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    BMT in SJIA patients

    BMT in SJIA patients

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    This paper discusses recent findings on hematopoietic stem cell transplantation (HSCT) in patients with refractory systemic juvenile idiopathic arthritis (SJIA) and associated lung disease. It encompasses insights from case studies, optimal timing for procedures, and the management of complications to improve patient outcomes. Long-term follow-ups post-HSCT show promising results, but highlight the need for more data to determine the best candidate profile.

    Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86
https://doi.org/10.1186/s12969-023-00868-x
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Pediatric Rheumatology
Part 5: Allogeneic HSCT in refractory SJIA 
with lung disease; recent cases from centers 
in North America & Europe
Alexei A. Grom1*, Scott W. Canna2†, Rolla F. Abu‑Arja3†, Rashmi Sinha4†, Luciana Peixoto4†, Elvira Cannizzaro5†, 
Shanmuganathan Chandrakasan6,7, Kyla Driest8
, Rebecca Marsh9, Bénédicte Neven10,11, Karen Onel12, 
Sampath Prahalad6
, Susan Prockop13, Pierre Quartier10,11, Johannes Roth14, Grant Schulert1, Juliana M.F. Silva15, 
Donna Wall16 and Ulrike Zeilhofer17
From 4th NextGen Therapies for SJIA and MAS virtual symposium
Virtual. 16-18 February 2022. https://www.systemicjia.org/nextgen22/
Abstract
It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed 
all available medications and may beneft from HSCT. The increasing experience with HSCT in SJIA, suggests 
that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remis‑
sion or reduced burden of disease. Longer follow-up, however, is needed to better defne the long-term outcomes. 
The discussion at the NextGen 2022 conference was focused on the optimal timing for the procedure, the need 
for a good control of infammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regi‑
mens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplanta‑
tion. There was unanimous agreement about the importance of long-term registries to address these questions.
Keywords Allogeneic HSCT, Refractory SJIA, SJIA-LD, MAS, HLA DRB1*15 alleles
†
Scott W. Canna, Rolla F. Abu-Arja, Rashmi Sinha, Luciana Peixoto and Elvira 
Cannizzaro contributed equally.
*Correspondence:
Alexei A. Grom
Alexi.Grom@cchmc.org
1
 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, 
University of Cincinnati, Cincinnati, OH, USA 2
 Rheumatology & Immune Dysregulation, The Children’s Hospital 
of Philadelphia, Philadelphia, PA, USA 3
 Department of BMT, Nationwide Children’s Hospital, Columbus, OH, USA 4
 Systemic JIA Foundation, Cincinnati, OH, USA
5
 Department of Rheumatology, University Children’s Hospital, Zurich, 
Switzerland
6
 Department of Pediatrics, School of Medicine, Emory University, Atlanta, 
GA, USA
7
 Afac Cancer and Blood Disorders Center, Children’s Healthcare 
of Atlanta, Emory University, Atlanta, GA, USA
8
 Department of Rheumatology, Nationwide Children’s Hospital, 
Columbus, OH, USA
9
 Division of Bone Marrow Transplantation and Immune Defciency, 
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
10 Pediatric Hematology‑Immunology and Rheumatology Department, 
Necker-Enfants- Malades University Hospital, Paris, France 11 Université Paris-Cité, Paris, France 12 Department of Rheumatology, HSS, New York City, NY, USA 13 Dana Farber/Boston Childrens Hospital Center for Cancer and Blood 
Disorders, Boston, MA, USA
14 Kantonsspital Luzern, University of Luzern, Luzern, Switzerland 15 Department of BMT, Great Ormond Street Hospital for Children, 
London, UK
16 16. Blood and Marrow Transplant/Cellular Therapy, Division 
of Haematology/Oncology, Hospital for Sick Children Toronto, Toronto, 
Canada
17 Department of BMT, University Children’s Hospital, Zurich, Switzerland
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Introduction
In the last decade, the discovery that IL-1 & IL-6 are key therapeutic targets in systemic juvenile idiopathic 
arthritis (SJIA) and the introduction of IL-1 and IL-6 inhibiting biologics have led to a dramatic improvement 
in the outcome of typical features of this disease. At the same time, starting with the publication by Kimura 
in 2013, there has been a growing recognition of a 
subset of children with mostly systemic disease who 
are refractory to biologics and develop recurrent 
macrophage activation syndrome (MAS) as well as 
a seemingly new life-threatening pulmonary complication (SJIA-LD). Tese patients typically stay on 
multiple immunosuppressive medications, are corticosteroid-dependent, face high risk of infection, steroid 
side efects, and relentless disease progression. Te earliest reported mortality rate in this group was as high 
as 68% [1], though later reports are less pessimistic: 
Saper et al. [2], estimate fve-year survival at 42% while 
Schulert et  al. [3], are seeing 95% survival rate in the 
cohort of patients followed by their group.
Despite lower mortality rates, good disease control 
in these patients is still hard to achieve. Given limited understanding of the underlying pathology, these 
patients are empirically treated with multiple immunosuppressive medications including both biologic 
and non-biologic DMARDs, while remaining on daily 
steroids. Further, there is a suspicion that the IL-1 and 
IL-6 inhibiting biologics may contribute to the development of the lung complications. In general, the level 
of immunosuppression in these patients is unsustainable long-term. Numerous infections, corticosteroid 
side effects and frequent admissions lead to a dramatically decreased quality of life. Marked growth 
retardation with complete growth cessation in some 
patients contribute to social isolation and depression. 
As a result, hematopoietic stem cell transplantation 
(HSCT) has emerged as a potential alternative therapeutic strategy.
Te earliest report of hematopoietic stem cell transplantation (HSCT) in an SJIA patient with pulmonary 
disease was published in 2018, followed by a few case 
reports. Since 2021, however, based on the information available through patient-driven networks, the 
idea of HSCT has become more acceptable to both parents of SJIA patients as well as the medical teams caring for SJIA patients. Improved conditioning regimens 
have led to the hope that re-setting the immune system 
through HSCT would lead to a complete remission of 
the systemic JIA and associated lung disease thus abolishing the need for immunosuppressive medications 
and corticosteroids.
Teams with expertise in HSCT for SJIA that typically 
including both a rheumatologist and bone marrow 
transplant (BMT) specialist, were invited to participate in the NextGen 2022 session focused on HSCT 
in SJIA with lung disease. The parent perspective was 
shared by two parents of SJIA patients who underwent 
transplantation. Finally, Dr. Silva who had published a 
case series on allogeneic transplantation in JIA (which 
included some SJIA patients) in 2018 was invited to 
present the long-term follow-up data on patients from 
that cohort.
Te goals of this NextGen session were to explore 
whether HSCT could be an efective strategy for patients 
who have become dependent on steroids and are on 
unsustainable levels of immunosuppression, or whose 
lung disease is progressing. Te key questions were:
1. Since preservation of good pulmonary function is an 
important predictor of good outcome, can HSCT be 
done safely in patients with SJIA-LD whose lungs are 
already damaged? Te degree of lung damage varies 
between SJIA-LD patients with many of them requiring night-time or full-time oxygen supplementation. 
Furthermore, some patients need tracheostomy and 
are ventilator dependent. Can these patients withstand HSCT?
2. Te innate immune cell activation appears to be the 
driving force in refractory SJIA pathology suggesting 
that bone marrow derived cells are key players in this 
disease. On the other hand, one of the main risk factors for the lung disease in SJIA is strikingly high levels of serum IL-18. Although the sources of IL-18 in 
SJIA have not been fully defned, there is some data 
suggesting that it is coming not only from the bone 
marrow- derived cells but also from the barrier tissues such as the epithelium gut. If this were the case, 
would HSCT be efective at controlling the immune 
disease and normalizing IL-18?
3. Phenotypically, the lung disease in these patients is 
a distinct type of interstitial lung disease with interstitial lymphocytic infltration and features of pulmonary alveolar proteinosis that is typically caused 
by dysfunction of macrophages. Can re-setting the 
immune system help control the lung disease? Will it 
stop LD progression and reverse some of the dam-
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age? Most of the previous experience with HSCT 
in SJIA is based on patients who did not have lung 
disease, so at this stage it is not clear what impact of 
HSCT on the lungs might be.
4. Another critical question is the optimal timing of the HSCT. Pre-HSCT organ damage, particularly pulmonary dysfunction, decreases the 
chances for a successful outcome of the procedure. 
Does moderate or severe lung damage mean that 
these patients are no longer good candidates for 
HSCT? If HSCT is indeed indicated, at what stage 
should it be considered? After failing multiple 
lines of approved medications? Should other nonapproved medications be tried first, or is it preferable to proceed with HSCT before organ damage 
reaches a certain degree? Indeed, the rate of lung 
disease progression varies between patients - some 
do not acquire much lung damage after years of 
SJIA-LD diagnosis, while others are admitted to 
the ICU at the time of the initial discovery of lung 
involvement.
Transplantation in SJIA ‑ a brief background
Autologous transplantation in SJIA
Between 1999 and 2007, multiple groups in Europe 
reported on treatment with autologous transplantation [4, 5] for patients with severe refractory arthritis 
and chronic inflammation. These patient cohorts were 
resistant to all drugs and had become steroid dependent. Transplant outcomes were mixed. Some patients 
did achieve remission, but there was also significant 
morbidity (especially disease relapse and MAS) and 
mortality.
Allogeneic transplantation in SJIA
In 2018, Dr. Silva and colleagues published a set of case 
studies of Allogeneic HSCT in refractory SJIA & JIA 
from Europe & US [6]. Notably, those cases had been 
diagnosed either as RF-negative Poly JIA or SJIA. They 
either had unremitting arthritis and/or MAS or were 
steroid dependent. Dr. Silva’s review highlighted that 
allogeneic transplantation could be effective in JIA & 
SJIA and lead to disease remission, though there were 
some relapses.
The HSCT in SJIA-Lung Disease session was introduced by the moderator Dr. Scott Canna. Parent participants were Luciana Peixoto & Pauline Acevedo. 
Long-term follow-up of allogeneic HSCT cases in 
SJIA was presented by Dr. Juliana Silva. Case presentations were provided by Elvira Cannizzaro & Ulrike 
Zeilhofer, Johannes Roth & Donna Wall, Karen Onel 
& Susan Prockop, Pierre Quartier & Bénédicte Neven, 
Kyla Driest & Rolla F. Abu-Arja, and Grant Schulert & 
Rebecca Marsh.
Understanding the patient experience with HSCT
Parents of two children diagnosed with SJIA-LD, who 
had undergone HSCT recounted their experience. Tey 
shared their child’s disease history, how the families and 
medical teams came to the decision to proceed with 
HSCT, the experience during transplantation, complications, and fnally, their lives after HSCT.
Patient story 1
Parent participant: Luciana Peixoto Mrs. Peixoto’s 
daughter, Beatriz, with previously normal health, was 
diagnosed with SJIA in September 2013 at Zurich 
Kinderspital. She was 11 years old at the time of diagnosis. For the next 5 years, her medical team tried several 
medications including multiple biologics, but could not 
control her fares completely and they were unable to 
wean her of steroids. Beatriz had one overt MAS episode 
and multiple episodes of sub-clinical MAS. Additionally, she had adverse reactions to biologics (rash and liver 
enzyme elevation) and numerous side efects from highdose steroids prompting initial discussions about HSCT 
for her difcult to control disease.
In 2016, after a drop in oxygen saturation, Beatriz was 
diagnosed with pulmonary hypertension and lung disease. She was mostly on prednisolone at this point (as 
there were no further medication options available at that 
time). Her quality of life was poor. When her medical 
team brought up the idea of HSCT again, the family and 
the patient herself were in agreement that HSCT was the 
best option.
Mrs. Peixoto gained further confdence in the plan 
after learning that her medical team had consulted with 
Dr. Juliana Silva from Newcastle who was following a 
case series of HSCT in SJIA. Her team was planning to 
follow the same protocol. Additionally, her team had 
identifed a suitable unrelated HLA matched donor, and 
had a backup plan of using the patient’s own stored cord 
blood stem cells if the allogeneic transplantation were 
not successful.
Te transplantation performed in March 2018 went 
relatively well, with side efects that included hair loss, 
mucositis, fever, low kidney function, increased need 
for oxygen, morphine for pain, and blood transfusions. 
Beatriz was discharged home on Day+30. About two 
weeks later she developed three vertebrae compression 
fractures due to osteoporosis and was in a lot of pain. 
At some point, the fever came back (MAS episode was 
suspected). She was admitted to the hospital for three
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more weeks and started to recover. Her lungs improved 
and over the next year, all signs of pulmonary hypertension resolved.
Four years post-transplant, Beatriz remains on Spiriva 
for lungs and hormone patch. She is a healthy young 
adult studying biochemistry and hoping to work as a 
researcher in drug development for rare diseases.
Patient story 2
Parent participant: Pauline Acevedo Mrs. Acevedo’s 
daughter, Valentina, was initially diagnosed in 2013 with 
atypical Kawasaki. Next, familial hemophagocytic lymphohistiocytosis was suspected. Finally, at the age of 18 
months, she was diagnosed with SJIA. For the next four 
years, in spite of multiple medication changes (including 
multiple biologics) and high-dose steroids, her disease 
remained poorly controlled. In 2016, the parents started 
noticing digital clubbing and a persistent dry cough. A 
year later, a bronchoscopy and lung biopsy, performed 
at Cincinnati Children’s Hospital, confrmed the diagnosis of Interstitial Lung Disease & Pulmonary Alveolar 
Proteinosis.
The biologics were stopped based on the suspicion 
that they were causing the lung disease (later they confirmed that her daughter carries the HLA type associated with SJIA-Lung Disease). Valentina stayed on 
jak-inhibitors and cyclosporine, but her physicians 
were unable to reduce oral steroids and she suffered 
from many side effects. In consultation with her medical team, the family decided to proceed with HSCT 
primarily due to not being able to wean steroids and 
uncontrolled SJIA.
She was 9 years old when her frst HSCT was performed in April 2021. Although her donor was fully 
matched (10/10), she rejected the graft. Te team started 
a search for another donor and the best option available 
was to use her 5/10 haploidentical father. Tis second 
was performed in May 2021. Te complications included 
central line infection, mucositis, an increased oxygen 
requirement, an ICU stay for 3 days, and mild GVHD. 
She stayed in the hospital for almost 4 months.
Since the HSCT, she has been doing well and has 
been mostly off steroids (now on a small dose of 
hydrocortisone due to adrenal issues from long-term 
usage of steroids). She has grown almost 3 inches and 
the digital clubbing is improving. Of note, her lungs 
are showing some nodules which doctors think are 
infection-related (perhaps PJP). She remains asymptomatic, but the team is following closely and doing 
chest CTs every two months. The family reports that 
Valentina looks and feels healthy and has a much better quality of life.
Long term follow‑up from earlier study of allo‑HSCT in SJIA 
published by Silva et al., in 2018.
Presenter: Juliana Silva (BMT), GOSH, United Kingdom
Dr. Silva presented a review and update of the patients 
from her previous publication [6] that included 16 
patients with SJIA who underwent allogeneic HSCT 
from fve European and US centers. Of the 16 patients, 5 
had rheumatoid factor–negative polyarticular JIA, and 11 
had SJIA refractory to standard therapy. Of the 11 SJIA 
patients, 5 also had a history of MAS, and 2 had failed 
previous autologous HSCT.
Te median follow-up was 2 ½ years. Eight patients 
were transplanted with matched unrelated donors 
(MUD), 4 with matched sibling donors (MSD), and 4 
with mismatched unrelated donors (mMUD). Reduced 
toxicity conditioning regimens were mostly used with 
Fludarabine, Melphalan, and Campath in 10 patients and 
Fludarabine, and Treosulfan in 6 patients.
Below are summary long-term results for the patients 
transplanted by 3 of the centers:
Te Great Ormond Street Hospital (GOSH) experience: Tis center transplanted 5 patients. Four of 
them achieved Complete Remission (CR), while 1 
died due to transplant-related toxicity. Tis patient 
had a previous autologous stem cell transplant. Two 
of the four surviving patients relapsed post-HSCT. 
One patient relapsed 2-year post-transplant with 
macrophage activation syndrome (MAS) that was 
treated and responded well to corticosteroids. Tat 
patient is now 8-years post HSCT and remains 
in complete remission (CR). Te second patient 
relapsed 10 years post HSCT and is now on treatment for arthritis.
Te Newcastle experience: Te team reported 8 
patients. Two patients achieved CR at 0.66 years 
(and at last follow-up, 9 years post-HSCT), and they 
remained in complete remission (CR). One patient 
achieved partial remission (PR), 3 patients relapsed 
(relapses were late at 1, 2, and 3 years post-HSCT), 1 
patient died from transplant-related toxicity (TMA), 
and 1 patient had no response (after HSCT this 
patient was diagnosed with PRG4 mutation - Camptodactyly-arthropathy-coxa vara-pericarditis syndrome).
The UCLH experience: The center performed 
HSCT for 3 patients. All achieved CR. One patient 
had declining chimerism 6 months post HSCT 
with autologous reconstitution but remains in clin-
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ical CR. One patient is only 2 months post-transplant in CR and it is too early to evaluate his longterm outcome.
Te CCHMC experience: Te team from CCHMC 
described two patients transplanted at CCHMC, who 
are 13, and 8 years post-HSCT respectively. Both are 
doing well and remain in remission. 
In summary, 16 patients received allo-HSCT for SJIA. 
Te median follow-up is 8.5 years. Eleven patients achieved 
CR, 2 PR, and 1 patient had no response (who was later 
found to have PRG4 mutation). Tere were 2 deaths due 
to transplant-related toxicity. Six patients relapsed (time to 
relapse post-transplant ranged from 1 to 10 years).
Dr. Silva noted that although these results show 
some promise, there are many unanswered questions. 
More data is needed to understand how to identify 
the subgroup of patients that will benefit from HSCT 
and to define the optimal timing for transplantation. 
Additionally, it is important to understand why some 
patients relapse after several years. Future prospective 
studies are needed to address these questions and to 
standardize transplant procedures.
Brief reports of new cases presented at NextGen 2022 
conference
Overall, 9 cases of HSCT for refractory SJIA were presented from 6 teams. Of the 9 patients, 5 had SJIA-Lung 
Disease, 1 case had some lung involvement with normal CT, 1 case had pneumonitis, while the other 2 cases 
were of refractory SJIA without lung disease. Six of the 9 
patients had the HLA type (HLADRB1*15) that has been 
associated with SJIA-Lung Disease. A brief description of 
each case presented at the conference follows next.
The Zurich experience: 3 cases of HSCT in SJIA, 2 
with SJIA‑Lung disease
Presenters: Elvira Cannizzaro (rheumatologist) & Ulrike 
Zeilhofer (BMT), University of Children’s Hospital Zurich, 
Switzerland
Case 1 Te frst patient was an 11-year-old female diagnosed with SJIA who had initially presented with fever, 
rash, splenomegaly, and hyperferritinemia. She was initially treated with prednisone, methotrexate and tocilizumab then switched to canakinumab, anakinra, and 
cyclosporin, with frequent prednisone pulses over 4.5 
years. Despite higher doses of canakinumab, the patient 
was having recurrent MAS episodes and developed persistent infammation with signs of chronic, interstitial 
lung disease. She later developed pulmonary hypertension. She remained steroid-dependent leading to signifcant side efects including osteoporosis, cataract, and 
growth stagnation. Additionally, she had an anaphylactic 
reaction to solumedrol IV and was switched to dexamethasone. Despite aggressive treatment with biological 
therapy, she had recurrent MAS and interstitial lung disease with pulmonary hypertension.
In 2018 (about 4.5 years into her disease), she received a 
9/10 MUD transplant with a conditioning regimen that 
included Fludarabine (30 mg/m2/day from days −8 to -3) 
and (Treosulfan 14 mg/m2/day from days −5 to -3). For 
GVHD prophylaxis she received Campath (0.2  mg/m2/
day from days −8 to-4), cyclosporin, and mycophenolate. 
She remained on dexamethasone through transplant for 
2 months.
Te patient’s initial course was uneventful. She 
attained neutrophil engraftment on Day+22 with 
100% donor chimerism but later developed severe back 
pain with MRI fndings of several osteoporotic vertebral bone fractures. She was treated with opiates and 
bisphosphonate infusions. Next, she developed CMV 
reactivation with secondary MAS with pancytopenia. 
Due to severe osteoporosis, she was treated with cyclosporin to avoid prednisone. Her recovery was slow, but 
she achieved full remission with improved lung function with no overnight oxygen requirement and resolving pulmonary hypertension with full donor chimerism 
on the last follow-up (3 years after transplant, last chimerism check was in June 2019).
Case 2 Te second patient was a 2 ½ years old male 
with a similar disease presentation including fever, skin 
rash, recurrent MAS, splenomegaly, and severe arthritis 
leading to immobility with interstitial lung disease (ILD) 
and oxygen dependency.
He received a 12/12 HLA MUD transplant with the 
same conditioning regimen as Case 1 above. He attained 
neutrophil engraftment on Day+20 but had a more 
complicated initial course with severe nausea, mucositis, several episodes of neutropenic fevers, HHV6 reactivation, E-coli sepsis, and several vertebral fractures. 
Following his initial discharge, he developed recurrent 
post-transplant MAS which was treated with methylprednisolone and then switched to dexamethasone 
per the HLH protocol, with a slow taper and no recurrence of MAS. On the last follow-up, he was found to 
have mixed donor chimerism (CD14 86% and CD3 76%) 
but he was doing clinically well of immunosuppression 
with improved lung disease and quality of life.
Both Cases 1 & 2 were of patients with refractory systemic JIA who were steroid-dependent leading to the 
development of signifcant side efects including osteoporosis, cataract, and growth stagnation. Despite aggressive
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treatment with biological therapy, they both had recurrent MAS and interstitial lung disease. Although both 
patients had a complicated transplant course both 
patients have achieved full remission and are doing well 
post-transplant.
Case 7 Te most recent case from Zurich is of a 3-yearold girl transplanted in November 2020. She had multiple MAS episodes, polyarthritis, was steroid dependent 
(with severe side efects). She also had allergic reactions 
to several medications.
She was transplanted with the same conditioning regimen as the frst 2 patients from Zurich: Treosulfan /
Fludarabine/ Campath. Her match was 10/10 matched 
unrelated donor and the transplantation course was 
uneventful. However, all donor cell lines (CD14, CD 15, 
and CD3) dropped around 3–4 months after transplantation. At frst, the arthritis was still controlled, but once 
steroids were stopped, she relapsed with her JIA that was 
again difcult to control.
Te team decided to proceed with a second HSCT 
which was performed in November 2021. She had 
another 10/10 matched unrelated donor. Tis time, the 
team decided to use a more intense conditioning regimen: Busulfan/Cyclophosphamide/ATG. Te transplantation course was initially uncomplicated, but in January 
2022, she had a generalized seizure and was diagnosed 
with EBV encephalitis. Although clinically she appeared 
well, there were concerning fndings in the MRI and CSF. 
She was treated with Valcyte, Rituximab, and one dose 
of CD45+RO cells with a good response. Currently, chimerism is at 100% percent for all cell lines. Steroids were 
stopped at the end of January 2022, but it remains too 
early to assess if the second HSCT will lead to long disease remission.
The Paris experience: 1 case of Haploidentical HSCT in SJIA
Presenters: Pierre Quartier (Rheumatology) & Bénédicte 
Neven (BMT), Necker‑Enfants‑Malades University Hospital, 
Paris, France
Case 3 Te team presented 2 patients, a case of HSCT 
for refractory SJIA performed 5 years ago [7] as well as 
a second HSCT for a refractory SJIA patient, who was 
transplanted very recently.
Tis center had previous experience with autologous 
transplantation in a few patients with severe Still’s Disease, but the patients presented with numerous complications after transplantation and continued to have fares.
Teir frst allogeneic transplantation in 2017, was a 
female SJIA patient, 3.7 years old who fulflled the eligibility criteria for HSCT. She had a severe systemic disease but did not have interstitial lung disease. She had 
proven refractory to both IL-1 and IL-6 blockers, as well 
as to thalidomide, methotrexate, and infiximab.
Te mother was the donor (although she had vitiligo), 
as there was no other donor available. Te haploidentical bone marrow transplantation was performed with a 
conditioning regimen of busulfan, fudarabine, campath, 
and post-transplant cyclophosphamide. She achieved full 
donor chimerism, but several complications occurred in 
the post-transplantation course: acute skin and gastrointestinal GVHD (treated with steroid therapy), infections 
and thrombocytopenia treated with intravenous immunoglobulins. At last follow-up, apart from vitiligo and 
asymptomatic hypothyroidism, the patient achieved full 
remission from arthritis and systemic disease with 100% 
chimerism.
Te other SJIA patient was transplanted 2 months ago. 
She is a 3-year-old with SJIA. She has had recurrent MAS 
and her disease has proven refractory to IL-1 blockers, 
tocilizumab, and baricitinib. After a severe SJIA fare 
without MAS, sirolimus was introduced. She has been 
on emapalumab for MAS and high-dose steroids. Te 
patient had very high IL-18 levels consistent with the 
phenotype of young children who do not respond to biologics and are at risk of lung disease.
The Columbus experience: 1 case of HSCT in SJIA with lung 
involvement
Presenters: Kyla Driest (Rheumatology) & Rolla F. Abu‑Arja 
(BMT), Nationwide Children’s Hospital, Columbus, United 
States
Case 4 Te team at Nationwide Children’s Hospital 
presented a 16-year-old female patient who initially presented with fever, rash, and arthritis [8]. Te patient was 
initially diagnosed with Celiac disease and then, SJIA. 
She was started on prednisone and etanercept. Due to 
continued arthritis, etanercept was replaced with tocilizumab followed by adalimumab.
Te patient had multiple admissions for fevers that were 
treated as infections with antibiotics while holding biologic therapy. On her 4th admission (5 months after the 
initial diagnosis) she developed overt MAS and her treatment regimen was changed to the combination of cyclosporin and canakinumab.
Her care was transferred to Nationwide Children’s 
at this point. Given the continued disease activity and 
side efects, cyclosporin was replaced with lefunomide 
and hydroxychloroquine. Te Canakinumab dose was
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increased to 300 mg every 4 weeks and then to 500 mg 
every 4 weeks due to smoldering MAS. She was then 
admitted for a severe MAS fare with limited response 
to high-dose solumedrol (1-gram IV Q daily). Next, her 
treatment was changed to anakinra, dexamethasone, 
IVIG, and tacrolimus. During this time, she started 
showing signs of dyspnea on exertion. Pulmonary function testing revealed low DLCO and mild obstruction 
with normal chest CT and echocardiogram.
At the age of 20, in 2018, she received an allogeneic 
bone marrow transplant from a 30-year-old male 10/10 
HLA MUD using a reduced-intensity conditioning regimen (Intermediate Alemtuzumab 0.3  mg/kg/dose SQ 
for 3 days (days −14 to -12) Fludarabine 30  mg/m2/
dose for 5 days (days −8 to -4) and Melphalan 70 mg/
m2/dose for 2 doses (days −2 and −1)). GVHD prophylaxis consisted of tacrolimus and methylprednisolone 
while she continued anakinra daily until engraftment 
and discontinued hydroxychloroquine before the start 
of the conditioning regimen. She achieved engraftment on Day+9 and was discharged on Day+14. Her 
peripheral blood chimerism was 99–100% donor in all 
cell lines. Complications included Grade 1 skin GVHD 
treated with topical corticosteroid therapy. She also 
developed EBV reactivation on Day 100 for which she 
received Rituxan which caused B cell aplasia lasting 
for 1 year. She was weaned of tacrolimus at 6 months 
post-transplant and prednisone at 18 months due to 
secondary adrenal insufciency. Due to prolonged 
prednisone use, she had slow immune reconstitution 
and remained on replacement IV immunoglobulin for 2 
years post-transplant.
Based on the last follow-up, the patient is now 3 ½ 
years post HSCT with complete resolution of arthritis, 
improvement in lung function, and DLCO. She is of 
immunosuppression with full immune reconstitution. 
Her Celiac disease has resolved.
The Emory‑Atlanta experience: 1 case of HSCT in SJIA
Presenters: Sampath Prahalad (Rheumatology) 
and Shanmuganathan Chandrakasan (BMT), CHOA, 
Emory‑Atlanta, United States)
Case 5 Tis case from Emory was that of a 19 year 
old African-American female referred for HSCT due to 
refractory SJIA, complicated by multiple MAS fares, 
and bacterial infections (primarily cutaneous abscesses). 
Her disease started at the age of 14 years and quickly 
evolved to a steroid-dependent SJIA state despite treatment with anakinra, tocilizumab, methotrexate, and 
cyclosporin A.
During the year preceding the HSCT, she had fve MAS 
fares, with two of them requiring an ICU admission. Her 
course was also complicated by CMV viremia and pneumonitis treated with ganciclovir. Many of her MAS/SJIA 
fares were also associated with muscle enzyme elevation. 
An immunologic workup revealed very high IL-18 levels (>200,000). In addition, a workup for HLH revealed a 
single allele mutation in STXBP2 and LYST, but her CD 
107 degranulation assay (a test for the functional integrity 
of the cytotoxic T cell degranulation (CTL) pathway) was 
normal. Based on that, primary HLH phenotype was felt 
unlikely.
Due to the refractory disease course, the team elected 
to proceed to allogeneic HSCT as a potentially curative 
option. At the age of 19 years, the patient underwent 9/10 
mismatched unrelated PBSC graft HCT following Campath/ Flu/ Mel/ Tiotepa conditioning. Peri-conditioning 
(despite Campath and fudarabine), she had a disease 
fare. Due to this fare during conditioning, she was restarted on anakinra. She achieved engraftment on Day 11 
with 100% donor cells in T and myeloid compartment. 
Her IL-18 levels improved from >200,000 to 903 two 
months post HSCT and remained below 2000 thereafter.
Her disease course was complicated by acute Grade 
III GVHD of the GI/ Skin, posterior reversible encephalopathy syndrome, and TA-TMA (Transplant-associated 
thrombotic microangiopathy) leading to worsening renal 
function requiring hemodialysis and later CVVH. Her 
aGVHD was managed with pulse steroids, infiximab, 
and extra corporeal photopheresis with a partial response 
and continuous steroid-dependent state. She also developed CMV pneumonitis and viremia. Her TA-TMA was 
managed with eculizumab. Despite aggressive support, 
she had progressive cardiorespiratory worsening and died 
on Day+133. Postmortem evaluation revealed extensive 
thrombotic microangiopathy with difuse bilateral kidney 
necrosis with microthrombi and difuse alveolar damage 
with hyaline membrane, difuse pulmonary hemorrhage, 
and numerous thrombi of diferent stages and small and 
large intestine with focal ischemic necrosis with microthrombi. Based on the autopsy, the death was primarily 
caused by refractory TA-TMA.
The Toronto/Ottawa experience: 1 case of HSCT 
in SJIA‑Lung Disease
Presenters: Johannes Roth (Rheumatology), University 
of Ottawa & Donna Wall (BMT), University of Toronto, 
Canada
Case 6 Te team from Canada presented a patient 
who received an allo-HSCT in 2020. It was a female who
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initially presented at the age of 3.5 years with high fevers, 
rash, and arthritis followed by pancytopenia, high ferritin leading the diagnosis of MAS. She was initially treated 
with a combination of prednisone, IVIG, and anakinra. 
Cyclosporine was added with no response. Anakinra 
was then replaced with tocilizumab, but she developed 
an adverse reaction to this medication, and was then 
switched to high dose canakinumab. Genetic panel testing was negative with whole-exome sequencing showing 
a variant of unknown signifcance in the NLRC4 gene. 
Tis variant was also present in the mother and was ultimately deemed as likely not pathogenic.
About 2 years into her disease course, she developed clubbing and lung disease. A lung biopsy confrmed the distinct 
phenotype associated with pulmonary alveolar proteinosis 
typically seen in patients with SJIA-Lung Disease. Initially, 
the lung disease was stable, but a year later she had another 
episode of severe MAS that triggered further progression 
of the lung disease and she became oxygen dependent. Te 
patient participated in a trial of an anti-IL-18 agent but 
dropped out in the double-blind phase of the trial and it 
is still unknown whether she received the drug or placebo. 
She was also treated with high doses of tofacitinib and 
emapalumab, with no clear response.
Te decision to proceed with HSCT was not an easy 
one as she was on supplemental 3–4  L of oxygen and 
lungs were very infamed. It involved the family, multiple 
medical teams from other hospitals, as well as experts 
in bioethics. Tere was no active infection on pre-transplant bronchoscopy. Te team optimized immunosuppression, and decided to continue emapalumab, steroids, 
and anakinra though the transplant procedure as part of 
graft versus host prophylaxis, as well as to control the 
underlying infammatory process.
She received a 10/10 HLA MUD peripheral stem cell transplant using a reduced toxicity conditioning regimen. Pretransplant immunotherapy (emapalumab, prednisone, and 
anakinra) was continued through the early transplant period.
Her transplant course was complicated with signifcant 
worsening of pulmonary function requiring temporary 
ventilatory support and dialysis at time of engraftment. 
Although her transplant recovery was slow, she showed 
fast resolution of arthritis and was able to stop anakinra 
and emapalumab following engraftment.
At 3 months post-transplant, she developed features 
of acute and chronic GVHD primarily involving the skin 
but had a quick response to ruxolitinib.
Te patient is now 16 months post-transplant with full 
donor chimerism, no clinical GVHD, and mild thrombocytopenia. Her respiratory function is improving based 
on imaging, resolving clubbing, and decreased oxygen 
support.
Case 6: Chest CT scan for lungs: Pre HSCT and 1-year post-HSCT
The Cincinnati experience: 1 case of HSCT in SJIA‑Lung 
Disease
Presenters: Grant Schulert (Rheumatology) & Rebecca Marsh 
(BMT), Cincinnati Children’s hospital, United States
Case 8 Te female patient who, in 2013 at the age of 10 
months presented with rash and fever and was initially 
diagnosed with Kawasaki disease but failed to improve 
despite treatment with IV immunoglobulins. At the age 
of 18 months, she developed MAS followed by arthritis 
and was then diagnosed with Systemic JIA. Te patient 
was initially treated with prednisone and cyclosporine but 
was unable to wean of prednisone. She was then started 
on tocilizumab, but had an infusion reaction, and was then 
switched to canakinumab. She had an excellent response 
initially but missed multiple doses due to recurrent infections and pneumonia. She developed chronic cough and 
clubbing with abnormal lung fndings on the chest CT 
scan. She continued to have recurrent MAS typically triggered by infections. A lung biopsy was performed and confrmed the diagnosis of SJIA-LD with PAP-like features.
She remained resistant to biological therapy with worsening lung disease with overnight hypoxia, recurrent MAS,
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chronic steroid dependence, and drug toxicity including 
growth failure, hypertension, and infections.
She received an allogeneic HSC transplant from a 
10/10 HLA MUD using a reduced-intensity conditioning regimen of Alemtuzumab, Fludarabine, Melphalan, 
and thiotepa. Te graft was TCR a/b CD19 depleted 
and there was no GVHD prophylaxis. Te patient did 
well Initially and achieved neutrophil engraftment on 
Day+13 with 100% donor chimerism, however, she 
developed acute secondary graft rejection on Day+32. 
She received a second transplant 6 weeks following the 
frst transplant using a parental haploidentical donor, 
with ATG, fudarabine with post-transplant cyclophosphamide, cyclosporin, and mycophenolate for GVHD 
prophylaxis. Te patient did well with count therapy 
and 97% donor chimerism. Transplant complications 
included Grade 1 Stage 1 skin GVHD that responded 
well to steroids. Te patient is now 7 months posttransplant and is doing well of immune suppression 
without major complications and with no systemic 
infammation. Tere has been improvement in clubbing 
and cushingoid features.
Case 8: Clubbing improvement: before and after HSCT (approximately 9 
months)
The New York experience: 1 case of HSCT in SJIA‑Lung 
Disease
Presenters: Karen Onel (Rheumatology) & Susan Prockop 
(BMT), HSS/MSKCC/NYH‑WC, New York, United States
Case 9 An 18-month-old male initially presented with 
fever, rash, and multiple-joint arthritis. For the next few 
years, his disease proved refractory to many medications, 
and he remained on high-dose steroids. At the age of 5 
years, he was referred to MSKCC for consideration for 
HSCT. He was steroid dependent, refractory to IL-1 and 
IL-6 inhibitors (anakinra, tocilizumab, & canakinumab), 
mycophenolate, rilonacept, cyclosporin, and tofacitinib. 
His course was complicated by recurrent MAS, systemic 
hypertrophic osteoarthropathy, and interstitial lung disease with clubbing. Lung biopsy showed difuse lymphocytic infltration with alveolar proteinosis.
At the time of referral, he was on daily prednisone dose 
of 1.2 mg/kg/day and monthly pulses of methylprednisolone 500 mg and cyclophosphamide. On genetic testing, 
he was found to have the HLADRB1*15, and candidate 
gene mutation (NLK). His lung disease continued to progress with evolving tachypnea and interstitial lung disease with cystic changes that led to the decision to move 
forward with allo-HSCT.
His pre-transplant evaluation identifed low-level CMV 
on bronchoalveolar lavage (BAL), for which he received 
induction ganciclovir prior to starting conditioning for 
HSCT. Te patient received a haploidentical HSCT from 
his 7/10 mother using a conditioning regimen of Busulfan (PK 60  mg*h/L) Fludarabine, ATG, and Rituximab, 
with post-transplant cyclophosphamide on Days+3 and 
+4, tacrolimus, and MMF for GVHD prophylaxis.
His transplant course was complicated with persistent 
fevers for the frst 2 weeks and at the time of engraftment 
on Day+21. Several weeks after engraftment he developed 
increasing respiratory distress with worsening of parenchymal changes by chest CT. A repeat BAL was negative 
for infections except for low-level CMV. His infammatory 
markers: CRP, Ferritin, and IL-6 levels were increased. He 
required admission to the pediatric intensive care and was 
placed on a high-fow nasal cannula. He received pulsed 
prednisone 1  mg/kg BID, resumed MMF and ultimately 
was discharged on overnight high-fow support.
Te patient is now 8 months post-haplo-HSCT with 
full donor chimerism in all lineages. He remains on tacrolimus and MMF and weaning prednisone (at the time 
of the meeting on 0.2  mg/kg/day). His immune reconstitution is slow due to prolonged prednisone use. Te 
patient remains on aggressive pulmonary toileting but 
is no longer on high-fow nasal cannula. Te chest CT 
showed marked improvement of parenchymal changes.
Summary of discussions
Te discussion, moderated by Dr. Canna, was wide-ranging, touching on many aspects of the cases presented. 
Te main themes are summarized below.
 Will the most refractory SJIA patients beneft from 
HSCT? First, Dr. Canna raised the question of whether
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there was a subset of patients with refractory systemic 
JIA, who have failed all available medications, who 
could potentially beneft from HSCT. How can we identify those patients early? Te refractory SJIA patients 
presented at NextGen were dependent on high doses 
of corticosteroids despite multiple immunosuppressive 
medications. While this population had signifcant periHSCT complications, most have achieved SJIA remission 
or experienced a decreased burden of SJIA, and improved 
lung function. Te follow-up, however, has not been long 
enough to defne the long-term outcomes.
Dr. Driest commented that rheumatologists, being 
aware of possible complications of HSCT, tend to keep 
looking for the next medicine with the hope that they 
will fnd the right one at some point. Given the number of drugs available as well as their possible combinations, this path can be very long. For their own patient, 
the team had changed medications multiple times and 
ultimately decided that it was time for a transplant rather 
than trying another combination.
Dr. Onel recounted that initially, their team was not 
in favor of HSCT. However, as the lung disease was rapidly progressing, and lung transplantation was proposed 
as the next step - their thinking changed. Teir concern 
was that poorly controlled underlying SJIA would reduce 
chances for successful lung transplantation. Additionally, there was a concern that the infammatory process 
can reoccur in the transplanted lung leading to new lung 
damage. A better approach might be to arrest the child’s 
lung disease with the ultimate immune ablation provided 
by HSCT.
 What is the optimal timing for transplants? / How to 
transplant before it’s too late, especially for lung patients? 
Next, Dr. Canna raised a question about the ideal timing to perform HSCT. Is it after patients have failed the 
approved biologic and non-biologic DMARDs or after 
trying other available immunosuppressive medications? 
Te cases presented at NextGen varied in terms of SJIA 
duration at the time of HSCT (from 1.9 to 8.2 years) with 
diferent degree of organ damage and toxicities from 
treatment. For one of the patients, the transplant was 
such a risky procedure, that the fnal decision was made 
with the involvement of the bioethics team. Is there a 
way to identify these patients earlier in the course of the 
disease?
A parent of an SJIA-LD patient raised the question 
about the clinical parameters that would make a patient 
no longer eligible for HSCT. Te consensus was that the 
fewer comorbidities would lead to fewer complications 
during HSCT. Conversely, a patient who spends years 
on corticosteroids and other immunosuppressants with 
frequent infections would be at higher risk for mortality, 
infections, and other side efects associated with HSCT.
Additionally, physicians agreed that although decreased 
pulmonary and cardiac function was a major concern, it 
was still possible to go through a transplant even if the 
patient was tracheostomy-dependent and on oxygen supplementation (with reasonable ventilator settings). In 
such cases, the fnal decision should be made by a multidisciplinary team based on very thorough evaluation.
Dr. Wall added that the transplant team must be prepared for numerous complications including ICU stays, 
especially if the patient had lung involvement. She added 
that for lung function, it is difcult to determine the exact 
cut-of point for HSCT eligibility when the lung is the 
target organ. Nevertheless, it is important to thoroughly 
evaluate lung function even if the imaging tests show 
severe lung infammation. Dr. Grom added that SJIALung patients often might be doing well and have preserved lung function despite impressive changes on high 
resolution chest CT.
One additional consideration is specifc to patients 
with severe growth delays (even growth failure), who are 
unable to get of steroids. For such patients, there is a 
need for a window of time after transplantation to catch 
up with growth before their growth plates close. As an 
example, for the patient from Cincinnati who had been 
on corticosteroids continuously for 9 years prior to the 
procedure, it took 18 months to complete her steroid 
taper post-BMT. She started growing at 8 months after 
transplant.
 Need for early referrals to the BMT team. Te BMT 
specialists emphasized the importance of early referrals 
of refractory patients to their teams, so they can stay 
involved with the patient and assess donor options.
Dr. Schulert from CCHMC shared that they were now 
referring any SJIA patients with a refractory course, who 
had failed both IL-1 and IL-6 blockade as well as jak-inhibition, to the BMT team.
 Plan for Retrospective Study and Need for Guidelines. 
Dr. Juliana Silva proposed starting a retrospective study 
with long-term follow-up of the cohort of transplanted 
SJIA-LD patients. She invited all the teams present to 
contribute to this efort that should include monitoring 
the rates of relapses and chimerism. She also emphasized 
the need for prospective studies of patients undergoing 
diferent standardized transplant procedures. Tus initially, the team used Flu/Melph/Campath as conditioning, but more recently they have changed the regimen to 
Fludarabine/Biosulphan with the hope that they would 
achieve better chimerism.
Dr. Abinun added that the existing European governmental HSCT guidelines were very conservative. He also 
emphasized the importance of publishing each case study 
so we could learn from these patients and improve these 
guidelines.
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 Is this group of patients too heterogeneous to draw 
conclusions from? Session participants had varied opinions about the heterogeneity of the refractory SJIA 
patients. Dr. Onel pointed out that there is a larger group 
of refractory SJIA patients who do not necessarily have 
lung disease but require multiple immunosuppressive 
drugs and cannot wean of steroids. She felt that refractory SJIA patients with parenchymal lung disease that 
have PAP features were a distinct and more homogenous group. Dr. Canna and Dr. De Benedetti thought 
that the SJIA patients with recurrent MAS associated 
with any organ involvement were on the same disease 
spectrum, even if the specifc organs involved were not 
the same. In contrast, Dr. Wall felt that the presented 
cohort of patients was still very heterogeneous with different mechanisms driving the disease. Tese diferent 
perspectives make it it difcult to come up with specifc 
guidelines.
 Conditioning Regimen and Chimerism. Te ideal conditioning regimen for HSCT for patients with SJIA has 
not been identifed. Specialists from two of the centers 
(Newcastle & Kinderspital) observed that the reduced 
intensity conditioning regimen utilizing treosulfan/
fudarabine might not be sufcient to ensure durable 
complete donor chimerism. Tis also came up in the 
long-term follow-up data presented by Dr. Silva where 
several of the patients relapsed and others had low chimerism. However, Dr. Silva pointed out that the relapse 
was not highly correlated with the drop in chimerism.
 Need to control infammation before HSCT and 
medications to be continued through transplant? Diferent teams had diferent opinions about the need for the 
continuation of the SJIA medications through the transplantation procedure. Te team from Canada emphasized the need for a full control of infammation prior 
to the transplant and GVHD prophylaxis. Teir patient 
was on anakinra and emapalumab prior to the transplant 
and continued these medications until engraftment. Te 
patient from CCHMC was on emapalumab before her 
second transplant.
Te NYC team decided to keep the patient on PO prednisone (1.2  mg/kg daily), monthly pulses of IV steroids, 
and cyclophosphamide during the time period leading 
up to the transplant, but they tried to minimize immunosuppression at the time of the graft infusion. Minimizing 
immune suppression in the context of haploidenticalHSCT with post-transplant cyclophosphamide is critical 
to the success of this approach.
Dr. Driest described their struggle with getting the dose 
of steroid right before the transplant for their patient who 
had been steroid dependent during the entire course of 
SJIA. Tey kept the patient on 20 mg of steroids as this 
was the dose that had previously controlled her disease. 
At any lower dose, she was felt to be in danger of faring. Teir patient also continued anakinra through the 
transplantation.
Dr. Quartier described that the French team tapered 
the dose of steroids during the pre-transplant conditioning regimen. Tey stopped the immunosuppressive treatments before HSCT, with the exception of emapalumab 
that was continued several weeks after HSCT in the second French patient.
 Risk Post-Transplant MAS. Two of the teams reported 
MAS post-transplant (Case 1 and Case 2). Case 1 had just 
1 episode, treated with cyclosporin. Case 2 had multiple 
episodes that were resolved with steroids pulses and ultimately, dexamethasone pulse. One of the cases (Case 5) 
reported a fare during conditioning regimen, pre HSCT, 
and she was re-started on anakinra. Te team for Case 9
reported a post-transplant episode of lung disease where 
it was unclear if it was MAS or another reason. Tat episode did resolve after treatment with steroids. Additionally, two patients (Case 6 & Case 8) who both had history 
of MAS were treated with emapalumab right before 
transplant and a few doses post-transplant.
 Improvement in Lung Disease post-transplant. Te 
Toronto/Ottawa team had seen signifcant improvement 
in the chest CT a year after the transplant. Te patient, 
however, remained on ruxolitinib post-transplant, and 
there was a question as to whether the improvement in 
the lung disease was due to HSCT or to the ruxolitinib. 
Indeed, ruxolitinib has been efective for lung disease in 
primary immunodefciencies like CT04. Tis also raised 
a second question whether ruxolitinib should be used for 
lung disease in SJIA before transplant in general. Dr. Wall 
mentioned that their patient had failed a diferent JAKinhibitor prior to the transplant. Currently, the team is 
happy with the lung response and does not want to discontinue ruxolitinib. Te fascinating part for them was 
that they had started sirolimus for an atypical rash for 
GVHD, and the rash exploded. Tey stopped sirolimus 
and went to ruxolitinib and the rash melted away. Overall, the team felt humbled with the results of this challenging transplant. Tey emphasized the importance of 
controlling the infammation pre-transplant and continuing the medications as part of GVHD prophylaxis. Dr. 
Roth added that he had been surprised by how reversible 
the advanced lung disease was in their patient. Even if 
some of this improvement could be attributed to the ruxolitinib, his team felt that most of the beneft was coming from resetting the immune system via HSCT. He also 
mentioned that they are increasing the use of ruxolitinib 
in patients for MAS.
 HLA Type. Dr. Canna also raised the question about 
the role of HLA-DRB1*15 which has recently been identifed as a risk factor for the lung disease in SJIA patients
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[2]. He was wondering whether the HLA type should be 
taken into consideration while looking for a donor. Dr. 
Prockop replied that typical donor HLA matching done 
for HSCT is more important for transplant outcome than 
considering the SJIA-LD HLA type as a way to screen 
donors.
 Long term morbidity. Dr. Nigrovic raised the issue of 
long-term morbidity after transplant, particularly secondary malignancies. Te BMT specialists pointed out 
that they did not see any such issues in their cases so far, 
though it is too soon to tell with this current cohort. Dr. 
Marsh thought that there was a risk of secondary malignancies, while Dr. Wall pointed out that so far, there were 
no reports of second malignancies for pediatric patients 
with infammatory disorders undergoing HSCT.
 Autologous Transplant. Dr. Canna next raised the 
question of whether autologous transplantation should 
be considered for these patients. Dr. Silva pointed out 
that autologous transplants were performed in SJIA in 
the past, but there were several relapses, and/or patients 
did not go into remission. Dr. Wall added that a reset of 
the immune system might be sufcient for adult patients, 
but not for pediatric patients (where genetic defects are 
more likely to be part of the pathology compared with 
adults), and therefore they need an allo-HSCT.
Dr. Abinun added that with autologous transplantation cases, MAS was a major issue in these patients, and 
that reducing infammation (pre-transplant) was the 
way to solve this problem. He mentioned that the Dutch 
group was closely studying the immune reconstitution 
following autologous transplantation and hopefully this 
research would provide more answers in the future.
 Control of infammation before HSCT, Chimerism 
and SJIA remission. Te importance of a good control of 
infammatory activity prior to HSCT was again brought 
up by several BMT specialists. Dr. Abinun commented 
that most issues he sees in these patients during transplantation are infammation-related, and the same issues 
can also have an impact on the post-HSCT course including chimerism. He also fnds is disheartening that even 
full donor chimerism in SJIA patients after HSCT, does 
not mean that the disease is cured. Perhaps, this suggests 
a role for non-hematopoietic cells in the development 
of SJIA. He discussed these issues in more detail in his 
recent publication [9].
 Insurance issues. All teams reported that they did not 
have insurance issues in HSCT getting approved. Dr. 
Marsh mentioned that for other similar patients who 
have an inborn error of immunity and no genetic diagnosis, they usually send a letter to the insurance company 
as part of the transplant package. It might take a followup conversation with someone at the insurance company 
but typically it’s not a barrier.
 Conditioning for refractory SJIA associated with liver 
disease. One of the parents asked about HSCT in patients 
with SJIA and liver involvement. Several BMT experts 
agreed that for patients with liver disease, there is a need 
to adjust the conditioning agents used.
Summary and future directions In summary, the entire 
group of the participants agreed that there is a subset of 
patients with refractory systemic JIA, who have failed 
all available medications and are likely to beneft from 
HSCT. Te increasing experience with HSCT in SJIA, 
suggests that despite the complicated post-HSCT course, 
short-term, the transplanted patients either achieved SJIA 
remission (or reduced burden of disease) with improved 
lung function. Longer follow-up, however, is needed to 
better defne the long-term outcomes.
Te optimal timing for the procedure still needs to be 
determined, but the emerging consensus is that it should 
occur earlier before signifcant organ damage is accumulated. Te group unanimously agreed that BMT teams 
should be consulted early, and both Rheumatology and 
BMT specialists should work together to determine when 
HSCT is appropriate. Increased pre-HSCT organ damage, lungs in particular, decreases the chances for a successful outcome of the procedure. However, since lungs 
are the target organ in SJIA-LD, patients with moderate 
or even severe lung damage still may be eligible for the 
procedure.
Although reduced intensity conditioning regimens 
have improved the outcome of HSCT in general, there 
is a remote concern that such regimens may increase the 
risk of SJIA relapse after the transplantation. Long term 
registries should help address this question.
Te entire group agreed that a good control of infammatory SJIA activity prior to HSCT markedly increases 
chances to achieve a good outcome, and therefore, it is 
reasonable to continue SJIA/MAS medications until 
transplantation. Te need to continue these medications 
(emapalumab and Jak-inhibitors in particular) after the 
procedure still needs to be determined.
Abbreviations
ATG Anti Thymocyte Globulin
BMT Bone marrow transplant
PO By mouth, orally
CSF Cerebrospinal fuid
CR Complete Remission
CT Computerized tomography
CMV Cytomegalovirus
CTL Cytotoxic T cells
DLCO Difusing capacity of the lungs for carbon monoxide
DMARDS Disease-modifying anti-rheumatic drug
EBV Epstein-Barr Virus
GI Gastrointestinal
GVHD Graft-versus-host disease
HSCT Haematopoietic Stem Cell Transplantation
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HLA Human Leukocyte Antigen
ICU Intensive care unit
IL Interleukin
IV Intravenous
JIA Juvenile Idiopathic Arthritis
LD Lung disease
MAS Macrophage Activation Syndrome
MRI Magnetic resonance imaging
MSD Matched sibling donors
MUD Matched unrelated donors
mMUD Mismatched unrelated donors
MMF Mycophenolate mofetil
PR Partial remission
PJP Pneumocystis jiroveci pneumonia
PAP Pulmonary alveolar proteinosis
SJIA Systemic Juvenile Idiopathic Arthritis
TA-TMA Transplant-associated thrombotic microangiopathy
TMA Transplant-related toxicity
Acknowledgements
Mario Abinun for the valuable contribution to the discussion during the 
session.
Mariana Correia Marques for taking session notes.
About this supplement
This article has been published as part of Pediatric Rheumatology Volume 21 
Supplement 1, 2023: Proceedings from the 4th NextGen Therapies for SJIA and MAS 
virtual symposium. The full contents of the supplement are available online 
at https://ped-​rheum.biomedcentral.com/articles/supplements/volume-​21-​
supplement-1.
Authors’ contributions
All authors participated in the meetings’ discussions and were involved in the 
preparation of the manuscript. The fnal version was reviewed by all 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 infuence 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.
Declarations
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
AAG received research grants from Novartis and Sobi; consulting fees from 
Novartis and Sobi; royalties from UpToDate Inc. and payment for development of 
CME slide presentation on MAS from Clinical Viewpoints. SWC received investiga‑
tor-initiated research grants from Histiocytosis Association; consulting fees from 
Simcha Therapeutics, Apollo Therapeutics, SOBI; received payment for expert 
testimony from Parker Poe Adams & Bernstein LLP; received payment for lectures 
and educational events from PracticePoint communications and SOBI. RA, RS, LP, 
EC, BN, JR, JMFS, DW & UZ have no conficts of interest or competing interests 
to declare. SC received consulting fees from SOBI (SAB). KD has no conficts of 
interest or competing interests to declare. RM participated on the Advisory Board 
of SOBI and Horizon. KO received funding from CARRA (Childhood Arthritis 
and Rheumatology Research Alliance) for attending meetings and/or travel. SP 
participated in the Macrophage Activation Syndrome Adjudication Committee, 
Novartis Pharma, 2016–2022; and royalties from Op Med Fellow for Doximity Inc. 
SP received investigator-initiated research grants from PIDTC C-SIDE NIH Study 
Grant; consulting fees from CellEvolve (no fees), SmartImmune, ADMA; royalties 
from IP related to the development of 3rd party VSTs with all rights assigned to 
Memorial Sloan Kettering Cancer Center; received payment for lectures and edu‑
cational events from Regeneron and Pierre Fabre; participated in Advisory Board 
from Atara Biotherapeutics, Stanford Trial Specifc DSMB and NYBC Cord Blood 
Trial DSMB; received support for the conduct of clinical trials through Boston 
Children’s Hospital from Atara Biotherapeutics and Allovir. PQ received consulting 
payments from Abbvie, Amgen, BMS, Chugai Roche, Novartis, Novimmune, Pfzer 
and Sweedish Orphan Biovitrum; received funding for attending meetings and 
travel from BMS, Chugai-Roche, Novartis and Pfzer; and participated in a data 
safety monitoring board for Sanof. GS received investigator-initiated research 
grants from IpiNovyx; and received consulting fees from Novartis and SOBI.
Published: 5 January 2024
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    BMT in SJIA patients

    • 1. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 https://doi.org/10.1186/s12969-023-00868-x MEETING REPORT Open Access © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Pediatric Rheumatology Part 5: Allogeneic HSCT in refractory SJIA with lung disease; recent cases from centers in North America & Europe Alexei A. Grom1*, Scott W. Canna2†, Rolla F. Abu‑Arja3†, Rashmi Sinha4†, Luciana Peixoto4†, Elvira Cannizzaro5†, Shanmuganathan Chandrakasan6,7, Kyla Driest8 , Rebecca Marsh9, Bénédicte Neven10,11, Karen Onel12, Sampath Prahalad6 , Susan Prockop13, Pierre Quartier10,11, Johannes Roth14, Grant Schulert1, Juliana M.F. Silva15, Donna Wall16 and Ulrike Zeilhofer17 From 4th NextGen Therapies for SJIA and MAS virtual symposium Virtual. 16-18 February 2022. https://www.systemicjia.org/nextgen22/ Abstract It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may beneft from HSCT. The increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remis‑ sion or reduced burden of disease. Longer follow-up, however, is needed to better defne the long-term outcomes. The discussion at the NextGen 2022 conference was focused on the optimal timing for the procedure, the need for a good control of infammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regi‑ mens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplanta‑ tion. There was unanimous agreement about the importance of long-term registries to address these questions. Keywords Allogeneic HSCT, Refractory SJIA, SJIA-LD, MAS, HLA DRB1*15 alleles † Scott W. Canna, Rolla F. Abu-Arja, Rashmi Sinha, Luciana Peixoto and Elvira Cannizzaro contributed equally. *Correspondence: Alexei A. Grom Alexi.Grom@cchmc.org 1 Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA 2 Rheumatology & Immune Dysregulation, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA 3 Department of BMT, Nationwide Children’s Hospital, Columbus, OH, USA 4 Systemic JIA Foundation, Cincinnati, OH, USA 5 Department of Rheumatology, University Children’s Hospital, Zurich, Switzerland 6 Department of Pediatrics, School of Medicine, Emory University, Atlanta, GA, USA 7 Afac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA 8 Department of Rheumatology, Nationwide Children’s Hospital, Columbus, OH, USA 9 Division of Bone Marrow Transplantation and Immune Defciency, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 10 Pediatric Hematology‑Immunology and Rheumatology Department, Necker-Enfants- Malades University Hospital, Paris, France 11 Université Paris-Cité, Paris, France 12 Department of Rheumatology, HSS, New York City, NY, USA 13 Dana Farber/Boston Childrens Hospital Center for Cancer and Blood Disorders, Boston, MA, USA 14 Kantonsspital Luzern, University of Luzern, Luzern, Switzerland 15 Department of BMT, Great Ormond Street Hospital for Children, London, UK 16 16. Blood and Marrow Transplant/Cellular Therapy, Division of Haematology/Oncology, Hospital for Sick Children Toronto, Toronto, Canada 17 Department of BMT, University Children’s Hospital, Zurich, Switzerland
    • 2. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 2 of 13 Introduction In the last decade, the discovery that IL-1 & IL-6 are key therapeutic targets in systemic juvenile idiopathic arthritis (SJIA) and the introduction of IL-1 and IL-6 inhibiting biologics have led to a dramatic improvement in the outcome of typical features of this disease. At the same time, starting with the publication by Kimura in 2013, there has been a growing recognition of a subset of children with mostly systemic disease who are refractory to biologics and develop recurrent macrophage activation syndrome (MAS) as well as a seemingly new life-threatening pulmonary complication (SJIA-LD). Tese patients typically stay on multiple immunosuppressive medications, are corticosteroid-dependent, face high risk of infection, steroid side efects, and relentless disease progression. Te earliest reported mortality rate in this group was as high as 68% [1], though later reports are less pessimistic: Saper et al. [2], estimate fve-year survival at 42% while Schulert et  al. [3], are seeing 95% survival rate in the cohort of patients followed by their group. Despite lower mortality rates, good disease control in these patients is still hard to achieve. Given limited understanding of the underlying pathology, these patients are empirically treated with multiple immunosuppressive medications including both biologic and non-biologic DMARDs, while remaining on daily steroids. Further, there is a suspicion that the IL-1 and IL-6 inhibiting biologics may contribute to the development of the lung complications. In general, the level of immunosuppression in these patients is unsustainable long-term. Numerous infections, corticosteroid side effects and frequent admissions lead to a dramatically decreased quality of life. Marked growth retardation with complete growth cessation in some patients contribute to social isolation and depression. As a result, hematopoietic stem cell transplantation (HSCT) has emerged as a potential alternative therapeutic strategy. Te earliest report of hematopoietic stem cell transplantation (HSCT) in an SJIA patient with pulmonary disease was published in 2018, followed by a few case reports. Since 2021, however, based on the information available through patient-driven networks, the idea of HSCT has become more acceptable to both parents of SJIA patients as well as the medical teams caring for SJIA patients. Improved conditioning regimens have led to the hope that re-setting the immune system through HSCT would lead to a complete remission of the systemic JIA and associated lung disease thus abolishing the need for immunosuppressive medications and corticosteroids. Teams with expertise in HSCT for SJIA that typically including both a rheumatologist and bone marrow transplant (BMT) specialist, were invited to participate in the NextGen 2022 session focused on HSCT in SJIA with lung disease. The parent perspective was shared by two parents of SJIA patients who underwent transplantation. Finally, Dr. Silva who had published a case series on allogeneic transplantation in JIA (which included some SJIA patients) in 2018 was invited to present the long-term follow-up data on patients from that cohort. Te goals of this NextGen session were to explore whether HSCT could be an efective strategy for patients who have become dependent on steroids and are on unsustainable levels of immunosuppression, or whose lung disease is progressing. Te key questions were: 1. Since preservation of good pulmonary function is an important predictor of good outcome, can HSCT be done safely in patients with SJIA-LD whose lungs are already damaged? Te degree of lung damage varies between SJIA-LD patients with many of them requiring night-time or full-time oxygen supplementation. Furthermore, some patients need tracheostomy and are ventilator dependent. Can these patients withstand HSCT? 2. Te innate immune cell activation appears to be the driving force in refractory SJIA pathology suggesting that bone marrow derived cells are key players in this disease. On the other hand, one of the main risk factors for the lung disease in SJIA is strikingly high levels of serum IL-18. Although the sources of IL-18 in SJIA have not been fully defned, there is some data suggesting that it is coming not only from the bone marrow- derived cells but also from the barrier tissues such as the epithelium gut. If this were the case, would HSCT be efective at controlling the immune disease and normalizing IL-18? 3. Phenotypically, the lung disease in these patients is a distinct type of interstitial lung disease with interstitial lymphocytic infltration and features of pulmonary alveolar proteinosis that is typically caused by dysfunction of macrophages. Can re-setting the immune system help control the lung disease? Will it stop LD progression and reverse some of the dam-
    • 3. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 3 of 13 age? Most of the previous experience with HSCT in SJIA is based on patients who did not have lung disease, so at this stage it is not clear what impact of HSCT on the lungs might be. 4. Another critical question is the optimal timing of the HSCT. Pre-HSCT organ damage, particularly pulmonary dysfunction, decreases the chances for a successful outcome of the procedure. Does moderate or severe lung damage mean that these patients are no longer good candidates for HSCT? If HSCT is indeed indicated, at what stage should it be considered? After failing multiple lines of approved medications? Should other nonapproved medications be tried first, or is it preferable to proceed with HSCT before organ damage reaches a certain degree? Indeed, the rate of lung disease progression varies between patients - some do not acquire much lung damage after years of SJIA-LD diagnosis, while others are admitted to the ICU at the time of the initial discovery of lung involvement. Transplantation in SJIA ‑ a brief background Autologous transplantation in SJIA Between 1999 and 2007, multiple groups in Europe reported on treatment with autologous transplantation [4, 5] for patients with severe refractory arthritis and chronic inflammation. These patient cohorts were resistant to all drugs and had become steroid dependent. Transplant outcomes were mixed. Some patients did achieve remission, but there was also significant morbidity (especially disease relapse and MAS) and mortality. Allogeneic transplantation in SJIA In 2018, Dr. Silva and colleagues published a set of case studies of Allogeneic HSCT in refractory SJIA & JIA from Europe & US [6]. Notably, those cases had been diagnosed either as RF-negative Poly JIA or SJIA. They either had unremitting arthritis and/or MAS or were steroid dependent. Dr. Silva’s review highlighted that allogeneic transplantation could be effective in JIA & SJIA and lead to disease remission, though there were some relapses. The HSCT in SJIA-Lung Disease session was introduced by the moderator Dr. Scott Canna. Parent participants were Luciana Peixoto & Pauline Acevedo. Long-term follow-up of allogeneic HSCT cases in SJIA was presented by Dr. Juliana Silva. Case presentations were provided by Elvira Cannizzaro & Ulrike Zeilhofer, Johannes Roth & Donna Wall, Karen Onel & Susan Prockop, Pierre Quartier & Bénédicte Neven, Kyla Driest & Rolla F. Abu-Arja, and Grant Schulert & Rebecca Marsh. Understanding the patient experience with HSCT Parents of two children diagnosed with SJIA-LD, who had undergone HSCT recounted their experience. Tey shared their child’s disease history, how the families and medical teams came to the decision to proceed with HSCT, the experience during transplantation, complications, and fnally, their lives after HSCT. Patient story 1 Parent participant: Luciana Peixoto Mrs. Peixoto’s daughter, Beatriz, with previously normal health, was diagnosed with SJIA in September 2013 at Zurich Kinderspital. She was 11 years old at the time of diagnosis. For the next 5 years, her medical team tried several medications including multiple biologics, but could not control her fares completely and they were unable to wean her of steroids. Beatriz had one overt MAS episode and multiple episodes of sub-clinical MAS. Additionally, she had adverse reactions to biologics (rash and liver enzyme elevation) and numerous side efects from highdose steroids prompting initial discussions about HSCT for her difcult to control disease. In 2016, after a drop in oxygen saturation, Beatriz was diagnosed with pulmonary hypertension and lung disease. She was mostly on prednisolone at this point (as there were no further medication options available at that time). Her quality of life was poor. When her medical team brought up the idea of HSCT again, the family and the patient herself were in agreement that HSCT was the best option. Mrs. Peixoto gained further confdence in the plan after learning that her medical team had consulted with Dr. Juliana Silva from Newcastle who was following a case series of HSCT in SJIA. Her team was planning to follow the same protocol. Additionally, her team had identifed a suitable unrelated HLA matched donor, and had a backup plan of using the patient’s own stored cord blood stem cells if the allogeneic transplantation were not successful. Te transplantation performed in March 2018 went relatively well, with side efects that included hair loss, mucositis, fever, low kidney function, increased need for oxygen, morphine for pain, and blood transfusions. Beatriz was discharged home on Day+30. About two weeks later she developed three vertebrae compression fractures due to osteoporosis and was in a lot of pain. At some point, the fever came back (MAS episode was suspected). She was admitted to the hospital for three
    • 4. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 4 of 13 more weeks and started to recover. Her lungs improved and over the next year, all signs of pulmonary hypertension resolved. Four years post-transplant, Beatriz remains on Spiriva for lungs and hormone patch. She is a healthy young adult studying biochemistry and hoping to work as a researcher in drug development for rare diseases. Patient story 2 Parent participant: Pauline Acevedo Mrs. Acevedo’s daughter, Valentina, was initially diagnosed in 2013 with atypical Kawasaki. Next, familial hemophagocytic lymphohistiocytosis was suspected. Finally, at the age of 18 months, she was diagnosed with SJIA. For the next four years, in spite of multiple medication changes (including multiple biologics) and high-dose steroids, her disease remained poorly controlled. In 2016, the parents started noticing digital clubbing and a persistent dry cough. A year later, a bronchoscopy and lung biopsy, performed at Cincinnati Children’s Hospital, confrmed the diagnosis of Interstitial Lung Disease & Pulmonary Alveolar Proteinosis. The biologics were stopped based on the suspicion that they were causing the lung disease (later they confirmed that her daughter carries the HLA type associated with SJIA-Lung Disease). Valentina stayed on jak-inhibitors and cyclosporine, but her physicians were unable to reduce oral steroids and she suffered from many side effects. In consultation with her medical team, the family decided to proceed with HSCT primarily due to not being able to wean steroids and uncontrolled SJIA. She was 9 years old when her frst HSCT was performed in April 2021. Although her donor was fully matched (10/10), she rejected the graft. Te team started a search for another donor and the best option available was to use her 5/10 haploidentical father. Tis second was performed in May 2021. Te complications included central line infection, mucositis, an increased oxygen requirement, an ICU stay for 3 days, and mild GVHD. She stayed in the hospital for almost 4 months. Since the HSCT, she has been doing well and has been mostly off steroids (now on a small dose of hydrocortisone due to adrenal issues from long-term usage of steroids). She has grown almost 3 inches and the digital clubbing is improving. Of note, her lungs are showing some nodules which doctors think are infection-related (perhaps PJP). She remains asymptomatic, but the team is following closely and doing chest CTs every two months. The family reports that Valentina looks and feels healthy and has a much better quality of life. Long term follow‑up from earlier study of allo‑HSCT in SJIA published by Silva et al., in 2018. Presenter: Juliana Silva (BMT), GOSH, United Kingdom Dr. Silva presented a review and update of the patients from her previous publication [6] that included 16 patients with SJIA who underwent allogeneic HSCT from fve European and US centers. Of the 16 patients, 5 had rheumatoid factor–negative polyarticular JIA, and 11 had SJIA refractory to standard therapy. Of the 11 SJIA patients, 5 also had a history of MAS, and 2 had failed previous autologous HSCT. Te median follow-up was 2 ½ years. Eight patients were transplanted with matched unrelated donors (MUD), 4 with matched sibling donors (MSD), and 4 with mismatched unrelated donors (mMUD). Reduced toxicity conditioning regimens were mostly used with Fludarabine, Melphalan, and Campath in 10 patients and Fludarabine, and Treosulfan in 6 patients. Below are summary long-term results for the patients transplanted by 3 of the centers: Te Great Ormond Street Hospital (GOSH) experience: Tis center transplanted 5 patients. Four of them achieved Complete Remission (CR), while 1 died due to transplant-related toxicity. Tis patient had a previous autologous stem cell transplant. Two of the four surviving patients relapsed post-HSCT. One patient relapsed 2-year post-transplant with macrophage activation syndrome (MAS) that was treated and responded well to corticosteroids. Tat patient is now 8-years post HSCT and remains in complete remission (CR). Te second patient relapsed 10 years post HSCT and is now on treatment for arthritis. Te Newcastle experience: Te team reported 8 patients. Two patients achieved CR at 0.66 years (and at last follow-up, 9 years post-HSCT), and they remained in complete remission (CR). One patient achieved partial remission (PR), 3 patients relapsed (relapses were late at 1, 2, and 3 years post-HSCT), 1 patient died from transplant-related toxicity (TMA), and 1 patient had no response (after HSCT this patient was diagnosed with PRG4 mutation - Camptodactyly-arthropathy-coxa vara-pericarditis syndrome). The UCLH experience: The center performed HSCT for 3 patients. All achieved CR. One patient had declining chimerism 6 months post HSCT with autologous reconstitution but remains in clin-
    • 5. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 5 of 13 ical CR. One patient is only 2 months post-transplant in CR and it is too early to evaluate his longterm outcome. Te CCHMC experience: Te team from CCHMC described two patients transplanted at CCHMC, who are 13, and 8 years post-HSCT respectively. Both are doing well and remain in remission.  In summary, 16 patients received allo-HSCT for SJIA. Te median follow-up is 8.5 years. Eleven patients achieved CR, 2 PR, and 1 patient had no response (who was later found to have PRG4 mutation). Tere were 2 deaths due to transplant-related toxicity. Six patients relapsed (time to relapse post-transplant ranged from 1 to 10 years). Dr. Silva noted that although these results show some promise, there are many unanswered questions. More data is needed to understand how to identify the subgroup of patients that will benefit from HSCT and to define the optimal timing for transplantation. Additionally, it is important to understand why some patients relapse after several years. Future prospective studies are needed to address these questions and to standardize transplant procedures. Brief reports of new cases presented at NextGen 2022 conference Overall, 9 cases of HSCT for refractory SJIA were presented from 6 teams. Of the 9 patients, 5 had SJIA-Lung Disease, 1 case had some lung involvement with normal CT, 1 case had pneumonitis, while the other 2 cases were of refractory SJIA without lung disease. Six of the 9 patients had the HLA type (HLADRB1*15) that has been associated with SJIA-Lung Disease. A brief description of each case presented at the conference follows next. The Zurich experience: 3 cases of HSCT in SJIA, 2 with SJIA‑Lung disease Presenters: Elvira Cannizzaro (rheumatologist) & Ulrike Zeilhofer (BMT), University of Children’s Hospital Zurich, Switzerland Case 1 Te frst patient was an 11-year-old female diagnosed with SJIA who had initially presented with fever, rash, splenomegaly, and hyperferritinemia. She was initially treated with prednisone, methotrexate and tocilizumab then switched to canakinumab, anakinra, and cyclosporin, with frequent prednisone pulses over 4.5 years. Despite higher doses of canakinumab, the patient was having recurrent MAS episodes and developed persistent infammation with signs of chronic, interstitial lung disease. She later developed pulmonary hypertension. She remained steroid-dependent leading to signifcant side efects including osteoporosis, cataract, and growth stagnation. Additionally, she had an anaphylactic reaction to solumedrol IV and was switched to dexamethasone. Despite aggressive treatment with biological therapy, she had recurrent MAS and interstitial lung disease with pulmonary hypertension. In 2018 (about 4.5 years into her disease), she received a 9/10 MUD transplant with a conditioning regimen that included Fludarabine (30 mg/m2/day from days −8 to -3) and (Treosulfan 14 mg/m2/day from days −5 to -3). For GVHD prophylaxis she received Campath (0.2  mg/m2/ day from days −8 to-4), cyclosporin, and mycophenolate. She remained on dexamethasone through transplant for 2 months. Te patient’s initial course was uneventful. She attained neutrophil engraftment on Day+22 with 100% donor chimerism but later developed severe back pain with MRI fndings of several osteoporotic vertebral bone fractures. She was treated with opiates and bisphosphonate infusions. Next, she developed CMV reactivation with secondary MAS with pancytopenia. Due to severe osteoporosis, she was treated with cyclosporin to avoid prednisone. Her recovery was slow, but she achieved full remission with improved lung function with no overnight oxygen requirement and resolving pulmonary hypertension with full donor chimerism on the last follow-up (3 years after transplant, last chimerism check was in June 2019). Case 2 Te second patient was a 2 ½ years old male with a similar disease presentation including fever, skin rash, recurrent MAS, splenomegaly, and severe arthritis leading to immobility with interstitial lung disease (ILD) and oxygen dependency. He received a 12/12 HLA MUD transplant with the same conditioning regimen as Case 1 above. He attained neutrophil engraftment on Day+20 but had a more complicated initial course with severe nausea, mucositis, several episodes of neutropenic fevers, HHV6 reactivation, E-coli sepsis, and several vertebral fractures. Following his initial discharge, he developed recurrent post-transplant MAS which was treated with methylprednisolone and then switched to dexamethasone per the HLH protocol, with a slow taper and no recurrence of MAS. On the last follow-up, he was found to have mixed donor chimerism (CD14 86% and CD3 76%) but he was doing clinically well of immunosuppression with improved lung disease and quality of life. Both Cases 1 & 2 were of patients with refractory systemic JIA who were steroid-dependent leading to the development of signifcant side efects including osteoporosis, cataract, and growth stagnation. Despite aggressive
    • 6. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 6 of 13 treatment with biological therapy, they both had recurrent MAS and interstitial lung disease. Although both patients had a complicated transplant course both patients have achieved full remission and are doing well post-transplant. Case 7 Te most recent case from Zurich is of a 3-yearold girl transplanted in November 2020. She had multiple MAS episodes, polyarthritis, was steroid dependent (with severe side efects). She also had allergic reactions to several medications. She was transplanted with the same conditioning regimen as the frst 2 patients from Zurich: Treosulfan / Fludarabine/ Campath. Her match was 10/10 matched unrelated donor and the transplantation course was uneventful. However, all donor cell lines (CD14, CD 15, and CD3) dropped around 3–4 months after transplantation. At frst, the arthritis was still controlled, but once steroids were stopped, she relapsed with her JIA that was again difcult to control. Te team decided to proceed with a second HSCT which was performed in November 2021. She had another 10/10 matched unrelated donor. Tis time, the team decided to use a more intense conditioning regimen: Busulfan/Cyclophosphamide/ATG. Te transplantation course was initially uncomplicated, but in January 2022, she had a generalized seizure and was diagnosed with EBV encephalitis. Although clinically she appeared well, there were concerning fndings in the MRI and CSF. She was treated with Valcyte, Rituximab, and one dose of CD45+RO cells with a good response. Currently, chimerism is at 100% percent for all cell lines. Steroids were stopped at the end of January 2022, but it remains too early to assess if the second HSCT will lead to long disease remission. The Paris experience: 1 case of Haploidentical HSCT in SJIA Presenters: Pierre Quartier (Rheumatology) & Bénédicte Neven (BMT), Necker‑Enfants‑Malades University Hospital, Paris, France Case 3 Te team presented 2 patients, a case of HSCT for refractory SJIA performed 5 years ago [7] as well as a second HSCT for a refractory SJIA patient, who was transplanted very recently. Tis center had previous experience with autologous transplantation in a few patients with severe Still’s Disease, but the patients presented with numerous complications after transplantation and continued to have fares. Teir frst allogeneic transplantation in 2017, was a female SJIA patient, 3.7 years old who fulflled the eligibility criteria for HSCT. She had a severe systemic disease but did not have interstitial lung disease. She had proven refractory to both IL-1 and IL-6 blockers, as well as to thalidomide, methotrexate, and infiximab. Te mother was the donor (although she had vitiligo), as there was no other donor available. Te haploidentical bone marrow transplantation was performed with a conditioning regimen of busulfan, fudarabine, campath, and post-transplant cyclophosphamide. She achieved full donor chimerism, but several complications occurred in the post-transplantation course: acute skin and gastrointestinal GVHD (treated with steroid therapy), infections and thrombocytopenia treated with intravenous immunoglobulins. At last follow-up, apart from vitiligo and asymptomatic hypothyroidism, the patient achieved full remission from arthritis and systemic disease with 100% chimerism. Te other SJIA patient was transplanted 2 months ago. She is a 3-year-old with SJIA. She has had recurrent MAS and her disease has proven refractory to IL-1 blockers, tocilizumab, and baricitinib. After a severe SJIA fare without MAS, sirolimus was introduced. She has been on emapalumab for MAS and high-dose steroids. Te patient had very high IL-18 levels consistent with the phenotype of young children who do not respond to biologics and are at risk of lung disease. The Columbus experience: 1 case of HSCT in SJIA with lung involvement Presenters: Kyla Driest (Rheumatology) & Rolla F. Abu‑Arja (BMT), Nationwide Children’s Hospital, Columbus, United States Case 4 Te team at Nationwide Children’s Hospital presented a 16-year-old female patient who initially presented with fever, rash, and arthritis [8]. Te patient was initially diagnosed with Celiac disease and then, SJIA. She was started on prednisone and etanercept. Due to continued arthritis, etanercept was replaced with tocilizumab followed by adalimumab. Te patient had multiple admissions for fevers that were treated as infections with antibiotics while holding biologic therapy. On her 4th admission (5 months after the initial diagnosis) she developed overt MAS and her treatment regimen was changed to the combination of cyclosporin and canakinumab. Her care was transferred to Nationwide Children’s at this point. Given the continued disease activity and side efects, cyclosporin was replaced with lefunomide and hydroxychloroquine. Te Canakinumab dose was
    • 7. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 7 of 13 increased to 300 mg every 4 weeks and then to 500 mg every 4 weeks due to smoldering MAS. She was then admitted for a severe MAS fare with limited response to high-dose solumedrol (1-gram IV Q daily). Next, her treatment was changed to anakinra, dexamethasone, IVIG, and tacrolimus. During this time, she started showing signs of dyspnea on exertion. Pulmonary function testing revealed low DLCO and mild obstruction with normal chest CT and echocardiogram. At the age of 20, in 2018, she received an allogeneic bone marrow transplant from a 30-year-old male 10/10 HLA MUD using a reduced-intensity conditioning regimen (Intermediate Alemtuzumab 0.3  mg/kg/dose SQ for 3 days (days −14 to -12) Fludarabine 30  mg/m2/ dose for 5 days (days −8 to -4) and Melphalan 70 mg/ m2/dose for 2 doses (days −2 and −1)). GVHD prophylaxis consisted of tacrolimus and methylprednisolone while she continued anakinra daily until engraftment and discontinued hydroxychloroquine before the start of the conditioning regimen. She achieved engraftment on Day+9 and was discharged on Day+14. Her peripheral blood chimerism was 99–100% donor in all cell lines. Complications included Grade 1 skin GVHD treated with topical corticosteroid therapy. She also developed EBV reactivation on Day 100 for which she received Rituxan which caused B cell aplasia lasting for 1 year. She was weaned of tacrolimus at 6 months post-transplant and prednisone at 18 months due to secondary adrenal insufciency. Due to prolonged prednisone use, she had slow immune reconstitution and remained on replacement IV immunoglobulin for 2 years post-transplant. Based on the last follow-up, the patient is now 3 ½ years post HSCT with complete resolution of arthritis, improvement in lung function, and DLCO. She is of immunosuppression with full immune reconstitution. Her Celiac disease has resolved. The Emory‑Atlanta experience: 1 case of HSCT in SJIA Presenters: Sampath Prahalad (Rheumatology) and Shanmuganathan Chandrakasan (BMT), CHOA, Emory‑Atlanta, United States) Case 5 Tis case from Emory was that of a 19 year old African-American female referred for HSCT due to refractory SJIA, complicated by multiple MAS fares, and bacterial infections (primarily cutaneous abscesses). Her disease started at the age of 14 years and quickly evolved to a steroid-dependent SJIA state despite treatment with anakinra, tocilizumab, methotrexate, and cyclosporin A. During the year preceding the HSCT, she had fve MAS fares, with two of them requiring an ICU admission. Her course was also complicated by CMV viremia and pneumonitis treated with ganciclovir. Many of her MAS/SJIA fares were also associated with muscle enzyme elevation. An immunologic workup revealed very high IL-18 levels (>200,000). In addition, a workup for HLH revealed a single allele mutation in STXBP2 and LYST, but her CD 107 degranulation assay (a test for the functional integrity of the cytotoxic T cell degranulation (CTL) pathway) was normal. Based on that, primary HLH phenotype was felt unlikely. Due to the refractory disease course, the team elected to proceed to allogeneic HSCT as a potentially curative option. At the age of 19 years, the patient underwent 9/10 mismatched unrelated PBSC graft HCT following Campath/ Flu/ Mel/ Tiotepa conditioning. Peri-conditioning (despite Campath and fudarabine), she had a disease fare. Due to this fare during conditioning, she was restarted on anakinra. She achieved engraftment on Day 11 with 100% donor cells in T and myeloid compartment. Her IL-18 levels improved from >200,000 to 903 two months post HSCT and remained below 2000 thereafter. Her disease course was complicated by acute Grade III GVHD of the GI/ Skin, posterior reversible encephalopathy syndrome, and TA-TMA (Transplant-associated thrombotic microangiopathy) leading to worsening renal function requiring hemodialysis and later CVVH. Her aGVHD was managed with pulse steroids, infiximab, and extra corporeal photopheresis with a partial response and continuous steroid-dependent state. She also developed CMV pneumonitis and viremia. Her TA-TMA was managed with eculizumab. Despite aggressive support, she had progressive cardiorespiratory worsening and died on Day+133. Postmortem evaluation revealed extensive thrombotic microangiopathy with difuse bilateral kidney necrosis with microthrombi and difuse alveolar damage with hyaline membrane, difuse pulmonary hemorrhage, and numerous thrombi of diferent stages and small and large intestine with focal ischemic necrosis with microthrombi. Based on the autopsy, the death was primarily caused by refractory TA-TMA. The Toronto/Ottawa experience: 1 case of HSCT in SJIA‑Lung Disease Presenters: Johannes Roth (Rheumatology), University of Ottawa & Donna Wall (BMT), University of Toronto, Canada Case 6 Te team from Canada presented a patient who received an allo-HSCT in 2020. It was a female who
    • 8. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 8 of 13 initially presented at the age of 3.5 years with high fevers, rash, and arthritis followed by pancytopenia, high ferritin leading the diagnosis of MAS. She was initially treated with a combination of prednisone, IVIG, and anakinra. Cyclosporine was added with no response. Anakinra was then replaced with tocilizumab, but she developed an adverse reaction to this medication, and was then switched to high dose canakinumab. Genetic panel testing was negative with whole-exome sequencing showing a variant of unknown signifcance in the NLRC4 gene. Tis variant was also present in the mother and was ultimately deemed as likely not pathogenic. About 2 years into her disease course, she developed clubbing and lung disease. A lung biopsy confrmed the distinct phenotype associated with pulmonary alveolar proteinosis typically seen in patients with SJIA-Lung Disease. Initially, the lung disease was stable, but a year later she had another episode of severe MAS that triggered further progression of the lung disease and she became oxygen dependent. Te patient participated in a trial of an anti-IL-18 agent but dropped out in the double-blind phase of the trial and it is still unknown whether she received the drug or placebo. She was also treated with high doses of tofacitinib and emapalumab, with no clear response. Te decision to proceed with HSCT was not an easy one as she was on supplemental 3–4  L of oxygen and lungs were very infamed. It involved the family, multiple medical teams from other hospitals, as well as experts in bioethics. Tere was no active infection on pre-transplant bronchoscopy. Te team optimized immunosuppression, and decided to continue emapalumab, steroids, and anakinra though the transplant procedure as part of graft versus host prophylaxis, as well as to control the underlying infammatory process. She received a 10/10 HLA MUD peripheral stem cell transplant using a reduced toxicity conditioning regimen. Pretransplant immunotherapy (emapalumab, prednisone, and anakinra) was continued through the early transplant period. Her transplant course was complicated with signifcant worsening of pulmonary function requiring temporary ventilatory support and dialysis at time of engraftment. Although her transplant recovery was slow, she showed fast resolution of arthritis and was able to stop anakinra and emapalumab following engraftment. At 3 months post-transplant, she developed features of acute and chronic GVHD primarily involving the skin but had a quick response to ruxolitinib. Te patient is now 16 months post-transplant with full donor chimerism, no clinical GVHD, and mild thrombocytopenia. Her respiratory function is improving based on imaging, resolving clubbing, and decreased oxygen support. Case 6: Chest CT scan for lungs: Pre HSCT and 1-year post-HSCT The Cincinnati experience: 1 case of HSCT in SJIA‑Lung Disease Presenters: Grant Schulert (Rheumatology) & Rebecca Marsh (BMT), Cincinnati Children’s hospital, United States Case 8 Te female patient who, in 2013 at the age of 10 months presented with rash and fever and was initially diagnosed with Kawasaki disease but failed to improve despite treatment with IV immunoglobulins. At the age of 18 months, she developed MAS followed by arthritis and was then diagnosed with Systemic JIA. Te patient was initially treated with prednisone and cyclosporine but was unable to wean of prednisone. She was then started on tocilizumab, but had an infusion reaction, and was then switched to canakinumab. She had an excellent response initially but missed multiple doses due to recurrent infections and pneumonia. She developed chronic cough and clubbing with abnormal lung fndings on the chest CT scan. She continued to have recurrent MAS typically triggered by infections. A lung biopsy was performed and confrmed the diagnosis of SJIA-LD with PAP-like features. She remained resistant to biological therapy with worsening lung disease with overnight hypoxia, recurrent MAS,
    • 9. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 9 of 13 chronic steroid dependence, and drug toxicity including growth failure, hypertension, and infections. She received an allogeneic HSC transplant from a 10/10 HLA MUD using a reduced-intensity conditioning regimen of Alemtuzumab, Fludarabine, Melphalan, and thiotepa. Te graft was TCR a/b CD19 depleted and there was no GVHD prophylaxis. Te patient did well Initially and achieved neutrophil engraftment on Day+13 with 100% donor chimerism, however, she developed acute secondary graft rejection on Day+32. She received a second transplant 6 weeks following the frst transplant using a parental haploidentical donor, with ATG, fudarabine with post-transplant cyclophosphamide, cyclosporin, and mycophenolate for GVHD prophylaxis. Te patient did well with count therapy and 97% donor chimerism. Transplant complications included Grade 1 Stage 1 skin GVHD that responded well to steroids. Te patient is now 7 months posttransplant and is doing well of immune suppression without major complications and with no systemic infammation. Tere has been improvement in clubbing and cushingoid features. Case 8: Clubbing improvement: before and after HSCT (approximately 9 months) The New York experience: 1 case of HSCT in SJIA‑Lung Disease Presenters: Karen Onel (Rheumatology) & Susan Prockop (BMT), HSS/MSKCC/NYH‑WC, New York, United States Case 9 An 18-month-old male initially presented with fever, rash, and multiple-joint arthritis. For the next few years, his disease proved refractory to many medications, and he remained on high-dose steroids. At the age of 5 years, he was referred to MSKCC for consideration for HSCT. He was steroid dependent, refractory to IL-1 and IL-6 inhibitors (anakinra, tocilizumab, & canakinumab), mycophenolate, rilonacept, cyclosporin, and tofacitinib. His course was complicated by recurrent MAS, systemic hypertrophic osteoarthropathy, and interstitial lung disease with clubbing. Lung biopsy showed difuse lymphocytic infltration with alveolar proteinosis. At the time of referral, he was on daily prednisone dose of 1.2 mg/kg/day and monthly pulses of methylprednisolone 500 mg and cyclophosphamide. On genetic testing, he was found to have the HLADRB1*15, and candidate gene mutation (NLK). His lung disease continued to progress with evolving tachypnea and interstitial lung disease with cystic changes that led to the decision to move forward with allo-HSCT. His pre-transplant evaluation identifed low-level CMV on bronchoalveolar lavage (BAL), for which he received induction ganciclovir prior to starting conditioning for HSCT. Te patient received a haploidentical HSCT from his 7/10 mother using a conditioning regimen of Busulfan (PK 60  mg*h/L) Fludarabine, ATG, and Rituximab, with post-transplant cyclophosphamide on Days+3 and +4, tacrolimus, and MMF for GVHD prophylaxis. His transplant course was complicated with persistent fevers for the frst 2 weeks and at the time of engraftment on Day+21. Several weeks after engraftment he developed increasing respiratory distress with worsening of parenchymal changes by chest CT. A repeat BAL was negative for infections except for low-level CMV. His infammatory markers: CRP, Ferritin, and IL-6 levels were increased. He required admission to the pediatric intensive care and was placed on a high-fow nasal cannula. He received pulsed prednisone 1  mg/kg BID, resumed MMF and ultimately was discharged on overnight high-fow support. Te patient is now 8 months post-haplo-HSCT with full donor chimerism in all lineages. He remains on tacrolimus and MMF and weaning prednisone (at the time of the meeting on 0.2  mg/kg/day). His immune reconstitution is slow due to prolonged prednisone use. Te patient remains on aggressive pulmonary toileting but is no longer on high-fow nasal cannula. Te chest CT showed marked improvement of parenchymal changes. Summary of discussions Te discussion, moderated by Dr. Canna, was wide-ranging, touching on many aspects of the cases presented. Te main themes are summarized below. Will the most refractory SJIA patients beneft from HSCT? First, Dr. Canna raised the question of whether
    • 10. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 10 of 13 there was a subset of patients with refractory systemic JIA, who have failed all available medications, who could potentially beneft from HSCT. How can we identify those patients early? Te refractory SJIA patients presented at NextGen were dependent on high doses of corticosteroids despite multiple immunosuppressive medications. While this population had signifcant periHSCT complications, most have achieved SJIA remission or experienced a decreased burden of SJIA, and improved lung function. Te follow-up, however, has not been long enough to defne the long-term outcomes. Dr. Driest commented that rheumatologists, being aware of possible complications of HSCT, tend to keep looking for the next medicine with the hope that they will fnd the right one at some point. Given the number of drugs available as well as their possible combinations, this path can be very long. For their own patient, the team had changed medications multiple times and ultimately decided that it was time for a transplant rather than trying another combination. Dr. Onel recounted that initially, their team was not in favor of HSCT. However, as the lung disease was rapidly progressing, and lung transplantation was proposed as the next step - their thinking changed. Teir concern was that poorly controlled underlying SJIA would reduce chances for successful lung transplantation. Additionally, there was a concern that the infammatory process can reoccur in the transplanted lung leading to new lung damage. A better approach might be to arrest the child’s lung disease with the ultimate immune ablation provided by HSCT. What is the optimal timing for transplants? / How to transplant before it’s too late, especially for lung patients? Next, Dr. Canna raised a question about the ideal timing to perform HSCT. Is it after patients have failed the approved biologic and non-biologic DMARDs or after trying other available immunosuppressive medications? Te cases presented at NextGen varied in terms of SJIA duration at the time of HSCT (from 1.9 to 8.2 years) with diferent degree of organ damage and toxicities from treatment. For one of the patients, the transplant was such a risky procedure, that the fnal decision was made with the involvement of the bioethics team. Is there a way to identify these patients earlier in the course of the disease? A parent of an SJIA-LD patient raised the question about the clinical parameters that would make a patient no longer eligible for HSCT. Te consensus was that the fewer comorbidities would lead to fewer complications during HSCT. Conversely, a patient who spends years on corticosteroids and other immunosuppressants with frequent infections would be at higher risk for mortality, infections, and other side efects associated with HSCT. Additionally, physicians agreed that although decreased pulmonary and cardiac function was a major concern, it was still possible to go through a transplant even if the patient was tracheostomy-dependent and on oxygen supplementation (with reasonable ventilator settings). In such cases, the fnal decision should be made by a multidisciplinary team based on very thorough evaluation. Dr. Wall added that the transplant team must be prepared for numerous complications including ICU stays, especially if the patient had lung involvement. She added that for lung function, it is difcult to determine the exact cut-of point for HSCT eligibility when the lung is the target organ. Nevertheless, it is important to thoroughly evaluate lung function even if the imaging tests show severe lung infammation. Dr. Grom added that SJIALung patients often might be doing well and have preserved lung function despite impressive changes on high resolution chest CT. One additional consideration is specifc to patients with severe growth delays (even growth failure), who are unable to get of steroids. For such patients, there is a need for a window of time after transplantation to catch up with growth before their growth plates close. As an example, for the patient from Cincinnati who had been on corticosteroids continuously for 9 years prior to the procedure, it took 18 months to complete her steroid taper post-BMT. She started growing at 8 months after transplant. Need for early referrals to the BMT team. Te BMT specialists emphasized the importance of early referrals of refractory patients to their teams, so they can stay involved with the patient and assess donor options. Dr. Schulert from CCHMC shared that they were now referring any SJIA patients with a refractory course, who had failed both IL-1 and IL-6 blockade as well as jak-inhibition, to the BMT team. Plan for Retrospective Study and Need for Guidelines. Dr. Juliana Silva proposed starting a retrospective study with long-term follow-up of the cohort of transplanted SJIA-LD patients. She invited all the teams present to contribute to this efort that should include monitoring the rates of relapses and chimerism. She also emphasized the need for prospective studies of patients undergoing diferent standardized transplant procedures. Tus initially, the team used Flu/Melph/Campath as conditioning, but more recently they have changed the regimen to Fludarabine/Biosulphan with the hope that they would achieve better chimerism. Dr. Abinun added that the existing European governmental HSCT guidelines were very conservative. He also emphasized the importance of publishing each case study so we could learn from these patients and improve these guidelines.
    • 11. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 11 of 13 Is this group of patients too heterogeneous to draw conclusions from? Session participants had varied opinions about the heterogeneity of the refractory SJIA patients. Dr. Onel pointed out that there is a larger group of refractory SJIA patients who do not necessarily have lung disease but require multiple immunosuppressive drugs and cannot wean of steroids. She felt that refractory SJIA patients with parenchymal lung disease that have PAP features were a distinct and more homogenous group. Dr. Canna and Dr. De Benedetti thought that the SJIA patients with recurrent MAS associated with any organ involvement were on the same disease spectrum, even if the specifc organs involved were not the same. In contrast, Dr. Wall felt that the presented cohort of patients was still very heterogeneous with different mechanisms driving the disease. Tese diferent perspectives make it it difcult to come up with specifc guidelines. Conditioning Regimen and Chimerism. Te ideal conditioning regimen for HSCT for patients with SJIA has not been identifed. Specialists from two of the centers (Newcastle & Kinderspital) observed that the reduced intensity conditioning regimen utilizing treosulfan/ fudarabine might not be sufcient to ensure durable complete donor chimerism. Tis also came up in the long-term follow-up data presented by Dr. Silva where several of the patients relapsed and others had low chimerism. However, Dr. Silva pointed out that the relapse was not highly correlated with the drop in chimerism. Need to control infammation before HSCT and medications to be continued through transplant? Diferent teams had diferent opinions about the need for the continuation of the SJIA medications through the transplantation procedure. Te team from Canada emphasized the need for a full control of infammation prior to the transplant and GVHD prophylaxis. Teir patient was on anakinra and emapalumab prior to the transplant and continued these medications until engraftment. Te patient from CCHMC was on emapalumab before her second transplant. Te NYC team decided to keep the patient on PO prednisone (1.2  mg/kg daily), monthly pulses of IV steroids, and cyclophosphamide during the time period leading up to the transplant, but they tried to minimize immunosuppression at the time of the graft infusion. Minimizing immune suppression in the context of haploidenticalHSCT with post-transplant cyclophosphamide is critical to the success of this approach. Dr. Driest described their struggle with getting the dose of steroid right before the transplant for their patient who had been steroid dependent during the entire course of SJIA. Tey kept the patient on 20 mg of steroids as this was the dose that had previously controlled her disease. At any lower dose, she was felt to be in danger of faring. Teir patient also continued anakinra through the transplantation. Dr. Quartier described that the French team tapered the dose of steroids during the pre-transplant conditioning regimen. Tey stopped the immunosuppressive treatments before HSCT, with the exception of emapalumab that was continued several weeks after HSCT in the second French patient. Risk Post-Transplant MAS. Two of the teams reported MAS post-transplant (Case 1 and Case 2). Case 1 had just 1 episode, treated with cyclosporin. Case 2 had multiple episodes that were resolved with steroids pulses and ultimately, dexamethasone pulse. One of the cases (Case 5) reported a fare during conditioning regimen, pre HSCT, and she was re-started on anakinra. Te team for Case 9 reported a post-transplant episode of lung disease where it was unclear if it was MAS or another reason. Tat episode did resolve after treatment with steroids. Additionally, two patients (Case 6 & Case 8) who both had history of MAS were treated with emapalumab right before transplant and a few doses post-transplant. Improvement in Lung Disease post-transplant. Te Toronto/Ottawa team had seen signifcant improvement in the chest CT a year after the transplant. Te patient, however, remained on ruxolitinib post-transplant, and there was a question as to whether the improvement in the lung disease was due to HSCT or to the ruxolitinib. Indeed, ruxolitinib has been efective for lung disease in primary immunodefciencies like CT04. Tis also raised a second question whether ruxolitinib should be used for lung disease in SJIA before transplant in general. Dr. Wall mentioned that their patient had failed a diferent JAKinhibitor prior to the transplant. Currently, the team is happy with the lung response and does not want to discontinue ruxolitinib. Te fascinating part for them was that they had started sirolimus for an atypical rash for GVHD, and the rash exploded. Tey stopped sirolimus and went to ruxolitinib and the rash melted away. Overall, the team felt humbled with the results of this challenging transplant. Tey emphasized the importance of controlling the infammation pre-transplant and continuing the medications as part of GVHD prophylaxis. Dr. Roth added that he had been surprised by how reversible the advanced lung disease was in their patient. Even if some of this improvement could be attributed to the ruxolitinib, his team felt that most of the beneft was coming from resetting the immune system via HSCT. He also mentioned that they are increasing the use of ruxolitinib in patients for MAS. HLA Type. Dr. Canna also raised the question about the role of HLA-DRB1*15 which has recently been identifed as a risk factor for the lung disease in SJIA patients
    • 12. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 12 of 13 [2]. He was wondering whether the HLA type should be taken into consideration while looking for a donor. Dr. Prockop replied that typical donor HLA matching done for HSCT is more important for transplant outcome than considering the SJIA-LD HLA type as a way to screen donors. Long term morbidity. Dr. Nigrovic raised the issue of long-term morbidity after transplant, particularly secondary malignancies. Te BMT specialists pointed out that they did not see any such issues in their cases so far, though it is too soon to tell with this current cohort. Dr. Marsh thought that there was a risk of secondary malignancies, while Dr. Wall pointed out that so far, there were no reports of second malignancies for pediatric patients with infammatory disorders undergoing HSCT. Autologous Transplant. Dr. Canna next raised the question of whether autologous transplantation should be considered for these patients. Dr. Silva pointed out that autologous transplants were performed in SJIA in the past, but there were several relapses, and/or patients did not go into remission. Dr. Wall added that a reset of the immune system might be sufcient for adult patients, but not for pediatric patients (where genetic defects are more likely to be part of the pathology compared with adults), and therefore they need an allo-HSCT. Dr. Abinun added that with autologous transplantation cases, MAS was a major issue in these patients, and that reducing infammation (pre-transplant) was the way to solve this problem. He mentioned that the Dutch group was closely studying the immune reconstitution following autologous transplantation and hopefully this research would provide more answers in the future. Control of infammation before HSCT, Chimerism and SJIA remission. Te importance of a good control of infammatory activity prior to HSCT was again brought up by several BMT specialists. Dr. Abinun commented that most issues he sees in these patients during transplantation are infammation-related, and the same issues can also have an impact on the post-HSCT course including chimerism. He also fnds is disheartening that even full donor chimerism in SJIA patients after HSCT, does not mean that the disease is cured. Perhaps, this suggests a role for non-hematopoietic cells in the development of SJIA. He discussed these issues in more detail in his recent publication [9]. Insurance issues. All teams reported that they did not have insurance issues in HSCT getting approved. Dr. Marsh mentioned that for other similar patients who have an inborn error of immunity and no genetic diagnosis, they usually send a letter to the insurance company as part of the transplant package. It might take a followup conversation with someone at the insurance company but typically it’s not a barrier. Conditioning for refractory SJIA associated with liver disease. One of the parents asked about HSCT in patients with SJIA and liver involvement. Several BMT experts agreed that for patients with liver disease, there is a need to adjust the conditioning agents used. Summary and future directions In summary, the entire group of the participants agreed that there is a subset of patients with refractory systemic JIA, who have failed all available medications and are likely to beneft from HSCT. Te increasing experience with HSCT in SJIA, suggests that despite the complicated post-HSCT course, short-term, the transplanted patients either achieved SJIA remission (or reduced burden of disease) with improved lung function. Longer follow-up, however, is needed to better defne the long-term outcomes. Te optimal timing for the procedure still needs to be determined, but the emerging consensus is that it should occur earlier before signifcant organ damage is accumulated. Te group unanimously agreed that BMT teams should be consulted early, and both Rheumatology and BMT specialists should work together to determine when HSCT is appropriate. Increased pre-HSCT organ damage, lungs in particular, decreases the chances for a successful outcome of the procedure. However, since lungs are the target organ in SJIA-LD, patients with moderate or even severe lung damage still may be eligible for the procedure. Although reduced intensity conditioning regimens have improved the outcome of HSCT in general, there is a remote concern that such regimens may increase the risk of SJIA relapse after the transplantation. Long term registries should help address this question. Te entire group agreed that a good control of infammatory SJIA activity prior to HSCT markedly increases chances to achieve a good outcome, and therefore, it is reasonable to continue SJIA/MAS medications until transplantation. Te need to continue these medications (emapalumab and Jak-inhibitors in particular) after the procedure still needs to be determined. Abbreviations ATG Anti Thymocyte Globulin BMT Bone marrow transplant PO By mouth, orally CSF Cerebrospinal fuid CR Complete Remission CT Computerized tomography CMV Cytomegalovirus CTL Cytotoxic T cells DLCO Difusing capacity of the lungs for carbon monoxide DMARDS Disease-modifying anti-rheumatic drug EBV Epstein-Barr Virus GI Gastrointestinal GVHD Graft-versus-host disease HSCT Haematopoietic Stem Cell Transplantation
    • 13. Grom et al. Pediatric Rheumatology 2023, 21(Suppl 1):86 Page 13 of 13 HLA Human Leukocyte Antigen ICU Intensive care unit IL Interleukin IV Intravenous JIA Juvenile Idiopathic Arthritis LD Lung disease MAS Macrophage Activation Syndrome MRI Magnetic resonance imaging MSD Matched sibling donors MUD Matched unrelated donors mMUD Mismatched unrelated donors MMF Mycophenolate mofetil PR Partial remission PJP Pneumocystis jiroveci pneumonia PAP Pulmonary alveolar proteinosis SJIA Systemic Juvenile Idiopathic Arthritis TA-TMA Transplant-associated thrombotic microangiopathy TMA Transplant-related toxicity Acknowledgements Mario Abinun for the valuable contribution to the discussion during the session. Mariana Correia Marques for taking session notes. About this supplement This article has been published as part of Pediatric Rheumatology Volume 21 Supplement 1, 2023: Proceedings from the 4th NextGen Therapies for SJIA and MAS virtual symposium. The full contents of the supplement are available online at https://ped-​rheum.biomedcentral.com/articles/supplements/volume-​21-​ supplement-1. Authors’ contributions All authors participated in the meetings’ discussions and were involved in the preparation of the manuscript. The fnal version was reviewed by all 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 infuence 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. Declarations 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 AAG received research grants from Novartis and Sobi; consulting fees from Novartis and Sobi; royalties from UpToDate Inc. and payment for development of CME slide presentation on MAS from Clinical Viewpoints. SWC received investiga‑ tor-initiated research grants from Histiocytosis Association; consulting fees from Simcha Therapeutics, Apollo Therapeutics, SOBI; received payment for expert testimony from Parker Poe Adams & Bernstein LLP; received payment for lectures and educational events from PracticePoint communications and SOBI. RA, RS, LP, EC, BN, JR, JMFS, DW & UZ have no conficts of interest or competing interests to declare. SC received consulting fees from SOBI (SAB). KD has no conficts of interest or competing interests to declare. RM participated on the Advisory Board of SOBI and Horizon. KO received funding from CARRA (Childhood Arthritis and Rheumatology Research Alliance) for attending meetings and/or travel. SP participated in the Macrophage Activation Syndrome Adjudication Committee, Novartis Pharma, 2016–2022; and royalties from Op Med Fellow for Doximity Inc. SP received investigator-initiated research grants from PIDTC C-SIDE NIH Study Grant; consulting fees from CellEvolve (no fees), SmartImmune, ADMA; royalties from IP related to the development of 3rd party VSTs with all rights assigned to Memorial Sloan Kettering Cancer Center; received payment for lectures and edu‑ cational events from Regeneron and Pierre Fabre; participated in Advisory Board from Atara Biotherapeutics, Stanford Trial Specifc DSMB and NYBC Cord Blood Trial DSMB; received support for the conduct of clinical trials through Boston Children’s Hospital from Atara Biotherapeutics and Allovir. PQ received consulting payments from Abbvie, Amgen, BMS, Chugai Roche, Novartis, Novimmune, Pfzer and Sweedish Orphan Biovitrum; received funding for attending meetings and travel from BMS, Chugai-Roche, Novartis and Pfzer; and participated in a data safety monitoring board for Sanof. GS received investigator-initiated research grants from IpiNovyx; and received consulting fees from Novartis and SOBI. Published: 5 January 2024 References 1. Kimura Y, Weiss JE, Haroldson KL, Lee T, Punaro M, Oliveira S, Rabinovich E, Riebschleger M, Antón J, Blier PR, Gerloni V, Hazen MM, Kessler E, Onel K, Passo MH, Rennebohm RM, Wallace CA, Woo P, Wulfraat N. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res. 2013;65(5):745–52. & Childhood Arthritis Rheumatology Research Alliance Carra Net Investigators 2. Saper VE, Ombrello MJ, Tremoulet AH, Consortium INCHARGE, et al. Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles Annals of the. Rheumatic Dis. 2022;81:406–15. 3. Schulert GS, Yasin S, Carey B, Chalk C, Do T, Schapiro AH, Husami A, Watts A, Brunner HI, Huggins J, Mellins ED, Morgan EM, Ting T, Trapnell BC, Wikenheiser-Brokamp KA, Towe C, Grom AA. Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: characterization and risk factors. Arthritis & rheumatology. 2019;71:1943–54 (Hoboken, N.J.). 11. 4. Delemarre E, Roord S, Wulfraat N, van Wijk F, Prakken B. Restoration of the immune balance by autologous bone marrow transplantation in juvenile idiopathic arthritis. Curr Stem Cell Res Therapy. 2011;6(1):3–9. 5. Wu Q, Pesenacker AM, Stansfeld A, King D, Barge D, Foster HE, Abinun M, Wedderburn LR. Immunological characteristics and T-cell receptor clonal diversity in children with systemic juvenile idiopathic arthritis undergo‑ ing T-cell-depleted autologous stem cell transplantation. Immunology. 2014;142(2):227–36. 6. Silva JMF, Ladomenou F, Carpenter B, Chandra S, Sedlacek P, Formankova R, Grandage V, Friswell M, Cant AJ, Nademi Z, Slatter MA, Gennery AR, Hambleton S, Flood TJ, Lucchini G, Chiesa R, Rao K, Amrolia PJ, Brogan P, Wedderburn LR, Glanville JM, Hough R, Marsh R, Abinun M, Veys P. Alloge‑ neic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis. Blood Adv. 2018;2(7):777–86. 7. Morelle G, Castelle M, Pinto G, et al. Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis. Pediatr Rheumatol. 2021;19:27. 8. Davidson N, Rangarajan HG, Driest K, Bajwa RPS, Polishchuk V, Abu-Arja RF. Allogeneic Hematopoietic Cell Transplant for Systemic Juvenile Idiopathic Arthritis and Macrophage Activation Syndrome, Case Reports in Rheuma‑ tology, vol. 2021, Article ID 9323141, 3 pages, 2021. 9. Abinun M, Slatter MA. Haematopoietic stem cell transplantation in paediat‑ ric rheumatic disease. Curr Opin Rheumatol. 2021;33(5):387–97. https://doi. org/10.1097/BOR.0000000000000823. PMID: 34261117. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional afliations.


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