Macrophage activation syndrome (MAS) is a rare but potentially life-threatening complication of rheumatic inflammatory diseases. Errors in the regulation of the immune system lead to severe immune activation with persistent "cytokine storm«. Macrophages are inflammatory cells called histiocytes when they leave the bloodstream and enter tissues in various organs. Macrophage activation syndrome (MAS) is also classified as a histiocyte disease in the form of hemophagocytic lymphohistiocytosis (HLH) (Grom AA, 2016).The condition can be divided into two main groups: 1. Primary disease form (hereditary) HLH that occurs in early childhood and without any other underlying disease. Caused by mutations (genetic). 2. Secondary / reactive HLH can occur at any age, often as a result of infections, severe rheumatic diseases, but is also seen in cancer and reaction to drugs. The condition is often referred to as MAS when a known rheumatic disease is present.
MAS can be triggered by infections that Epstein-Barr virus (EBV) and influenza virus in predisposed persons. These often have a disease, such as high disease activity in (juvenile arthritis (sJIA), juvenile SLE). The immune system's macrophages are over-activated and trigger storm of cytokines (TNF, IL-1, IL-6, IL18, interferon gamma (IFNγ) and more) which in themselves damage the organs. The most common related rheumatic diseases are Adult stills disease, antiphospholipid syndrome (APLs), juvenile arthritis (systemic form), but also drugs (NSAID, acetylsalicylic acid), NLRC4 inflammatory mutation mediated (monogenetic (hereditary) cases), Rheumatoid arthritis, systemic lupus erythematosus (SLE) may be present.
The symptoms of Macrophage activation syndrome MAS/HLH include significantly affected and worsened general condition and persistent high fever, without fever peaks. Increasing sleepiness, lethargy, confusion, irritability and altered mental function show that the brain is affected. Bleeding in the skin can trigger purpura or mucosal bleeding. Stomach symptoms may stem from an enlarged liver (hepatomegalyi) and large spleen (splenomegaly). Rapid pulse and palpitations are also seen.
- High fever, Personality changes, epileptic seizures
- Blood tests with high CRP, but relatively low lowering reaction (SR), low number of platelets (thrombocytes), white blood cells (leukocytes, neutropenia below 1000/mm3), low fibrinogen and hemoglobin, as well as rising liver enzymes, ferritin and triglycerides.
Medical history maps symptoms (see above) in predisposed persons (see causes of illness above).
Clinical examination if Macrophage activation syndrome (MAS) is suspected, first aim to rule out other causes as far as possible by routine examination. In particular, special signs of illness, body temperature and whether there is pre-dried liver or spleen, signs of abnormal bleeding or disease in the nervous system are assessed.
Laboratory tests for mapping may include CRP, SR, hgb, leukocytes with differential counts, platelets, electrolytes, liver, kidney and thyroid function tests, D-dimer, ferritin, coagulation factors (INR, fibrinogen, D-dimer), triglyceride, glucose and creatine kinase CK. Soluble IL-2 receptor, ANA and antiphospholipid antibody (lupus anticoagulant, anti-cardiolipin and beta-2 glycoprotein) also be relevant. Urine sting. Blood cultures, viral investigations on EBV, CMV, adenovirus, COVID-19
- 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
- Marker for macrophage activation is soluble CD163 and correspondingly for lymphocyte activation is lugly 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
- Flow cytometry of blood: Low NK cells may occur.
- Ferritin / SR ratio of at least 21,5 has shown 82% sensitivity and 78% specificity for MAS in systemic JIA compared to systemic JIA without MAS (reference: Eloseily EMA, 2019)
- Number of white blood cells slightly elevated (4,6-16,3). Systemic JIA usually results in significantly elevated values (12-22)
Reference: Minola F, 2019
Imaging. MR head, CT examination cervical, CT examination thorax, CT examination abdomen, ultrasound of the abdominal area.
Spinal fluid examinations
Bone marrow biopsy: Sign to hemofagocytose (damage to blood cells and their precursors)
Criteria for diagnosis
Molecular diagnosis compatible with HLA. These include detected pathological mutation of PRF1, UNC1D or STX13 or
2. At least 5 of 8 criteria below:
- Fever. Temperature peaks above 38.5°C for at least 7 days
- Splenomegaly, palpable spleen greater than 3 cm below the left costal arch
- Cytopenia in two or more cell lines: Hemoglobin less than 9.0 g/dL, or Platelets more than 100,000/µL, or absolute neutrophilia less than 1000/µL
- Hypertriglyceridemia or hypofibrinogenemia: Fasting triglycerides above 2.0 mmol/L, or more than 3 standard deviations (SD) above the normal value for age, or Fibrinogen less than 1.5 g/L, or more than 3 SD below the normal value for age
- Hemophagocytosis: Detected in bone marrow, spleen, or lymph node; No evidence of malignancy
- Low or absent natural killer cell activity
- Serum ferritin level more than 500 µg/L (but more than 3000 µg/L is a more realistic cut-off to rule out infections and autoimmune diseases
- Soluble CD25 (IL-2 receptor) more than 2400 U/mL (2 SD above reference value: not age-related reference values) (soluble IL-2 receptor measurement can be requested from the Immunological Laboratory Oslo University Hospital)
Classification criteria for MAS have been prepared by EULAR and ACR (Ravelli A, 2016)
Ferritin >684 ng/ml and at least two of the following:
- Platelets ≤181 x 103/mL
- AST >48 u/L
- Trigycerides >156 mg/dL
- Fibrinogen ≤ 360 mg/dL
- DRESS syndrome (Drug triggered)
- Kawasaki syndrome (children)
- Corona/COVID-19 infection
- Systemic lupus erythematosus (SLE)
- Systemic JIA in children / Still's disease in (young) adults
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)
Hospitalization is always appropriate for signs of MAS. Examples of signs of illness that require treatment: In case of brain/CNS symptoms, cytopenias, coagulopathy and ferritin above 3000 ng/mL or rapidly increasing ferritin or increased sCD25 (soluble IL-2 receptor). In case of too low blood pressure, fever, without response to broad-spectrum antibiotics and ferritin above 3000 ng/mL or rapidly increasing ferritin or increased sCD25.
Medicines used in MAS are Methylprednisolone (SoluMedrol) in high doses intravenously for three consecutive days, sometimes longer. Traditionally, one has then supplemented with ciclosporin A, intravenous immunoglobulin (IVIG), etoposide, cyclophosphamide (Sendoxan) or fresh frozen plasma in some cases. The later years are used interleukin-1 inhibitors (anakinra/Kineret), alternatively IL-6 inhibitors (tocilizumab/RoActemra) more often, especially in the case of underlying rheumatic disease. For drug selection and dosage refer to specialist literature (Eloseily EC, 2018).