Super detailed clinical experience, Professor Li Caifeng explained the diagnosis and treatment of MAS

*For medical professionals only

The state of high inflammation is the culprit of MAS

MAS refers to secondary HLH secondary to rheumatic immune diseases, which accounts for about 10% to 15% of all secondary ^HLHs[1], and like other HLHs, MAS is acute, rapidly progressive, and life-threatening

Professor Li Caifeng introduced, "The clinical manifestations of MAS include a series of symptoms of systemic multisystem involvement, such as intracranial hypertension and cerebral edema of the central nervous system, white lung, gastrointestinal bleeding, hypotension, circulatory failure, DIC, liver function abnormalities and other multi-organ system injuries, which are acute and severe, and progress rapidly

In terms of primary disease, MAS is more likely to occur in systemic jiaudic arthritis (sJIA), systemic lupus erythematosus, juvenile dermatomyositis, Kawasaki disease, ankylosing spondylitis, and autoinflammatory diseases, among which sJIA is most prone to MAS

The immunological mechanism of MAS is that IFN-γ drives the activation of M1 macrophages, releasing a large number of tumor necrosis factor, pro-inflammatory cytokines such as IL-6, IL-1, and IL-18, and then cascading between cytokines and immune cells, eventually forming a cytokine storm, causing multi-organ damage^[1

"As early as the 1970s, there have been literature reports of cases of MAS," Professor Li Caifeng introduced, "the early view that MAS is a series of diseases caused by drugs, and then gradually recognized that MAS is due to abnormal activation of

Early identification is key to dealing with MAS

The diagnosis of MAS is different from other types of HLH, and high inflammatory status in PATIENTS can cause acute organ injury, and if the patient meets the HLH diagnostic criteria before treatment, treatment will be delayed and treatment will be delayed
.

Therefore, early diagnosis and early treatment of MAS is very important
.

In terms of early recognition of MAS, Professor Li Caifeng shared his clinical experience, "For example, the fever type of sJIA patients is generally manifested as flaccid fever, and the body temperature has obvious peaks and valleys
.

If patients have MAS, high fever will occur continuously, at this time, patients can have hepatosplenomegaly, systemic lymphadenopathy, rash, bleeding tendencies, etc.
, in addition, it can also involve the central nervous system, respiratory system, digestive system, circulatory system, etc.
to cause corresponding clinical symptoms
.

”

In order to warn of MAS early, Professor Li Caifeng summarized 5 highly feasible clinical testing projects for us:

• Blood routine: due to the presence of blood phagocytosis, dynamic monitoring of blood routines can observe the dynamic decline of white blood cells and platelets;

• Biochemical indicators: Alanine transaminases (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), blood cholesterol (CHOL) increases, albumin decreases, sodium and calcium ions decrease when MAS occurs, and monitoring these biochemical indicators can help diagnose MAS;

• Coagulation function: MAS is prone to mucocutaneous bleeding, gastrointestinal bleeding, which is due to the abnormal coagulation function, at this time the detection of coagulation function can find a significant decrease in fibrinogen (Fib), D-dimer (D-dimer) and fibrin degradation products (FDP) increased;

• Serum ferritin: ferritin is also a very sensitive indicator of MAS, and the patient's ferritin in the body can be rapidly elevated to thousands or even tens of thousands;

• Erythrocyte sedimentation rate:ERH accelerates when rheumatic immune disease is active, and erythrocyte sediment rate may return to normal
  when MAS is combined.
  
  

• Serum ferritin > 684 μg/L

• Platelet ≤ 181×10⁹/L;
• AST＞48 U/L；
• Triglycerides> 1560 mg/L;
• Fib≤3600 mg/L
  。
  

Professor Li Caifeng introduced, "The diagnostic criteria for MAS and the diagnostic criteria for other types of HLH are not exactly the same, and the diagnosis of MAS must be made by comparing the various indicators of patients longitudinally in order to diagnose
them earlier.
"
“

Treatment of MAS, only fast and not broken

Professor Li Caifeng stressed that "for treatment, it is very important to recognize MAS"
.

Aggressive treatment can also save lives
in patients who are suspected and unable to make a detailed differential diagnosis in the short term.

• For patients with MAS, high-dose methylprednisolone shock therapy is currently the recommended first-line treatment option, which can quickly control the inflammatory storm, reduce multi-organ edema caused by high inflammatory states, and save lives
  .
  
  

• In addition to hormonal shock, cyclosporine is also an internationally recommended therapeutic agent
  .
  
  

• In terms of biologics, IL-1 receptor antagonists (Anakinra) are also internationally recommended therapeutics
  .
  
  According to the recommendation of the 2021 ACR, monoclonal antibodies such as IL-6 and IL-1 are conditionally recommended, and some large molecule mouse-derived monoclonal antibodies will promote macrophage activation, which may aggravate the disease performance, so it is necessary to choose
  according to the patient's inflammatory status.
  

• Etoposide (VP-16) may be used in patients with refractory MAS, but VP-16 tends to cause a decrease in white blood cells and increase the risk of
  infection.
  
  Chemotherapy
  is currently used less often in cases of early diagnosis of MAS.
  

Professor Li Caifeng also mentioned, "In addition to early diagnosis and early treatment, for some patients who may have MAS, such as blood cells, biochemical indicators, etc.
are developing, controlling the active state of inflammation and primary disease and avoiding the development of disease to MAS is also a particularly important preventive measure.
"

In addition to this, it is also very important
to prevent infection.

"IFN-γ plays a very important role in the development of MAS, which stimulates macrophages to constantly activate and secrete cytokines
.

Anti-IFN-γ monoclonal antibodies (emaliumab) are available for the treatment of refractory primary HLH
.

Emaliyumab is also being studied internationally in sJIA-MAS, enrolling 14 patients worldwide, with a decline in CXCL-9 (IFN-γ downstream product) after treatment, with a significant downward trend of about two weeks and continued to maintain
.

IFN-γ is an important target and is expected to be applied to MAS patients in the future to bring benefits
to them.

Professor Li Caifeng said
.

■ An open-label, single-arm, multicenter clinical study (NCT03311854) exploring the safety, tolerability, pharmacokinetics, and efficacy of emaliizumab in patients with sJIA-MAS enrolled 14 patients with high-dose glucocorticoid impact for 3 days or more and who did not respond to other therapies such as cyclosporine A, who discontinued the drug for 4 weeks or after symptom resolution, followed by a 4-week discontinuation follow-up period, with the primary efficacy endpoint being complete remission
.

Thirteen patients achieved complete remission in week 4, 11 patients in week 8 maintained complete remission, and the combined use of glucocorticoid doses decreased by 50% or more during treatment and follow-up, while a rapid decrease in the concentration of chemokin CXCL9 (IFNγ induced by ifNγ induced production, which can reflect IFNγ levels) in all patients was observed, and the concentration of CXCL9 in 9 patients decreased to 300pg/ at 2 weeks.
ml (baseline median value of 10883 pg/ml) suggests that emaliyuzumab can quickly neutralize IFNγ, thereby controlling MAS activity and being well tolerated and safe ^[3
].

■ A global multicenter study of the application of emaliumab in patients with MAS is underway, with the participation of 3 research centers in China, which is a two-cohort, open, single-arm, multicenter study evaluating the efficacy, safety and tolerability, pharmacokinetics and pharmacodynamics of emaliumab in children and adults with MAS secondary to Stil disease (including sJIA and AOSD), or SLE secondary MAS, Looking forward to the results of patient efficacy and safety data in
China.

• Professor, Director of the Department of Rheumatology, Beijing Children's Hospital, Capital Medical University
• Member of the First Pediatric Nephropathy Rheumatology and Immunology Group of the Beijing Medical Association Branch, term of office of three years (since June 2013)
• Member of the Second Committee of the Rheumatology and Immunology Physicians Branch of the Chinese Medical Doctor Association, term of office of three years (since 2012.
  9 of the Chinese Medical Doctor Association)
• Deputy Leader of the Immunology Group of the 16th Committee of the Science Branch of the Chinese Medical Association (since September 12, 2013)
• Deputy Secretary-General of the 16th Committee of the Science Branch of Chinese Medical Association (since March 9, 2013)
• Member of the 16th Committee of the Science Branch of Chinese Medical Association (since December 28, 2012)
• Editorial Board Member of National Higher Education Medical Digitalization Planning Textbook (National Medical Electronic Bookbag) - Pediatrics, the first medical digital textbook in China (from 2013.
  10)
• Corresponding Editorial Board Member of the 1st Editorial Board of Chinese Clinical Journal of Practical Pediatrics (since November 1, 2012)
• Member of the 6th Editorial Board of the Journal of Clinical Pediatrics (since April 2012)
• Editorial Board Member, Chinese Journal of Lupus, two-year term (CSTAR, July 18, 2013)
• Executive Director of Internal Medicine Specialist Branch of Beijing Medical Doctor Association (since July 2013)
• Standing Committee Member of the Rheumatology Expert Committee of the Cross-Strait Medical and Health Exchange Association (since 2013)

Rheumatology and Immunology Group, Pediatricians Branch of Chinese Medical Doctor Association.
Expert Consensus on the Diagnosis and Treatment of Macrophage Activation Syndrome Associated with Rheumatic Diseases in Children No.
2: Systemic Jiauterial Arthritis[J].
CJPP, 2020, 35(11):831-834.

[2] Ravelli A, Minoia F, Davi S, et al.
2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative[J].
Arthritis Rheumatol, 2016,68(3):566-576.

[3] Efficacy of Emapalumab, an Anti-IFNγ Antibody in Patients with Macrophage Activation Syndrome (MAS) Complicating Systemic Juvenile Idiopathic Arthritis (sJIA) Who Had Failed High-Dose Glucocorticoids (GCs).
2022 ACR ABSTRACT NUMBER: L20.