L’IMMUNOTERAPIA (AIT) ATTUALE Giovanni Passalacqua Allergy & Respiratory Diseases Dept.Internal Medicine- University of Genoa ITALY

IMMUNOTERAPIA SPECIFICA (ITS) Somministrazione di estratti allergenici purificati (prima a dosi crescenti e poi a dose di mantenimento), al fine di ottenere la riduzione della risposta clinica all’allergene stesso. L’immunoterapia allergene specifica è un vaccino a tutti gli effetti La via tradizionale di somministrazione è quella iniettiva sottocutanea (SCIT), ad oggi affiancata anche dalla via sublinguale (SLIT)

Immunol Allergy Clin North Am. 2016

Rands DA. Anaphylactic reaction to desensitization for allergic rhinitis and astma Br Med J 1980; 281: 854 Ewan PW. Anaphylactic reaction to desensitization. Br Med J 1980; 281: 1069 Frankland AW. Anaphylactic reaction to desensitization. Br Med J 1980; 281: 1429

Committee on the safety of medicines (CMS) CMS Update Desensitizing vaccines Br Med J 1986; 293: fatalities since 1957 certainly due to IT 11 of them since 1980

Dal 1910 fino agli anni ’70: Prescrizione ingiustificata dell’ITS Prescrizione non corretta Pratica non adeguata, senza regole precauzionali e con estratti scadenti DUBBIA EFFICACIA E SCARSA SICUREZZA

Committee on the Safety of Medicines Desensitizing vaccines BMJ deaths due to SCIT Non-injection routes for immunotherapy... the overall aim of improving safety of immunotherapy and making it more convenient for the patients... EAACI IT Position Paper 1993

Standards for practical allergen-specific immunotherapy. Allergy 2006 Allergen immunotherapy: A practice parameter third update JACI 2011 WHO Pos Pap. Therapeutical vaccines for allergic diseases Allergy 1998

L'ITS e' mirata all'allergene causale e non all'organo principalmente coinvolto.” L’ITS non è un trattamento di ultima scelta da usare se i farmaci falliscono, ma è complementare ad essi. L’ITS è efficace nelle allergie da - Inalanti (acari, pollini, alcuni funghi, epitelio di gatto) - Veleno di imenotteri

SCIT - Meta-analysis: Symptom score Calderon M et al 2007 RINITE SINTOMI RINITE FARMACI

SYMPTOM SCORE Cochrane 2010

SYMPTOMS MEDICATIONS Meta-analysis of the efficacy of sublingual immunotherapy in allergic asthma in pediatric patients, 3 to 18 years of age. M Penagos, G Passalacqua, E Compalati, C Baena-Cagnani, S Orozco, A Pedroza GW Canonica

WHO pos pap (1998): 4 trials ARIA pos pap (2001): 22 trials EAACI pos pap (2006): 36 trials 1st WAO pos pap (2009): 60 trials 2nd WAO pos pap (2013): 77 trials After 2013: 87 trials

The optimal maintenance dose has been clearly identified (by dose-ranging studies) only for SLIT tablets. The efficacy has been anyway proven over a wide range of doses, and therfore the recommendation of the manufacturers should be followed. OPTIMAL DOSES (dose-finding studies) DURHAM 2006: 15 mcg Phl p 5/day DIDIER 2007: 25 mcg Group 5 /day CRETICOS 2013: 12 mcg Amb a 1/day BERGMANN 2014: 28/120 Der p 1/Der f 1/day MOSBECH 2014: 6 SQ/day (70 mcg day) NOLTE 2015: 12 DU/day (equivalent to 6 SQ/day)

SCITSLIT Clinical efficacy: RhinitisIa Clinical Efficacy: AsthmaIa Clinical efficacy: Children (rhinitis) Children (asthma) Ib Ia Prevention of new sensitizationsIbIIa Longterm effectIbIIa Prevention of asthmaIIb ARIA Update on immunotherapy SR Durham and G.Passalacqua JACI 2007

Mild intermitt. Mild persistent Moderate- severe intermitt. Moderate- severe persistent Indications Intermitt. Mild Moderate Severe IMMUNOTHERAPY. RHINITIS ASTHMA HIGH RISK? Not cost- effective?

I fattori da valutare nella prescrizione dell’ITS 1Il disturbo deve essere IgE - mediato (skin test o RAST positivi) 2L’allergene responsabile deve essere individuato con sicurezza 3Valutare la gravità e la durata dei sintomi 4 l trattamento farmacologico é sufficientemente ben tollerato? 5 Il paziente é in grado di affrontare l’ITS? (costi, impegno, stile di vita) 6È disponibile un vaccino standardizzato? 7L’efficacia del vaccino che si intende usare é dimostrata?

CAUSAL ROLE OF THE ALLERGEN(S): Clinical history and exposure SKIN TESTING RAST ASSAY NASAL (CONJUNCTIVAL) CHALLENGE SLIT (IT in general) for the clinically relevant allergen(s) Preferably one, but in selected cases 2 or 3 extracts. MOLECULAR DIAGNOSIS

janfebmaraprmayjunjul 300 BIRCH GRASS CYPRESS OLIVE

maraprmayjunjulaugsep 300 GRASS RAGWEED oct PARIETARIA MITE

GRASS Phl p 1 Phl p 5 Phl p 6 Phl p 7 (profilin) Phl p 12 (CBP) BIRCH Bet v 1 Bet v 2 (profilin) Bet v 3 (CBP) PARIETARIA Par j 1 Par j 2 Par j 3 (profilin)

Lockey RF et al. JACI 1987 Period: fatalities Reid MJ et al. JACI 1993 Period fatalities FATALITIES FATALITIES: 1/ injections

RISK FACTORS Based on nonfatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Use of new vials Technical errors Based on fatal reactions Uncontrolled asthma Severe asthma Use of betablockers Rush immunotherapy Build-up phase Use of new vials Technical errors Estimated incidence of fatalities < 1/ injections

No fatal event reported since cases of anaphylaxis in 20 years SLIT

SLIT: KNOWN SIDE EFFECTS Local: oral itching-swelling stomach-ache nausea-vomiting Systemic:Urticaria/angioedema Rhinitis Asthma Anaphylaxis Relatively frequent. Usually self-resolve after the first doses without treatment. If persist reduce the dose. Rare. Give symptomatic treatment and reduce the dose. If persist, stop SLIT Exceptional. Treat properly and stop SLIT

Aspetti pratici. In Italia è formalmente un “named patient product” (preparato dalla ditta per ciascun paziente dietro indicazione), anche se ad oggi i vaccini per AIT vengono preparati su scala industriale, come i farmaci e quindi uguali per tutti i pazienti. Due soli prodotti SLIT (graminacee) sono registrati come farmaco Gli estratti sono standardizzati (ossia è nota la quantità di allergene maggiore e la potenza) Con la SCIT Si effettua una fase di induzione graduale (solitamente 1/sett per 2 mesi), seguita da una fase di mantenimento (1/mese). Con la SLIT la fase di induzione può essere omessa Per allergeni pollinici si può effettuare un trattamento pre- costagionale. Per allergeni perenni, il trattamento è continuativo. Durata consigliata 3-5 anni, da sospendere se dopo 2 anni non si ha beneficio.

Ascertain that the dose and preparation are correct Assess the clinical condition of the patient Record date, hour, dose, reactions at previous injection Use upper outer surface of arm Ensure sterile technique Use 1mL syringe Inject at 45º by deep subcutaneous route Record any local/systemic reaction A waiting period of 30 min after injection is recommended SCIT: PRACTICAL ASPECTS

COSA OCCORRE PER LA SCIT: Adrenalina (iniezione i.m.) Broncodilatatore short acting Steroide orale e i.v. Antistaminico orale e i.v. Set da infusione Ossigeno Ambu

settimane mesi Flac 1Flac 2Flac 3 INDUZIONE O BUILD-UPMANTENIMENTO

SLIT: PRACTICAL ASPECTS SLIT is self-administered at home by the patient. SLIT can be adminstered as mono-dose vials, drops, pre dosed spray or tablets After prescription, the first dose must be given under direct medical control The preparation (drops, tablets, spray-dose) should be assumed in the morning, being the patient fastened. The dose should be kept under the tongue for 1-2 minutes (until dissolved for tablets), then swallowed. The patient must be instructed on the possible (local) side effects, and on how to manage them.

The omission of the build-up phase seems not to increase the risk of adverse events. Build up is usually not done with the more recent tablet preparations Short build-up courses (1-5 days) can be applied, according to the manufacturer’s suggestion and to own experience

Explain to patients the possible side effects Explain that side effects tend to disappear after few doses Suggest medications (e.g. oral antihistamines) to control local side effects if any Administer the first dose under medical supervision

Practical aspects. SCIT BUILD-UP: Usually recommended (4-8 wks) MAINTENANCE: usually every 4 wks DURATION: 3-5 yrs PROTOCOL: continuous or pre-coseasonal (with the MPL- adjuvanted SCIT, only 4 preseasonal injections) SLIT PREPARATION: drops, pre-dosed spray, tablets BUILD-UP: Very short (days) or absent MAINTEINANCE: Preferably daily (can vary according to the manufacturer). DURATION: 3-5 yrs PROTOCOL: Preferred pre- coseasonal (continuous for HDM)

INIZIO: Prima della stagione di pollinazione (2 mesi) In qualsiasi momento per i perenni SCHEMA: Tradizionale, cluster, rush MANTENIMENTO: Prestagionale, precostagionale, continuo DURATA: Almeno 3-5 anni, poi se beneficio sospendere Se non beneficio dopo 2 anni sospendere VALUTAZIONE: Clinica (riduzione dei sintomi e dei farmaci)

PROS: Preventing reactions Avoiding severe reactions Diminishing reactions’intensity CONS: May mask symptoms’ onset May delay appropriate treatment PREMEDICATION: ?

JACI 2016

EFFETTI “SPECIALI” DELL’AIT Efficacia a lungo termine dopo la sospensione Prevenzione di nuove sensibilizzazioni Riduzione del rischio di insorgenza di asma Modificazione della risposta immunitaria

Passalacqua G. Ann Allergy Asthma Immunol. 2011;107:401– 406. AIT: carry-over EFFECT

AUTHOR (ref)ALLERGENPATIENTSDURATION SITLONG-LASTING EFFECT Mosbech (36)Grass2.5 years6 years Grammer (37)Ragweed61 adult/children 4 months2 years Hedlin (38)Cat/dog32 adult/chidren 3 years5 years Des Roches (39)Mite40 adult1-4 years3 years Ariano (40)Parietaria35 adult4 years Durham (41)Grass52 adult3-4 years3 years Eng (43)Grass25 children3 years12 years

Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study Jacobssen, Allergy 2007

PREVENTIVE EFFECTS OF SUBLINGUAL IMMUNOTHERAPY IN CHILDHOOD. AN OPEN RANDOMIZED CONTROLLED STUDY MAURIZIO MAROGNA MD 1, D.TOMASSETTI 1, A. BERNASCONI 1, F.COLOMBO 1, ALESSANDRO MASSOLO BS 2, A. DI RIENZO BUSINCO 4, GIORGIO W CANONICA MD 3, GIOVANNI PASSALACQUA MD 3 AND SALVATORE TRIPODI MD 4 1 Pneumology Unit, Cuasso al Monte, Macchi Hospital Foundation, Varese 2 Department of Animal Biology, University of Pavia, Pavia 3 Allergy & Respiratory Diseases,Department of Internal Medicine, Genoa University 4 Pediatric Allergy Unit, S. Pertini Hospital, Rome AAAI 2008, 101: 261

CONTROLS NS *** baseline3rd year PERSISTENT ASTHMA % PATIENTS SLIT *** baseline3rd year MONOSENSITIZED PATIENTS % PATIENTS

ADMINISTRATION Liposomes Intralymphatic (ILIT) Epicutaneous (EPIT) Biolistic injection Mucoadhesive substances ADJUVANTS Alum-alginates Bacterial wall derived DNA-adjuvants RECOMBINANT/ ENGINEERED Recombinant purified Hypoallergenic isoforms Peptides Chimeric proteins (constructs) GENIC VACCINATION c-DNA Plasmids Replicons NEW INDICATIONS Food allergy Latex Atopic dermatitis Nickel? New approaches for Immunotherapy Milk Egg Peanut

Passalacqua G, Canonica GW. WAO J 2015

Azione rapida Effetto preventivo Effetti collaterali Costo Lunga durata NO SI NO ALTO SIT SI BASSO NO FARMACI

CONCLUSIONI Farmacoterapia e immunoterapia hanno meccanismi diversi Il loro effetto è additivo L’ITS consente un risparmio di farmaci sintomatici L’ITS ha effetti preventivi e a lungo termine che i farmaci non hanno L’ITS agisce contemporaneamente su naso e bronchi FARMACI E ITS NON SONO MUTUAMENTE ESCLUSIVI