Indian Journal of Rheumatology 2009 DecemberReview Article

Volume 4, Number 4; pp. 162–167

Macrophage activation syndrome II/II

K Shanmuganandan1, J Kotwal2

ABSTRACT

Macrophage activation syndrome (MAS) is a rare systemic disorder which results from uncontrolled activation andproliferation 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 asMAS, occurs in a number of autoimmune disorders including systemic onset juvenile idiopathic arthritis, systemic lupuserythematosus (SLE), adult onset Still’s disease and other disorders. In this second of the two part series, the clini-cal features and management are described.

Keywords: Macrophage activation syndrome, haemophagocytosis, secondary haemophagocytic lymphohistiocytosis,Still’s disease.

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

INTRODUCTION

Macrophage activation syndrome (MAS) results in signifi-cant morbidity and mortality. MAS results from uncontrolledactivation and proliferation of T cells and excessive activat-ion of macrophages. It usually occurs as a complication ofvarious systemic inflammatory rheumatic diseases, mostcommonly systemic onset juvenile idiopathic arthritis.1 It hasalso been reported with systemic lupus erythematosus (SLE),dermatomyositis, Kawasaki disease (KD) and other systemicinflammatory rheumatic diseases.2

In the last issue of the Journal, the pathobiology andmolecular mechanisms of causation of MAS was elucidated.3

In this issue, the clinical features and management issues arediscussed with particular reference to rheumatic diseases.

CLINICAL AND LABORATORY FEATURES

The initial presentation and the clinical features of MAS areprotean and depend upon the primary condition or thebackground illness.

The hallmark clinical and laboratory features includehigh fever, hepatosplenomegaly, lymphadenopathy, pan-cytopaenia, liver dysfunction, disseminated intravascularcoagulation (DIC), hypofibrinogenaemia, hyperferritinaemia,and hypertriglyceridaemia. Despite marked systemic inflam-mation, the erythrocyte sedimentation rate (ESR) is para-doxically depressed, caused by low fibrinogen levels. Thelow ESR helps to differentiate the disorder from a flare ofthe underlying rheumatic disorder, in which case the ESR isusually elevated. A bone marrow biopsy or aspirate usuallyshows haemophagocytosis. Clinical features, according tothe organ system involved, are given in Table 1.

The clinical presentation is, in many aspects, similar tosystemic inflammatory response syndrome (SIRS). Manypatients also present with multiple organ failure.5 Rare casesof nephrotic syndrome have also been reported.6

Since MAS is a relatively rare condition occurring overand above a background illness, the diagnosis is often missedunless there is a high index of suspicion.7 It often presentsonly with non-specific features, thus eluding the diagnosisand delaying the management which often proves fatal.Palazzi et al. has reported that the clinical and laboratoryfindings of HLH-MAS were present for up to two weeks of

Macrophage activation syndrome II/II Review Article 163

presentation with febrile illness, before diagnosis could bemade.8

They may have a mononuclear pleocytosis of the cerebralspinal fluid and evidence of parameningeal infiltrations, sub-dural effusions, retinal haemorrhages and hypodense or ne-crotic areas, demonstrated by magnetic resonance imagingof the brain.9 In a report from the Histiocyte Society, childrenwith an abnormal CSF had a higher risk of death and neuro-logic sequelae.10

MAS IN RHEUMATIC DISEASES

MAS is most often associated with systemic onset juvenileinflammatory arthritis (SoJIA) and can be the first presentingfeature of SoJIA. In adults, MAS is less frequently reportedin other rheumatologic disorders such as rheumatoid arthritisand SLE,2,11 MAS erythematosus.11 MAS has also been de-scribed in association with Behcet’s syndrome and ankylos-ing 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 acetylsalicylicacid and NSAIDs, DMARDs such as gold salts, methotrex-ate, sulfasalazine and penicillamine and biologic drugs likeetanercept.13–15

Apart from children with systemic juvenile idiopathicarthritis (SJIA), MAS may also occur less commonly inthose with polyarticular juvenile idiopathic arthritis, juve-nile SLE, and KD.16–22 In a few cases, MAS may be occult

and may be detected only by investigations.23 Rarely, MASmay be the presenting manifestation of systemic rheumaticdiseases in childhood.24 However, certain subtle clinical andspecific laboratory features which could differentiate thesetwo conditions are described in Table 2.

A seminal study of 13 cases of MAS from India foundthat a majority of the patients had an underlying connectivetissue disease like SoJIA, SLE, and adult Still’s disease. Themortality was 38.4%.25 The accompanying editorial high-lights that a high mortality is uncommon and emphasizesthat MAS is often missed in clinical practice.26

Diagnosis

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

Diagnostic criteria

The initial 1991 diagnostic criteria of HLH (Table 3) hasbeen widely applied for the diagnosis of MAS on the background of the underlying illness13–15,27 being idiopathicarthritis.

However, additional criteria are increasingly being usedfor early diagnosis and treatment.28–31. This is as in nearly20% of cases; documenting haemophagocytosis on the firstbone marrow specimen is difficult or not possible.32 How-ever, inability to demonstrate haemophagocytosis on the initialspecimen should not prevent prompt institution of treat-ment, provided other clinical criteria are fulfilled.33 However,

Table 1 Clinical and laboratory features of MAS

Organ system Feature

General Hectic fever, malaise, anorexia with or without weight loss and failure to thrive

Hematological Anaemia, leucopaenia, system thrombocytopaenia, pancytopaenia,

echymosis, prolonged aPTT

Dermatological4 Non-specific maculopapular rash, erythroderma, generalized purpuric macules and papules, morbilliform eruptions

Neurological Seizures, ataxia, hemiplegia, mental status changes, irritability40

Reticuloendothelial lymphadenopathy hepatosplenomegaly

Pulmonary ARDS

Cardiovascular Myocarditis, capillary leak syndrome

Table 2 Differentiating features between systemic onset juve-nile idiopathic arthritis and MAS

Feature SoJIA MAS

Fever Intermittent ContinuousJoint Present May be absentinflammationPlatelets Thrombocytosis ThrombocytopaeniaESR Elevated DecreasedTransamnitis Absent PresentCoagulopathy Absent Present

164 Indian Journal of Rheumatology 2009 December; Vol. 4, No. 4 Shanmuganandan and Kotwal

there are a few caveats with these criteria: since sIL-2 levelsvary greatly according to age, one must know the age-related normal levels to correctly judge these. RegardingNK cell function, patients with the autoimmune lympho-proliferative syndrome (ALPS) have decreased numbers ofNK cells and may present with splenomegaly and cytopae-nias secondary to the presence of auto antibodies. In MASoccurring in SoJIA, leucocytosis rather than cytopaenias

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

Management

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

Table 3 Diagnostic criteria for HLH27

Major criteria:(1) Fever: Peak temperature > 38.5ºC 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, orPlatelets < 100,000/μL, orAbsolute neutrophil count < 1000/μL

(4) Hypertriglyceridaemia or hypofibrinogenaemia:Fasting triglycerides > 2.0 mmol/L, or more than 3 standard deviations (SD) above the normal value for age, orFibrinogen < 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 μg/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, solubleCD25 (sIL-2 receptor) > 2400 U/mL Either the first of these three additional criteria, or a combination of second and third, maysubstitute 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/μL)(2) Elevated levels of aspartate aminotransferase (> 59 IU/L)(3) Decreased white blood cell count (< 4000/μL)(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 criterionEvidence of macrophage hemophagocytosis in the bone marrow aspirate

Diagnostic requirementThe 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.

Macrophage activation syndrome II/II Review Article 165

the standard of care for primary HLH. The HLH protocolgiven in Table 5, therefore, merits mention though it is hardlyever used in the management of MAS.

Supportive care is important and includes managementof underlying disorder precipitating MAS, correction of co-agulopathy, treatment of triggering infection with appropriateanti-microbial agents and removal of potential triggeringmedications like NSAIDs.

High-dose steroid—parenteral methylprednisolone ordexamethasone is the first line of therapy.36 One schedule ispulse intravenous methylprednisolone 1000 mg/day for threeconsecutive days, followed by high-dose oral prednisone(60 mg/day, for at least 4 weeks depending on the clinical re-sponse and thereafter tapered slowly). More than half of thepatients treated with steroids have favourable outcome.14,16

Cyclosporine (3–5 mg/kg) has been used effectively inthe treatment of MAS, especially in MAS associated withJIA.13,37,38 Stephan et al. reported that cyclosporine was effec-tive in 12 patients, five of whom received first line treatmentand seven who received second line treatment when steroidsfailed.39 Ravelli has proposed a “switch off effect of cyclo-sporine wherein there is a rapid resolution of clinical andlaboratory features of MAS within 12–24 hours of initia-tion of therapy with this immunosuppressant drug”.40

The mechanism of action, in addition to inhibition of 1L-2production of lymphocytes, is that of a direct inhibition ofproduction of IL-6, IL-1 and TNF-α from macrophages andinhibition of expression of inducible nitric oxide synthetaseand cyclooxygenase-2, leading to a decreased production ofnitric oxide and prostaglandin.41

Thus, many rheumatologists routinely add cyclosporineto steroids in the management of MAS. It has been pro-posed that cyclosporine be used as a preferred first line of

therapy in MAS due to its rapid onset of action and highefficacy.42

Other drugs used include etopside, IVIG, TNF blockadeand IL1ra. Fishman et al. used etoposide in a patient with fea-tures of MAS in SoJIA, probably as an extension of its usein primary HLH.43 Though etoposide is an integral part ofinitial protocol in primary HLH (HLH 2004 protocol), casereports of its use in MAS is sparse. Intravenous immunoglob-ulin has been used as a second line of treatment in MAS,not responding to corticosteroids. Tristano et al. have reportedthe successful use of IVIG in MAS.44 IVIG induces expres-sion of the inhibitor Fc[g]RIIB receptor on effector cells,which in turn mediates inhibitory intracellular signallingthereby stopping macrophage activation and TNF blockade.

Though intuitively TNF blockers could be consideredfor MAS, paradoxical use of etarnecept in SoJIA has precip-itated MAS.45–47 However, efficacy of etarnecept in the treat-ment of resistant MAS has also been reported.48,49

IL1RA

IL1Ra, anakinra has been successfully used in the treatmentof MAS in a child with SoJIA.50,51

One approach is to treat with corticosteroids, startingwith pulse methylprednisolone and to introduce second lineagents including cyclosporine or etoposide or intravenousimmunoglobulin if the response to corticosteroids is poor orif there is worsening or multiorgan involvement. Anotherapproach is to classify patients into high risk and low riskgroups. The high-risk groups are those with CNS involve-ment, severe bleeding diathesis, severe renal impairment,

Table 5 HLH 2004 protocol*

Initial management

0–8 weeks 0–2 weeks 3–8 weeksInj Etoposide 150 mg /m2 twice a week 150 mg once a weekInj dexamethasone 10 mg/m2/day 5 mg/m2/day for 2 weeks

2.5 mg/m2/day for 2 weeks1.25 mg/m2 for 1 weekTapered off in 8th week

Cyclosporine 6 mg/kg for 8 weeks

Continuation phase 9–40 weeksInj Etoposide 150 mg/m2 every fortnightlyInj dexamaethasone 10 mg/m2 every fortnightlyCyclosporine 6 mg/kg

Additional medications include: (a) Cotrimaxozole prophylaxis week 2–40, (b) Oral anti-mycotic agents week 1–9, (c) IVIG q 4 weekly during inductionand continuation phase.

166 Indian Journal of Rheumatology 2009 December; Vol. 4, No. 4 Shanmuganandan and Kotwal

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

Prognosis

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 aredelayed diagnosis, severe coagulopathy and multisysteminvolvement.

CONCLUSION

MAS is a multisystem disorder affecting a wide spectrumof rheumatologic and non-rheumatologic illness. Recogniz-ing the condition is difficult due to the absence of charac-teristic features and the presence of overlapping clinicalfeatures. Clinical manifestations include a disseminated in-travascular coagulation-like picture with cytopaenias, hyper-ferritinaemia, coagulopathy and cardiovascular collapse. Ahigh index of suspicion and early directed and specific in-vestigations are essential for (early) diagnosis and treat-ment. Biomarkers such as sCD25 and sCD163 are importantdiagnostic tools that are likely to be used in the diagnosticarmamentarium. Standardized treatment protocols and im-mune suppressive regimes go a long way in the mitigationof mortality and morbidity.

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