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 clinicaall’allergene stesso.

L’immunoterapia allergene specifica è un vaccinoa tutti gli effetti

La via tradizionale di somministrazione è quella iniettivasottocutanea (SCIT), ed è disponibile in alternativa anche la via sublinguale

Leonard Noon 1877-1913

NOON

1928 1960

Uso empirico

1986 2005

Studi randomizzati

ISHIZAKA

IgE

1986 2005

SLITPeptidi Allergeni

ricombinantiLiposomi,Adiuvanti

DNA-Based

ITS

AllergoidiTh1/Th2

1990

Meccanismi

DURHAM

ROMAGNANI

1998

WHOPos Pap

Rands DA. Anaphylactic reaction to desensitization for allergic rhinitis and astmaBr 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 vaccinesBr Med J 1986; 293:948

26 fatalities since 1957 certainly due to IT11 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 vaccinesDesensitizing vaccines

BMJ 198626 deaths due to SCIT

Non-injection routes for immunotherapyNon-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 second updateJACI 2007

WHO Pos Pap. Therapeutical vaccines for allergic diseasesAllergy 1998

L'ITS e' mirata invece 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

Passalacqua G, Canonica GW. Clin Exp Allergy 2011

Cochrane 2010

MEDICATIONS

BHR

Cochrane 2010

SCIT SLIT

Clinical efficacy: Rhinitis Ia Ia

Clinical Efficacy: Asthma Ia Ia

Clinical efficacy: Children (rhinitis)Children (asthma)

IbIb

IaIa

Prevention of new sensitizations Ib IIa

Longterm effect Ib IIa

Prevention of asthma IIb IIb

ARIA Update on immunotherapySR Durham and G.PassalacquaJACI 2007

Aspetti pratici.

In Italia è un “patient named product” (preparato dalla dittaper ciascun paziente dietro indicazione specialistica.

Gli estratti sono standardizzati (ossia è nota la quantità di allergene maggiore e la potenza)

Si effettua una fase di graduale incremento del dosaggio(solitamente 1/sett per 2 mesi), seguita da una fase di mantenimento (1/mese).

Per allergeni pollinici si può effettuare un trattamento pre-stagionale. Per allergeni perenni, il trattamento è continuativo. Durata consigliata 3-5 anni, da sospendere se dopo 2 anni non si ha beneficio.

Mildintermitt.

MildpersistentModerate-

severeintermitt.

Moderate-severe

persistent

Indications

Intermitt.Mild

ModerateSevere

IMMUNOTHERAPY.

RHINITIS

ASTHMA HIGHRISK?

Not cost-effective?

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 sintomi4 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

SLIT (IT in general) for the clinically relevant allergen(s)Preferably one, but in selected cases 2 or 3 extracts.

Verificare ed annotare la dose, l’ora e il sito di iniezioneVisitare il paziente!!!Iniezione sottocutaneaAspirare per escludere di iniettare in un vasoTempo di osservazione 30 minuti

PROS:Preventing reactionsAvoiding severe reactionsDiminishing reactions’intensity

CONS:May mask symptoms’ onsetMay delay appropriate treatment

PREMEDICATION:

1 2 3 4 5 6 7 8 9 10 11 124 5 6 7 8 9 10 11 12

0.2 0.4 0.6 0.2 0.4 0.6 0.2 0.4 0.6 0.8 0.8

settimane

mesi

Flac 1 Flac 2 Flac 3

INDUZIONE O BUILD-UP MANTENIMENTO

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)

•Co-existent uncontrolled asthma (within the UK, presence of asthma is considered a relative contraindication). •Patients taking beta blockers •Patients with other medical/immunological disease •Small children (less than 5 years) •Pregnancy (maintenance injections may be continued during pregnancy) •Patients unable to comply with the immunotherapy protocol

CONTRAINDICATIONS

POSTPONE INJECTION IF:Concurrent ilnessAsthmaExacerbation of allergy

GRADING OF SYSTEMIC REACTIONS1) Nonspecific reactions (likely non IgE-mediated) disomfort, nausea, headache, arthralgia

2) Mild systemic reactions mild rhinitis/asthma (PEF>60%) responding to b2 agonists/antihistamines

3) Non life-threatening systemic reactions Urticaria, angioedema, severe asthma (PEF<60%) Responding well to treatment

4) Anaphylaxis itching, urticaria, bronchospasm, with HYPOTENSION requiring intensive care

Malling & Weeke, Allergy 1993

Lockey RF et al. JACI 1987Period: 1945-1984

46 fatalities

Reid MJ et al. JACI 1993Period 1985-1989

17 fatalities

FATALITIES

FATALITIES: 1/2.000.000 injections

RISK FACTORS

Based on nonfatal reactions

Uncontrolled asthmaSevere asthmaUse of betablockersRush immunotherapyUse of new vialsTechnical errors

Based on fatal reactions

Uncontrolled asthmaSevere asthmaUse of betablockersRush immunotherapyBuild-up phaseUse of new vialsTechnical errors

Estimated incidence of fatalities < 1/2.000.000 injections

COSA OCCORRE:

Adrenalina (iniezione i.m.)Broncodilatatore short actingSteroide orale e i.v.Antistaminico orale e i.v.Set da infusione

OssigenoAmbu

EFFETTI “SPECIALI” DELL’ITS

Efficacia a lungo termine dopo la sospensione

Prevenzione di nuove sensibilizzazioni

Riduzione del rischio di insorgenza di asma

Modificazione della risposta immunitaria

Effect of SIT or ICS on asthmaShaikh et al Clin.Exp.Allergy 1997; 27:1279-84

0123456789

ICSIT

Symptom Score Treatment discontinued

months3 6 9 12 15 18 21 24

AUTHOR (ref) ALLERGEN PATIENTS DURATION SIT LONG-LASTINGEFFECT

Mosbech (36) Grass 2.5 years 6 years

Grammer (37) Ragweed 61 adult/children

4 months 2 years

Hedlin (38) Cat/dog 32 adult/chidren

3 years 5 years

Des Roches (39) Mite 40 adult 1-4 years 3 years

Ariano (40) Parietaria 35 adult 4 years 4 years

Durham (41) Grass 52 adult 3-4 years 3 years

Eng (43) Grass 25 children 3 years 12 years

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

Jacobssen, Allergy 2007

1970tiesORAL IT

1986, Scadding et al1st DBPC trial

1998, firstTablet SLIT

1993. SLIT is Mentioned in anEAACI pos pap

1998: WHOSLIT is accepted

1997, Tari, 1st pediatric trial

2001: ARIAdocument

2004 1st METAANALYSIS

2005: SLIT in children below the age of 5

2005-2009: Large randomized controlled trialsStudies on the mechanism of action

2004: Preventive effectCompliance

20 y

ears

THE LITERATURE

60 RDBPC TRIALS

8 RANDOMIZED OPEN TRIALS

6 COMPARATIVE (SLIT vs SCIT)

5 TRIALS IN OTHER DISEASES

JACI 2010

SCIT SLIT

Clinical efficacy: Rhinitis Ia Ia

Clinical Efficacy: Asthma Ia Ia

Clinical efficacy: Children (rhinitis)Children (asthma)

IbIb

IaIa

Prevention of new sensitizations Ib IIa

Longterm effect Ib IIa

Prevention of asthma IIb IIb

ARIA Update on immunotherapySR Durham and G.PassalacquaJACI 2007 in press

WAO POSITION PAPER 2009ON SUBLINGUAL IMMUNOTHERAPY

Allergy, Dec 2009 WAO Journal, Nov 2009

CHAIRS: GW Canonica, J Bousquet, RF Lockey, T.Casale

Mildintermitt.

MildpersistentModerate-

severeintermitt.

Moderate-severe

persistent

Indications

Intermitt.Mild

ModerateSevere

IMMUNOTHERAPY.

RHINITIS

ASTHMA HIGHRISK?

Not cost-effective?

The optimal maintenance dose has been clearly identified (by dose-ranging studies) only for grass tablets.It is 15-25 mcg major allergen per day (30 times an equivalent SCIT course)

Dose ranging studies are lacking for the remaining alllergens

The efficacy has been anyway proven over a wide range of doses, and therfore the recommendation of the manufacturers should be followed.

   NO BUILD UP 7/60   MAINTENANCE DAILY 31/60MAINTENANCE 3/wk 20/60MAINTENANCE 2/wk 7/60MAINTENANCE 1/wk 2/60   POLLEN CONTINUOUS 8/43POLLEN PRESEASONAL 3/43POLLEN COSEASONAL 3/43POLLEN PRECOSEASONAL

29/43

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

Jan Feb Apr JunMar May JulDec

preseasonal

Pre-coseasonal

Pollen count

coseasonal

   NO BUILD UP 7/60   MAINTENANCE DAILY 31/60MAINTENANCE 3/wk 20/60MAINTENANCE 2/wk 7/60MAINTENANCE 1/wk 2/60   POLLEN CONTINUOUS 8/43POLLEN PRESEASONAL 3/43POLLEN COSEASONAL 3/43POLLEN PRECOSEASONAL

29/43

No fatal or near-fatal event reported since 1986

6 cases of anaphylaxis

SLIT

SLIT: KNOWN SIDE EFFECTS

Local: oral itching-swelling stomach-ache nausea-vomiting

Systemic: Urticaria/angioedemaRhinitisAsthma

Anaphylaxis

Relatively frequent.Usually self-resolve after the first doses without treatment. If persistreduce the dose.

Rare. Give symptomatictreatment and reduce the dose. If persist, stop SLIT

Exceptional. Treat properly and stop SLIT

CONTRAINDICATIONS

Systemic immunological diseases Immunodeficiecies

Malignancies Cardiovascular diseases

Severe/uncontrolled asthma

Age < 5 years (relative contraindication)

Modified from WHO 1998

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

PROBLEM:

Recommendations differ among guidelines

PROBLEM:

The vast majority of patientsare polysensitized

30

60

90

120

150

180

210

240

270

jan feb mar apr may jun jul

300

BIRCH

GRASS

CYPRESS OLIVE

30

60

90

120

150

180

210

240

270

mar apr may jun jul aug sep

300

GRASS

RAGWEED

oct

PARIETARIA

MITE

Vrtala S

Allergy 2008

CONCLUSIONIFarmacoterapia 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

Azione rapida

Effetto preventivo

Effetti collaterali

Costo

Lunga durata

NO

SI

SI

NO

ALTO

SIT

SI

SI

BASSO

NO

NO

FARMACI