Management of Macrophage Activation Syndrome (MAS) in Children: Diagnosis and Treatment Guidelines

1. Vahid Ziaee MD Children Medical Centre Tehran University of Medical Sciences Management of Macrophage Activation Syndrome (MAS)

2. Hemophagocytic Lympho- Histiocytosis • HLH a term that describes a spectrum of disease processes characterized by accumulations of well-differentiated mononuclear cells with a macrophage phenotype • Current classification of HLH: • Primary or familial HLH (FHLH) • Secondary or reactive HLH (ReHLH) • It may be difficult to distinguish one from the other. • Genetic variants may predispose patients to HLH at any age Dr V. Ziaee; Children’s Medical Center

3. Primary HLH (FHLH) • FHLH Characteristics: • Autosomal recessive immune disorders • Genetic defects • Clinically presented within the first two months of life. Dr V. Ziaee; Children’s Medical Center

4. Primary HLH • FHL can be divided into 5 subtypes: • FHL1 – caused by unknown defect on chromosome 9 • FHL2 – caused by deficiency of Perforin • FHL3 – caused by deficiency of Munc 13-4 • FHL4 – caused by deficiency of Syntaxin 11 • FHL5 – caused by deficiency of Munc 18-2 • Chediak-Higashi & Griscelli II syndromes are characterized by partial albinism and immune deficiency • XLP is characterized by massive lympho-proliferation and immune deficiency. Dr V. Ziaee; Children’s Medical Center

5. Diagnostic Criteria 1 2 3 4 5 6 7 8 Dr V. Ziaee; Children’s Medical Center

6. Diagnostic guideline   Dr V. Ziaee; Children’s Medical Center

7. Diagnosis of MAS Diagnosis requires: >2 Laboratory criteria >2 Lab + Clinical criteria Addition of ferritin >500 ng/ml may better discriminate MAS vs systemic infection. Adapted from: Davi, et al. Arthritis Rheumatol. 2014 Oct;66(10):2871-80.

8. New Diagnostic Criteria 1 2 3 4 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. Ravelli A, t al; Ann Rheum Dis. 2016 Mar;75(3):481-9. Dr V. Ziaee; Children’s Medical Center

9. 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. Ravelli A, t al; Ann Rheum Dis. 2016 Mar;75(3):481-9. Dr V. Ziaee; Children’s Medical Center

10. Dynamic Changes, Cut-Off Points, Sensitivity, and Specificity of Laboratory Data to Differentiate Macrophage Activation Syndrome from Active Disease. Assari R, Ziaee V, Mirmohammadsadeghi A, Moradinejad MH. Dis Markers. 2015;2015:424381. Dr V. Ziaee; Children’s Medical Center

11. Comparison of Lab. Data Dr V. Ziaee; Children’s Medical Center

12. Ferritin > 10,000 mg/L appear to be specific and sensitive for HLH. • In patients without a significant medical history and a new onset of febrile illness with highly elevated ferritin levels, the diagnosis of HLH should be evaluated. Dr V. Ziaee; Children’s Medical Center

13. Treatment • Control of underlying disease • IV Ig • Supportive therapy with antibiotic profilaxy, G-CSF??, Electrolyte imbalance, …. • Immunosuppressive therapy is controversial • Blood products (Plt?, Packed cell?, FFP) Dr V. Ziaee; Children’s Medical Center

14. Treatment in Rheumatologic Disorders • Should be started as soon as possible. • IVIg • Corticosteroids (pulse therapy) • Cyclosporin A • Plasma­phoresis • Biologic agents (not clear) • Other immunosuppressive agents Dr V. Ziaee; Children’s Medical Center

15. Treatment in Rheumatologic Disorders • HLH protocol in persistent cases • Persistent cases to HLH Protocol: • Anti Thymo-Glubulin • Alemtuzumab (Anti-CD52) • Plasma exchange • Bone Marrow Transplantation • IFN-ᵞ?? Dr V. Ziaee; Children’s Medical Center

16. Treatment protocol Overview for HLH (HLH-2004) Dr V. Ziaee; Children’s Medical Center

17. Dr V. Ziaee; Children’s Medical Center

18. ReHLH / MAS Treatment • Applicability of HLH 04 protocol to Re-HLH syndromes (e.g., MAS) and to adult populations is not been established • Mutliple groups support a graded-approach, with corticosteroids alone as initial treatment Dr V. Ziaee; Children’s Medical Center

19. MAS Treatment Options Dr V. Ziaee; Children’s Medical Center

20. Summary of Treatment • Suppression of Inflammation: • Corticosteroids, IVIg, Cyclosporin, Anticytotoxic agants • Elimination of achived immune cells and (infected) APCs: • Corticosteroids, Etoposide, T-cell antibodies (ATG, Rituximab, Abetecept) • Elimination of trigger: • Anti-infectious therapy • Supportive therapy (neutropenia, coagulopathy): • Antifungals, antibiotics, FFP • Replacement of defective immune system: • Bone marrow transplantation Dr V. Ziaee; Children’s Medical Center

21. Treatment Notes • Several series suggest outcomes are poor in Re-HLH if infection control measures are used alone. • Re-HLH triggered by leishmaniasis may be treated solely with amphotericin • Multiple groups agree that HLH 2004 should be initiated for relapses of Re-HLH, despite etiology. • HSCT has best overall outcome among all single treatment modalities across all patient populations Dr V. Ziaee; Children’s Medical Center

22. Dr V. Ziaee; Children’s Medical Center

23. Dr V. Ziaee; Children’s Medical Center

24. Prognosis • Without therapy, mortality of patients with HLH is high • Those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment. • Patients treated on the HLH-2004 protocol had a median survival of 54 percent at 6.2 years (249 patients, median age eight months).

25. Dr V. Ziaee; Children’s Medical Center