M EETING REPOR T Open Access

Proceedings from the 2

Next Gen

Therapies for Systemic Juvenile Idiopathic

Arthritis and Macrophage Activation

Syndrome symposium held on October

3-4, 2019

Scott W. Canna

1†

, Grant S. Schulert

2*†

, Adriana de Jesus

, Alex Pickering

, Hermine Brunner

, Massimo Gadina

Stewart Levine

, Raphaela Goldbach-Mansky

, Jonathan Boutelle

, Rashmi Sinha

, Fabrizio DeBenedetti

Alexei Grom

and on behalf of the NextGen 2019 Participants

From NextGen Therapies for SJIA & MAS – 2019

Bethesda, MD, USA. 3-4 October 2019

Abstract

For reasons poorly understood, and despite the avail ability of biological medications blockin g IL-1 and IL-6 that have

markedly improved overall disease control, children with Systemic Juvenile Idiopathic Arthritis (SJIA) are now increasingly

diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD). On October 3–4, 201 9,

atwo-daymeeting,NextGen Therapies for Systemic Juvenile Idiopathic Arthritis (SJIA) & macrophage activation syndrome (MAS)

organized by the Systemic JIA Foundation (www.systemicjia.org/) in Washington, DC brought together scientists, clinicians,

parents and FDA representatives with the objectives (1) to integrate clinical and research findings in MAS and SJIA-LD, and

(2) to develop a shared understanding of this seemingly new pulmonary complicati on of SJIA. The current manuscript

summarizes discussions and conclusions of the meeting.

Keywords: Systemic juvenile idiopathic arthritis, Macrophage activation syndrome, Hemophagocytic lymphohistiocytosis,

Interferonopathy, Interstitial lung disease, Pulmonary alveolar proteinosis, Alveolar macrophages

Introduction

Systemic Juvenile Idiopathic Arthritis (SJIA), formerly Still’s

Disease, is an autoinflammatory disorder known for marked

systemic, predominantly innate immune activation [1]. The

adult counterpart is Adult Onset Still’sDisease[2]. About

15% of SJIA patients will also develop overt macrophage

activation syndrome (MAS), an episodic hyper-inflammatory

state caused by excessive activation and expansion of macro-

phages with hemophagocytic properti es and predominant ly

CD8+ T lymphocytes [3]. It is accompanied by a surge in

IFN-γ and downstream chemokines [4], as well as strikingly

high serum levels of IL-18 [5]. MAS has bee n associ ated wi th

significant morbidity and mortality. For reasons poorly

understood, and despite the availability of biological medica-

tions blocking IL-1 and IL-6 that have markedly improved

overall disease control [6, 7], MAS rates have remained un-

changed [8–10]. Additionally, children with SJIA and MAS

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* Correspondence: Grant.schulert@cchmc.org; Alexi.Grom@cchmc.org

†

Scott W. Canna and Grant S. Schulert contributed equally to this work.

Division of Rheumatology, Cincinnati Children’s Hospital Medical Center and

Department of Pediatrics, University of Cincinnati College of Medicine,

Cincinnati, USA

Full list of author information is available at the end of the article

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53

https://doi.org/10.1186/s12969-020-00444-7

are now increasin gly diagnosed with life-threatening chronic

complications, including hepatitis and lung disease (SJIA-LD)

[11–13]. Evaluation of lung biopsies of these patients reveals

severe inflammation with features of pulmonary alveolar pro-

teinosis (PAP), endogenous lipoid pneumonia, and fibrosis

[12, 13], all supporting that SJIA

−

LD is chronic and likely di-

agnosed late when irreversible tissue damage has already oc-

curred. Hence, there is a profound scientific gap of how to

diagnose SJIA-LD early, elucidate risk factors, and develop

therapeutic strategies to improve its prognosis.

Conference goals and overview

As MAS and lung disease (LD) in SJIA appear to be re-

lated, on October 3–4, 2019, a two-day meeting, NextGen

Therapies for SJIA & MAS organized by the Systemic JIA

Foundation (www.systemicjia.org/) in Washington, DC

brought together scientists, clinicians, parents and FDA

representatives with the objectives (1) to integrate clinical

and research findings in MAS and SJIA-LD, and (2) to de-

velop a shared understanding of this seemingly new pul-

monary complication of SJIA. In her introduction, Dr.

Sinha, the President of the Systemic JIA Foundation,stated

that the longer-term goals of the meeting were to develop

a strategy to enable the early diagnosis of SJIA-LD and im-

prove the management of SJIA-LD, based on the current

state of knowledge of this condition. The meeting in-

cluded in depth presentations and open discussions of un-

published research findings. Dr. Sinha emphasized the

role of parental participation in this process, to ensure that

their voices are heard in planning of future observational

studies and clinical trials.

Section 1: patient perspectives

Understanding the patient experience of SJIA-LD /

moderator: Dr. Rashmi Sinha; panelists: Anna Carlson,

Regina Minerva, Emily Schumacher

Three parents of children diagnosed with SJIA-LD re-

ported their child’s experience, highlighting the lack of

apparent pulmonary symptoms prior to diagnosis of

SJIA-LD, a common feature that may contribute to delay

in diagnosis. These testimonials provided crucial detail

and context for the natura l history of SJIA-LD, and are

consistent with the pictures offered by three recent pub-

lications [12–14]. All three patients have had a rather re-

sistant systemic component of the disease with recurrent

MAS, and as a result, have been exposed to multiple

medications including several biologics. The parents em-

phasized the need for relatively safe therapies that could

be initiated preventively when a child shows early signs

of MAS and/or the lung disease, instead of the highly

immunosuppressive treatment regimens that are typic-

ally used for full-blown MAS.

Patient story - Anna Carlson

Ms. Carlson’s daughter was diagnosed with SJIA in No-

vember 2016, at the age of 1 year. She was started on

corticosteroids and canakinumab. Within 2 months, her

parents started noticing a dry hacking cough and “pneu-

monia” like symptom s that were unresponsive to antibi-

otics. Her fevers return ed and canakinumab dose was

increased. In May 2017, a high-resolution chest com-

puter tomography (HRCT) was obtained and the child

was diagnosed with interstitial lung disease (ILD). Over-

night pulse oximetry revealed significant hypoxia (desat-

uration episodes down to the 40s). She was admitted to

the hospital, and within a few days the lung disease pro-

gressed to respiratory failure requiring admission to an

Intensive Care Unit (ICU). During this 100 day “big sick”

(as Ms. Carlson terms this event) her child required 13

days of Extra-Corporeal Membrane Oxygenation

(ECMO). After being weaned from ECMO, she devel-

oped a severe case of MAS with ferritin rapidly increas-

ing to 280,000 ng/mL, and 10-week treatment with

etoposide was initiated.

A tracheostomy tube was placed due to continuous

need for ventilator and oxygen supplementation, as well

as G-tube to prevent aspiration. After 2 months of being

bed-ridden, her child required extensive physical, occu-

pational and speech therapy to relearn the most basic of

activities. In August 2018, about a year after “the big

sick”, a lung biopsy revealed PAP. Noticeably, her child

did not develop clubbing until 1 year after the start of

her lung symptoms.

For the past year, Ms. Carlson’s child’s SJIA has been

mostly controlled (with normal labs and no rash or

fever), but the lung disease persists, and is easily exacer-

bated by infections, which typically prompt ICU read-

missions with increasing needs for supplemental oxygen

(up to 20 l per minute) and more robust ventilator sup-

port. The side effects of her immunosuppressive regimen

have led to profound neutrop enia, with absolute neutro-

phil counts falling to zero. A JAK-inhibitor was recently

started, and the family is hopeful that the combination

of biologics, JAK inhibitor and antibiotic prophylaxis will

help her child.

Ms. Carlson emphasized the need for better medica-

tion options to control the progression of SJIA-LD, and

to manage the delicate balance between adequate im-

munosuppression and the patient’s ability to fight infec-

tions. She is concerned that there are few available

options for treating SJIA-LD, and that her daughter has

tried most of those medications. She did not know what

they would try next if her daughter’s disease persisted.

Following the NextGen conference, Ms. Carlson’s

child has experienced new lung symptoms, such as fre-

quent blood in sputum, significant increase in mucus

production.

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 2 of 15

Patient story - Emily Schumacher

Ms. Schumacher described the story of her daughter,

who is now 6 years old. She first developed signs of

SJIA-like disease in 2015 with fevers and rash, initially

thought to be a viral illness. Initial treatment of her SJIA

included subcutaneous injections of tocilizumab. Since

there was no response, tocilizumab was replaced with

high dose daily anakinra injections. Cyclosporine and

methotrexate were added few weeks later. SJIA remained

active, and anakinra was next replaced with ca nakinu-

mab without improvement of SJIA symptoms.

Despite all the efforts to avoid corticosteroids, oral

prednisolone was started in July 2016, and the child con-

tinued to remain chronically steroid dependent 3 years

later. In the same year, intravenous tocilizumab was ini-

tiated with the hope that inf usions would work better

then subcutaneous injections. Unfortunately, the child

had an unu sual reaction during her 3rd infusion, with

tachycardia, and tachypnea requiring additional oxygen

supplementation. After this event, tocilizumab was per-

manently discontinued.

The family was referred for a second opinion to Cin-

cinnati Children’s Hospital, where they were informed

that the child was in the state of mild subclinical MAS.

The doctors also noticed mildly increa sed respiratory

rate and subtle clubbing of the fingers, but her HRCT

showed only subtle abnorm alities. A repeat HRCT 1 year

later, however, suggested significantly worsening pul-

monary disease; a lung biopsy performed about 1 month

later confirmed PAP and SJIA-LD. At that time, myco-

phenolate was added to her drug regimen.

Prior to being diagnosed with SJIA-LD, Ms. Schuma-

cher’s child never had any apparent lung symptoms, and

her peripheral pulse oximetry had been consistently nor-

mal. Apart from the clubbed fingers and mildly in-

creased respiratory rate with physical activity, the child

certainly lacked overt signs of lung disease at the time of

SJIA-LD diagnosis.

With the combination of SJIA, subclinical MAS, and

SJIA-LD, her child has been on up to 10 daily medica-

tions including oral corticosteroids, high dose anakinra,

cyclosporine, methotrexate, and abatacept. In May 2018,

overt MAS prompted another hospital admission, likely

triggered by cytomegalovirus (CMV). Emily was having

difficulty clearing the CMV virus and required continu-

ous antiviral treatme nt in addition to MAS therapy. For

the last year, each attempt to decrease either corticoste-

roids or antivirals, was followed by early signs of subclin-

ical MAS.

Ms. Schumacher is worried that the current cocktail of

medications which seemingly cannot be weaned, is not a

sustainable therapeutic strategy. She strongly feels that

daily corticosteroids for long periods of time are not an

appropriate treatment for children. Her child is not

growing and recently developed a vertebral compression

fracture. Her rheumatologist is constantly struggling to

balance immunosuppression to keep the disease at bay

with giving the child the ability to fight off infections.

Overall, Ms. Schumacher is concerned that options are

running out to control her child’s disease. She would like

better treatment choices than steroids and currently

available biologics, since those fail to control her child’s

disease.

After NextGen conference, Ms. Schumacher’s daugh-

ter was switched from cyclosporine to tacrolimus. That

helped for a few weeks, but now again she is having fre-

quent fevers and her laboratory test results keep raising

concerns for subclinical MAS (e.g., low platelet count).

Her team would like to start tofacitinib but have not

been able to get insurance approval thus far.

Patient story - Regina Minerva

Ms. Minerva’s daughter was diagnosed with SJIA in July

2017, at 13 months of age, and started on prednisolone

and anakinra. As prednisolone was tapered, SJIA signs

and symptoms returned with laboratory tests showing

low levels of systemic inflammation. In April 2018, when

her inflammatory markers rose further, she was seen by

hematologist / oncologist, who ruled out malignancy,

but noted that her blood cell counts were suggestive of

“low grade MAS”.

In May 2018, Ms. Minerva started noticing that her

child’s fingertips and toes were red and sore (Fig. 1). By

September 2018, she noticed enlargement of some toes.

Looking at the postings within SJIA Parents Network,

she learnt of other children who had similar finger and

toe enlargement, and were subsequently diagnosed with

lung disease. In meantime, her medical team ruled out

pulmonary hypertension with an ECHO. In January

2019, however her chest X-rays were abnormal. In May

2019, she was diagnosed with interstitial lung disease

based on typical HRCT findings.

In May–June 2019, her child’s laboratory evaluations

showed what her doctors described as “smoldering

MAS”; while the trends in some symptoms and lab test

results were suggestive of part ial MAS, the child did not

have the features of “overt MAS”. On June 22, however,

the child woke up with high fever and was immediately

evaluated in the emergency room where lab tests re-

vealed full-blown MAS with ferritin of 31,000 ng/mL.

In spite of several doses of intravenous (IV) pulse cor-

ticosteroids and cyclosporine, her child’s MAS markers

kept on worsening. Increasing the dose of anakinra to

10 mg/kg/day did not reverse the trend. Ms. Minerva

posted about her child’s MAS in the SJIA Parents Net-

work, and learned about the emapalumab clinical trial at

Cincinnati Children’s. She was then connected to the

doctors running the clinical trial.

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 3 of 15

In the meantime, her child’s MAS markers continued to

worsen, her oxygenation started falling, and they were

transferred to the ICU. Ms. Minerva and her husband re-

quested participation in the trial. On June 28th, they were

transferred to Cincinnati, and given the first dose of ema-

palumab as part of NCT03311854, when ferritin was at

75,000 ng/mL. After the first infusion, her fevers resolved,

oxygenation returned to normal, and ferritin came down

to 50,000 ng/mL. She resumed eating and drinking. By the

third infusion, her ferritin came down to 7000 ng/mL, and

she was returning to her normal self.

At the time of the workshop, Ms. Minerva’s child was

3 months past her emapalumab treatment. Her labs were

normal with the exception of mildly increased LDH. Her

breathing was normal, and the most recent HRCT

showed improvement from May 2019. The girl was hav-

ing the energy of a child with normal health. She

remained on all the medications for SJIA, though her

doctors were slowly tapering steroids. Regina was hope-

ful that her child would continue to do well, but she was

also concerned about the return of inflammation, espe-

cially the MAS and lung symptoms. She emphasized the

need for the rapies that could help when a child first

shows early signs of MAS and lung disease, instead of

ones that can only be used when the child is in full

blown MAS.

Post NextGen conference, Ms. Minerva’s child contin-

ued to feel well and had normal labs. More recently, she

had a flare triggered by a viral illness with laboratory test

results pointing to subclinical MAS (platelets fell, and

ferritin went up to 6000 ng/mL). The dose of anakinra

was increased, and a pulse corticosteroids was adminis-

tered to bring the flare under control. Ms. Miner va is

concerned that there are no good additional options

available to keep her child’s disease under control. She

believes that the only medicine that brought her child’s

MAS under control, empalumab, is only available as a

rescue medication (via a clinical trial), and not for on-

going or prophylactic usage.

Discussion about patient stories

Both parents and clinicians agreed that there was a sub-

set of children with SJIA whom clinicians should watch

more closely for the development of SJIA-LD, including

those with SJIA onset under age 2 years, with predomin-

antly systemic features and limited arthritis, recurrent or

“smoldering” MAS , anaphylaxis-like reaction to a bio-

logic medication, and highly elevated serum IL-18 levels

[12–14]. The parents strongly felt that for these SJIA pa-

tients, clinicians should have a low threshold for HRCT

evaluation.

The group felt that as a general rule, children with SJIA

under the age of 6 years who fall into this high risk group,

should have a baseline chest radiograph, and overnight

pulse oximetry; for the patients older than 6 years, pul-

monary function testing as well as regular screening with

a 6 min walk should also be performed. In the presence of

any abnormalities in the above-listed tests, further imaging

with HRCT of the chest is recommended. Chest CT

should also be obtained if any additional features typical

of SJIA-LD are present (e.g., growth failure, tachypnea,

chronic non-productive cough, periungual erythema or

swelling, digital clubbing as well any acute pulmonary de-

compensation). Episodes of routine pulmonary conditions

with an abnormal chest radiograph should be followed up

to ensure that the abnormal findings resolve. Parents and

caregivers expressed the need for low radiation imaging

options for initial and ongoing evaluation of SJIA-LD.

Section 2: mechanistic insights into SJIA-LD

Report from Goldbach-Mansky & Canna labs / Dr. Raphaela

Goldbach-Mansky

Dr. Goldbach-Mansky, whose recent research interests

have been focused on monogenic interferonopathies,

measured IFN-scores in 66 consecutive patients with no

clear genetic diagnosis seen at the NIAID for presumed

undifferentiated autoinflammatory diseases. Among 41

patients with elevated IFN scores, 8 had recurrent epi-

sodes of MAS, features of pulmonary alveolar proteino-

sis (PAP) and extremely high serum IL-18 levels, and

thus, were named “IL-18 PAP-MAS” [ 14 ]. This subgroup

of patients, whose presentation included erythematous

clubbing and eventual PAP, included some described

above as SJIA-LD. These 8 patients had intermediately

high IFN scores, which were lower than the values ob-

served in the monogenic interferonopathies such as

CANDLE. A ratio of interferon-response genes that can

Fig. 1 Clubbing in the fingers (with permission of Ms. Minerva)

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 4 of 15

be induced by IFNα/β and IFNγ over those induced by

IFNα/β alone was higher in the IL-18 PAP-MAS patients

compared to the autoinflammatory Type -I interferono-

pathies CANDLE and SAVI, suggesting a combined role

of the Type-I IFNs (IFN-α and IFN- β ) as well as Type II

interferon (IFN-γ) in the immune dysregulation. Within

the “IL-18 PAP-MAS” group, the IFN score correlated

weakly with total IL-18 levels suggesting that IFN gene

expression may further be co-regulated by IL-18. No

unique genetic defect was identified for this group of pa-

tients, but cytokine analyses in the blood revealed eleva-

tion of hematopoietic stem cell factors that was

associated with high serum IL-18 levels, a phenomenon

described in other patients with high serum IL-18 levels

(including the monogenic MAS predisposing disease

NLRC4-MAS), but not in patients with other IL-1 medi-

ated autoinflammatory diseases [15 ] or the autoi nflam-

matory Type-I interferonopathies, CANDLE and SAVI.

Elevated hematopoietic stem cell factors may indicate a

distinct downstream pathway tha t can contribute to

macrophage dysfunction in patients with high IL-18

levels [14]. The presence of free IL-18 in the bronchoal-

veolar lavage (BAL) fluid of patients with IL-18 PAP-

MAS raises the question whether stem cell factors, when

induced locally in the bro nchial tree and or the lung,

may also contribute to the alveolar macrophage dysfunc-

tion and be an additional target for treatment.

Report from Grom & Schulert labs / Dr. Alexei Grom

Drs. Grom and Schulert reported on the Cincinnati co-

hort of patient with SJIA-LD that have many overlapping

features with the “IL-18 PAP-MAS” described by Dr.

Goldbach-Mansky. The vast majority of SJIA-LD pa-

tients had recurrent episodes of MAS, features of PAP

and extremely high serum IL-18 levels [12]. SJIA-LD pa-

tients lacked genetic, serologic, or functional evidence of

GM-CSF pathway dysfunction typical of familial or auto-

immune PAP where dysfunction of alveolar macro-

phages leads typically to accumulation of pulmonary

surfactant in alveolar space [16]. SJIA-LD lungs had a

striking prominence of alveolar septal expansion by an

interstitial lymphocytic infiltrate and fibrosis with re-

modeling that are usually absent in familial or auto-

immune PAP. Additionally, in SJIA-ILD (but not familial

or autoimmune PAP) the bronchoalveolar lavage (BAL)

fluid contained elevated levels of IL-18 and IFN-induced

chemokines CXCL-9 and -10. Transcriptional profiling

of SJIA-ILD lung tissue identified upregulated T-cell and

interferon activation ne tworks, again suggesting patho-

physiologic overlap with the cohort described by Dr.

Goldbach-Mansky.

Due to significant overlap in genes induced by type I

and type II interferons, the relative involvement of these

cytokines in SJIA-LD still needs to be clarified. However,

the fact that most patients with SJIA-LD have had MAS,

suggests that the inflammatory cytokine milieu that

drives macrophage dysfunction in MAS may also pro-

mote dysfu nction of alveolar macrophages. Interferon

gamma (IFN-γ) has been increasingly recognized as a

pivotal cytokine in MAS [4], and therefore, the IFN-

induced signature in the lung biopsies is most likely

driven by IFN-γ. Consistent with this hypothesis, mice

with T-cell restricted overexpression of T-bet driving

IFN-γ production demonstrated both dysfunction of

bone marrow macrophages, resulting in erythrophagocy-

tosis and alveolar macrophage dysfunction with develop-

ment of PAP-like lung pathology [ 17]. Combined, these

observations suggest that targeting IFN-induced path-

ways might be a therapeutic option in SJIA-LD. In con-

trast, given the presence of alveolar septal expansion and

the likely different underlying defect lea ding to the accu-

mulation of pulmonary proteinosis in SJIA-LD, trad-

itional treatments for primary PAP such as whole lung

lavage may not be helpful in SJIA-LD patients.

Alveolar macrophage dysfunction in lung disease: Dr.

Stewart Levine

Since lung macrophages have a clear role in the patho-

genesis of SJIA-LD, Dr. Levine presented new pulmon-

ary insights into a range of lung disorders with

macrophage dysfunction that might be informative re-

garding the pathobiology of SJIA-LD. So far, hereditary

or autoimmune PAP have served as the main reference

point for the alveolar lung disease in SJIA, so it was

helpful to start considering other lung diseases which

also have macrophage dysfunction. The three other dis-

eases that he presented were Lipoid Pneumonia,

Asthma, and High-fat Diet-induced Lung Disease (see

Table 1).

Lipoid pneumonia was identified as part of the

spectrum of SJIA-LD in two recent publications [12, 13].

Lipoid pneumonia is an uncommon disease character-

ized by the accumulation of intra-alveolar lipids and

lipid-laden macrophages [18]. The typical etiology of

Table 1 Lung Diseases Caused by Macrophage Dysfunction

Disease Macrophage Dysfunction

Pulmonary Alveolar

Proteinosis (PAP)

Surfactant accumulation in alveolar

macrophages and alveoli

Lipoid Pneumonia Lipid-laden macrophages and accumulation

of intra-alveolar lipids

House Dust Mite + Virus-

induced Asthma

Up-regulated apolipoprotein E (APOE)

production by alveolar macrophages with

resultant NLRP3 inflammasome activation

and secretion of mature IL-1β

High-fat Diet-induced

Lung Disease

Lipid-laden macrophages, increased lung

cholesterol content, increased pro-

inflammatory cytokines (interferon-γ, TNF

and IL-6).

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 5 of 15

lipoid pneumonia is due to the exogenous inhalation or

aspiration of oils or lipids into the lung, but endogenous

etiologies have also been described in patients with PAP,

Niemann-Pick disease (which is a lipid-storage disorder)

and undifferentiated connective tissue disease, as well as

a consequence of airway obstruction due to tumor.

Dr. Levine reviewed that alveolar macrophage function

could be pro-inflammatory in the setting of asthma.

Under norma l conditions, alveolar macrophages primar-

ily receive inhibitory signals which are anti-inflammatory

[19]. However, in disease states, activating signals can

override the normal inhibitory mechanisms that sup-

press macrophage activation. Dr. Levine’s lab has shown

that this can occur in asthma where pro-inflammatory

stimuli, such as house dust mite (HDM) antigen, can in-

duce apolipoprotein E (APOE) production by alveolar

macrophages [20]. When APOE levels are sufficiently

high, such as when a viral infection is superimposed

upon HDM exposure, APOE can function as a pro-

inflammatory danger signal that activates the NLRP3

inflammasome and induces secretion of mature IL-1β by

alveolar macrophages.

Dr. Levine next reviewed murin e models of high-fat

diet induced lung macrophage dysfunction that may

have some similarities with macrophage dysfunction in

SJIA-LD. When mice are fed a high-fat diet, this induces

systemic inflammation and oxidative stress that causes

pathological lung remodeling manifested by emphysema,

sarcoid-like granulomatous inflammation, pulmonary fi-

brosis, and pulmonary hypertension [21]. Lungs from

mice fed a high-fat diet show increased numbers of pul-

monary macrophages, increased lung cholesterol con-

tent, lipid-laden macrophages, and increases in

bronchoalveolar fluid cytokines (IFN-γ, TNF and IL-6).

Thus, in the appropriate setting, such as high-fat diet-

induced systemic inflammation or house dust mite plus

viral infection, alveolar mac rophages can be con verted

from an anti-inflammatory cell that maintains normal

pulmonary homeostasis into a pro-inflammatory cell

that may promote disease pathogenesis. The concept of

the alveolar macrophage as a target cell that amplifies

inflammation may also be relevant for SJIA-LD.

Dr. Levine reviewed that alveolar macrophage popu-

lations in the lung are heterogeneous and can be

broadly divided into two c ategories. Tissue-resident

alveolar macrophages (TR-AMs) are the most abun-

dant immune cell in the lung under normal condi-

tions [22, 23]. TR-AMs represent a long-lived, self-

renewing population that are derived from the fetal

yolk sac and liver and function to maintain normal

pulmonary homeostasis and gas e xchange. In contrast,

monocyte-derived alveolar macrophages (Mo-AMs)

are recruited into the lung from the blood in the set-

ting of inflammation where they have cytotoxic,

antimicrobial, and pro-fibrotic functions. Thus, Mo-

AMs augment inflammation, which suggests a role for

these cells in SJIA-LD. Once inflammation resolves

and homeostasis is restored, Mo-AMs undergo apop-

tosis or differentiate into cells tha t phenotypically re-

semble TR-AMs. Single cell RNA-seq experiments in

a mouse model of LPS-induced inflammation have

identified two distinct populations of TR-AMs and

three populatio ns of MO-AMs. Thus, single cell

RNA-seq might represent a method to drill deeper

into macrophage pathobiology in SJIA-LD.

Section 3: current approaches to management and

outcomes of SJIA-LD

Learnings from Cincinnati SJIA-LD patient cohort / Dr.

Grant Schulert

Dr. Schulert provided a short update on the cohort of

SJIA-LD patients evaluated at Cincinnati Children’s.

They have now evaluated 27 children with SJIA-LD

including 9 patients since submission of their initial

manuscript [12]. Of those 27 patients, only 1 (4%)

has died, which is in marked contrast to the larger,

multisite cohorts [11, 13]. The reasons for this im-

proved outcome are not known, but may include earl-

ier diagnosis, and introduction of T-c ell targeted

therapies, such as mycophenolate mofetil and tacroli-

mus, as well as azathioprine and anti-inflammatory

and prophylactic antibiotic. The treatment for SJIA-

LD may also adapt some of the new approaches used

in the treatment for MA S rather than SJIA, specific-

ally treatments that can target T cell activation and

interferon pathways including JAK inhibition.

Dr. Schulert also noted that their practice has been

continuing anti-cytokine biologics to gain control of

MAS and inflammation of active SJIA as an essential

step in treatment of SJIA-LD. Controlling MAS in these

patients is utterly important but often challenging. Dr.

Schulert also noted there are several patients in the Cin-

cinnati SJIA-LD cohort who have markedly improved

and even resolved features of lung disease over several

years. Indeed, these patients were able to achieve full

control of their underlying SJIA and MAS with contin-

ued biologics along with therapies noted above.

There was also some discussion regarding possible role

of biologic medications and geographic distribution of

patients. Biologics are used now near universally

throughout North American and Europe but SJIA-LD

cases seem much more prevalent in the US, and even

possible regional clusters within the US. This would be

consistent with other environmental factors or triggers

playing a role, which needs to be considered and investi-

gated moving forward.

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 6 of 15

Section 4: potentially targetable pathways and candidate

therapeutics for SJIA-LD

Review of biomarkers; IL18 as a biomarker and a target /

Dr. Scott Canna

Dr. Canna presented a serum proteomics study per-

formed in collaboration with Cincinnati and Stanford

aimed at the identification of novel lung disease bio-

markers that was eventually presented at American Col-

lege of Rheumatology (ACR) 2019 Annual Meeting [24].

IL-18 has long been a biomarker of interest in patients

with SJIA and MAS. IL-18 is uniformly and dramatically

elevated in patients with active MAS. It is likewise

chronically elevated, regardless of disease activity, in a

few rare monogenic situations including gain-of-

function mutations in NLRC4 [15], XIAP-deficiency

[25], and c-terminal mutations in CDC42 regardless of

disease activity [26, 27]. It is more variably elevated in

active and inactive SJIA, with some patients’ levels as

high as in active MAS and other patients’ level near-

normal. Dr. Canna presented ongoing work related to

IL-18 as a biomarker of MAS risk [5, 28–31], a host sus-

ceptibility factor for the development of MAS, and it ’s

peculiar elevation in SJIA-LD patients out of proportion

to such patients’ degree of MAS activity. The latter point

was supported by an unpublished multi-center collab-

orative serum proteomics study presented at the ACR

2019 Annual Meeting [24].

This study also sugges ted novel pathways in MAS,

biomarkers of lung inflammation/damage, and poten-

tially a role for type 2 immune responses in SJIA-LD.

In addition, one SJIA-LD patient has shown a promis-

ing response to compassionate-use treatm ent with an

IL-18 blocking strategy [32], and a clinical trial of IL-

18 blockade in NLRC4 and XIAP patients is ongoing

(NCT03113760). Corroborating the recent work of

Schulert et al. [12], Dr. Can na’s unpublished observa-

tions s uggest elevation of total and free IL-18 in BAL

fluid of SJIA-LD patients, but not in various controls.

IL-18 is produced constitutively by some macro-

phages, but also by intestinal epithelial cells, keratino-

cytes, and bronchial epithelial cells. It is not known

where the high IL-18 in SJIA and MAS derives from.

Functionally, IL-18 is best known as an amplifier of

Type 1 immune responses and specifically of IFN-γ

produ ction. The connectio ns between IFN-γ and

MAS, and potentially lung disease, were discussed by

Dr. de Benedetti. While, IL-18 has been shown to

amplify immune responses other than IFN-γ,includ-

ing anti-bacterial (Type 17) or allergic (Type 2) re-

sponses, depending on the immune context, some of

the transcriptional evidence from Schule rt et al. [12]

suggests that Type 1 inflammatory re sponses/IFN-γ

maybeanimportantpartofSJIA-LD.

An overview of selective JAK-i nhibitors and relevance for

SJIA-LD / Dr. Massimo Gadina

Given some pathophysiologic overlap between SJIA-LD

and interferonopathies, a group of auto-inflammatory

diseases where targetin g JAK-STAT signaling pathways

often produces a good clinical response, Dr. Gadina pre-

sented an overview of this therapeutic strategy. JAKs are

phosphotransferases that bind the intrac ellular domains

of cytokine receptors and transmit signals to activate im-

mune responses [33]. Cytokines that signal via JAKs in-

cludes many interleukins, interferons, colony stimulating

factors and hormone-like cytokines (such as erythropoi-

etin and growth hormone). The receptors for these cyto-

kines signal via various combinations of four JAKs

(JAK1, JAK2, JAK3 and TYK2). First-generation JAK

inhibitors, such as tofacitinib and baricitinib block more

than one JAK, and thereby can inhibit a large number of

cytokines and growth factors; these and other pan-JAK

inhibitors are being investigated as therapeutic agents

for a wide variety of autoimmune diseases. Based on

some similarities between SJIA-LD and interferonopa-

thies such as SAVI, JAK-inhibitors (tofacitinib) have

been used in a few children with SJIA-LD, with mild im-

provement in some of them. More data and experience

are needed to understand the efficacy and safety of this

class of medications in the treatment of SJIA-LD.

Dr. Gadina also presented an overview of newer, more

selective JAK-inhibitors as well as their safety and effect-

iveness in other diseases. Few next generation JAK in-

hibitors have already reached the market or are in an

advanced status of development. Nonetheless, it appears

that selective JAK inhibitors do not necessarily reduce

the risk of infection compared with first generation JAK

inhibitors. Common side effects observed include infec-

tion, anemia , neutropenia, lymphopenia and hyperlipid-

emia. It has become apparent that, in children,

tofacitinib increases the risk of chickenpox which corre-

lates with the observed increased rates on Herpes zoster

flares in adults.

There was also discussion of whether broader JAK-

inhibitors might interfere with the erythropoietin and

growth hormone signaling pathways leading to anemia

and growth delays. Dr. Gadina highlighted, however, that

in patients with the autoinflammatory Type-1 interfero-

nopathy, CANDLE, treatment with baricitinib resulted

in improved disease control and concomitantly patients

resumed relatively normal growth. This suggests that

better disease and inflammation control might be pre-

dominant over the potential effects of the drug on

growth hormone signaling. As many cytokine receptors

and growth receptors use JAK-STATs for signaling, in-

cluding the growth hormone receptor, concerns regard-

ing off target effects of JAK inhibition in children remain

till more data become available.

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 7 of 15

The possibility to combine a JAK inhibitor with a bio-

logic was discussed and compared with a combined

therapy of a JAK inhibitor with methotrexate or cortico-

steroids. So far, the data are limited to few anecdotal

cases and larger studies are needed to assess the safety

of a combination therapy. Finally, at least in the case of

baricitinib, the drug half-life is weight based and shorter

in children than in adults, and an increase in frequency

of administration and in doses may be needed to achieve

therapeutic efficacy.

Is targeting IFNγ-induced pathways likely to be effective

in SJIA-LD? / Dr. Fabrizio De Benedetti

Dr. De Benedetti reviewed evidence supporting targeting

IFNγ-related pathways in SJIA-LD. A growing body of

evidence, albeit indirect, supports the hypo thesis that

IFNγ may be a pathogenic mediator of SJIA-LD: 1) the

vast majority of SJIA-LD patients have a history of MAS,

often recurrent [11–13], and IFNγ is implicated as the

pivotal cytokine in MAS; 2) in the 12 months preceding

onset of the lung disease, patients with SJIA-LD have ris-

ing ferritin and levels are higher than those of SJIA pa-

tient without lung disease [13]; 3) a prominent IFN-

induced signature is present in lung biopsies of SJIA-LD

patients with overexpression of genes spe cifically upreg-

ulated by IFNγ [12]; and 4) mice with t-bet CD4 re-

stricted overexpression develop an inflammatory PAP,

characterized by a CD4 infiltrate (similar to that present

in SJIA-LD lungs) and by a prominent IFN-γ signature

[17]. Finally, in these mice abnormal differentiation of

tissue macrophages was demon strated suggesting a shift

towards M1 macrophage and subsequ ent inability to

clear surfactant proteins, again pointing to a derange-

ment of macrophage differentiation as a potential

mechanism.

Altogether, these observations suggest that therapeutic

neutralization of IFN-γ should be considered as a poten-

tial therapeutic approach in SJIA-LD. Emapa lumab is an

anti-IFNγ antibody that has been approved by the FDA

for patients with primary hemophagocytic lymphohistio-

cytosis (HLH). The preliminary results of the ongoin g

phase II trial of emapalumab in MAS/SJIA showed

complete response in all of the 9 patients enrolled, all of

whom had previously failed conventional therapies [34].

New drug discovery: computational approaches to drug

repurposing by reversing gene expression in SJIA-LD /

Drs. Grant Schulert & Alex Pickering

Alex Pickering from Harvard Medical School described

an innovative computational approach to understanding

SJIA-LD and also identifying repurposed drugs. This

project is the result of a collaboration between the

Cincinnati Children’s, Harvard University and the Sys-

temic JIA Foundation. It relies on an approach called

connectivity mapping on RNA-Seq data. Conn ectivity

mapping uses a gene expression profile from patients to

search for drugs and genetic manipulations that have ei-

ther similar or opposing effects on gene expression.

Drugs that oppose the gene expression changes observed

in the patients are predicted therapeutics. Genetic ma-

nipulations that either oppose or mimic these gene ex-

pression changes suggest a role of the manipulated gene

in the disease process.

Early results appear promising and highlight the op-

portunity to identif y additional therapeutic targets and

approved drugs that can reverse the disease signature.

Out of ~ 7000 genetic manipulations, those that correl-

ate most strongly with gene expression in whole lung

samples from patients with SJIA-LD either upregulate

IFN-γ or NF-kB signaling. IFN-γ signaling in lung NK,

T, endothelial, and macrophage cells from a SJIA-LD pa-

tient also appeared to be upregulated. As compared to

the same cell types from an uninvolved biopsy (Fig. 2),

IFITM1, a type I and II interferon induced transmem-

brane protein that inhibits viral cytoplasmic entry (doi:

https://doi.org/10.1074/jbc. M115.657346,) and PSMB10,

a IFNγ-regulated component of the immunoproteosome,

were among the top most significantly upregulated genes

(Fig. 3).

Section 5: overlapping clinical phenotypes that may share

common disease mechanisms with SJIA-LD

Patient experience of MAS-liver patients / moderator:

Rashmi Sinha; panelists: Zulayka Martinez, Katie Pierce

Patients with lung disease are not the only subgroup of

SJIA patients with MAS and predominant organ-specific

involvement. Another small, but distinct subgroup of pa-

tients from the SJIA Parents Network is patients with

MAS and liver involvement. Two parents of children di-

agnosed with SJIA, MAS, and persistent liver issues re-

ported their child’s experience specifically highlighting

the connection between recurrent MAS and persistent

liver disease.

Patient story - Zulayka Martinez

Ms. Martinez recounted the story of her daughter, who is

now 6 years old. At the age of 4 years, they first started no-

ticing recurrent rashes. Two months later, in April 2018,

she started getting fevers as well. The laboratory test pat-

tern pointed to SJIA, but her rashes were atypical, and she

had marked generalized enlargement of her lymph nodes.

After a long investigative workup which included several

MRIs, X-rays, HRCT scans, ultrasound studies, and a bone

marrow biopsy, other diseases were ruled out, and she was

diagnosed with SJIA. Because of prominent MAS features,

the child received multiple pulses of IV corticosteroids

and improved. She was also started on anakinra and,

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 8 of 15

initially, had a good response to it. In November 2018, she

was unwell again. While general laboratory test results

were suggestive of only mild systemic inflammation, the

liver function tests were persistently elevated and kept ris-

ing (AST/ALT above 200’s unit/L).

In January 2019, she was admitted with rashes and gen-

eralized pains. Her medical team decided to replace ana-

kinra with tocilizumab. During the first infusion, she

developed a strange pruritic rash, and complained of

throat pain that compromised her ability to swallow. She

finally improved, mainly in response to IV corticosteroids.

Anakinra was added back to the tocilizumab. She

responded well to the addition of anakinra and was better

for a few days, but then the inflammatory activity started

rising again. During the second infusion of toclizumab,

she started to gag, and her blood pressure dropped. The

infusion was stopped immediately, and the treatment with

tocilizumab was permanently discontinued.

Fig. 2 UMAP dimensionality reduction after integrating an affected and unaffected lung sample from a patient with SJIA-LD

Fig. 3 NK- and T-cell clusters split by sample (TEST = affected, CTRL = unaffected) and colored by pre-integration expression of IFITM1 and

PSMB10. Analyses performed with Seurat version 3.0

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 9 of 15

By the beginning of February 2019, her liver function

tests were rising again (AST 425 unit/L, ALT 512 unit/

L), and her serum total IL-18 level reached 364,588 pg/

mL (up from 183,292 pg/mL 2 months earlier). By the

end of February 2019, she was admitted for increasing

liver enzymes (AST 981 unit/L, ALT 704 unit/L) associ-

ated with moderate hyperferritinemia (ferritin 465 ng/

ml), which could not be controlled even with IV pulse

corticosteroids. Hepatology was consulted and a live r bi-

opsy was obtained. The liver biopsy results were incon-

clusive, but did not show signs characteristic of drug

injury. Her team felt comf ortable increasing the dose of

anakinra, but within 4 days, her liver enzymes further in-

creased (AST - 4070 unit/L, ALT - 4557 unit/L). Her

ferritin was 540 ng/ml, and LDH reached 8170 unit/L.

Anakinra was discontinued, and her SJIA symptoms

returned: rash, fevers, intense body and throat pain.

She got some relief with IV corticosteroids and was

next started on canakinumab. Over the next few weeks,

her inflammatory markers started improving. The liver

markers mildly improved, but still remained highly ele-

vated (LDH 2575 unit/L, AST 1206 unit/L, ALT 2079

unit/L), and total IL18 was at 245,581 pg/mL. Regularly

scheduled pulse steroids were used to keep the liver dis-

ease under some degree of control. In the meantime,

additional staining of the liver biopsy with anti-CD163

and anti-CD8 antibodies revealed histopathologic fea-

tures suggestive of MAS.

Liver enzymes started rising again and in the fall of

2019, tacrolimus was added to her treatment regimen

with some improvement: within a week, LDH dropped

from 4020 to 1753 unit/L; AST from 1034 to 241 unit/L,

and ALT from 1601 to 499 unit/L.

Ms. Martinez noted that her daughter’s symptoms

were primarily fevers, rash, pain, sore throat and ele-

vated liver function tests. She did not have true arthritis.

Her team has found serum total IL-18 to be very useful

in tracking her disease activity, and it is now being mon-

itored monthly. LDH seems to be another useful marker.

She also noted that the only medication that works for

her daughter are IV corticosteroids, and she now receives

an infusion at least weekly, and often more frequently

when the child is in a flare. She is tired of the many side

effects that her child is experiencing including marked

growth retardation, weight gain, and mood changes. She

would like to have more medication options suitable for

cases of SJIA, MAS and associated liver disease.

Since the NextGen conference, Ms. Martinez’sdaughter

has had a few mild flares. However, since adding tacroli-

mus, her daughter’s lab test abnormalities have improved

and overall she has been doing better. The frequency of

canakinumab injections has been increased. Oral cortico-

steroids are being slowly tapered, but IV corticosteroid

pulses are still administered every 2 weeks.

Patient story - Kate & Jonathan Pierce

Mr. and Mrs. Pierce’s 2 years old daughter was diag-

nosed with SJIA at the age of 8 months after several

weeks of recurrent fe vers and rash. She was initially sus-

pected to have atypical Kawasaki disease, but she did not

respond to IVIG, and several ECHO studies were nor-

mal. After further testing, the diagnosis was changed to

Systemic JIA. Her disease was initially controlled with

anakinra and prednisone, but after 3 months of the

treatment, with corticosteroid taper, her fevers and rash

returned. In spite of switchin g biologics to canakinumab

and increasing her prednisone dose, her fevers persisted

and inflammatory markers continued to rise.

In October 2018, she developed MAS. She recovered

quickly with tocilizumab and IV corticosteroids, but 10

days later, the MAS recurred for a second time. This

MAS episode was more difficult to treat and was charac-

terized by increasing liver inflammation in spite of im-

provement in all other MAS markers. During this

hospitalization she was found to have cytomegalovirus

(CMV) infection which was thought to explain her per-

sistent liver inflammation. The inflammation was even-

tually controlled and her steroids were slowly tapered.

She received five infusions of tocilizumab, before she

developed an anaphylactic type reaction to the drug.

After this reaction, tocilizumab was replaced with cana-

kinumab, and the dose of corticosteroids was increased

again followed by a very slow taper.

Mrs. Pierce noted that her daughter’s typical SJIA

symptoms were fever, rash, and enlarged spleen and

liver. She did not have true arthritis. Remarkably, her

total IL-18 levels were always very elevated, particularly

during or right after MAS. After the last MAS episode,

total her IL-18 was at 361,000 pg/mL.

By the beginning of 2019, once she completed her

steroid taper, her LFTs were again elevated, though the

rest of lab test results were mostly normal (ferritin in

the 30s ng/mL, still low hemoglobin, with WBC count

of 8.0 K, and platelet count at 200 K). CMV was no lon-

ger detectable in her blood.

A liver biopsy was performed in April 2019. Though

results of the biopsy were inconclusive, there were

“punched out lesions of hepatocellular necrosis” which

were felt to be related to the inflammation from SJIA or

MAS. There were no signs of active CMV infection in

the liver.

For the past year, she has struggled with persistent in-

flammation causing nightly fevers and elevated inflam-

matory markers, including liver enzymes. She has been

on corticosteroids for most of this time, causing signifi-

cant growth delay.

Since this summer, her team has been trying different

drug combinations to effectively control her inflamma-

tion. They first tried adding anakinra to the

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 10 of 15

canakinumab for a month. When that did not help, they

next tried adding tacrolimus to her regimen. For about a

month, her labs completely normalized, but then the in-

flammatory markers started rising again and fevers

returned.

Her team did a renewed search for drugs to control

her inflammation, and considered a range of options

including Rilonacept, thalidomide and JAK-inhibitors.

She was recently started on tofacitinib with the hope

that this will result in better control of her inflamma-

tion and help wean corticosteroids. However, her

daughter has been flaring again recently. Her team is

continuing with tofacitinib, but also started the initial

evaluation for possible hematopoietic stem cell

transplantation.

Mr. and Mrs. Pierce are interested in other drug op-

tions to control her daughter’s inflammation, as steroids

have severe side effects when used long term, and none

of the biologic medications can control her child’s dis-

ease, especially the MAS and liver inflammation.

Pathology in recurrent MAS with liver involvement / Drs.

Alexei Grom & Fabrizio DeBenedetti

It has been recognized that a subset of patients who do

not meet full criteria for SJIA or overt MAS, may have

recurrent or “smolde ring/incomplete MAS”. A propor-

tion of these patients have predominantly liver involve-

ment. Wouters, et al. previously described typical

histopathologic findings in these patients: sinusoidal in-

flammatory infiltrate is a prominent feature and consists

both of increased number of CD8+ T lymphocytes and

highly activated Kupffer cells with some of them exhibit-

ing hemophagocytic activity [35]. The CD8 immuno-

staining in these patients typically identifies large

numbers of CD8 positive lymph ocytes both in the portal

infiltrates and in the sinusoidal infiltrates. The CD163

immunostaining marks large numbers of activated mac-

rophages with plump contours both in the portal areas

and in the sinusoids. Immunostaining for cytokines

identifies CD8+ T cells as the main producers of large

amounts of IFN-γ.

Consistent with this study, three patients with pre-

dominant liver involvement recently evaluated by Dr. De

Benedetti (2 of whom fully met the ILAR criteria for

SJIA), had similar histopathologic pattern, including

large numbers of CD68+ macrophages. Their liver biop-

sies showed highly increased levels of mRNA for IFNγ-

induced genes, while other classical pro-inflammatory

cytokines were not markedly increased, including IL-18,

IL-6 and TNF-α. Type I IFN induced gene expression

was also roughly normal. These observations suggest

that IFN-γ and IFN-induced pathways might be an at-

tractive therapeutic target in this patient populatio n as

well [36].

“Persistent partial MAS” as the common link between

SJIA-LD and MAS-liver patients / group discussion

The discussion was then focused on “persistent partial”

or “smoldering”” MAS as the common link between

both sets of patients.

Parent observations

Several parents of both SJIA-LD and SJIA-Liver patients

described that their children were in a state of what was

best described as “smoldering MAS” for prolonged pe-

riods of time. They would have low-grade fever, some

rash, and fatigue. Lab tests would show some features of

MAS, but not full-blown MAS. Clinicians who had

treated such patien ts agreed with this observation and

emphasized that treating such patients with existing

medications was challenging.

Since most children with SJIA-LD have a low level of

persistent inflammatory activity and some laboratory ab-

normalities typical of MAS without meeting the full Ravel-

li’s 2016 MAS criteria [37], the point was made that a

substantial proportion of children with SJIA-LD might

have “smoldering” MAS. The concept of “smoldering”

MAS has not been formalized, and since this is a potential

target for any future studies and clinical trials, the group

sought to generate a preliminary definition, criteria and

possible an alternative term to describe this state. The

group discussed several terms for this clinical state, and

while no consensus was achieved, a majority of partici-

pants endorsed the phrase “persistent partial MAS”.

The group identified the potential characteristics to

define “persistent partial MAS”: in a patient with active

SJIA and persistent inflammation (provided that infec-

tion or other causes have been ruled out), there should

be newly worsening or persistently abnormal values for

at least 6 weeks (with inability to taper medications be-

cause of worsening values) indicating:

 liver abnormalities

 disorder of hematopoiesis

 coagulopathy

 highly elevated serum IL-18 with modestly elevated

CXCL9

The presence of all 4 of these should support the diag-

nosis of “persistent partial MAS”. Numeric laboratory

values for the three components of the definition still

needs to be defined in the future.

Section 6: planning for future clinical trials

Alternative designs for a trial for recurrent MAS with

organ (lung / liver) involvement

Dr. Rashmi Sinha then summarized the patient perspec-

tive regarding the need for new treatments for patients

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 11 of 15

with MAS and lung / liver involvement. The entire

group recognized that patients who have recurrent MAS

associated with SJIA, SJIA-LD or MAS with Liver Dis-

ease not only have high mortality, but also have disease-

and medication-related morbidities that slowly accumu-

late, affecting all aspects of the child’s health-related

quality of life. With input from representatives from the

FDA, possible approaches to the design and implemen-

tation of a clinical trial for this population were

discussed. Potential therapeutic strategies included

neutralization of IFN-γ with emapalumab, JAK-

inhibitors, and/or IL-18 inhibitors.

The group felt that the study design should address

the current unmet need, take into consideration patient

reported outcomes, and should also meet the regulatory

requirements to gain approval for this indication. Appro-

priate outcome measures should be considered including

patient reported outcome (PRO) measures as well as

meeting (as yet unidentified) “MAS remis sion” criteria.

There was an agreement that the ability to taper cortico-

steroids, as well as other concomitant medications,

should be avoided as a primary outcome measure, but

must be used as secondary measures, given the clinical

relevance of the comorbidities associated with the mul-

tiple chronic therapies of these children.

Developing patient-reported outcomes measures for

clinical / session moderated by: Dr. Hermine Brunner

Dr. Brunner reviewed currently available PRO measures

of health-related quality of life that have been validated

and including those used in the clinical trial of toci-

lizumab in SJIA [6]. These PRO measures, however,

were mainly aimed at the assessment of the effects of

the arthritic and, to a lesser degree, the systemic compo-

nents of the disease. Therefore, the current PRO mea-

sures are unlikely to be sensitive enough to fully capture

“persistent-partial” SJIA and/or SJIA-LD, and future

work is needed to develop such a measurement tool.

Summary of parent observations

Parents shared what signs they use to judge whether

their child is doing better or worse. They described both

systemic and lung spe cific symptoms, but also reported

a complex interaction between the lung and systemic

symptoms of the underlying SJIA (e.g., a child might be

affected due to shortness of breath (due to lung symp-

toms), and/or tired and achy (due to systemic symp-

toms). Potential outcome measures suggested by the

parents are listed in Table 2.

The parents then discussed potential “lung-relevant”

PRO candidate items that, from their prospective, could

distinguish between worsening lung disease and worsen-

ing systemic component of SJIA (Table 3).

For further refinement, the list generated will be (1) dis-

seminated among a larger group of parents through the Sys-

temic JIA Foundati on network, and (2) discussed with

experts to explore whether the Patient-Reported Outcomes

Measurement Information System (PROMIS; www.health-

measures.net) could be used to design a PRO measure to be

used in trials of medications to treat SJIA-LD.

Measuring and tracking lung disease progression: options

& challenges, Dr. Grant Schulert

Dr. Schulert reported on his work with Dr. Yukiko Kimura

to establish validated criteria to measure and track lung pro-

gression through the CARRA Registry network. He pre-

sented and discussed components of this measure including

a lung specific global assessment (SJIA-LD Severity Score),

and physician lung global assessment (PLGA). Potential spe-

cific items could include oxygen requirement, cough, exercise

intolerance, therapy intensity, and the degree of the redness

ofthedigitsaswellasthe%oftheinvolvedareaofthelungs

on HRCT. Drs. Schulert and Kimura hope to establish a co-

hort through the CARRA Registry to collect a small number

of such measures prospectively to track disease evolution,

along with obtaining biosamples through the CARRA Bio-

banks in the US and Canada.

Section 7: conclusions & future steps

Plans for a new international refractory SJIA project:

ReSyst

The meeting recognized that there are subgroups of re-

fractory SJIA patients (including SJIA-LD, liver-

Table 2 Potential Parent Reported Outcome Measures - For

Systemic & Lung Disease

Lack of energy / decreased physical activity/being sluggish

Behaviors like sitting on the couch and playing with iPad, or just sitting

quietly

Fatigue - reporting tiredness after minor exertion

Disturbed sleep at night

Not wanting to get out of bed

Grumpy behavior: being annoyed without reason, with siblings and

parents

Less smiling and laughing behavior

Reduced exploratory behavior / reduced sense of curiosity

Decreased interest in play

Lack of appetite

Cough

Labored breathing

Breathlessness with every day-life activities (i.e., climbing stairs)

Decreased ability to run around

Increased respiratory rate

O2 requirement (for patients who use oxygen supplementation)

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 12 of 15

predominant MAS, and resistant/d estructive arthritis,

among others) who need to be identified quickly and

treated appropriately. Identifying the appro priate treat-

ments will mean addressing the challenges of 1) small

patient numbers, 2) high patient complexity/severity,

and 3) the lack of approved treatment options. While

the rest of the meeting focused on the efforts to under-

stand and treat SJIA-LD, there is also a clear need for a

parallel effort to recognize and understand refractory

SJIA in general.

The meeting closed with a discussion between clini-

cians, researchers, and parents regarding the efforts to

create an international consortium focused on under-

standing of treatment-resistant SJIA (ReSyst). This effort

includes groups from the US, Canada, the Netherlands,

and Italy. Such an effort would leverage several existing

networks including Pediatric Rh eumatology European

Society (PReS), the European Reference Centers, Child-

hood Arthritis Research Alliance (CARRA), and UCAN

CAN-DU. As a first step, the group agreed upon a

provisional definition of refractory SJIA shown in

Table 4.

More disc ussions will follow regarding funding and

the logistics of collaborations needed between the orga-

nizations to collect clinical data and biospecimens on

these patients.

Conclusions

In conclusion, the mortality rate of children with

SJIA-LD is h igh, and effective targeted t reatments re-

main elusive. This underscores the urgent nee d to

diagnose SJIA-LD early, elucidate risk factors, and de-

velop therapeutic strategies to improve its prognosis.

Environmental and genetic factors are likely to con-

tribute to the development of the lung disease, but

increasing e vidence suggests that SJIA-LD may b e

caused by alveolar macrophage dysfunction with con-

tributions from the SJIA/MAS i nflammatory milieu

and possibly, from increa sing use of the IL-1 and IL-

6 blocking therapies. Potential novel therapeutic strat-

egies i nclude targeting (1) IFN-γ with the monoclonal

anti-IFNγ antibody emapalumab; (2) the IFNγ-

induced pathways with Janus kinase inhibitors, and

(3) IL-18 with the IL18-blocking agent tadekinig alfa

or other agents. Any potential clinical trial des ign in

Refractory SJIA, or SJIA-LD more specifically, should

address the current unmet need, should take into

consideration patient re ported outcomes, and should

aim for regulatory approval for this i ndication. Im-

portantly, the perspective of patients and families

must be frequently and s eriously considered at all

phases of such trials.

Abbreviations

ACR: American College of Rheumatology; AOSD: Adult onset still’s disease;

APOE: Aapolipoprotein E; BAL: Bronchoalveolar lavage; CARRA: Childhood

Arthritis Research Alliance; CMV: Cytomegalovirus; ECMO: Extra-Corporeal

membrane oxygenation; sHLH : Secondary hemophagocytic

lymphohistiocytosis; HRCT: High-resolution chest computer tomography;

ICU: Intensive Care Unit; ILD: Interstitial lung disease; IFN-γ: Interferon

gamma; IV: Intravenous; IVIG: Intravenous Immunoglobulins; LFT: Liver

function test; Mo-AMs: Monocyte-derived alveolar macrophages;

MRI: Magnetic resonance imaging; NIAID: National Institute of Allergy and

Infectious Diseases; NIAMS: National Institute of Arthritis and Musculoskeletal

and Skin Diseases; PAP: Pulmonary alveolar proteinosis; PRO: Patient reported

outcome; PReS: Pediatric Rheumatology European Society; scRNA-

Seq: Single-cell RNA-sequencing; TR-AMs: Tissue-resident alveolar

macrophages; WBC: White Blood Cells

Acknowledgements

NextGen 2019 Participants: Beth Gottlieb, Rae Yeung, Mona Riskalla, Sampath

Prahalad, Sara Alehashemi, Shan Chandrakasan, Bas Vastert, Yuki Kimura.

Parents: Anna Carlson, Emily Schumacher, Regina Minerva, Jonathan Pierce,

Kate Pierce , Zulayka Martinez, Kari Cupp, Leah Bush, Wendy Costello, Vincent

DelGaizo).

Authors’ contributions

SWC, GSS, ADeJ, AP, HB, MG, SL, RGM, JB, RS, FDB and AAG were invited

speakers at the symposium. Other physicians BG, RY, MR, SP, SA, SC, BV, YK

and parents AC, ES, RM, JP, KP, ZM, KC, LB, WC, VDG were actively

Table 3 Lung-relevant PRO Candidate Items

Lung Disease - Specific SJIA - Specific

Symptoms Flushing Fever

Cough Rash

Labored breathing Chest pain

Pruritis Joint pain

Joints stiffness

Fatigue

Low energy

Decreased appetite

Decreased physical activity

Feeling sad

Lack of engagement/participation

Lack of curiosity

Decreased interest in play

Signs Heart rate Fever

Respiratory rate Rash

Oxygen requirement Joint swelling

Growth failure Hepatomegaly

Erythematous clubbing Splenomegaly

Lymphadenopathy

Poor linear growth

Table 4 Provisional Classification Criteria for Refractory SJIA

Failure to respond to IL-1 AND IL-6 blocking biologics (failure = inability

to resolve arthritis, systemic symptoms, or liver dysfunction, or being

steroid dependent)

≥2 episodes of MAS in a 2 year period

Development of SJIA-LD

Canna et al. Pediatric Rheumatology 2020, 18(Suppl 1):53 Page 13 of 15

participating in the discussions. RS and AAG wrote the first draft of the

manuscript. All the authors reviewed the manuscript and provided their

input. The final version of the manuscript was approved by all the authors.

Funding

Funding for the symposium was provided by the SJIA Foundation.

Publication costs have been covered by the SJIA Foundation.

The SJIA Foundation did not have any direct influence on the research and

results being presented.

Availability of data and materials

All the data discussed during the meeting have now been published and

appropriately referenced at the end of the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have reviewed the manuscript and provided their consent to

publish. All the patients mentioned in the manuscript gave their permissions

to use full names.

Competing interests

Dr. Canna received clinical trial support from AB2Bio. Dr. Schulert has

received consulting fees from SOBI and Novartis (less than $10,000 each). Dr.

Brunner has received consulting fees from Bristol-Myers Squibb, Pfizer, Jans-

sen, Eli Lilly, Roche, and Novartis (less than $10,000 each). Dr. Grom has re-

ceived consulting fees from SOBI and Novartis (less than $10,000 each) and

research support from SOBI, Novartis, and AB2 Bio. Dr. Gadina has a Collab-

orative Research and Development Agreement related to JAK inhibitors with

Pfizer. Dr. De Benedetti has received research grants from Abbvie, Pfizer, Eli-

Lilly, Roche, Novartis, NovImmune, Sanofi, and SOBI. Dr. Rashmi Sinha serves

as the president of the SJIA Foundation. No other disclosures relevant to this

article were reported.

Author details

University of Pittsburgh, Pittsburg, PA, USA.

Division of Rheumatology,

Cincinnati Children ’s Hospital Medical Center and Department of Pediatrics,

University of Cincinnati College of Medicine, Cincinnati, USA.

Intramural

Research Program, National Institute of Allergy and Infectious Diseases, NIH,

North Bethesda, USA.

Harvard Medical School, Boston, MA, USA.

SJIA

Foundation, Cincinnati, USA.

Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Received: 26 May 2020 Accepted: 17 June 2020

Published: 15 July 2020

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