Hidden killer-new progress in diagnosis and treatment of macrophage activation syndrome (MAS)

It is only for medical professionals to read for reference.
Emerging drugs ignite a spark of hope and bring confidence to clinical treatment.
Macrophage activation syndrome (MAS) is a serious complication of rheumatic diseases with potentially fatal risks
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Aiming at such a hidden killer as MAS, we specially invite Professor Tian Xinping from the Department of Rheumatology and Immunology of Peking Union Medical College Hospital to introduce us the current status and progress of diagnosis and treatment of MAS
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MAS is a serious complication of rheumatic diseases, with potentially fatal risks
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MAS belongs to secondary hemophagocytic lymphohistiocytosis (HLH).
At present, there is no unified understanding of the pathogenesis, mainly including cytolytic function defects, macrophage activation and cytokine storm [1]
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Systemic juvenile idiopathic arthritis (sJIA) is the most common cause of MAS, and systemic lupus erythematosus (SLE) and adult still disease (ASOD) are also common causes [2]
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MAS accounts for 10%-15% of secondary HLH, of which the incidence of sJIA-MAS is about 10%-40%, and the incidence of AOSD-MAS also reaches about 15%[1,3-4]
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Due to the hidden symptoms of MAS, the unbalanced understanding of the disease, and the difficulty in early recognition, the actual incidence of MAS may be higher than the current cognition
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Facing the increasing number of patients year by year, MAS, a potentially fatal disease, has attracted everyone's attention [1]
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Diagnosis of MAS is based on the diagnostic criteria of HLH-2004.
However, the diagnostic criteria are not suitable for early diagnosis of MAS.
For example, splenomegaly and methrinemia in the criteria are also common in active sJIA.
Performance, cannot be used as a criterion for the identification of primary disease activity and secondary MAS
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In addition, the active phase of sJIA patients is often accompanied by the increase of white blood cells, platelets and fibrinogen.
When blood cell reduction and hypofibrinogenemia in the HLH-2004 diagnostic criteria are met, MAS has often developed to the later stage, and the treatment at this time is obviously difficult Increase [1]
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In 2005, Ravelli et al.
formulated the preliminary diagnostic guidelines for MAS in sJIA, and then further established the classification criteria for sJIA-MAS in 2014
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In 2016, the European Union against Rheumatism (EULAR)/American College of Rheumatology (ACR)/International Children's Rheumatology Trial Organization (PRINTO) released a new classification standard for sJIA-MAS
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In 2009, Parodi et al.
formulated a diagnostic guideline for JSLE-MAS, but this diagnostic method has not been widely used
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KD and JDM merged with MAS so far, no internationally recognized diagnostic recommendations have been issued [1]
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Among them, the HScore diagnostic criteria have also been developed for adult patients, which is the first effective scoring standard for the diagnosis of secondary HLH [5]
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The current clinical diagnosis mainly refers to the HLH-2004 diagnostic criteria and the sJIA-MAS diagnostic criteria issued by EULAR/ACR/PRINTO in 2016 (Table 1) [1]
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Table 1: sJIA-MAS diagnostic criteria in different guidelines As mentioned above, these diagnostic criteria have certain limitations, so in the real world, continuous monitoring of the relative changes of patient parameters may be the best way to identify and diagnose MAS early [6]
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Therapeutic drugs are in the ascendant, and MAS is progressing rapidly and has a high case fatality rate.
It should be actively intervened as soon as possible
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Real-time monitoring of the dynamic changes of clinical and laboratory indicators, early diagnosis, active removal of predisposing factors and early application of immunosuppressive therapy are the keys to improving the prognosis of MAS
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The onset of MAS is mostly accompanied by the disease activity of the primary disease.
At this time, it is necessary to clarify the focus and direction of treatment, and the treatment plan adopted is mainly to take into account the activities of MAS and the primary disease
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The treatment of MAS should be based on a combination of multiple disciplines including rheumatism, hematological tumors, and critical care medicine.
The treatment options include traditional immunosuppressive therapy, new cytokine blockers and other adjuvant therapies
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But so far, there is no effective evidence to support the recommendation of MAS treatment guidelines [1]
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Once MAS is diagnosed, high-dose glucocorticoid (GC) shock therapy is currently the internationally recognized first choice treatment
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The calcineurin inhibitor cyclosporine A (CsA) can be used as the first-line treatment of MAS, combined with high-dose GC in the early stage, or as a sequential combination therapy after hormone resistance in some patients
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When high-dose GC shock combined with CsA treatment is ineffective, etoposide (VP16) can be used for treatment [1]
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New cytokine blockers may be effective against MAS with insufficient response to hormones and CsA, such as interleukin-1 (IL-1) receptor antagonist Anakinra, IFN-γ monoclonal antibody Emapalumab, CD20 monoclonal antibody, JAK 1/2 inhibitor
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Anakinra is the first-line drug to treat the primary disease of sJIA, so it is also beneficial to control the disease activity of the primary disease while treating MAS
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A retrospective study on the efficacy of Anakinra in the treatment of patients with MAS [7] included 763 patients, of which 43 patients had clinical manifestations that met the definitions of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC)
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The patients were randomly assigned to receive placebo or Anakinra at a 1:1 rate, intravenously at 2.
0 mg/kg/hr for 72 hours
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The results of this study confirmed that Anakinra can significantly improve the 28-day survival rate of sepsis patients with HBD/DIC characteristic of MAS, but does not change the prognosis of patients with non-HBD/DIC sepsis
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In 2020, a retrospective study by Eloseily EM et al.
reported that Anakinra is effective for non-malignant-related children with sHLH/MAS, especially in patients who are early in the course of the disease and have underlying rheumatism
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In the absence of malignant tumors, early initiation of Anakinra to treat sHLH is associated with reduced mortality [8]
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The preliminary research results of Emapalumab in the treatment of sJIA-MAS are exciting [9] and arouse everyone's attention
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This is a phased study (NCT03311854), an open-label, single-arm, international multi-center study of sJIA (or highly suspected sJIA)-MAS active patients with high-dose GC response less than 3 days using Emapalumab
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A total of 9 patients were enrolled in the study, treated with Emapalumab 6mg/kg (initial dose), and then injected with Emapalumab at a dose of 3mg/kg every 3 days until the 15th day, and then injected twice a week for 2 weeks
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The results of the study confirmed that the use of Emapalumab in sJIA-MAS patients who have previously received treatment can quickly and effectively neutralize IFN-γ, and the plasma CXCL 9 level significantly decreases during the treatment period (Figure 1)
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Figure 1: Emapalumab used in sJIA-MAS patients, plasma CXCL 9 levels were significantly reduced.
All clinical and laboratory parameters of MAS patients gradually improved.
All patients achieved CR (ie MAS remission).
During the treatment, GC was also in all patients.
Decrease gradually (Figure 2)
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Figure 2: During treatment, GC gradually reduced the incidence of adverse reactions of Emapalumab treatment to 77.
8% (7/9), mostly mild; 2 patients had serious adverse reactions (22.
2%), of which 1 case was cytomegalovirus ( CMV) reactivation may be related to Emapalumab treatment, and recovery after standard treatment; Emapalumab dose reduction and adverse outcomes did not occur, suggesting that Emapalumab is safe and tolerable
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In the past, some literatures reported the efficacy of IL-6 receptor antagonist tocilizumab on patients with sJIA-MAS[10,11].
Although tocilizumab may have substantial clinical and laboratory changes, some patients are in MAS still occurs during the application of tocilizumab, so the current consensus does not recommend IL-6 receptor antagonists for the treatment of MAS [1]
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Other drugs such as JAK 1/2 inhibitor Ruxolitinib, TNF-α antagonist Infliximab, CD20 monoclonal antibody Rituximab, etc.
have only sporadic case reports, and no clinical studies have confirmed their efficacy [12-14]
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So far, there is no effective evidence to support the recommendation of MAS treatment guidelines, and the diagnostic criteria also have many shortcomings.
The road ahead is long and hindered
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Although different drugs have been tried for the treatment of MAS, the treatment options for MAS are still very limited, and there is still a long way to go
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However, Emapalumab, Anakinra, and more emerging drugs under exploration have ignited a spark of hope and brought confidence to clinical treatment.
It is believed that further large-sample studies in the future will illuminate a smooth path for MAS
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 Expert profileProfessor Tian Xinping, chief physician, doctoral supervisor, and professor of the Department of Rheumatology, Peking Union Medical College Hospital, secretary of the Chinese Society of Rheumatology, Member of the Standing Committee of the Chinese Medical Association Rheumatology Branch and Director General, Deputy Director of the Rheumatology Branch of the Asia-Pacific Society of Bioimmunology Member of the Internal Medicine Branch of the Beijing Medical Association Member of the Cross-Strait Medical and Health Exchange Association Rheumatology Expert Committee Vasculitis Branch Chairman of the World Lupus Nephropathy Research Collaboration Group (LNTN) Member of the International Vasculitis Clinical Research Alliance (VCRC) Member Reference: [1 ] Rheumatism Immunology Group of Pediatrics Branch of Chinese Medical Doctor Association, et al.
Chinese Journal of Practical Pediatrics 2020.
11;35(11):825-831.
[2] Hemophagocytic Syndrome Chinese Expert Alliance, et al.
Chinese Medical Journal, 2018, 98( 2):91-95.
[3]Jordan MB,et al.
Pediatr Blood Cancer.
2019 Nov;66(11):e27929.
[4]Piero Ruscitti,et al.
Autoimmun Rev.
2017 Jan;16(1): 16-21.
[5]Fardet L,et al.
Arthritis Rheumatol 2014;66:2613–20[6]Tang S,et al.
Semin Arthritis Rheum.
2021 Feb;51(1):198-210[7]Shakoory B,et al.
Crit Care Med.
2016 Feb;44(2):275-81.
[8]Eloseily EM et al.
Arthritis Rheumatol.
2020 Feb;72(2):326-334.
[9]Benedetti FD, et al.
2019 ACR/ARP Annual Meeting,ABSTRACT NUMBER:L06;Unpublished[10]Schulert GS,et al.
Arthritis Care Res(Hoboken).
2018 Mar;70(3):409-419.
[11]Shimizu M, et al.
Pediatr Rheumatol Online J.
2020 Jan 10;18(1):2.
[12]Wang H,et al.
Semin Hematol.
2020 Jan;57(1):26-30.
[13]Kiuchi Z,et al.
Scand J Rheumatol.
2019 May;48(3):246-248.
[ 14]Liu AC,et al.
Clin Rheumatol.
2018 Jan;37(1):93-100.
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