Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial

Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial Timothy Hahn, George Tomlinson, Yukiko Kimura, Vincent Del Gaizo, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8368751/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background: Systemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disease associated with substantial morbidity, including macrophage activation syndrome (MAS), sJIA-associated lung disease, and glucocorticoid (GC)-related toxicity. CARRA’s FiRst Line Options for sJIA Treatment (FROST) study demonstrated favorable short-term outcomes with early biologic therapy, but long-term outcomes have not yet been described. Methods: Patients with new-onset sJIA enrolled in FROST (2016–2019) were followed longitudinally through the CARRA Registry. Four consensus treatment plans (CTPs) were evaluated, including biologic (IL-1 or IL-6 inhibitors) and non-biologic approaches. Long-term follow-up occurred through 36 months. The primary outcome was achievement of clinically inactive disease (CID) by Wallace/ACR provisional criteria without concurrent GC use at 24 and 36 months. Secondary outcomes included CID irrespective of GC use, cJADAS-10 ≤ 2.5 without fever, medication utilization, and safety events. Adverse events were expressed as events per 100 person-years. Results: Seventy-three patients were enrolled; 87.6% initiated biologic therapy. At 24 and 36 months, 41 and 32 patients, respectively, had evaluable data for the primary outcome. CID without GC use was achieved by 58.5% of patients at 24 months and 65.5% at 36 months. At both time points, over 80% of patients achieved cJADAS-10 ≤ 2.5 without fever and without GC use. Nearly all patients were off GCs at 24 and 36 months (> 90%). The cumulative proportion of patients achieving CID at any time during follow-up increased to 78.8% by 24 months and 87.6% by 36 months. At last follow-up, 42.5% of the cohort was off all DMARDs. Over 228.2 person-years of observation, serious adverse events occurred at a rate of 6.6 per 100 person-years; MAS was the most common SAE. No cases of sJIA-associated lung disease were identified. Conclusions: Patients with sJIA enrolled in FROST demonstrated continued clinical improvement during long-term follow-up, with increasing rates of clinically inactive disease and high rates of glucocorticoid discontinuation. Serious adverse events were uncommon and largely related to disease activity. These findings support early biologic therapy as an effective and durable first-line strategy for sJIA. Systemic juvenile idiopathic arthritis juvenile idiopathic arthritis biologics treatment outcomes Figures Figure 1 Figure 2 Background Systemic Juvenile Idiopathic Arthritis (sJIA) is an autoinflammatory condition characterized by an abnormal innate immune response and significant systemic inflammation driven by massive overproduction of proinflammatory cytokines, in particular IL-1 and IL-6 1,2 . The most common symptoms include fever, arthritis, and a distinguishing evanescent rash. sJIA is associated with life threatening complications including macrophage activation syndrome (MAS) and the more recently described sJIA associated lung disease (sJIA-LD) 3–5 . Historically, there was also significant morbidity related to chronic steroid exposure which was often necessary to control disease. Considerable advances in the understanding of the inflammation in sJIA over the past two decades have led to more targeted therapies including IL-1 and IL-6 inhibitors. In 2022 the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published the results of a prospective observational study called FiRst Line Options for sJIA Treatment (FROST), which was designed to compare the effectiveness of 4 Consensus Treatment Plans (CTPs) in new-onset systemic JIA (sJIA) 6 . The CTPs were grouped into biologic CTPs, in which patients were initially treated with an IL-1 inhibitor (anakinra or canakinumab) or IL-6 inhibitor (tocilizumab), and non-biologic CTPs, which included glucocorticoids (GC) alone or methotrexate with or without glucocorticoids. In FROST, 86% of patients were treated according to one of the biologic CTPs (IL-1 inhibitors or IL-6 inhibitors) at enrollment. The most commonly reported reasons for choosing a biologic CTP were likelihood of effectiveness for systemic features, minimization of systemic glucocorticoids, and likelihood of effectiveness for arthritis. Half of the patients who started on a non-biologic CTP at enrollment started a biologic during the first three months of follow up. The small number of patients treated with non-biologic CTPs made it impossible to compare rates of achieving clinically inactive disease (CID) between the biologics and nonbiologic treatment groups 7 . Nevertheless, there were encouraging results from the study, which included that the majority of patients were able to achieve a state of CID without concurrent use of glucocorticoids at 9 months. The most frequently reported safety events included MAS and hospitalization for flare of underlying disease. All patients enrolled in FROST were also enrolled in the CARRA Registry 8 , which allowed for continued observation of clinical status, medication usage, and safety events. The purpose of this study is to describe the long-term clinical and safety outcomes for patients enrolled in the FROST trial. Methods The methodology used to develop the four CTPs has been previously reported 9,10 , as has the design of the FROST study 6,11 . FROST enrolled patients from 2016 to 2019 from 32 CARRA sites throughout the US and Canada. Long-term follow up included study visits occurring every 3 months between 12- and 24-months post enrollment, subsequently continuing to have follow up visits every 6 months (+/- 3-month window) in the CARRA Registry until they aged out of pediatric rheumatology care, transferred care to a non-CARRA Registry site, were discharged from rheumatology care due to long-term remission, or were lost to follow up, defined as no study visit for 15 consecutive months. The CTPs included recommendations for the timing of clinical reassessment and adjustment of glucocorticoids and DMARDs over the first 9 months of treatment. Beyond 9 months, the timing of clinical follow up, tapering of glucocorticoids, and sequence of medication changes was determined solely by the treating physician and the patient/family. Serious adverse events (SAE) were recorded, along with prespecified safety events that may not have met SAE criteria, including MAS. The primary study outcome was achievement of CID according to the Wallace/American College of Rheumatology provisional criteria without use of glucocorticoids at 24- and 36-months. 7 Selected secondary outcomes included CID irrespective of current GC use, clinical juvenile idiopathic arthritis disease activity score based on 10 joints (cJADAS-10) ≤ 2.5 without current fever or GC use, cJADAS-10 ≤ 2.5 without current fever irrespective of GC use, GC use independent of CID, any biologic or non-biologic DMARD use, and proportion of the entire cohort achieving CID at any point during follow up. The proportion of the cohort having achieved CID at each study visit and the proportion achieving CID at any point up to and including each study visit were both calculated and plotted over time. Criteria for CID requires that patients have (1) no active arthritis (2) no systemic features of sJIA (3) no active uveitis (4) physician global assessment of disease activity score of zero (5) duration of morning stiffness ≤ 15 minutes (6) ESR or CRP within normal limits, if available. The cJADAS-10 ranges from 0–30 and is composed of joint count (maximum of 10), physician global assessment (0–10), and patient/parent global assessment (0–10). We used the cutoff for defining inactive disease in polyarticular JIA of a cJADAS-10 of ≤ 2.5 but also required the absence of fever 12 . Because the height of fever is not collected in the CARRA Registry, the systemic Juvenile Arthritis Disease Activity Score (sJADAS) could not be calculated 13 . Both the 24- and 36-month visits had a 6 month visit window (i.e., 18 to 24 months and 30 to 36 months, respectively). For patients with more than one study visit during the six-month window, they were considered to have achieved CID if they met the definition of CID at any one of the study visits. For study visits where individual components needed to define CID or cJADAS-10 were missing, the patient was not included in the analysis (i.e., a complete case analysis with no imputation was performed). This resulted in different denominators for some outcome measures at a specific time point. Recent medication use at a study visit was defined as either being on the medication at the visit or having stopped the medication within the 2 months prior to the visit to ensure that disease was in stable remission off medication. Data at the time of last study follow-up visit is also presented. Adverse events are expressed as events per 100 person-years, defined as the cumulative duration of safety follow-up across all participants. The CARRA Registry and FROST were approved by the Duke IRB Results Baseline characteristics of the 73 patients enrolled in FROST are shown in Table 1 including those who were included in the analysis of the primary outcome at 24 and 36 months (N = 41 and N = 32, respectively). Due to missed visits, not all patients included in the 36-month outcome were included in the 24-month outcome assessment. As expected, the majority of patients in long-term follow-up had started on a biologic CTP (87.6%). During the follow-up period, the most frequently administered medication was anakinra, utilized in 68.5% of patients at some point. Canakinumab was the second most common treatment, prescribed to 56.2% of patients, followed by tocilizumab, which was used in 26% of cases. Notably, 19.1% of patients received both an IL-1 inhibitor and an IL-6 inhibitor at some time during the follow-up period. By 36 months there was only 1 patient in follow up who had started on a non-biologic CTP. Disease activity at baseline, measured by median cJADAS-10, physician global assessment, patient global assessment, joint count and all lab measures, for patients included in long-term follow up was similar as for the entire cohort. Table 1 Baseline patient characteristics for the entire cohort and for patients with follow up at 24 and 36 months. All Patients Month 24 Patients Month 36 Patients n 73 41 32 Follow Up (years) 3.3 [1.6, 4.4] 3.5 [2.4, 4.5] 4.4 [3.4, 5.5] CTP (%) Glucocorticoids 6 ( 8.2) 3 ( 7.3) 0 ( 0.0) Methotrexate 4 ( 5.5) 2 ( 4.9) 1 ( 3.1) IL-1 inhibitor 59 ( 80.8) 35 ( 85.4) 30 ( 93.8) IL-6 inhibitor 4 ( 5.5) 1 ( 2.4) 1 ( 3.1) Age 6.8 [4.1, 11.0] 7.1 [4.0, 11.5] 6.1 [4.6, 11.3] Male sex (%) 44 ( 60.3) 25 ( 61.0) 23 ( 71.9) Physician global assessment 7.0 [5.0, 7.0] 7.0 [5.0, 7.5] 7.0 [5.0, 7.0] Patient global assessment 6.0 [3.2, 8.0] 5.5 [3.0, 8.0] 6.0 [3.0, 8.0] Number of active joints 4.0 [2.0, 8.0] 5.0 [2.0, 9.5] 5.0 [2.0, 8.8] Fever (%) 73 (100.0) 41 (100.0) 32 (100.0) Arthritis (%) 73 (100.0) 41 (100.0) 32 (100.0) Rash (%) 70 ( 95.9) 38 ( 92.7) 30 ( 93.8) Lymphadenopathy (%) 24 ( 32.9) 14 ( 34.1) 11 ( 34.4) Hepatomegaly or Splenomegaly (%) 15 ( 20.5) 7 ( 17.1) 5 ( 15.6) Serositis (%) 7 ( 9.6) 5 ( 12.2) 5 ( 15.6) ESR (mm/hr) 73.0 [57.0, 97.0] 75.0 [58.0, 97.0] 67.5 [53.0, 97.0] CRP (mg/dL) 9.0 [4.7, 16.0] 12.2 [5.4, 16.2] 8.9 [5.2, 15.5] Ferritin (ng/mL) 829.0 [249.0, 2603.0] 604.5 [234.4, 1543.7] 859.0 [346.0, 2367.2] Hemoglobin (g/dL) 10.1 [8.9, 11.2] 10.0 [8.9, 11.4] 10.1 [9.0, 11.2] WBC (x10^3) 12.2 [8.5, 19.1] 11.5 [8.8, 15.8] 11.3 [8.9, 19.0] Platelets (x10^3) 458.0 [353.0, 571.0] 399.0 [331.5, 570.5] 397.0 [360.5, 500.2] CHAQ 1.4 [0.5, 2.0] 1.2 [0.2, 1.9] 1.1 [0.1, 2.0] cJADAS-10 17.0 [10.5, 21.5] 17.0 [10.8, 21.2] 17.0 [11.5, 21.0] Race (%) Asian 6 ( 8.2) 4 ( 9.8) 5 ( 15.6) Black 7 ( 9.6) 5 ( 12.2) 2 ( 6.2) Hispanic 13 ( 17.8) 4 ( 9.8) 4 ( 12.5) White 42 ( 57.5) 24 ( 58.5) 18 ( 56.2) Other 1 ( 1.4) 0 ( 0.0) 0 ( 0.0) Missing 4 ( 5.5) 4 ( 9.8) 3 ( 9.4) As of April 2024, there were 27 FROST patients still actively following up in the CARRA Registry. Thirty-five patients had been lost to follow up. The remaining 11 patients either withdrew consent, transitioned to adult rheumatology or were deceased (Table 2 ). Table 2 Status in the CARRA Registry of the at the time of the analysis for the 73 patients enrolled in FROST Status n % Still active 27 37.0% De facto loss-to-follow-up 35 47.9% Disease remission 6 8.2% Subject withdrew consent 3 4.1% Transitioned to adult rheumatology 1 1.4% Deceased 1 1.4% The primary outcome of CID without concurrent use of glucocorticoid was available for 41 patients at 24 months and 32 patients at 36 months. More patients had data available for calculating cJADAS-10 at both visits. Table 3 summarizes the clinical outcomes at 24 and 36 months. At 24 months 58.5% of patients were in CID without concurrent use of glucocorticoids. This percentage increased to 65.5% at 36 months. There was 1 additional patient in CID but still on glucocorticoids at 24 months. At 24 months and 36 months the percentage of patients that had cJADAS-10 ≤ 2.5 without fever and without current glucocorticoid use was 81.6% and 80.0%, respectively. Almost all patients were off glucocorticoids at 24 months (90.5%) and at 36 months (90.6%). Table 3 Clinical outcomes at 24 and 36 months 24 months 36 months CID without current GC use 24/41 (58.5%) 21/32 (65.6%) CID irrespective of current GC use 25/41 (61.0%) 21/31 (67.7%) CID without GC or recent biologic use 10/49 (20.4%) 8/33 (24.2%) cJADAS ≤ 2.5 and no fever without current GC use 40/49 (81.6%) 32/40 (80.0%) cJADAS ≤ 2.5 and no fever irrespective of current GC use 42/47 (89.4%) 32/36 (88.9%) cJADAS ≤ 2.5 and no fever without current GC use or recent biologic use 19/53 (35.8%) 17/40 (42.5%) On GC 4/42 (9.5%) 3/32 (9.4%) Recent Biologic use 30/41 (73.2%) 25/32 (78.1%) Figure 1 shows the cumulative proportion of patients reaching CID at any time during follow up. This percentage continued to increase throughout the duration of the long-term follow-up reaching 78.8% of patients at 24 months and 87.6% by 36 months. Figure 2 shows how the proportion of patients in CID at the specified study visit increases up to 15 months after enrollment then fluctuates for the duration of the study period. Adverse events are summarized in Table 4 . There was a total of 228.2 person-years of safety observation with a median of 3.3 years (IQR 1.6, 4.4) per patient. There were 15 SAEs observed for a frequency of 6.6 per 100-patient years. The median time between enrollment and SAE was 218 days. There was 1 death due to acute liver failure occurring 2.6 years after enrollment which was previously reported 6 . The most commonly reported SAE was MAS which occurred in 6 subjects. Two of those patients were not receiving biologics or methotrexate at the time of MAS and the others were all receiving IL-1i at the time of MAS. No patients enrolled in FROST were subsequently diagnosed with sJIA-LD during long-term follow-up; however, screening for sJIA-LD was not systematic or protocolized. Table 4 Serious Adverse Events Event CTCAE grade Current Biologic and Non-Biologic use Acute Liver Failure 5 Anakinra Hepatitis 4 Anakinra, Tocilizumab Protein Losing Enteropathy 3 Anakinra Severe injection site reactions 3 Anakinra Infection requiring IV abx 3 Canakinumab Appendicitis 3 Golimumab MAS 4 Anakinra MAS 3 Canakinumab MAS 3 Canakinumab MAS 3 None MAS 3 Anakinra, Canakinumab MAS 3 None SJIA Flare 3 Canakinumab SJIA Flare 3 Anakinra, cyclosporine SJIA Flare 2 Anakinra, Cyclosporine, methotrexate Disease status at the last study visit was analyzed for the entire cohort. Importantly, for 35.6% of patients, CID could not be calculated at the most recent study visit due to missing data. Therefore, analysis was limited to patients whose last study visit included all the variables needed to calculate CID status (n = 47). Overall, 50.6% of these patients were in CID at the last study visit. This includes 9 patients whose last visit occurred within 3 months after enrollment. When limited to subjects whose last study visit occurred at 24 months or later (n = 38), 50% s were in CID. At the last study visit 42.5% of all 73 patients were off all DMARDs. Discussion The long-term outcomes of the FROST trial provide valuable insights into the evolving therapeutic landscape of sJIA, underscoring the effectiveness and safety of early biologic use in achieving a state of inactive disease. As previously reported, the majority of patients in FROST had achieved CID (57%) or had a cJADAS-10 of ≤ 2.5 without fever or glucocorticoids (75%) at 9 months. This current study demonstrated that for patients who did not have complete response in the first 9–12 months there is still opportunity for them to achieve CID. This was best demonstrated by the increase in the proportion of patients meeting the primary endpoint of CID at 24 months from 58.5% to 65.5% at 36 months a trend best demonstrated in Fig. 1 . It was also highly encouraging to see that nearly all patients were off glucocorticoids at 24 months after enrollment while nearly half of patients were off all DMARDs at the last study visit. Our observations regarding sJIA outcomes are consistent with other cohorts with longer observation times that showed patients with sJIA have the highest chance of remission off medications among all JIA categories. In a prospective single center cohort of children with systemic juvenile idiopathic arthritis (sJIA) managed with a treat to target approach and followed for five years, 96% of patients achieved remission at the five-year time point, with the majority (75%) discontinuing all medications by that time. 14 This study, in conjunction with a similar follow up study, suggests that early initiation of anakinra, followed by biomarker-guided discontinuation, may be associated with high remission rates both within the first year and at long-term follow-up 15 . Similar long term outcomes were reported from a large retrospective cohort in which 98% of patients were in remission at a median of 5 years after starting treatment with 48.8% in remission off medication. 16 In a small cohort of children with JIA from Nordic countries, more than 80% of patients with sJIA had inactive disease and 85% were off medications at 18 years of follow up 17 . In Canadian children with sJIA, 70% of children were in remission off medications after an average of 6 years of follow up 18 . When interpreting the long-term data, it is important to consider the potential clinical courses that patients with sJIA might follow. Many patients will have a monophasic course while others will follow a polyphasic course characterized by periods of disease remission and disease flares which may vary in severity, or a chronic course which does not remit. It is possible that a significant proportion of patients lost to follow up were patients with monophasic disease who self-elected to no longer follow up due to remission off medications, which is a common scenario in pediatric rheumatology. Only patients who were discharged from care by the treating physician were included in the “disease remission” category. This may have resulted in a falsely low proportion of patients achieving CID at 2 and 3 years in our study, as these patients were not included in the numerator or the denominator. Patients with polyphasic or relapsing chronic disease may be a reason that we saw that the cumulative incidence of achieving CID was higher than the proportion of patients in CID in the specified time points for the cross-sectional analysis. It is possible that many of the subjects who were not in a state of CID at 24 and 36 months had been in CID, but experienced a flare of their disease at that visit. This highlights the critical need to better understand the factors that lead to disease flares once patients achieve CID. This study was not designed to evaluate flares, much less the etiology of flares; thus, we cannot identify if flares were related to potentially modifiable factors such as intentional medication withdrawal or non-adherence or from non-modifiable factors such as incidental infection. Adverse events reported during the long term follow up of the FROST study occurred at a rate similar to or less than what has been reported in prior clinical trials of biologics in systemic JIA 19–22 . No patients were diagnosed with sJIA-LD during follow up. However, lung disease screening was not systematic or protocolized. Additionally, there may have been selection bias during enrollment in FROST, as patients who could not be safely treated with a CTP were not eligible. This may have excluded patients with significant MAS at diagnosis, a factor that has been reported to be associated with increased risk of developing lung disease 4,5 . The FROST study had several limitations that have been previous discussed, including lack of randomization, missing data, and challenges with enrollement 6 . In the long-term follow-up cohort a significant percentage of patients were lost to follow prior to the 2 and 3 year outcome assessment. Although we cannot say for certain, we suspect many patients were lost to follow-up due to inactive disease and self-discontinuation of care. If these patients had been included in the analysis, the proportion achieving the primary endpoint would have been higher. In the time since the FROST study was completed, new guidelines put forth by the American College of Rheumatology included recommendations for the initial treatment of patients with treatment-naïve sJIA with and without MAS. For sJIA without MAS the guidelines included a conditional recommendation against oral glucocorticoids as initial monotherapy and strong recommendation against conventional synthetic DMARDS (methotrexate or calcineurin inhibitors) as initial monotherapy. Conversely, biologic DMARDs including anakinra, canakinumab, and tocilizumab were conditionally recommended as initial monotherapy 23 . Similar recommendations for treatment of Still’s disease were published by the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PReS) in 2024 24 . These recommendations included strong agreement regarding initiation of an IL-1 or an IL-6 inhibitor as early as possible when the diagnosis is established. This approach is supported by studies that showed increased remission rates for patients starting biologic treatment early in the course of the disease. 25 The results of FROST support the recommendations that biologics as first line treatment leads to good outcomes for the majority of patients with sJIA. Conclusions Patients with sJIA enrolled in FROST continued to improve during the 2nd and 3rd year of follow-up, with the majority of observable patients achieving CID and discontinuing GCs. SAEs were not common and were predominantly due to disease flare or MAS. The FROST cohort will continue to be followed in the CARRA Registry, providing further longer-term information about the contemporary course of sJIA patients. Declarations Ethics approval and consent to participate The CARRA Registry and the FROST study were approved by the Duke IRB. Participating sites had IRB approval from their local IRB. All subjects consented to participate in FROST and in The Registry. Consent for publication All subjects enrolled in FROST consented to allowing their data to be published. Competing interests TB receives consulting fees from UCB. All other authors have no competing interests. Funding Funding for this project was provided to CARRA, Inc. in part by Genentech, a member of the Roche Group. Acknowledgements The authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA. Funding for this project was provided to CARRA, Inc. in part by Genentech, a member of the Roche Group. This work could not have been accomplished without the aid of the following organizations: The NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) & the Arthritis Foundation. We would also like to thank all participants and hospital sites that recruited patients for the CARRA Registry. The authors thank the following CARRA Registry site principal investigators, sub- investigators and research coordinators: R. Agbayani, S. Akoghlanian, E. Allenspach, E. Anderson, S. Ardoin, S. Armendariz, I. Balboni, L. Ballenger, S. Ballinger, F. Barbar-Smiley, K. Baszis, H. Bell-Brunson, H. Benham, W. Bernal, T. Bigley, B. Binstadt, M. Blakley, J. Bohnsack, A. Brown, M. Buckley, D. Bullock, B. Cameron, S. Canna, E. Cassidy, J. Chang, V. Chauhan, T. Chinn, P. Chira, A. Cooper, J. Cooper, C. Correll, L. Curiel-Duran, M. Curry, A. Dalrymple, D. De Ranieri, F. Dedeoglu, M. DeGuzman, N. Delnay, V. Dempsey, J. Dowling, J. Drew, K. Driest, Q. Du, D. Durkee, M. Eckert, C. Edens, M. Elder, S. Fadrhonc, L. Favier, B. Feldman, I. Ferguson, B. Ferreira, L. Fogel, E. Fox, R. Fuhlbrigge, J. Fuller, N. George, D. Gerstbacher, M. Gillispie-Taylor, I. Goh, D. Goldsmith, S. Grevich, T. Griffin, M. Guevara, P. Guittar, M. Hager, T. Hahn, O. Halyabar, M. Hance, S. Haro, J. Harris, J. Hausmann, K. Hayward, L. Henderson, A. Hersh, S. Hillyer, L. Hiraki, M. Hiskey, P. Hobday, C. Hoffart, M. Holland, M. Hollander, M. Horwitz, J. Hsu, A. Huber, M. Ibarra, C. Inman, S. Jackson, K. James, G. Janow, S. Jones, K. Jones, J. Jones, C. Justice, U. Khalsa, B. Kienzle, S. Kim, Y. Kimura, M. Kitcharoensakkul, T. Klausmeier, K. Klein, M. Klein-Gitelman, S. Kramer, J. Lai, B. Lang, S. Lapidus, E. Lawson, R. Laxer, P. Lee, T. Lee, M. Lerman, D. Levy, S. Li, C. Lin, N. Ling, M. Lo, S. Lvovich, J. Maller, A. Martyniuk, K. McConnell, I. McHale, E. Meidan, E. Mellins, M. Miller, R. Modica, K. Moore, T. Moussa, V. Mruk, E. Muscal, K. Nanda, L. Nassi, J. Neely, L. Newhall, P. Nigrovic, B. Nolan, E. Oberle, O. Okeke, M. Oliver, K. O'Neil, R. Oz, A. Paller, J. Patel, P. Pepmueller, K. Phillippi, R. Pooni, S. Protopapas, B. Puplava, S. Radhakrishna, S. Ramsey, H. Reid, S. Ringold, M. Riordan, M. Riskalla, M. Ritter, M. Rodriquez, K. Rojas, M. Rosenkranz, T. Rubinstein, C. Sandborg, L. Scalzi, K. Schikler, K. Schmidt, E. Schmitt, R. Schneider, C. Seper, J. Shalen, R. Sheets, S. Shenoi, J. Shirley, E. Silverman, V. Sivaraman, C. Smith, J. Soep, M. Son, L. Spiegel, H. Stapp, S. Stern, A. Stevens, B. Stevens, K. Stewart, E. Stringer, R. Sundel, M. Sutter, R. Syed, R. Syed, T. Tanner, G. Tarshish, S. Tarvin, M. Tesher, A. Thatayatikom, B. Thomas, D. Toib, K. Torok, C. Toruner, S. Tse, T. Valcarcel, N. Vasquez, R. Vehe, J. Velez, E. von Scheven, S. Vora, L. Wagner-Weiner, D. Wahezi, M. Waterfield, P. Weiss, J. Weiss, A. White, L. Woolnough, T. Wright, M. Yee, R. Yeung, K. Yomogida, Y. Zhao, A. Zhu. Authors' information (optional) Not Applicable References Pardeo M, Bracaglia C, De Benedetti F. Systemic juvenile idiopathic arthritis: New insights into pathogenesis and cytokine directed therapies. Best Pract Res Clin Rheumatol 2017;31:505-16. Kimura Y, Vastert S. Systemic Juvenile Idiopathic Arthritis. In: Petty R, Laxer R, Lindsley C, Wedderburn L, Mellins E, Fuhlbrigge R, eds. Textbook of Pediatric Rheumatology. 8 ed. Philadelphia, PA: Elsevier; 2021:216-27. Kimura Y, Weiss JE, Haroldson KL, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2013;65:745-52. Schulert GS, Yasin S, Carey B, et al. Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors. Arthritis Rheumatol 2019;71:1943-54. Saper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis 2019;78:1722-31. Beukelman T, Tomlinson G, Nigrovic PA, et al. First-line options for systemic juvenile idiopathic arthritis treatment: an observational study of Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans. Pediatr Rheumatol Online J 2022;20:113. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:929-36. Beukelman T, Kimura Y, Ilowite NT, et al. The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months. Pediatr Rheumatol Online J 2017;15:30. DeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2012;64:1001-10. Kimura Y, DeWitt EM, Beukelman T, et al. Adding canakinumab to the Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for systemic juvenile idiopathic arthritis: Comment on the article by DeWitt et al. Arthritis Care Res (Hoboken) 2014;66:1430-1. Nigrovic PA, Beukelman T, Tomlinson G, Feldman BM, Schanberg LE, Kimura Y. Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST). Clin Trials 2018;15:268-77. Trincianti C, Van Dijkhuizen EHP, Alongi A, et al. Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2021;73:1966-75. Tibaldi J, Pistorio A, Aldera E, et al. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 2020;59:3505-14. Ter Haar NM, van Dijkhuizen EHP, Swart JF, et al. Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study. Arthritis Rheumatol 2019;71:1163-73. Erkens R, Den Engelsman G, De Roock S, et al. Biomarker-guided Treatment-and-stop-strategy for Recombinant IL-1Receptor Antagonist (Anakinra) in Patients with Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2024;76:9. Barut K, Adrovic A, Sahin S, et al. Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: A single-center experience. International Journal of Rheumatic Diseases 2019;22:1661-9. Glerup M, Rypdal V, Arnstad ED, et al. Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow-Up in the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort. Arthritis Care Res (Hoboken) 2020;72:507-16. Chhabra A, Robinson C, Houghton K, et al. Long-term outcomes and disease course of children with juvenile idiopathic arthritis in the ReACCh-Out cohort: a two-centre experience. Rheumatology (Oxford) 2020;59:3727-30. Nigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545-55. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396-406. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385-95. Brunner HI, Ruperto N, Ramanan AV, et al. Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 2024;63:2535-46. Onel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken) 2022;74:521-37. Fautrel B, Mitrovic S, De Matteis A, et al. EULAR/PReS recommendations for the diagnosis and management of Still’s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still’s disease. Annals of the Rheumatic Diseases 2024;83:1614-27. Bindoli S, De Matteis A, Mitrovic S, Fautrel B, Carmona L, De Benedetti F. Efficacy and safety of therapies for Still’s disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still’s disease. Annals of the Rheumatic Diseases 2024;83:1731-47. Additional Declarations Competing interest reported. TB receives consulting fees from UCB. All other authors have no competing interests. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 10 Mar, 2026 Reviews received at journal 10 Mar, 2026 Reviews received at journal 02 Mar, 2026 Reviews received at journal 28 Feb, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers agreed at journal 14 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers invited by journal 09 Feb, 2026 Editor assigned by journal 25 Dec, 2025 Submission checks completed at journal 25 Dec, 2025 First submitted to journal 15 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8368751","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589197824,"identity":"6a1dc432-b5d1-4da5-8904-30cd718b4dba","order_by":0,"name":"Timothy Hahn","email":"data:image/png;base64,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","orcid":"","institution":"Penn State Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Timothy","middleName":"","lastName":"Hahn","suffix":""},{"id":589197825,"identity":"03f5c0b1-7324-43f1-aa1e-a4aa3e35a48f","order_by":1,"name":"George Tomlinson","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"George","middleName":"","lastName":"Tomlinson","suffix":""},{"id":589197826,"identity":"4cf3014f-5f61-40a2-90bc-1e3da3b53be6","order_by":2,"name":"Yukiko Kimura","email":"","orcid":"","institution":"Joseph M Sanzari Children's Hospital, Hackensack Meridian School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yukiko","middleName":"","lastName":"Kimura","suffix":""},{"id":589197827,"identity":"a7dfecd9-7c03-4d11-b5a4-9ccef28fd902","order_by":3,"name":"Vincent Del Gaizo","email":"","orcid":"","institution":"Childhood Arthritis and Rheumatology Research Alliance","correspondingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"Del","lastName":"Gaizo","suffix":""},{"id":589197828,"identity":"ed575e82-8569-41cc-9c7c-acf2b71fae9c","order_by":4,"name":"Timothy Beukelman","email":"","orcid":"","institution":"Childhood Arthritis and Rheumatology Research Alliance","correspondingAuthor":false,"prefix":"","firstName":"Timothy","middleName":"","lastName":"Beukelman","suffix":""}],"badges":[],"createdAt":"2025-12-15 17:08:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8368751/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8368751/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102462883,"identity":"3f78ffb0-0710-4193-978f-abb8d4fa947d","added_by":"auto","created_at":"2026-02-12 01:12:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":81927,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative proportion of patients achieving CID for the first time during long term follow\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8368751/v1/78e47c447a575933239795da.png"},{"id":102462884,"identity":"2d790fba-8286-4af0-b547-181db8c62eb3","added_by":"auto","created_at":"2026-02-12 01:12:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31593,"visible":true,"origin":"","legend":"\u003cp\u003eProportion of patients in CID at each study visit with 95% confidence interval\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8368751/v1/f7aff4c7152cbd45c5b2e146.png"},{"id":102746014,"identity":"9834bcd6-a98b-4208-bdad-03052f979a07","added_by":"auto","created_at":"2026-02-16 08:55:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":655147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8368751/v1/b6e1c77a-83a3-4b2b-9eab-f9d4fdf20394.pdf"}],"financialInterests":"Competing interest reported. TB receives consulting fees from UCB. All other authors have no competing interests.","formattedTitle":"Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial","fulltext":[{"header":"Background","content":"\u003cp\u003eSystemic Juvenile Idiopathic Arthritis (sJIA) is an autoinflammatory condition characterized by an abnormal innate immune response and significant systemic inflammation driven by massive overproduction of proinflammatory cytokines, in particular IL-1 and IL-6\u003csup\u003e1,2\u003c/sup\u003e. The most common symptoms include fever, arthritis, and a distinguishing evanescent rash. sJIA is associated with life threatening complications including macrophage activation syndrome (MAS) and the more recently described sJIA associated lung disease (sJIA-LD)\u003csup\u003e3\u0026ndash;5\u003c/sup\u003e. Historically, there was also significant morbidity related to chronic steroid exposure which was often necessary to control disease.\u003c/p\u003e \u003cp\u003eConsiderable advances in the understanding of the inflammation in sJIA over the past two decades have led to more targeted therapies including IL-1 and IL-6 inhibitors. In 2022 the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published the results of a prospective observational study called FiRst Line Options for sJIA Treatment (FROST), which was designed to compare the effectiveness of 4 Consensus Treatment Plans (CTPs) in new-onset systemic JIA (sJIA)\u003csup\u003e6\u003c/sup\u003e. The CTPs were grouped into biologic CTPs, in which patients were initially treated with an IL-1 inhibitor (anakinra or canakinumab) or IL-6 inhibitor (tocilizumab), and non-biologic CTPs, which included glucocorticoids (GC) alone or methotrexate with or without glucocorticoids.\u003c/p\u003e \u003cp\u003eIn FROST, 86% of patients were treated according to one of the biologic CTPs (IL-1 inhibitors or IL-6 inhibitors) at enrollment. The most commonly reported reasons for choosing a biologic CTP were likelihood of effectiveness for systemic features, minimization of systemic glucocorticoids, and likelihood of effectiveness for arthritis. Half of the patients who started on a non-biologic CTP at enrollment started a biologic during the first three months of follow up. The small number of patients treated with non-biologic CTPs made it impossible to compare rates of achieving clinically inactive disease (CID) between the biologics and nonbiologic treatment groups\u003csup\u003e7\u003c/sup\u003e. Nevertheless, there were encouraging results from the study, which included that the majority of patients were able to achieve a state of CID without concurrent use of glucocorticoids at 9 months. The most frequently reported safety events included MAS and hospitalization for flare of underlying disease.\u003c/p\u003e \u003cp\u003eAll patients enrolled in FROST were also enrolled in the CARRA Registry\u003csup\u003e8\u003c/sup\u003e, which allowed for continued observation of clinical status, medication usage, and safety events. The purpose of this study is to describe the long-term clinical and safety outcomes for patients enrolled in the FROST trial.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe methodology used to develop the four CTPs has been previously reported\u003csup\u003e9,10\u003c/sup\u003e, as has the design of the FROST study\u003csup\u003e6,11\u003c/sup\u003e. FROST enrolled patients from 2016 to 2019 from 32 CARRA sites throughout the US and Canada. Long-term follow up included study visits occurring every 3 months between 12- and 24-months post enrollment, subsequently continuing to have follow up visits every 6 months (+/- 3-month window) in the CARRA Registry until they aged out of pediatric rheumatology care, transferred care to a non-CARRA Registry site, were discharged from rheumatology care due to long-term remission, or were lost to follow up, defined as no study visit for 15 consecutive months.\u003c/p\u003e \u003cp\u003eThe CTPs included recommendations for the timing of clinical reassessment and adjustment of glucocorticoids and DMARDs over the first 9 months of treatment. Beyond 9 months, the timing of clinical follow up, tapering of glucocorticoids, and sequence of medication changes was determined solely by the treating physician and the patient/family. Serious adverse events (SAE) were recorded, along with prespecified safety events that may not have met SAE criteria, including MAS.\u003c/p\u003e \u003cp\u003eThe primary study outcome was achievement of CID according to the Wallace/American College of Rheumatology provisional criteria without use of glucocorticoids at 24- and 36-months.\u003csup\u003e7\u003c/sup\u003e Selected secondary outcomes included CID irrespective of current GC use, clinical juvenile idiopathic arthritis disease activity score based on 10 joints (cJADAS-10)\u0026thinsp;\u0026le;\u0026thinsp;2.5 without current fever or GC use, cJADAS-10\u0026thinsp;\u0026le;\u0026thinsp;2.5 without current fever irrespective of GC use, GC use independent of CID, any biologic or non-biologic DMARD use, and proportion of the entire cohort achieving CID at any point during follow up. The proportion of the cohort having achieved CID at each study visit and the proportion achieving CID at any point up to and including each study visit were both calculated and plotted over time.\u003c/p\u003e \u003cp\u003eCriteria for CID requires that patients have (1) no active arthritis (2) no systemic features of sJIA (3) no active uveitis (4) physician global assessment of disease activity score of zero (5) duration of morning stiffness\u0026thinsp;\u0026le;\u0026thinsp;15 minutes (6) ESR or CRP within normal limits, if available. The cJADAS-10 ranges from 0\u0026ndash;30 and is composed of joint count (maximum of 10), physician global assessment (0\u0026ndash;10), and patient/parent global assessment (0\u0026ndash;10). We used the cutoff for defining inactive disease in polyarticular JIA of a cJADAS-10 of \u0026le;\u0026thinsp;2.5 but also required the absence of fever\u003csup\u003e12\u003c/sup\u003e. Because the height of fever is not collected in the CARRA Registry, the systemic Juvenile Arthritis Disease Activity Score (sJADAS) could not be calculated\u003csup\u003e13\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBoth the 24- and 36-month visits had a 6 month visit window (i.e., 18 to 24 months and 30 to 36 months, respectively). For patients with more than one study visit during the six-month window, they were considered to have achieved CID if they met the definition of CID at any one of the study visits.\u003c/p\u003e \u003cp\u003eFor study visits where individual components needed to define CID or cJADAS-10 were missing, the patient was not included in the analysis (i.e., a complete case analysis with no imputation was performed). This resulted in different denominators for some outcome measures at a specific time point.\u003c/p\u003e \u003cp\u003eRecent medication use at a study visit was defined as either being on the medication at the visit or having stopped the medication within the 2 months prior to the visit to ensure that disease was in stable remission off medication. Data at the time of last study follow-up visit is also presented. Adverse events are expressed as events per 100 person-years, defined as the cumulative duration of safety follow-up across all participants. The CARRA Registry and FROST were approved by the Duke IRB\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eBaseline characteristics of the 73 patients enrolled in FROST are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e including those who were included in the analysis of the primary outcome at 24 and 36 months (N\u0026thinsp;=\u0026thinsp;41 and N\u0026thinsp;=\u0026thinsp;32, respectively). Due to missed visits, not all patients included in the 36-month outcome were included in the 24-month outcome assessment. As expected, the majority of patients in long-term follow-up had started on a biologic CTP (87.6%). During the follow-up period, the most frequently administered medication was anakinra, utilized in 68.5% of patients at some point. Canakinumab was the second most common treatment, prescribed to 56.2% of patients, followed by tocilizumab, which was used in 26% of cases. Notably, 19.1% of patients received both an IL-1 inhibitor and an IL-6 inhibitor at some time during the follow-up period. By 36 months there was only 1 patient in follow up who had started on a non-biologic CTP. Disease activity at baseline, measured by median cJADAS-10, physician global assessment, patient global assessment, joint count and all lab measures, for patients included in long-term follow up was similar as for the entire cohort.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline patient characteristics for the entire cohort and for patients with follow up at 24 and 36 months.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMonth 24 Patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMonth 36 Patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow Up (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.3 [1.6, 4.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5 [2.4, 4.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.4 [3.4, 5.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCTP (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucocorticoids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 ( 8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 ( 7.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 ( 0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMethotrexate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 ( 5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 ( 4.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 ( 3.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-1 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 ( 80.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35 ( 85.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 ( 93.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 ( 5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 ( 2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 ( 3.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.8 [4.1, 11.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.1 [4.0, 11.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.1 [4.6, 11.3]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 ( 60.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 ( 61.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 ( 71.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysician global assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.0 [5.0, 7.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 [5.0, 7.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.0 [5.0, 7.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient global assessment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0 [3.2, 8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5 [3.0, 8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0 [3.0, 8.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of active joints\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.0 [2.0, 8.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0 [2.0, 9.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.0 [2.0, 8.8]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArthritis (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32 (100.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRash (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70 ( 95.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 ( 92.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 ( 93.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphadenopathy (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 ( 32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 ( 34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 ( 34.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatomegaly or Splenomegaly (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 ( 20.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 ( 17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 ( 15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerositis (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 ( 9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 ( 12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 ( 15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.0 [57.0, 97.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.0 [58.0, 97.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e67.5 [53.0, 97.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.0 [4.7, 16.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.2 [5.4, 16.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.9 [5.2, 15.5]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e829.0 [249.0, 2603.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e604.5 [234.4, 1543.7]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e859.0 [346.0, 2367.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.1 [8.9, 11.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.0 [8.9, 11.4]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.1 [9.0, 11.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (x10^3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.2 [8.5, 19.1]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.5 [8.8, 15.8]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.3 [8.9, 19.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets (x10^3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e458.0 [353.0, 571.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e399.0 [331.5, 570.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e397.0 [360.5, 500.2]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCHAQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.4 [0.5, 2.0]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2 [0.2, 1.9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.1 [0.1, 2.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecJADAS-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.0 [10.5, 21.5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.0 [10.8, 21.2]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17.0 [11.5, 21.0]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRace (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 ( 8.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 ( 9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 ( 15.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlack\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 ( 9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 ( 12.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 ( 6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHispanic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 ( 17.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 ( 9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 ( 12.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 ( 57.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 ( 58.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 ( 56.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 ( 1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 ( 0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 ( 0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 ( 5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 ( 9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 ( 9.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs of April 2024, there were 27 FROST patients still actively following up in the CARRA Registry. Thirty-five patients had been lost to follow up. The remaining 11 patients either withdrew consent, transitioned to adult rheumatology or were deceased (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eStatus in the CARRA Registry of the at the time of the analysis for the 73 patients enrolled in FROST\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStatus\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStill active\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37.0%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDe facto loss-to-follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease remission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubject withdrew consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.1%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransitioned to adult rheumatology\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeceased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.4%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe primary outcome of CID without concurrent use of glucocorticoid was available for 41 patients at 24 months and 32 patients at 36 months. More patients had data available for calculating cJADAS-10 at both visits. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarizes the clinical outcomes at 24 and 36 months. At 24 months 58.5% of patients were in CID without concurrent use of glucocorticoids. This percentage increased to 65.5% at 36 months. There was 1 additional patient in CID but still on glucocorticoids at 24 months. At 24 months and 36 months the percentage of patients that had cJADAS-10\u0026thinsp;\u0026le;\u0026thinsp;2.5 without fever and without current glucocorticoid use was 81.6% and 80.0%, respectively. Almost all patients were off glucocorticoids at 24 months (90.5%) and at 36 months (90.6%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes at 24 and 36 months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e 24 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCID without current GC use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24/41 (58.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21/32 (65.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCID irrespective of current GC use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25/41 (61.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21/31 (67.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCID without GC or recent biologic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10/49 (20.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8/33 (24.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecJADAS\u0026thinsp;\u0026le;\u0026thinsp;2.5 and no fever without current GC use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40/49 (81.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32/40 (80.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecJADAS\u0026thinsp;\u0026le;\u0026thinsp;2.5 and no fever irrespective of current GC use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42/47 (89.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32/36 (88.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecJADAS\u0026thinsp;\u0026le;\u0026thinsp;2.5 and no fever without current GC use or recent biologic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19/53 (35.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17/40 (42.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn GC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4/42 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3/32 (9.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecent Biologic use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30/41 (73.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25/32 (78.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the cumulative proportion of patients reaching CID at any time during follow up. This percentage continued to increase throughout the duration of the long-term follow-up reaching 78.8% of patients at 24 months and 87.6% by 36 months. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows how the proportion of patients in CID at the specified study visit increases up to 15 months after enrollment then fluctuates for the duration of the study period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAdverse events are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. There was a total of 228.2 person-years of safety observation with a median of 3.3 years (IQR 1.6, 4.4) per patient. There were 15 SAEs observed for a frequency of 6.6 per 100-patient years. The median time between enrollment and SAE was 218 days. There was 1 death due to acute liver failure occurring 2.6 years after enrollment which was previously reported\u003csup\u003e6\u003c/sup\u003e. The most commonly reported SAE was MAS which occurred in 6 subjects. Two of those patients were not receiving biologics or methotrexate at the time of MAS and the others were all receiving IL-1i at the time of MAS. No patients enrolled in FROST were subsequently diagnosed with sJIA-LD during long-term follow-up; however, screening for sJIA-LD was not systematic or protocolized.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerious Adverse Events\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCTCAE grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCurrent Biologic and Non-Biologic use\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Liver Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHepatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra, Tocilizumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein Losing Enteropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere injection site reactions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection requiring IV abx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAppendicitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGolimumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra, Canakinumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSJIA Flare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCanakinumab\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSJIA Flare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra, cyclosporine\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSJIA Flare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAnakinra, Cyclosporine, methotrexate\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDisease status at the last study visit was analyzed for the entire cohort. Importantly, for 35.6% of patients, CID could not be calculated at the most recent study visit due to missing data. Therefore, analysis was limited to patients whose last study visit included all the variables needed to calculate CID status (n\u0026thinsp;=\u0026thinsp;47). Overall, 50.6% of these patients were in CID at the last study visit. This includes 9 patients whose last visit occurred within 3 months after enrollment. When limited to subjects whose last study visit occurred at 24 months or later (n\u0026thinsp;=\u0026thinsp;38), 50% s were in CID. At the last study visit 42.5% of all 73 patients were off all DMARDs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe long-term outcomes of the FROST trial provide valuable insights into the evolving therapeutic landscape of sJIA, underscoring the effectiveness and safety of early biologic use in achieving a state of inactive disease. As previously reported, the majority of patients in FROST had achieved CID (57%) or had a cJADAS-10 of \u0026le;\u0026thinsp;2.5 without fever or glucocorticoids (75%) at 9 months. This current study demonstrated that for patients who did not have complete response in the first 9\u0026ndash;12 months there is still opportunity for them to achieve CID. This was best demonstrated by the increase in the proportion of patients meeting the primary endpoint of CID at 24 months from 58.5% to 65.5% at 36 months a trend best demonstrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. It was also highly encouraging to see that nearly all patients were off glucocorticoids at 24 months after enrollment while nearly half of patients were off all DMARDs at the last study visit.\u003c/p\u003e \u003cp\u003eOur observations regarding sJIA outcomes are consistent with other cohorts with longer observation times that showed patients with sJIA have the highest chance of remission off medications among all JIA categories. In a prospective single center cohort of children with systemic juvenile idiopathic arthritis (sJIA) managed with a treat to target approach and followed for five years, 96% of patients achieved remission at the five-year time point, with the majority (75%) discontinuing all medications by that time.\u003csup\u003e14\u003c/sup\u003e This study, in conjunction with a similar follow up study, suggests that early initiation of anakinra, followed by biomarker-guided discontinuation, may be associated with high remission rates both within the first year and at long-term follow-up\u003csup\u003e15\u003c/sup\u003e. Similar long term outcomes were reported from a large retrospective cohort in which 98% of patients were in remission at a median of 5 years after starting treatment with 48.8% in remission off medication.\u003csup\u003e16\u003c/sup\u003e In a small cohort of children with JIA from Nordic countries, more than 80% of patients with sJIA had inactive disease and 85% were off medications at 18 years of follow up\u003csup\u003e17\u003c/sup\u003e. In Canadian children with sJIA, 70% of children were in remission off medications after an average of 6 years of follow up\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhen interpreting the long-term data, it is important to consider the potential clinical courses that patients with sJIA might follow. Many patients will have a monophasic course while others will follow a polyphasic course characterized by periods of disease remission and disease flares which may vary in severity, or a chronic course which does not remit. It is possible that a significant proportion of patients lost to follow up were patients with monophasic disease who self-elected to no longer follow up due to remission off medications, which is a common scenario in pediatric rheumatology. Only patients who were discharged from care by the treating physician were included in the \u0026ldquo;disease remission\u0026rdquo; category. This may have resulted in a falsely low proportion of patients achieving CID at 2 and 3 years in our study, as these patients were not included in the numerator or the denominator. Patients with polyphasic or relapsing chronic disease may be a reason that we saw that the cumulative incidence of achieving CID was higher than the proportion of patients in CID in the specified time points for the cross-sectional analysis. It is possible that many of the subjects who were not in a state of CID at 24 and 36 months had been in CID, but experienced a flare of their disease at that visit. This highlights the critical need to better understand the factors that lead to disease flares once patients achieve CID. This study was not designed to evaluate flares, much less the etiology of flares; thus, we cannot identify if flares were related to potentially modifiable factors such as intentional medication withdrawal or non-adherence or from non-modifiable factors such as incidental infection.\u003c/p\u003e \u003cp\u003eAdverse events reported during the long term follow up of the FROST study occurred at a rate similar to or less than what has been reported in prior clinical trials of biologics in systemic JIA\u003csup\u003e19\u0026ndash;22\u003c/sup\u003e. No patients were diagnosed with sJIA-LD during follow up. However, lung disease screening was not systematic or protocolized. Additionally, there may have been selection bias during enrollment in FROST, as patients who could not be safely treated with a CTP were not eligible. This may have excluded patients with significant MAS at diagnosis, a factor that has been reported to be associated with increased risk of developing lung disease\u003csup\u003e4,5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe FROST study had several limitations that have been previous discussed, including lack of randomization, missing data, and challenges with enrollement\u003csup\u003e6\u003c/sup\u003e. In the long-term follow-up cohort a significant percentage of patients were lost to follow prior to the 2 and 3 year outcome assessment. Although we cannot say for certain, we suspect many patients were lost to follow-up due to inactive disease and self-discontinuation of care. If these patients had been included in the analysis, the proportion achieving the primary endpoint would have been higher.\u003c/p\u003e \u003cp\u003e In the time since the FROST study was completed, new guidelines put forth by the American College of Rheumatology included recommendations for the initial treatment of patients with treatment-na\u0026iuml;ve sJIA with and without MAS. For sJIA without MAS the guidelines included a conditional recommendation against oral glucocorticoids as initial monotherapy and strong recommendation against conventional synthetic DMARDS (methotrexate or calcineurin inhibitors) as initial monotherapy. Conversely, biologic DMARDs including anakinra, canakinumab, and tocilizumab were conditionally recommended as initial monotherapy\u003csup\u003e23\u003c/sup\u003e. Similar recommendations for treatment of Still\u0026rsquo;s disease were published by the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PReS) in 2024\u003csup\u003e24\u003c/sup\u003e. These recommendations included strong agreement regarding initiation of an IL-1 or an IL-6 inhibitor as early as possible when the diagnosis is established. This approach is supported by studies that showed increased remission rates for patients starting biologic treatment early in the course of the disease.\u003csup\u003e25\u003c/sup\u003e The results of FROST support the recommendations that biologics as first line treatment leads to good outcomes for the majority of patients with sJIA.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePatients with sJIA enrolled in FROST continued to improve during the 2nd and 3rd year of follow-up, with the majority of observable patients achieving CID and discontinuing GCs. SAEs were not common and were predominantly due to disease flare or MAS. The FROST cohort will continue to be followed in the CARRA Registry, providing further longer-term information about the contemporary course of sJIA patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe CARRA Registry and the FROST study were approved by the Duke IRB. Participating sites had IRB approval from their local IRB. All subjects consented to participate in FROST and in The Registry.\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eAll subjects enrolled in FROST consented to allowing their data to be published.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TB receives consulting fees from UCB. All other authors have no competing interests.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eFunding for this project was provided to CARRA, Inc. in part by Genentech, a member of the Roche Group.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors wish to acknowledge CARRA and the ongoing Arthritis Foundation financial support of CARRA. Funding for this project was provided to CARRA, Inc. in part by Genentech, a member of the Roche Group. This work could not have been accomplished without the aid of the following organizations: The NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) \u0026amp; the Arthritis Foundation. \u0026nbsp;We would also like to thank all participants and hospital sites that recruited patients for the CARRA Registry. The authors thank the following CARRA Registry site principal investigators, sub- investigators and research coordinators: R. Agbayani, S. Akoghlanian, E. Allenspach, E. Anderson, S. Ardoin, S. Armendariz, I. Balboni, L. Ballenger, S. Ballinger, F. Barbar-Smiley, K. Baszis, H. Bell-Brunson, H. Benham, W. Bernal, T. Bigley, B. Binstadt, M. Blakley, J. Bohnsack, A. Brown, M. Buckley, D. Bullock, B. Cameron, S. Canna, E. Cassidy, J. Chang, V. Chauhan, T. Chinn, P. Chira, A. Cooper, J. Cooper, C. Correll, L. Curiel-Duran, M. Curry, A. Dalrymple, D. De Ranieri, F. Dedeoglu, M. DeGuzman, N. Delnay, V. Dempsey, J. Dowling, J. Drew, K. Driest, Q. Du, D. Durkee, M. Eckert, C. Edens, M. Elder, S. Fadrhonc, L. Favier, B. Feldman, I. Ferguson, B. Ferreira, L. Fogel, E. Fox, R. Fuhlbrigge, J. Fuller, N. George, D. Gerstbacher, M. Gillispie-Taylor, I. Goh, D. Goldsmith, S. Grevich, T. Griffin, M. Guevara, P. Guittar, M. Hager, T. Hahn, O. Halyabar, M. Hance, S. Haro, J. Harris, J. Hausmann, K. Hayward, L. Henderson, A. Hersh, S. Hillyer, L. Hiraki, M. Hiskey, P. Hobday, C. Hoffart, M. Holland, M. Hollander, M. Horwitz, J. Hsu, A. Huber, M. Ibarra, C. Inman, S. Jackson, K. James, G. Janow, S. Jones, K. Jones, J. Jones, C. Justice, U. Khalsa, B. Kienzle, S. Kim, Y. Kimura, M. Kitcharoensakkul, T. Klausmeier, K. Klein, M. Klein-Gitelman, S. Kramer, J. Lai, B. Lang, S. Lapidus, E. Lawson, R. Laxer, P. Lee, T. Lee, M. Lerman, D. Levy, S. Li, C. Lin, N. Ling, M. Lo, S. Lvovich, J. Maller, A. Martyniuk, K. McConnell, I. McHale, E. Meidan, E. Mellins, M. Miller, R. Modica, K. Moore, T. Moussa, V. Mruk, E. Muscal, K. Nanda, L. Nassi, J. Neely, L. Newhall, P. Nigrovic, B. Nolan, E. Oberle, O. Okeke, M. Oliver, K. O'Neil, R. Oz, A. Paller, J. Patel, P. Pepmueller, K. Phillippi, R. Pooni, S. Protopapas, B. Puplava, S. Radhakrishna, S. Ramsey, H. Reid, S. Ringold, M. Riordan, M. Riskalla, M. Ritter, M. Rodriquez, K. Rojas, M. Rosenkranz, T. Rubinstein, C. Sandborg, L. Scalzi, K. Schikler, K. Schmidt, E. Schmitt, R. Schneider, C. Seper, J. Shalen, R. Sheets, S. Shenoi, J. Shirley, E. Silverman, V. Sivaraman, C. Smith, J. Soep, M. Son, L. Spiegel, H. Stapp, S. Stern, A. Stevens, B. Stevens, K. Stewart, E. Stringer, R. Sundel, M. Sutter, R. Syed, R. Syed, T. Tanner, G. Tarshish, S. Tarvin, M. Tesher, A. Thatayatikom, B. Thomas, D. Toib, K. Torok, C. Toruner, S. Tse, T. Valcarcel, N. Vasquez, R. Vehe, J. Velez, E. von Scheven, S. Vora, L. Wagner-Weiner, D. Wahezi, M. Waterfield, P. Weiss, J. Weiss, A. White, L. Woolnough, T. Wright, M. Yee, R. Yeung, K. Yomogida, Y. Zhao, A. Zhu.\u003c/p\u003e\n\u003cp\u003eAuthors' information (optional)\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003cbr\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePardeo M, Bracaglia C, De Benedetti F. Systemic juvenile idiopathic arthritis: New insights into pathogenesis and cytokine directed therapies. Best Pract Res Clin Rheumatol 2017;31:505-16.\u003c/li\u003e\n\u003cli\u003eKimura Y, Vastert S. Systemic Juvenile Idiopathic Arthritis. In: Petty R, Laxer R, Lindsley C, Wedderburn L, Mellins E, Fuhlbrigge R, eds. Textbook of Pediatric Rheumatology. 8 ed. Philadelphia, PA: Elsevier; 2021:216-27.\u003c/li\u003e\n\u003cli\u003eKimura Y, Weiss JE, Haroldson KL, et al. Pulmonary hypertension and other potentially fatal pulmonary complications in systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2013;65:745-52.\u003c/li\u003e\n\u003cli\u003eSchulert GS, Yasin S, Carey B, et al. Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease: Characterization and Risk Factors. Arthritis Rheumatol 2019;71:1943-54.\u003c/li\u003e\n\u003cli\u003eSaper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis 2019;78:1722-31.\u003c/li\u003e\n\u003cli\u003eBeukelman T, Tomlinson G, Nigrovic PA, et al. First-line options for systemic juvenile idiopathic arthritis treatment: an observational study of Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans. Pediatr Rheumatol Online J 2022;20:113.\u003c/li\u003e\n\u003cli\u003eWallace CA, Giannini EH, Huang B, Itert L, Ruperto N. American College of Rheumatology provisional criteria for defining clinical inactive disease in select categories of juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2011;63:929-36.\u003c/li\u003e\n\u003cli\u003eBeukelman T, Kimura Y, Ilowite NT, et al. The new Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry: design, rationale, and characteristics of patients enrolled in the first 12 months. Pediatr Rheumatol Online J 2017;15:30.\u003c/li\u003e\n\u003cli\u003eDeWitt EM, Kimura Y, Beukelman T, et al. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 2012;64:1001-10.\u003c/li\u003e\n\u003cli\u003eKimura Y, DeWitt EM, Beukelman T, et al. Adding canakinumab to the Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for systemic juvenile idiopathic arthritis: Comment on the article by DeWitt et al. Arthritis Care Res (Hoboken) 2014;66:1430-1.\u003c/li\u003e\n\u003cli\u003eNigrovic PA, Beukelman T, Tomlinson G, Feldman BM, Schanberg LE, Kimura Y. Bayesian comparative effectiveness study of four consensus treatment plans for initial management of systemic juvenile idiopathic arthritis: FiRst-Line Options for Systemic juvenile idiopathic arthritis Treatment (FROST). Clin Trials 2018;15:268-77.\u003c/li\u003e\n\u003cli\u003eTrincianti C, Van Dijkhuizen EHP, Alongi A, et al. Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score\u0026nbsp;Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2021;73:1966-75.\u003c/li\u003e\n\u003cli\u003eTibaldi J, Pistorio A, Aldera E, et al. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 2020;59:3505-14.\u003c/li\u003e\n\u003cli\u003eTer Haar NM, van Dijkhuizen EHP, Swart JF, et al. Treatment to Target Using Recombinant Interleukin-1 Receptor Antagonist as First-Line Monotherapy in New-Onset Systemic Juvenile Idiopathic Arthritis: Results From a Five-Year Follow-Up Study. Arthritis Rheumatol 2019;71:1163-73.\u003c/li\u003e\n\u003cli\u003eErkens R, Den Engelsman G, De Roock S, et al. Biomarker-guided Treatment-and-stop-strategy for Recombinant IL-1Receptor Antagonist (Anakinra) in Patients with Systemic Juvenile Idiopathic Arthritis. Arthritis Rheumatol 2024;76:9.\u003c/li\u003e\n\u003cli\u003eBarut K, Adrovic A, Sahin S, et al. Prognosis, complications and treatment response in systemic juvenile idiopathic arthritis patients: A single-center experience. International Journal of Rheumatic Diseases 2019;22:1661-9.\u003c/li\u003e\n\u003cli\u003eGlerup M, Rypdal V, Arnstad ED, et al. Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow-Up in the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort. Arthritis Care Res (Hoboken) 2020;72:507-16.\u003c/li\u003e\n\u003cli\u003eChhabra A, Robinson C, Houghton K, et al. Long-term outcomes and disease course of children with juvenile idiopathic arthritis in the ReACCh-Out cohort: a two-centre experience. Rheumatology (Oxford) 2020;59:3727-30.\u003c/li\u003e\n\u003cli\u003eNigrovic PA, Mannion M, Prince FH, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011;63:545-55.\u003c/li\u003e\n\u003cli\u003eRuperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396-406.\u003c/li\u003e\n\u003cli\u003eDe Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2385-95.\u003c/li\u003e\n\u003cli\u003eBrunner HI, Ruperto N, Ramanan AV, et al. Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 2024;63:2535-46.\u003c/li\u003e\n\u003cli\u003eOnel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Arthritis Care Res (Hoboken) 2022;74:521-37.\u003c/li\u003e\n\u003cli\u003eFautrel B, Mitrovic S, De Matteis A, et al. EULAR/PReS recommendations for the diagnosis and management of Still\u0026rsquo;s disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still\u0026rsquo;s disease. Annals of the Rheumatic Diseases 2024;83:1614-27.\u003c/li\u003e\n\u003cli\u003eBindoli S, De Matteis A, Mitrovic S, Fautrel B, Carmona L, De Benedetti F. Efficacy and safety of therapies for Still\u0026rsquo;s disease and macrophage activation syndrome (MAS): a systematic review informing the EULAR/PReS guidelines for the management of Still\u0026rsquo;s disease. Annals of the Rheumatic Diseases 2024;83:1731-47.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Systemic juvenile idiopathic arthritis, juvenile idiopathic arthritis, biologics, treatment, outcomes","lastPublishedDoi":"10.21203/rs.3.rs-8368751/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8368751/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eSystemic juvenile idiopathic arthritis (sJIA) is a severe autoinflammatory disease associated with substantial morbidity, including macrophage activation syndrome (MAS), sJIA-associated lung disease, and glucocorticoid (GC)-related toxicity. CARRA\u0026rsquo;s FiRst Line Options for sJIA Treatment (FROST) study demonstrated favorable short-term outcomes with early biologic therapy, but long-term outcomes have not yet been described.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003e Patients with new-onset sJIA enrolled in FROST (2016\u0026ndash;2019) were followed longitudinally through the CARRA Registry. Four consensus treatment plans (CTPs) were evaluated, including biologic (IL-1 or IL-6 inhibitors) and non-biologic approaches. Long-term follow-up occurred through 36 months. The primary outcome was achievement of clinically inactive disease (CID) by Wallace/ACR provisional criteria without concurrent GC use at 24 and 36 months. Secondary outcomes included CID irrespective of GC use, cJADAS-10\u0026thinsp;\u0026le;\u0026thinsp;2.5 without fever, medication utilization, and safety events. Adverse events were expressed as events per 100 person-years.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eSeventy-three patients were enrolled; 87.6% initiated biologic therapy. At 24 and 36 months, 41 and 32 patients, respectively, had evaluable data for the primary outcome. CID without GC use was achieved by 58.5% of patients at 24 months and 65.5% at 36 months. At both time points, over 80% of patients achieved cJADAS-10\u0026thinsp;\u0026le;\u0026thinsp;2.5 without fever and without GC use. Nearly all patients were off GCs at 24 and 36 months (\u0026gt;\u0026thinsp;90%). The cumulative proportion of patients achieving CID at any time during follow-up increased to 78.8% by 24 months and 87.6% by 36 months. At last follow-up, 42.5% of the cohort was off all DMARDs. Over 228.2 person-years of observation, serious adverse events occurred at a rate of 6.6 per 100 person-years; MAS was the most common SAE. No cases of sJIA-associated lung disease were identified.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003ePatients with sJIA enrolled in FROST demonstrated continued clinical improvement during long-term follow-up, with increasing rates of clinically inactive disease and high rates of glucocorticoid discontinuation. Serious adverse events were uncommon and largely related to disease activity. These findings support early biologic therapy as an effective and durable first-line strategy for sJIA.\u003c/p\u003e","manuscriptTitle":"Two- and 3-Year Outcomes of the Childhood Arthritis and Rheumatology Research Alliance FiRst Line Options for sJIA Treatment (FROST) Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-12 01:12:05","doi":"10.21203/rs.3.rs-8368751/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-10T20:36:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-10T11:42:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T21:32:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-28T11:18:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194305359739111856366892626772096999496","date":"2026-02-17T10:26:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335768049846988340455559020827182444942","date":"2026-02-14T10:31:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"93019541543794536661513564948133468040","date":"2026-02-11T09:32:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218511031567620221413215316439713588485","date":"2026-02-10T20:06:54+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-09T08:23:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-25T13:14:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-25T13:13:25+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Rheumatology","date":"2025-12-15T16:56:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"349494cd-90b5-44b0-9e8a-bf4026350258","owner":[],"postedDate":"February 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T15:53:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-12 01:12:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8368751","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8368751","identity":"rs-8368751","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}