macrophage activation syndrome

[Guest guest]

My last thoughts on this is that I still swear I read somewhere that

sometimes MAS manifests itself with meningitis-like symptoms and that if

there is a sore neck accompanied with fever and nausea and they can't find

any other reason, to have them check for this. I wish I could find out

where I read this...or maybe it was in my immunology class. If I do, I

will find the source and let everyone know.

kathy

[Guest guest]

Hi Bob,

I'm sending this right from the archives/ website. Anton sent

this in when 's daughter had MAS. I think maybe Anton's son

Vivien also had this happen. There are a few papers here that

will aid in your understanding. Please know that Tori and, of course,

you and the rest of the family, will be in our thoughts.

Sending positive energies,

Georgina and

1. MACROPHAGE ACTIVATION SYNDROME AT JUVENILE CHRONIC ARTHRITIS

ONSET.

06/1999, 6th EPRC, 6-9 June 99, Glasgow

Notes: Macrophage activation syndrome (MAS) is a disorder

characterized by

high prolonged fever, liver dysfunction, encephalopathy, cytopenias

and

abnormal coagulation. Different etiologies such as familial

hemophagocytic

lymphocytosis, congenital immunodeficiencies and viral infections have

been

implicated. More recently, cases of juvenile chronic arthritis (JCA),

mainly

long-standing disease, have been associated with the development of

MAS.

We describe 3 patients who developed JCA and MAS at the same time.

Case 1: This is a 22 months old boy, who presented 2 weeks of spiking

fever,

evanescent rash and arthritis of the right hip. Echocardiography

showed mild

pericardial effusion. Ibuprofen was indicated, developing transient

improvement within 48 hours. On day 5 malaise, high fever, vomiting

and mood

depression appeared. Within hours the patient status worsened,

developing

excitation, abdominal distention and tachypnea. Then he developed

extreme

bradychardia without response to resuscitation maneuvers. Autopsy

showed

prominent hemophagocytosis in lymph nodes, lamina propia of the

stomach and

small bowel, liver, spleen, brain and bone marrow. No signs of viral

or

other type of infection was found.

Case 2: This is an 8 year old girl with abdominal pain, vomiting,

erythematous rash and fever. A week later, she developed arthritis of

wrists

and small joints of the hands. On day 10 she presented hepatomegaly,

cytopenias and abnormal coagulation. Bone marrow showed prominent

hemophagocytosis. She responded to IV steroids and Gammaglobulin.

After 7

months of follow up she continues with arthritis of knees, ankles and

MTPs.

Case 3: This is a 4 year old boy with fever and polyarthritis 8 weeks

prior

to the development of hepatic failure. He was admitted to our hospital

after

10 days of the liver involvement, IV steroids were given, but he died

20

hours after his admission to the hospital. Bone marrow showed

prominent

hemophagocytosis.Laboratory FindingsPt. 1Pt. 2Pt.

3ESR12/6----100/42Hemoglobin8.7/7.49.2/7.49.8/9.5WBC663618000/37007800

/5000P

latelets543,000/----270,000/37,000381,0

72 " 36 " ----PTT42%40%----Prothrombin2815/1480233/--------SGOT/SGPT00/70,

00We

have described 3 patients who have developed systemic JCA and MAS

closely in

time. They all presented the clinical, hematological and

histopathological

findings of MAS. The fulminant course of patient 1 did not allow us to

confirm the diagnosis of JCA according to the duration of the

arthritis,

nevertheless other possible causes of MAS were ruled out. As far as we

know

the concurrence of MAS at the onset of JCA has been rarely described.

2. Beraud V, Kone Paut I, Sebahoun G, Berbis P. [Macrophage

activation

syndrome. Cutaneous manifestations] Syndrome d'activation des

macrophages.

Manifestations cutanees. Ann.Dermatol.Venereol. 1995; 122: 632-6.

3. De Benedetti F, Pignatti P, Massa M et al. Soluble tumour

necrosis

factor receptor levels reflect coagulation abnormalities in systemic

juvenile chronic arthritis. Br.J.Rheumatol. 1997; 36: 581-8.

Notes: The objective was to evaluate tumour necrosis factor (TNF)

status in

patients with systemic juvenile chronic arthritis (s- JCA). Plasma

levels of

TNF-alpha, and serum levels of soluble TNF receptor 1 and 2 (sTNFR1

and

sTNFR2) were measured using specific immunoassays in 20 patients with

s-JCA,

10 with polyarticular JCA and 15 with pauciarticular JCA, and in 20

controls

comparable for age. In patients with active s-JCA, circulating levels

of

TNF- alpha, sTNFR1 and sTNFR2 were significantly (P < 0.001) higher

than

those of controls. The levels of sTNFR1 and sTNFR2, but not those of

TNF-alpha, were associated with the persistence and severity of

systemic

symptoms and were significantly correlated with prolongation of

partial

thromboplastin time and decrease in prothrombin activity. In two

patients

evaluated during a s-JCA- associated macrophage activation syndrome, a

marked increase in sTNFR1 and sTNFR2 was found. Our results suggest

that in

s-JCA, TNF is involved in systemic manifestations, in the subclinical

coagulation abnormalities, and in the development of the macrophage

activation syndrome

4. Imagawa T, Katakura S, Mori M, Aihara Y, Mitsuda T, Yokota S. [A

case

of macrophage activation syndrome developed with systemic juvenile

rheumatoid arthritis]. Ryumachi 1997; 37: 487-92.

Notes: 97399941 Address: Department of Pediatrics, Yokohama City

University

School of Medicine We reported a child of macrophage activation

syndrome

(MAS) associated with the course of systemic juvenile rheumatoid

arthritis

(sJRA). The clinical and laboratory findings in our case was ascribed

to the

overproduced inflammatory cytokines especially TNF-alpha by activated

macrophages. Moreover, macrophage-colony stimulating factor (M-CSF)

was also

elevated in the active phase of the disease, and decreased in the

convalescent phase, indicating that M-CSF can be the most potent

stimulator

of macrophages to produce inflammatory cytokines. Cyclosporine A along

with

plasmaexchange and corticosteroid, instead of VP16 or other

immunosuppresive

agents, was effecting in the management of this severe,

life-threatening MAS

Type: JOURNAL ARTICLE ISSN: 0300-9157 Language: Jpn

5. ML. Clinical aspects of juvenile rheumatoid arthritis.

Curr.Opin.Rheumatol. 1997; 9: 423-7.

Notes: This paper reviews studies in epidemiology, differential

diagnosis,

clinical manifestations, and treatment of juvenile rheumatoid

arthritis

(JRA) that have appeared during the past year. One epidemiologic study

suggested a decreased incidence recently; however, changes over time

in the

ethnic and racial characteristics of the patients studied may also

have

played a role. Findings from an Australian study suggested that some

studies

may underestimate the true incidence of JRA if visits of physicians

are the

only basis for the studies. Finally, a Canadian study of incidence

showed no

seasonal correlations-- except for the Prairie region--raising the

possibility that the disease varies by region because of environmental

factors or variations in ethnic background. Differential diagnostic

issues

were covered in several reports. One study suggested that elevations

in

lactate dehydrogenase levels identified children with malignancies who

presented with musculoskeletal symptoms. Another study of children

with Lyme

disease failed to find any patients with asymmetric joint involvement,

in

contrast to JRA patients. Two studies from Europe reached opposite

conclusions regarding whether the incidence of celiac disease was

increased

in JRA patients. Clinical studies included a French study showing

increased

production of interleukin-6 and interleukin-1-Ra during fever spikes

in

children with systemic JRA. An Italian study explored the potential

role of

interleukin-6 in the anemia of JRA patients. An American study

confirmed

decreases in markers of bone formation in JRA patients. Two treatment

studies addressed the use of intravenous gamma globulin in JRA.

Another

report described two JRA patients who developed nodules while

receiving

methotrexate. Finally, a report added confirmation to the successful

use of

cyclosporine for macrophage activation syndrome in JRA Type: JOURNAL

ARTICLE

Type: REVIEW Type: REVIEW, TUTORIAL ISSN: 1040-8711 Language: Eng

6. Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM.

Efficacy

of cyclosporine A in the treatment of macrophage activation syndrome

in

juvenile arthritis: report of five cases [see comments]. J Pediatr

1996;

129: 750-4.

Abstract: OBJECTIVES: To evaluate the efficacy of cyclosporine A in

the

treatment of macrophage activation syndrome (MAS) occurring in

children with

juvenile arthritis. STUDY DESIGN: MAS developed in two boys and three

girls

with systemic juvenile arthritis (four) and polyarticular juvenile

arthritis

(one). In three children whose condition was life-threatening,

increased

parenteral administration of corticosteroids failed to improve their

condition; therefore cyclosporine A (2 to 5 mg/kg per day) was added.

In two

other patients with less severe clinical manifestations, cyclosporine

A

alone (2 to 8 mg/kg per day) was given. RESULTS: After the

introduction of

cyclosporine A, rapid improvement was obtained in all patients and

apyrexia

occurred within 24 to 48 hours. The biologic abnormalities disappeared

more

slowly (up to 5 weeks for liver enzymes). CONCLUSIONS: These

observations

underline the usefulness of cyclosporine A in this complication. The

use of

this drug may circumvent the need for increased doses of

corticosteroids in

some patients. The mechanism of action of cyclosporine A remains

speculative, but these results indicate indirectly that T-helper

lymphocytes

may play a role in the pathogenesis of MAS

Notes: 97074817

ISSN: 0022-3476

7. SB. Cyclosporine in activated macrophage and histiocytic

syndromes. Journal of Pediatrics 1997; 130: 1012-3.

8. Ravelli A, De Benedetti F, Viola S, i A. Macrophage

activation

syndrome in systemic juvenile rheumatoid arthritis successfully

treated with

cyclosporine. J.Pediatr. 1996; 128: 275-8.

Notes: A macrophage activation syndrome, possibly related to

methotrexate

toxicity, developed in a boy with systemic juvenile rheumatoid

arthritis.

Corticosteroid administration was ineffective, whereas a prompt

response to

cyclosporine was observed. Two months later, Pneumocystis carinii

pneumonia

developed

9. Ravelli, A., Viola, S., De Benedetti, F., Migliavacca, D.,

Mongini, E.,

i, A., and i. DRAMATIC EFFICACY OF CYCLOSPORINE A IN

CORTICOSTEROID RESISTANT MACROPHAGE ACTIVATION SYNDROME. 1999. 6th

European Pediatric Rheumatology Congress, Glasgow. 1999.

Abstract: Macrophage activation syndrome (MAS) is a potentially

life-threatening complication of rheumatologic diseases. Recently, it

has

been reported that cyclosporine A (CyA) may be effective in the

treatment of

this syndrome. We have observed a dramatic efficacy of CyA in 2

children

with MAS refractory to corticosteroid treatment.

Patient #1: A 9-year-old boy developed an unspecified systemic

inflammatory

syndrome that resolved with prednisone therapy. Three months after

prednisone stop he was readmitted with fever, thrombocytopenia,

microangiopathic anemia, macrohematuria, renal insufficiency, and

severe

neurologic involvement consistent with a thrombotic thrombocytopenic

purpura. Repeated plasma exchange led to complete recovery. One week

later

he developed intermittent high fever, liver failure, leukopenia,

thrombocytopenia, evidence of intravascular coagulation, and

hypertriglyceridemia. Urinalysis was normal. Plasma ferritin peaked

from

30.000 to 540.000 ng/ml. Bone marrow aspirate disclosed

hemophagocytosis.

Treatment with iv methylprednisolone, 4 mg/Kg/day was begun. Since

this did

not affect the course of MAS, we started iv CyA, 3 mg/kg/day. Fever

disappeared within 6 hours and patient's clinical conditions and

laboratory

abnormalities improved rapidly.

Patient #2: A 11-year-old girl was diagnosed as having systemic lupus

erythematosus (SLE) based on the association of arthritis, leukopenia,

nephritis, ANA and anti-DNA antibodies. Prednisone therapy allowed

improvement of clinical manifestations, decrease of ANA titre, and

disappearance of anti-DNA antibodies within one month. Shortly

afterwards,

when the lupus disease was quiescent, she developed unexplained high

fever

that was unaffected by a 7-day treatment with ceftriaxone. Laboratory

investigations showed leukopenia, anaemia, thrombocytopenia, ESR

increase,

hypertriglyceridemia, and increased LDH, whereas autoantibody levels

were

unchanged and serum complement fractions were normal. Plasma ferritin

reached 9265 ng/ml and there was evidence of macrophage

hemophagocytosis in

the bone marrow. Due to the inefficacy of prednisone, 2 mg/kg/day,

oral CyA,

5 mg/kg/day was begun. This resulted in resolution of fever within 24

hours

and prompt improvement of laboratory changes.

Conclusions: Our observations provide evidence that CyA can reverse

dramatically the clinical and laboratory abnormalities in patients

with MAS

that are refractory to corticosteroid treatment.

10. Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM.

Macrophage activation syndrome and rheumatic disease in childhood: a

report

of four new cases. Clin.Exp.Rheumatol. 1993; 11: 451-6.

Notes: A macrophage activation syndrome (MAS) developed in four

children

with chronic rheumatic diseases. The presentation included fever,

hepatic

and splenic enlargement, profound depression of blood counts, lowering

of

ESR, elevation of SGOT/PT and hypofibrinogenemia. The most

characteristic

sign of MAS was the presence in the bone marrow aspirate of well

differentiated macrophages showing active haemophagocytosis with

haematopoietic elements in their cytoplasm. Activation of the

macrophage was

also illustrated by high levels of monokines in the serum of 2

patients.

This immuno-hematological process of unknown etiology can be triggered

by

ubiquitous events such as infections and treatment with

anti-inflammatory

drugs. It is a potentially lethal complication which should be

diagnosed

rapidly, since administration of high-dose steroids with

discontinuation of

potentially toxic drugs can induce remission. Cyclosporin A was

effective in

two patients and may be of value in the management of the

macrophage-activation syndrome. Its efficacy supports the central

involvement of a T-cell dysfunction. It must be borne in mind that

children

with rheumatic diseases, especially the systemic form of juvenile

chronic

arthritis, are highly vulnerable to life-threatening macrophage

activation,

which appears to be more frequent than previously recognized. Very

careful

monitoring of apparently " innocent " drugs and intercurrent viral

infections

is thus required

[ ] macrophage activation syndrome

> From: Skis@a...

>

> Does anybody have any experience with macrophage activation syndrome

in

> combination with systemic JRA? If so please respond ASAP with

details.

> Thanks

--- End forwarded message ---

[Guest guest]

Thank you Michele, I appreciate it.

Take care.

Patty

[Guest guest]

In a message dated 2/27/04 2:03:19 PM Eastern Standard Time,

MTepper@... writes:

<<

> splenic enlargement, profound depression of blood counts, lowering

of ESR,

> elevation of SGOT/PT and hypofibrinogenemia. The most

characteristic sign of

> MAS was the presence in the bone marrow aspirate of well

differentiated

> macrophages showing active haemophagocytosis with haematopoietic

elements in

> their cytoplasm. Activation of the macrophage was also illustrated

by high

> levels of monokines in the serum of 2 patients. This immuno-

hematological

> process of unknown etiology can be triggered by ubiquitous events

such as >>

This is like reading Latin. Any idea of what it means? Layman terms. We

always celebrate at lower sed rates, but this seems to say it's a symptom????

Thanks.

Patty

[Guest guest]

Found this in my JRA folder. I'll keep looking for any info that I can

dig up. Michele

macrophage activation syndrome

: J Rheumatol 2001 Apr;28(4):865-7 Related Articles, Books

Methotrexate as a possible trigger of macrophage activation syndrome in

systemic juvenile idiopathic arthritis.

Ravelli A, Caria MC, Buratti S, Malattia C, Temporini F, i A.

Dipartimento di Scienze Pediatriche, Universita di Pavia, Istituto di

Ricovero e Cura a Carattere Scientifico S. Matteo, Italy.

Macrophage activation syndrome (MAS) is a potentially life threatening

complication of chronic rheumatic diseases, particularly systemic

juvenile

idiopathic arthritis (JIA). A number of triggers have been related to

the

development of MAS, including viral infections, nonsteroidal

antiinflammatory

drug therapy, and gold salt injections. We describe a patient with

systemic

JIA who developed MAS shortly after receiving methotrexate, suggesting

that

this drug can be regarded as a potential trigger of MAS in children with

JIA.

PMID: 11327264 [PubMed - in process]

To manage your subscription settings, please visit:

For links to websites about JRA:

http://www.geocities.com/Heartland/Village/8414/Links.html

[Guest guest]

Found this one too.

> Clin Exp Rheumatol 1993 Jul-Aug;11(4):451-6 Related Articles,

Books, LinkOut

>

>

> Macrophage activation syndrome and rheumatic disease in childhood:

a report

> of four new cases.

>

> Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM.

>

> Pediatric Rheumatology Unit, Hopital des Enfants Malades, Paris,

France.

>

> A macrophage activation syndrome (MAS) developed in four children

with

> chronic rheumatic diseases. The presentation included fever,

hepatic and

> splenic enlargement, profound depression of blood counts, lowering

of ESR,

> elevation of SGOT/PT and hypofibrinogenemia. The most

characteristic sign of

> MAS was the presence in the bone marrow aspirate of well

differentiated

> macrophages showing active haemophagocytosis with haematopoietic

elements in

> their cytoplasm. Activation of the macrophage was also illustrated

by high

> levels of monokines in the serum of 2 patients. This immuno-

hematological

> process of unknown etiology can be triggered by ubiquitous events

such as

> infections and treatment with anti-inflammatory drugs. It is a

potentially

> lethal complication which should be diagnosed rapidly, since

administration

> of high-dose steroids with discontinuation of potentially toxic

drugs can

> induce remission. Cyclosporin A was effective in two patients and

may be of

> value in the management of the macrophage-activation syndrome. Its

efficacy

> supports the central involvement of a T-cell dysfunction. It must

be borne in

> mind that children with rheumatic diseases, especially the

systemic form of

> juvenile chronic arthritis, are highly vulnerable to life-

threatening

> macrophage activation, which appears to be more frequent than

previously

> recognized. Very careful monitoring of apparently " innocent " drugs

and

> intercurrent viral infections is thus required.

>

> PMID: 8403593 [PubMed - indexed for MEDLINE]

[Guest guest]

Found one more. These are in archives back in May,2001 if anyone

wants to follow the threads about this. If you get through the

medical jargon, there is good info in these.

> Hi Bob,

>

> I'm sending this right from the archives/ website. Anton

sent

> this in when 's daughter had MAS. I think maybe Anton's

son

> Vivien also had this happen. There are a few papers here that

> will aid in your understanding. Please know that Tori and, of

course,

> you and the rest of the family, will be in our thoughts.

>

> Sending positive energies,

> Georgina and

>

>

> 1. MACROPHAGE ACTIVATION SYNDROME AT JUVENILE CHRONIC ARTHRITIS

> ONSET.

> 06/1999, 6th EPRC, 6-9 June 99, Glasgow

> Notes: Macrophage activation syndrome (MAS) is a disorder

> characterized by

> high prolonged fever, liver dysfunction, encephalopathy,

cytopenias

> and

> abnormal coagulation. Different etiologies such as familial

> hemophagocytic

> lymphocytosis, congenital immunodeficiencies and viral infections

have

> been

> implicated. More recently, cases of juvenile chronic arthritis

(JCA),

> mainly

> long-standing disease, have been associated with the development

of

> MAS.

>

> We describe 3 patients who developed JCA and MAS at the same time.

>

> Case 1: This is a 22 months old boy, who presented 2 weeks of

spiking

> fever,

> evanescent rash and arthritis of the right hip. Echocardiography

> showed mild

> pericardial effusion. Ibuprofen was indicated, developing transient

> improvement within 48 hours. On day 5 malaise, high fever,

vomiting

> and mood

> depression appeared. Within hours the patient status worsened,

> developing

> excitation, abdominal distention and tachypnea. Then he developed

> extreme

> bradychardia without response to resuscitation maneuvers. Autopsy

> showed

> prominent hemophagocytosis in lymph nodes, lamina propia of the

> stomach and

> small bowel, liver, spleen, brain and bone marrow. No signs of

viral

> or

> other type of infection was found.

>

> Case 2: This is an 8 year old girl with abdominal pain, vomiting,

> erythematous rash and fever. A week later, she developed arthritis

of

> wrists

> and small joints of the hands. On day 10 she presented

hepatomegaly,

> cytopenias and abnormal coagulation. Bone marrow showed prominent

> hemophagocytosis. She responded to IV steroids and Gammaglobulin.

> After 7

> months of follow up she continues with arthritis of knees, ankles

and

> MTPs.

>

> Case 3: This is a 4 year old boy with fever and polyarthritis 8

weeks

> prior

> to the development of hepatic failure. He was admitted to our

hospital

> after

> 10 days of the liver involvement, IV steroids were given, but he

died

> 20

> hours after his admission to the hospital. Bone marrow showed

> prominent

> hemophagocytosis.Laboratory FindingsPt. 1Pt. 2Pt.

> 3ESR12/6----

100/42Hemoglobin8.7/7.49.2/7.49.8/9.5WBC663618000/37007800

> /5000P

> latelets543,000/----270,000/37,000381,0

>

> 72 " 36 " ----PTT42%40%----Prothrombin2815/1480233/--------

SGOT/SGPT00/70,

> 00We

> have described 3 patients who have developed systemic JCA and MAS

> closely in

> time. They all presented the clinical, hematological and

> histopathological

> findings of MAS. The fulminant course of patient 1 did not allow

us to

> confirm the diagnosis of JCA according to the duration of the

> arthritis,

> nevertheless other possible causes of MAS were ruled out. As far

as we

> know

> the concurrence of MAS at the onset of JCA has been rarely

described.

>

> 2. Beraud V, Kone Paut I, Sebahoun G, Berbis P. [Macrophage

> activation

> syndrome. Cutaneous manifestations] Syndrome d'activation des

> macrophages.

> Manifestations cutanees. Ann.Dermatol.Venereol. 1995; 122: 632-6.

>

> 3. De Benedetti F, Pignatti P, Massa M et al. Soluble tumour

> necrosis

> factor receptor levels reflect coagulation abnormalities in

systemic

> juvenile chronic arthritis. Br.J.Rheumatol. 1997; 36: 581-8.

> Notes: The objective was to evaluate tumour necrosis factor (TNF)

> status in

> patients with systemic juvenile chronic arthritis (s- JCA). Plasma

> levels of

> TNF-alpha, and serum levels of soluble TNF receptor 1 and 2

(sTNFR1

> and

> sTNFR2) were measured using specific immunoassays in 20 patients

with

> s-JCA,

> 10 with polyarticular JCA and 15 with pauciarticular JCA, and in

20

> controls

> comparable for age. In patients with active s-JCA, circulating

levels

> of

> TNF- alpha, sTNFR1 and sTNFR2 were significantly (P < 0.001)

higher

> than

> those of controls. The levels of sTNFR1 and sTNFR2, but not those

of

> TNF-alpha, were associated with the persistence and severity of

> systemic

> symptoms and were significantly correlated with prolongation of

> partial

> thromboplastin time and decrease in prothrombin activity. In two

> patients

> evaluated during a s-JCA- associated macrophage activation

syndrome, a

> marked increase in sTNFR1 and sTNFR2 was found. Our results

suggest

> that in

> s-JCA, TNF is involved in systemic manifestations, in the

subclinical

> coagulation abnormalities, and in the development of the macrophage

> activation syndrome

>

> 4. Imagawa T, Katakura S, Mori M, Aihara Y, Mitsuda T, Yokota S.

[A

> case

> of macrophage activation syndrome developed with systemic juvenile

> rheumatoid arthritis]. Ryumachi 1997; 37: 487-92.

> Notes: 97399941 Address: Department of Pediatrics, Yokohama City

> University

> School of Medicine We reported a child of macrophage activation

> syndrome

> (MAS) associated with the course of systemic juvenile rheumatoid

> arthritis

> (sJRA). The clinical and laboratory findings in our case was

ascribed

> to the

> overproduced inflammatory cytokines especially TNF-alpha by

activated

> macrophages. Moreover, macrophage-colony stimulating factor (M-

CSF)

> was also

> elevated in the active phase of the disease, and decreased in the

> convalescent phase, indicating that M-CSF can be the most potent

> stimulator

> of macrophages to produce inflammatory cytokines. Cyclosporine A

along

> with

> plasmaexchange and corticosteroid, instead of VP16 or other

> immunosuppresive

> agents, was effecting in the management of this severe,

> life-threatening MAS

> Type: JOURNAL ARTICLE ISSN: 0300-9157 Language: Jpn

>

> 5. ML. Clinical aspects of juvenile rheumatoid arthritis.

> Curr.Opin.Rheumatol. 1997; 9: 423-7.

> Notes: This paper reviews studies in epidemiology, differential

> diagnosis,

> clinical manifestations, and treatment of juvenile rheumatoid

> arthritis

> (JRA) that have appeared during the past year. One epidemiologic

study

> suggested a decreased incidence recently; however, changes over

time

> in the

> ethnic and racial characteristics of the patients studied may also

> have

> played a role. Findings from an Australian study suggested that

some

> studies

> may underestimate the true incidence of JRA if visits of

physicians

> are the

> only basis for the studies. Finally, a Canadian study of incidence

> showed no

> seasonal correlations-- except for the Prairie region--raising the

> possibility that the disease varies by region because of

environmental

> factors or variations in ethnic background. Differential

diagnostic

> issues

> were covered in several reports. One study suggested that

elevations

> in

> lactate dehydrogenase levels identified children with malignancies

who

> presented with musculoskeletal symptoms. Another study of children

> with Lyme

> disease failed to find any patients with asymmetric joint

involvement,

> in

> contrast to JRA patients. Two studies from Europe reached opposite

> conclusions regarding whether the incidence of celiac disease was

> increased

> in JRA patients. Clinical studies included a French study showing

> increased

> production of interleukin-6 and interleukin-1-Ra during fever

spikes

> in

> children with systemic JRA. An Italian study explored the

potential

> role of

> interleukin-6 in the anemia of JRA patients. An American study

> confirmed

> decreases in markers of bone formation in JRA patients. Two

treatment

> studies addressed the use of intravenous gamma globulin in JRA.

> Another

> report described two JRA patients who developed nodules while

> receiving

> methotrexate. Finally, a report added confirmation to the

successful

> use of

> cyclosporine for macrophage activation syndrome in JRA Type:

JOURNAL

> ARTICLE

> Type: REVIEW Type: REVIEW, TUTORIAL ISSN: 1040-8711 Language: Eng

>

> 6. Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM.

> Efficacy

> of cyclosporine A in the treatment of macrophage activation

syndrome

> in

> juvenile arthritis: report of five cases [see comments]. J Pediatr

> 1996;

> 129: 750-4.

> Abstract: OBJECTIVES: To evaluate the efficacy of cyclosporine A

in

> the

> treatment of macrophage activation syndrome (MAS) occurring in

> children with

> juvenile arthritis. STUDY DESIGN: MAS developed in two boys and

three

> girls

> with systemic juvenile arthritis (four) and polyarticular juvenile

> arthritis

> (one). In three children whose condition was life-threatening,

> increased

> parenteral administration of corticosteroids failed to improve

their

> condition; therefore cyclosporine A (2 to 5 mg/kg per day) was

added.

> In two

> other patients with less severe clinical manifestations,

cyclosporine

> A

> alone (2 to 8 mg/kg per day) was given. RESULTS: After the

> introduction of

> cyclosporine A, rapid improvement was obtained in all patients and

> apyrexia

> occurred within 24 to 48 hours. The biologic abnormalities

disappeared

> more

> slowly (up to 5 weeks for liver enzymes). CONCLUSIONS: These

> observations

> underline the usefulness of cyclosporine A in this complication.

The

> use of

> this drug may circumvent the need for increased doses of

> corticosteroids in

> some patients. The mechanism of action of cyclosporine A remains

> speculative, but these results indicate indirectly that T-helper

> lymphocytes

> may play a role in the pathogenesis of MAS

> Notes: 97074817

> ISSN: 0022-3476

>

> 7. SB. Cyclosporine in activated macrophage and

histiocytic

> syndromes. Journal of Pediatrics 1997; 130: 1012-3.

>

> 8. Ravelli A, De Benedetti F, Viola S, i A. Macrophage

> activation

> syndrome in systemic juvenile rheumatoid arthritis successfully

> treated with

> cyclosporine. J.Pediatr. 1996; 128: 275-8.

> Notes: A macrophage activation syndrome, possibly related to

> methotrexate

> toxicity, developed in a boy with systemic juvenile rheumatoid

> arthritis.

> Corticosteroid administration was ineffective, whereas a prompt

> response to

> cyclosporine was observed. Two months later, Pneumocystis carinii

> pneumonia

> developed

> 9. Ravelli, A., Viola, S., De Benedetti, F., Migliavacca, D.,

> Mongini, E.,

> i, A., and i. DRAMATIC EFFICACY OF CYCLOSPORINE A IN

> CORTICOSTEROID RESISTANT MACROPHAGE ACTIVATION SYNDROME. 1999.

6th

> European Pediatric Rheumatology Congress, Glasgow. 1999.

> Abstract: Macrophage activation syndrome (MAS) is a potentially

> life-threatening complication of rheumatologic diseases. Recently,

it

> has

> been reported that cyclosporine A (CyA) may be effective in the

> treatment of

> this syndrome. We have observed a dramatic efficacy of CyA in 2

> children

> with MAS refractory to corticosteroid treatment.

>

> Patient #1: A 9-year-old boy developed an unspecified systemic

> inflammatory

> syndrome that resolved with prednisone therapy. Three months after

> prednisone stop he was readmitted with fever, thrombocytopenia,

> microangiopathic anemia, macrohematuria, renal insufficiency, and

> severe

> neurologic involvement consistent with a thrombotic

thrombocytopenic

> purpura. Repeated plasma exchange led to complete recovery. One

week

> later

> he developed intermittent high fever, liver failure, leukopenia,

> thrombocytopenia, evidence of intravascular coagulation, and

> hypertriglyceridemia. Urinalysis was normal. Plasma ferritin

peaked

> from

> 30.000 to 540.000 ng/ml. Bone marrow aspirate disclosed

> hemophagocytosis.

> Treatment with iv methylprednisolone, 4 mg/Kg/day was begun. Since

> this did

> not affect the course of MAS, we started iv CyA, 3 mg/kg/day. Fever

> disappeared within 6 hours and patient's clinical conditions and

> laboratory

> abnormalities improved rapidly.

>

> Patient #2: A 11-year-old girl was diagnosed as having systemic

lupus

> erythematosus (SLE) based on the association of arthritis,

leukopenia,

> nephritis, ANA and anti-DNA antibodies. Prednisone therapy allowed

> improvement of clinical manifestations, decrease of ANA titre, and

> disappearance of anti-DNA antibodies within one month. Shortly

> afterwards,

> when the lupus disease was quiescent, she developed unexplained

high

> fever

> that was unaffected by a 7-day treatment with ceftriaxone.

Laboratory

> investigations showed leukopenia, anaemia, thrombocytopenia, ESR

> increase,

> hypertriglyceridemia, and increased LDH, whereas autoantibody

levels

> were

> unchanged and serum complement fractions were normal. Plasma

ferritin

> reached 9265 ng/ml and there was evidence of macrophage

> hemophagocytosis in

> the bone marrow. Due to the inefficacy of prednisone, 2 mg/kg/day,

> oral CyA,

> 5 mg/kg/day was begun. This resulted in resolution of fever within

24

> hours

> and prompt improvement of laboratory changes.

>

> Conclusions: Our observations provide evidence that CyA can reverse

> dramatically the clinical and laboratory abnormalities in patients

> with MAS

> that are refractory to corticosteroid treatment.

>

> 10. Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur

AM.

> Macrophage activation syndrome and rheumatic disease in childhood:

a

> report

> of four new cases. Clin.Exp.Rheumatol. 1993; 11: 451-6.

> Notes: A macrophage activation syndrome (MAS) developed in four

> children

> with chronic rheumatic diseases. The presentation included fever,

> hepatic

> and splenic enlargement, profound depression of blood counts,

lowering

> of

> ESR, elevation of SGOT/PT and hypofibrinogenemia. The most

> characteristic

> sign of MAS was the presence in the bone marrow aspirate of well

> differentiated macrophages showing active haemophagocytosis with

> haematopoietic elements in their cytoplasm. Activation of the

> macrophage was

> also illustrated by high levels of monokines in the serum of 2

> patients.

> This immuno-hematological process of unknown etiology can be

triggered

> by

> ubiquitous events such as infections and treatment with

> anti-inflammatory

> drugs. It is a potentially lethal complication which should be

> diagnosed

> rapidly, since administration of high-dose steroids with

> discontinuation of

> potentially toxic drugs can induce remission. Cyclosporin A was

> effective in

> two patients and may be of value in the management of the

> macrophage-activation syndrome. Its efficacy supports the central

> involvement of a T-cell dysfunction. It must be borne in mind that

> children

> with rheumatic diseases, especially the systemic form of juvenile

> chronic

> arthritis, are highly vulnerable to life-threatening macrophage

> activation,

> which appears to be more frequent than previously recognized. Very

> careful

> monitoring of apparently " innocent " drugs and intercurrent viral

> infections

> is thus required

>

> [ ] macrophage activation syndrome

>

>

> > From: Skis@a...

> >

> > Does anybody have any experience with macrophage activation

syndrome

> in

> > combination with systemic JRA? If so please respond ASAP with

> details.

> > Thanks

> --- End forwarded message ---

[Guest guest]

From: gmckin@...

Date: Tue May 22, 2001 1:47 pm

Subject: Fwd: Re: macrophage activation syndrome

Hi Bob,

I'm sending this right from the archives/ website. Anton sent

this in when 's daughter had MAS. I think maybe Anton's son

Vivien also had this happen. There are a few papers here that

will aid in your understanding. Please know that Tori and, of course,

you and the rest of the family, will be in our thoughts.

Sending positive energies,

Georgina and

1. MACROPHAGE ACTIVATION SYNDROME AT JUVENILE CHRONIC ARTHRITIS ONSET.

06/1999, 6th EPRC, 6-9 June 99, Glasgow

Notes: Macrophage activation syndrome (MAS) is a disorder characterized

by high prolonged fever, liver dysfunction, encephalopathy, cytopenias

and abnormal coagulation. Different etiologies such as familial

hemophagocytic lymphocytosis, congenital immunodeficiencies and viral

infections have been implicated. More recently, cases of juvenile

chronic arthritis (JCA), mainly long-standing disease, have been

associated with the development of MAS.

We describe 3 patients who developed JCA and MAS at the same time.

Case 1: This is a 22 months old boy, who presented 2 weeks of spiking

fever, evanescent rash and arthritis of the right hip. Echocardiography

showed mild pericardial effusion. Ibuprofen was indicated, developing

transient improvement within 48 hours. On day 5 malaise, high fever,

vomiting and mood depression appeared. Within hours the patient status

worsened, developing excitation, abdominal distention and tachypnea.

Then he developed extreme bradychardia without response to resuscitation

maneuvers. Autopsy showed prominent hemophagocytosis in lymph nodes,

lamina propia of the stomach and small bowel, liver, spleen, brain and

bone marrow. No signs of viral or other type of infection was found.

Case 2: This is an 8 year old girl with abdominal pain, vomiting,

erythematous rash and fever. A week later, she developed arthritis of

wrists and small joints of the hands. On day 10 she presented

hepatomegaly, cytopenias and abnormal coagulation. Bone marrow showed

prominent hemophagocytosis. She responded to IV steroids and

Gammaglobulin. After 7 months of follow up she continues with arthritis

of knees, ankles and MTPs.

Case 3: This is a 4 year old boy with fever and polyarthritis 8 weeks

prior to the development of hepatic failure. He was admitted to our

hospital after 10 days of the liver involvement, IV steroids were given,

but he died 20 hours after his admission to the hospital. Bone marrow

showed prominent hemophagocytosis.

Laboratory FindingsPt. 1Pt. 2Pt.3

ESR12/6----100/42Hemoglobin8.7/7.49.2/7.49.8/9.5WBC663618000/37007800

/5000Platelets543,000/----270,000/37,000381,0

72 " 36 " ----PTT42%40%----Prothrombin2815/1480233/--------SGOT/SGPT00/70,

00

We have described 3 patients who have developed systemic JCA and MAS

closely in time. They all presented the clinical, hematological and

histopathological findings of MAS. The fulminant course of patient 1 did

not allow us to confirm the diagnosis of JCA according to the duration

of the arthritis, nevertheless other possible causes of MAS were ruled

out. As far as we know the concurrence of MAS at the onset of JCA has

been rarely described.

2. Beraud V, Kone Paut I, Sebahoun G, Berbis P.

[Macrophage activation syndrome. Cutaneous manifestations] Syndrome

d'activation des macrophages. Manifestations cutanees.

Ann.Dermatol.Venereol. 1995; 122: 632-6.

3. De Benedetti F, Pignatti P, Massa M et al. Soluble tumour

necrosis factor receptor levels reflect coagulation abnormalities in

systemic juvenile chronic arthritis. Br.J.Rheumatol. 1997; 36: 581-8.

Notes: The objective was to evaluate tumour necrosis factor (TNF)

status in patients with systemic juvenile chronic arthritis (s- JCA).

Plasma levels of TNF-alpha, and serum levels of soluble TNF receptor 1

and 2 (sTNFR1 and sTNFR2) were measured using specific immunoassays in

20 patients with s-JCA, 10 with polyarticular JCA and 15 with

pauciarticular JCA, and in 20 controls comparable for age.

In patients with active s-JCA, circulating levels of TNF- alpha, sTNFR1

and sTNFR2 were significantly (P < 0.001) higher than those of controls.

The levels of sTNFR1 and sTNFR2, but not those of TNF-alpha, were

associated with the persistence and severity of systemic symptoms and

were significantly correlated with prolongation of partial

thromboplastin time and decrease in prothrombin activity. In two

patients evaluated during a s-JCA- associated macrophage activation

syndrome, a marked increase in sTNFR1 and sTNFR2 was found. Our results

suggest that in s-JCA, TNF is involved in systemic manifestations, in

the subclinical coagulation abnormalities, and in the development of the

macrophage activation syndrome

4. Imagawa T, Katakura S, Mori M, Aihara Y, Mitsuda T, Yokota S. [A

case of macrophage activation syndrome developed with systemic juvenile

rheumatoid arthritis]. Ryumachi 1997; 37: 487-92.

Notes: 97399941 Address: Department of Pediatrics, Yokohama City

University School of Medicine We reported a child of macrophage

activation syndrome (MAS) associated with the course of systemic

juvenile rheumatoid arthritis (sJRA). The clinical and laboratory

findings in our case was ascribed to the overproduced inflammatory

cytokines especially TNF-alpha by activated macrophages. Moreover,

macrophage-colony stimulating factor (M-CSF) was also elevated in the

active phase of the disease, and decreased in the convalescent phase,

indicating that M-CSF can be the most potent stimulator of macrophages

to produce inflammatory cytokines. Cyclosporine A along with

plasmaexchange and corticosteroid, instead of VP16 or other

immunosuppresive agents, was effecting in the management of this severe,

life-threatening MAS

Type: JOURNAL ARTICLE ISSN: 0300-9157 Language: Jpn

5. ML. Clinical aspects of juvenile rheumatoid arthritis.

Curr.Opin.Rheumatol. 1997; 9: 423-7.

Notes: This paper reviews studies in epidemiology, differential

diagnosis, clinical manifestations, and treatment of juvenile rheumatoid

arthritis (JRA) that have appeared during the past year. One

epidemiologic study suggested a decreased incidence recently; however,

changes over time in the ethnic and racial characteristics of the

patients studied may also have played a role. Findings from an

Australian study suggested that some studies may underestimate the true

incidence of JRA if visits of physicians are the only basis for the

studies. Finally, a Canadian study of incidence showed no seasonal

correlations-- except for the Prairie region--raising the possibility

that the disease varies by region because of environmental factors or

variations in ethnic background. Differential diagnostic issues were

covered in several reports. One study suggested that elevations in

lactate dehydrogenase levels identified children with malignancies who

presented with musculoskeletal symptoms. Another study of children

with Lyme disease failed to find any patients with asymmetric joint

involvement, in contrast to JRA patients. Two studies from Europe

reached opposite conclusions regarding whether the incidence of celiac

disease was increased in JRA patients. Clinical studies included a

French study showing increased production of interleukin-6 and

interleukin-1-Ra during fever spikes in children with systemic JRA. An

Italian study explored the potential role of interleukin-6 in the anemia

of JRA patients. An American study confirmed decreases in markers of

bone formation in JRA patients. Two treatment studies addressed the use

of intravenous gamma globulin in JRA.

Another report described two JRA patients who developed nodules while

receiving methotrexate. Finally, a report added confirmation to the

successful use of cyclosporine for macrophage activation syndrome in JRA

Type: JOURNAL ARTICLE

Type: REVIEW Type: REVIEW, TUTORIAL ISSN: 1040-8711 Language: Eng

6. Mouy R, Stephan JL, Pillet P, Haddad E, Hubert P, Prieur AM.

Efficacy of cyclosporine A in the treatment of macrophage activation

syndrome in juvenile arthritis: report of five cases [see comments]. J

Pediatr 1996; 129: 750-4.

Abstract: OBJECTIVES: To evaluate the efficacy of cyclosporine A in

the treatment of macrophage activation syndrome (MAS) occurring in

children with juvenile arthritis.

STUDY DESIGN: MAS developed in two boys and three girls with systemic

juvenile arthritis (four) and polyarticular juvenile arthritis (one). In

three children whose condition was life-threatening, increased

parenteral administration of corticosteroids failed to improve their

condition; therefore cyclosporine A (2 to 5 mg/kg per day) was added.

In two other patients with less severe clinical manifestations,

cyclosporine A alone (2 to 8 mg/kg per day) was given.

RESULTS: After the introduction of cyclosporine A, rapid improvement was

obtained in all patients and apyrexia occurred within 24 to 48 hours.

The biologic abnormalities disappeared more slowly (up to 5 weeks for

liver enzymes).

CONCLUSIONS: These observations underline the usefulness of cyclosporine

A in this complication. The use of this drug may circumvent the need for

increased doses of corticosteroids in some patients. The mechanism of

action of cyclosporine A remains speculative, but these results indicate

indirectly that T-helper lymphocytes may play a role in the pathogenesis

of MAS

Notes: 97074817

ISSN: 0022-3476

7. SB. Cyclosporine in activated macrophage and histiocytic

syndromes. Journal of Pediatrics 1997; 130: 1012-3.

8. Ravelli A, De Benedetti F, Viola S, i A.

Macrophage activation syndrome in systemic juvenile rheumatoid arthritis

successfully treated with cyclosporine. J.Pediatr. 1996; 128: 275-8.

Notes: A macrophage activation syndrome, possibly related to

methotrexate toxicity, developed in a boy with systemic juvenile

rheumatoid arthritis. Corticosteroid administration was ineffective,

whereas a prompt response to cyclosporine was observed. Two months

later, Pneumocystis carinii pneumonia developed

9. Ravelli, A., Viola, S., De Benedetti, F., Migliavacca, D.,

Mongini, E., i, A., and i.

DRAMATIC EFFICACY OF CYCLOSPORINE A IN CORTICOSTEROID RESISTANT

MACROPHAGE ACTIVATION SYNDROME. 1999. 6th

European Pediatric Rheumatology Congress, Glasgow. 1999.

Abstract: Macrophage activation syndrome (MAS) is a potentially

life-threatening complication of rheumatologic diseases. Recently, it

has been reported that cyclosporine A (CyA) may be effective in the

treatment of this syndrome. We have observed a dramatic efficacy of CyA

in 2 children with MAS refractory to corticosteroid treatment.

Patient #1: A 9-year-old boy developed an unspecified systemic

inflammatory syndrome that resolved with prednisone therapy. Three

months after prednisone stop he was readmitted with fever,

thrombocytopenia, microangiopathic anemia, macrohematuria, renal

insufficiency, and severe neurologic involvement consistent with a

thrombotic thrombocytopenic purpura. Repeated plasma exchange led to

complete recovery. One week later he developed intermittent high fever,

liver failure, leukopenia, thrombocytopenia, evidence of intravascular

coagulation, and hypertriglyceridemia. Urinalysis was normal. Plasma

ferritin peaked from 30.000 to 540.000 ng/ml. Bone marrow aspirate

disclosed hemophagocytosis. Treatment with iv methylprednisolone, 4

mg/Kg/day was begun. Since this did not affect the course of MAS, we

started iv CyA, 3 mg/kg/day. Fever disappeared within 6 hours and

patient's clinical conditions and laboratory abnormalities improved rapidly.

Patient #2: A 11-year-old girl was diagnosed as having systemic lupus

erythematosus (SLE) based on the association of arthritis, leukopenia,

nephritis, ANA and anti-DNA antibodies. Prednisone therapy allowed

improvement of clinical manifestations, decrease of ANA titre, and

disappearance of anti-DNA antibodies within one month. Shortly

afterwards, when the lupus disease was quiescent, she developed

unexplained high fever that was unaffected by a 7-day treatment with

ceftriaxone. Laboratory investigations showed leukopenia, anaemia,

thrombocytopenia, ESR increase, hypertriglyceridemia, and increased LDH,

whereas autoantibody levels were unchanged and serum complement

fractions were normal. Plasma ferritin reached 9265 ng/ml and there was

evidence of macrophage hemophagocytosis in the bone marrow. Due to the

inefficacy of prednisone, 2 mg/kg/day, oral CyA, 5 mg/kg/day was begun.

This resulted in resolution of fever within 24 hours and prompt

improvement of laboratory changes.

Conclusions: Our observations provide evidence that CyA can reverse

dramatically the clinical and laboratory abnormalities in patients

with MAS that are refractory to corticosteroid treatment.

10. Stephan JL, Zeller J, Hubert P, Herbelin C, Dayer JM, Prieur AM.

Macrophage activation syndrome and rheumatic disease in childhood: a

report of four new cases. Clin.Exp.Rheumatol. 1993; 11: 451-6.

Notes: A macrophage activation syndrome (MAS) developed in four

children with chronic rheumatic diseases. The presentation included

fever, hepatic and splenic enlargement, profound depression of blood

counts, lowering of ESR, elevation of SGOT/PT and hypofibrinogenemia.

The most characteristic sign of MAS was the presence in the bone marrow

aspirate of well differentiated macrophages showing active

haemophagocytosis with haematopoietic elements in their cytoplasm.

Activation of the macrophage was also illustrated by high levels of

monokines in the serum of 2 patients. This immuno-hematological process

of unknown etiology can be triggered by ubiquitous events such as

infections and treatment with anti-inflammatory drugs. It is a

potentially lethal complication which should be diagnosed rapidly, since

administration of high-dose steroids with discontinuation of

potentially toxic drugs can induce remission. Cyclosporin A was

effective in two patients and may be of value in the management of the

macrophage-activation syndrome. Its efficacy supports the central

involvement of a T-cell dysfunction. It must be borne in mind that

children with rheumatic diseases, especially the systemic form of

juvenile chronic arthritis, are highly vulnerable to life-threatening

macrophage activation, which appears to be more frequent than previously

recognized. Very careful monitoring of apparently " innocent " drugs and

intercurrent viral infections is thus required

[ ] macrophage activation syndrome

> From: Skis@a...

>

> Does anybody have any experience with macrophage activation syndrome

> in combination with systemic JRA? If so please respond ASAP with

> details.

> Thanks