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MAS and HLH
1. MAS the 4th be with you
MAS and HLH
No conflicts of interest to disclose.
Devanshu Verma
May 4, 2022
2. What is HLH?
• Hemophagocytic lymphohistiocytosis
= Lots of lymphocytes that eat red blood cells
Macrophage with
ingested RBCs
3. Not a single disease but a syndrome
• Clinical manifestations of various conditions
• Manifest with uncontrolled systemic inflammation due to excessive
activation and proliferation of T cells and well-differentiated non-
neoplastic macrophages
• Mostly CD8+ T cells
• Mostly CD163+ macrophages
• CD163 = Macrophage hemoglobin scavenger receptor
• Hyperinflammation causes tissue damage
12. X-linked Lymphoproliferative Disorder 1
• Deficiency of SAP (SLAM
Associated Protein)
• Gene SH2D1A on X chromosome
• Catastrophic EBV infection HLH
• Intestinal lymphoma
• Vasculitic lesions in lungs, brain
13. Medium & Small Vessel Vasculitis in XLP1
Case of HLH in 13-month-old boy treated and stable
until age 10 that progressed to low IgG on IVIG, leg
atrophy from denervation neuropathy, negative
ANCA, ANA progressed to resp failure requiring
intubation and passed after 1 month. Autopsy
revealed widespread microscopic necrotizing arteritis
resembling PAN including in CNS, cardiac, renal, testes
and pancreas, and chorioretinitis. Found to have
altered SAP gene and diagnosed with XLP.
https://pubmed.ncbi.nlm.nih.gov/11133747/
14. X-linked Lymphoproliferative Disorder 2
• Deficiency of XIAP
• T cells deficient in XIAP are
defective in pathogen clearance
• Loss of inflammasome clearance
• Deficient XIAP = dysregulated gut
innate immunity = 30% boys
develop IBD
15. North American Consortium for Histiocytosis
(NACHO) - 2019
https://pubmed.ncbi.nlm.nih.gov/31339233/
16. Life Threatening Complication of sJIA
• Macrophage activation syndrome (MAS) = form of HLH
• 10% of sJIA patients
• Subclinical MAS may be in 30-40% of active sJIA
https://juvenilearthritisnews.com/2020/02/14/actemra-can-mask-
macrophage-activation-syndrome-systemic-jia-study-reports/
17. Simple Video of HLH
https://vimeo.com/406196004
https://vimeo.com/gamifant?embedded=true&source=owner_name&owner=110035876
18. Consider MAS in any sJIA patient if:
• Decreasing fibrinogen decreasing ESR
• Increasing CRP and D-dimers
• Decreasing WBC and platelet counts
• Increasing LFTs
• Increasing triglycerides
• Ferritin > 3000 to 10000 ng/mL
• Increasing soluble alpha chain of IL-2 receptor (sCD25)
• Increasing CD163. Because CD163 = Macrophage hemoglobin
scavenger receptor
19. Common Manifestations
• High fevers
• Hepatosplenomegaly
• Lymphadenopathy
• Severe cytopenias
• Liver dysfunction
• Coagulopathy decreasing fibrinogen + increasing PT, PTT DIC
• Hypertriglyceredemia
• CNS involvement = seizures
20. Less likely MAS in sJIA if:
• Normal sIL-2R
• High WBC
• No cytopenias
• High fibrinogen
• Lymphadenopathy (may be malignancy)
• Normal LFTs
21. Symptoms in Relation to Cytokines
• Fever IL-1 & IL-6
• Pancytopenia TNFa and IFNy
• Hypertriglyceridemia TNFa inhibits LPL
• Hypofibrinogenemia Macrophages activate
plasminogen hyperfibrinolysis
• Elevates sIL-2 Activated lymphocytes
• High LFTs, organ Sx Organ infiltration by lymphocytes
22. Why is Ferritin High?
https://pubmed.ncbi.nlm.nih.gov/17968951/
Macrophage surface
Enzyme activation to
break down heme
RBCs take up by
macrophages
Need more ferritin to
transport excess iron to
bone marrow
23. CD8 T Cells
Cycle of activation and
recruitment of more
macrophages
Negative feedback when
antigenic stimulation is
eliminated (via clearance
of infected cells)
24. Lack of negative feedback in HLH
Self damaging cycle of
proliferation
30. General Approach
• Identify that there is hyperinflammation (ferritin, CD25)
• Find and treat any triggers (infection, flares)
• Treat the hyperinflammation (steroids)
• Rule out any immune system defects
• Immunoreplacement if needed
31. Find Triggers
• HLH is not occur spontaneously
• Each flare may have the same or separate trigger
• In addition to infections, look for malignancy consider PET-CT
• May have underlying immune defect check perforin (FHL2), SAP (X-
linked lymphoproliferative 1), XIAP ((X-linked lymphoproliferative 2)
34. Biopsy
• May not be positive early in disease course
• Activated macrophages staining with CD163+ (Heme scavengers
receptor) showing hemophagocytosis in bone marrow
35. Treatment Phase 1: Induction
• Acutely reign-in out of control immune activation
• Treat underlying infectious triggers
• Limit organ damage
1) Supportive care
1) Antibiotics/fungals/virals
2) Transfusions RBC, platelets, FFP, cryoprecipitate
2) Immunosuppression
1) Steroids: dexamethasone 10 mg/m2/day over 4 weeks or IV SoluMedrol
pulse (30 mg/kg) x 3 days
1) Dexamethasone has better CNS penetration in case of seizures, etc
2) DMARDs
36. Treatment Phase 2: Definitive Therapy
• Prevent future recurrences
• Correct underlying immune defect, if possible, with bone marrow
transplant
38. HLH-94 Protocol
• Etoposide = 150 mg/m2 per dose
• If CNS involvement weekly intrathecal methotrexate (6 – 12 mg
depending on age) and hydrocortisone until 1 week after resultion
of CNS symptoms
39. Give Enough Treatment to Control Disease
and Prevent Damage
• May not need full HLH-94 based induction
• May be able to treat with less aggressive therapy with steroids +/-
anakinra alone
41. IFN-gamma higher in MAS than active sJIA
https://ard.bmj.com/content/76/1/166.long
42. No correlation with IL-6 and TNFa in MAS vs
active sJIA
https://ard.bmj.com/content/76/1/166.long
Canakinumab and tocilizumab
are NOT effective
43. Tocilizumab not really effective for MAS
• Study compared 12 patients on Actemra (age 8.5 years average) with
18 untreated participants (average age 5.5 years).
• Of patients on TCZ, two were diagnosed with full-blown MAS
• Remaining 10 individuals were diagnosed with possible MAS
• Of 18 untreated patients, 10 had full-blown MAS and eight possible
MAS
• Full-blown MAS was defined as the time of most severe MAS.
• Possible MAS referred to characteristic laboratory features without
clinical features of MAS
44. Uncertain validity in using 2016 classification criteria in TCZ
treated patients – absence of fever or insufficient increases in
ferritin compared to untreated patients
