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

10 ottobre 2014

Reazioni da ipersensibilità ai farmaci antinfiammatori non steroidei (FANS)

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acid, Meclofenamic acid, Flufenamic acid Tolfenamic acid Selective COX-2 inhibitors (Coxibs) Celecoxib, Rofecoxib (withdrawn from market), Etoricoxib Valdecoxib (withdrawn from the market)

NSAIDs classified according to the chemical structure NSAIDs classified according to the chemical structure

ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS Type A Type A

80% of all side effects

Type B Type B

15-20% of all side effects

Idiosyncratic reactions Hypersensitivity reactions Immune mediated (drug allergy) Non immune mediate “pseudoallergy” IgE - mediated Non IgE - mediated Predictable, strictly dose dependent Pharmacological side effects (e.g. gastrointestinal bleeding under treatment with NSAID, or bradycardia with β bloker treatment) Not predictable, usually not dose dependent, sometimes reactions to very small amounts

Johansson SGO et al. J Allergy Clin Immunol 2004

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

REAZIONI DA IPERSENSIBILITA’ AI FARMACI

• Più del 15% di tutte le reazioni avverse

ai farmaci

• 7% nella popolazione generale
• 10-20% pazienti ospedalizzati

• 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 Dona I et al. J Investig Allergol Clin Immunol 2012

PREVALENZA DELLE REAZIONI DA IPERSENSIBILITA’ AI FARMACI ANTINFIAMMATORI NON STEROIDEI

Torres MJ et al. Immunol Allergy Clin North Am. 2014 Torres MJ et al. Immunol Allergy Clin North Am. 2014

ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS Type A Type A

80% of all side effects

Type B Type B

15-20% of all side effects

Idiosyncratic reactions Hypersensitivity reactions Immune mediated (drug allergy) Non immune mediate “pseudoallergy” IgE - mediated Non IgE - mediated Predictable, strictly dose dependent Pharmacological side effects (e.g. gastrointestinal bleeding under treatment with NSAID, or bradycardia with β bloker treatment) Not predictable, usually not dose dependent, sometimes reactions to very small amounts

Johansson SGO et al. J Allergy Clin Immunol 2004

I mediatori infiammatori non sono liberati attraverso specifici meccanismi immunologici. I farmaci antinfiammatori non steroidei sono quelli maggiormente responsabili di queste reazioni , insieme a chemioterapici, biologici, con sempre maggiore frequenza.

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.

Pathophysiological characteristics of sensitivity to acetylsalicylic acid or NSAIDs

Hypersensitivity reactions

Immediate reactions Immediate reactions

Are those occurring Are those occurring within 1 h within 1 h after the last drug admistration after the last drug admistration

Nonimmediate reactions Nonimmediate reactions

Are those occurring Are those occurring more than 1 h more than 1 h after the last drug administration after the last drug administration

TIMING OF REACTION

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

Kowalski ML et al. Allergy 2013

TIMING OF REACTION

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY

Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs

Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs

• Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)
• NSAIDs induced delayed hypersensitivity reactions (NIDHR)

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) 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)

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY

Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs

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).

Diagnosis

• well-documented history
• provocation test (to confirm the presence of hypersensitivity to aspirin and
• ther 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) NSAIDs-exacerbated respiratory disease (NERD) NSAIDs-exacerbated respiratory disease (NERD)

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY

Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs

Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs

• Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)
• NSAIDs induced delayed hypersensitivity reactions (NIDHR)

Epidemiology

• NSAIDs may be an aggravating factor in approximately 10–30% of adults with

chronic urticaria (older studies up to 50%) 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

• wheals and/or angioedema
• appear usually 0.5–6 h after drug ingestion
• suffer from chronic spontaneous urticaria that can be also exacerbated by triggers
• ther than NSAIDs (infections, antibiotics, physical factors, stress)
• dose dependent (greater when CU is active, less intense when CU is in remission
• r under control)
• may precede the onset of chronic spontaneous urticaria by years

NSAIDs-exacerbated cutaneous disease (NECD) NSAIDs-exacerbated cutaneous disease (NECD)

Diagnosis

• a history (usually not reliable)
• provocation test (if underlying skin disease is controlled):
• oral provocation test with the culprit drug to confirm the hypersensitivity

should be done if the history is unclear or when a definite diagnosis is required (has to be judged)

• oral provocation test with the alternative NSAIDs to confirm/exclude a

cross-reactive type of hypersensitivity: (if aspirin is not the culprit drug, an

• ral challenge test with aspirin should be performed)

Management

• avoidance of culprit NSAIDs as well as other NSAIDs with strong COX-1

inhibitory activity

• oral tolerance tests with alternative analgesic drug
• weak inhibitor of COX-1, paracetamol
• preferential COX-2 inhibitors, such as nimesulide, or meloxicam
• selective COX2 inhibitors (coxibs) (tolerated 75–90%)

NSAIDs-exacerbated cutaneous disease (NECD) NSAIDs-exacerbated cutaneous disease (NECD)

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY

Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs

Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs

• Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)
• NSAIDs induced delayed hypersensitivity reactions (NIDHR)

NSAIDs-induced urticaria/angioedema (NIUA) NSAIDs-induced urticaria/angioedema (NIUA) 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

• wheals and/or angioedema
• appear usually within the first hour
• healthy subjects (without history of chronic spontaneous urticaria)
• aspirin and other strong COX-1 inhibitors almost invariably induce

symptoms

• weak COX-1 inhibitors may induce symptoms in up to 25% of patients,

especially when high doses are used (e.g., 1000 mg or more of paracetamol)

• selective COX-2 inhibitors (coxibs) are usually well tolerated.

Diagnosis

• a history (usually not reliable)
• provocation test (if underlying skin disease is controlled):
• oral provocation test with the culprit drug to confirm the hypersensitivity

should be done if the history is unclear or when a definite diagnosis is required (has to be judged)

• oral provocation test with the alternative NSAIDs to confirm/exclude a

cross-reactive type of hypersensitivity: (if aspirin is not the culprit drug, an

• ral challenge test with aspirin should be performed)

Management

• avoidance of culprit NSAIDs as well as other NSAIDs with strong COX-1

inhibitory activity

• oral tolerance tests with alternative analgesic drugs are recommended

preferential COX-2 inhibitors, such as nimesulide, or meloxicam weak inhibitor of COX-1, paracetamol selective COX2 inhibitors (coxibs) NSAIDs-induced urticaria/angioedema (NIUA) NSAIDs-induced urticaria/angioedema (NIUA)

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs

• Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)
• Single NSAIDs induced delayed hypersensitivity reactions (NIDHR)

Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) Epidemiology

• up to 30% of all NSAIDs-induced skin reactions
• usually do not have a history of chronic urticaria or asthma
• may have a history of hypersensitivity to food or other drugs (e.g., antibiotics)

Pathomechanisms

• symptoms and timing of reactions suggest an allergic type I mechanism
• in a small proportion of patients, specific IgE can be detected in the skin test, in the

serum or on peripheral blood basophils Clinical presentation

• from mild urticaria and localized angioedema to laryngeal edema and anaphylaxis
• single NSAID or to several NSAIDs belonging to the same chemical group and

good tolerance to other chemically unrelated NSAIDs

• may develop within seconds (e.g., after intravenous injection of metamizol) or

minutes (after oral exposure)

Diagnosis

• history of immediate symptoms, of tolerance to other chemically unrelated

drugs

• oral challenge with a chemically unrelated strong COX-1 inhibitor to verify

the possible existence of cross-intolerance by challenge with alternative NSAIDs (usually aspirin), has to be judged

• skin tests with the culprit drug
• documented for pyrazolones (other-than-pyrazolones NSAIDs

has not been proven in large series positive skin tests)

• decrease with the time elapsed from the reaction
• drug-specific IgE in serum is not recommended
• Basophil activation test (CD63/CD203) with a culprit drug has been reported to

be of diagnostic value for metamizol, but not for other NSAIDs

• the most frequently described causes of this type of reaction are pyrazolones,

ibuprofen, diclofenac, aspirin, and paracetamol Management

• patient can safely take other chemically unrelated NSAIDs

Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA) Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)

• NSAIDs exacerbated respiratory disease (NERD)
• NSAIDs exacerbated cutaneous disease (NECD)
• NSAIDs induced urticaria/angioedema (NIUA)

TYPES OF NSAIDS HYPERSENSITIVITY TYPES OF NSAIDS HYPERSENSITIVITY Non-immunologically mediated (cross-reactive) hypersensitivity reactions to NSAIDs Immunologically mediated (non-cross-reactive) hypersensitivity reactions to NSAIDs

• Single NSAID induced urticaria/angioedema or anaphylaxis (SNIUAA)
• Single NSAIDs induced delayed hypersensitivity reactions (NIDHR)

Single NSAIDs induced delayed hypersensitivity reactions (NIDHR) Single NSAIDs induced delayed hypersensitivity reactions (NIDHR) Epidemiology

• the prevalence is not known

Pathomechanisms

• stimulation of drug-specific CD4+ and CD8+ T cells through their T-cell

receptors (TCR) Clinical presentation

• more than 24 h (usually within 24–48 h) after exposure
• the skin is the organ most frequently involved,
• mild symptoms (usually) such as MPE, FDEs, photosensitivity reactions, delayed

urticaria, contact dermatitis

• more severe reactions such as SJS/TEN, Acute Generalized Exanthematous

Pustulosis (AGEP), Drug-Induced Hypersensitivity Syndrome (DIHS/DRESS), occur less frequently

• other organ-specific reactions involving lung (pneumonitis) or kidneys (nephritis)

have been observed rarely

Diagnosis

• clinical history
• Intradermal skin test with delayed reading with NSAIDs (is more sensitive than

patch tests)

• patch tests with specific NSAIDs, particularly in cases of contact dermatitis,

FDE (‘in loco patch testing’) and Photoallergic reactions (Photopatch tests), but not sufficiently standardized

• drug provocation tests with culprit (there is no standardized protocol)
• can be considered: MPE, delayed urticaria, and FDEs
• contraindicated: bullous drug eruptions such as TEN, Stevens–Johnson

syndrome, AGEP, or organ-specific reactions (e.g., nephritis)

• drug provocation with alternative NSAIDs can be performed in all other

situations

• lymphocyte transformation test (LTT), there are limited data on the diagnostic

value and cannot be recommended for routine diagnosis Single NSAIDs induced delayed hypersensitivity reactions (NIDHR) Single NSAIDs induced delayed hypersensitivity reactions (NIDHR)

Algorithm for the diagnosis of acute forms of nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity Algorithm for the diagnosis of acute forms of nonsteroidal anti-inflammatory drugs (NSAIDs) hypersensitivity

Provocation challenges in patients with a history of acute reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) Provocation challenges in patients with a history of acute reactions to nonsteroidal anti-inflammatory drugs (NSAIDs)

Diagnostic procedures in delayed type of hypersensitivity to NSAIDs Diagnostic procedures in delayed type of hypersensitivity to NSAIDs

Oral challenge with NSAID (i) with a culprit drug to confirm hypersensitivity, remains the gold standard (all patients with equivocal history should be tested)

• oral provocation test (negative predictive value: 97.8%, positive

predictive value: close to 100%)

• inhaled provocation test with lysine aspirin
• intranasal provocation test with soluble aspirin or ketorolac

(ii) with other than causative NSAIDs (usually challenge test with aspirin) in order to confirm/exclude cross-reactivity (iii) with the most likely tolerated alternative drug - tolerance Test - (e.g., selective COX-2 inhibitor or paracetamol if NERD has been diagnosed)

• Ambiente protetto
• Test di provocazione: tempi più lunghi fra le dosi
• Test di provocazione: tempi di osservazione più lunghi
• Test di provocazione: in due sedute
• Aspetti medico legali

Conclusioni/Riflessioni Conclusioni/Riflessioni INDAGINE ANAAO-SWG LE CONDIZIONI DI LAVORO DEI MEDICI OSPEDALIERI.

Grazie per l’attenzione

The clinical presentation varies upon the drugs involved. (the most frequent elicitors) Maculopapular Eruptions (MPE) ibuprofen Naproxen Fixed Drug Eruption (FDE) Metamizol Paracetamol mefenamic acid Allergic Photocontact Dermatitis the topical and oral use of NSAIDs (e.g., ketoprofen) Contact Dermatitis Bufesamab Ketoprofen Diclofenac Single NSAIDs induced delayed hypersensitivity reactions (NIDHR) Single NSAIDs induced delayed hypersensitivity reactions (NIDHR)

Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN)

• xicams (especially)

followed by COX-2 inhibitors (valdecoxib and celecoxib) diclofenac paracetamol Acute Generalized Exanthematous Pustulosis (AGEP) ibuprofen nimesulide celecoxib, etoricoxib, valdecoxib, metamizol, paracetamol Single case of DIHS ibuprofen Single NSAIDs induced delayed hypersensitivity reactions (NIDHR) Single NSAIDs induced delayed hypersensitivity reactions (NIDHR)