Macrophage Activation Syndrome

What is Macrophage Activation Syndrome?

Macrophage activation syndrome (MAS) is a resultant of systemic inflammatory disease conditions, which include a complication of the rheumatic disease. Macrophage activation syndrome can be developed in children, as a complication of systemic juvenile idiopathic arthritis.

In adults, Macrophage activation syndrome develops due to the complication of Still’s disease. Apart from these inflammatory disorders, different auto-inflammatory dysfunctions like Kawasaki disease, systemic lupus erythematosus, and periodic fever syndromes can trigger the onset of adult- and childhood Macrophage activation syndrome.

The devastating inflammatory reaction caused by dysfunctional and uncontrolled immune reaction influences Macrophage activation syndrome and this involves the persistent stimulation and spreading out of T lymphocytes and macrophages. Resulting of this leads to substantial hypersecretion of pro-inflammatory cytokines.

Initially, this pathognomonic aspect limits in bone marrow and then gradually spread to every cell of the body and affects different organ and resultant of this causes a life-threatening situation. Almost 20% to 30% of Macrophage activation syndrome affected patients get die due to the multi organ failure occur due to Macrophage activation syndrome.

Image 1 – Classification Criteria for Macrophage Activation Syndrome

Incidence Rate

Macrophage Activation Syndrome is considered as a rare syndrome. However, yet now 100 cases of Macrophage Activation Syndrome is mentioned in medical literature. Retrospective study data showed that 6.7 percent children in a tertiary care center diagnosed with Macrophage Activation Syndrome over twenty years of time span.

Signs and Symptoms

The following are the symptomatic approach of Macrophage activation syndrome:

• High and non-abating fever
• Hepatosplenomegaly, in which liver and spleen size swell up abnormally in high rate
• Generalized lymphadenopathy, in which lymph nodes become severely enlarged
• Central nervous system dysfunction
• Hemorrhagic manifestations

Apart from these symptoms, characteristic features of abnormal diagnostic findings also indicative of Macrophage activation syndrome, which include:

• Pancytopenia, in which all the cellular components blood, including RBCs, WBCs, and Platelets level reduce
• Increased ferritin (type of blood cell protein) level
• Enhancement of liver enzymes such as alanine transaminase, aspartate transaminase and others enzymes like lactate dehydrogenase etc.
• Augmentation of triglycerides, D-dimers,
• Activation of soluble CD25 [sCD25] (a type of soluble interleukin-2 (IL-2) receptor)
• Reduction of fibrinogen levels.
• Biopsy test showed hemophagocytic activity

Causes

Granzymes, perforin, and other serene like proteases containing cytolytic granules release to the target cells and mediate the cytotoxic activity of natural killer (NK) and CD8+ T lymphocytes.

Cytolytic granules release associated with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis and other abnormal mutation severely affect the cytotoxic function of NK cells and cytotoxic T lymphocytes (CTLs) by secreting pro-inflammatory cytokinins such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and macrophage-colony-stimulating factor (M-CSF). Spreading of these pro-inflammatory cytokinins leads to tissue necrosis and organ failure.

Image 2 – Causes, Mechanism of Macrophage Activation Syndrome

Image 3 – Cytokine Storm in Macrophage Activation Syndrome

Diagnosis

Clinical researchers suggested several biomarkers for detection of Macrophage Activation Syndrome, as no single biomarker yet now identified. The different possible biomarkers, which has a role in an indication of Macrophage Activation Syndrome are soluble markers sCD25 and sCD163, FSTL-1 and β2-microglobulin. However, no specific guideline yet develop to establish single biomarker for diagnosis of Macrophage Activation Syndrome.

Treatment

There is no evidence validated treatment available for Macrophage Activation Syndrome. Depending upon the different medical literature the treatment of Macrophage Activation Syndrome are as follows:

High-dose corticosteroid therapy

• First line treatment for Macrophage Activation Syndrome is considered as high-dose corticosteroid therapy. In the case of severe case, the intravenous route is usually chosen for administering the drug. According to the medical case study report, steroid therapy is effective and safe for a patient with renal complication association.
• The selection of steroidal medication is depending upon clinician’s choice. But different medical case series showed that dexamethasone palmitate prescribed for a patient having resistance with pulse methylprednisolone.

Cyclosporine A

• T-cell blocking agent, such as Cyclosporine A also showed efficacy against Macrophage Activation Syndrome. Usually, Cyclosporine A is given as monotherapy for treating Macrophage Activation Syndrome. But it can also prescribe in combination with steroid drugs. It has found that Cyclosporine A is also effective and provide life-saving guard in a patient with steroid resistance.

Etoposide

• Etoposide is usually prescribed along with first or second line treatment option. In combination regimen, Etoposide induces rapid recovery for patients with steroid and Cyclosporine A Macrophage Activation Syndrome with providing any serious adverse event.

Intravenous immunoglobulin therapy

• In some patients, intravenous immunoglobulin therapy also prescribes as mono-therapy and in some patient, it shows the very effective result, however, in general, it does not effective much.

Anakinra

• Anakinra is prescribed for patients, who do not show a response to treatment with steroids, intravenous immunoglobulin therapy, and Cyclosporine A and provide an effective result.
• Yet now, medical literature reported case history does not show any promising result with Anti-TNFα therapy.

Life expectancy

Multi-organ failure is one of the major cause of death in the case of Macrophage Activation Syndrome. The mortality rate is significantly high in children with systemic lupus erythematosus patients associated with acute pancreatitis in comparison with adult systemic lupus erythematosus patients.

References

1. Ravelli A. Macrophage activation syndrome. Curr Opin Rheumatol. 2002 Sep;14(5):548-52. https://www.ncbi.nlm.nih.gov/pubmed/12192253
2. Angelo Ravelli, Francesca Minoia, Sergio Davı, et. al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis; ARTHRITIS & RHEUMATOLOGY DOI 10.1002/ART.39332; http://www.rheumatology.org/Portals/0/Files/A-and-R-Classification-Criteria-Macrophage-Activation-Syndrome-2016.pdf
3. Alexei A. Grom, (2010); Macrophage Activation Syndrome; http://www.the-rheumatologist.org/article/macrophage-activation-syndrome/
4. Angelo Ravelli, (2016); Macrophage Activation Syndrome; http://emedicine.medscape.com/article/1380671-overview#a6
5. V. Boom, J. Anton, P. Lahdenne, et.al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis; ediatric Rheumatology201513:55; DOI: 10.1186/s12969-015-0055-3; https://ped-rheum.biomedcentral.com/articles/10.1186/s12969-015-0055-3