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

IMMUNOTERAPIA SPECIFICA (AIT) 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)

IgE WHO 1986 1998 2000 ILIT EPIT 2014 2009 2000 UK CSM VIT Th1/Th2 ISHIZAKA LICHTENSTEIN NOON UK CSM FRANKLAND 1st RDBPC trial IgE Randomized trials EMPIRICAL USE VIT Allergoids 1911 1954 1965 1978 1986 SLIT 1st RDBPC trial Th1/Th2 WHO Pos Pap Liposomes Adjuvants ROMAGNANI DURHAM SLIT tablet Allergoids Mechanisms 1986 1998 2000 FOOD ALLERGY Recombinants Peptides SLIT BIG TRIALS ILIT EPIT DNA- ITS Preventive effect ARIA WAO SLIT Pos Pap 2014 2009 2000

Committee on the safety of medicines (CMS) CMS Update Desensitizing vaccines Br Med J 1986; 293:948 26 fatalities since 1957 certainly due to IT 11 of them since 1980

DUBBIA EFFICACIA E SCARSA SICUREZZA 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

( Shamji MH & Durham SR, JACI 2017;140:1485-98 ).

Where does IT preferentially works? INFLAMMATION IgE REACTION Hymenoptera Allergy Seasonal rhinitis Atopic dermatitis Asthma Food Allergy Perennial rhinitis

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

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

SYMPTOM SCORE Cochrane 2010

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 SYMPTOMS MEDICATIONS

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

Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis Durham SR, JACI 2006 > 800 pts

JACI 2013

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)

IMPROVEMENT VS PLACEBO IN THE SLIT BIG TRIALS AUTHOR Frew 2005 Dahl 2006 Durham 2006 Didier 2007 Ott 2008 Wahn 2009 Bufe 2009 Blaiss 2011 Nelson 2011 Wahn 2012 Cox 2012 Nolte 2013 Creticos 2013 Bergmann 2014 Creticos 2014 PTS 350 634 855 628 211 278 253 707 438 207 273 565 784 509 429 ALLER Grass Mite Ragweed SYMPT -29% -30% -21% -28% -33% -24% -26 % -20% -27% -22% -40% DRUGS -32% -38% -28% -24% -34% -20% -26% -18%

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

I fattori da valutare nella prescrizione dell’ITS 1 Il disturbo deve essere IgE - mediato (skin test o RAST positivi) 2 L’allergene responsabile deve essere individuato con sicurezza 3 Valutare 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) 6 È disponibile un vaccino standardizzato? 7 L’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 MOLECULAR DIAGNOSIS SLIT (IT in general) for the clinically relevant allergen(s) Preferably one, but in selected cases 2 or 3 extracts.

jan feb mar apr may jun jul BIRCH CYPRESS OLIVE GRASS 300 270 240 210 180 150 120 90 60 30 jan feb mar apr may jun jul

MITE PARIETARIA GRASS RAGWEED mar apr may jun jul aug sep oct 300 270 240 210 PARIETARIA 180 150 120 GRASS 90 60 RAGWEED 30 mar apr may jun jul aug sep oct

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)

FATALITIES Lockey RF et al. JACI 1987 Period: 1945-1984 46 fatalities Reid MJ et al. JACI 1993 Period 1985-1989 17 fatalities FATALITIES: 1/2.000.000 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 < 1/2.000.000 injections

NEAR FATAL SEVERE ASTHMA ASTHMA (Control) UNCONTROLLED ASTHMA (respiratory failure) SEVERE ASTHMA (Control) UNCONTROLLED ASTHMA

SLIT No fatal event reported since 1986 15 cases of anaphylaxis in 20 years

Primary endpoint The primary efficacy analysis shows a statistically significant reduced risk for asthma exacerbations for both treatment doses versus placebo. Time to first moderate or severe asthma exacerbation Placebo 6 SQ-HDM 12 SQ-HDM N = 834 Vierchow JC et al., EAACI 2014, Abstract N. 414

Stepwise approach to control asthma symptoms and reduce risk Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference REVIEW RESPONSE ASSESS ADJUST TREATMENT Symptoms Exacerbations Side-effects Patient satisfaction Lung function Asthma medications Non-pharmacological strategies Treat modifiable risk factors STEP 5 STEP 4 STEP 3 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Refer for add-on treatment e.g. tiotropium,* anti-IgE, anti-IL5* Med/high ICS/LABA Low dose ICS/LABA** Low dose ICS Other controller options Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* Med/high dose ICS Low dose ICS+LTRA (or + theoph*) Add tiotropium* High dose ICS + LTRA (or + theoph*) Add low dose OCS As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol# RELIEVER • Provide guided self-management education (self-monitoring + written action plan + regular review) • Treat modifiable risk factors and comorbidities, e.g. smoking, obesity, anxiety • Advise about non-pharmacological therapies and strategies, e.g. physical activity, weight loss, avoidance of sensitizers where appropriate • Consider stepping up if … uncontrolled symptoms, exacerbations or risks, but check diagnosis, inhaler technique and adherence first • Consider adding SLIT in adult HDM-sensitive patients with allergic rhinitis who have exacerbations despite ICS treatment, provided FEV1 is >70% predicted • Consider stepping down if … symptoms controlled for 3 months + low risk for exacerbations. Ceasing ICS is not advised. REMEMBER TO... SLIT added as an option GINA 2017, Box 3-5 (1/8) © Global Initiative for Asthma

Passalacqua G, Nowak-Węgrzyn A, Canonica GW. JACI IP 2016 in press Author (year) Patients enrolled Age range Allergen (preparation) Duration % patients with Local AE in the active groups * Dahl (2006) 634 18-65 Grass (tablet) 8 mo Oral itching 46%; Mouth edema 18%; Throat itching 9% Durham (2006) 855 Grass , 3 doses (tablet) 6 mo 75-90, not detailed Didier (2007) 628 18-45 Oral itching 19.7-25.8; Mouth edema 3.2-6.3; Throat itching 9-14.4; Tongue edema 3.2-5.6 Ott (2008) 211 8-65 Grass (solution) 4 mo ** 69%, not detailed. Most AE defined as local Wahn (2009) 278 5-17 5 mo Oral itching 32%; Mouth edema 13%; Throat itching 8% Bufe (2009) 253 5-16 Oral itching 33%; Swollen lips 7%; Throat itching 10% Blaiss (2011) 345 70% overall. Mainly oral itching, oral edema, throat itching, oral swelling. Not detailed Nelson (2011) 439 18-63 83% overall. Oral itching 35%; Mouth edema 8%; Throat itching 30%; swollen tongue 5% Wahn (2012) 207 4-12 Oral itching 72%; Throat itching 11% Cox (2012) 473 82% . Mostly oropharingeal pruritus DeBot (2012) 257 6-18 Mite (solution) 2 years Oral pharyngeal irritation/swelling 11%, gastrointestinal complaints 85% Nolte (2013) 565 18-50 Ragweed, 2 doses(tablet) 1 year Oral itching 19%; Mouth/tongue edema 15%; Throat itching 26%; pharyngeal edema 4.2% Creticos (2013) 784 Ragweed, 3 doses (tablet) Oral/tongue itching 15%; Mouth edema 8%; Throat itching 13% Bergmann (2014) 509 Mite, 2 doses 1 year + follow-up Oral/tongue itching 40%; Mouth/tongue edema 35%; Throat itching 33%; Pharyngeal edema 5% Creticos (2014) 429 18-55 Ragweed (solution) Oral/tongue itching 4%; Mouth edema 6%; Diarrhea/dyspepsia 4% Mosbech (2014) 604 14-65 Mite, 3 doses (tablet) Oral/tongue itching 2-19%; Mouth edema 4-8%; Throat itching 3-7% Maloney (2014) 1,501 5-65 Oral/tongue itching 18%; Mouth edema 13%; Throat itching 23% Wang (2014) 484 14-50 Abdominal pain, swollen tongue, oral pruritus, cheilitis and mouth oedema all mild and more frequent in the active group (no detail) Okamoto (2015) 532 12-64 Cedar (solution) 18 mo Mouth edema 3.8%, stomatitis and troat irritation 1.9%, oral itching 1.1%

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.

SCIT: PRACTICAL ASPECTS 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

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

INDUZIONE O BUILD-UP MANTENIMENTO Flac 1 Flac 2 Flac 3 0.2 0.4 0.6 0.2 0.4 0.6 0.2 0.4 0.6 0.8 0.8 1 2 3 4 5 6 7 8 9 10 11 12 settimane 4 5 6 7 8 9 10 11 12 mesi

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 SLIT 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). 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)

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

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

AIT: carry-over EFFECT Semplificare e tenere conto della diapo della bea Passalacqua G. Ann Allergy Asthma Immunol. 2011;107:401– 406. 55

AAAI 2011

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

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

Allergic Rhinitis & AIT : EAACI Guidelines on Allergen Immunotherapy : Executive Statement

PREDICTIVE BIOMARKERS? PROBLEMS: Allergen extracts are not all standardized Not all products are standardized and supported by clinical trials If 30% of children with ascerteined allergic rhinitis will develop asthma, should we treat all AR children with AIT? PREDICTIVE BIOMARKERS?

Passalacqua G, Canonica GW. WAO J 2015

THANK YOU ! Contact at passalacqua@unige.it