article  CAS  PubMed  Google Scholar 

  56. Chitnavis M, Stein DJ, Commins S, Schuyler AJ, Behm B (2017) First-dose anaphylaxis to infliximab: a case of mammalian meat allergy. J Allergy Clin Immunol Pract 5:1425–1426

    Article  PubMed  Google Scholar 

  57. Jerath MR, Kwan M, Kannarkat M, Mirakhur B, Carey L, Valgus J et al (2009) A desensitization protocol for the mAb cetuximab. J Allergy Clin Immunol 123:260–262

    Article  CAS  PubMed  Google Scholar 

  58. Murdaca G, Spano F, Puppo F (2013) Selective TNF-alpha inhibitor-induced injection site reactions. Expert Opin Drug Saf 12:187–193

    Article  CAS  PubMed  Google Scholar 

  59. Chen CB, Wu MY, Ng CY, Lu CW, Wu J, Kao PH et al (2018) Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies. Cancer Manag Res 10:1259–1273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bulur I, Keseroglu HO, Saracoglu ZN, Gonul M (2015) Symmetrical drug-related intertriginous and flexural exanthema (Baboon syndrome) associated with infliximab. J Dermatol Case Rep 9:12–14

    Article  PubMed  PubMed Central  Google Scholar 

  61. Castells M (2017) Drug hypersensitivity and anaphylaxis in cancer and chronic inflammatory diseases: the role of desensitizations. Front Immunol 8:1472

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Gamarra RM, McGraw SD, Drelichman VS, Maas LC (2006) Serum sickness-like reactions in patients receiving intravenous infliximab. J Emerg Med 30:41–44

    Article  PubMed  Google Scholar 

  63. Karmacharya P, Poudel DR, Pathak R, Donato AA, Ghimire S, Giri S et al (2015) Rituximab-induced serum sickness: A systematic review. Semin Arthritis Rheum 45:334–340

    Article  PubMed  Google Scholar 

  64. Bayer G, Agier MS, Lioger B, Lepelley M, Zenut M, Lanoue MC et al (2019) Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study. Eur J Intern Med 67:59–64

    Article  CAS  PubMed  Google Scholar 

  65. Barakat L, Torres MJ, Phillips EJ, Caminati M, Chang YS, Caimmi D et al (2020) Biological treatments in allergy: prescribing patterns and management of hypersensitivity reactions. J Allergy Clin Immunol Pract

  66. Dreyfus DH, Randolph CC (2006) Characterization of an anaphylactoid reaction to omalizumab. Ann Allergy Asthma Immunol 96:624–627

    Article  PubMed  Google Scholar 

  67. Pilette C, Coppens N, Houssiau FA, Rodenstein DO (2007) Severe serum sickness-like syndrome after omalizumab therapy for asthma. J Allergy Clin Immunol 120:972–973

    Article  PubMed  Google Scholar 

  68. Eapen A, Kloepfer KM (2018) Serum sickness-like reaction in a pediatric patient using omalizumab for chronic spontaneous urticaria. Pediatr Allergy Immunol 29:449–450

    Article  PubMed  Google Scholar 

  69. Molderings GJ, Dumoulin FL, Homann J, Sido B, Textor J, Mucke M et al (2020) Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness. Naunyn Schmiedebergs Arch Pharmacol 393:1573–1580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Her M, Kavanaugh A (2016) Alterations in immune function with biologic therapies for autoimmune disease. J Allergy Clin Immunol 137:19–27

    Article  CAS  PubMed  Google Scholar 

  71. Ribas A, Wolchok JD (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350–1355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ramos-Casals M (2020) Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 21

  73. Hu J-R, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG et al (2019) Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 115:854–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Postow MA, Sidlow R, Hellmann MD (2018) Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 378:158–168

    Article  CAS  PubMed  Google Scholar 

  75. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 378:1277–1290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hellmann MD, Paz-Ares L, Bernabe Caro R, Zurawski B, Kim S-W, Carcereny Costa E et al (2019) Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med 381:2020–2031

    Article  CAS  PubMed  Google Scholar 

  77. Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chavez A, Keegan N, Khamashta MA et al (2020) Immune-related adverse events of checkpoint inhibitors. Nat Rev Dis Primers 6:38

    Article  PubMed  Google Scholar 

  78. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE et al (2018) Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol 4:173

    Article  PubMed  Google Scholar 

  79. Johnson DB, Jakubovic BD, Sibaud V, Sise ME (2020) Balancing cancer immunotherapy efficacy and toxicity. J Allergy Clin Immunol: In Pract 8:2898–906.

  80. Akturk HK, Kahramangil D, Sarwal A, Hoffecker L, Murad MH, Michels AW (2019) Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis. Diabet Med 36:1075–1081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Shivaji UN, Jeffery L, Gui X, Smith SCL, Ahmad OF, Akbar A et al (2019) Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management. Therap Adv Gastroenterol 12:1756284819884196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Salem J-E, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A et al (2018) Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 19:1579–1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Johnson DB, Manouchehri A, Haugh AM, Quach HT, Balko JM, Lebrun-Vignes B et al (2019) Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study. J Immunother Cancer 7:134

    Article  PubMed  PubMed Central  Google Scholar 

  84. Wang DY, Salem J-E, Cohen JV, Chandra S, Menzer C, Ye F et al (2018) Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 4:1721

    Article  PubMed  PubMed Central  Google Scholar 

  85. Darnell EP, Mooradian MJ, Baruch EN, Yilmaz M, Reynolds KL (2020) Immune-related adverse events (irAEs): diagnosis, management, and clinical pearls. Curr Oncol Rep 22:39

    Article  PubMed  Google Scholar 

  86. Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM et al (2018) Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 36:1714–1768

    Article  CAS  PubMed  Google Scholar 

  87. Dolladille C, Ederhy S, Sassier M, Cautela J, Thuny F, Cohen AA et al (2020) Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol 6:865–871

    Article  PubMed  Google Scholar 

  88. Eggermont AMM, Kicinski M, Blank CU, Mandala M, Long GV, Atkinson V et al (2020) Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo: a secondary analysis of a randomized clinical trial. JAMA Oncol 6:519–527

    Article  PubMed  PubMed Central  Google Scholar 

  89. Fujii T, Colen RR, Bilen MA, Hess KR, Hajjar J, Suarez-Almazor ME et al (2018) Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. Invest New Drugs 36:638–646

    Article  CAS  PubMed  Google Scholar 

  90. Cortellini A, Buti S, Agostinelli V, Bersanelli M (2019) A systematic review on the emerging association between the occurrence of immune-related adverse events and clinical outcomes with checkpoint inhibitors in advanced cancer patients. Semin Oncol 46:362–371

    Article  CAS  PubMed  Google Scholar 

  91. Perez-De-Lis M, Retamozo S, Flores-Chavez A, Kostov B, Perez-Alvarez R, Brito-Zeron P et al (2017) Autoimmune diseases induced by biological agents. A review of 12,731 cases (BIOGEAS Registry). Expert Opin Drug Saf 16:1255–71

  92. Her M, Kavanaugh A (2016) Alterations in immune function with biologic therapies for autoimmune disease. Journal of Allergy and Clinical Immunology 137:19–27

    Article  CAS  PubMed  Google Scholar 

  93. Conrad C, Di Domizio J, Mylonas A, Belkhodja C, Demaria O, Navarini AA et al (2018) TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat Commun 9:25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Guerra I, Perez-Jeldres T, Iborra M, Algaba A, Monfort D, Calvet X et al (2016) Incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease: a nationwide cohort study. Inflamm Bowel Dis 22:894–901

    Article  PubMed  Google Scholar 

  95. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40:1725

    Article  CAS  PubMed  Google Scholar 

  96. Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR et al (2012) Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677–2686

    Article  PubMed  PubMed Central  Google Scholar 

  97. Borchers AT, Leibushor N, Cheema GS, Naguwa SM, Gershwin ME (2011) Immune-mediated adverse effects of biologicals used in the treatment of rheumatic diseases. J Autoimmun 37:273–288

    Article  CAS  PubMed  Google Scholar 

  98. Perez-Alvarez R, Pérez-de-Lis M, Ramos-Casals M (2013) Biologics-induced autoimmune diseases. Curr Opin Rheumatol 25:56–64

    Article  CAS  PubMed  Google Scholar 

  99. Sokumbi O, Wetter DA, Makol A, Warrington KJ (2012) Vasculitis associated with tumor necrosis factor-alpha inhibitors. Mayo Clin Proc 87:739–745

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Shivaji UN, Jeffery L, Gui X, Smith SCL, Ahmad OF, Akbar A et al (2019) Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management. Ther Adv Gastroenterol 12:175628481988419

    Article  CAS  Google Scholar 

  101. Atiqi S, Hooijberg F, Loeff FC, Rispens T, Wolbink GJ (2020) Immunogenicity of TNF-Inhibitors Front Immunol 11:312

    Article  CAS  PubMed  Google Scholar 

  102. Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW et al (2011) Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 305:1460–1468

    Article  CAS  PubMed  Google Scholar 

  103. Moots RJ, Xavier RM, Mok CC, Rahman MU, Tsai W-C, Al-Maini MH et al (2017) The impact of anti-drug antibodies on drug concentrations and clinical outcomes in rheumatoid arthritis patients treated with adalimumab, etanercept, or infliximab: Results from a multinational, real-world clinical practice, non-interventional study. PLoS One 12:e0175207

  104. Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T et al (2017) Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs 31:299–316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Singh JA, Wells GA, Christensen R, Tanjong Ghogomu E, Maxwell L, Macdonald JK et al (2011) Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev CD008794

  106. Henrickson SE, Ruffner MA, Kwan M (2016) Unintended immunological consequences of biologic therapy. Curr Allergy Asthma Rep 16:46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Davis BP, Ballas Z (2017) Biologic response modifiers: indications, implications, and insights. J Allergy Clin Immunol 139:1445–1456

    Article  CAS  PubMed  Google Scholar 

  108. Kalliolias GD, Ivashkiv LB (2016) TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 12:49–62

    Article  CAS  PubMed  Google Scholar 

  109. Keystone EC (2011) Does anti-tumor necrosis factor-α therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis?: a review of longterm data. J Rheumatol 38:1552–1562

    Article  CAS  PubMed  Google Scholar 

  110. Garcia-Doval I, Cohen AD, Cazzaniga S, Feldhamer I, Addis A, Carretero G et al (2017) Risk of serious infections, cutaneous bacterial infections, and granulomatous infections in patients with psoriasis treated with anti–tumor necrosis factor agents versus classic therapies: Prospective meta-analysis of Psonet registries. J Am Acad Dermatol 76:299–308

    Article  CAS  PubMed  Google Scholar 

  111. Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP et al (2006) Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 54:2368–2376

    Article  CAS  PubMed  Google Scholar 

  112. Keystone EC (2011) Does anti-tumor necrosis factor-alpha therapy affect risk of serious infection and cancer in patients with rheumatoid arthritis?: a review of longterm data. J Rheumatol 38:1552–1562

    Article  CAS  PubMed  Google Scholar 

  113. Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saag M et al (2007) Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor α antagonists. Arthritis Rheum 56:1125–1133

    Article  CAS  PubMed  Google Scholar 

  114. Dinarello CA, Simon A, van der Meer JWM (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discovery 11:633–652

    Article  CAS  PubMed  Google Scholar 

  115. Mantovani A, Dinarello CA, Molgora M, Garlanda C (2019) Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity 50:778–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Evavold CL, Kagan JC (2019) Inflammasomes: threat-assessment organelles of the innate immune system. Immunity 51:609–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Beukelman T, Xie F, Baddley JW, Chen L, Mannion ML, Saag KG et al (2016) The risk of hospitalized infection following initiation of biologic agents versus methotrexate in the treatment of juvenile idiopathic arthritis. Arthritis Res Ther 18:210

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Salliot C, Dougados M, Gossec L (2009) Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials. Ann Rheum Dis 68:25–32

    Article  CAS  PubMed  Google Scholar 

  119. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C et al (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131

    Article  CAS  PubMed  Google Scholar 

  120. Rose-John S, Winthrop K, Calabrese L (2017) The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol 13:399–409

    Article  CAS  PubMed  Google Scholar 

  121. Kang S, Tanaka T, Narazaki M, Kishimoto T (2019) Targeting Interleukin-6 Signaling in Clinic. Immunity 50:1007–1023

    Article  CAS  PubMed  Google Scholar 

  122. Schaper F, Rose-John S (2015) Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor Rev 26:475–487

    Article  CAS  PubMed  Google Scholar 

  123. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D et al (2017) Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 377:317–328

    Article  CAS  PubMed  Google Scholar 

  124. van Rhee F, Wong RS, Munshi N, Rossi JF, Ke XY, Fossa A et al (2014) Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 15:966–974

    Article  PubMed  CAS  Google Scholar 

  125. Garbers C, Heink S, Korn T, Rose-John S (2018) Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov 17:395–412

    Article  CAS  PubMed  Google Scholar 

  126. Schiff MH, Kremer JM, Jahreis A, Vernon E, Isaacs JD, van Vollenhoven RF (2011) Integrated safety in tocilizumab clinical trials. Arthritis Res Ther 13:R141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Morel J, Constantin A, Baron G, Dernis E, Flipo RM, Rist S et al (2017) Risk factors of serious infections in patients with rheumatoid arthritis treated with tocilizumab in the French Registry REGATE. Rheumatology (Oxford) 56:1746–1754

    Article  CAS  Google Scholar 

  128. Pawar A, Desai RJ, Solomon DH, Santiago Ortiz AJ, Gale S, Bao M et al (2019) Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann Rheum Dis 78:456–464

    Article  CAS  PubMed  Google Scholar 

  129. Rutherford AI, Patarata E, Subesinghe S, Hyrich KL, Galloway JB (2018) Opportunistic infections in rheumatoid arthritis patients exposed to biologic therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Rheumatology 57:997–1001

    Article  PubMed  Google Scholar 

  130. Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T et al (2014) Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol 41:15–23

    Article  CAS  PubMed  Google Scholar 

  131. Socié G, Caby-Tosi MP, Marantz JL, Cole A, Bedrosian CL, Gasteyger C et al (2019) Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis. Br J Haematol 185:297–310

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. McNamara LA, Topaz N, Wang X, Hariri S, Fox L, MacNeil JR (2017) High risk for invasive meningococcal disease among patients receiving eculizumab (Soliris) despite receipt of meningococcal vaccine. MMWR Morb Mortal Wkly Rep 66:734–737

    Article  PubMed  PubMed Central  Google Scholar 

  133. Crew PE, Abara WE, McCulley L, Waldron PE, Kirkcaldy RD, Weston EJ et al (2019) Disseminated gonococcal infections in patients receiving eculizumab: a case series. Clin Infect Dis 69:596–600

    Article  PubMed  Google Scholar 

  134. Matucci A, Maggi E, Vultaggio A (2014) Cellular and humoral immune responses during tuberculosis infection: useful knowledge in the era of biological agents. J Rheumatol Suppl 91:17–23

    Article  CAS  PubMed  Google Scholar 

  135. Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC et al (2016) 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol 68:1–26

    Article  PubMed  Google Scholar 

  136. Cao BL, Qasem A, Sharp RC, Abdelli LS, Naser SA (2018) Systematic review and meta-analysis on the association of tuberculosis in Crohn’s disease patients treated with tumor necrosis factor-alpha inhibitors (Anti-TNFalpha). World J Gastroenterol 24:2764–2775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zhang Z, Fan W, Yang G, Xu Z, Wang J, Cheng Q et al (2017) Risk of tuberculosis in patients treated with TNF-alpha antagonists: a systematic review and meta-analysis of randomised controlled trials. BMJ Open 7:e012567

  138. Sands BE, Sandborn WJ, Panaccione R, O’Brien CD, Zhang H, Johanns J et al (2019) Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 381:1201–1214

    Article  CAS  PubMed  Google Scholar 

  139. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR et al (2016) Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 375:1946–1960

    Article  CAS  PubMed  Google Scholar 

  140. Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C et al (2009) Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. 373:8

  141. Vignali DA, Kuchroo VK (2012) IL-12 family cytokines: immunological playmakers. Nat Immunol 13:722–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Papp KA, Griffiths CE, Gordon K, Lebwohl M, Szapary PO, Wasfi Y et al (2013) Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol 168:844–854

    Article  CAS  PubMed  Google Scholar 

  143. Major EO (2010) Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 61:35–47

    Article  CAS  PubMed  Google Scholar 

  144. Misbah SA (2017) Progressive multi-focal leucoencephalopathy-driven from rarity to clinical mainstream by iatrogenic immunodeficiency. Clin Exp Immunol 188:342–352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Card T, Xu J, Liang H, Bhayat F (2018) What is the risk of progressive multifocal leukoencephalopathy in patients with ulcerative colitis or Crohn′s disease Treated With Vedolizumab? Inflamm Bowel Dis 24:953–959

    Article  PubMed  PubMed Central  Google Scholar 

  146. Berger JR, Fox RJ (2016) Reassessing the risk of natalizumab-associated PML. J Neurovirol 22:533–535

    Article  CAS  PubMed  Google Scholar 

  147. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM et al (2015) IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med 21:719–729

    Article  CAS  PubMed  Google Scholar 

  148. Srinivas C, Odsbu I, Linder M (2020) Risk of common infections among individuals with psoriasis in Sweden: a nationwide cohort study comparing secukinumab to ustekinumab. Pharmacoepidemiol Drug Saf 29:1562–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Li X, Bechara R, Zhao J, McGeachy MJ, Gaffen SL (2019) IL-17 receptor-based signaling and implications for disease. Nat Immunol 20:1594–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Zwicky P, Unger S, Becher B (2020) Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J Exp Med 217

  151. Meroni PL, Zavaglia D, Girmenia C (2018) Vaccinations in adults with rheumatoid arthritis in an era of new disease-modifying anti-rheumatic drugs. Clin Exp Rheumatol 36:317–328

    PubMed  Google Scholar 

  152. Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M et al (2020) 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 79:39–52

    Article  CAS  PubMed  Google Scholar 

  153. Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C et al (2010) Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum 62:64–74

    Article  CAS  PubMed  Google Scholar 

  154. Alvarez-Cuesta E, Madrigal-Burgaleta R, Angel-Pereira D, Urena-Tavera A, Zamora-Verduga M, Lopez-Gonzalez P et al (2015) Delving into cornerstones of hypersensitivity to antineoplastic and biological agents: value of diagnostic tools prior to desensitization. Allergy 70:784–794

    Article  CAS  PubMed  Google Scholar 

  155. Lieberman P, Rahmaoui A, Wong DA (2010) The safety and interpretability of skin tests with omalizumab. Ann Allergy Asthma Immunol 105:493–495

    Article  PubMed  Google Scholar 

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Funding

SAS is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, through Grant T32AI007062.

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Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Allergy, and Immunology, UNC School of Medicine, Chapel Hill, NC, USA

    Jamie L. Waldron & Mildred Kwan

  2. Department of Pediatrics, Division of Allergy & Immunology, UNC School of Medicine, Chapel Hill, NC, USA

    Stephen A. Schworer

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  1. Jamie L. Waldron
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JLW, SAS, and MK performed literature search and wrote the article. JLW and SAS contributed equally to the article as co-first authors.

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Correspondence to Mildred Kwan.

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Waldron, J.L., Schworer, S.A. & Kwan, M. Hypersensitivity and Immune-related Adverse Events in Biologic Therapy. Clinic Rev Allerg Immunol 62, 413–431 (2022). https://doi.org/10.1007/s12016-021-08879-w

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