Macrophage activation syndrome (MAS) is a life-threatening condition caused by excessive activation and proliferation of T lymphocytes and haemophagocytic macrophages. Although MAS has been reported in association with almost any rheumatic disease, it is by far most common in systemic juvenile idiopathic arthritis. Flares of the underlying disease or infection are most common triggers of MAS. The pathognomonic feature of MAS is typically found in bone marrow: numerous, well-differentiated macrophagic histiocytes phagocytosing normal haematopoietic elements. The expansion of these histiocytes leads to a massive systemic inflammatory reaction associated with three cardinal clinical features: severe cytopenias, liver dysfunction, and coagulopathy consistent with disseminated intravascular coagulation. Clinically, MAS is strikingly similar to the autosomal recessive disorders collectively known as familial haemophagocytic lymphohistiocytosis (FHLH). FHLH has been associated with various genetic defects affecting the cytolytic pathway. Cytolytic function is profoundly depressed in MAS patients as well, and this abnormality is caused by both genetic and acquired factors. Studies in animals suggest that uncontrolled expansion of activated CD8+ T lymphocytes secreting cytokines that activate macrophages is central to the pathophysiology of haemophagocytic syndromes. Consistent with this view, the combination of steroids and ciclosporin, an immunosuppressant that preferentially inhibits T lymphocytes, is an effective treatment for the majority of MAS patients. Patients in whom MAS remains active despite this treatment present a serious challenge and require more aggressive immunosuppression. However, in MAS triggered by infection, the optimal level of immunosuppression is difficult to determine. As a result, reported mortality rates reach 20%.

INTRODUCTION:Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is increasingly recognized and associated with potentially life-threatening complications. Diagnosis is challenging as SJIA-LD is complex and frequently presents with subtle or no respiratory symptoms, necessitating CT imaging or other tests to detect budding dysfunction. We hypothesized that xenon and proton lung MRI could identify SJIA-LD-associated structural changes and functional deficits. METHODS:Thirty-one participants aged 5-15 (16 healthy, 7 SJIA without diagnosed lung disease [SJIA-non-LD], 8 SJIA-LD) underwent MRI for this cross-sectional study. Participants underwent xenon ventilation MRI (14 healthy/6 SJIA-non-LD/7 SJIA-LD), xenon gas-exchange MRI (12 healthy/3 SJIA-non-LD/5 SJIA-LD), and/or proton ultrashort echo time (UTE) MRI (12 healthy/5 SJIA-non-LD/7 SJIA-LD). Ventilation defect percentage (VDP) and ratios of xenon signal in alveolar membrane (Membrane), red blood cells (RBC), and gas were calculated from xenon MR images. CTs and PFTs were obtained from participant medical records where available for comparison. RESULTS:RBC/Membrane differed significantly (p = 0.014) between healthy individuals and SJIA-LD patients, and corresponded with DLCO results in a limited sample of participants with both measurements. VDP did not differ significantly between groups (p = 0.30), but was abnormally high in 3/7 SJIA-LD patients. SJIA-LD pattern findings in UTE MRI were detected in 4/7 SJIA-LD patients and in no healthy or SJIA-non-LD participants (p < 0.001). CONCLUSION:Xenon and proton lung MRI can identify SJIA-LD-associated pulmonary abnormalities, with RBC/Membrane showing particular promise for characterization of pulmonary diffusion limitation in SJIA-LD. Future studies will evaluate lung MRI for SJIA-LD phenotyping and longitudinal monitoring of SJIA-associated lung function changes.

OBJECTIVE:To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. METHODS:A systematic literature search was performed in both EMBASE and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. RESULTS:Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatological conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported Janus kinase inhibitor in MAS. CONCLUSION:High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, the global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.

Patient-reported outcomes (PROs) are critical assessment tools for clinical practice, observational studies, and interventional trials. While families of children with systemic juvenile idiopathic arthritis (SJIA) and SJIA-associated lung disease (SJIA-LD) report significant limitations in their quality of life, existing PROs for juvenile idiopathic arthritis may not properly measure the full impact of these disorders. Our objective was to utilize a newly developed lung symptom survey as well as existing, validated Patient-Reported Outcomes Measurement Information System (PROMIS) measures in children with SJIA with and without LD. Participants were parents/guardians of SJIA patients ≤ 18 years and were invited to participate using the Cincinnati Children’s Hospital Medical Center (CCHMC) JIA Registry, and memberships in the Systemic JIA Foundation, and SJIA Facebook Group. Participants provided proxy-reports for their child using several PRO questionnaires [CCHMC Lung Symptom Survey; PROMIS Asthma Impact, Sleep Disturbance, Sleep Impairment Forms] and selected demographic and SJIA specific information. There were 139 responses, of which 40.3

Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (sJIA), driven by excessive activation of T cells and macrophages, resulting in a cytokine storm. IFN-γ and IL-18 play crucial roles, with monocyte and macrophage hyperresponsiveness to IFN-γ amplifying MAS-related inflammation. Familial Mediterranean Fever (FMF), an autosomal recessive disease, is characterized by recurrent fever episodes due to MEFV gene mutations. Despite intense inflammation in FMF, MAS is rare. This study aimed to compare in vitro responsiveness of peripheral blood mononuclear cells (PBMCs) to IFN-γ between sJIA/MAS and FMF patients. Five sJIA/MAS and five FMF patients were included. PBMCs were stimulated in vitro with IFN-γ for 45 min. Levels of IFN-γ-induced chemokines CXCL9, CXCL10, and IL-18 in supernatants were measured using cytometric bead arrays before and after stimulation. PBMCs from MAS patients produced higher baseline CXCL9 levels compared to FMF patients in a flare, with differences increasing post-IFN-γ stimulation. IFN-γ stimulation also upregulated IL-18 production in MAS patients but not in FMF patients. Enhanced responsiveness to IFN-γ distinguishes sJIA/MAS from FMF patients, which may explain the lower occurrence of MAS in FMF.

A subset of patients with systemic juvenile idiopathic arthritis (sJIA) develop sJIA-associated lung disease (sJIA-LD). Allogeneic hematopoietic stem cell transplant (HSCT) is a treatment option for patients with refractory sJIA and can ameliorate associated lung disease. Infusion of T-replete grafts into sJIA-LD patients who have a high background of preexisting systemic and pulmonary inflammation may contribute to risks of inflammatory complications or graft versus host disease following allogeneic HSCT. We hypothesized that a T cell–depleted approach would achieve durable engraftment while minimizing the risks of GVHD, pulmonary complications, and TRM. We report our single-center retrospective analysis of 4 pediatric patients with sJIA-LD who underwent allogeneic HSCT with reduced intensity conditioning (RIC) with alemtuzumab (days 14-12), fludarabine (150 mg/2 over days -8 to -4), melphalan (140 mg/m2 on day -3), and thiotepa (200 mg/m2 on day -2) and received either a CD34+-selected (n = 3) or TCR-αβ–depleted (n = 1) peripheral blood stem cell product. Patient and transplant characteristics are shown in Table 1. All patients had highly refractory disease and were heavily pretreated with a median of 8 (6-12) lines of sJIA-directed therapy. At the time of HSCT, three patients required respiratory support (supplemental O2 in n = 2, overnight BiPAP with supplemental O2 in n = 1). Table 1. Transplant characteristics All patients engrafted with >95% donor chimerism (range, 9-10 days post-HSCT). One patient experienced secondary graft failure on day +43 requiring a second HSCT with a haploidentical parental donor and post-transplant cyclophosphamide (Table 1). Second HSCT was complicated by grade 1 (skin) acute GVHD. None of the other patients developed acute or chronic GVHD or significant pulmonary complications. All had significant improvement in their pulmonary status and were able to discontinue their respiratory support (Figure 1). At a median follow up of 19.8 months (range, 6-36 months), all patients have 100% donor chimerism. None of the patients have had relapse of their sJIA. IL-18 levels declined post-HSCT to near normal levels in all patients (Table 1). Figure 1. Progress of pulmonary disease pre- and post-HSCT. High-resolution CT chest images of patient #1 pre- (A) and 2.5 years post- (B) HSCT. (C) This shows percent predicted FEV1 and FVC and lowest SpO2 in 6-minute walk test for patients #1-3 (patient 4 unable to reliably perform spirometry). Our experience suggests that allogeneic HSCT with a T cell–depleted approach for patients with sJIA-LD offers durable engraftment with low risk of GVHD, pulmonary complications, and TRM.

Rationale: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is increasingly common and associated with significant and potentially life-threatening complications. Diagnosis is challenging as patients frequently present with mild respiratory symptoms, and pulmonary function testing for screening is difficult in young children. Xenon (Xe) ventilation magnetic resonance imaging (MRI) measures regional airflow obstruction, and Xe gas-exchange MRI is a spectroscopic imaging technique that discriminates Xe in the airspaces from Xe diffused in interstitial tissue and/or blood plasma or bound to hemoglobin, akin to a spatially-resolved diffusion-capacity measurement. We hypothesized Xe MRI would reveal abnormal ventilation and gas-exchange features in children with SJIA-LD. Methods: Twenty-two participants – 14 healthy (6 female, 5ꟷ13 years) and 8 with SJIA-LD (6 female, 5ꟷ15 years) – underwent Xe ventilation MRI using a 2D multi-slice Cartesian sequence at 3T. Eighteen participants (12 healthy and 6 with SJIA-LD) underwent Xe gas-exchange MRI using a 3D radial sequence. Ventilation defect percentage (VDP) was defined as the percent of voxels with intensity lower than 60% of the mean intensity in segmented, bias-corrected Xe ventilation images. Images of Xe as free gas in the alveoli (Gas), diffused in alveolar membrane (Mbr), and bound to hemoglobin in red blood cells (RBC) were reconstructed from gas-exchange data and normalized to one another to produce images of Mbr/Gas, RBC/Gas, and RBC/Mbr. Groups were compared using Wilcoxon rank-sum tests. Results: VDP was statistically significantly higher (p = 0.015) in the SJIA-LD group (median = 2.0%; interquartile range = 11%) than in the healthy group (1.1%; 0.7%). RBC/Mbr was statistically significantly lower (p = 0.024) in the SJIA-LD group (0.40; 0.07) than in the healthy group (0.49; 0.11). No statistically significant groupwise differences in Mbr/Gas (p = 0.96) or RBC/Gas (p = 0.34) were observed. The figure shows example Xe ventilation and RBC/Mbr images for each of the two groups, as well as boxplots comparing these two outcomes between the groups. Ventilation defects and low RBC/Mbr were observed in the SJIA-LD participant compared to the healthy participant. Conclusion: Xe MRI revealed differences in ventilation and diffusion between healthy children and those with SJIA-LD, similar to reported features in adult interstitial lung diseases. Lower RBC/Mbr in SJIA-LD suggests abnormalities such as interstitial inflammation and/or fibrosis that allow increased accumulation of Xe in the diffusion barrier, impeding transfer to RBCs. Ongoing work aims to develop Xe MRI biomarkers to screen children with SJIA for early lung disease.

Objective:To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods:Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results:Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion:We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Macrophage activation syndrome (MAS) is a life-threatening episode of hyperinflammation driven by excessive activation and expansion of T cells (mainly CD8) and hemophagocytic macrophages producing proinflammatory cytokines. MAS has been reported in association with almost every rheumatic disease, but it is by far most common in systemic juvenile idiopathic arthritis (SJIA). Clinically, MAS is similar to familial or primary hemophagocytic lymphohistiocytosis (pHLH), a group of rare autosomal recessive disorders linked to various genetic defects all affecting the perforin-mediated cytolytic pathway employed by NK cells and cytotoxic CD8 T lymphocytes. Decreased cytolytic activity in pHLH patients leads to prolonged survival of target cells associated with increased production of proinflammatory cytokines that overstimulate macrophages. The resulting cytokine storm is believed to be responsible for the frequently fatal multiorgan system failure seen in MAS. Whole exome sequencing as well as targeted sequencing of pHLH-associated genes in patients with SJIA-associated MAS demonstrated increased "burden" of rare protein-altering variants affecting the cytolytic pathway compared to healthy controls, suggesting that as in pHLH, genetic variability in the cytolytic pathway contributes to MAS predisposition. Functional studies of some of the novel variants have shown that even in a heterozygous state, their presence partially reduces cytolytic activity that may lead to increased cytokine production.

ObjectivePrognostic factors associated with medication discontinuation in children with juvenile dermatomyositis (JDM) remain largely elusive. We aim to identify the predictors of medication‐free remission (MFR) in children with JDM.MethodsIn this retrospective study, patients diagnosed with JDM according to Peter & Bohan criteria and followed for ≥18 months at a tertiary care center from 2006 through 2022 were included. Data extracted included demographics, physical examination, laboratory results, and medications. MFR was defined as inactive JDM after discontinuation of all systemic immunosuppressives for ≥6 months, in line with international consensus guidelines for trials of therapies in idiopathic inflammatory myopathies. A two‐sided P < 0.05 was considered statistically significant.ResultsOf 55 patients with JDM (63.6% female, age median [interquartile range (IQR)] 6 [3.5–12] years), 29 (52.7%) achieved MFR after a median (IQR) of 33 (22.5–55.2) months. MFR was more common in those who were younger at JDM diagnosis (median 5 vs 8 years, P = 0.008), had early resolution of disease activity (median 11 vs 18 months, P < 0.001), and presented with Gottron papules (χ2 = 5.25; P = 0.022) and elevated lactate dehydrogenase (χ2 = 4.82, P = 0.028). Diagnosis of JDM before 5 years old (odds ratio 4.5, 95% confidence interval [CI] 1.2–16.7) was the only predictor of MFR in our multivariate model (area under the curve 0.65, 95% CI 0.53–0.76).ConclusionHalf of our patients with JDM achieved MFR. Age at JDM diagnosis may be an important predictor of achieving MFR.

Abstract Background Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA). Methods Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months. Results At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25–5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48–9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03–8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02–5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57–5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23–5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46–9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76–7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07–3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10–4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15–8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders. Conclusion Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.

The substantial morbidity and mortality associated with refractory systemic JIA underlies the need for new treatment approaches. However, progress in this area has been limited by the difficulty of enrolling these patients in clinical trials with traditional designs, particularly in patients presenting with the life-threatening macrophage activation syndrome. At the NextGen 2022 conference, there was group consensus that using historical cohorts as a control group to avoid the need for a placebo-arm or drug withdrawal was highly desirable and might be acceptable for clinical trials in MAS to support medication efficacy and safety. However, if historic controls were used in a trial, it would be important to ensure that the historic cohort matches the study group in terms of clinical characteristics (such as disease severity and exposure to other medications), and that disease outcome in both groups is assessed using the same outcome measures. The discussions at the NextGen 2022 conference focused on the potential strategies to achieve these goals.

OBJECTIVE:Syndrome of undifferentiated recurrent fevers (SURF) is characterized by recurrent fevers and autoinflammation without a confirmed molecular diagnosis of a hereditary recurrent fever syndrome, and not fulfilling criteria for periodic fever, adenitis, pharyngitis, aphthous stomatitis syndrome (PFAPA). The goal of this study was to characterize clinical features of patients with SURF compared to patients with PFAPA and to analyze their cytokine signature, genetic variations, and responses to treatment. METHODS:We enrolled 46 patients observed at Cincinnati Children's Hospital Medical Center. Baseline data and inflammatory cytokines were collected at enrollment, and their clinical course was followed. Cytokine analysis was performed using a cytokine multiplex assay. Many patients had specific or whole exome genetic testing. RESULTS:The prevalence of rash and arthralgias were higher in patients with SURF compared to patients with PFAPA. Pharyngitis and adenopathy were less frequent. A subset of patients with SURF clustered together with elevated proinflammatory cytokines and more frequently required biologic therapy. Focused analysis of whole exome sequencing  data revealed that variants of unknown clinical significance (VUCS) were frequently identified in genes implicated in B cell development, immunodeficiencies, and inflammatory bowel disease risk. Treatments for patients with SURF commonly included on-demand steroids, colchicine, and anti-interleukin-1 therapy. CONCLUSION:Our findings suggest SURF is a heterogeneous group but has distinct clinical and immunologic features from disorders such as PFAPA. Patients have frequent VUCS, which may have relevance to disease pathogenesis. A subset of patients showed more inflammation and an increased need for biologic therapy. Further research is necessary to define whether there exist distinct SURF endotypes and to better predict treatment outcomes.

It has been increasingly recognized that there is a subset of patients with refractory systemic JIA, who have failed all available medications and may benefit 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 remission or reduced burden of disease. Longer follow-up, however, is needed to better define 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 inflammatory SJIA activity prior to HSCT, and the role of the reduced intensity conditioning regimens as there was a remote concern that such regimens might increase the risk of SJIA relapse after the transplantation. There was unanimous agreement about the importance of long-term registries to address these questions.

OBJECTIVE:We examine levels of candidate blood-based biomarkers (CBBs) in patients with juvenile idiopathic arthritis (JIA) treated with tofacitinib. METHODS:Patients with JIA who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBBs (S100A8/9, S100A12, interleukin-18 [IL-18], serum amyloid A, resistin, vascular endothelial growth factor, angiopoietin-1, angiopoietin-2, matrix metalloproteinase 8 [MMP8], MMP2, tissue inhibitor of metalloproteinases 1, leptin, chemokine [C-X-C motif] ligand 9, soluble IL-2 receptor, intercellular adhesion molecule 1, soluble tumor necrosis factor receptor, IL-6, IL-23, monocyte chemotactic protein 1, chemokine [C-C motif] ligand 18 [CCL18], and CCL20). Association of CBBs with JIA response to treatment from baseline to week 18 were assessed. RESULTS:This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. Thirty-five percent (50 of 143) of patients had a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement, whereas 90, 121, and 137 (63%, 85%, and 96%) achieved JIA-ACR70, 50, and 30 improvement at week 18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in Juvenile Arthritis Disease Activity Score (JADAS-27) or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with week 18 improvement in JADAS-27 and JIA-ACR90 response after adjusting for age, sex, JIA disease duration, and baseline resistin (r2 0.79, SE 0.070, P < 0.01, and odds ratio [95% confidence interval] 1.134 [1.018-1.264]). HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (P = 0.0097). CONCLUSION:Among the CBBs included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

Although the introduction of the IL-1 and IL-6 inhibiting biologics in 2012 has revolutionized the treatment and markedly improved outcomes for many patients with SJIA, about 20% of these patients continue to have active disease, have markedly decreased quality of life and high disease activity as well as treatment-related morbidity and mortality. There is a clear need to define these disease states, and then use these definitions as the basis for further studies into the prevalence, clinical features, and pathophysiologic mechanisms. While such patients are most likely to benefit from novel therapies, they are very difficult to enroll in the ongoing clinical trials given the unique features of their disease and large numbers of background medications. The discussions at the NextGen 2022 conference focused on strategies to overcome these obstacles and accelerate studies in refractory SJIA.