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Mastocitosi nella pratica allergologica quotidiana

Patrizia Bonadonna, Allergologia Azienda Ospedaleira Universitaria Integrata: di Verona

Mast Cells

MASTOCYTOSIS

SKIN LIVER SPLEEN BONE MARROW G-I TRACT LYMPH NODES

gene KIT Receptor for Sterm Cell Factor MUTATION D816V

Pathogenesis

CUTANEOUS MASTOCYTOSIS (80-90%) SYSTEMIC MASTOCYTOSIS

(10-20%)

WHO Classification 2001

• Urticaria Pigmentosa
• Diffuse cutaneous mastocytosis
• Cutaneous Mastocytoma
• Teleangectasia Macularis

Eruptiva Perstans (TMEP) children adults

2/3 of cases

90 % of CM in adults is SM

Cutaneous Mastocytosis

Urticaria Pigmentosa

Darier’s sign

DD: Dermatoghraphism!

MAJOR CRITERIA

Multifocal dense infiltrates

• f mast cells in BM
• r

in other extra-cutaneous

• rgans

MINOR CRITERIA a) Abnormal morphology of extra-cutaneous mast cells (spindle- shaped) b) Increased serum tryptase level (> 20 ng/ml) c) Mutation in the KIT proto-

• ncogene at codon 816

( D816V mutation) in an extra- cutaneous organ d) Expression of CD2 and/or CD25 on BM mast cells

• r

1 MAJOR CRITERION + 1 MINOR CRITERION

Systemic Mastocytosis

DIAGNOSIS:

3 MINOR CRITERIA

MMAS Monoclonal MC Activation Syndrome

“…..with unexplained and /or recurrent anaphylaxis , without skin lesions and without the major criterion but with proof of mast cell clonality”

Sonneck Inter Arch 2007

Patients with 1 or 2 of the MINOR CRITERIA and

K.Brockow Allergy 2008

• T. Gulen Clin Exp Allergy 2013
• D. Gonzales de Olano Cl Exp

Allergy 2007

210 patients 210 patients Triggers of Anaphylaxis in SM patients

Prevalence of Clonal Mast Cells Disorders in Patients with Hymenoptera Venom Allergy

Bonadonna P.Curr Opin Allergy Clin Immunol 2010

379

subjects with

HVA 44 pts TRYPTASE  11.4 34 consented

BM aspiration

BM biopsy

Flow cytometric analysis of MCs KIT MUTATION

Skin, ID and Serum assay for HVA

375 positive 4 negative

10 refused

14/33 42.4% 20/34 58.8% 17/31 54.8% 26/33 78.8%

Bonadonna P. Zanotti R. et al JACI: 2009

88.2%Clonal Mast Cell Diseases

• 61.7% ISM
• 26.5% MMAS

Do patients with venom- induced anaphylaxis and SM have a characteristic phenotype ?

• 4 / 21 ISM = 19% with skin involvement ( UP)

(Bonadonna P et al . JACI 2009 Mar; 123:680-6)

• 5/ 21 ISM = 23% with skin involvement (4 UP +

( De Olano GZ et al JACI 2008 Feb;121: 519-26) 1 TMEP)

Skin Involvement in Patients with Systemic Mastocytosis and HVA

Haematologica 2011 ,96 482-483 MMAS ISMs- ISMs+

Characteristics

4 72 20

Male gender, n° (%)

4 (100)

51 (71%)

11 (55%)

Age at diagnosis, median (range)

59 (52-69) 52 (19-74) 43 (27-60) Grading of Systemic reaction to HV n° (%)

• I
• II
• III
• IV

1 (25) 1 (25) 2 (50) 1 (1) 2 (3) 5 (7)

64 (89%) 20 (100%)

sIgE and skin test for HV, n° (%)

• Vespula
• Polistes
• Apis
• Bombo
• Crabro
• Negative

3 (75) 1 (25) 35 (49) 21 (29) 8 (11) 1 (1) 1 (1)

6 (8%)

7 (35) 7 (35) 3 (15)

3 (15%) basal s-Tryptase, median (range) ng/mL

18.2 (17.4-23.3) 24.0 (8.4-68) 29.6 (9.9-103)

Atypical MC type I >25% of BMMC, n° (%)

2 (50) 51 (71) 19 (95)

BM Multifocal, dense MC aggregates, n° (%)

17 (24%) 11(55%)

BM D816V mutation of KIT, n° (%)

4 (100)° 54/63 (78) 19/19 (100)

BM MCs CD25 pos by flow citometry

• median % of MNC (range)

67/67 (100%)

0.06 (0.003-0.6)

20 (100%)

0.08 (0.008-1.4)

Álvarez-Twose et al., JACI 2013

Distribution of clinical symptoms in between acute episodes

Clinical and laboratory features of patients with insects ISM-

• I. Alvarez Twose, R.Zanotti, P.Bonadonna et al. JACI.2013

Therefore, anaphylaxis in these patients with ISM- and HVA could mainly be related to pathological alterations in mast cell activation processes rather than mast cell numbers per se.

Which patients, in absence of skin involvement and with characteristics that could strongly indicate a Clonal Mast Cell disease would have to undergo a complete haematological work up?

SCORE < 2: low probability of clonal MCAD SCORE  2: high probability of clonal-MCAD Variable score Gender Male +1 Female

• 1

Clinical symptoms Absence of urticaria and angioedema +1 Urticaria and/or angioedema

• 2

Presyncope and/or syncope +3 basal Tryptase <15 ng/mL

• 1

>25 ng/mL +2

• I. Alvarez Twose J Allergy Clin Immunol. 2010

Scoring model proposed by the REMA (Red Española de Mastocitosis)

Sensitivity and Specificity of REMA score in SM patients without skin lesions

• I. Alvarez-Twose, R. Zanotti, P. Bonadonna et al JACI 2013

A Clonal Mast cell Disorder cannot be excluded in subjects with systemic severe HVA, but with normal sBT

Clonal Mast Cell Disorders in Patients with Severe Hymenoptera Allergy and Normal Tryptase

Zanotti R and Bonadonna P. Submitted 2014

22 pts HVA anaphylaxis with :

• No skin lesions
• Anaphylaxis with hypotension
• Basal tryptase ≤ 10.g/l
• BM evaluation( BM smear and biopsy)
• Detection of D816V mutation of KIT
• Flow-cytometry analysis
• REMA scored evaluted

Total n°patients :22

Clonal Mast Cell Disorder (N=16) non-Clonal Mast Cell Disorder (N=6) p Male sex, n° (%) 11 (68.8%) 3 (50.0%) ns Age, median (IQR) 60,5 (15%) 63 (16%) ns Tryptase, median ng/mL (IQR) 8.6 (2.27%) 7.1 (2.33%) 0.033 Allergy test negative n° (%) 1 (6.2%) 1 (16.7%) ns Angiodema + Urticaria n° (%) 2 (12.5%) 5 (83.3%) 0.004 REMA SCORE ≥ 2 REMA SCORE≤ 2 14 (87,5%) 2 (3,2%) 1 (16.7%) 5 ( 83.3%) 0.004

age sBT ng/mL HVA Kit mutation MC CD25 positive (% of BM MNC) >25% atypical BM MC Final Diagnosis 65 9.0 Polistes d neg 0.001 neg MMAS 61 10.8 Vespula D816V 0.210 pos ISM 60 8.4 Polistes d D816V 0.006 pos ISM 64 10 Polistes d D816V 0.032 pos ISM 63 8.9 Polistes d D816V 0.002 pos ISM 65 10.7 Vespula D816V 0.078 pos ISM 50 7.8 Vespula D816V 0.006 pos ISM 51 8.0 Crabro D816V 0.040 pos ISM 52 7.2 Polistes d D816V 0.004 pos ISM 51 6.6 Vespula D816V 0.001 pos ISM 39 9.4 Polistes d D816V 0.030 pos ISM 66 7.5 Vespids D816V 0.009 pos ISM 35 4.2 Vespula D816V 0.002 pos ISM 67 11.2 Vespula D816V 0.004 pos ISM 42 8.3 Apis D816V 0.023 pos ISM 74 8.8 Vespula D816V 0.130 pos ISM 55 4.0 Vespids neg 0.000 neg non-CMD 69 7.9 Vespula neg 0.000 neg non-CMD 54 8.5 Vespula neg 0.000 neg non-CMD 61 7.7 Vespula neg 0.000 neg non-CMD 65 6.3 Crabro neg 0.000 neg non-CMD 75 6.5 Apis neg 0.000 neg non-CMD

In all cases of ISM the diagnosis was based only on minor criteria, since the major criterion was not present at BM biopsy.

Flow cytometry : atypical BM Mast cells that co- express CD25 and CD2 Flow cytometry : atypical BM Mast cells that co- express CD25 and CD2

CD25+ CD2+ CD25- CD2-

• gc. Dr. Omar Perbellini

Multiparametric study CD45/CD34/CD117/CD25/CD2

Escribano L, 1998, Blood,91:2731-36 Sánchez-Muñoz L et al Methods Cell Biol. 2011;103:333-59 Perbellini O et al Cytometry B Clin Cytom. 2011;80:362-8

Management of patients with HVA and Mastocytosis

Skin test: sensitivity > 90%

specificity > 90%

Diagnosis

Specific IgE

• Is it possible and safe to perform skin

tests in Mastocytosis patients with HVA? YES 92 ISM : No Reaction Prick test:100 mcg/ml

Intradermal Test: 0,001- 0,01-0,1-1 mcg/ml

Skin / intradermal and serological tests

375 POSITIVES

Tryptase  11.4 ng/ml 3 ISM 1 MMAS

NEGATIVES

4

JACI 2009 123: 680-686

Diagnostic tests negative in patients with Systemic Mastocytosis and HVA

379 pts

Basophil histamine release test could be a suitable diagnostic option in skin testing and sIgE - negative patients with mastocytosis

2009 2009

• None of the patients had adverse reactions to the skin tests. (Prick

e ID)

• Increasing dilution to 10 mcg it is not useful in the diagnosis

45 positive specific and /or

skin tests

45 positive specific and /or

skin tests

7 negative

( ID 10 mcg: 4 pos all extracts)

7 negative

( ID 10 mcg: 4 pos all extracts) 6 controls : SM pts ,No reactions, tests negative 6 controls : SM pts ,No reactions, tests negative

63 SM

52 Systemic Reactions 11 LLR

63 SM

52 Systemic Reactions 11 LLR

Results in negative patients

• The use of a concentration of 10 μg/ml for IDTs

is useless

• BAT test did not add valuable information

Venom Immunotherapy

Venom Immunotherapy in Patients with Clonal Mast Cell Disorders: Efficacy, Safety and Practical Considerations.

Multidisciplinary Mastocytosis Outpatient Clinic

Verona, Italy

Spanish Network on Mastocytosis REMA Allergy accepted

Demographic Characteristics:

Total Population (%) Italian vs Spanish p Patients

84 45 39

/ Mean age [range] 51.2 [26-81] 53.2 [29-81] 49.8 [26-77] ns Male 70 (83%) 37 (82%) 33 (84%) ns Diagnosis SM ISM+ skin lesions 12 (14%) 7 (15%) 5 (13%) ns ISM- skin lesions 65 (77%) 35 (77%) 30 (77%) MMAS 7 (9%) 3 (8%) 4 (10%) Severity reactions to 1 st sting Grade 1 1 (1.2%) 1 (2.3%) ns Grade 2 7 (8.3%) 3 (6.7%) 4 (10%) Grade 3 8 (9.5%) 8 (20%) Grade 4 68 (81%) 41 (91%) 27 (70%) Grade 4 + loss of consciousness 53 (63%) 32 (71%) 21 (54%) ns

Demographic Characteristics:

Total Population (%) Italian vs Spanish p Patients 84 45 39 / Mean age [range] 51.2 [26-81] 53.2 [29-81] 49.8 [26-77] ns

Male 70 (83%) 37 (82%) 33 (84%) ns

Diagnosis SM ISM+ skin lesions 12 (14%) 7 (15%) 5 (13%) ns ISM- skin lesions 65 (77%) 35 (77%) 30 (77%) MMAS 7 (9%) 3 (8%) 4 (10%) Severity reactions to 1 st sting Grade 1 1 (1.2%) 1 (2.3%) ns Grade 2 7 (8.3%) 3 (6.7%) 4 (10%) Grade 3 8 (9.5%) 8 (20%) Grade 4 68 (81%) 41 (91%) 27 (70%) Grade 4 + loss of consciousness 53 (63%) 32 (71%) 21 (54%) ns

Male/Female

70/84 (83)

Demographic Characteristics:

Total Population (%) Italian vs Spanish p Patients 84 45 39 / Mean age [range] 51.2 [26-81] 53.2 [29-81] 49.8 [26-77] ns Male 70 (83%) 37 (82%) 33 (84%) ns Diagnosis SM

ISM+ skin lesions 12 (14%) 7 (15%) 5 (13%)

ns

ISM- skin lesions 65 (77%) 35 (77%) 30 (77%) MMAS 7 (9%) 3 (8%) 4 (10%)

Severity reactions to 1 st sting Grade 1 1 (1.2%) 1 (2.3%) ns Grade 2 7 (8.3%) 3 (6.7%) 4 (10%) Grade 3 8 (9.5%) 8 (20%) Grade 4 68 (81%) 41 (91%) 27 (70%) Grade 4 + loss of consciousness 53 (63%) 32 (71%) 21 (54%) ns

Demographic Characteristics:

Total Population (%) Italian vs Spanish p Patients 84 45 39 / Mean age [range] 51.2 [26-81] 53.2 [29-81] 49.8 [26-77] ns Male 70 (83%) 37 (82%) 33 (84%) ns Diagnosis SM ISM+ skin lesions 12 (14%) 7 (15%) 5 (13%) ns ISM- skin lesions 65 (77%) 35 (77%) 30 (77%) MMAS 7 (9%) 3 (8%) 4 (10%)

Severity reactions 1 st sting Grade 1 1 (1.2%) 1 (2.3%) ns Grade 2 7 (8.3%) 3 (6.7%) 4 (10%) Grade 3 8 (9.5%) 8 (20%) Grade 4 68 (81%) 41 (91%) 27 (70%) loss of consciousness 53 (63%) 32 (71%) 21 (54%) ns

Demographic Characteristics:

Total Population (%) Italian vs Spanish p Patients 84 45 39 / Mean age [range] 51.2 [26-81] 53.2 [29-81] 49.8 [26-77] ns Male 70 (83%) 37 (82%) 33 (84%) ns Diagnosis SM ISM+ skin lesions 12 (14%) 7 (15%) 5 (13%) ns ISM- skin lesions 65 (77%) 35 (77%) 30 (77%) MMAS 7 (9%) 3 (8%) 4 (10%)

Severity reactions 1 st sting Grade 1 1 (1.2%) 1 (2.3%) ns Grade 2 7 (8.3%) 3 (6.7%) 4 (10%) Grade 3 8 (9.5%) 8 (20%) Grade 4 68 (81%) 41 (91%) 27 (70%) loss of consciousness 53 (63%) 32 (71%) 21 (54%) ns

Safety: Reactions During Build-up Phase

VIT protocols: Conventional Rush modified Rush 24 57 3

LLR

2 pts 4 pts I 1 pt II 2 III 1 IV

Reaction Severity

10 adverse reactions = 12% of patients but only 4.7% had systemic reactions!

• Honeybee VIT was used in 3 out of 4 systemic reactions
• No pts. had reactions during maintenance

p:0,73

Efficacy: Reactions in Case of Field Re- Stings

Spanish Population Italian Population Total patients Restung 24 26 Total sting Number 52 38 Number Reactions 3 4

50 ( 59.5%) patients received a total of 95 Hymenoptera stings

7 reactions

43 pts (86%) 5 pts (10%) 2 pts (4%)

VIT conferred full protection in 86% of patients!

Pts who died despite VIT had stopped immunotherapy and died afterwards

It is recommended continue VIT for life

Immunotherapy: how long?

( Oude Elberink JNK JACI 1997)

• Provide these patients with an

emergency kit with EPINEPHRINE and explain how to use it

How many adrenaline auto-injectors ?

15-32% pts require a further dose of i.m. adrenaline after first administration

• A. Muraro EAACI anaphylaxis guidelines Allergy 2014

HYMENOPTERA

ANAPHYLAXIS

FOOD

ANAPHYLAXIS

DRUG

ANAPHYLAXIS N°

244 51 86

Male/female

173/71

29/22*

28/58 **

Mean age

43

43

42

Grade III (%)

120 (49.2)

27 (52.9%)

13 (15.1%)**

Grade IV (%)

124 (50.8)

24 (47.1%)

73 (84.9%) **

Full-blown anaphylaxis (%)

59 (24.2)

17 (33.3%)

35 (40.7%)

Tryptase ng/mL, mean ± SD

7.7 ± 10.8

4.9 ± 2.6

6.6 ± 4.8

Raised serum tryptase (%)

34 (13.9) 2 (3.9%) * 7 (8.1)

Clonal mast cell disorder in BM tested patients (%)

27/28 (96.4) 1/2 (50) * 1/5 (20.0)**

Clonal mast cell disorder (%)

27/244 (11.1) 1/51 (2.0)* 1/86 (1.2)**

(P.Bonadonna R .Zanotti et al Allergy 2009)

How to manage patients with mastocytosis and who have to take drugs??

Male / Female 72/28%

210 patients

(163 adults 47 children) Asthma Rhinitis Conjunctivitis Atopic Dermatitis Urticaria Anaphylaxis 7.3% (12) 31.2% (51) 24.5% (40) 2.4% (4) 25.7% (42) 22% (36) Unknown Hymenoptera Drugs 9 (25%) Food Etiology

NSAIDs (n= 4) β-lactams (n= 2) Streptomycin (n= 1) Phenylephrine (n= 1) Anesthesia (N= 1)

K.Brockow 2008

• NSAID (n=3)
• Contrast Media (n=2)
• Amoxicillin ( n=1)
• Codeine (n=1)
• Local Anaesthetic (n=1)

18%

T.Gulen Clin Exp Allergy 2013

5% = 2 reactions to Diclofenac 36/84 ( 43%) SM pts had had at least one episode of Anaphylactic Reactions

NSAID Non Steroidal Antinflammatory Drugs:

• NO in pts. with previous reactions
• YES in pts. who tolerated NSAID ( after the diagnosis of

mastocytosis)

• YES Oral provocation test
• PARACETAMOL is a safe alternative choice
• The frequency of adverse reactions to NSAIDs in

patients with mastocytosis is estimated as higher than in general population

• There are no epidemiological studies to support

this statement

MAST CELL DISEASES AND USE OF ANTIBIOTICS

• NO in pts. with previous reactions
• YES in pts. who tolerated Antibiotics ( after

the diagnosis of mastocytosis)

• YES Oral provocation test
• Clarithromycin seems to be is a safe

alternative choice

• Anestesiology. 2013 Oct 16

Mastocytosis et anesthesie: Centre National de References des Mastocytoses

Mastocytosis Networks

Spanish Network of Mastocytosis : REMA ( Red Espagnola Mastocitosis ) Italian Network of Mastocytosis: RIMA ( Rete Italiana Mastocitosi)

Recommendations on Anaesthesia

Prior to anaesthesia  Ideally, individual risk should be evaluated in all patients prior to surgery and anaesthesia, in a multidisciplinary setting with haematology, dermatology, anaesthesiology and allergist experts Continue regular antimediator therapy for mastocytosis Patients with suspected reactions during previous anaesthesia or suspected drug allergies should ideally be investigated with skin and in vitro tests to identify responsible allergens

Recommendations on Anaesthesia

Prior to anaesthesia

• Antihistamines, H1 (Clorfenamina 10mg i.m o e.v)

and H2 (Ranitidina 100 mg e.v) blockers to reduce histamine release

• Benzodiazepines to reduce anxiety/psychological

stress

• Hydrocortisone 100 mg or methylprednisolone 125

to dampen immune response

• Other drugs such as Montelukast, Cromoglycate can

be considered

In children the evidence shows that premedication is not necessary Children with extensive skin disease should be anaesthetized with caution (yes to premedication) Use of premedication

(Carter MC Anesth Analg 2008: 22 children from National Institute of Health - Bethesda)

Recommendations during the Anaesthesia

During the anaesthesia  Continue the monitoring the blood pression better not use the armlet  Prudence recommends administration of incremental dose infusion rather than single boluses

• f needed drugs (opioids, muscle relaxants) known

to activate mast cells  Sudden temperature changes in patients and the

• perating room, infusion of cold solutions, wide

tissue trauma, frictions and other mechanical factors should all be avoided

PERIOPERATIVE DRUGS LOW RISK AVOID (if it is possible) Intravenous analgesics Opioids Fentanyl Morphine Sulfentanyl Codein Remifentanyl Alfentanyl Analgesic Paracetamol (acetaminophen) General Anaesthetics Hypnotics Propofol Thiopental Etomidate Ketamina Benzodiazepine Midazolam Halogenated gases and nitrous oxide Desflurane Isoflurane Sevoflurane Nitrous oxide Neuromuscular Blocking Agents Depolarizing NMBA Succinylcholine Nondepolarizing steroidal NMBAs Pancuronium Rocuronium Vecuronium Nondepolarizing benzylisoquinolin NMBAs Cis-atracurium Atracurium Mivacurium Anticholinergic Atropine Plasma substitutes Cristalloids Gelatine Albumin Local Anaesthetics Amide-type

Multidisciplinary Mastocytosis Outpatient Clinic (VR, Italy)

Local Anesthetic: Lidocaine Tot 363 168 ISM+ 179 ISM- 16 MMAS

• No Allergic Reaction
• 3 Vaso -Vagal Syndromes
• 10 Premedicated ( with anti H1 +H2)

(unpublished data)

Radio Contrast Media and Mastocytosis

Studied mastocytosis Patients N (%) of patients with drug hypersensitivity N (%) of patients with RCM hypersensitivity Gonzales de Olano (2007) 163 adults; 47 children 9 adults (25%) None Alvarez-Twose (2012) 111 children 4 (3.6 %) None Brockow (2008) 74 adults 46 children 8 adults (22%) 2 adults (25%)

YES Premedication !

Allergy Unit Patrizia Bonadonna, Carla Lombardo Haematology Roberta Zanotti, Massimiliano Bonifacio, Anna Artuso Dermatology Donatella Schena Laboratory Beatrice Caruso Pathology Alberto Zamò - Chiara Colato Gastroenterology Morena Tebaldi Pediatrics Ada Zaccaron Molecolar Biology Giovanna De Matteis Immunology Giovanna Zanoni

Multidisciplinary Mastocytosis Outpatient Clinic Multidisciplinary Mastocytosis Outpatient Clinic

Aenesthesia Alessandro Bisoffi Varani Reumathology Marta Biondan; Maurizio Rossini Cytofluorimetry Omar Perbellini, Francesca Zoppi, Francesca Zampieri