Macrophage Activation Syndrome & Biological Medications

[Guest guest]

The paradox of macrophage activation syndrome triggered by biologic

medications.

http://www.pedrheumonlinejournal.org

Antonella Buoncompagni, Loy, Ilaria Sala, Angelo Ravelli Genova, Italy

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

childhood rheumatic diseases, particularly systemic juvenile idiopathic

arthritis (S-JIA), which is characterized by fever, hepatosplenomegaly,

lymphoadenopathy, profound depression of all three blood cell lines,

deranged liver function, intravascular coagulation, and central nervous

system dysfunction. [1] The diagnostic hallmark of the syndrome is found in

the bone marrow aspiration, which reveals widespread signs of macrophage

hemophagocytosis.

The clinical and pathologic manifestations of MAS are thought to result from

the activation and uncontrolled proliferation of T-lymphocytes and

well-differentiated macrophages, which leads to an unrestricted release of

inflammatory cytokines, such as TNF-, interleukin-1 and interleukin-6. The

cause of the immunologic derangement in MAS is unknown. Recently, markedly

decreased natural killer cell function and, in some cases, depressed

perforin expression have been identified in patients with S-JIA and it has

been suggested that these abnormalities may explain the distinctive

susceptibility of these patients to the development of MAS. [2-3]

MAS is a serious condition that is associated with considerable morbidity

and high risk of fatal outcome. Early diagnosis and immediate therapeutic

intervention are, therefore, critical. The treatment of MAS has

traditionally been based on the administration of high-dose corticosteroids

and, more recently, cyclosporine A. [1] The demonstration that TNF- may

play a central role in the pathogenesis of the clinical and laboratory

manifestations of the syndrome and the observation that increased serum

levels of this cytokine occurs in the acute phase of MAS have provided the

rationale for proposing inhibition of TNF- as a way to reduce the

consequences of the excessive activation of macrophages. [1] Prahalad et al

reported a dramatic clinical response to etanercept in a 7-year-old boy with

a S-JIA-like syndrome and MAS who responded to high-dose corticosteroid

therapy, but experienced two episodes of acute clinical deterioration after

the reduction of the dose of corticosteroids. [4] The favorable outcome in

this patient led to suggest that TNF antagonists represent an effective

adjunctive therapeutic agent in MAS.

This important therapeutic achievement has been subsequently challenged by

the description of a case of MAS apparently triggered by an anti-TNF agent.

Ramanan and Schneider reported a 4.5-year-old girls with S-JIA who

developed, after 4 doses of etanercept, a mildly pruritic giant urticarial

rash adjacent to the injection sites and, 4 days later, a diffuse urticarial

rash associated with improvement in arthritis symptoms, but laboratory

evidence of MAS. [5] In the absence of a flare of systemic disease, an

identifiable infection, or any other recent change in medication, etanercept

was considered the most likely inciting factor.

In this issue of the Pediatric Rheumatology Online Journal,

Lurati et al describe an 18-year-old girl with S-JIA who developed MAS

during therapy with another biologic medication, the recombinant

interleukin-1 receptor antagonist anakinra. [6] The syndrome occurred after

the 10th dose of the drug and no evidence of other triggering factors,

notably infection, was found. While writing this commentary, we have also

admitted a 15-year-old boy with S-JIA who developed a full-blown MAS episode

during treatment with anakinra.

These observations contrast with the recent anecdotal evidence regarding the

excellent response of resistant S-JIA patients to anakinra therapy. [7-10]

In addition, one of these resistant S-JIA patients had an episode of MAS

which responded partially to corticosteroids, cyclosporine A, and VP-16. [9]

This episode occurred before the start of anakinra. Interestingly, anakinra

treatment appeared to lead to improvement not only in the systemic and joint

symptoms of the underlying disease, but also in the residual laboratory

abnormalities of MAS.

How does one explain the paradoxical occurrence of MAS during treatment with

medications that are designed to antagonize the cytokines believed to be

responsible for its development? Because MAS may represent the severe end of

the spectrum of a very active systemic disease, one possible explanation is

that the biologic agent was unable to control the disease activity and,

thus, to prevent MAS. Systemic JIA is one of the more difficult forms of JIA

to manage and it is known that a number of patients may not respond

adequately to biologic therapies. [11] Alternatively, the syndrome might

have been triggered by a drug-related toxic effect, similarly to what has

been observed for other antirheumatic medications, including nonsteroidal

antiinflammatory drugs, parenteral gold salts, sulfasalazine, and

methotrexate. [1] A further hypothesis is that MAS was induced by an

undetected infection. It is known that biologic therapies may increase the

susceptibility to infection, including those that may trigger MAS. Notably,

instances of MAS in patients on biologics in whom a viral infection, rather

than the drug, was found to be the inciting factor have been described.

[12-13]

In conclusion, the reported instances of MAS during treatment

with biologic medications suggest that the administration of these agents

may occasionally induce (or be associated with) this complication in

patients with S-JIA. It is, however, important not to generate undue alarm

about the safety of these drugs in this subset of JIA patients. The

introduction of biologics holds great promise in the management of this

often aggressive and challenging form of JIA. [10,14] Simply, these

observations should serve as a reminder that patients with S-JIA are

uniquely susceptible to the development of this potentially serious

complication and that, therefore, they deserve very careful clinical

monitoring for MAS. The recently published preliminary diagnostic guidelines

for the syndrome represent a valuable clinical tool to facilitate timely

diagnosis and prompt therapeutic intervention. [15]

References

1. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol. 2002;14:

548-52.

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

Natural killer cell dysfunction is a distinguishing feature of systemic

onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Arthritis Res Ther. 2005;7:R30-R37.

3. Wulffraat NM, Rijkers GT, Elst E, Brooimans R, Kuis W. Reduced perforin

expression in systemic juvenile idiopathic arthritis is restored by

autologous stem-cell transplantation. Rheumatology. 2003;42:375-9.

4. Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom A.. Etanercept in the

treatment of macrophage activation syndrome. J Rheumatol. 2001;28:2120-4.

5. Ramanan AV, Schneider R. Macrophage activation syndrome following

initiation of etanercept in a child with systemic onset juvenile rheumatoid

arthritis. J Rheumatol. 2003;30:401-3.

6. Lurati A, Teruzzi B, Salmaso A, Demarco G, Pontikaki I, Gattinara M.

Macrophage activation syndrome (MAS) during anti-IL1 receptor therapy

(anakinra) in a patient affected by systemic onset idiopathic juvenile

arthritis (soJIA). Pediatr. Rheumatol Online J. 2005;3(1).

7. Irigoyen PI, Olsen J, Hom C, Ilowite NT. Treatment of systemic juvenile

rheumatoid arthritis with anakinra [abstract]. Arthritis Rheum. 2004;50

Suppl:S437.

8. Henrickson M. Efficacy of anakinra in refractory systemic arthritis

[abstract]. Arthritis Rheum. 2004;50 Suppl:S438.

9. Verbsky JW, White AJ. Effective use of the recombinant interleukin1

receptor antagonist anakinra in therapy resistant systemic onset juvenile

rheumatoid arthritis. J Rheumatol. 2004;31:2071-5.

10. Pasqual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of

interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile

idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med.

2005;201:1479-86.

11. Eberhard BA, Ilowite NT. Response of systemic onset juvenile rheumatoid

arthritis to etanercept: is the glass half full or half empty? J Rheumatol.

2005;32;763-5.

12. Sarwar H, Espinoza LR, Gedalia A. Macrophage activation syndrome and

etanercept in children with systemic juvenile rheumatoid arthritis [letter].

J Rheumatol. 2004;31:623.

13. Skripak JM, Rodgers GL, Martucci C, et al. Disseminated herpes simplex

(HSV) infection precipitating macrophage activation syndrome (MAS) in a

child with systemic juvenile idiopathic arthritis (SJIA) undergoing therapy

with infliximab [abstract]. Pediatr Rheumatol Online J. 2003;vol.1(3):S58.

14. De Benedetti F, i A. Targeting the interleukin-6 receptor: a new

treatment for systemic juvenile idiopathic arthritis? Arthritis Rheum.

2005;52:687-93.

15. Ravelli A, Magni-Manzoni S, Pistorio A, Basana C, Foti T, Ruperto N et

al. Preliminary diagnostic guidelines for macrophage activation syndrome

complicating systemic juvenile idiopathic arthritis. J Pediatr.

2005;146:598-604.

[Guest guest]

Some info that was posted before about MAS.

Macrophage Activation Syndrome & Biological Medications

The paradox of macrophage activation syndrome triggered by biologic

medications.

http://www.pedrheumonlinejournal.org

Antonella Buoncompagni, Loy, Ilaria Sala, Angelo Ravelli Genova,

Italy

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

of

childhood rheumatic diseases, particularly systemic juvenile idiopathic

arthritis (S-JIA), which is characterized by fever, hepatosplenomegaly,

lymphoadenopathy, profound depression of all three blood cell lines,

deranged liver function, intravascular coagulation, and central nervous

system dysfunction. [1] The diagnostic hallmark of the syndrome is found

in

the bone marrow aspiration, which reveals widespread signs of macrophage

hemophagocytosis.

The clinical and pathologic manifestations of MAS are thought to result

from

the activation and uncontrolled proliferation of T-lymphocytes and

well-differentiated macrophages, which leads to an unrestricted release

of

inflammatory cytokines, such as TNF-, interleukin-1 and interleukin-6.

The

cause of the immunologic derangement in MAS is unknown. Recently,

markedly

decreased natural killer cell function and, in some cases, depressed

perforin expression have been identified in patients with S-JIA and it

has

been suggested that these abnormalities may explain the distinctive

susceptibility of these patients to the development of MAS. [2-3]

MAS is a serious condition that is associated with considerable

morbidity

and high risk of fatal outcome. Early diagnosis and immediate

therapeutic

intervention are, therefore, critical. The treatment of MAS has

traditionally been based on the administration of high-dose

corticosteroids

and, more recently, cyclosporine A. [1] The demonstration that TNF- may

play a central role in the pathogenesis of the clinical and laboratory

manifestations of the syndrome and the observation that increased serum

levels of this cytokine occurs in the acute phase of MAS have provided

the

rationale for proposing inhibition of TNF- as a way to reduce the

consequences of the excessive activation of macrophages. [1] Prahalad et

al

reported a dramatic clinical response to etanercept in a 7-year-old boy

with

a S-JIA-like syndrome and MAS who responded to high-dose corticosteroid

therapy, but experienced two episodes of acute clinical deterioration

after

the reduction of the dose of corticosteroids. [4] The favorable outcome

in

this patient led to suggest that TNF antagonists represent an effective

adjunctive therapeutic agent in MAS.

This important therapeutic achievement has been subsequently challenged

by

the description of a case of MAS apparently triggered by an anti-TNF

agent.

Ramanan and Schneider reported a 4.5-year-old girls with S-JIA who

developed, after 4 doses of etanercept, a mildly pruritic giant

urticarial

rash adjacent to the injection sites and, 4 days later, a diffuse

urticarial

rash associated with improvement in arthritis symptoms, but laboratory

evidence of MAS. [5] In the absence of a flare of systemic disease, an

identifiable infection, or any other recent change in medication,

etanercept

was considered the most likely inciting factor.

In this issue of the Pediatric Rheumatology Online Journal,

Lurati et al describe an 18-year-old girl with S-JIA who developed MAS

during therapy with another biologic medication, the recombinant

interleukin-1 receptor antagonist anakinra. [6] The syndrome occurred

after

the 10th dose of the drug and no evidence of other triggering factors,

notably infection, was found. While writing this commentary, we have

also

admitted a 15-year-old boy with S-JIA who developed a full-blown MAS

episode

during treatment with anakinra.

These observations contrast with the recent anecdotal evidence regarding

the

excellent response of resistant S-JIA patients to anakinra therapy.

[7-10]

In addition, one of these resistant S-JIA patients had an episode of MAS

which responded partially to corticosteroids, cyclosporine A, and VP-16.

[9]

This episode occurred before the start of anakinra. Interestingly,

anakinra

treatment appeared to lead to improvement not only in the systemic and

joint

symptoms of the underlying disease, but also in the residual laboratory

abnormalities of MAS.

How does one explain the paradoxical occurrence of MAS during treatment

with

medications that are designed to antagonize the cytokines believed to be

responsible for its development? Because MAS may represent the severe

end of

the spectrum of a very active systemic disease, one possible explanation

is

that the biologic agent was unable to control the disease activity and,

thus, to prevent MAS. Systemic JIA is one of the more difficult forms of

JIA

to manage and it is known that a number of patients may not respond

adequately to biologic therapies. [11] Alternatively, the syndrome might

have been triggered by a drug-related toxic effect, similarly to what

has

been observed for other antirheumatic medications, including

nonsteroidal

antiinflammatory drugs, parenteral gold salts, sulfasalazine, and

methotrexate. [1] A further hypothesis is that MAS was induced by an

undetected infection. It is known that biologic therapies may increase

the

susceptibility to infection, including those that may trigger MAS.

Notably,

instances of MAS in patients on biologics in whom a viral infection,

rather

than the drug, was found to be the inciting factor have been described.

[12-13]

In conclusion, the reported instances of MAS during

treatment

with biologic medications suggest that the administration of these

agents

may occasionally induce (or be associated with) this complication in

patients with S-JIA. It is, however, important not to generate undue

alarm

about the safety of these drugs in this subset of JIA patients. The

introduction of biologics holds great promise in the management of this

often aggressive and challenging form of JIA. [10,14] Simply, these

observations should serve as a reminder that patients with S-JIA are

uniquely susceptible to the development of this potentially serious

complication and that, therefore, they deserve very careful clinical

monitoring for MAS. The recently published preliminary diagnostic

guidelines

for the syndrome represent a valuable clinical tool to facilitate timely

diagnosis and prompt therapeutic intervention. [15]

References

1. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol.

2002;14:

548-52.

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

Natural killer cell dysfunction is a distinguishing feature of systemic

onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Arthritis Res Ther. 2005;7:R30-R37.

3. Wulffraat NM, Rijkers GT, Elst E, Brooimans R, Kuis W. Reduced

perforin

expression in systemic juvenile idiopathic arthritis is restored by

autologous stem-cell transplantation. Rheumatology. 2003;42:375-9.

4. Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom A.. Etanercept in the

treatment of macrophage activation syndrome. J Rheumatol.

2001;28:2120-4.

5. Ramanan AV, Schneider R. Macrophage activation syndrome following

initiation of etanercept in a child with systemic onset juvenile

rheumatoid

arthritis. J Rheumatol. 2003;30:401-3.

6. Lurati A, Teruzzi B, Salmaso A, Demarco G, Pontikaki I, Gattinara M.

Macrophage activation syndrome (MAS) during anti-IL1 receptor therapy

(anakinra) in a patient affected by systemic onset idiopathic juvenile

arthritis (soJIA). Pediatr. Rheumatol Online J. 2005;3(1).

7. Irigoyen PI, Olsen J, Hom C, Ilowite NT. Treatment of systemic

juvenile

rheumatoid arthritis with anakinra [abstract]. Arthritis Rheum. 2004;50

Suppl:S437.

8. Henrickson M. Efficacy of anakinra in refractory systemic arthritis

[abstract]. Arthritis Rheum. 2004;50 Suppl:S438.

9. Verbsky JW, White AJ. Effective use of the recombinant interleukin1

receptor antagonist anakinra in therapy resistant systemic onset

juvenile

rheumatoid arthritis. J Rheumatol. 2004;31:2071-5.

10. Pasqual V, Allantaz F, Arce E, Punaro M, Banchereau J. Role of

interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile

idiopathic arthritis and clinical response to IL-1 blockade. J Exp Med.

2005;201:1479-86.

11. Eberhard BA, Ilowite NT. Response of systemic onset juvenile

rheumatoid

arthritis to etanercept: is the glass half full or half empty? J

Rheumatol.

2005;32;763-5.

12. Sarwar H, Espinoza LR, Gedalia A. Macrophage activation syndrome and

etanercept in children with systemic juvenile rheumatoid arthritis

[letter].

J Rheumatol. 2004;31:623.

13. Skripak JM, Rodgers GL, Martucci C, et al. Disseminated herpes

simplex

(HSV) infection precipitating macrophage activation syndrome (MAS) in a

child with systemic juvenile idiopathic arthritis (SJIA) undergoing

therapy

with infliximab [abstract]. Pediatr Rheumatol Online J.

2003;vol.1(3):S58.

14. De Benedetti F, i A. Targeting the interleukin-6 receptor: a

new

treatment for systemic juvenile idiopathic arthritis? Arthritis Rheum.

2005;52:687-93.

15. Ravelli A, Magni-Manzoni S, Pistorio A, Basana C, Foti T, Ruperto N

et

al. Preliminary diagnostic guidelines for macrophage activation syndrome

complicating systemic juvenile idiopathic arthritis. J Pediatr.

2005;146:598-604.