More about Macrophage Activation Syndrome

[Guest guest]

Macrophage activation syndrome in children with systemic-onset juvenile

chronic arthritis.

Acta Haematol. 2005;113(2):124-9.

Kounami S, Yoshiyama M, Nakayama K, Okuda M, Okuda S, Aoyagi N, Yoshikawa N.

Departmentof Pediatrics, Wakayama Medical University, Kimiidera, Wakayama

City, Japan. nami@...

Macrophage activation syndrome (MAS) is a life-threatening complication in

children with rheumatic diseases, particularly systemic-onset juvenile

chronic arthritis (SOJCA). Because of the potential fatality of this

condition, prompt recognition and immediate therapeutic intervention are

important.

This study assessed the clinical features of nine MAS events in five

children with SOJCA. Nonremitting fever and decreased platelet and white

blood cell counts led to a diagnosis of MAS. The urinary beta2-microglobulin

(beta2MG) level was a sensitive indicator of MAS. Serum levels of beta2MG

and soluble interleukin-2 receptor were also elevated. These biologic

markers reflecting hyperactivated cellular immunity are useful indicators of

MAS.

Four children treated with cyclosporin A (CSP) achieved rapid and complete

recovery, but one patient without CSP died due to rapidly progressive

respiratory failure. All children treated with CSP responded quickly, and

fever abated within 36 h of initiation of treatment. CSP should be added to

first-line therapy of MAS.

Copyright 2005 S. Karger AG, Basel

PMID: 15802891 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

[Macrophage activation syndrome associated with systemic juvenile

idiopathic arthritis]

J Pediatr (Rio J). 2004 Nov-Dec;80(6):517-22.

Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A, CM,

Kiss MH.

Faculdade de Medicina, Universidade de Sao o, FMUSP, Sao o, SP.

clovisaas@...

OBJECTIVE: To describe the characteristics of macrophage activation

syndrome associated with juvenile idiopathic arthritis.

DESCRIPTION: This is a retrospective study involving 462 patients with

juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered from

systemic onset juvenile idiopathic arthritis and developed macrophage

activation syndrome. The median age of the juvenile idiopathic arthritis

onset was 3 years and 10 months and the median duration of juvenile

idiopathic arthritis before macrophage activation syndrome was 8 years and 4

months.

All of them presented with fever, jaundice, hepatosplenomegaly, bleeding,

pancytopenia, abnormal liver function tests and abnormal coagulation

profile. Three cases presented associated infections and one patient

developed macrophage activation syndrome two weeks after the administration

of sulfasalazine. Three patients died and the macrophage hemophagocytosis

was present in five.

The treatment of macrophage activation syndrome included pulse therapy

with methylprednisolone in all of them, cyclosporine A in three, plasma

exchange in two and intravenous immunoglobulin in two.

COMMENTS: Macrophage activation syndrome is a complication of the systemic

onset juvenile idiopathic arthritis with a high morbidity and mortality

rate.

PMID: 15622430 [PubMed - indexed for MEDLINE]

-----------------------------------------------------------

Natural killer cell dysfunction is a distinguishing feature of systemic

onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Arthritis Res Ther. 2005;7(1):R30-7. Epub 2004 Nov 10.

Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A, Grom

AA. 1Division of Hematology/Oncology, Children's Hospital Medical Center,

Cincinnati, Ohio, USA.

Macrophage activation syndrome (MAS) has been reported in association with

many rheumatic diseases, most commonly in systemic juvenile rheumatoid

arthritis (sJRA). Clinically, MAS is similar to hemophagocytic

lymphohistiocytosis (HLH), a genetic disorder with absent or depressed

natural killer (NK) function. We have previously reported that, as in HLH,

patients with MAS have profoundly decreased NK activity, suggesting that

this abnormality might be relevant to the pathogenesis of the syndrome. Here

we examined the extent of NK dysfunction across the spectrum of diseases

that comprise juvenile rheumatoid arthritis (JRA).

Peripheral blood mononuclear cells (PBMC) were collected from patients

with pauciarticular (n= 4), polyarticular (n = 16), and systemic (n = 20)

forms of JRA. NK cytolytic activity was measured after co-incubation of

PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell receptor

[TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells were

also assessed for perforin and granzyme B expression by flow cytometry.

Overall, NK cytolytic activity was significantly lower in patients with sJRA

than in other JRA patients and controls. In a subgroup of patients with

predominantly sJRA, NK cell activity was profoundly decreased: in 10 of 20

patients with sJRA and in only 1 of 20 patients with other JRA, levels of NK

activity were below two standard deviations of pediatric controls (P =

0.002). Some decrease in perforin expression in NK cells and cytotoxic T

lymphocytes was seen in patients within each of the JRA groups with no

statistically significant differences. There was a profound decrease in the

proportion of circulating CD56bright NK cells in three sJRA patients, a

pattern similar to that previously observed in MAS and HLH. In conclusion, a

subgroup of patients with JRA who have not yet had an episode of MAS showed

decreased NK function and an absence of circulating CD56bright population,

similar to the abnormalities observed in patients with MAS and HLH. This

phenomenon was particularly common in the systemic form of JRA, a clinical

entity strongly associated with MAS.

PMID: 15642140 [PubMed - indexed for MEDLINE]

------------------------------------------------------

Macrophage activation syndrome and reactive hemophagocytic

lymphohistiocytosis: the same entities?

Current Opinion in Rheumatology. 15(5):587-590, September 2003.

Grom, ei A. MD

Abstract:

Purpose of the review: One of the most perplexing features of systemic-onset

juvenile rheumatoid arthritis is the association with macrophage activation

syndrome, a life-threatening complication caused by excessive activation and

proliferation of T cells and macrophages. The main purpose of the review is

to summarize current understanding of the relation between macrophage

activation syndrome and other clinically similar hemophagocytic disorders.

Recent findings: Clinically, macrophage activation syndrome has strong

similarities with familial and virus-associated reactive hemophagocytic

lymphohistiocytosis. The better understood familial hemophagocytic

lymphohistiocytosis is a constellation of rare, autosomal recessive immune

disorders. The most consistent immunologic abnormalities in patients with

familial hemophagocytic lymphohistiocytosis are decreased natural killer and

cytotoxic cell functions. In approximately one third of familial

hemophagocytic lymphohistiocytosis patients, these immunologic abnormalities

are secondary to mutations in the gene encoding perforin, a protein that

mediates cytotoxic activity of natural killer and cytotoxic CD8+ T cells.

Several recent studies have suggested that profoundly depressed natural

killer cell activity and abnormal levels of perforin expression may be a

feature of macrophage activation syndrome in systemic-onset juvenile

rheumatoid arthritis as well. Although it has been proposed that in both

hemophagocytic lymphohistiocytosis and macrophage activation syndrome,

natural killer and cytotoxic cell dysfunction may lead to inadequate control

of cellular immune responses, the exact nature of such dysregulation and the

relation between macrophage activation syndrome and hemophagocytic

lymphohistiocytosis still remain to be determined.

-----------------------------------------------------------------------

Reactive haemophagocytic syndrome in children with inflammatory disorders. A

retrospective study of 24 patients.

Rheumatology (Oxford). 2001 Nov;40(11):1285-92.

Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM.

Unite d'Hematologie et d'Oncologie Pediatriques, Hotel Dieu,

Clermont-Ferrand, Service de Pediatrie, Hopital Nord, Marseille, France.

BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a little-known

life-threatening complication of rheumatic diseases in children. It reflects

the extreme vulnerability of these patients, especially those with

systemic-onset juvenile chronic arthritis (JCA). This immunohaematological

process may be triggered by events such as herpes virus infection and

non-steroidal anti-inflammatory drug therapy. Treatment has not been

standardized.

METHODS: We characterized this unusual disorder and determined its incidence

by carrying out a retrospective study of patients identified over a 10-yr

period in French paediatric units.

RESULTS: Twenty-four cases (nine males, 15 females) were studied. Eighteen

had typical systemic-onset JCA, two had polyarthritis, two had lupus and two

had unclassifiable disorders. Clinical features at diagnosis included high

spiking fever (24 patients), enlargement of the liver and spleen (14),

haemorrhagic diathesis (six), pulmonary involvement (12) and neurological

abnormalities (coma or seizures) (12).

RHS was the first manifestation of systemic disease in three cases.

Admission to intensive care was required in ten cases. Hypofibrinogenaemia,

elevated liver enzymes and hypertriglyceridaemia were found consistently.

Phagocytic histiocytes were found in 14 of 17 bone marrow smears.

RHS was presumed to have been precipitated by infection in 11 cases (four

Epstein-Barr virus, three varicella-zoster virus, one parvovirus B19, one

sackie virus, one Salmonella, one Pneumocystis carinii) and by the

introduction of medication in three cases (Salazopyrin plus methotrexate;

morniflumate; aspirin). Macrophage activation was indicated by high levels

of monokines in the serum of two patients. Twenty patients had only one

episode, three had an early relapse and one patient had two relapses.

The treatment regimen was tailored to each child as the clinical course was

variable. There was no response to intravenous immunoglobulins, which were

used in four cases. Intravenous steroids at doses ranging from conventional

to pulse methylprednisolone induced remission in 15 of 21 episodes when used

alone as the first-line treatment. Cyclosporin A was consistently and

rapidly effective, both when used as second-line therapy in all seven of the

episodes in which steroids failed and in all five patients who received it

as their first-line treatment. This supports a central role of T lymphocytes

in the haemophagocytic syndrome. Two patients died. One patient with lupus

died of congestive fulminant heart failure after 4 days, despite treatment

with intravenous steroids and immunoglobulins, and one patient with

systemic-onset JCA died from multiorgan failure despite aggressive therapy

with pulsed steroids and etoposide.

CONCLUSIONS: RHS may be a more common complication of systemic disease in

childhood than previously thought. This life-threatening complication should

be diagnosed promptly, as it calls for the immediate withdrawal of

potentially triggering medications, anti-infective therapy when relevant,

and urgent immunosuppressive treatment, measures that are very often

effective. Cyclosporin A may be the drug of choice.

PMID: 11709613 [PubMed - indexed for MEDLINE]

--------------------------------------------------

Macrophage activation syndrome: a potentially fatal complication of

rheumatic disorders.

Arch Dis Child. 2001 Nov;85(5):421-6:

Sawhney S, Woo P, Murray KJ.

Department of Rheumatology, Great Ormond Street Hospital, London, UK.

AIMS: To review the precipitating events, clinical features, treatment, and

outcome of macrophage activation syndrome (MAS).

METHODS: Retrospective review of cases of MAS from a prospectively collected

database of children with rheumatic diseases from 1980 to 2000.

RESULTS: Nine patients (eight girls) were considered to have evidence of

MAS. The primary diagnosis was systemic onset juvenile idiopathic arthritis

in seven, enthesitis related arthritis in one, and chronic infantile

neurological cutaneous articular syndrome in one. Mean age of onset was 5.7

years, and duration prior to MAS, 4.2 years.

No medication was identified as a trigger. Eight had infections prior to

MAS; specific infectious agents were identified in four. High grade fever,

new onset hepatosplenomegaly, and lymphadenopathy were common clinical

features. Platelet counts fell dramatically, from an average of 346 to 99 x

10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell from

115 to 28 mm/h. Eight had abnormal liver function during the disease course,

and six had coagulopathy. Bone marrow examination supported the diagnosis

with definite haemophagocytosis in four of seven.

All received high dose steroids (eight intravenous, one oral), five

cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two of

three patients with significant renal impairment died.

CONCLUSION: MAS is a rare and potentially fatal complication of childhood

rheumatic disorders. Most of our patients were female, and most cases were

preceded by infection. Bone marrow studies support the diagnosis. Deranged

renal function may be a poor prognostic sign. Aggressive early therapy is

essential.

PMID: 11668110 [PubMed - indexed for MEDLINE]

[Guest guest]

More about Macrophage Activation Syndrome

Macrophage activation syndrome in children with systemic-onset juvenile

chronic arthritis.

Acta Haematol. 2005;113(2):124-9.

Kounami S, Yoshiyama M, Nakayama K, Okuda M, Okuda S, Aoyagi N,

Yoshikawa N.

Departmentof Pediatrics, Wakayama Medical University, Kimiidera,

Wakayama

City, Japan. nami@...

Macrophage activation syndrome (MAS) is a life-threatening

complication in

children with rheumatic diseases, particularly systemic-onset juvenile

chronic arthritis (SOJCA). Because of the potential fatality of this

condition, prompt recognition and immediate therapeutic intervention are

important.

This study assessed the clinical features of nine MAS events in five

children with SOJCA. Nonremitting fever and decreased platelet and white

blood cell counts led to a diagnosis of MAS. The urinary

beta2-microglobulin

(beta2MG) level was a sensitive indicator of MAS. Serum levels of

beta2MG

and soluble interleukin-2 receptor were also elevated. These biologic

markers reflecting hyperactivated cellular immunity are useful

indicators of

MAS.

Four children treated with cyclosporin A (CSP) achieved rapid and

complete

recovery, but one patient without CSP died due to rapidly progressive

respiratory failure. All children treated with CSP responded quickly,

and

fever abated within 36 h of initiation of treatment. CSP should be added

to

first-line therapy of MAS.

Copyright 2005 S. Karger AG, Basel

PMID: 15802891 [PubMed - indexed for MEDLINE]

----------------------------------------------------------

[Macrophage activation syndrome associated with systemic juvenile

idiopathic arthritis]

J Pediatr (Rio J). 2004 Nov-Dec;80(6):517-22.

Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A, CM,

Kiss MH.

Faculdade de Medicina, Universidade de Sao o, FMUSP, Sao o, SP.

clovisaas@...

OBJECTIVE: To describe the characteristics of macrophage activation

syndrome associated with juvenile idiopathic arthritis.

DESCRIPTION: This is a retrospective study involving 462 patients with

juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered

from

systemic onset juvenile idiopathic arthritis and developed macrophage

activation syndrome. The median age of the juvenile idiopathic arthritis

onset was 3 years and 10 months and the median duration of juvenile

idiopathic arthritis before macrophage activation syndrome was 8 years

and 4

months.

All of them presented with fever, jaundice, hepatosplenomegaly,

bleeding,

pancytopenia, abnormal liver function tests and abnormal coagulation

profile. Three cases presented associated infections and one patient

developed macrophage activation syndrome two weeks after the

administration

of sulfasalazine. Three patients died and the macrophage

hemophagocytosis

was present in five.

The treatment of macrophage activation syndrome included pulse therapy

with methylprednisolone in all of them, cyclosporine A in three, plasma

exchange in two and intravenous immunoglobulin in two.

COMMENTS: Macrophage activation syndrome is a complication of the

systemic

onset juvenile idiopathic arthritis with a high morbidity and mortality

rate.

PMID: 15622430 [PubMed - indexed for MEDLINE]

-----------------------------------------------------------

Natural killer cell dysfunction is a distinguishing feature of systemic

onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Arthritis Res Ther. 2005;7(1):R30-7. Epub 2004 Nov 10.

Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A,

Grom

AA. 1Division of Hematology/Oncology, Children's Hospital Medical

Center,

Cincinnati, Ohio, USA.

Macrophage activation syndrome (MAS) has been reported in association

with

many rheumatic diseases, most commonly in systemic juvenile rheumatoid

arthritis (sJRA). Clinically, MAS is similar to hemophagocytic

lymphohistiocytosis (HLH), a genetic disorder with absent or depressed

natural killer (NK) function. We have previously reported that, as in

HLH,

patients with MAS have profoundly decreased NK activity, suggesting that

this abnormality might be relevant to the pathogenesis of the syndrome.

Here

we examined the extent of NK dysfunction across the spectrum of diseases

that comprise juvenile rheumatoid arthritis (JRA).

Peripheral blood mononuclear cells (PBMC) were collected from patients

with pauciarticular (n= 4), polyarticular (n = 16), and systemic (n =

20)

forms of JRA. NK cytolytic activity was measured after co-incubation of

PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell

receptor

[TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells

were

also assessed for perforin and granzyme B expression by flow cytometry.

Overall, NK cytolytic activity was significantly lower in patients with

sJRA

than in other JRA patients and controls. In a subgroup of patients with

predominantly sJRA, NK cell activity was profoundly decreased: in 10 of

20

patients with sJRA and in only 1 of 20 patients with other JRA, levels

of NK

activity were below two standard deviations of pediatric controls (P =

0.002). Some decrease in perforin expression in NK cells and cytotoxic T

lymphocytes was seen in patients within each of the JRA groups with no

statistically significant differences. There was a profound decrease in

the

proportion of circulating CD56bright NK cells in three sJRA patients, a

pattern similar to that previously observed in MAS and HLH. In

conclusion, a

subgroup of patients with JRA who have not yet had an episode of MAS

showed

decreased NK function and an absence of circulating CD56bright

population,

similar to the abnormalities observed in patients with MAS and HLH. This

phenomenon was particularly common in the systemic form of JRA, a

clinical

entity strongly associated with MAS.

PMID: 15642140 [PubMed - indexed for MEDLINE]

------------------------------------------------------

Macrophage activation syndrome and reactive hemophagocytic

lymphohistiocytosis: the same entities?

Current Opinion in Rheumatology. 15(5):587-590, September 2003.

Grom, ei A. MD

Abstract:

Purpose of the review: One of the most perplexing features of

systemic-onset

juvenile rheumatoid arthritis is the association with macrophage

activation

syndrome, a life-threatening complication caused by excessive activation

and

proliferation of T cells and macrophages. The main purpose of the review

is

to summarize current understanding of the relation between macrophage

activation syndrome and other clinically similar hemophagocytic

disorders.

Recent findings: Clinically, macrophage activation syndrome has strong

similarities with familial and virus-associated reactive hemophagocytic

lymphohistiocytosis. The better understood familial hemophagocytic

lymphohistiocytosis is a constellation of rare, autosomal recessive

immune

disorders. The most consistent immunologic abnormalities in patients

with

familial hemophagocytic lymphohistiocytosis are decreased natural killer

and

cytotoxic cell functions. In approximately one third of familial

hemophagocytic lymphohistiocytosis patients, these immunologic

abnormalities

are secondary to mutations in the gene encoding perforin, a protein that

mediates cytotoxic activity of natural killer and cytotoxic CD8+ T

cells.

Several recent studies have suggested that profoundly depressed natural

killer cell activity and abnormal levels of perforin expression may be a

feature of macrophage activation syndrome in systemic-onset juvenile

rheumatoid arthritis as well. Although it has been proposed that in both

hemophagocytic lymphohistiocytosis and macrophage activation syndrome,

natural killer and cytotoxic cell dysfunction may lead to inadequate

control

of cellular immune responses, the exact nature of such dysregulation and

the

relation between macrophage activation syndrome and hemophagocytic

lymphohistiocytosis still remain to be determined.

-----------------------------------------------------------------------

Reactive haemophagocytic syndrome in children with inflammatory

disorders. A

retrospective study of 24 patients.

Rheumatology (Oxford). 2001 Nov;40(11):1285-92.

Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur

AM.

Unite d'Hematologie et d'Oncologie Pediatriques, Hotel Dieu,

Clermont-Ferrand, Service de Pediatrie, Hopital Nord, Marseille, France.

BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a

little-known

life-threatening complication of rheumatic diseases in children. It

reflects

the extreme vulnerability of these patients, especially those with

systemic-onset juvenile chronic arthritis (JCA). This

immunohaematological

process may be triggered by events such as herpes virus infection and

non-steroidal anti-inflammatory drug therapy. Treatment has not been

standardized.

METHODS: We characterized this unusual disorder and determined its

incidence

by carrying out a retrospective study of patients identified over a

10-yr

period in French paediatric units.

RESULTS: Twenty-four cases (nine males, 15 females) were studied.

Eighteen

had typical systemic-onset JCA, two had polyarthritis, two had lupus and

two

had unclassifiable disorders. Clinical features at diagnosis included

high

spiking fever (24 patients), enlargement of the liver and spleen (14),

haemorrhagic diathesis (six), pulmonary involvement (12) and

neurological

abnormalities (coma or seizures) (12).

RHS was the first manifestation of systemic disease in three cases.

Admission to intensive care was required in ten cases.

Hypofibrinogenaemia,

elevated liver enzymes and hypertriglyceridaemia were found

consistently.

Phagocytic histiocytes were found in 14 of 17 bone marrow smears.

RHS was presumed to have been precipitated by infection in 11 cases

(four

Epstein-Barr virus, three varicella-zoster virus, one parvovirus B19,

one

sackie virus, one Salmonella, one Pneumocystis carinii) and by the

introduction of medication in three cases (Salazopyrin plus

methotrexate;

morniflumate; aspirin). Macrophage activation was indicated by high

levels

of monokines in the serum of two patients. Twenty patients had only one

episode, three had an early relapse and one patient had two relapses.

The treatment regimen was tailored to each child as the clinical course

was

variable. There was no response to intravenous immunoglobulins, which

were

used in four cases. Intravenous steroids at doses ranging from

conventional

to pulse methylprednisolone induced remission in 15 of 21 episodes when

used

alone as the first-line treatment. Cyclosporin A was consistently and

rapidly effective, both when used as second-line therapy in all seven of

the

episodes in which steroids failed and in all five patients who received

it

as their first-line treatment. This supports a central role of T

lymphocytes

in the haemophagocytic syndrome. Two patients died. One patient with

lupus

died of congestive fulminant heart failure after 4 days, despite

treatment

with intravenous steroids and immunoglobulins, and one patient with

systemic-onset JCA died from multiorgan failure despite aggressive

therapy

with pulsed steroids and etoposide.

CONCLUSIONS: RHS may be a more common complication of systemic disease

in

childhood than previously thought. This life-threatening complication

should

be diagnosed promptly, as it calls for the immediate withdrawal of

potentially triggering medications, anti-infective therapy when

relevant,

and urgent immunosuppressive treatment, measures that are very often

effective. Cyclosporin A may be the drug of choice.

PMID: 11709613 [PubMed - indexed for MEDLINE]

--------------------------------------------------

Macrophage activation syndrome: a potentially fatal complication of

rheumatic disorders.

Arch Dis Child. 2001 Nov;85(5):421-6:

Sawhney S, Woo P, Murray KJ.

Department of Rheumatology, Great Ormond Street Hospital, London, UK.

AIMS: To review the precipitating events, clinical features, treatment,

and

outcome of macrophage activation syndrome (MAS).

METHODS: Retrospective review of cases of MAS from a prospectively

collected

database of children with rheumatic diseases from 1980 to 2000.

RESULTS: Nine patients (eight girls) were considered to have evidence of

MAS. The primary diagnosis was systemic onset juvenile idiopathic

arthritis

in seven, enthesitis related arthritis in one, and chronic infantile

neurological cutaneous articular syndrome in one. Mean age of onset was

5.7

years, and duration prior to MAS, 4.2 years.

No medication was identified as a trigger. Eight had infections prior to

MAS; specific infectious agents were identified in four. High grade

fever,

new onset hepatosplenomegaly, and lymphadenopathy were common clinical

features. Platelet counts fell dramatically, from an average of 346 to

99 x

10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell

from

115 to 28 mm/h. Eight had abnormal liver function during the disease

course,

and six had coagulopathy. Bone marrow examination supported the

diagnosis

with definite haemophagocytosis in four of seven.

All received high dose steroids (eight intravenous, one oral), five

cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two

of

three patients with significant renal impairment died.

CONCLUSION: MAS is a rare and potentially fatal complication of

childhood

rheumatic disorders. Most of our patients were female, and most cases

were

preceded by infection. Bone marrow studies support the diagnosis.

Deranged

renal function may be a poor prognostic sign. Aggressive early therapy

is

essential.

PMID: 11668110 [PubMed - indexed for MEDLINE]

[Guest guest]

These are great articles. Scary, but as I always say-knowledge is

power.

n was admitted to a large Children's Hospital with a ped

rheumy. No one had seen MAS before, except the ped rheumy. The

treatment was begun immediately. If the ped rheumy had spent a day

or two trying to figure things out and waited on the correct

treatment of steroids and cyclosporine, I would shudder to think what

would have happened.

We will forever be cautious with all doctors and hospitals with

n. If they aren't aware of MAS, we have to be the educators for

them. (n, 17, systemic)

On Jan 16, 2007, at 8:34 AM, Tepper, Michele wrote:

>

>

> More about Macrophage Activation Syndrome

>

> Macrophage activation syndrome in children with systemic-onset

> juvenile

> chronic arthritis.

> Acta Haematol. 2005;113(2):124-9.

>

> Kounami S, Yoshiyama M, Nakayama K, Okuda M, Okuda S, Aoyagi N,

> Yoshikawa N.

> Departmentof Pediatrics, Wakayama Medical University, Kimiidera,

> Wakayama

> City, Japan. nami@...

>

> Macrophage activation syndrome (MAS) is a life-threatening

> complication in

> children with rheumatic diseases, particularly systemic-onset juvenile

> chronic arthritis (SOJCA). Because of the potential fatality of this

> condition, prompt recognition and immediate therapeutic

> intervention are

> important.

>

> This study assessed the clinical features of nine MAS events in five

> children with SOJCA. Nonremitting fever and decreased platelet and

> white

> blood cell counts led to a diagnosis of MAS. The urinary

> beta2-microglobulin

> (beta2MG) level was a sensitive indicator of MAS. Serum levels of

> beta2MG

> and soluble interleukin-2 receptor were also elevated. These biologic

> markers reflecting hyperactivated cellular immunity are useful

> indicators of

> MAS.

>

> Four children treated with cyclosporin A (CSP) achieved rapid and

> complete

> recovery, but one patient without CSP died due to rapidly progressive

> respiratory failure. All children treated with CSP responded quickly,

> and

> fever abated within 36 h of initiation of treatment. CSP should be

> added

> to

> first-line therapy of MAS.

>

> Copyright 2005 S. Karger AG, Basel

> PMID: 15802891 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> [Macrophage activation syndrome associated with systemic juvenile

> idiopathic arthritis]

> J Pediatr (Rio J). 2004 Nov-Dec;80(6):517-22.

>

> Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A,

> CM,

> Kiss MH.

> Faculdade de Medicina, Universidade de Sao o, FMUSP, Sao o,

> SP.

> clovisaas@...

>

> OBJECTIVE: To describe the characteristics of macrophage activation

> syndrome associated with juvenile idiopathic arthritis.

>

> DESCRIPTION: This is a retrospective study involving 462 patients with

> juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered

> from

> systemic onset juvenile idiopathic arthritis and developed macrophage

> activation syndrome. The median age of the juvenile idiopathic

> arthritis

> onset was 3 years and 10 months and the median duration of juvenile

> idiopathic arthritis before macrophage activation syndrome was 8 years

> and 4

> months.

>

> All of them presented with fever, jaundice, hepatosplenomegaly,

> bleeding,

> pancytopenia, abnormal liver function tests and abnormal coagulation

> profile. Three cases presented associated infections and one patient

> developed macrophage activation syndrome two weeks after the

> administration

> of sulfasalazine. Three patients died and the macrophage

> hemophagocytosis

> was present in five.

>

> The treatment of macrophage activation syndrome included pulse therapy

> with methylprednisolone in all of them, cyclosporine A in three,

> plasma

> exchange in two and intravenous immunoglobulin in two.

>

> COMMENTS: Macrophage activation syndrome is a complication of the

> systemic

> onset juvenile idiopathic arthritis with a high morbidity and

> mortality

> rate.

>

> PMID: 15622430 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> Natural killer cell dysfunction is a distinguishing feature of

> systemic

> onset juvenile rheumatoid arthritis and macrophage activation

> syndrome.

> Arthritis Res Ther. 2005;7(1):R30-7. Epub 2004 Nov 10.

>

> Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A,

> Grom

> AA. 1Division of Hematology/Oncology, Children's Hospital Medical

> Center,

> Cincinnati, Ohio, USA.

>

> Macrophage activation syndrome (MAS) has been reported in association

> with

> many rheumatic diseases, most commonly in systemic juvenile rheumatoid

> arthritis (sJRA). Clinically, MAS is similar to hemophagocytic

> lymphohistiocytosis (HLH), a genetic disorder with absent or depressed

> natural killer (NK) function. We have previously reported that, as in

> HLH,

> patients with MAS have profoundly decreased NK activity, suggesting

> that

> this abnormality might be relevant to the pathogenesis of the

> syndrome.

> Here

> we examined the extent of NK dysfunction across the spectrum of

> diseases

> that comprise juvenile rheumatoid arthritis (JRA).

>

> Peripheral blood mononuclear cells (PBMC) were collected from patients

> with pauciarticular (n= 4), polyarticular (n = 16), and systemic (n =

> 20)

> forms of JRA. NK cytolytic activity was measured after co-

> incubation of

> PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell

> receptor

> [TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells

> were

> also assessed for perforin and granzyme B expression by flow

> cytometry.

>

> Overall, NK cytolytic activity was significantly lower in patients

> with

> sJRA

> than in other JRA patients and controls. In a subgroup of patients

> with

> predominantly sJRA, NK cell activity was profoundly decreased: in

> 10 of

> 20

> patients with sJRA and in only 1 of 20 patients with other JRA, levels

> of NK

> activity were below two standard deviations of pediatric controls (P =

> 0.002). Some decrease in perforin expression in NK cells and

> cytotoxic T

> lymphocytes was seen in patients within each of the JRA groups with no

> statistically significant differences. There was a profound

> decrease in

> the

> proportion of circulating CD56bright NK cells in three sJRA

> patients, a

> pattern similar to that previously observed in MAS and HLH. In

> conclusion, a

> subgroup of patients with JRA who have not yet had an episode of MAS

> showed

> decreased NK function and an absence of circulating CD56bright

> population,

> similar to the abnormalities observed in patients with MAS and HLH.

> This

> phenomenon was particularly common in the systemic form of JRA, a

> clinical

> entity strongly associated with MAS.

>

> PMID: 15642140 [PubMed - indexed for MEDLINE]

> ------------------------------------------------------

>

> Macrophage activation syndrome and reactive hemophagocytic

> lymphohistiocytosis: the same entities?

> Current Opinion in Rheumatology. 15(5):587-590, September 2003.

> Grom, ei A. MD

>

> Abstract:

> Purpose of the review: One of the most perplexing features of

> systemic-onset

> juvenile rheumatoid arthritis is the association with macrophage

> activation

> syndrome, a life-threatening complication caused by excessive

> activation

> and

> proliferation of T cells and macrophages. The main purpose of the

> review

> is

> to summarize current understanding of the relation between macrophage

> activation syndrome and other clinically similar hemophagocytic

> disorders.

>

> Recent findings: Clinically, macrophage activation syndrome has strong

> similarities with familial and virus-associated reactive

> hemophagocytic

> lymphohistiocytosis. The better understood familial hemophagocytic

> lymphohistiocytosis is a constellation of rare, autosomal recessive

> immune

> disorders. The most consistent immunologic abnormalities in patients

> with

> familial hemophagocytic lymphohistiocytosis are decreased natural

> killer

> and

> cytotoxic cell functions. In approximately one third of familial

> hemophagocytic lymphohistiocytosis patients, these immunologic

> abnormalities

> are secondary to mutations in the gene encoding perforin, a protein

> that

> mediates cytotoxic activity of natural killer and cytotoxic CD8+ T

> cells.

>

> Several recent studies have suggested that profoundly depressed

> natural

> killer cell activity and abnormal levels of perforin expression may

> be a

> feature of macrophage activation syndrome in systemic-onset juvenile

> rheumatoid arthritis as well. Although it has been proposed that in

> both

> hemophagocytic lymphohistiocytosis and macrophage activation syndrome,

> natural killer and cytotoxic cell dysfunction may lead to inadequate

> control

> of cellular immune responses, the exact nature of such

> dysregulation and

> the

> relation between macrophage activation syndrome and hemophagocytic

> lymphohistiocytosis still remain to be determined.

>

> ----------------------------------------------------------

>

> Reactive haemophagocytic syndrome in children with inflammatory

> disorders. A

> retrospective study of 24 patients.

> Rheumatology (Oxford). 2001 Nov;40(11):1285-92.

>

> Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur

> AM.

> Unite d'Hematologie et d'Oncologie Pediatriques, Hotel Dieu,

> Clermont-Ferrand, Service de Pediatrie, Hopital Nord, Marseille,

> France.

>

> BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a

> little-known

> life-threatening complication of rheumatic diseases in children. It

> reflects

> the extreme vulnerability of these patients, especially those with

> systemic-onset juvenile chronic arthritis (JCA). This

> immunohaematological

> process may be triggered by events such as herpes virus infection and

> non-steroidal anti-inflammatory drug therapy. Treatment has not been

> standardized.

>

> METHODS: We characterized this unusual disorder and determined its

> incidence

> by carrying out a retrospective study of patients identified over a

> 10-yr

> period in French paediatric units.

>

> RESULTS: Twenty-four cases (nine males, 15 females) were studied.

> Eighteen

> had typical systemic-onset JCA, two had polyarthritis, two had

> lupus and

> two

> had unclassifiable disorders. Clinical features at diagnosis included

> high

> spiking fever (24 patients), enlargement of the liver and spleen (14),

> haemorrhagic diathesis (six), pulmonary involvement (12) and

> neurological

> abnormalities (coma or seizures) (12).

>

> RHS was the first manifestation of systemic disease in three cases.

> Admission to intensive care was required in ten cases.

> Hypofibrinogenaemia,

> elevated liver enzymes and hypertriglyceridaemia were found

> consistently.

> Phagocytic histiocytes were found in 14 of 17 bone marrow smears.

>

> RHS was presumed to have been precipitated by infection in 11 cases

> (four

> Epstein-Barr virus, three varicella-zoster virus, one parvovirus B19,

> one

> sackie virus, one Salmonella, one Pneumocystis carinii) and by the

> introduction of medication in three cases (Salazopyrin plus

> methotrexate;

> morniflumate; aspirin). Macrophage activation was indicated by high

> levels

> of monokines in the serum of two patients. Twenty patients had only

> one

> episode, three had an early relapse and one patient had two relapses.

>

> The treatment regimen was tailored to each child as the clinical

> course

> was

> variable. There was no response to intravenous immunoglobulins, which

> were

> used in four cases. Intravenous steroids at doses ranging from

> conventional

> to pulse methylprednisolone induced remission in 15 of 21 episodes

> when

> used

> alone as the first-line treatment. Cyclosporin A was consistently and

> rapidly effective, both when used as second-line therapy in all

> seven of

> the

> episodes in which steroids failed and in all five patients who

> received

> it

> as their first-line treatment. This supports a central role of T

> lymphocytes

> in the haemophagocytic syndrome. Two patients died. One patient with

> lupus

> died of congestive fulminant heart failure after 4 days, despite

> treatment

> with intravenous steroids and immunoglobulins, and one patient with

> systemic-onset JCA died from multiorgan failure despite aggressive

> therapy

> with pulsed steroids and etoposide.

>

> CONCLUSIONS: RHS may be a more common complication of systemic disease

> in

> childhood than previously thought. This life-threatening complication

> should

> be diagnosed promptly, as it calls for the immediate withdrawal of

> potentially triggering medications, anti-infective therapy when

> relevant,

> and urgent immunosuppressive treatment, measures that are very often

> effective. Cyclosporin A may be the drug of choice.

>

> PMID: 11709613 [PubMed - indexed for MEDLINE]

> --------------------------------------------------

>

> Macrophage activation syndrome: a potentially fatal complication of

> rheumatic disorders.

> Arch Dis Child. 2001 Nov;85(5):421-6:

>

> Sawhney S, Woo P, Murray KJ.

> Department of Rheumatology, Great Ormond Street Hospital, London, UK.

>

> AIMS: To review the precipitating events, clinical features,

> treatment,

> and

> outcome of macrophage activation syndrome (MAS).

>

> METHODS: Retrospective review of cases of MAS from a prospectively

> collected

> database of children with rheumatic diseases from 1980 to 2000.

>

> RESULTS: Nine patients (eight girls) were considered to have

> evidence of

> MAS. The primary diagnosis was systemic onset juvenile idiopathic

> arthritis

> in seven, enthesitis related arthritis in one, and chronic infantile

> neurological cutaneous articular syndrome in one. Mean age of onset

> was

> 5.7

> years, and duration prior to MAS, 4.2 years.

>

> No medication was identified as a trigger. Eight had infections

> prior to

> MAS; specific infectious agents were identified in four. High grade

> fever,

> new onset hepatosplenomegaly, and lymphadenopathy were common clinical

> features. Platelet counts fell dramatically, from an average of 346 to

> 99 x

> 10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell

> from

> 115 to 28 mm/h. Eight had abnormal liver function during the disease

> course,

> and six had coagulopathy. Bone marrow examination supported the

> diagnosis

> with definite haemophagocytosis in four of seven.

>

> All received high dose steroids (eight intravenous, one oral), five

> cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two

> of

> three patients with significant renal impairment died.

>

> CONCLUSION: MAS is a rare and potentially fatal complication of

> childhood

> rheumatic disorders. Most of our patients were female, and most cases

> were

> preceded by infection. Bone marrow studies support the diagnosis.

> Deranged

> renal function may be a poor prognostic sign. Aggressive early therapy

> is

> essential.

>

> PMID: 11668110 [PubMed - indexed for MEDLINE]

>

>

[Guest guest]

I agree - knowledge is power. I hang on to articles like these as these

are questions that seem to pop up on the list every so often. If someone

can even gain a bit of useful knowledge from them I think it is great.

That to me is what is great about the list. Before this, I had never

heard of MAS, or uveitis or even the AS ended up being diagnosed

with, among other things. The knowledge I gained has made me a better

advocate for my child. Michele ( 19, spondy)

________________________________

From: [mailto: ] On

Behalf Of Price

Sent: Tuesday, January 16, 2007 11:12 AM

Subject: Re: More about Macrophage Activation Syndrome

These are great articles. Scary, but as I always say-knowledge is

power.

n was admitted to a large Children's Hospital with a ped

rheumy. No one had seen MAS before, except the ped rheumy. The

treatment was begun immediately. If the ped rheumy had spent a day

or two trying to figure things out and waited on the correct

treatment of steroids and cyclosporine, I would shudder to think what

would have happened.

We will forever be cautious with all doctors and hospitals with

n. If they aren't aware of MAS, we have to be the educators for

them. (n, 17, systemic)

On Jan 16, 2007, at 8:34 AM, Tepper, Michele wrote:

>

>

> More about Macrophage Activation Syndrome

>

> Macrophage activation syndrome in children with systemic-onset

> juvenile

> chronic arthritis.

> Acta Haematol. 2005;113(2):124-9.

>

> Kounami S, Yoshiyama M, Nakayama K, Okuda M, Okuda S, Aoyagi N,

> Yoshikawa N.

> Departmentof Pediatrics, Wakayama Medical University, Kimiidera,

> Wakayama

> City, Japan. nami@...

<mailto:nami%40mail.wakayama-med.ac.jp>

>

> Macrophage activation syndrome (MAS) is a life-threatening

> complication in

> children with rheumatic diseases, particularly systemic-onset juvenile

> chronic arthritis (SOJCA). Because of the potential fatality of this

> condition, prompt recognition and immediate therapeutic

> intervention are

> important.

>

> This study assessed the clinical features of nine MAS events in five

> children with SOJCA. Nonremitting fever and decreased platelet and

> white

> blood cell counts led to a diagnosis of MAS. The urinary

> beta2-microglobulin

> (beta2MG) level was a sensitive indicator of MAS. Serum levels of

> beta2MG

> and soluble interleukin-2 receptor were also elevated. These biologic

> markers reflecting hyperactivated cellular immunity are useful

> indicators of

> MAS.

>

> Four children treated with cyclosporin A (CSP) achieved rapid and

> complete

> recovery, but one patient without CSP died due to rapidly progressive

> respiratory failure. All children treated with CSP responded quickly,

> and

> fever abated within 36 h of initiation of treatment. CSP should be

> added

> to

> first-line therapy of MAS.

>

> Copyright 2005 S. Karger AG, Basel

> PMID: 15802891 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> [Macrophage activation syndrome associated with systemic juvenile

> idiopathic arthritis]

> J Pediatr (Rio J). 2004 Nov-Dec;80(6):517-22.

>

> Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A,

> CM,

> Kiss MH.

> Faculdade de Medicina, Universidade de Sao o, FMUSP, Sao o,

> SP.

> clovisaas@... <mailto:clovisaas%40icr.hcnet.usp.br>

>

> OBJECTIVE: To describe the characteristics of macrophage activation

> syndrome associated with juvenile idiopathic arthritis.

>

> DESCRIPTION: This is a retrospective study involving 462 patients with

> juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered

> from

> systemic onset juvenile idiopathic arthritis and developed macrophage

> activation syndrome. The median age of the juvenile idiopathic

> arthritis

> onset was 3 years and 10 months and the median duration of juvenile

> idiopathic arthritis before macrophage activation syndrome was 8 years

> and 4

> months.

>

> All of them presented with fever, jaundice, hepatosplenomegaly,

> bleeding,

> pancytopenia, abnormal liver function tests and abnormal coagulation

> profile. Three cases presented associated infections and one patient

> developed macrophage activation syndrome two weeks after the

> administration

> of sulfasalazine. Three patients died and the macrophage

> hemophagocytosis

> was present in five.

>

> The treatment of macrophage activation syndrome included pulse therapy

> with methylprednisolone in all of them, cyclosporine A in three,

> plasma

> exchange in two and intravenous immunoglobulin in two.

>

> COMMENTS: Macrophage activation syndrome is a complication of the

> systemic

> onset juvenile idiopathic arthritis with a high morbidity and

> mortality

> rate.

>

> PMID: 15622430 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> Natural killer cell dysfunction is a distinguishing feature of

> systemic

> onset juvenile rheumatoid arthritis and macrophage activation

> syndrome.

> Arthritis Res Ther. 2005;7(1):R30-7. Epub 2004 Nov 10.

>

> Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A,

> Grom

> AA. 1Division of Hematology/Oncology, Children's Hospital Medical

> Center,

> Cincinnati, Ohio, USA.

>

> Macrophage activation syndrome (MAS) has been reported in association

> with

> many rheumatic diseases, most commonly in systemic juvenile rheumatoid

> arthritis (sJRA). Clinically, MAS is similar to hemophagocytic

> lymphohistiocytosis (HLH), a genetic disorder with absent or depressed

> natural killer (NK) function. We have previously reported that, as in

> HLH,

> patients with MAS have profoundly decreased NK activity, suggesting

> that

> this abnormality might be relevant to the pathogenesis of the

> syndrome.

> Here

> we examined the extent of NK dysfunction across the spectrum of

> diseases

> that comprise juvenile rheumatoid arthritis (JRA).

>

> Peripheral blood mononuclear cells (PBMC) were collected from patients

> with pauciarticular (n= 4), polyarticular (n = 16), and systemic (n =

> 20)

> forms of JRA. NK cytolytic activity was measured after co-

> incubation of

> PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell

> receptor

> [TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells

> were

> also assessed for perforin and granzyme B expression by flow

> cytometry.

>

> Overall, NK cytolytic activity was significantly lower in patients

> with

> sJRA

> than in other JRA patients and controls. In a subgroup of patients

> with

> predominantly sJRA, NK cell activity was profoundly decreased: in

> 10 of

> 20

> patients with sJRA and in only 1 of 20 patients with other JRA, levels

> of NK

> activity were below two standard deviations of pediatric controls (P =

> 0.002). Some decrease in perforin expression in NK cells and

> cytotoxic T

> lymphocytes was seen in patients within each of the JRA groups with no

> statistically significant differences. There was a profound

> decrease in

> the

> proportion of circulating CD56bright NK cells in three sJRA

> patients, a

> pattern similar to that previously observed in MAS and HLH. In

> conclusion, a

> subgroup of patients with JRA who have not yet had an episode of MAS

> showed

> decreased NK function and an absence of circulating CD56bright

> population,

> similar to the abnormalities observed in patients with MAS and HLH.

> This

> phenomenon was particularly common in the systemic form of JRA, a

> clinical

> entity strongly associated with MAS.

>

> PMID: 15642140 [PubMed - indexed for MEDLINE]

> ------------------------------------------------------

>

> Macrophage activation syndrome and reactive hemophagocytic

> lymphohistiocytosis: the same entities?

> Current Opinion in Rheumatology. 15(5):587-590, September 2003.

> Grom, ei A. MD

>

> Abstract:

> Purpose of the review: One of the most perplexing features of

> systemic-onset

> juvenile rheumatoid arthritis is the association with macrophage

> activation

> syndrome, a life-threatening complication caused by excessive

> activation

> and

> proliferation of T cells and macrophages. The main purpose of the

> review

> is

> to summarize current understanding of the relation between macrophage

> activation syndrome and other clinically similar hemophagocytic

> disorders.

>

> Recent findings: Clinically, macrophage activation syndrome has strong

> similarities with familial and virus-associated reactive

> hemophagocytic

> lymphohistiocytosis. The better understood familial hemophagocytic

> lymphohistiocytosis is a constellation of rare, autosomal recessive

> immune

> disorders. The most consistent immunologic abnormalities in patients

> with

> familial hemophagocytic lymphohistiocytosis are decreased natural

> killer

> and

> cytotoxic cell functions. In approximately one third of familial

> hemophagocytic lymphohistiocytosis patients, these immunologic

> abnormalities

> are secondary to mutations in the gene encoding perforin, a protein

> that

> mediates cytotoxic activity of natural killer and cytotoxic CD8+ T

> cells.

>

> Several recent studies have suggested that profoundly depressed

> natural

> killer cell activity and abnormal levels of perforin expression may

> be a

> feature of macrophage activation syndrome in systemic-onset juvenile

> rheumatoid arthritis as well. Although it has been proposed that in

> both

> hemophagocytic lymphohistiocytosis and macrophage activation syndrome,

> natural killer and cytotoxic cell dysfunction may lead to inadequate

> control

> of cellular immune responses, the exact nature of such

> dysregulation and

> the

> relation between macrophage activation syndrome and hemophagocytic

> lymphohistiocytosis still remain to be determined.

>

> ----------------------------------------------------------

>

> Reactive haemophagocytic syndrome in children with inflammatory

> disorders. A

> retrospective study of 24 patients.

> Rheumatology (Oxford). 2001 Nov;40(11):1285-92.

>

> Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur

> AM.

> Unite d'Hematologie et d'Oncologie Pediatriques, Hotel Dieu,

> Clermont-Ferrand, Service de Pediatrie, Hopital Nord, Marseille,

> France.

>

> BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a

> little-known

> life-threatening complication of rheumatic diseases in children. It

> reflects

> the extreme vulnerability of these patients, especially those with

> systemic-onset juvenile chronic arthritis (JCA). This

> immunohaematological

> process may be triggered by events such as herpes virus infection and

> non-steroidal anti-inflammatory drug therapy. Treatment has not been

> standardized.

>

> METHODS: We characterized this unusual disorder and determined its

> incidence

> by carrying out a retrospective study of patients identified over a

> 10-yr

> period in French paediatric units.

>

> RESULTS: Twenty-four cases (nine males, 15 females) were studied.

> Eighteen

> had typical systemic-onset JCA, two had polyarthritis, two had

> lupus and

> two

> had unclassifiable disorders. Clinical features at diagnosis included

> high

> spiking fever (24 patients), enlargement of the liver and spleen (14),

> haemorrhagic diathesis (six), pulmonary involvement (12) and

> neurological

> abnormalities (coma or seizures) (12).

>

> RHS was the first manifestation of systemic disease in three cases.

> Admission to intensive care was required in ten cases.

> Hypofibrinogenaemia,

> elevated liver enzymes and hypertriglyceridaemia were found

> consistently.

> Phagocytic histiocytes were found in 14 of 17 bone marrow smears.

>

> RHS was presumed to have been precipitated by infection in 11 cases

> (four

> Epstein-Barr virus, three varicella-zoster virus, one parvovirus B19,

> one

> sackie virus, one Salmonella, one Pneumocystis carinii) and by the

> introduction of medication in three cases (Salazopyrin plus

> methotrexate;

> morniflumate; aspirin). Macrophage activation was indicated by high

> levels

> of monokines in the serum of two patients. Twenty patients had only

> one

> episode, three had an early relapse and one patient had two relapses.

>

> The treatment regimen was tailored to each child as the clinical

> course

> was

> variable. There was no response to intravenous immunoglobulins, which

> were

> used in four cases. Intravenous steroids at doses ranging from

> conventional

> to pulse methylprednisolone induced remission in 15 of 21 episodes

> when

> used

> alone as the first-line treatment. Cyclosporin A was consistently and

> rapidly effective, both when used as second-line therapy in all

> seven of

> the

> episodes in which steroids failed and in all five patients who

> received

> it

> as their first-line treatment. This supports a central role of T

> lymphocytes

> in the haemophagocytic syndrome. Two patients died. One patient with

> lupus

> died of congestive fulminant heart failure after 4 days, despite

> treatment

> with intravenous steroids and immunoglobulins, and one patient with

> systemic-onset JCA died from multiorgan failure despite aggressive

> therapy

> with pulsed steroids and etoposide.

>

> CONCLUSIONS: RHS may be a more common complication of systemic disease

> in

> childhood than previously thought. This life-threatening complication

> should

> be diagnosed promptly, as it calls for the immediate withdrawal of

> potentially triggering medications, anti-infective therapy when

> relevant,

> and urgent immunosuppressive treatment, measures that are very often

> effective. Cyclosporin A may be the drug of choice.

>

> PMID: 11709613 [PubMed - indexed for MEDLINE]

> --------------------------------------------------

>

> Macrophage activation syndrome: a potentially fatal complication of

> rheumatic disorders.

> Arch Dis Child. 2001 Nov;85(5):421-6:

>

> Sawhney S, Woo P, Murray KJ.

> Department of Rheumatology, Great Ormond Street Hospital, London, UK.

>

> AIMS: To review the precipitating events, clinical features,

> treatment,

> and

> outcome of macrophage activation syndrome (MAS).

>

> METHODS: Retrospective review of cases of MAS from a prospectively

> collected

> database of children with rheumatic diseases from 1980 to 2000.

>

> RESULTS: Nine patients (eight girls) were considered to have

> evidence of

> MAS. The primary diagnosis was systemic onset juvenile idiopathic

> arthritis

> in seven, enthesitis related arthritis in one, and chronic infantile

> neurological cutaneous articular syndrome in one. Mean age of onset

> was

> 5.7

> years, and duration prior to MAS, 4.2 years.

>

> No medication was identified as a trigger. Eight had infections

> prior to

> MAS; specific infectious agents were identified in four. High grade

> fever,

> new onset hepatosplenomegaly, and lymphadenopathy were common clinical

> features. Platelet counts fell dramatically, from an average of 346 to

> 99 x

> 10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell

> from

> 115 to 28 mm/h. Eight had abnormal liver function during the disease

> course,

> and six had coagulopathy. Bone marrow examination supported the

> diagnosis

> with definite haemophagocytosis in four of seven.

>

> All received high dose steroids (eight intravenous, one oral), five

> cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two

> of

> three patients with significant renal impairment died.

>

> CONCLUSION: MAS is a rare and potentially fatal complication of

> childhood

> rheumatic disorders. Most of our patients were female, and most cases

> were

> preceded by infection. Bone marrow studies support the diagnosis.

> Deranged

> renal function may be a poor prognostic sign. Aggressive early therapy

> is

> essential.

>

> PMID: 11668110 [PubMed - indexed for MEDLINE]

>

>

[Guest guest]

I agree with , great articles, thank you.I have been reading all I can to

understand MAS and this was great.Luckily Jordan's MAS was brought under control

by the Kineret, but we have to watch for it for the rest of her life they

say.Jordans MAS was brought on by Sulfasalizine which the doctors had prescribed

for Urticaria.I am grateful and thankful for the very knowledgeable doctors in

Boston and they got it under control.I would like to thank all you in this group

that help out with all you have been through and all the knowledge you have

learned and share with the rest of us.It makes this disease easier to deal with.

Thank you again,

a and Jordan (9,systemic)

Price <bc.price@...> wrote:

These are great articles. Scary, but as I always say-knowledge is

power.

n was admitted to a large Children's Hospital with a ped

rheumy. No one had seen MAS before, except the ped rheumy. The

treatment was begun immediately. If the ped rheumy had spent a day

or two trying to figure things out and waited on the correct

treatment of steroids and cyclosporine, I would shudder to think what

would have happened.

We will forever be cautious with all doctors and hospitals with

n. If they aren't aware of MAS, we have to be the educators for

them. (n, 17, systemic)

On Jan 16, 2007, at 8:34 AM, Tepper, Michele wrote:

>

>

> More about Macrophage Activation Syndrome

>

> Macrophage activation syndrome in children with systemic-onset

> juvenile

> chronic arthritis.

> Acta Haematol. 2005;113(2):124-9.

>

> Kounami S, Yoshiyama M, Nakayama K, Okuda M, Okuda S, Aoyagi N,

> Yoshikawa N.

> Departmentof Pediatrics, Wakayama Medical University, Kimiidera,

> Wakayama

> City, Japan. nami@...

>

> Macrophage activation syndrome (MAS) is a life-threatening

> complication in

> children with rheumatic diseases, particularly systemic-onset juvenile

> chronic arthritis (SOJCA). Because of the potential fatality of this

> condition, prompt recognition and immediate therapeutic

> intervention are

> important.

>

> This study assessed the clinical features of nine MAS events in five

> children with SOJCA. Nonremitting fever and decreased platelet and

> white

> blood cell counts led to a diagnosis of MAS. The urinary

> beta2-microglobulin

> (beta2MG) level was a sensitive indicator of MAS. Serum levels of

> beta2MG

> and soluble interleukin-2 receptor were also elevated. These biologic

> markers reflecting hyperactivated cellular immunity are useful

> indicators of

> MAS.

>

> Four children treated with cyclosporin A (CSP) achieved rapid and

> complete

> recovery, but one patient without CSP died due to rapidly progressive

> respiratory failure. All children treated with CSP responded quickly,

> and

> fever abated within 36 h of initiation of treatment. CSP should be

> added

> to

> first-line therapy of MAS.

>

> Copyright 2005 S. Karger AG, Basel

> PMID: 15802891 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> [Macrophage activation syndrome associated with systemic juvenile

> idiopathic arthritis]

> J Pediatr (Rio J). 2004 Nov-Dec;80(6):517-22.

>

> Silva CA, Silva CH, Robazzi TC, Lotito AP, Mendroni Junior A,

> CM,

> Kiss MH.

> Faculdade de Medicina, Universidade de Sao o, FMUSP, Sao o,

> SP.

> clovisaas@...

>

> OBJECTIVE: To describe the characteristics of macrophage activation

> syndrome associated with juvenile idiopathic arthritis.

>

> DESCRIPTION: This is a retrospective study involving 462 patients with

> juvenile idiopathic arthritis. Seven (1.5%) of those patients suffered

> from

> systemic onset juvenile idiopathic arthritis and developed macrophage

> activation syndrome. The median age of the juvenile idiopathic

> arthritis

> onset was 3 years and 10 months and the median duration of juvenile

> idiopathic arthritis before macrophage activation syndrome was 8 years

> and 4

> months.

>

> All of them presented with fever, jaundice, hepatosplenomegaly,

> bleeding,

> pancytopenia, abnormal liver function tests and abnormal coagulation

> profile. Three cases presented associated infections and one patient

> developed macrophage activation syndrome two weeks after the

> administration

> of sulfasalazine. Three patients died and the macrophage

> hemophagocytosis

> was present in five.

>

> The treatment of macrophage activation syndrome included pulse therapy

> with methylprednisolone in all of them, cyclosporine A in three,

> plasma

> exchange in two and intravenous immunoglobulin in two.

>

> COMMENTS: Macrophage activation syndrome is a complication of the

> systemic

> onset juvenile idiopathic arthritis with a high morbidity and

> mortality

> rate.

>

> PMID: 15622430 [PubMed - indexed for MEDLINE]

> ----------------------------------------------------------

>

> Natural killer cell dysfunction is a distinguishing feature of

> systemic

> onset juvenile rheumatoid arthritis and macrophage activation

> syndrome.

> Arthritis Res Ther. 2005;7(1):R30-7. Epub 2004 Nov 10.

>

> Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH, Filipovich A,

> Grom

> AA. 1Division of Hematology/Oncology, Children's Hospital Medical

> Center,

> Cincinnati, Ohio, USA.

>

> Macrophage activation syndrome (MAS) has been reported in association

> with

> many rheumatic diseases, most commonly in systemic juvenile rheumatoid

> arthritis (sJRA). Clinically, MAS is similar to hemophagocytic

> lymphohistiocytosis (HLH), a genetic disorder with absent or depressed

> natural killer (NK) function. We have previously reported that, as in

> HLH,

> patients with MAS have profoundly decreased NK activity, suggesting

> that

> this abnormality might be relevant to the pathogenesis of the

> syndrome.

> Here

> we examined the extent of NK dysfunction across the spectrum of

> diseases

> that comprise juvenile rheumatoid arthritis (JRA).

>

> Peripheral blood mononuclear cells (PBMC) were collected from patients

> with pauciarticular (n= 4), polyarticular (n = 16), and systemic (n =

> 20)

> forms of JRA. NK cytolytic activity was measured after co-

> incubation of

> PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell

> receptor

> [TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells

> were

> also assessed for perforin and granzyme B expression by flow

> cytometry.

>

> Overall, NK cytolytic activity was significantly lower in patients

> with

> sJRA

> than in other JRA patients and controls. In a subgroup of patients

> with

> predominantly sJRA, NK cell activity was profoundly decreased: in

> 10 of

> 20

> patients with sJRA and in only 1 of 20 patients with other JRA, levels

> of NK

> activity were below two standard deviations of pediatric controls (P =

> 0.002). Some decrease in perforin expression in NK cells and

> cytotoxic T

> lymphocytes was seen in patients within each of the JRA groups with no

> statistically significant differences. There was a profound

> decrease in

> the

> proportion of circulating CD56bright NK cells in three sJRA

> patients, a

> pattern similar to that previously observed in MAS and HLH. In

> conclusion, a

> subgroup of patients with JRA who have not yet had an episode of MAS

> showed

> decreased NK function and an absence of circulating CD56bright

> population,

> similar to the abnormalities observed in patients with MAS and HLH.

> This

> phenomenon was particularly common in the systemic form of JRA, a

> clinical

> entity strongly associated with MAS.

>

> PMID: 15642140 [PubMed - indexed for MEDLINE]

> ------------------------------------------------------

>

> Macrophage activation syndrome and reactive hemophagocytic

> lymphohistiocytosis: the same entities?

> Current Opinion in Rheumatology. 15(5):587-590, September 2003.

> Grom, ei A. MD

>

> Abstract:

> Purpose of the review: One of the most perplexing features of

> systemic-onset

> juvenile rheumatoid arthritis is the association with macrophage

> activation

> syndrome, a life-threatening complication caused by excessive

> activation

> and

> proliferation of T cells and macrophages. The main purpose of the

> review

> is

> to summarize current understanding of the relation between macrophage

> activation syndrome and other clinically similar hemophagocytic

> disorders.

>

> Recent findings: Clinically, macrophage activation syndrome has strong

> similarities with familial and virus-associated reactive

> hemophagocytic

> lymphohistiocytosis. The better understood familial hemophagocytic

> lymphohistiocytosis is a constellation of rare, autosomal recessive

> immune

> disorders. The most consistent immunologic abnormalities in patients

> with

> familial hemophagocytic lymphohistiocytosis are decreased natural

> killer

> and

> cytotoxic cell functions. In approximately one third of familial

> hemophagocytic lymphohistiocytosis patients, these immunologic

> abnormalities

> are secondary to mutations in the gene encoding perforin, a protein

> that

> mediates cytotoxic activity of natural killer and cytotoxic CD8+ T

> cells.

>

> Several recent studies have suggested that profoundly depressed

> natural

> killer cell activity and abnormal levels of perforin expression may

> be a

> feature of macrophage activation syndrome in systemic-onset juvenile

> rheumatoid arthritis as well. Although it has been proposed that in

> both

> hemophagocytic lymphohistiocytosis and macrophage activation syndrome,

> natural killer and cytotoxic cell dysfunction may lead to inadequate

> control

> of cellular immune responses, the exact nature of such

> dysregulation and

> the

> relation between macrophage activation syndrome and hemophagocytic

> lymphohistiocytosis still remain to be determined.

>

> ----------------------------------------------------------

>

> Reactive haemophagocytic syndrome in children with inflammatory

> disorders. A

> retrospective study of 24 patients.

> Rheumatology (Oxford). 2001 Nov;40(11):1285-92.

>

> Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur

> AM.

> Unite d'Hematologie et d'Oncologie Pediatriques, Hotel Dieu,

> Clermont-Ferrand, Service de Pediatrie, Hopital Nord, Marseille,

> France.

>

> BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a

> little-known

> life-threatening complication of rheumatic diseases in children. It

> reflects

> the extreme vulnerability of these patients, especially those with

> systemic-onset juvenile chronic arthritis (JCA). This

> immunohaematological

> process may be triggered by events such as herpes virus infection and

> non-steroidal anti-inflammatory drug therapy. Treatment has not been

> standardized.

>

> METHODS: We characterized this unusual disorder and determined its

> incidence

> by carrying out a retrospective study of patients identified over a

> 10-yr

> period in French paediatric units.

>

> RESULTS: Twenty-four cases (nine males, 15 females) were studied.

> Eighteen

> had typical systemic-onset JCA, two had polyarthritis, two had

> lupus and

> two

> had unclassifiable disorders. Clinical features at diagnosis included

> high

> spiking fever (24 patients), enlargement of the liver and spleen (14),

> haemorrhagic diathesis (six), pulmonary involvement (12) and

> neurological

> abnormalities (coma or seizures) (12).

>

> RHS was the first manifestation of systemic disease in three cases.

> Admission to intensive care was required in ten cases.

> Hypofibrinogenaemia,

> elevated liver enzymes and hypertriglyceridaemia were found

> consistently.

> Phagocytic histiocytes were found in 14 of 17 bone marrow smears.

>

> RHS was presumed to have been precipitated by infection in 11 cases

> (four

> Epstein-Barr virus, three varicella-zoster virus, one parvovirus B19,

> one

> sackie virus, one Salmonella, one Pneumocystis carinii) and by the

> introduction of medication in three cases (Salazopyrin plus

> methotrexate;

> morniflumate; aspirin). Macrophage activation was indicated by high

> levels

> of monokines in the serum of two patients. Twenty patients had only

> one

> episode, three had an early relapse and one patient had two relapses.

>

> The treatment regimen was tailored to each child as the clinical

> course

> was

> variable. There was no response to intravenous immunoglobulins, which

> were

> used in four cases. Intravenous steroids at doses ranging from

> conventional

> to pulse methylprednisolone induced remission in 15 of 21 episodes

> when

> used

> alone as the first-line treatment. Cyclosporin A was consistently and

> rapidly effective, both when used as second-line therapy in all

> seven of

> the

> episodes in which steroids failed and in all five patients who

> received

> it

> as their first-line treatment. This supports a central role of T

> lymphocytes

> in the haemophagocytic syndrome. Two patients died. One patient with

> lupus

> died of congestive fulminant heart failure after 4 days, despite

> treatment

> with intravenous steroids and immunoglobulins, and one patient with

> systemic-onset JCA died from multiorgan failure despite aggressive

> therapy

> with pulsed steroids and etoposide.

>

> CONCLUSIONS: RHS may be a more common complication of systemic disease

> in

> childhood than previously thought. This life-threatening complication

> should

> be diagnosed promptly, as it calls for the immediate withdrawal of

> potentially triggering medications, anti-infective therapy when

> relevant,

> and urgent immunosuppressive treatment, measures that are very often

> effective. Cyclosporin A may be the drug of choice.

>

> PMID: 11709613 [PubMed - indexed for MEDLINE]

> --------------------------------------------------

>

> Macrophage activation syndrome: a potentially fatal complication of

> rheumatic disorders.

> Arch Dis Child. 2001 Nov;85(5):421-6:

>

> Sawhney S, Woo P, Murray KJ.

> Department of Rheumatology, Great Ormond Street Hospital, London, UK.

>

> AIMS: To review the precipitating events, clinical features,

> treatment,

> and

> outcome of macrophage activation syndrome (MAS).

>

> METHODS: Retrospective review of cases of MAS from a prospectively

> collected

> database of children with rheumatic diseases from 1980 to 2000.

>

> RESULTS: Nine patients (eight girls) were considered to have

> evidence of

> MAS. The primary diagnosis was systemic onset juvenile idiopathic

> arthritis

> in seven, enthesitis related arthritis in one, and chronic infantile

> neurological cutaneous articular syndrome in one. Mean age of onset

> was

> 5.7

> years, and duration prior to MAS, 4.2 years.

>

> No medication was identified as a trigger. Eight had infections

> prior to

> MAS; specific infectious agents were identified in four. High grade

> fever,

> new onset hepatosplenomegaly, and lymphadenopathy were common clinical

> features. Platelet counts fell dramatically, from an average of 346 to

> 99 x

> 10(9)/l. Mean erythrocyte sedimentation rate (in three patients) fell

> from

> 115 to 28 mm/h. Eight had abnormal liver function during the disease

> course,

> and six had coagulopathy. Bone marrow examination supported the

> diagnosis

> with definite haemophagocytosis in four of seven.

>

> All received high dose steroids (eight intravenous, one oral), five

> cyclosporin, two cyclophosphamide, and one antithymocyte globulin. Two

> of

> three patients with significant renal impairment died.

>

> CONCLUSION: MAS is a rare and potentially fatal complication of

> childhood

> rheumatic disorders. Most of our patients were female, and most cases

> were

> preceded by infection. Bone marrow studies support the diagnosis.

> Deranged

> renal function may be a poor prognostic sign. Aggressive early therapy

> is

> essential.

>

> PMID: 11668110 [PubMed - indexed for MEDLINE]

>

>