Neutropénies Idiopathiques de l’Adulte - marih.fr · T r a n si tor y n eu tr op en i a 1 ( < 1% ) F ol l ow u p < 1y ea r or l a ck of d a ta 22 /123 ( 17.9% ) C on g en i ta

Neutropénies Idiopathiques de l’Adulte

Dr Flore Sicre de Fontbrune - Nantes - 22 septembre 2017

Neutropénie Idiopathique Chronique de l’Adulte

• PNN < 1,5 G/L

• > 3 mois

• Exclusion des formes secondaires

• Exclusion des formes auto-immunes primitives ie anticorps anti-granuleux

2

Définition Théorique ou Pratique ?


• PNN < 1,5 G/L

• > 3 mois

• Exclusion des formes secondaires

• Exclusion des formes auto-immunes primitives ie anticorps anti-granuleux

3

Définition Théorique ou Pratique ?

En pratique : • Rarement explorés si > 1 G/L • Délai de 3 mois uniquement dans les formes modérées ou sévères

asymptomatiques • Pas de test diagnostique pour les formes ethniques • Différences entre auto-immunes primitives et idiopathiques ?

Neutropénie Auto-Immune Primitive de l’Adulte

4

GIFT GAT

MAIGA


5

Difficultés techniques

GIFT : PNN pts GAT : PNN donneur phénotypés

Faux positifs

Anti HLA I Complexes immuns

GCSF Grossesse

Faux négatifs

Faible sensibilité (titre/affinité)

MAIGA

Test + mais Ag non identifié


6

Difficultés techniques

GIFT : PNN pts GAT : PNN donneur phénotypés

Faux positifs

Anti HLA I Complexes immuns

GCSF Grossesse

Faux négatifs

Faible sensibilité (titre/affinité)

MAIGA

Test + mais Ag non identifié

NEUTROPÉNIE AUTO-IMMUNES PRIMITIVES

& NEUTROPÉNIES IDIOPATHIQUES ADULTES

Epidémiologie similaire (adulte) Démarche diagnostique similaire

Prise en charge thérapeutique similaire Pas de données objectives pour les différencier


Epidémiologie = maladie rare

Dale D. – The severe Chronic Regsitry International Registry, 10 years FU - Supportive Cancer Therapy 2005

PNN < 0,5G/L, > 3 mois, non exhaustif - 1163 patients sur 35 pays

Nette prépondérance féminine


Epidémiologie

Dale D. – un update on the diagnosis and treatment avec CIN – Current opinion in Hematology 2017

CIN + AIN


Epidémiologie

Registre Français

1993-2014

2134 patients (tout patient signalé)

Sévère Modérée sympto

> 3 mois FU > 1 an

178 pts

Primitive

108

797 constitutionnelles Age médian 28 21;40

Femme 79%

NCSIA DÉMARCHE DIAGNOSTIQUE PNN < 1.5 G/L isolated

• Familial history

• Clinical evaluation

Clinical & biological evaluation

- Myeloid and lymphoid malignancies

- Secondary immune neutropenia

- Large Granular Leukemia

- Primary immune deficiency

- HIV and HCV infections

Chronic Primary Neutropenia

Evaluate neutrophil antibodies

- Early onset

- Cyclic neutropenia

- Familial history of neutropenia

or myeloid malignancies

- Lymphoedema, warts,

pulmonary disease,

immunodeficiency or

monocytopenia

Suspect

&

Evaluate

Genetic disease

Chronic

Secondary

Neutropenia

Yes

No

Yes

No

Blood 2015

Ethnic neutropenia

- Moderate

- Ancient

- No symptoms

- Ethnical origin

=> surveillance

NCSIA vs neutropénie ethnique ?

≠ neutropénie constitutionnelle

= variation de la normale

Asymptomatique

Pas de test biologique ayant VPP/VPN suffisante

Faisceau d’argument (origine ethnique, NFS antérieures, recul)

Afrique sub-saharienne / Amérique du Nord / Antilles

Moyen Orient

Et probablement toutes les ethnies dans une moindre mesure …

Parfois très profondes (< 0,5 G/L)

NCSIA vs neutropénie ethnique ?

Etude US (<1.5 G/L) : - « Whites » : 0.8 % - « Afro-americans » : 4.5 % - « Mexican- americans »: 0.38 %

Etude Moyen Orient - « Arabs » : 10.7 % - « Arabs bedouins » : 20 % - Ouganda : 30 %

Hsieh, Ann Intern Med 2007

Denic, BMC Blood disorders , 2009

NCSIA vs hémopathie myéloïde

Etude Danoise (NFS prescrites par les MG sur 20% population - > 378 000

pts sur 5,5 ans), prévalence neutropénie

- Aigue < 1.8 G/L : 2 %

- Aigue <1.5 G/L : 0,9 %

- Chroniques < 1.8 G/L : 0,12 %

- Chroniques < 1.5 G/L : 0,06 %

Andersen, J Intern Med 2016




- Aigue < 1.8 G/L : 2 %

- Aigue <1.5 G/L : 0,9 %

- Chroniques < 1.8 G/L : 0,12 %

- Chroniques < 1.5 G/L : 0,06 %

-> Survenue pathologie dans les 4 ans ? maladies auto immunes*, infections virales, hémopathies


Infections virales : VIH +++, HCV, HBV

Hémopathies : LAM, MDS




- Aigue < 1.8 G/L : 2 %

- Aigue <1.5 G/L : 0,9 %

- Chroniques < 1.8 G/L : 0,12 %

- Chroniques < 1.5 G/L : 0,06 %

-> Survenue pathologie dans les 4 ans ? maladies auto immunes*, infections virales, hémopathies


Infections virales : VIH +++, HCV, HBV

Hémopathies : LAM, MDS

Neutropénie aigue ou chronique

- Risque de mortalité accrue dans les 4 ans

- Quelque soit la sévérité

- Augmente avec la sévérité

- PNN < 0.5 G/L = IC 40 % hémopathie 4 ans

NCSIA vs Neutropénies secondaires

Sicre Blood 2015

Etude rétrospective (cohorte prospective) : 108 pts PNN < 0,5 ou < 1 G/L + spt FU médian 8.3 ans

Table S2: Causes of exclusion from the study

Patients excluded

All patients 123

Gender male 37 /123 (30%)

Exclusion reason

Pancytopenia 3 /123 (2.4%)

ANC > 0.5 109/L 39 /123 (31.7%)

Transitory neutropenia 1 (<1%)

Follow up < 1year or lack of data 22 /123 (17.9%)

Congenital neutropenia 14 /123 (11.4%)

Suspected* 11

Confirmed 3

MonoMAC syndrome 1

ELANE mutation 1

G6PC3 mutation 1

Large granular leukemia 14 /123 (11.4%)

Felty's syndrome 4 /123 (3.25%)

Sjogren's syndrome 11 (8.9%)

Systemic lupus erythematosus 2 (1.6%)

Myelodysplastic syndrome 8 (6.5%)

Others 5 (4.0%)

Others hematological malignancies 1

HCV infection 1

HIV infection 1

Drug toxicity 2

Footnotes: in the absence of genetic confirmation, congenital neutropenia was considered when the first

manifestations were reported during infancy (5 patients) and/or when an associated congenital organ dysfunction

(3 patients) was present, when neutropenia was diagnosed in a first degree relative (1 patient) or when an

immune deficiency was associated (2 patients).

Exclus 123 patients


• Neutropénies médicamenteuses

• Neutropénies AI associées aux hémopathies lymphoïdes

• LLC

• LNH B bas grade

Schivdel, Ann Hematol 2013

Visco, Am J Hematol 2014

Rare Anti PNN ou chronic T cell lymphocytosis (Rustagi, BJH 1987) Complications infectieuses, pronostique sévère (EVANS)


• Lupus érythémateux disséminé

• Syndrome de Goujerot Sjogren

• Thyroïdite auto-immunes

• ANCA

Lupus Erythémateux Disséminé

• 3 études de prévalence

• Neutropénie modérée ++

• 25-40 % ( def PNN < 1.5-2.5 G/L)

• Neutropénie sévère < 4%

• Associée à l’évolutivité de la maladie

• Association aux infections controversée (TTT IS)

• Réponse GCSF

Linda, Sem Arth Rheum 2014

Syndrome de Goujerot Sjogren

PNN < 1 G/L (10%) : 50% hospitalisation pour infection (vs 9%, p=0.002) Facteur prédictif majeur LNH

NCSIA vs Neutropénies secondaires • Thyroïdites auto-immunes

• Association fréquente ++

• Chronologie variable

• Evolution dissociée

• Lien de causalité ?

• Cases reports ++

• Marqueur d’auto-immunité à rechercher +++

• ANCA

• Neutropénie sévère

• Mécanisme humoral ++

• Association à des vascularites à ANCA rares

• Formes le + souvent cutanées

Antineutrophil Cytoplasmic Antibodies, Autoimmune

Neutropenia, and Vasculitis

Peter C. Grayson, MD1, J. Mark Sloan, MD2, John L. Niles, MD3, Paul A. Monach, MD, PhD1,

and Peter A. Merkel, MD, MPH1

1Vasculitis Center, Section of Rheumatology and the Clinical Epidemiology Unit, Department of

Medicine, Boston University Medical Center, Boston, MA

2Section of Hematology/Oncology, Department of Medicine, Boston University Medical Center,

Boston, MA

3Renal Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA

Abstract

Objectives—Reports of an association between antineutrophil cytoplasmic antibodies (ANCA)

and autoimmune neutropenia have rarely included cases of proven vasculitis. A case of ANCA-

associated vasculitis (AAV) with recurrent neutropenia is described and relevant literature on the

association between ANCA, neutropenia, and vasculitis is reviewed.

Methods—Longitudinal clinical assessments and laboratory findings are described in a patient

with AAV and recurrent episodes of profound neutropenia from December 2008 – October 2010.

A PubMed database search of the medical literature was performed for papers published from

1960 through October 2010 to identify all reported cases of ANCA and neutropenia.

Results—A 49 year-old man developed recurrent neutropenia, periodic fevers, arthritis, biopsy-

proven cutaneous vasculitis, sensorineural hearing loss, epididymitis, and positive tests for ANCA

with specificity for antibodies to both proteinase 3 and myeloperoxidase. Antineutrophil

membrane antibodies were detected during an acute neutropenic phase and were not detectable in

a post-recovery sample, whereas ANCA titers did not seem to correlate with neutropenia. An

association between ANCA and neutropenia has been reported in 74 cases from 24 studies in the

context of drug/toxin exposure, underlying autoimmune disease, or chronic neutropenia without

underlying autoimmune disease. In these cases, the presence of atypical ANCA patterns and other

antibodies were common; however, vasculitis was uncommon and when it occurred was usually

limited to the skin and in cases of underlying toxin exposure.

Conclusions—ANCA is associated with autoimmune neutropenia, but systemic vasculitis rarely

occurs in association with ANCA and neutropenia. The interaction between neutrophils and

ANCA may provide insight into understanding both autoimmune neutropenia and AAV.

© 2011 Elsevier Inc. All rights reserved

Corresponding Author: Peter C. Grayson MD Vasculitis Center, Section of Rheumatology Boston University School of Medicine 72East Concord Street Boston, MA 02118 [email protected] phone: 617-414-2508 Fax: 617-414-2510. Reprint Requests: Peter A.Merkel, MD, MPH Vasculitis Center, Section of Rheumatology Boston University School of Medicine 72 East Concord StreetBoston, MA 02118.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our

customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of

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COMPETING INTERESTS None

NIH Public AccessAuthor ManuscriptSemin Arthritis Rheum. Author manuscript; available in PMC 2012 December 1.

Published in final edited form as:

Semin Arthritis Rheum. 2011 December ; 41(3): 424–433. doi:10.1016/j.semarthrit.2011.02.003.

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Grayson, Semin Arthritis and Rheum 2011

Original article

Antineutrophil cytoplasmic antibody-associated neutropenia

Paul Coppoa,1, David Gheza,1, Vincent Fuentesb, Djaouida Bengoufac, Eric Oksenhendlera,Bruno Triboutd, Jean-Pierre Clauvela, Kaiss Lassouedb,*

aService d’Immuno-Hematologie, Hopital Saint-Louis, ParisbService d’Immunologie, CHU d’Amiens, France

cLaboratoire d’Immunopathologie, Hopital Saint-Louis, ParisdService de Pathologie Vasculaire, CHU d’Amiens, France

Received 14 January 2004; received in revised form 1 July 2004; accepted 31 August 2004

Abstract

Background: Antineutrophil cytoplasmic antibodies (ANCA) can be associated with various disorders. However, their association with

neutropenia has never been reported.

Methods: Nine patients with chronic unexplained neutropenia and ANCA were studied. Clinical charts were extensively analyzed and all

patients underwent hematological and immunological investigations.

Results: All patients (6 women and 3 men) were Caucasian and had a mean age of 49 years (range 16–67 years). All presented with a

neutropenia below 1.5 109/L for more than 6 months. The neutropenia was b0.5 109/L in six cases and moderate in three. There was no

evidence of toxic- or drug-related neutropenia or of ahematological malignancy. Autoimmune anemiaand/or thrombocytopenia werepresent

in five patients. ANCA, with various specificities, were present in all patients. ANCA were associated with various other autoantibodies in

eight patients, including antisurface-neutrophil antibodies in three cases. Four of the six patients with severe neutropenia experienced

infections. Five patients were treated with hematopoietic growth factors, steroids, intravenous immunoglobulins, splenectomy, methotrexate

and/or cyclophosphamide, allowing the neutrophil count to be restored transiently or permanently.

Conclusions: A subset of patients with neutropenia of possible autoimmune origin may develop ANCA. Their detection would provide

strong evidence of an autoimmune mechanism. Neutropenia should be added to the list of ANCA-associated diseases.

D 2004 Elsevier B.V. All rights reserved.

Keywords: Neutropenia; Antineutrophil cytoplasmic antibodies; Autoimmunity

1. Introduction

Antineutrophil cytoplasmic antibodies (ANCA) are

autoantibodies that are directed against different neutrophil

antigens. When detected by immunofluorescence on etha-

nol-fixed human neutrophils, ANCA usually displays three

major patterns: cytoplasmic (cANCA), perinuclear

(pANCA), and atypical (xANCA). The main targets of

ANCA are either myeloperoxydase (MPO) or proteinase 3

(PR3) [1–4], but they may also be directed against

lactoferrin, elastase, cathepsin, lysozyme [5], bactericidal

permeability increasing protein (BPI), and azurocidin [6].

ANCA are observed in a large spectrum of diseases [7–19].

Their specificity can make them a helpful tool in the

diagnosis of primary systemic vasculitides [20]. Anti-PR3

antibodies (Abs) are strongly associated with Wegener’s

diseaseand, to a lesser extent, with microscopic polyarteritis

and necrotizing crescentic glomerulonephritis [7–9]. Anti-

MPO antibodies are often associated with systemic vascu-

litis but can also be found in various autoimmune disorders

and connective tissuediseaseswithout evidenceof vasculitis

[10,11,13,14,16–18]. Other specificity is not considered to

0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved.

doi:10.1016/j.ejim.2004.08.009

* Corresponding author. Serviced’Immunologie, Faculte deMedecine,

3 rue des Louvels, F-80036 Amiens Cedex 1, France. Tel.: +33 3 22 82 79

06; fax: +33 3 22 82 79 07.

E-mail address: [email protected] (K. Lassoued).1 Contributed equally to this work.

European Journal of Internal Medicine 15 (2004) 451–459

www.elsevier.com/locate/ejim

Coppo Eur J Int Med 2011

NCSIA vs Lympho-proliférations LGL

• Caractérisation phénotypique (CMF) :

• LGL T : TCRαβ, CD3+ CD8+ CD4- CD57+.

• LGL NK : CD3-CD8+CD57+CD16+

• Clone T : LGL T, syndrome de Felty

OMS 2008

leucémies à LGL T

lymphoproliférations chroniques NK

Excès de LGL, > 6 mois, sans autre étiologie

Critères diagnostiques n’incluent ni clonalité, ni seuil


Entité clinique :

• 55 – 60 ans

• Splénomégalie, manifestations articulaires (PR atypique)

• Neutropénie (asymptomatique), érythroblastopénie

• Auto-immunité biologique : FR/hypergamma

• Evolution chronique, indolente (mais hétérogène)

Attention aux formes secondaires : • Hémopathies myéloïdes (SMD) • Hémopathies lymphoïdes • Infections virales chroniques • Asplénie


Dinmohamed AG

1ère étude prévalence non biaisée Registre des cancer aux Pays Bas = Exhaustivité > 95%


Dinmohamed AG

1ère étude prévalence non biaisée Registre des cancer aux Pays Bas = Exhaustivité > 95%

Equivalent à prévalence de 1600 cas en France sur 20 ans

NCSIA vs Déficit immunitaire

• DICV • ALPS • CID

• IPEX / CD25 deficiency • Neutropénies sévères congénitales • Syndrome MonoMAC

Euroclass trial, Wehr Blood 2008

NCSIA DÉMARCHE DIAGNOSTIQUE PNN < 1.5 G/L isolated

• Familial history

• Clinical evaluation

Clinical & biological evaluation

- Myeloid and lymphoid malignancies

- Secondary immune neutropenia

- Large Granular Leukemia

- Primary immune deficiency

- HIV and HCV infections

Chronic Primary Neutropenia

Evaluate neutrophil antibodies

- Early onset

- Cyclic neutropenia

- Familial history of neutropenia

or myeloid malignancies

- Lymphoedema, warts,

pulmonary disease,

immunodeficiency or

monocytopenia

Suspect

&

Evaluate

Genetic disease

Chronic

Secondary

Neutropenia

Yes

No

Yes

No

Blood 2015

Ethnic neutropenia

- Moderate

- Ancient

- No symptoms

- Ethnical origin

=> surveillance

Bilan proposé sauf neutropénie ethnique

Frottis

Myélogramme + caryo, pas systématique mais toujours - si < 0,5 G/L (1 G/L pour certains) - Si infection(s) - Si autre anomalie même minime (thrombopénie, macrocytose…)

Phénotype lymphocytaire avec recherche de LGL T & NK et hémopathie

lymphoïde B EPP : hypo ou hypergamma, pic

Sérologies hépatites B, C et VIH

FAN, FR, Anti SSA/SSB, ANCA

BOM pour certains en cas de neutropénie profonde et myélo NC


References Number, type of patients / type of neutropenia

Severity of neutropenia

Ratio F/M Median age (Years)

Clinical auto immunity

AIN explored? AIN Outcome and follow up

Kyle, 19681 & Kyle, 198013 Unicentric

15 (primary, adults)

ANC 0.5-1G/L (n=2) and <0.5 G/L (n=12)

14/1 41 Yes Yes 13% No severe infection Follow up: 15 y

Van der Veen, 198514 Multicentric

49 (primary, adults and children)

ANC 1-1.8 G/L (n=19), 0.5-1 G/L (n=15), <0.5 G/L

(n=15)

31/18 Na, 12 < 20 years including 9 < 10

years

Yes, no autoimmunity

Yes 15% Bacterial infection in 26%

Hartman, 19945 Unicentric

148 (primary & secondary)

ANC< 1.5 G/L Na Na Na Yes 36% Na, biological studies only

Bux, 19917 Multicentric

101 (primary, mainly children) median age 12

months

ANC <1.5 G/L, median ANC 0.250

G/L

Na 12 months No Yes 96% Few severe bacterial infections in primary AIN

Logue, 19914 Multicentric

71 (adults)

ANC <1.5 G/L 51/20 46.2 Na Yes 32% Recurrent infections in 14% (FU unknown).

Dale, 200311 & Dale, 200612 Multicentric

224 (adults) ANC < 0.5 G/L 171/53 Na No Na Na Na

Dancey, 198015 Unicentric

10 (adults)

ANC < 0.5 G/L (n=3), ANC 0.5-2

G/L (n=7)

5/5 49 No No Na No infection and no aphtous stomatitis with a median follow up of 2.2y. Follow up: 2.2 y

Fattizzo, Eur Jour of Intern Med 2015 Multicentric Propsective

76 (primary adults, prospective)

ANC < 1.5 G/L, ANC < 0.5 G/L (n=9)

Median 1.27 G/L

51/33 56 (15-86)

Na Yes 35% Grade 2 infections only in 25% 12 patients : SMD, LGL, HCL FU 5 years

Papadaki, 199916 Unicentric

32 ANC < 0.5 G/L (n=1) ANC 1 – 1.5 G/L

(n=31)

28/4 60 No Yes No Follow up: 7.5 y



Sicre Blood 2015


Sicre Blood 2015



Blood cell count

Sicre Blood 2015

Caractéristiques hématologiques


Blood cell count

Sicre Blood 2015

Caractéristiques hématologiques


Caractéristiques immunologiques

Gammaglobulins


Manifestations associées



Table S4: Severe bacterial infections

Severe bacterial infections

Number of patients with severe bacterial infections

At least 1 27/108 (24.5%)

1 15/108 (13.9%)

2 7/108 (6.5%)

3 5/108 (4.6%)

Total number of severe bacterial infections 45

Abscess/cellulitis 24 (53%)

Pneumonia 7 (15%)

Tonsil phlegmon's 4 (9%)

Pyelonephritis 4 (9%)

Peritonitis 2

Adenitis 2

Osteitis 1

Arthritis 1

Septic shock 2

Intensive care unit admission 3

Table S4: Severe bacterial infections

Severe bacterial infections

Number of patients with severe bacterial infections

At least 1 27/108 (24.5%)

1 15/108 (13.9%)

2 7/108 (6.5%)

3 5/108 (4.6%)

Total number of severe bacterial infections 45

Abscess/cellulitis 24 (53%)

Pneumonia 7 (15%)

Tonsil phlegmon's 4 (9%)

Pyelonephritis 4 (9%)

Peritonitis 2

Adenitis 2

Osteitis 1

Arthritis 1

Septic shock 2

Intensive care unit admission 3

IC 3.7 % 1 y 21 % 5 & 10 y 39 % 20 y




Traitements

Réponse 40%

Médiane 3 mois


Traitements

Evaluation difficile car hétérogénéité des indications - Echec (réfractaire = 4%) - Intolérance (céphalées, douleurs osseuses : fréquent -> baisser la dose) - Epargne du GCSF (peur de l’hémopathie secondaire)

Petites séries le plus souvent de réponses favorables… - Endoxan - Methotrexate - Ciclosporine - Campath, Rituximab - Corticoïdes : réponse fréquente mais cortico-dépendance forte dose - Splénectomie : échecs

Formes réfractaire au GCSF (> 15 jours, 5 à 10 μg/kg/j)

- 4 patientes consécutives - neutropénies très sévères, compliquées infections sévères - idiopathiques 3 / AI 1 - 3 sur 4 réponse rapide (7 à 15 jours), complète au Néoral

50% de réponse


Traitements


Risque leucémique

Cohorte française : Aucune évolution vers LAM / SMD

5 cas rapportés dans la littérature - 1 seul avait reçu du GCSF - 2 : histoire familiale d’hémopathie myéloïde (monoMAC,

SBDS, SMD familial ?)


Neutropénie chronique acquises sévère ou symptomatique :

o BOM si myélogramme de richesse diminuée

o Recherche d’anticorps anti-granuleux

o Bilan de thyroïdite auto immune

o Clone T (recherche)

o Adultes jeunes, pas de NFS antérieure normale,

monocytopenie ou lymphopénie : à discuter GATA2/SBDS

Risque leucémique

www.marih.fr - [email protected]

Centres de référence maladies rares

Associations de patients

Sociétés savantes

Documents

Neutropénies Idiopathiques de l’Adulte - marih.fr · T r a n si tor y n eu tr op en i a 1 ( < 1% ) F ol l ow u p < 1y ea r or l a ck of d a ta 22 /123 ( 17.9% ) C on g en i ta