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NSAIDs AND ANGIOEDEMA Mario Sánchez-Borges sanchezbmario@gmail.com.

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Presentation on theme: "NSAIDs AND ANGIOEDEMA Mario Sánchez-Borges sanchezbmario@gmail.com."— Presentation transcript:

1 NSAIDs AND ANGIOEDEMA Mario Sánchez-Borges

2 Angioedema Quincke HI (1882)
Deep dermal, subcutaneous and/or mucous swelling usually lasting 1 to 3 days Clinical picture: Erythematous or skin- colored, non-pitting, swelling of face, genitalia, limbs, upper respiratory and intestinal mucosa

3 Classification of drug-induced angioedema based on the pathogenesis
Mechanism Drugs Immunologic IgE-mediated PCN, cephalosporins Immune complexes/complement PCN, antisera Non immunologic Interference with metabolism of arachidonic acid ASA, NSAIDs Kinin-dependent ACEIs Direct mast cell degranulation Opiates

4 Drug-induced angioedema
Immunologically mediated: rituximab, alteplase, fluoxetine, larinodase, lepirudin, tacrolimus IgE-mediated:  lactams, NM blockers, pyrazolones, quinolones Non allergic: NSAIDs, ACEIs

5 Drug-induced angioedema
NSAIDs ACEIs Angiotensin II receptor antagonists Antibiotics ( lactams) RCM Proton pump inhibitors Statins Fibrinolytic agents Estrogens Diuretics Calcium channel blockers Beta blockers Psychotropic drugs (serotonin reuptake inhibitors)

6 Presumed causes of angioedema
Number (%) Allergic angioedema* 48 (45.7) NSAID-induced angioedema 21 (20.0) Idiopathic angioedema 19 (18.1) Associated with contact urticaria 4 (3.8) Acquired C1 INH deficiency Associated with chronic idiopathic or AI CU 3 (2.9) Associated with urticarial vasculitis 2 (1.9) Infections and infestations ACEi-induced angioedema 1 (1.0) Hereditary angioedema Associated with physical urticaria *AE occurring within 1 to 2 hours of exposure to the offending allergen, caused by immediate type hypersensitivity reaction. Kulthanan K et al. Clin Develop Immunol 2007; 2007: 26438

7 National prevalence of angioedema in Japan
Inomata N. Allergology International 2012; 61:

8 Drugs associated with angioedema without urticaria
Pharmacological group Drug Mechanism ACEIs Captopril, enalapril, lisinopril, ramipril perindopril, imidapril quinapril, trandolapril zofenopril, benazepril cilazapril, fosinopril, moexipril Inhibition of kinin degradation Angiotensin II type receptor antagonists Candesartan, valsartan, losartan, olmesartan, irbesartan Unknown. Bradikinin? NSAIDs ASA, NSAIDs Interference with AA metabolism Fibrinolytic agents Plasminogen activator, streptokinase Increased production of bradykinin Estrogen Combined oral contraceptive C1-esterase inhibitor deficiency? Others: metoprolol, calcium channel antagonists, amiodarone, risperidone, paroxetine

9 Modified from: Powell RJ et al. Clin Exp Allergy 2015; 45: 547-65
Spontaneous Urticaria/AE Modified from: Powell RJ et al. Clin Exp Allergy 2015; 45: Further appropriate tests negative URTICARIA ANGIOEDEMA Exclusion of all known precipitating factors Lesions >24 h or systemic features Associated AI disorder IgE-mediated allergy (latex, food, animal) On a drug known to cause or aggravate urticaria AE Other tests (skin biopsy) Trial off drug No vasculitis Urticarial vasculitis Drug-induced urticaria and/or AE UAI DPU

10 Modified from: Powell RJ et al. Clin Exp Allergy
Spontaneous urticaria/AE Modified from: Powell RJ et al. Clin Exp Allergy 2015; 45: Further testing negative Exclusion of all known precipitating factors ANGIOEDEMA On a drug known to cause or aggravate Angioedema On ACE inhibitor Low C4  low or normal C1inh Low C4 with paraprotein Consider trial off drug Stop ACE inhibitor ACQUIRED C1 ESTERASE INHIBITOR DEFICIENCY (ACQUIRED AE) DRUG-INDUCED URTICARIA AND/OR ANGIOEDEMA HEREDITARY ANGIOEDEMA

11 Angioedema and non-steroidal anti-inflammatory drugs

12 Angioedema and non-steroidal anti-inflammatory drugs
ASA/NSAIDs can induce acute urticaria/AE (NSAID-induced U/AE/anaphylaxis)1 A substantial proportion, up to 40%, of patients with CU experience exacerbations when exposed to ASA/NSAIDs2–4 CU with NSAID hypersensitivity is termed ASA/NSAID-exacerbated cutaneous disease (AECD)5–7 ASA = aspirin 1. Kowalski M, et al. Allergy 2013; 2. Warin. Br J Dermatol 1960; 3. Moore-Robinson and Warin. Br Med J 1967; 4. Doeglas HM. Br J Dermatol 1975; 5. Sánchez-Borges M, et al. Med Clin North Am 2010; 6. Sánchez-Borges M, et al. Immunol Allergy Clin North Am 2013; 7. Sánchez-Borges M, et al. J Eur Acad Derm Venereol 2014.

13 Classification of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs
Type Clinical picture Timing Underlying disease Cross-reactivity Putative mechanism Aspirin-exacerbated respiratory disease (AERD) Bronchial obstruction, dyspnea, nasal congestion, rhinorrhea Immediate Asthma/rhinosinusitis Cross-reactive Nonallergic: COX-1 inhibition Aspirin/NSAID-exacerbated cutaneous disease (AECD) Wheals and/or AE Chronic urticaria COX-1 inhibition NSAID-induced urticaria/AE None Unknown (COX-1 inhibition?) Single NSAID-induced urticaria/AE or anaphylaxis Wheals/AE/ anaphylaxis Non-cross reactive Allergic: IgE-mediated Single NSAID-induced delayed reactions Various (FDE, SJS/TEN, nephritis) Delayed (>24 h) T-cell mediated AE = angioedema Kowalski M, et al. Allergy 2013;68:1219–32.

14 Prevalence of ASA sensitivity in patients with Chronic Urticaria
Various authors: 10 to 40%1,2,3 Sánchez-Borges M et al: 12.2 % %4 Higher prevalence if urticaria is active 1. Settipane RA, et al. Allergy 1980;35:149̶‒54; 2. Stevenson DD and Simon RA. 1998; 3. Doeglas HM. Br J Dermatol 1975; 4. Sánchez-Borges M et al, J Eur Acad Dermatol Venereol 2014.

15 Subtypes of chronic urticaria (n=423)
Sánchez-Borges M et al. Eur Ann Allergy Clin Immunol 2014; 46: 210-5 Subtype n % Chronic spontaneous urticaria * 294 69.5 Dermographic urticaria 61 14.4 Autoimmune urticaria (CAIU) 12 - ACE-induced AE 7 1.6 Papular urticaria 6 1.4 Solar urticaria 5 1.1 Mastocytosis 3 0.7 Cholinergic urticaria 2 0.4 Cold-induced urticaria Delayed pressure urticaria 1 0.2 Contact urticaria Losartan-induced AE Oxcarbazepine-induced urticaria Aquagenic urticaria Candesartan-induced urticaria Urticarial vasculitis Combinations¶ 24 5.6 *Includes 49 patients with AECD (16.6%).¶Combinations: CSU and dermographic urticaria (18), CAIU and AECD (3), CSU and dermographic urticaria and cold-induced urticaria (1), CSU and solar urticaria (1), dermographic urticaria and solar urticaria (1).

16 NSAID-induced lip angioedema
Lip angioedema induced by diclofenac in a 30-year- old patient with CSU

17 Aspirin/NSAID-exacerbated cutaneous disease (AECD)
Female, 17 years old, with CSU + AE occurring 30 min after taking ibuprofen

18 Aspirin/NSAID-exacerbated cutaneous disease (AECD)
(Also called aspirin-induced urticaria) Prevalence 10–40% of adults with CSU; up to 50% in old studies Dose-dependent; more if CU is active (1/3 vs 2/3) Clinical picture Urticaria and/or angioedema 0.5 to 6 hours after drug ingestion Pathogenesis COX-1 inhibition and  cysteinyl leukotrienes Diagnosis Medical history Oral provocation test starting with 1/10 of the dose and increasing every 2 hours until symptoms occur or therapeutic dose is reached Management Avoidance of COX-1 inhibitors Alternative NSAIDs: Coxibs, nimesulide, meloxicam, paracetamol (after tolerance test) Opioids Treatment of CSU according to guidelines

19 Park HS, Kowalski M, Sánchez-Borges M
Park HS, Kowalski M, Sánchez-Borges M. Middleton’s Allergy: Principles and Practice, 8th Edn., 2014.

20 J Eur Acad Dermatol Venereol. 2015; 29(4):698-701

21 AECD is a Subphenotype of Chronic Spontaneous Urticaria
* * * * * * * % *p<0.05 Sánchez-Borges M et al, J Eur Acad Derm Venereol Apr;29(4):

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23 Subtypes of urticaria in children with acute or chronic urticaria
Acute urticaria (n= 71) Chronic urticaria (n=52) Subtypes n % Spontaneous 32 45.0 35 67.3 Papular 28 39.4 Dermographic 5 9.6 Drug-induced 7.0 AECD 1 4 7.6 5.6 3 5.7 Food-induced 2 2.8 1 1.9 URT infection 1.4 Cold-induced Mastocytosis Spontaneous + solar Aquagenic 1 AECD: aspirin-exacerbated cutaneous disease. Sánchez-Borges M, Capriles-Hulett A, Caballero F, González L. Alergia 2014; 61: 90-98

24 NSAID facial angioedema in children according to their age
Age (years) n NSAID facial AE n (%) Male/female 0-5 493 10 (2.0) 7/3 6-10 361 14 (3.8) 9/5 11-15 121 10 (8.2) 8/2 16-21 32 7 (21.8) 1/6 Total 1007 41 (4.07) 25/16 Chi-square test: a vs b N.S. a vs c p= a vs d p= b vs c p=0.05. b vs d p= c vs d p=0.002

25 NSAID facial angioedema in children according to their age
% Age (years) Capriles Behrens E, Caplin J, Sánchez-Borges M. J Investig Allergol Clin Immunol 2000; 10: 277-9

26 Oral Mite Anaphylaxis Oral mite anaphylaxis (OMA), also known as the Pancake syndrome, is characterized by severe acute allergic symptoms triggered by the ingestion of mite- contaminated foods. More frequently, clinical manifestations include breathlessness, angioedema, wheezing, rhinorrhea, cough, stridor, and dysphagia.

27 Oral mite anaphylaxis: demographics
Number of cases 170 Age range 6-71 years Gender: Female/Male 98/71 Location Spain 59 Venezuela 47 Japan 40 USA 7 Brazil 2 Singapore 2 Belgium 2 Taiwan 1 Panama 10 Foods Pancakes, beignets, pizza dough, sponge cake, cupcakes, okonomi-yaki, tako-yaki, tempura, polenta, scones, grits, steak and chicken parmigiana , chorizo, cured ham NSAID hypersensitivity 75/170 (44.1 %) Sánchez-Borges M, Fernández-Caldas E. Curr Opin Allergy Immunol 2015, Sánchez-Borges M et al. J Allergy Clin Immunol 2013; 131: Sánchez-Borges M et al. Cutis 1997; 59:

28 Oral mite anaphylaxis: Clinical picture
Clinical manifestations Number of patients Breathlessness 35 Angioedema 27 Wheezing 12 Cough Rhinorrhea 11 Urticaria 8 Dysphagia 7 Stridor Abdominal cramps 4 Conjunctivitis Dysphonia 3 Skin rash 2 Sneezing Cyanosis Vomiting 1 Pruritus Tachycardia Sánchez-Borges M et al. J Allergy Clin Immunol 1997; 99:

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31 Muchas Gracias!!!


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