Aspirin and non steroid anti-inflammatory drugs (NSAIDs)


Aspirin and NSAIDs are widely used drugs in the field of pain and inflammatory disorders.
 
Incidence
Aspirin induced asthma
 
  • asthmatic adults: 10%

Aspirin induced urticaria
 
  • chronic urticaria: 21 to 30% (mean 23%)
  • rhinitis and asthma: 1.5%
  • normal individuals: 0.3%.

Risk factors
Female gender (urticaria).
 
HLA DQW2 (controversial), decrease of incidence of DPB1 0401 in both aspirin-tolerant and aspirin-sensitive asthmatics.
 
Atopy (localized periorbital edema).
 
Clinical manifestations
General: anaphylactoid reaction, (zomepirac, tolmetine, diclofenac).
 
Rhinoconjunctivitis/asthma: chronic eosinophilic rhinosinusitis with or without nasal polyps and secondary purulent infection of the paranasal sinuses; then asthma, usually severe and corticodependant. Classic triad: rhinitis with nasal polyps, asthma and ASA sensitivity.
 
Cutaneous: chronic urticaria (in free patients and in patients with chronic urticaria), angioedema, isolated periorbital edema (younger subjects; atopy, intolerance to multiple NSAIDs not structurally related), Lyell’s syndrome (fenbrufen, indomethacin, piroxicam), purpura (phenylbutazone, salicylate, derivatives), photodermatitis (naproxen, piroxicam, tiaprofenic acid, benoxaprofen).
 
Haematological: eosinophilia, cytopenia.
 
Respiratory: hypersensitivity, pneumonitis (fever, cough, pulmonary infiltrates): most reactions occur in patients with inflammatory arthritis. Drugs involved: naproxen, sulindac, ibuprofen, azapropazone, indomethacin, piroxicam, phenylbutazone, oxyphenylbutazone, diclofenac.
 
New triad: atopy, NSAIDs sensitivity and oral anaphylaxis from aeroallergens (mites).
 
Diagnostic methods
Cutaneous testing
 
Usually ineffective and negative ; one case of positive cutaneous test with aspirin polylysine 2 mg/ ml in a patient with urticaria.
 
Specific IgE (controversial)
 
IgE antibodies against platelet antigens.
 
Specific antibodies to salicyloyl and O-methylsalicyloyl (RAST-RAST inhibition).
 
Controlled oral challenges: gold standard in the diagnostic of NSAID hypersensitivity
 
Urticaria (aspirin).
 
Day 1: placebo. Day 2: 100 mg , 200 mg. Day 3: 325 mg , 650 mg
 
Urticarial responses are measured by skin scores recorded every 2 hours.
 
Rhinosinusitis/asthma.
 
Oral challenge (single blind or double blind)
 
Day 1Day 2Day 3
8 H00 AMplaceboASA 3 or 30 mg150 mg
11H00 AMplaceboASA 60 mg325 mg
2H00 PMplaceboASA 100 mg650 mg
 
Classical response (86%): FEV1 decrease > 20% + naso-ocular reaction.
 
Asthma only: FEV1 decrease > or = 20%
 
Rhinitis: naso-ocular reaction only.
 
Mild asthma: FEV1 decrease 15 to 20% combined with naso-ocular reaction.
 
No reaction.
 
 
 
Bronchial inhalation challenge with Lysine-ASA.
 
Lysine-acetylsalicylate conjugate, available as a powder, soluble in water (ASA-Lysine: 11.25 mg, 22.5 mg, 45 mg , 90 mg, 180 mg, 360 mg).
 
No severe bronchoconstriction.
 
Easier to perform.
 
 
 
Other drugs (single-blind, placebo-controlled drug challenge).

Paracetamol 100 mg, 250 mg, 500 mg, at 60 minute intervals.

Isonixin 100 mg, 400 mg, at 60 minute intervals.

Salsalate 500 mg, 1000 m at 60 minute intervals.

Diflunisal 100 mg, 500 mg, at 60 minute intervals.

Mefenamic acid 50 mg, 125 mg, 250 mg at 60 minute intervals.

Clonixin 50 mg, 125 mg at 60 minute intervals.

Diclofenac 25 mg, 50 mg at 120 minute intervals.

Piroxicam 10 mg, 20 mg at 120 minute intervals.

Ketoprofen 10 mg, 25 mg, 50 mg at 120 minute intervals.

Mechanisms
Leukotriene C4, histamine and tryptase are released from cells in ASA-sensitive asthmatics following ASA challenge.
 
Leukotriene over-production is related to marked eosinophilic infiltration of the mucosa.
 
Administration of aspirin shifts the metabolism of arachidonic acid towards the 5-lipooxygenase pathway with synthesis of leukotriene sulfidopeptides (LTC4, LTD4, LTE4) which are potent bronchoconstrictors.
 
Metabolites of arachidonic acid (LTC4, LTD4, LTE4) may be detected in urine and bronchial and nasal fluid following aspirin challenge.
 
Platelets have been implicated in the pathogenesis of asthma intolerance, since they release free radicals of O2 and cytocidal mediators in response to NSAIDs.
Platelets from ASA-sensitive patients become cytotoxic in the presence of ASA.
 
Studies performed in patients suffering from asthma due to aspirin intolerance have demonstrated higher levels of IL5, an elevated count of eosinophils, and higher levels of ECP compared to aspirin-tolerant asthmatic patients.
 
 
Sensitivity to aspirin-like drugs in ASA-sensitive patients.
 
  • prostaglandin synthetase inhibitors: indomethacin 100%, fenoprofen 100%, naproxen 100%, zomepirac 80 to 100%, ibuprofen 97%, mefenamic acid 60%, phenylbutazone 42%
  • no prostaglandin synthetase inhibitors: sodium salicylate < 1%, choline salicylate < 1%, salicylate < 1%, propoxyphene < 1%

Management
Urticaria
 
Avoidance of ASA/NSAIDs.
 
Long-term desensitization does not appear feasible for patients with ASA/NSAIDs-induced urticaria.
 
 
Hypersensitivity pneumonitis
 
Avoidance.
 
Use of systemic corticosteroids.
 
 
Rhinosinusitis/asthma
 
Avoidance of all NSAIDs.
 
Asthmatics with normal sinus X-rays or CT scans of the sinuses. and asthmatics with clear evidence of IgE-mediated allergy are at low risk of ASA sensitivity.
 
Desensitization.
 
ASA desensitization may be considered in patients with:
  • uncontrolled respiratory inflammation despite appropriate treatment (local and systemic corticosteroids).
     
  • patients requiring frequent sinus surgery.
     
  • patients with arthritis or recurrent arterial thromboembolic diseases.

Aspirin desensitization is accompanied by a reduced aspirin-induced production of sulfido peptide leukotrienes (LTE4).

Do not administer topical ophtalmic ketorolac, flurbiprofen, suprofen, and diclofenac in asthmatic patients with ASA sensitivity due to the risk of bronchospasm.
 
Nimesulide (4 nitro-2 phenoxymethane-sulfon-anilide) is an NSAID-inhibiting cox2 and is well-tolerated in 90 to 100% of asthmatics and 92.8 to 98% of NSAID-intolerant patients.
 
Imidazole salicylate, a new NSAID, which inhibits Tx A2 synthesis without interfering with cyclooxygenase pathway, is safe in ASA-intolerant patients.
 

References

  1. Szczeklik A, Dworski R, Mastalerz L, Prokop A, Sheller J.R, Nizankowska E, Cmiel A, Oates J.A, "Salmeterol prevents aspirin-induced attacks of asthma and interferes with eicosanoïd metabolism", Am. J. Respir. Crit. Care. Med, 1998 ; 158: 1168-72
  2. Zhu D.X, Zhao J.L, Mo L, Li H.T, "Drug allergy: identification and characterization of IgE-reactivities to aspirin and related compounds", J. Invest. Allergol. Clin. Immunol., 1997 ; 7 (3): 160-8
  3. Quiralte J, Blanco C, Castillo R, Delgado J, Carrillo T, "Intolerance to non steroidal inflammatory drugs: results of controlled drug challenges in 98 patients", J. Allergy. Clin. Immunol., 1996 ; 98 (3): 678-85
  4. Nasser S.M, Pfister R, Christie P.E, Sousa A.R, Barker J, Schmitz-Schumann M, Lee P.H, "Inflammatory cell populations in bronchial biopsies from aspirin-sensitive asthmatic subjects", Am. J. Respir. Crit. Care. Med, 1996 ; 153 (1): 90-6
  5. Bochenek G, Nizankowska E, Szczeklik A, "The atopy trait in hypersensitivity to non steroidal anti-inflammatory drugs", Allergy, 1996 ; 51: 16-23
  6. Nasser S.M, Patel M, Bell G.S, Lee T.H, "The effect of aspirin desensitization on urinary leukotriene E4 concentrations in aspirin-sensitive asthma", Am. J. Respir. Crit. Care. Med, 1995 ; 151 (5): 1326-30
  7. Lee T.H, "Mechanism of aspirin sensitivity", Am. Rev. Respir. Dis., 1992 ; 145 (2.2): S34-6
  8. Stevenson D.D, Simon R.A, "Sensitivity to aspirin and non steroidal anti-inflammatory drugs", In. Allergy. (Middleton E.R, Reed C.E, eds) page 1747-65. St Louis CV Mosby 1992

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.