Definition

Macrophage activation syndrome (MAS) is a life-threatening but rare complication of inflammatory rheumatic disease. Improper regulation of the immune system leading to severe immune activation with “Cytokine storm". Synonyms are reactive or secondary hemophagocytic lympho-histiocytosis (HLH) or reactive hemophagocytic syndrome (RHS). The condition can be divided into two main groups

• Primary disease form (hereditary) HLH that occurs in early childhood and without underlying other disease. Caused by mutations (genetic)
• Secondary / reactive HLH can occur at any age, often due to infections, cancer or rheumatic diseases. The condition is often referred to as MAS when known rheumatic disease is present

Disease Cause

Macrophages are activated and triggered storm of cytokines (TNF, IL-6, IL18 and more). The most common related diseases are:

• Adult Stills disease
• Antifosfolipid Syndrome (APLs)
• Epstein-Barr virus (EBV) and other infections
• Juvenile arthritis (systemic form)
• Medications (NSAID, Acetylsalicylic acid)
• NLRC4 inflammatory mutation mediated (Monogenetic (hereditary) cases)
• Rheumatoid arthritis
• Systemic Lupus erythematosus

Symptoms of by macrophage activation syndrome (MAS)

• Persistent fever
• Purpura of the skin
• Hepatomegaly (big liver) (95%)
• Splenomegaly (big spleen)
• Mental Changes (33%)
• Organ failure (Heart / Tachycardia, Lungs / Tachypne, Decreasing Body Temperature / Hypothermia)

Medical Examination Findings

Typical findings at HLH / MAS

• Inflammation (high values ​​for CRP, but falling blood drop reaction (SR) due to falling levels of fibrinogen (differential diagnosis Adult stills disease: Increasing s-fibrinogen values).
• Low number of blood cells (cytopenia): often fall rapidly the week before MAS (low values ​​of platelets, Leukcytes, Hemoglobin)
• The triglyceride level increases
• Fibrinogen levels fall (below 2,5g / L)
• Ferritin over 500-1000 μg / ml
• ASAT increased more than 3 x at 50-90%
• Coagulopathy: long prothrombin time (PT) and activated thromboplastin time (aPTT). INR> 1,5
• The marker for macrophage activation is soluble CD163 and similar to lymphocyte activation ugly IL-2 receptor (can be ordered from Immunological lab OUS). Values ​​above 2400U / ml are typical of HLH / MAS. Soluble IL-2 receptor is included in diagnostic criteria, but is not specific
  • Increased level of soluble IL-2 receptor also in other inflammatory diseases (RA, SLE, Sarcoidosis, psoriasis), infections and cancer (especially lymphoma)
• Bone marrow biopsy
  • Signs of hemofagocytose (damage to blood cells and their precursors)
• Flow cytometry of blood: Low NK cells may occur.

“Red flags”

• High fever
• High liver enzymes, ferritin, CRP and pro-calcitonin
• Neutropenia (less than 1000 / mm3)
• Myocarditis, convulsions

Criteria for diagnosis

• Read about classification criteria for MAS / HLH here

Incorrect diagnosis (Similar conditions / Differential diagnoses)

• Read about differential diagnoses for MAS / HLH here

Checklist when diagnostic uncertainty

• Cell counts with differential count. All three cell arrays can be attacked by MAS and show low cell counts (cytopenia)
• Blood cultures (exclude infection)
• Coagulation factors (INR, fibrinogen (low), D-dimer)
• Spinal fluid (exclude infection)
• Viral examinations on EBV, CMV, Adenovirus
• Bone marrow (MAS or other disease)
• MRI examination of the brain (other disease)
• CT examination of the neck (other disease)
• X-ray of lungs (other disease)
• CT or ultrasound examination of the abdomen (other disease)

Complications

Most commonly: pleurisy, lung hemorrhage, interstitial pneumonitis, pericarditis, peritoneal acites, kidney, CNS, DIC, Uveitt. Inflammation of the colon. Hemophagocytosis (HPS) most often among children under one year of age.

Treatment and follow-up

• Read about the treatment and follow-up of MAS / HLH here (Bindvevssykdommer.no)

Literature

• Bracaglia C, 2017
• Deane S, 2010
• Grans Compendium in Rheumatology

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