Transcript nsaid hypersensitivity: tricky cases

NSAID
HYPERSENSITIVITY:
TRICKY CASES
Mario Sánchez-Borges
[email protected]
Disclosure
In relation to this presentation, I declare that there are no conflicts of interest.
A conflict of interest is any situation in which a speaker or immediate family members have interests, and those may cause a conflict with the current presentation. Conflicts of
interest do not preclude the delivery of the talk, but should be explicitly declared. These may include financial interests (eg. owning stocks of a related company, having received
honoraria, consultancy fees), research interests (research support by grants or otherwise), organisational interests and gifts.
PATIENT 1
• Male, 43 years old
• 14 days ago he experienced eyelid edema, dyspnea and
conjunctival itching 30 minutes after im injection of dipyrone
• Treated with iv corticosteroid and oral clorpheniramine
• Past history: Asthma. Rhinosinusitis
• Skin prick tests:
Allergen
Diameter (mm)
Allergen
Diameter (mm)
D. pteronyssinus
10
G. domesticus
6
D. farinae
7
P. americana
4
B. tropicalis
5
Glycerosaline
sol
0
L. destructor
6
Histamine
6
WHAT IS YOUR DIAGNOSIS?
1. Samter’s syndrome
2. Chronic spontaneous urticaria/angioedema
3. Anaphylaxis to Pyrazolone
4. Erythema multiforme
5. Mastocytosis
CLASSIFICATION OF HYPERSENSITIVITY REACTIONS TO NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
Type
Clinical
picture
Timing
Underlying disease
Cross-reactivity
Aspirin-exacerbated
respiratory disease
(AERD)
Bronchial
obstruction,
dyspnea,
nasal
congestion,
rhinorrhea
Immediate
Asthma/rhinosinusitis
Cross-reactive
Nonallergic:
COX-1 inhibition
Aspirin/NSAIDexacerbated cutaneous
disease (AECD)
Wheals
and/or AE
Immediate
Chronic urticaria
Cross-reactive
COX-1 inhibition
NSAID-induced
urticaria/angioedema
Wheals
and/or AE
Immediate
None
Cross-reactive
Unknown (COX-1
inhibition?)
Single NSAID-induced
urticaria/angioedema
or anaphylaxis
Wheals/AE/
anaphylaxis
Immediate
None
Non-cross
reactive
Single NSAID-induced
delayed reactions
Various
(FDE,
SJS/TEN,
nephritis)
Delayed
(>24 h)
None
Non-cross
reactive
Kowalski M et al, Allergy. 2013 ;68 :1219-32.
Putative
mechanism
Allergic: IgEmediated
T-cell mediated
DIAGNOSTIC INVESTIGATIONS
1. Patch test with dipyrone
2. Intradermal test with pyrazolone
3. OPT with COX-1 inhibitor
4. Measurement of serum Tryptase
5. Basophil activation test
Algorithm for the management of patients with urticaria, angioedema and
anaphylaxis induced by NSAIDs
History of
reactions to multiple
NSAIDs
Confirmatory OPT with
COX-1 Inhibitor
+
OPT with unrelated
NSAID
-
OPT with
alternative
NSAID
(non COX-1
inhibitor)
-
History of
reactions to a
single NSAID
Treatment
+
Treat as multiple
NSAID reactor
-
Treatment
+
Avoid NSAIDs
Treatment HIGH RISK PHENOTYPE
Sánchez-Borges M. Med Clin North Am 2010; 94: 853-864
Park HS, Kowalski M, Sánchez-Borges M. Middleton’s Allergy 2014, p. 1296-1309.
2 hours 30 min
CLASSIFICATION OF HYPERSENSITIVITY REACTIONS TO NONSTEROIDAL ANTI-INFLAMMATORY
DRUGS
Type
Clinical
picture
Timing
Underlying disease
Cross-reactivity
Aspirin-exacerbated
respiratory disease
(AERD)
Bronchial
obstruction,
dyspnea,
nasal
congestion,
rhinorrhea
Immediate
Asthma/rhinosinusitis
Cross-reactive
Nonallergic:
COX-1 inhibition
Aspirin/NSAIDexacerbated cutaneous
disease (AECD)
Wheals
and/or AE
Immediate
Chronic urticaria
Cross-reactive
COX-1 inhibition
NSAID-induced
urticaria/angioedema
Wheals
and/or AE
Immediate
None
Cross-reactive
Unknown (COX-1
inhibition?)
Single NSAID-induced
urticaria/angioedema
or anaphylaxis
Wheals/AE/
anaphylaxis
Immediate
None
Non-cross
reactive
Single NSAID-induced
delayed reactions
Various
(FDE,
SJS/TEN,
nephritis)
Delayed
(>24 h)
None
Non-cross
reactive
Kowalski M et al, Allergy. 2013 ;68 :1219-32.
Putative
mechanism
Allergic: IgEmediated
T-cell mediated
MANAGEMENT?
1. Avoid COX-1 inhibitors
2. OPT with Celecoxib
3. OPT with Nimesulide
4. OPT with Meloxicam
5. All of the above
6. None of the above
PATIENT 2
Angioedema in a 22 years old patient

Female, 22 years old, showing recurrent eyelid and hand
edema for one year, accompanied with dysphonia

Exacerbation after taking Excedrin (acetaminophen/ ASA/
caffeine), and during P.O. after receiving i.m. ketoprofen.

Past history: Thyroidectomy, hypercolesterolemia, Insulin
resistance, vaso-vagal syncope, rhinitis.

Treatments Zyrtec, Benadryl. Current: Glucophage, Synthroid.

Laboratory: CRP 0.6 ASTO 170 Rheumatoid factor, anti-TPO and
anti-Tg Abs: negative. C3 141 C4 24.6 IgE 146.1 UI/mL

Immediate-type hypersensitivity skin tests: Cockroach 3 mm.
Dp 8 mm. Df 10 mm. Bt 9 mm.

ASST: 0 mm

APST: 0 mm
Diagnosis
1.
Ramipril-induced AE
2.
Type III angioneurotic edema
3.
Chronic spontaneous AE
4.
Chronic autoimmune U/AE
5.
ASA/NSAID exacerbated cutaneous disease
(AECD)
ASPIRIN-EXACERBATED
CUTANEOUS DISEASE (AECD)
Hypersensitivity reactions induced by
ASA/NSAIDs manifested as wheals or
angioedema occurring in patients with a
history of chronic spontaneous urticaria
Sánchez-Borges M et al. Eur J Dermatol Venereol 2014 (in press)
Sánchez-Borges M et al. Immunol Allergy Clin North Am 2013; 33: 251-62
Sánchez-Borges Met al. Clin Med North Am 2010; 94: 853-64.
AECD is a Subphenotype of Chronic Spontaneous Urticaria
90
80
70
60
*
*
50
%
*
40
*
*
30
*
*
20
10
0
Duration
Head
Wheals
Tolerant
*p<0.05
AE
Wheals+AE
Total AE
Positive STs
AECD
Sánchez-Borges M et al, J Eur Acad Derm Venereol. 2015 Apr;29(4):698-701
Treatment of choice for her underlying disease
1.
Dapsone
2.
Acupuncture
3.
Allergen-specific immunotherapy
4.
Second generacion antihistamines
5.
Omalizumab
Management of Aspirin-exacerbated cutaneous disease
• Avoidance of COX-1 inhibitors
• Weak COX-1 inhibitors (acetaminophen) for fever or mild
pain
• Preferential COX-2 inhibitors (nimesulide, meloxicam) for
pain and inflammation
• Selective COX-2 inhibitors (coxibs: rofecoxib, etoricob,
celecoxib) for pain and inflammation
• Desensitization not usually recommended
• Management of chronic spontaneous urticaria and
angioedema as per guidelines
Recommended treatment algorithm for CSU (EAACI/GA2LEN/EDF/WAO
Guidelines)
Step
Intervention
First
Considerations
Modern sg-AHs
Strong recommendation
High-quality evidence
Low cost and worldwide availability
Very good safety profile
Good efficacy
Strong recommendation
High-quality evidence
Low cost, good safety profile, good efficacy
Second
If symptoms
persist after
2 weeks
Increase dosage up to
fourfold of modern sg-AHs
Third
If symptoms
persist after 14 further
weeks
Add on to modern sg-Ahs one of
the following:
Ciclosporin
Strong recommendation
High-quality evidence, medium to high cost,
moderate safety profile, good efficacy
Montelukast
Weak recommendation
Low quality evidence
Low cost, good safety, low efficacy
Omalizumab
Strong recommendation
High-quality evidence, high cost, very good
safety profile, very good efficacy
Short course (max 10 days) of corticosteroids may also be
used at all times for acute exacerbations
Weak recommendation, low-quality
evidence, low cost, worldwide availability,
good efficacy during intake, but very low for
lasting efficacy
Patient 3
• Female, 22 years
• Macules initially
erythematous and
later on hypercromic,
ocasionally
pruriginous, for the
last 12 months
• Frequent intake of
mefenamic acid for
dysmenorrhea
• Past history: atopic
rhinitis and
dermatitis
Diagnosis?
1.
2.
3.
4.
5.
Intradermal nevi
Sweet’s syndrome
Melanosis
Fixed drug eruption
Melanoma
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/NSAIDexacerbated
cutaneous disease
(AECD)
Wheals
and/or AE
Immediate
Chronic urticaria
Cross-reactive
COX-1 inhibition
NSAID-induced
urticaria/angioedem
a
Wheals
and/or AE
Immediate
None
Cross-reactive
Unknown (COX-1
inhibition?)
Immediate
None
Non-cross
reactive
Delayed
(>24 h)
None
Non-cross
reactive
Single NSAID-induced Wheals/AE/
urticaria/angioedem anaphylaxis
a or anaphylaxis
Single NSAID-induced Various (FDE,
delayed reactions
SJS/TEN,
nephritis)
Kowalski M et al, Allergy. 2013 ;68 :1219-32.
Allergic: IgEmediated
T-cell mediated
DRUG-INDUCED CUTANEOUS REACTIONS
Lesion
Frequency
%
Acneiform eruption
8
13.6
Angioedema
2
3.4
Drug-induced LE
1
1.7
Ictyosis
1
1.7
Fixed drug eruption
15
25.4
Irritating contact dermatitis
1
1.7
Lichenoid dermatitis
1
1.7
Maculopapular rash
3
5.1
Morbiliform rash
4
6.8
Photosensitivity reaction
1
1.7
Pytiriasis rosada
1
1.7
Steroid-induced striae
1
1.7
Urticaria
19
32.2
TOTAL
59
100.0
Inbaraj SD et al. J Clin Diagn Res. 2012 Dec;6(10):1688-91.
FDE- INDUCING DRUGS
ANTIBIOTICS
NSAIDs
• Fluoroquinolones
(ciprofloxacin, ofloxacin,
norfloxacin)
• Diclofenac, Nimesulide,
• Amoxycilin
• Tetracyclines
• Doxyciclin
• Azythromicin
• TMP-SMX
• Metronidazole
• Tinidazole
Aspirin, Mefenamic acid,
Ibuprofen
ANTIEPILEPTICS
• Barbiturics, Phenytoin
ANTIMICOTICS
• Fluconazole
OTHER
Pseudoefedrine
Varadraj Vasant Pai et al. Indian J Dermatol Venereol Leprol 2014; 80: 194
FDE: Involved sites
Varadraj Vasant Pai et al. Indian J Dermatol Venereol Leprol 2014; 80: 194
RECOMMENDATIONS FOR THIS PATIENT
1. Analgesia with opioids
2. Avoidance of fenamates
3. Pain relief with flufenamic acid
4. Relief of dysmenorrhea with
psychotherapy
5. Cold compresses on the lower
abdomen
CHEMICAL CLASSIFICATION OF NSAIDS
Chemical group
Salicylic acid
derivatives
Drug
Aspirin (acetylsalicylic acid), sodium salicylate,
salsalate, diflunisal, sulfasalazine
Para-aminophenol Acetaminophen (paracetamol)
Propionic acid
derivatives
Ibuprofen, naproxen, fenoprofen, flurbiprofen,
ketoprofen, oxaprozin
Acetic acid
derivatives
Diclofenac, etodolac, ketorolac, indomethacin,
sulindac, tolmetin, nabumetone
Enolic acid
deivatives
Pyrazolones: phenylbutazone, dypirone
Oxicams: Piroxicam, meloxicam, tenoxicam,
lornoxicam
Fenamic acid
derivatives
(Fenamates)
Mefenamic acid, meclofenamic acid, flufenamic acid,
tolfenamic acid
Selective COX-2
Celecoxib, rofecoxib, valdecoxib*, etoricoxib
inhibitors (Coxibs)
* Withdrawn from the market.