Desensitization in non-steroidal anti-inflammatory drugs (NSAID) hypersensitivity

1. Desensitization in non-steroidal anti-inflammatory drugs (NSAID) hypersensitivity Ricardo Cardona Villa, M.D. MSc in Immunology - Allergist Chief of Clinical Allergology Service IPS Universitaria - Clínica León XIII Medical School Universidad de Antioquia

2. Acetylsalycilic acid (ASA) A model of NSAID TheEnd of Suffering http://goyotovar.lasideas.es/wp-content/imagenes/aspirina.jpg

3. Acetylsalycilic acid is extracted from the tree "Salix alba",called salicin, discovered in 1827

4. The creator of Aspirin, Felix Hoffmann and a package circa 1900. History • The product was registered as Aspirin by Felix Hoffman 1980 Stevenson et al described two patients with previous ASA induced asthmatic reactions

5. Chemical classification of NSAIDs Mario Sánchez-Borges. WAO Journal 2008; 1: 29-33

6. Terminology Selectivity:agentsthatinhibitmore oneenzymethantheother, but can inhibitboth of them (Meloxicam, Nimesulide) Specificity:agentsthatinhibitonlyoneenzyme at doses that produce maximumclinicalefficacy(Celecoxib - Etoricoxib - Lumiracoxib)

7. Classification of some NSAIDs Mario Sánchez-Borges.WAO Journal 2008; 1: 29-33

8. Membrane phospholipids glucocorticoids Endotoxins cytokines mitogens (–) (–) arachidonic acid COX-1 (+) Selective inhibitors of COX-2 (–) (–) (–) COX-2 "Classic NSAIDs" Meloxicam Celecoxib Rofecoxib Stomach: PGE2/PGI2 Kidney: PGE2/PGI2 Platelets: TxA2 Endothelium: PGI2 Inflammation: macrophages synoviocytes Physiological effects Inflammatory mediators Concept COX

9. PARAMETER HOMOLOGY REGULATION TISSUE EXPRESSION COX-1 Similar to COX-2 ( 60%*- 75%) Constitutive Most tissues, but particularly platelets, stomach and kidney COX-1 / COX-2 comparison COX-2 Similar to COX-1 ( 60%*- 75%) Inducible Inflammatory stimuli and mitogens in macrophages/monocytes, synoviocytes, chondrocytes, fibroblasts, endothelial cells. Constitutive in CNS and kidney

10. COX-1 and COX-2 structure COX-1 COX-2 C-terminal active site C-terminal active site Valin at 523 allows the access to the hydrophilic pocket Hydrophobic Channel Hydrophobic Channel Isoleucine at 523, closes the hydrophilic pocket Hydrophilic pocket N-terminal N-terminal Arginin At 120 Arginin at120 Kurumbail R G, Stevens A M, Gierse J K, McDonald J J, et al. Nature. 1996;384:644–648

11. Claudia Jenneck, Uwe Juergens, Markus Buecheler, and Natalija Novak Ann Allergy Asthma Immunol. 2007;99:13–21. Membrane phospholipids Arachidonic acid Lipoxygenase pathway Cyclooxygenase pathway 5-Lipoxygenase (5-LO) Cyclooxygenase Shunt from COX – towards the LO-pathway COX-1 COX-2 LT-A4 ASA/ NSAID Change of the COX-2 structure LTA4 hydrolase LTC4 synthase PG-E2 Generation of products of the LO-pathway LT-B4 Cys-leucotriene LTC4, LTD4, LTE4 Reduced inhibition

12. Johansson SGO, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol.2004;113:832-836. Mario Sánchez-Borges WAO Journal 2008;1:29 - 33 Using the classification proposed by the Committee of the World Allergy Organization, the following types of hypersensitivity reactions should be considered: Non-allergic hypersensitivity Allergic hypersensitivity

13. 1.Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis Clinical Manifestations Sànchez Borges, M. Clinical management of non steroidal anti-inflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal.

14. Clinical Manifestations 1.Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis 1.2 Late reactions 1.2.1 Skin diseases 1.2.2 Pneumonitis 1.2.3 Aseptic meningitis 1.2.4 Nephritis 1.2.5 Hepatitis Sànchez Borges, M. Clinical management of non steroidal anti-inflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal.

15. Clinical Manifestations 1.Allergic hypersensitivity 1.1 Immediate reactions 1.1.1 Urticaria and Angioedema 1.1.2 Allergic Anaphylaxis 1.2 Late reactions 1.2.1 Skin diseases 1.2.2 Pneumonitis 1.2.3 Aseptic meningitis 1.2.4 Nephritis 1.2.5 Hepatitis 2. Nonallergic hypersensitivity 2.1 Respiratory Hypersensitivity 2.2 Skin Hypersensitivity 2.3 Non-allergic anaphylaxis Sànchez Borges, M. Clinical management of non steroidal anti-inflammatory drug hypersensitivity. 2008;1:29-33. WAO Journal.

16. Andrzej Szczeklik and Marek Sanak M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca European Journal of Pharmacology 533 (2006) 145–155 J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 Classification: Respiratory pattern Includes respiratory disease exacerbated by ASA, the Tetrad of Samter (nasal polyposis, rhinosinusitis, asthma and intolerance to ASA) and ASA-induced asthma.

17. Mario Sánchez-Borges M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca WAO Journal 2008;1:29Y33 J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 SkinPattern Including urticaria and angioedema induced by NSAIDs urticaria and angioedema induced by multiple drugs and urticaria and angioedema induced by a single drug.

18. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca Mario Sánchez-Borges J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 WAO Journal 2008;1:29-33 MixedPattern It presents with skin and respiratory symptoms including urticaria and angioedema associated with cough, breathlessness, runny nose, wheezing, tearing or conjunctival irritation

19. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca Mario Sánchez-Borges J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 WAO Journal 2008;1:29-33 SystemicPattern Anaphylactic reactions are type I hypersensitivity, usually observed in simple reactors who tolerate other chemically unrelated NSAIDs IgE antibodies specific for the allergen.

20. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca Mario Sánchez-Borges J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 WAO Journal 2008;1:29-33 Management The management of patients with intolerance to NSAIDs depends on their medical history. The patient should be classified assimple reactor or cross reactor and according to the type of reaction eithercutaneous or systemic.

21. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca Mario Sánchez-Borges J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 WAO Journal 2008;1:29-33 When the patient is asimple reactor,oral provocation testing with an NSAID of a different chemical group involved is recommended. If the test isnegative, the patient may receive treatment with NSAIDs testing and avoid the suspected medication. If the test ispositive,the patient should be handled as a cross reactor.

22. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca Mario Sánchez-Borges J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 WAO Journal 2008;1:29-33 When the patient is classified as across reactor, an oral challenge test can be performed with a weak COX-1 inhibitor or preferential COX-2, or with a specific COX-2 inhibitor. If the test isnegative,it can be administered to the patient and ifpositivetry oral challenge with another COX-2 specific inhibitor. If the latter (previous) test ispositive,avoid all NSAIDs

23. Another COX-2 Mario Sánchez-Borges, Arnaldo Capriles-Hulett and Fernan Caballero-Fonseca Weak COX-1 Inhibitors Acethaminofen Salsalate Desensitization Am J Clin Dermatol 2002; 3 (9): 599-607 Algorithm for clinical management of skin NSAID-induced reactions

24. Modificated of Mario Sánchez-Borges, Arnaldo Capriles-Hulett and Fernan Caballero-Fonseca Am J Clin Dermatol 2002; 3 (9): 599-607 *

25. W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Position paper • The indications for drug provocation testing can be divided into 4 groups that are intertwined: • To exclude hypersensitivity– in history not suggestive of hypersensitivity to the drug and in patients with nonspecific symptoms, such as vagal symptoms by local anesthesia

26. Position paper W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 2.To provide safety– pharmacology and / or structural unrelated drugs as proven hypersensitivity to other antibiotics in patients allergic to beta-lactams. This can also be helpful in anxious people who could reject the drug recommended without tolerance tests

27. Position paper W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 3.To exclude cross-reactivityof related drugs in proven hypersensitivity, such as a cephalosporin in a patient allergic to penicillin or an alternative to NSAIDs in asthmatic patients sensitive to ASA

28. Position paper W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 4.To establish a firm diagnosisin history suggestive of drug hypersensitivity to allergic tests negative, inconclusive or unavailable, such as a maculopapular rash during treatment with Aminopenicillin with negative allergy tests

29. W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 A drug provocation test is the controlled administration of a drug in order to diagnose hypersensitivity reactions The challenge test should be done under medical supervision for an alternative drug, structurally or pharmacologically related to the suspect medicine. The provocation test drug is also known as challenge or controlled re-challenge, drug challenge, incremental challenge, re-challenge or test of tolerance.

30. W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly Allergy 2003: 58: 854–863 Regarding the limitations of drug provocation test, consider the "gold standard“ to establish or refute the diagnosis of hypersensitivity to a substance. Although allergic symptoms can be reproduced, so can the adverse reaction by another mechanism After provocation test,it is desirable to keep the patient under observation for 24 hours,but local restrictions may affect this ideal

31. Protocol of nasal aspirin challenge Basal nasal symptoms, nasal inspiratory flows and volumes are recorded during the first 30 minutes every 10 minutes. Then for the evaluation ofspecific nasal hyperreactivity,are challenged with 0.9% NaCl (80 ul) instilled into each nostril with an Eppendorf pipette. E. Nizankowska-Mogilnicka, G. Bochenek, L. Mastalerz, M. S´wierczynska, C. Picado,et al. Allergy 2007: 62: 1111–1118

32. Protocol of nasal aspirin challenge Nasal symptoms, nasal inspiratory flow and volume are measured within 30 minutes every 10 minutes. If there is a change from20% in the values recorded upper airway is hyperreactive and therefore the challenge can not be done. Finally, 80 ul of L-ASA are instilled into each nostril (total aspirin dose: 16 mg) E. Nizankowska-Mogilnicka, G. Bochenek, L. Mastalerz, M. S´wierczynska, C. Picado,et al. Allergy 2007: 62: 1111–1118

33. Nasal provocation tests may be the first choice in the diagnosis of NSAID intolerance Instillation: Syringe MILEWSKI M, MASTALERZ L,NIZANKOWSKA E, SZCZEKLIK A. Nasal provocation test with lysine-aspirin for diagnosis of aspirin-sensitive asthma. J Allergy Clin Immunol 1998;101:581–586. CASADEVALL J, VENTURA PJ, MULLOL J, PICADO C. Intranasal challenge with aspirin in the diagnosis of aspirin intolerance asthma: evaluation of nasal response by acoustic rhinometry. horax 2000;55:921–924.

34. Inspiratory flow meter Control of peak nasal inspiratory flow is an objective measure of response, which has high specificity S. JIMENEZ-TIMON J., VIGARA Y.M., CIMARRA C., MARTINEZ CERA. Nasal challenge in patients allergic to Alternaria. Allergy 1997, 52. 37, 208–209. HOLMSTROM M., SCADDING G.K., LUND V.J., DARBY Y.C., . Assessment of nasal obstruction. A comparison between rhinomanometry and nasal inspiratory peak flow. Rhinology 1990;28:191–196. KRAYENBUHL M.C., HUDSPITH B.N. SCADDING G.K., BROSTOFF J. Nasal response to allergen and hyper-osmolar challenge. Clin Allergy 1988;18:157–164.

35. L. J. Cormican, S. Farooque, D. R. Altmannw and T. H. Lee Clin Exp Allergy 2005; 35:717–722 In conclusion, a history of previous reaction after ingestion of aspirin is not a reliable guide to the diagnosis of aspirin hypersensitivity (AH). Since there is no other in vitro test of AH,the challenge of aspirin is the only diagnostic tool available

36. M. Sánchez-Borges, A. Capriles-Hulett, F. Caballero-Fonseca J Invest Allergol Clin Immunol 2004; Vol. 14(4): 329-334 Management of patients with Aspirin-Exacerbated Respiratory Disease (AERD)

37. M. Pilar Berges-Gimeno and Donald D. Stevenson JOURNAL OF ASTHMA Vol. 41, No. 4, pp. 375–384, 2004 Desensitization is a term used in a broad sense, refers to the elimination of reactions to ASA byrepeated exposure and increasing doses of medication

38. Tips • During the desensitization with ASA, there is a continuous inhibition of COX-1 and of phospholipase A2. This leads to a decrease in the synthesis of LTs and prostanoids. • Recipients (patients) cysLT1 are "down regulated“, then there is a "leveling" of the effects of the LTs. Studies have shown that during acute desensitization there is a slight decrease in TXB2 and LTB4. • During chronic desensitization, the synthesis of LTB4 substantially decreases Ferreri NR, Howland WC, Stevenson DD, Spiegelberg HL. Release of leukotrienes, prostaglandins, and histamine into nasal secretions of aspirin-sensitive asthmatics during reactions to aspirin. Am Rev Respir Dis 1988;137:847–854. Juergens UR, Christiansen SC, Stevenson DD, Zuraw BL. Inhibition of monocyte leukotriene B4 production after aspirin desensitization. J Allergy Clin Immunol 1995;96:148–156.

39. General requirements for aspirin desensitization ASA desensitization should be performed ina place capable of providing advancedcardiac care, ventilator support and continuous monitoring by qualified personnel. Thesupervising physician must be available immediately to the bedside of the patient after the drug is first applied, and recognize early warning signs. This is whenthe most severe and unpredictable reactionsalmost always occur Eric Macy, MD Jonathan A. Bernstein, MD; Mariana C. Castells, MD, Ph; Sandra M. Gawchik, DO; Tak H. Lee, MD, ScD, FRCPath, FRCP; Russell A. Settipane, MD¶; Ronald A. Simon, MD; Jeffrey Wald, MD; and Katharine M. Woessner, MD; for the Aspirin Desensitization Joint Task Force Ann Allergy Asthma Immunol. 2007;98:172–174.

40. 1. AERD* patients who have no concomitant respiratory disease butwho have moderate or severe asthma, nasal congestion intractableor both on the basis of REIA. These patients should be considered for aspirin desensitization after treatment failure with topical corticosteroids, LTR1A, and 5-LO INH. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization * AERD: Aspirin-Exacerbated Respiratory Disease

41. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization 2.AERD patients with concomitant respiratory diseases which are under aggressive therapybut have not responded to treatment,including topical corticosteroids, LTR1A and 5-LO INH. 3.AERD patientswith a history of multiple polyps.

42. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. Candidates for ASA desensitization 4.Patients requiringsystemic corticosteroidsto control AERD. 5.AERD patients who require aspirinfor other diseases.

43. Candidates for ASA desensitization 6.Others…...

44. In a long-term study of65 patients with ASAintolerance who underwent desensitization, there was a significant decrease in the number of infectious sinusitis and the use of prednisone with improvement in smell and symptoms of asthma and rhinitis. The need for sinus surgery decreased from one every 3 years to once every 9 years. This study demonstrated the beneficial effect of long-term desensitization to ASA over a period of 6 years Stevenson DD, Hankammer MA, Mathison DA. Aspirin desensitization treatment of aspirin sensitive patients with rhinosinusitis asthma: long term outcomes. J Allergy Clin Immunol. 1996;98:751-758.

45. Asubsequent study by Berges-Gimeno and colleagues with172 patients demonstrated a percentage improvement of 67% patients at 6 months of treatment, which persisted for 1 to 5 yearswith reduction in the occurrence of purulent sinusitis about 5 episodes per year to less than half Berges-Gimeno, P, Simon RA, Stevenson DD. Long term treatment with aspirin desensitization in asthmatic patients with aspirin exacerbated respiratory disease. J Allergy Clin Immunol 2003;111:180-186.

46. The traditional model of desensitization to ASA have been administered for3 days,increasing doses of the drug until the patient tolerated 650 mg without adverse effects. The patient should continue receiving a daily dose of 650 mg every 12 hours Oliver P. and Ludger K. Aspirin desensitization in aspirin intolerance: update on current standars and recent improvements. Current Opinion in Allergy and Clinical immunology. 2006;6:161-166

47. Jennifer Altamura Namaz y and Ronald A. Simon Ann Allergy Asthma Immunol 2002;89:542–550. Scripps Clinic ASA Oral challenge Protocol FEV1 everyhourfor 3 hoursaftereachdose. Placebo day: FEV1 baselineorfirst AM value >70% predicted. First, AM FEV1 valueshouldbewithin ±5% from placebo. FEV1 valuesshouldnotchange (i.e. <15%) during 9-hour placebo challenges.

48. Donald D. Stevenson and Ronald A. Simon J Allergy Clin Immunol 2006;118:801-4. • Protocol • One to 7 days before challenge, determine airway stability. • FEV1 >60% of predicted value (>1.5 L absolute). • FEV1 every hour x 3 hours – <10% variability. • Start or continue montelukast, 10 mg every day. • Start or continue ICSs/LABs. • Start SCS burst for low FEV1 or any bronchial instability. • Discontinue antihistamines 48 hours before challenge.

49. Castells, M. Desensitization for drug allergy. Current Opinion in Allergy and Clinical Immunology.2006;6:476-481. White AA, Stevenson DD, Simon RA. The blocking effect of essential controller medications during aspirin challenges in patients with aspirine xacerbated respiratory disease. Ann Allergy Asthma Immunol 2005; 95:330–335. Rapid desensitization There is a rapid desensitization protocol in7 hours based on the controlled administration of increasing doses of ASA 90-minute intervals until the patient can tolerate a dose of 650 mg, measuring lung function using FEV1 and considering significant a decrease of over 20 % from the baseline.

50. Mariana Castells Curr Opin Allergy Clin Immunol 6:476–481. 2006 White AA, Stevenson DD, Simon RA. The blocking effect of essential controller medications during aspirin challenges in patients with aspirinexacerbated respiratory disease. Ann Allergy Asthma Immunol 2005; 95:330–335. Desensitizationtoaspirin in a patientwithasthma Aspirin to be continued at 650 mg orally, twice a day.