SJIA with relapsing MAS

Alexei Grom, MD

Cincinnati Children's Hospital Medical Center

NextGen Therapies in SJIA, Still's & MAS Washington DC November 13-15

SJIA with refractory course

• · Despite recently approved IL-1 and IL-6 blocking agents, about 20% of patients with SJIA develop a refractory disease course
• · fail to respond to all the approved biologic and non-biologic DMARDs
• · persistent disease activity requiring maintenance therapy with glucocorticoids
• · Several distinct clinical patterns of refractory disease
• · Refractory SJIA with predominantly persistent arthritis
• · Refractory SJIA with predominantly systemic features
• · SJIA with chronic parenchymal lung disease
• · SJIA with relapsing MAS
• · Includes a subgroup with predominantly liver involvement
• · Most of these patients do not meet eligibility criteria in the ongoing clinical trials in SJIA

Erkens et al, Rheum Dis Clin North Am 2021;47:585

SJIA patients with relapsing MAS


SJIA patients with relapsing MAS

• · These patients appear at risk for sJIA-associated lung disease
• · A large proportion of these patients have predominantly liver involvement
SJIA with relapsing MAS with Predominantly Liver Involvement

• · Persistently elevated liver enzymes with lab features of subclinical MAS (but do not meet full criteria for MAS)
• · Highly characteristic findings in liver biopsy
• -Sinusoidal inflammatory infiltrate that consists both of increased number of T lymphocytes and CD163+ macrophages
• -Highly activated Kupffer cells with some of them exhibiting hemophagocytic activity
• -Marked predominance of CD8+ T cells of CD4+
• -Immunostaining for cytokines identifies CD8+ T cells as the main producers of large amounts of IFN γ
• · May have normal bone marrow biopsy
• · Increased serum levels of CXCL9 suggestive of high INFγ activity in tissues
Liver Biopsy in MAS/sJIA



Republished with permission of American Society of Hematology (ASH), from Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFNγ -producing lymphocytes and IL-6- and TNFγ -producing macrophages, Billiau et al. Blood 105, 2015; permission conveyed through Copyright Clearance Center, Inc.

Liver Biopsy in MAS/sJIA



Republished with permission of American Society of Hematology (ASH), from Macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, IFNγ -producing lymphocytes and IL-6- and TNFγ -producing macrophages, Billiau et al. Blood 105, 2015; permission conveyed through Copyright Clearance Center, Inc.

Liver biopsy: CD163 staining in SJIA



Elevated Ast/Alt, no other lab features of

MAS with Predominantly Liver Involvement

• · Similar histologic pattern observed by Prencipe et al. in 3 patients (2 of whom fully met the ILAR criteria for sJIA):
• -Large numbers of portal/periportal CD68+ macrophages and T cells
• · Liver biopsies showed highly increased levels of mRNA for IFN γ -induced genes, while other classical pro-inflammatory cytokines IL-18, IL-6 and TNF α were not markedly increased
• -Type I IFN induced gene expression was also roughly normal
MAS with Predominantly Liver Involvement

• · JAKi?
• · CyA?
• · MMF?
• · Emapalumab?
Challenges with clinical trials in 'smoldering MAS'

• · Do not fully meet criteria for MAS
• · Not eligible for MAS trials
• · If predominantly systemic features
• · Due to the absence of arthritis cannot be dx as SJIA and are not eligible for ongoing SJIA trails
• · Due to the absence of genetic dx, cannot be enrolled in the ongoing trials in inflammasopathies (such as anti-IL18/IL1 therapeutics in NLRC4 GoF)
• · Outcome measures for systemic aspect of the disease are not well defined
• · Options are modifying ACR JIA measures, or using Autoinflammatory Disease Activity Index, or Systemic JADAS
• · No clear how to handle numerous background medications (most trials require withdrawal with variable washout periods)