U.O.S. Allergologia e Immunologia Clinica Ospedale San Giovanni di - PowerPoint PPT Presentation

U.O.S. Allergologia e Immunologia Clinica Ospedale San Giovanni di Dio Azienda Sanitaria di Firenze Responsabile: Dr. Maurizio Severino Responsabile: Dr. Maurizio Severino Stefania Capretti, Giuseppe Ermini, Maria L Iorno, Donatella Macchia, Elisa Meucci, , Elisa Meucci, Sergio Testi Sergio Testi Reazioni da ipersensibilità ai farmaci antinfiammatori non steroidei (FANS) 10 ottobre 2014

NSAIDs classified according to the chemical structure NSAIDs classified according to the chemical structure Chemical group Drug Salicyllic acid derivates 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 derivatives Pyrazolones, Phenylbutazone, Dipirone, Oxicams , Piroxicam Meloxicam , Tenoxicam, Lornoxicam Fenamic acid derivatives (Fenamates) Mefenamic acid , Meclofenamic acid, Flufenamic acid Tolfenamic acid Selective COX-2 inhibitors (Coxibs) Celecoxib , Rofecoxib (withdrawn from market), Etoricoxib Valdecoxib (withdrawn from the market)

Not predictable, usually ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS not dose dependent, sometimes reactions to very small amounts Type A Type B Type A Type B 80% of all side effects 15-20% of all side effects Hypersensitivity reactions Idiosyncratic reactions Immune mediated Non immune mediate (drug allergy) “pseudoallergy” Predictable, strictly dose dependent Pharmacological side effects (e.g. gastrointestinal bleeding IgE - mediated under treatment with NSAID, or bradycardia with β bloker treatment) Non IgE - mediated Johansson SGO et al. J Allergy Clin Immunol 2004

REAZIONI DA IPERSENSIBILITA’ AI FARMACI • Più del 15% di tutte le reazioni avverse ai farmaci • 7% nella popolazione generale • 10-20% pazienti ospedalizzati Demoly P et al. Curr Opinion Allergy Clin Immunol 2001 Lazarou J et al. JAMA 1998 Gomes ER et al. Curr Opinion Allergy Clin Immunol 2005

PREVALENZA DELLE REAZIONI DA IPERSENSIBILITA’ AI FARMACI ANTINFIAMMATORI NON STEROIDEI • sembra essere la più alta dopo quella degli antibiotici • in alcuni Centri però le Reazioni Avverse a tali farmaci sembrano essere quelle più frequenti in assoluto • stimata fra lo 0.6 e il 5.7% nella popolazione generale (le percentuali variano significativamente in relazione alla popolazione studiata, al metodo di valutazione e al tipo di reazione) Hedman J et al. Int J Epidemiol 1999 Torres MJ et al. Immunol Allergy Clin North Am. 2014 Dona I et al. J Investig Allergol Clin Immunol 2012 Torres MJ et al. Immunol Allergy Clin North Am. 2014

Not predictable, usually ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS not dose dependent, sometimes reactions to very small amounts Type A Type B Type A Type B 80% of all side effects 15-20% of all side effects I mediatori infiammatori Hypersensitivity reactions Idiosyncratic reactions non sono liberati attraverso specifici meccanismi immunologici. Immune mediated Non immune mediate (drug allergy) “pseudoallergy” I farmaci antinfiammatori non steroidei sono quelli Predictable, strictly dose dependent maggiormente Pharmacological side effects responsabili di queste (e.g. gastrointestinal bleeding IgE - mediated under treatment with NSAID, or reazioni , insieme a bradycardia with β bloker chemioterapici, biologici, treatment) con sempre maggiore Non IgE - mediated frequenza . Johansson SGO et al. J Allergy Clin Immunol 2004

Pathophysiological characteristics of sensitivity to acetylsalicylic acid or NSAIDs Pharmacological reactions induced by NSAIDs are dependent on inhibition of the COX-1 pathway and presumed immunologic mediated reactions are dependent on drug-specific IgE production against an NSAID. Blanca M, Perez E, Garcia JJ, Miranda A, Terrados S, Vega JM, Suau R. Angioedema and IgE antibodies to aspirin: a case report. Ann Allergy. 1989 Apr;62(4):295-8.

TIMING OF REACTION Hypersensitivity reactions Immediate reactions Immediate reactions Nonimmediate reactions Nonimmediate reactions Are those occurring Are those occurring Are those occurring Are those occurring more than 1 h more than 1 h within 1 h within 1 h after the last drug administration after the last drug administration after the last drug admistration after the last drug admistration

Specifically, a roundtable was organized to establish a consensus on some controversial issues regarding the diagnosis of hypersensitivity reactions to NSAIDs. Kowalski (Lodz, Poland) acted as chairman, and the other participants were Asero (Paderno Dugnano, Italy), Blanca (Malaga, Spain), Sanchez-Borges (Caracas, Venezuela), and Woessner (San Diego, Calif). Participants agreed with the classification proposed by Kowalski, which distinguished between acute (appearing from a few minutes to several hours after the last NSAID administration) and delayed (appearing after >24 hours) reactions (Table II) Romano A et al. JACI 2011

TIMING OF REACTION Kowalski ML et al. Allergy 2013

Chemical group Drug TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY Salicyllic acid derivates Chemical group Aspirin (acetylsalicylic acid) , Sodium salicylate, Drug Salsalate Diflunisal, Sulfasalazine, Salicyllic acid derivates Aspirin (acetylsalicylic acid) , Sodium salicylate, Salsalate Para-aminophenol Acetaminophen ( paracetamol) Diflunisal, Sulfasalazine, Propionic acid derivatives Ibuprofen , Naproxen, Fenoprofen, Flurbiprofen, Para-aminophenol Acetaminophen ( paracetamol) Ketoprofen Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs Oxaprozin Propionic acid derivatives Ibuprofen , Naproxen, Fenoprofen, Flurbiprofen, Ketoprofen Acetic acid derivatives Diclofenac , Etodolac, Ketorolac , Indomethacin, Oxaprozin Sulindac Tolmetin, Nabumetone Acetic acid derivatives Diclofenac , Etodolac, Ketorolac , Indomethacin, Sulindac Enolic acid derivatives Pyrazolones, Phenylbutazone, Dipirone, - NSAIDs exacerbated respiratory disease (NERD) Tolmetin, Nabumetone Oxicams , Piroxicam Enolic acid derivatives Pyrazolones, Phenylbutazone, Dipirone, Meloxicam , Tenoxicam, Lornoxicam - NSAIDs exacerbated cutaneous disease (NECD) Fenamic acid derivatives (Fenamates) Oxicams , Piroxicam Mefenamic acid , Meclofenamic acid, Meloxicam , Tenoxicam, Lornoxicam Flufenamic acid Tolfenamic acid Fenamic acid derivatives (Fenamates) Mefenamic acid , Meclofenamic acid, - NSAIDs induced urticaria/angioedema (NIUA) Flufenamic acid Selective COX-2 inhibitors (Coxibs) Celecoxib , Rofecoxib (withdrawn from market), Tolfenamic acid Etoricoxib Valdecoxib (withdrawn from the market) Selective COX-2 inhibitors (Coxibs) Celecoxib , Rofecoxib (withdrawn from market), Etoricoxib Valdecoxib (withdrawn from the market) Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs - Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) - NSAIDs induced delayed hypersensitivity reactions (NIDHR)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs - NSAIDs exacerbated respiratory disease (NERD) - NSAIDs exacerbated cutaneous disease (NECD) - NSAIDs induced urticaria/angioedema (NIUA) Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs - Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) - NSAIDs induced delayed hypersensitivity reactions (NIDHR)

NSAIDs-exacerbated respiratory disease (NERD) NSAIDs-exacerbated respiratory disease (NERD) Epidemiology • 4.3 to 20%, • female gender, • skin prick test positivity to aeroallergens Pathomechanisms of NERD • inhibition of COX-1 (cysteinyl leukotrienes (LTs) are major but not exclusive mediators) • represent a cross-reactive type of nonallergic drug hypersensitivity Clinical presentation • bronchial obstruction, dyspnea and nasal congestion/rhinorrhea • develops within 0.5 –3 h • patients with an underlying chronic airway respiratory disease (Asthma/ rhinosinusitis/nasal polyps).

NSAIDs-exacerbated respiratory disease (NERD) NSAIDs-exacerbated respiratory disease (NERD) Diagnosis • well-documented history • provocation test (to confirm the presence of hypersensitivity to aspirin and other cross-reactive NSAIDs): • oral provocation test with aspirin (sensitivity ranges from 89 to 90%) • inhalation provocation test with lysine aspirin (L-ASA), • nasal challenges with (L-ASA) Management • avoidance of aspirin and other cross-reacting NSAIDs • well tolerated • weak inhibitor of COX-1, paracetamol in low (<1000 mg) doses, • selective COX2 inhibitors (1–2% with unstable asthma may also react) • antileukotriene drugs, sinus surgery, chronic treatment with aspirin after desensitization (600–1200 mg daily)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs - NSAIDs exacerbated respiratory disease (NERD) - NSAIDs exacerbated cutaneous disease (NECD) - NSAIDs induced urticaria/angioedema (NIUA) Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs - Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) - NSAIDs induced delayed hypersensitivity reactions (NIDHR)