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Wrong concepts in drug hypersensitivity and its impact on clinical management Werner J Pichler, MD [email protected] ADR-AC GmbH, Bern Switzerland NO CONFLICT OF INTEREST TO DECLARE Common statements on drug allergy correct Drug allergy is dose independent Drug allergy requires a sensitization phase to the drug itself Small molecules are not recognized by the immune system Drug allergy is not predictable

yes no

Amoxicillin Allergy Immediate, IgE Delayed, T cell a patient with recurrent, febrile sinusitis and bronchitis is treated with amoxicillin 3x750mg/d for 10d. She tolerates it well. After 2 yrs she has again a sinusitis and bronchitis with fever. She takes a 750mg dose of amoxicillin: after 10 min she complains about malaise, palmoplantar itch, redness all over, difficulty to breath, collaps. At skin testing (i.d.) after 4wk she develops a generalized urticaria in min.

Immediate reaction to very low doses of amoxicillin (skin tests) She takes 3x750mg for 7d, but then develops generalized pruritus and a measles like rash. She stops treatment, and gets anti-H1 and topical corticosteroids. LTT positive with SI of 8; Delayed reaction to normal doses of amoxicillin Amoxicillin Allergy Immediate, IgE Delayed, T cell

a patient with recurrent, febrile sinusitis and bronchits is treated with amoxicillin 3x750mg/d for 10d. She tolerates it well. After 2 yrs she has again a sinusitis and bronchitis with fever. She takes a 750mg dose of amoxicillin: after 10 min she complains about malaise, palmo-plantar itch, redness all over, difficulty to breath, collaps. At skin testing (i.d.) after 4wk she develops a generalized urticaria in min. Immediate reaction to very low doses of amoxicillin (skin tests) She takes 3x750mg for 7d, but then develops generalized

pruritis and a measles like rash. She stops treatment, and gets anti-H1 and topical corticosteroids. LTT positive with SI of 8; Delayed reaction to normal doses of amoxicillin Amoxicillin Allergy: Role of drug concentration depends on initiation/effector phase and on mechanism (T, IgE) 1) Concentration differs: Sensitization effector phase Sensitization requires often normal doses (>100mg to mg) effector phase (IgE): ng or less 2) Concentration differs: IgE T cell reaction

IgE reactions can occur to very small amounts of drug. T cell reactions often require normal (therapeutic) doses of drug D O S E D I F F E R S Drug concentration and immune mechanism

No effect S Y M P T O M S Dose for Anaphylaxis Start of desensitization

femtomolar Dose for IgE picomolar Therapeutic efficacy Induction of T and B cells, T cell mediated exanthems nanomolar micromolar

concentration differ for induction and elicitation Is dose reduction more effective in or IgE mediated reactions ? S Y M P T O M No pharmacological effect No effect of drug

Insufficient for T cell dependent DHR Still IgE mediated DHR 8mg 100x 80mg T-cell pharmacological effect DHR: T-cell mediated

DHR: IgE mediated 800mg 10x YES: Lowering the dose by 10x may suffice to eliminate T cell related symptoms , but is still causing IgE mediated reactions Drug dose & drug allergy Immune reactions are (of course) dose dependent: the higher the dose, the faster, the severer the symptoms (IgE, T cell) !!! IgE mediated reactions occur already at very low doses: it occurs below the concentrations needed for pharmacological effects (but it is nevertheless dose dependent) Further reducing the dose results in less symptoms and may allow desensitization.

Amoxicillin cross-reactivity: role of affinity & drug concentration picomolar IgE induced by amoxicillin high piperacillin low nanomolar A cross-reactive compound binds

with lower affinity to IgE/TCR: It requires a higher concentration to elicit the same level of symptoms cefadroxil micromolar Clinical impact dose dependence: Reducing the dose is always a good advise to minimize or avoid potential symptoms of DHR crossreactivity: cross-reactive drugs bind (mostly) less affine to IgE/TCR. Higher doses needed to elicit the same symptoms. Common statements on drug allergy correct

Drug allergy is dose independent Drug allergy requires a sensitization phase to the drug itself Small molecules are not recognized by the immune system Drug allergy is not predictable yes no IgE-mediated anaphylaxis w/o prior exposure

Examples radio-contrast media cephalosporins NMBA (e.g. rocuronium) dyes (patent blue) chlorhexidine .. chlorhexidine iodihexanol perioperative anaphylaxis Anaphylaxis at first sight the acute symptoms appear in patients without prior exposure

Mostly i.v. applied drugs Mostly high concentrations Often relative large molecules, often bi- or polyvalent Severe reactions like cardiac arrest, asystoly Anaphylaxis at first sight Three possibilities: 1. Sensitization to the drug in environment: e.g. chlorhexidine in cosmetics, dental hygiene products, etc.. Some sensitizations are often hidden ! Patent blue anaphylaxis: Do you ask your patient whether she was wearing blue shoes???

Anaphylaxis at first sight Three possibilities: 1. Sensitization to the drug in environment: e.g. chlorhexidine in cosmetics 2. Sensitization to a small, common epitope in environment and drug Pholcodin Baldo et al. CEA, 2007 NMBA, tubocurarine Quarternary ammonium Anaphylaxis at first sight Three possibilities: 1. Sensitization to the drug in environment:

e.g. chlorhexidine in cosmetics 2. Sensitization to a small, common epitope in environment and drug 3. Very high drug concentrations may compensate for low affinity Affinity/ dissociation constant [P] P Clinical impact: Sensitization to the drug itself is not an absolute requirement for IgE mediated anaphylaxis Anaphylaxis at first sight may occur with high concentrations, iv application, large drugs

Common statements on drug allergy correct Drug allergy is dose independent Drug allergy requires a sensitization phase to the drug itself Drug allergy is not predictable Small molecules are not recognized by the immune system yes no

Drug allergy is not predictable ? P-i concept: binding of drug to certain HLA molecules changes the HLA-peptide conformation and elicit immune reactions; If the drug binds with high affinity to only a certain HLA-protein (e.g. HLA-B*57:01), this reaction is predictable by typing for HLA. TCR p-i concept (p-i HLA) a drug fits into a particular HLA molecule the drug binds to a unique region in the HLA by van der Waals

forces (only B*57:01). The {peptide-drug-HLA} complex is then recognized by the TCR like an allo-allele HLA HLA-peptide-TCR complex HLA-B*5701: binding groove for abacavir Illing et al, Nature 2012 Ostrov D et al, PNAS 2012 Drug allergy is not predictable ? Certain T cell mediated drug allergies can be

avoided by excluding patients with a certain HLA from drug treatment Abacavir (HLA-B*57:01) Carbamazepine (HLA-B*15:02) Allopurinol (HLA-B*58:01) Common statements on drug allergy correct Drug allergy is dose independent Drug allergy requires a sensitization phase to the drug itself Drug allergy is not predictable Small molecules are not recognized by the immune system yes no

Small molecules and the immune system Riboflavin story: Riboflavin is Vitamin B2 It is synthesized by bacteria and mushrooms, like e.g. mycobacterium tuberculosis, E. coli direct recognition of small molecules by specialized T cells ! Riboflavin story

precursor compounds (e.g. 5-A-RU) of riboflavin is presented as small molecule on special, MHC1-like molecules (MR1). The reactive T cells are CD4- CD8- + TCR (invariant, mucosa associated invariant T cells, MAIT): These recognize riboflavin precursor and act by cytotoxicity, IFNg+ Kjer-Nielsen L, et al. MR1 presents microbial vitamin B , metabolites to MAIT cells. Nature. 2012 29;491:717-23 MHC 1 vs MR1 MHC 1 MR1 MHC related1

MHC-1 vs MR1 binding cleft Small molecules are not recognized by the immune system Small molecules can interact with the specific immune system: Via p-i: CDR2/Vb20-TCR (Sulfamethoxazole): sulfaallergy (?) riboflavin precursor molecules presented by MR1 to MAIT cells: first line defense to mycobacteria The immune system has developed tools to recogize specifically small molecules Common statements on drug allergy Drug allergy is dose independent Drug allergy does not always require a sensitization phase to the drug itself

Drug allergy is not sometimes predictable Small molecules are not recognized by the immune system: MR1/MAIT and p-i-stimulations Clinical impact: Always consider dose! A dose reduction is always worth a try (is not always sufficient) risk of anaphylaxis at first sight: i.v. injecton of high concentrations of large molecules Certain DHR are avoidable, as they are predictable The immune system has established a system to directly interact with small molecules: DHR is no more exotic Thank you very much Wrong concepts in drug hypersensitivity

5. Drug allergy is dependent on hapten mechanism: ONLY A MINORITY OF DRUG REACTIONS ARE DUE TO HAPTEN MECHANISM 6. Drug allergy is an allergy NO, DRUG ALLERGY IS OFTEN NOT DIRECTED TO THE DRUG ITSELF, IT IS AN ALLO-IMMUNE REACTION 7. Reactions appearing within hrs are not T cell mediated: SOME T CELL MEDIATED REACTIONS IN HIGHLY SENSITZED PATIENTS CAN OCCUR WITHIN HOURS: ABACAVIR, VEMURAFENIB, AMOXICILLIN; CARBAMAZEPIN Protein-ligand binding/affinity The dissociation constant is commonly used to describe the AFFINITY between a ligand (such as a DRUG) and a protein i.e. how tightly a ligand binds to a particular protein.

AFFINITY is defined by where L and P represent molar complex, respectively concentrations of the protein, ligand and The smaller the dissociation constant, the more tightly bound the ligand is, or the higher the affinity between ligand and protein: For example, a ligand with a nanomolar (nM) dissociation constant binds more tightly to a particular protein than a ligand with a micromolar (M)M) dissociation constant. nanomolar is more affine than micromolar Adverse drug reactions Type A reaction

Type B reaction Pharmacological action Predictable Dose dependent Rational 1 Not pharmacological action 2 Not predictable 3 Not dose dependent 4 Bizarre As more becomes known about the mechanisms of specific adverse drug effects, this classification will be revised further and classification of currently unclassifiable reactions will become easier IR Edwards, JK Aronson: Adverse drug reactions: definitions, diagnosis, and management,

LANCET, 356: 9237; 1255-1259, 2000 Adverse drug reactions Type A reaction Pharmacological action Predictable Dose dependent Rational Type B reaction immune mediated 1 Not pharmacological action 2 Not predictable 3 Not dose dependent 4 Bizarre (immune-mediated = complex diseases !!)

Some immune mediated reactions are off target (pharmacological) activities of the drug on immune receptors. - In the time of personalized medicine, they are, are least partly predictable and avoidable; - dose dependence? Origin of wrong statements 1. Classification of type A and B reactions MD Rawlins, JW Thompson: Pathogenesis of adverse drug reactions; Textbook of adverse drug reactions, Oxford (1977 & 1981), DM Davies (Ed.), Oxford Univ. Press, p. 10 & p. 11 2. Classification of drug allergy as immediate and delayed forms (<1hr, >6hr); Johansson SG, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001 Sep;56(9):813-24.

Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis macht, da ein Ding kein Gift ist. - Paracelsus (1493-1541) - All things are poison, and nothing is without poison; only the dose permits something not to be poisonous. (Some) Type B ADRs are dose dependent. Role of drug concentration Pharmacology Immunology initiation > < elicitation

no effect effect toxic effect Concentration Simple, one cell model naive > < effector of immune response The IgE/Fc-IgE-RI system is geared to react to extremely small doses Affinity maturation for B-cells Complex, > 1 cell involved, naive>< memory, IgE Riboflavin

synthesis pathway in E.coli Drug concentration and immune mechanism No symptoms S Y M P T O M Dosis for Desensitization

IgE Dose for Anaphylaxis Dose for anaph femtomolar picomolar T-cell reactions Induction of T and B cells

nanomolar For DRESS mmolar Lowering the dose eliminates symptoms even in IgE (desesitization) amoxicillin cross-reactivity: role of affinity & drug concentration Higher drug concentration needed to elicit symptoms

piperacillin S Y M P T O M S cefadroxil anaphylaxis amoxicillin No symptoms

high affinity piperacillin low urticaria Low high Very low cefadroxil According to

a molecule (L) can bind to IgE (P), if provided in sufficiently high concentrations (binding with low affinity) If the molecule is large and can bind with various epitopes to IgE, crosslinking and anaphylaxis may occur L [ ] [P] Kd= L [ P]

dose reduction: different effect on or IgE mediated reactions S Y M P T O M No effect of drug No pharmacological effect No T cell reaction

Only IgE mediated DHR 8mg 100x 80mg pharmacological effect + DHR: T-cell mediated + DHR: IgE mediated 800mg 10x

T-cell

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