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):

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:

31. Muchas Gracias!!!