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Indian Journal of Rheumatology 2009 December Volume 4, Number 4; pp.

162167

Review Article

Macrophage activation syndrome II/II


K Shanmuganandan1, J Kotwal2

ABSTRACT
Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. Primary haemophagocytic lymphohistiocytosis (HLH) is recognized as having a genetic basis, but the secondary haemophagocytic syndrome (HS), also referred to as MAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), adult onset Stills disease and other disorders. In this second of the two part series, the clinical features and management are described. Keywords: Macrophage activation syndrome, haemophagocytosis, secondary haemophagocytic lymphohistiocytosis, Stills disease.

INTRODUCTION
Macrophage activation syndrome (MAS) results in significant morbidity and mortality. MAS results from uncontrolled activation and proliferation of T cells and excessive activation of macrophages. It usually occurs as a complication of various systemic inflammatory rheumatic diseases, most commonly systemic onset juvenile idiopathic arthritis.1 It has also been reported with systemic lupus erythematosus (SLE), dermatomyositis, Kawasaki disease (KD) and other systemic inflammatory rheumatic diseases.2 In the last issue of the Journal, the pathobiology and molecular mechanisms of causation of MAS was elucidated.3 In this issue, the clinical features and management issues are discussed with particular reference to rheumatic diseases.

CLINICAL AND LABORATORY FEATURES


The initial presentation and the clinical features of MAS are protean and depend upon the primary condition or the background illness.

The hallmark clinical and laboratory features include high fever, hepatosplenomegaly, lymphadenopathy, pancytopaenia, liver dysfunction, disseminated intravascular coagulation (DIC), hypofibrinogenaemia, hyperferritinaemia, and hypertriglyceridaemia. Despite marked systemic inflammation, the erythrocyte sedimentation rate (ESR) is paradoxically depressed, caused by low fibrinogen levels. The low ESR helps to differentiate the disorder from a flare of the underlying rheumatic disorder, in which case the ESR is usually elevated. A bone marrow biopsy or aspirate usually shows haemophagocytosis. Clinical features, according to the organ system involved, are given in Table 1. The clinical presentation is, in many aspects, similar to systemic inflammatory response syndrome (SIRS). Many patients also present with multiple organ failure.5 Rare cases of nephrotic syndrome have also been reported.6 Since MAS is a relatively rare condition occurring over and above a background illness, the diagnosis is often missed unless there is a high index of suspicion.7 It often presents only with non-specific features, thus eluding the diagnosis and delaying the management which often proves fatal. Palazzi et al. has reported that the clinical and laboratory findings of HLH-MAS were present for up to two weeks of

1 Department of Internal Medicine, 2Department of Pathology, AFMC, Pune, Maharashtra, India. Correspondence: Lt Col K Shanmuganandan, email: kshanmu5520@yahoo.com

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Table 1 Clinical and laboratory features of MAS Organ system General Feature Hectic fever, malaise, anorexia with or without weight loss and failure to thrive Anaemia, leucopaenia, thrombocytopaenia, pancytopaenia, echymosis, prolonged aPTT Non-specific maculopapular rash, erythroderma, generalized purpuric macules and papules, morbilliform eruptions Seizures, ataxia, hemiplegia, mental status changes, irritability40 lymphadenopathy hepatosplenomegaly ARDS Myocarditis, capillary leak syndrome

Table 2 Differentiating features between systemic onset juvenile idiopathic arthritis and MAS Feature Fever Joint inflammation Platelets ESR Transamnitis Coagulopathy SoJIA Intermittent Present Thrombocytosis Elevated Absent Absent MAS Continuous May be absent Thrombocytopaenia Decreased Present Present

Hematological system Dermatological4

Neurological Reticuloendothelial Pulmonary Cardiovascular

presentation with febrile illness, before diagnosis could be made.8 They may have a mononuclear pleocytosis of the cerebral spinal fluid and evidence of parameningeal infiltrations, subdural effusions, retinal haemorrhages and hypodense or necrotic areas, demonstrated by magnetic resonance imaging of the brain.9 In a report from the Histiocyte Society, children with an abnormal CSF had a higher risk of death and neurologic sequelae.10

and may be detected only by investigations.23 Rarely, MAS may be the presenting manifestation of systemic rheumatic diseases in childhood.24 However, certain subtle clinical and specific laboratory features which could differentiate these two conditions are described in Table 2. A seminal study of 13 cases of MAS from India found that a majority of the patients had an underlying connective tissue disease like SoJIA, SLE, and adult Stills disease. The mortality was 38.4%.25 The accompanying editorial highlights that a high mortality is uncommon and emphasizes that MAS is often missed in clinical practice.26

Diagnosis
MAS should be suspected when there is constellation of following features: high fever, unresponsive to antibiotics, fatigue, falling ESR, maculopapular rash, failure to thrive, central nervous system symptoms, hepatosplenomegaly, lymphadenopathy, cytopaenias, coagulopathy, abnormal liver function tests and elevated ferritin levels. However, in practice the diagnosis is often difficult and therefore delayed due to overlapping clinical and laboratory features. Table 3 lists a few differentiating features between SoJIA and MAS.36

MAS IN RHEUMATIC DISEASES


MAS is most often associated with systemic onset juvenile inflammatory arthritis (SoJIA) and can be the first presenting feature of SoJIA. In adults, MAS is less frequently reported in other rheumatologic disorders such as rheumatoid arthritis and SLE,2,11 MAS erythematosus.11 MAS has also been described in association with Behcets syndrome and ankylosing spondylitis.12 Many factors have been implicated as triggers for MAS: viral agents such as varicella-zoster virus, hepatitis A, Epstein-Barr and coxsackie B, therapies with acetylsalicylic acid and NSAIDs, DMARDs such as gold salts, methotrexate, sulfasalazine and penicillamine and biologic drugs like etanercept.1315 Apart from children with systemic juvenile idiopathic arthritis (SJIA), MAS may also occur less commonly in those with polyarticular juvenile idiopathic arthritis, juvenile SLE, and KD.1622 In a few cases, MAS may be occult

Diagnostic criteria
The initial 1991 diagnostic criteria of HLH (Table 3) has been widely applied for the diagnosis of MAS on the background of the underlying illness1315,27 being idiopathic arthritis. However, additional criteria are increasingly being used for early diagnosis and treatment.2831. This is as in nearly 20% of cases; documenting haemophagocytosis on the first bone marrow specimen is difficult or not possible.32 However, inability to demonstrate haemophagocytosis on the initial specimen should not prevent prompt institution of treatment, provided other clinical criteria are fulfilled.33 However,

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Table 3 Diagnostic criteria for HLH27 Major criteria: (1) Fever: Peak temperature > 38.5C for seven or more days (2) Splenomegaly: Spleen palpated > 3 cm below the left costal margin (3) Cytopaenia involving two or more cell lines: Haemoglobin < 9.0 g/dL, or Platelets < 100,000/L, or Absolute neutrophil count < 1000/L (4) Hypertriglyceridaemia or hypofibrinogenaemia: Fasting triglycerides > 2.0 mmol/L, or more than 3 standard deviations (SD) above the normal value for age, or Fibrinogen < 1.5 g/L, or more than 3SD below the normal value for age (5) Hemophagocytosis: Demonstrated in bone marrow, spleen, or lymph node. No evidence for malignancy. Alternative criteria: (a) Low or absent natural killer count (b) Serum ferritin level > 500 g/L (c) Soluble CD25 (sIL-2 receptor) > 2400 U/mL The diagnosis of HLH requires the presence of all five major criteria. Either criterion (a) or a combination of criteria (b) and (c) may substitute for one of the major criteria. Additional criteria for the diagnosis of HLH include: Low or absent NK-cell activity, serum ferritin concentration > 500 mg/L, soluble CD25 (sIL-2 receptor) > 2400 U/mL Either the first of these three additional criteria, or a combination of second and third, may substitute for one of the major clinical criteria listed above.

Table 4 Preliminary diagnostic guidelines for macrophage activation system complicating SoJIA34 Laboratory criteria (1) Decreased platelet count (< 2.6 lakh/L) (2) Elevated levels of aspartate aminotransferase (> 59 IU/L) (3) Decreased white blood cell count (< 4000/L) (4) Hypofibrinogenaemia (< 2.5 g/L) Clinical criteria (1) Central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures, coma) (2) Haemorrhages (purpura, easy bruising, mucosal bleeding) (3) Hepatomegaly (3 cm below the costal arch) Histopathological criterion Evidence of macrophage hemophagocytosis in the bone marrow aspirate Diagnostic requirement The diagnosis of MAS requires the presence of any two or more laboratory criteria or of any two or three or more clinical or laboratory criteria. A bone marrow aspirate for the demonstration of haemophagocytosis may be required only in doubtful cases.

there are a few caveats with these criteria: since sIL-2 levels vary greatly according to age, one must know the agerelated normal levels to correctly judge these. Regarding NK cell function, patients with the autoimmune lymphoproliferative syndrome (ALPS) have decreased numbers of NK cells and may present with splenomegaly and cytopaenias secondary to the presence of auto antibodies. In MAS occurring in SoJIA, leucocytosis rather than cytopaenias

are common; hence, specific diagnostic guideline for MAS SoJIA has been proposed by Ravelli et al. (Table 4).34

Management
The management of MAS is empirical. Many of the drugs used are similar to HLH protocols.35 The HLH protocol is

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Table 5 HLH 2004 protocol* Initial management 08 weeks Inj Etoposide Inj dexamethasone 02 weeks 150 mg /m2 twice a week 10 mg/m2/day 38 weeks 150 mg once a week 5 mg/m2/day for 2 weeks 2.5 mg/m2/day for 2 weeks 1.25 mg/m2 for 1 week Tapered off in 8th week

Cyclosporine Continuation phase 940 weeks Inj Etoposide Inj dexamaethasone Cyclosporine

6 mg/kg for 8 weeks 150 mg/m2 every fortnightly 10 mg/m2 every fortnightly 6 mg/kg

Additional medications include: (a) Cotrimaxozole prophylaxis week 240, (b) Oral anti-mycotic agents week 19, (c) IVIG q 4 weekly during induction and continuation phase.

the standard of care for primary HLH. The HLH protocol given in Table 5, therefore, merits mention though it is hardly ever used in the management of MAS. Supportive care is important and includes management of underlying disorder precipitating MAS, correction of coagulopathy, treatment of triggering infection with appropriate anti-microbial agents and removal of potential triggering medications like NSAIDs. High-dose steroidparenteral methylprednisolone or dexamethasone is the first line of therapy.36 One schedule is pulse intravenous methylprednisolone 1000 mg/day for three consecutive days, followed by high-dose oral prednisone (60 mg/day, for at least 4 weeks depending on the clinical response and thereafter tapered slowly). More than half of the patients treated with steroids have favourable outcome.14,16 Cyclosporine (35 mg/kg) has been used effectively in the treatment of MAS, especially in MAS associated with JIA.13,37,38 Stephan et al. reported that cyclosporine was effective in 12 patients, five of whom received first line treatment and seven who received second line treatment when steroids failed.39 Ravelli has proposed a switch off effect of cyclosporine wherein there is a rapid resolution of clinical and laboratory features of MAS within 1224 hours of initiation of therapy with this immunosuppressant drug.40 The mechanism of action, in addition to inhibition of 1L-2 production of lymphocytes, is that of a direct inhibition of production of IL-6, IL-1 and TNF- from macrophages and inhibition of expression of inducible nitric oxide synthetase and cyclooxygenase-2, leading to a decreased production of nitric oxide and prostaglandin.41 Thus, many rheumatologists routinely add cyclosporine to steroids in the management of MAS. It has been proposed that cyclosporine be used as a preferred first line of

therapy in MAS due to its rapid onset of action and high efficacy.42 Other drugs used include etopside, IVIG, TNF blockade and IL1ra. Fishman et al. used etoposide in a patient with features of MAS in SoJIA, probably as an extension of its use in primary HLH.43 Though etoposide is an integral part of initial protocol in primary HLH (HLH 2004 protocol), case reports of its use in MAS is sparse. Intravenous immunoglobulin has been used as a second line of treatment in MAS, not responding to corticosteroids. Tristano et al. have reported the successful use of IVIG in MAS.44 IVIG induces expression of the inhibitor Fc[g]RIIB receptor on effector cells, which in turn mediates inhibitory intracellular signalling thereby stopping macrophage activation and TNF blockade. Though intuitively TNF blockers could be considered for MAS, paradoxical use of etarnecept in SoJIA has precipitated MAS.4547 However, efficacy of etarnecept in the treatment of resistant MAS has also been reported.48,49

IL1RA
IL1Ra, anakinra has been successfully used in the treatment of MAS in a child with SoJIA.50,51 One approach is to treat with corticosteroids, starting with pulse methylprednisolone and to introduce second line agents including cyclosporine or etoposide or intravenous immunoglobulin if the response to corticosteroids is poor or if there is worsening or multiorgan involvement. Another approach is to classify patients into high risk and low risk groups. The high-risk groups are those with CNS involvement, severe bleeding diathesis, severe renal impairment,

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multiorgan failure or failure to respond to initial therapy. The high-risk groups are treated with corticosteroids, cyclosporine with or without etoposide. The low-risk group is treated with corticosteroids alone.

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Prognosis
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MAS is a life threatening disorder and fatalities are not uncommon when diagnosed late or if there is presence of multiorgan involvement. The mortality of MAS has varied from 8 to 22%.50 The poor prognostic factors are delayed diagnosis, severe coagulopathy and multisystem involvement.

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CONCLUSION
MAS is a multisystem disorder affecting a wide spectrum of rheumatologic and non-rheumatologic illness. Recognizing the condition is difficult due to the absence of characteristic features and the presence of overlapping clinical features. Clinical manifestations include a disseminated intravascular coagulation-like picture with cytopaenias, hyperferritinaemia, coagulopathy and cardiovascular collapse. A high index of suspicion and early directed and specific investigations are essential for (early) diagnosis and treatment. Biomarkers such as sCD25 and sCD163 are important diagnostic tools that are likely to be used in the diagnostic armamentarium. Standardized treatment protocols and immune suppressive regimes go a long way in the mitigation of mortality and morbidity.

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