The changing face of SJIA

Grant Schulert, MD PhD

Associate Professor of Pediatrics

Division of Rheumatology, Cincinnati Children's Hospital Medical Center

Department of Pediatrics, University of Cincinnati College of Medicine

Complicated or refractory SJIA

• · Outcomes for children with SJIA have markedly improved with introduction of cytokine-directed biologic therapy (principally anti-IL-1 and IL-6)
• · However, some children fail to respond or have a treatment refractory course
• · Can include:
• - Persistent systemic features
• - Persistent arthritis
• - Steroid dependence
• - Recurrent macrophage activation syndrome including subclinical or 'persistent partial MAS'
• - Other complications including lung disease

Defining refractory SJIA

• · Refractory SJIA (broadly)
• - Failure to respond to IL-1 AND IL-6 blocking biologics (failure=inability to resolve arthritis, systemic symptoms, or liver dysfunction, or being glucocorticoid dependent) OR
• - ≥2 episodes of MAS in a 2 year period OR
• - Development of SJIA-LD

Defining refractory SJIA

• · 'Persistent partial MAS'
• - A patient with active SJIA and persistent inflammation
• - Newly worsening or persistently abnormal laboratory features consistent with MAS for at least 6 weeks
• · Liver abnormalities
• · Disorders of hematopoiesis
• · Coagulopathy
• · Elevated IL-18 and CXCL9
• - Does not meet criteria for overt MAS

What is refractory SJIA biologically?

• · Most severe patients (correct treatments but strong not enough)?
• · Different disease phenotype (different pathways and needing different treatments)?
• · Unable to tolerate treatments (side effects or drug reactions)?
• · Complications triggered by treatments

New refractory courses - IBD

• · Anecdotally - also increasing
• · Case series lead by Betsy Mellins in 2021 identified 16 patients
• · Key differences from CARRA Registry SJIA patients (order, more MAS, more IBD history, more non-White race)
• · After diagnosis most transitioned (often successfully) to TNFi

New refractory courses - lung disease

• · 'SJIA-LD' likely encompasses several disease phenotypes (see Saper 2019)
• · Most common phenotype
• -Early onset SJIA w/ high IL-18
• -Acute erythematous clubbing
• -Pleural, septal and/or peribronchovascular thickening on CT
• -Lymphocytic interstitial inflammation with PAP/ELP on biopsy
• -History of use (and failure +/- reaction to) IL-1/6-inhibitors
• · Prevalence?
• -6.8% in 2019 Cincinnati cohort
• -1.6% in Dutch cohort
• -19.9% in Chinese 2 center cohort (!)

Might 'SJIA-LD' be a distinct phenotype of the disorders classified as 'SJIA'??

• · Much younger age of onset
• · Higher levels of IL-18
• · Different cellular activation patterns
• · Higher incidence of overt or persistent partial MAS (much higher than 10% rate from historical literature)
• · Strong association with Trisomy 21
• · Different HLA associations (HLA-DRB1*15)
• · Atypical responses to biologics

A


Atypical rashes in systemic JIA - definitely bad but maybe not always DRESS?

• · 30 patients with atypical rashes vs xx with 'typical' Stills rash
• - Fixed urticaria, fixed macular and/or papular rash, pigmented or dyschromic (hyper- and/or hypochromic) papules or plaques, erythema and/or edema of the eyelids and back of the hands (dermatomyositis-like), scaly-crusted erythema.
• · Atypical rashes had higher CRP and ferritin at onset, more MAS (27% vs 10%), more failure of first-line Rx, more biologics needed, and more likely to have persistent disease course (biologics 2+ years from diagnosis)

What about HLA-DRB1*15? Could this be marker for refractory disease phenotypes?

• · How common is this in SJIA?
• - IN CHARGE (ILAR): 24%
• - Utrecht cohort (non-ILAR): 26%, no diff w/ or w/o arthritis
• · So, ~25% carry this … and about 25% of SJIA is refractory??
• · Some evidence DRB1*15 is higher in refractory courses
• - Higher in SJIA-LD (regardless of overt drug reactions) in several studies
• - Higher in selectively genotyped, referral center cohorts (49% Boston, 74% Minn)
• - Higher in Accelerate (70%+; not all genotyped yet)