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Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry

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Journal Title: Blood
Authors and Corporations: Fioredda, Francesca, Farruggia, Piero, Beccaria, Andrea, Trizzino, Antonino, Notarangelo, LuciaDora, Lanza, Tiziana, Rotulo, Andrea, Ceccherini, Isabella, Guarina, Angela, Grossi, Alice, Verzegnassi, Federico, Mastrodicasa, Elena, Luti, Laura, Barone, Angelica, Russo, Giovanna, Porretti, Laura, Pillon, Marta, Miano, Maurizio, Dufour, Carlo
In: Blood, 134, 2019, Supplement_1, p. 3585-3585
Media Type: E-Article
Language: English
published:
American Society of Hematology
Subjects:
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rft.atitle Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
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rft.issn 0006-4971
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rft.issue Supplement_1
rft.jtitle Blood
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rft.pub American Society of Hematology
rft.date 2019-11-13
x.date 2019-11-13T00:00:00Z
rft.spage 3585
rft.volume 134
abstract <jats:p>Background Autoimmune neutropenia is a chronic reduction of absolute neutrophil below the threshold for age, due to peripheral destruction by specific antibodies (AaN). "Primary autoimmune neutropenia" (pAN) usually appears in early infancy and generally resolve within 18-24 months, while "Secondary autoimmune Neutropenia" (sAN) rises later in life and is usually accompanied by autoimmune features. Very few descriptions on the topic are available in the literature. Aim of the study: to describe from a clinical and immunological point of view a cohort of subjects affected with sAN included registered in the Italian Neutropenia Registry (INR) and to compare these data with those from subjects diagnosed with pAN still in the INR .</jats:p> <jats:p>Patient and methods Subjects with neutropenia and positivity of AaN lasting for more than 2 years in subjects older than 5 years of life ( up to 18) or patients affected with neutropenia (plus AaN) associated with autoimmune features registered in the INR from 2005 to 2018 were considered eligible for the present study. Antibodies against neutrophils were always detected throught indirect test .</jats:p> <jats:p>Results: Data from 40 patients affected with sAN (26 females, 65%) were collected. Median age at diagnosis was of 11.6 years (0-21.558mo) with a median follow up of 17 months (0-159mo). The degree of Neutropenia was mild in 12.5%(5/40), moderate in 35% (14/40) and severe in 52.5% (21/40) Neutropenia was diagnosed by chance in half of the cohort and in only 10% (4/40) (10%) definitively resolved . Neutropenia coexisted with leucopenia in almost all the of subjects (36/40, 88%), and moreover, autoimmune haemolytic anemia and thrombocytopenia was concomitant to neutropenia in 12% (5/40) and 32.5% in (13/40) of cases respectively.</jats:p> <jats:p>As for clinical history, 15% (6/40) subjects (15%) were completely asymptomatic , while the remaining 85% (36/40) (85%) had clinical signs of infections and/or autoimmunity features . Infections were documented in 60% (24/40) (60%) of patients. Severe infections namely sepsis , meningitis, pneumonia, osteomyielitis and broad absesses/flemmons were identified in 21% (5/24) of the group. Other type of infections are listed Figure 1A. Apparently there was no correlation between severity of infections and degree of neutropenia ( p=0.2 Fisher' exact test) Autoimmune features and/or autoimmunity markers were present in 30/40 (75% ) of the entire cohort . Thyroiditis and artralgia/arthritis were the most common signs which accounted both for 17,5% of the total episodes. Positivity of ANA and Direct antibodies test ( DAT) were showed in 42% and 29% of cases respectively. (Fig 1B, 1C)</jats:p> <jats:p>As for immunological characteristic 37% (12/32) of the studied subjects were frankly lymphocytopenic, 19% (6/32) had borderline values , while the remaining 44% (14/32) had normal lymphocytes subclasses. In terms of frequency of sub-classes depletion CD19 + and NK were the most frequently decreased subsets. ( Fig 1D) . Dosage of serum immunoglobulin (IgG, IgM and IgA) were shown for all three classes were abnormal (either increased or diminished) in 74% (28/38) of patients (Fig 1D).</jats:p> <jats:p>Mutation analysis performed by Next Generation Sequencing in 16/40 subjects and pathogenic variants of : TACI, TINF 2, CASP 8, CASP 10, PI3K, CARD 11 genes were identified in 4/16 (25%).</jats:p> <jats:p>As for treatment, in 25 % of cases needed Granulocyte-Colony Stimulating Factor to control infections. Rapamicin, micophenolate mofetil, steroids, intravenous immunoglobulin were necessary in 25% (10/40) of patients cases, being (4 of them were already treated on with G-CSF)</jats:p> <jats:p>Comparison with a group of 236 pAN patients of the INR showed that sAN were older at diagnosis (P&amp;lt;0.0001), had far inferior rate of resolution (P&amp;lt;0,0001), were more frequently leucopenic (p&amp;lt;0,0001), more rarely with monocitosis (p=0.015), had more frequently CD19 and NK depletion (p&amp;lt;0.00019), associated cytopenia and autoimmune symptoms and markers ( p&amp;lt;0.0001) while infection burden were slightly increased but not significantly different compared with pAN( p=0.2).</jats:p> <jats:p>Conclusions This registry study describes the clinical phenotype of sAN appearing in childhood and by comparative analysis shows that sAN substantially differs from pAN. sAN indeed appears an epiphenomenon of a complex immunological disturbances rather than a disease itself. Occasionally mutations of genes of immunodeficiency/disimmunity can be demonstrated</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
authors Array ( [rft.aulast] => Fioredda [rft.aufirst] => Francesca )
Array ( [rft.aulast] => Farruggia [rft.aufirst] => Piero )
Array ( [rft.aulast] => Beccaria [rft.aufirst] => Andrea )
Array ( [rft.aulast] => Trizzino [rft.aufirst] => Antonino )
Array ( [rft.aulast] => Notarangelo [rft.aufirst] => LuciaDora )
Array ( [rft.aulast] => Lanza [rft.aufirst] => Tiziana )
Array ( [rft.aulast] => Rotulo [rft.aufirst] => Andrea )
Array ( [rft.aulast] => Ceccherini [rft.aufirst] => Isabella )
Array ( [rft.aulast] => Guarina [rft.aufirst] => Angela )
Array ( [rft.aulast] => Grossi [rft.aufirst] => Alice )
Array ( [rft.aulast] => Verzegnassi [rft.aufirst] => Federico )
Array ( [rft.aulast] => Mastrodicasa [rft.aufirst] => Elena )
Array ( [rft.aulast] => Luti [rft.aufirst] => Laura )
Array ( [rft.aulast] => Barone [rft.aufirst] => Angelica )
Array ( [rft.aulast] => Russo [rft.aufirst] => Giovanna )
Array ( [rft.aulast] => Porretti [rft.aufirst] => Laura )
Array ( [rft.aulast] => Pillon [rft.aufirst] => Marta )
Array ( [rft.aulast] => Miano [rft.aufirst] => Maurizio )
Array ( [rft.aulast] => Dufour [rft.aufirst] => Carlo )
doi 10.1182/blood-2019-126526
languages eng
url http://dx.doi.org/10.1182/blood-2019-126526
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x.subjects Cell Biology
Hematology
Immunology
Biochemistry
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author Fioredda, Francesca, Farruggia, Piero, Beccaria, Andrea, Trizzino, Antonino, Notarangelo, LuciaDora, Lanza, Tiziana, Rotulo, Andrea, Ceccherini, Isabella, Guarina, Angela, Grossi, Alice, Verzegnassi, Federico, Mastrodicasa, Elena, Luti, Laura, Barone, Angelica, Russo, Giovanna, Porretti, Laura, Pillon, Marta, Miano, Maurizio, Dufour, Carlo
author_facet Fioredda, Francesca, Farruggia, Piero, Beccaria, Andrea, Trizzino, Antonino, Notarangelo, LuciaDora, Lanza, Tiziana, Rotulo, Andrea, Ceccherini, Isabella, Guarina, Angela, Grossi, Alice, Verzegnassi, Federico, Mastrodicasa, Elena, Luti, Laura, Barone, Angelica, Russo, Giovanna, Porretti, Laura, Pillon, Marta, Miano, Maurizio, Dufour, Carlo, Fioredda, Francesca, Farruggia, Piero, Beccaria, Andrea, Trizzino, Antonino, Notarangelo, LuciaDora, Lanza, Tiziana, Rotulo, Andrea, Ceccherini, Isabella, Guarina, Angela, Grossi, Alice, Verzegnassi, Federico, Mastrodicasa, Elena, Luti, Laura, Barone, Angelica, Russo, Giovanna, Porretti, Laura, Pillon, Marta, Miano, Maurizio, Dufour, Carlo
author_sort fioredda, francesca
branch_nrw Electronic Resources
container_issue Supplement_1
container_start_page 3585
container_title Blood
container_volume 134
description <jats:p>Background Autoimmune neutropenia is a chronic reduction of absolute neutrophil below the threshold for age, due to peripheral destruction by specific antibodies (AaN). "Primary autoimmune neutropenia" (pAN) usually appears in early infancy and generally resolve within 18-24 months, while "Secondary autoimmune Neutropenia" (sAN) rises later in life and is usually accompanied by autoimmune features. Very few descriptions on the topic are available in the literature. Aim of the study: to describe from a clinical and immunological point of view a cohort of subjects affected with sAN included registered in the Italian Neutropenia Registry (INR) and to compare these data with those from subjects diagnosed with pAN still in the INR .</jats:p> <jats:p>Patient and methods Subjects with neutropenia and positivity of AaN lasting for more than 2 years in subjects older than 5 years of life ( up to 18) or patients affected with neutropenia (plus AaN) associated with autoimmune features registered in the INR from 2005 to 2018 were considered eligible for the present study. Antibodies against neutrophils were always detected throught indirect test .</jats:p> <jats:p>Results: Data from 40 patients affected with sAN (26 females, 65%) were collected. Median age at diagnosis was of 11.6 years (0-21.558mo) with a median follow up of 17 months (0-159mo). The degree of Neutropenia was mild in 12.5%(5/40), moderate in 35% (14/40) and severe in 52.5% (21/40) Neutropenia was diagnosed by chance in half of the cohort and in only 10% (4/40) (10%) definitively resolved . Neutropenia coexisted with leucopenia in almost all the of subjects (36/40, 88%), and moreover, autoimmune haemolytic anemia and thrombocytopenia was concomitant to neutropenia in 12% (5/40) and 32.5% in (13/40) of cases respectively.</jats:p> <jats:p>As for clinical history, 15% (6/40) subjects (15%) were completely asymptomatic , while the remaining 85% (36/40) (85%) had clinical signs of infections and/or autoimmunity features . Infections were documented in 60% (24/40) (60%) of patients. Severe infections namely sepsis , meningitis, pneumonia, osteomyielitis and broad absesses/flemmons were identified in 21% (5/24) of the group. Other type of infections are listed Figure 1A. Apparently there was no correlation between severity of infections and degree of neutropenia ( p=0.2 Fisher' exact test) Autoimmune features and/or autoimmunity markers were present in 30/40 (75% ) of the entire cohort . Thyroiditis and artralgia/arthritis were the most common signs which accounted both for 17,5% of the total episodes. Positivity of ANA and Direct antibodies test ( DAT) were showed in 42% and 29% of cases respectively. (Fig 1B, 1C)</jats:p> <jats:p>As for immunological characteristic 37% (12/32) of the studied subjects were frankly lymphocytopenic, 19% (6/32) had borderline values , while the remaining 44% (14/32) had normal lymphocytes subclasses. In terms of frequency of sub-classes depletion CD19 + and NK were the most frequently decreased subsets. ( Fig 1D) . Dosage of serum immunoglobulin (IgG, IgM and IgA) were shown for all three classes were abnormal (either increased or diminished) in 74% (28/38) of patients (Fig 1D).</jats:p> <jats:p>Mutation analysis performed by Next Generation Sequencing in 16/40 subjects and pathogenic variants of : TACI, TINF 2, CASP 8, CASP 10, PI3K, CARD 11 genes were identified in 4/16 (25%).</jats:p> <jats:p>As for treatment, in 25 % of cases needed Granulocyte-Colony Stimulating Factor to control infections. Rapamicin, micophenolate mofetil, steroids, intravenous immunoglobulin were necessary in 25% (10/40) of patients cases, being (4 of them were already treated on with G-CSF)</jats:p> <jats:p>Comparison with a group of 236 pAN patients of the INR showed that sAN were older at diagnosis (P&amp;lt;0.0001), had far inferior rate of resolution (P&amp;lt;0,0001), were more frequently leucopenic (p&amp;lt;0,0001), more rarely with monocitosis (p=0.015), had more frequently CD19 and NK depletion (p&amp;lt;0.00019), associated cytopenia and autoimmune symptoms and markers ( p&amp;lt;0.0001) while infection burden were slightly increased but not significantly different compared with pAN( p=0.2).</jats:p> <jats:p>Conclusions This registry study describes the clinical phenotype of sAN appearing in childhood and by comparative analysis shows that sAN substantially differs from pAN. sAN indeed appears an epiphenomenon of a complex immunological disturbances rather than a disease itself. Occasionally mutations of genes of immunodeficiency/disimmunity can be demonstrated</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec>
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spelling Fioredda, Francesca Farruggia, Piero Beccaria, Andrea Trizzino, Antonino Notarangelo, LuciaDora Lanza, Tiziana Rotulo, Andrea Ceccherini, Isabella Guarina, Angela Grossi, Alice Verzegnassi, Federico Mastrodicasa, Elena Luti, Laura Barone, Angelica Russo, Giovanna Porretti, Laura Pillon, Marta Miano, Maurizio Dufour, Carlo 0006-4971 1528-0020 American Society of Hematology Cell Biology Hematology Immunology Biochemistry http://dx.doi.org/10.1182/blood-2019-126526 <jats:p>Background Autoimmune neutropenia is a chronic reduction of absolute neutrophil below the threshold for age, due to peripheral destruction by specific antibodies (AaN). "Primary autoimmune neutropenia" (pAN) usually appears in early infancy and generally resolve within 18-24 months, while "Secondary autoimmune Neutropenia" (sAN) rises later in life and is usually accompanied by autoimmune features. Very few descriptions on the topic are available in the literature. Aim of the study: to describe from a clinical and immunological point of view a cohort of subjects affected with sAN included registered in the Italian Neutropenia Registry (INR) and to compare these data with those from subjects diagnosed with pAN still in the INR .</jats:p> <jats:p>Patient and methods Subjects with neutropenia and positivity of AaN lasting for more than 2 years in subjects older than 5 years of life ( up to 18) or patients affected with neutropenia (plus AaN) associated with autoimmune features registered in the INR from 2005 to 2018 were considered eligible for the present study. Antibodies against neutrophils were always detected throught indirect test .</jats:p> <jats:p>Results: Data from 40 patients affected with sAN (26 females, 65%) were collected. Median age at diagnosis was of 11.6 years (0-21.558mo) with a median follow up of 17 months (0-159mo). The degree of Neutropenia was mild in 12.5%(5/40), moderate in 35% (14/40) and severe in 52.5% (21/40) Neutropenia was diagnosed by chance in half of the cohort and in only 10% (4/40) (10%) definitively resolved . Neutropenia coexisted with leucopenia in almost all the of subjects (36/40, 88%), and moreover, autoimmune haemolytic anemia and thrombocytopenia was concomitant to neutropenia in 12% (5/40) and 32.5% in (13/40) of cases respectively.</jats:p> <jats:p>As for clinical history, 15% (6/40) subjects (15%) were completely asymptomatic , while the remaining 85% (36/40) (85%) had clinical signs of infections and/or autoimmunity features . Infections were documented in 60% (24/40) (60%) of patients. Severe infections namely sepsis , meningitis, pneumonia, osteomyielitis and broad absesses/flemmons were identified in 21% (5/24) of the group. Other type of infections are listed Figure 1A. Apparently there was no correlation between severity of infections and degree of neutropenia ( p=0.2 Fisher' exact test) Autoimmune features and/or autoimmunity markers were present in 30/40 (75% ) of the entire cohort . Thyroiditis and artralgia/arthritis were the most common signs which accounted both for 17,5% of the total episodes. Positivity of ANA and Direct antibodies test ( DAT) were showed in 42% and 29% of cases respectively. (Fig 1B, 1C)</jats:p> <jats:p>As for immunological characteristic 37% (12/32) of the studied subjects were frankly lymphocytopenic, 19% (6/32) had borderline values , while the remaining 44% (14/32) had normal lymphocytes subclasses. In terms of frequency of sub-classes depletion CD19 + and NK were the most frequently decreased subsets. ( Fig 1D) . Dosage of serum immunoglobulin (IgG, IgM and IgA) were shown for all three classes were abnormal (either increased or diminished) in 74% (28/38) of patients (Fig 1D).</jats:p> <jats:p>Mutation analysis performed by Next Generation Sequencing in 16/40 subjects and pathogenic variants of : TACI, TINF 2, CASP 8, CASP 10, PI3K, CARD 11 genes were identified in 4/16 (25%).</jats:p> <jats:p>As for treatment, in 25 % of cases needed Granulocyte-Colony Stimulating Factor to control infections. Rapamicin, micophenolate mofetil, steroids, intravenous immunoglobulin were necessary in 25% (10/40) of patients cases, being (4 of them were already treated on with G-CSF)</jats:p> <jats:p>Comparison with a group of 236 pAN patients of the INR showed that sAN were older at diagnosis (P&amp;lt;0.0001), had far inferior rate of resolution (P&amp;lt;0,0001), were more frequently leucopenic (p&amp;lt;0,0001), more rarely with monocitosis (p=0.015), had more frequently CD19 and NK depletion (p&amp;lt;0.00019), associated cytopenia and autoimmune symptoms and markers ( p&amp;lt;0.0001) while infection burden were slightly increased but not significantly different compared with pAN( p=0.2).</jats:p> <jats:p>Conclusions This registry study describes the clinical phenotype of sAN appearing in childhood and by comparative analysis shows that sAN substantially differs from pAN. sAN indeed appears an epiphenomenon of a complex immunological disturbances rather than a disease itself. Occasionally mutations of genes of immunodeficiency/disimmunity can be demonstrated</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>No relevant conflicts of interest to declare.</jats:p> </jats:sec> Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry Blood
spellingShingle Fioredda, Francesca, Farruggia, Piero, Beccaria, Andrea, Trizzino, Antonino, Notarangelo, LuciaDora, Lanza, Tiziana, Rotulo, Andrea, Ceccherini, Isabella, Guarina, Angela, Grossi, Alice, Verzegnassi, Federico, Mastrodicasa, Elena, Luti, Laura, Barone, Angelica, Russo, Giovanna, Porretti, Laura, Pillon, Marta, Miano, Maurizio, Dufour, Carlo, Blood, Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry, Cell Biology, Hematology, Immunology, Biochemistry
title Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
title_full Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
title_fullStr Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
title_full_unstemmed Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
title_short Secondary Autoimmune Neutropenia: Data from the Italian Neutropenia Registry
title_sort secondary autoimmune neutropenia: data from the italian neutropenia registry
topic Cell Biology, Hematology, Immunology, Biochemistry
url http://dx.doi.org/10.1182/blood-2019-126526