1. GLORIA Module 11: Drug Allergy (Part 1) Definition, Epidemiology and Pathogenesis of Drug Allergy an educational program of Updated: June 2011

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7. GLORIA MODULE 11: Drug Allergy (Part 1) Definition, Epidemiology and Pathogeneses of Drug Allergy Authors Werner Pichler, Switzerland Bernard Thong, Singapore

8. Learning Objectives Understand the difference between –Adverse drug reaction –Drug hypersensitivity –Drug allergy Understand the epidemiology and risk factors for drug allergy Understand the pathogenesis and immunological mechanisms underlying the different phenotypes of drug allergy

9. Drug related side effects Potentially dangerous –4th leading cause of death in the USA Lazaru J. et al. JAMA (1998) 279: 200-205) Altogether frequent – but rare for each drug Very heterogeneous clinical symptoms –affecting quasi all organs –often mild, sometimes life threatening

10. Classification of adverse drug reactions Type A: predictable; strictly dose dependent –80% of all side effects –Pharmacological side effects (e.g. gastrointestinal bleeding under treatment with NSAID) Type B: not predictable; usually not dose dependent, and sometimes reactions to very small amounts –15-20% of all side effects –Immunologic/allergic –Non-immune mediated, “pseudoallergic” –Idiosyncratic

11. Nomenclature Immune mediated drug hypersensitivity (drug allergy) –Clinical symptoms due to different types of specific immune reactions (T-cell & B-cell/Ig mediated) Non immune mediated drug hypersensitivity (non-allergic drug hypersensitivity) –Symptoms and signs similar to immune mediated hypersensitivity, but failure to demonstrate a specific immune process to the drug –Older term: “pseudoallergy” Idiosyncrasy –symptoms and signs due to some genetic alterations, e.g. an enzyme deficiency: e.g. hemolytic anaemia due to certain drugs in patients with G-6- P-deficiency Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832-6

12. Nomenclature Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 2004;113:832-6 Drug hypersensitivity Drug allergyNon-allergic hypersensitivity IgE-mediated Non IgE mediated drug allergy drug allergy eg: Non-specific histamine release, Arachidonic acid pathway activation, Bradykinin pathway alteration, Complement activation

13. Epidemiology Adverse drug reactions (ADRs) have been reported to account for 3 to 6% of all hospital admissions and occur in 10 to 15% of hospitalized patients. Drug allergy has been estimated to account for up to a third of all ADRs. Most epidemiologic studies have dealt with ADRs or adverse drug events, with few focusing on drug allergy alone. In hospitalized patients, the incidence of cutaneous allergic reactions from the rates of hospitalization for ADRs, disclosed an estimated rate of 2.2 per 100 patients and 3 per 1,000 courses of drug therapy. The true incidence of drug-induced anaphylaxis is also unknown, as most studies have been based on all causes of anaphylaxis or all causes (both allergic and nonallergic) of ADRs. The estimated incidence of Stevens-Johnson Syndrome (SJS), which may occur secondary to ADR, is 0.4 to 1.2 per 1 million people per year; the estimated incidence for TEN is 1.2 to 6 per 1 million people per year.

14. Epidemiology Limitations of current epidemiological data –Includes all ADR –Does not differentiate immunologically and non- immunologically mediated drug hypersensitivity –Different study populations Inpatients or outpatients –Different methodologies –Different methods of assessing drug imputability –Different methods of data analyses Gomes ER, et al. Curr Opin Allergy Clin Immunol 2005;5:309-16

15. Risk factors Drug-related factors –Nature of the drug –Degree of exposure (dose, duration, frequency) –Route of administration –Cross-sensitization Host-related factors –Age –Sex –Genetic factors (HLA type, Acetylator status) –Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma) –Previous drug reaction –Multiple allergy syndrome

16. Drug-related risk factors Nature of the drug –Hapten concept (intrinsically reactive) –Pro-hapten concept (requires conversion to reactive intermediates) –Danger concept (drug related cytotoxicity enhancing immune response) –Pharmacological interaction concept (direct non-covalent binding to immune receptors, T-cell receptors, MHC) Degree of exposure –Dose, duration, frequency, intermittent repeated administration Route –Topical, oral, parenteral Cross-sensitization –Reactivity either to drugs with a close structural chemical relationship or to immunochemically similar metabolites.

17. Host-related risk factors Age –Most of the studies among children and adults not comparable Sex –No evidence, with the possible exception of cutaneous reactions, that allergic drug reactions are more common in females than in males. Genetic factors (HLA type, Acetylator status) Concurrent medical illness (e.g. Ebstein-Barr Virus (EBV), human immunodeficiency virus (HIV), asthma) Previous drug reaction Multiple allergy syndrome –May have a predilection to more than one non-cross-reacting medication, but the existence of this condition is controversial.

18. Genetic risk factors Immunogenetic disposition together with race: 1.HLA-B*1502: Carbamazepine: SJS/TEN, DRESS; Han Chinese but not Caucasians 2.HLA-B*5801: Allopurinol: DHS/DRESS like, Han Chinese 3.HLA-B*5701: Abacavir: DRESS like, Caucasians, but not Hispanics or Africans

19. Viral infections & autoimmunity Viral infections & autoimmunity: Generalized immune stimulation in the frame of Acute EBV infections: maculopapular exanthem with aminopenicillins HIV infections: –Sulfonamides: MPE, SJS/TEN, DRESS –SJS/TEN to various drugs is 500 fold more frequent –Nevirapine and abacavir: frequent side effects Drug induced autoimmunity: –Drug-induced Lupus –Drug-induced vasculitis

20. Pathophysiology of drug reactions Antigenicity of drugs –Hapten concept –Prohapten concept –p-i (pharmacological interaction with immune receptors) concept Classification of drug reactions –Type I –Type II –Type III –Type IV a, b, c, d reactions

21. Hapten, prohapten and p-i concept Hapten –chemically reactive drug –able to bind covalently to proteins Prohapten –chemically non reactive drug –becomes reactive upon metabolism (transformation of prohapten  hapten) p-i concept –parent, chemically non reactive drug –unable to bind covalently to proteins –can nevertheless interact with “immune receptors” like T-cell receptors for antigen and elicit an immune response

22. How can drugs stimulate the immune system (I)? Hapten/prohapten concept –The hapten-carrier complex (e.g. penicillin covalently bound to albumin) leads to formation of neoantigens: these will be recognized by the immune system (hapten- specific Ig on B-cells and by T-cells) –The binding of haptens to cellular structures may be associated with stimulation of the innate immune system. This provides “danger signals”, e.g. leading to upregulation of CD40/CD86 on Dendritic Cells

23. Hapten concept: Possible reactive sites of benzylpenicillin Benzylpenicillin (PenG) PenG is a hapten like drug, as it can rapidly form covalent bonds to other proteins. 1) via the b-lactam ring (1), which opens and tends to form a bridge to lysin: „major determinant“. 2) via the thiazolidin moiety (2) of the penicillin: forming „minor determinant“

24. Hapten concept Binding of a chemically reactive structure to 1) soluble proteins (IgE, IgG) or 2) membrane bound proteins (  IgG + T-cell reactions) or 3/4) the MHC-peptide complexes (I & II) directly (  only T-cells) Distinct clinical consequences of hapten carrier formation depending on binding to soluble or cell bound proteins penicillin processing Ig

25. Drug (hapten) presentation to immune system (B & T cells) Potentially highly immunogenic Immunostimulatory properties (activation of dendritic cells) B and T cell response Clinical : “everything” binding to cell-bound and soluble proteins Ig: anaphylaxis, hemolytic anemia, thrombocytopenia... T-cell: contact dermatitis, hepatitis, interstitial lung disease, MPE, AGEP, TEN,.... MPE: maculopapular drug exanthema, AGEP: acute generalized exanthematous pustulosis, TEN: Toxic epidermal necrolysis

26. Prohapten - Metabolism required - e.g. Sulfamethoxazole Hypersensitivity - Cribb & Spielberg, 1992 Gill et al., 1997 sulfamethoxazole sulfamethoxazole hydroxylamine nitroso sulfamethoxazole sulfamethoxazole protein conjugate HYPERSENSITIVITY ANTIGEN PROCESSING IMMUNE RESPONSE GSH R = N O CH 3

27. Metabolism is required to generate reactive compounds, which then behave like haptens and bind to soluble and cell bound proteins. Prohapten concept sulfamethoxazole (SMX) metabolism inert reactive SMX-NO

28. Drug (prohapten) presentation to immune system (B & T cells) Many drugs are potentially highly immunogenic as they are transformed to chemically active intermediates Potent and rapid intracellular detoxification mechanism (i.e. GSH) may prevent immunogenicity of the generated reactive metabolites It is possible that the liver may play a role as a tolerogenic organ ---------------------------------------------------------------------------------------- Clinical: potentially immunogenic for B- and T-cells; Immunogenicity and clinical manifestation might be restricted to the organ where metabolism (generation of hapten and stimulation of innate immunity) takes place, namely the liver (hepatitis) or kidney (interstitial nephritis)

29. How can drugs stimulate the immune system (II) ? Pharmacological interaction with immune receptors (p-i concept) –direct stimulation of T-cells by drugs binding to the T-cell receptors for antigen –no involvement of the innate immune system, and no generation of an own immune response to the drug –stimulation of preactivated T-cells with additional specificity

30. The p-i concept: Pharmacological Interaction of drugs with immune Receptors A chemically inert drug, unable to covalently bind to some proteins, „happens“ to bind to some of the 10 12 -10 15 distinct immune receptors (as it does to other proteins/receptors). This drug-receptor interaction can under certain circumstances activate specific immune cells. The subsequent reaction imitates a specific immune response.

31. a)Binding of the drug to TCR, providing an initial signal b)Additional MHC- TCR interaction, supplementing the signal c)Readiness of the T cell to react (low threshold level of activation) peptide *) elaborated for T-cell receptors (TCR) only The p-i-concept: Pharmacological interaction of drugs with immune receptors*

32. T-cell recognition of hapten like drugs: covalent drug binding to MHC-peptide T-cell TCR O N CH 3 SOO NH NO Covalent binding (SMX-NO) MHC+ peptide APC (e.g. activated keratinocyte, DC,...) „Classical“ immune response to hapten carrier compound

33. Labile, non covalent binding of SMX itself to TCR; This initial stimulation is supplemented by TCR-MHC interaction Direct stimulation of T-cells by non- hapten like drugs: direct interaction with the TCR T-cell TCR MHC+ peptide APC (e.g. activated keratinocyte) 2 1 Sulfamethoxalole (SMX) O N CH 3 SOO NH NH 2

34. SUMMARY: “Antigenicity” of drugs Chemical (hapten) Stable protein/peptide modification (covalent) MHC-APC directed (processing and metabolism) Very heterogeneous and often combined immune responses (Ig, T- cells.....) Structural (fitting into TCR) No covalent binding TCR – T cell directed No processing/no metabolism Only T-cell reactions of different types (exanthema, DRESS, AGEP.....) O N CH 3 SOO NH NH 2 HAPTENP-I CONCEPT

35. Gell & Coombs Classification of Hypersensitivity reactions Type I Type IIType III Immune reactantIgEIgG AntigenSoluble antigen Cell- or matrix- associated antigen Soluble antigen Effector Mast-cell activation FcR + cells (phagocytes, NK cells) FcR + cells Complement Example of hypersen-sitivity reaction Allergic rhinitis, asthma, systemic anaphylaxis Some drug allergies (e.g. penicillin) Serum sickness, Arthus reaction Ag platelets blood vessel immune complex Ab - platelet Type IV T cell MHC-presented antigen T-cells, via cytokines recrutement of monocytes, eosinophils, neutrophils(?) Many different diseases: Different forms of exanthems, eczema, contact dermatitis Cytokines cytotoxicity

36. Delayed reactions Due to drug specific T cells T-cells secrete different cytokines The cytokines activate and recruit distinct effector cells Cytotoxic mechanism are always involved, in some severe reactions (SJS/TEN) even dominating the clinical symptoms Similar mechanism in skin as in internal organs (e.g. interstitial nephritis)

37. Mechanism of immune mediated exanthems T-cells recognize the drug and exert, depending on their function, a specific pathology Bullous Exanthem Acute generalized exanthematous pustulosis (AGEP) Maculopapular exanthem (MPE)

38. MPE: infiltration of T cells in dermis and epidermis CD4 + CD8 +

39. Perforin and Granzyme B Are important for cell- mediated cytotoxicity Are preformed in granules of cytotoxic T-cells (CTLs, NK) Are released during exocytosis of granules and form pores in the cell membrane of the target cell with subsequent fragmentation of DNA. CTL Killing of e.g. keratinocytes or hepatocytes

40. Perforin+ and Granzyme B+ cells infiltrate into the epidermis Perforin Granzyme B

41. hydropic degeneration eosinophils keratinocyte cell necrosis mononuclear cell infiltrate ICD541 LFA -1 keratinocyte MHC II TCR Drug specific CD4+ T cell - granzymeB perforin In MPE infiltrating T cells are killing keratinocytes and orchestrate an inflammatory process, which is often eosinophil rich

42. Comparison of MPE and Bullous Exanthem Higher activation of circulating T-cells (CD4 and CD8) in bullous exanthem Higher activation of CD8+ T-cells in the skin of patients with bullous exanthem Bullous exanthem: CD8  MPE: CD4 

43. Why are cytotoxic CD8+ T cells more dangerous than CD4+ T cells ? CD8 T cells can kill all cells, not only activated MHC II+ cells CD8CD4 Activated, MHC II+ MHC I

44. T-cells recognize the drug and exert, depending on their function, a specific pathology Amoxicillin Bullous exanthem MHC-I (+ MHC-II) CD8+ > CD4+ cytotoxicity (CD8+) IFN  ; IL-5 MPE MHC-II CD4+ cytotoxicity (CD4+) IL-5; IFN  AGEP MHC-II + I CD4+ & CD8+ cytotoxicity IL-8; IL-5, IL-17 (?)

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