There are over 100 rheumatic diseases and approximately 300,000 children with a pediatric rheumatic disease (PRD) in the United States. The most common PRDs are juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and juvenile dermatomyositis (JDM). Effective and safe medications are essential because there are generally no cures for these conditions. Etanercept was the first biologic therapy for the treatment of JIA, approved in 1999. Since then, other biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) blocking relevant immunologic pathways have been approved for the treatment of JIA, resulting in a marked improvement of disease prognosis. Conversely, there is only one bDMARD that has been approved for cSLE, but none are approved for the treatment of JDM. Lack of approved therapeutic options, with established dosing regimens and known efficacy and safety, remains a central challenge in the treatment of all PRDs, including autoinflammatory diseases, and for complications of PRDs. This review provides an overview of bDMARD and tsDMARD treatments studied for the treatment of various subtypes of JIA, summarizes information from bDMARD studies in other PRDs, with a focus on pivotal trials that led to regulatory approvals, and highlights improved outcomes in patients with JIA with the reception of these newer medications. Further, we outline barriers and challenges in the treatment of other PRDs. Last, we summarize the current regulatory landscape for bDMARD studies and medication approvals for patients with PRDs.

Background: Cerebrovascular accidents (CVA) are one of the most devastating neurologic manifestations of childhood-onset systemic lupus erythematosus (cSLE). The spectrum of CVA in cSLE (CVAcSLE) includes thromboembolic, ischemic, and hemorrhagic events. Despite the severity and potentially disabling effects of CVA, large epidemiologic studies are lacking. Studies of adult-onset systemic lupus erythematosus (aSLE) suggest higher CVA severity and poorer outcomes with aSLE compared to other adults with CVA. Comparative studies on CVA in aSLE and cSLE are lacking. Objectives: To understand the epidemiology of CVAcSLE, and compare CVA outcomes between cSLE and aSLE. Methods: This retrospective cohort study utilized de-identified data over a 20-year period from an international federated real-world patient database (TriNetX). We included all patients with ICD-9 and/or ICD-10 codes corresponding to SLE. The TriNetX database automatically excludes patients greater than 90 years old to maintain confidentiality of the patients. We defined cSLE and aSLE as patients aged ≤ 18 years and ≥ 19 years respectively at the first recorded ICD code corresponding to SLE. We defined CVA as the presence of ICD-9 and/or ICD-10 codes corresponding to transient ischemic attack and/or CVA. Results: Of the 112, 081, 954 patients in the TriNetX cohort, 21803 (0.02%) patients had SLE. Most patients with SLE were female (86%), White (66%) and non-Hispanic (89%) (Table 1). The prevalence of SLE was highest in the United States South compared to other regions (Table 1). The prevalence of CVA was 19% (n = 4123) in SLE patients overall, 8% (n = 30) in cSLE and 19% (n = 4093) in aSLE. In both cSLE and aSLE, the prevalence of CVA was highest in White patients followed by Black and other races; and also higher in non-Hispanic versus Hispanic patients. There was no significant difference in CVA prevalence by sex in both cSLE and aSLE. The odds of having CVA in aSLE was higher than in cSLE [OR 2.90; 95% CI (2.00, 4.21)]. The significantly higher risk in aSLE versus cSLE remained even after adjusting for age, sex, and race [OR 2.19; 95% CI (1.42 – 3.37)]. The risk of CVA was higher in females versus males [OR 1.16; 95% CI (1.05, 1.29)]. There was no significant difference in the 90-day readmission rate following CVA in cSLE compared to aSLE. Conclusion: cSLE is associated with a high risk of CVA as 1 out of 12 children with cSLE will develop a CVA. Given that aSLE patients with CVA have a higher risk of CVA recurrence, and poorer outcomes compared to other non-SLE adults with CVA, further studies are needed on CVA risk factors and longer-term outcomes in cSLE. REFERENCES: NIL. Acknowledgements: This research was funded in part by the 2023 Lupus Research Alliance Diversity in Lupus Research Career Development Award, by NIAMS P30 Core Center grant (AR076316), and the University of Cincinnati Center for Clinical and Translational Science and Training. Disclosure of Interests: None declared.

Cognitive dysfunction (CD) is a neurologic complication of pediatric systemic lupus erythematosus (SLE) that remains poorly understood and understudied, despite the potential negative effects of CD on long-term socioeconomic status and quality of life. Data regarding the prevalence and risk factors for CD in pediatric SLE as well as the optimal screening, treatment, and long-term outcomes for CD are lacking. In this review, we present current knowledge on CD in pediatric SLE with a focus on the application to clinical practice. We discuss the challenges in diagnosis, clinical screening methods, potential impacts, and interventions for this complication. Finally, we discuss the remaining gaps in our knowledge of CD in pediatric SLE, and avenues for future research efforts.

Background: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a poorly understood and heterogeneous manifestation of SLE. Common major NPSLE syndromes include strokes, seizures, myelitis, and aseptic meningitis. Easily obtainable biomarkers are needed to assist in early diagnosis and improve outcomes for NPSLE. A frequent end-result of major syndromes is neuronal or glial injury. Blood-based neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) have been utilized as markers for monitoring disease activity and/or severity in other neurodegenerative and neuroinflammatory diseases; however, they have not been evaluated in active major NPSLE. Methods: This was a case-control study. We enrolled patients aged 12-60 years with active major NPSLE, SLE without active major NPSLE, and healthy controls. Active NPSLE was defined as being <6 months from last new or worsening neuropsychiatric symptom. Demographics, clinical data, and serum or plasma biosamples were collected. Results: Thirteen patients with active major NPSLE, 13 age/sex/kidney function matched SLE controls without active major NPSLE, and 13 age/sex matched healthy controls (mean ages 26.8, 27.3, 26.6 years) were included. 92% of each group were female. Major syndromes included stroke (5), autonomic disorder (3), demyelinating disease (2), aseptic meningitis (2), sensorimotor polyneuropathy (2), cranial neuropathy (1), seizures (1), and myelopathy (2). Mean (standard deviation) blood NfL and GFAP were 3.6 pg/ml (2.0) and 50.4 pg/ml (15.0), respectively, for the healthy controls. Compared to healthy controls, SLE without active major NPSLE had mean blood NfL and GFAP levels 1.3 pg/ml (p = .42) and 1.2 pg/ml higher (p = .53), respectively. Blood NfL was on average 17.9 pg/ml higher (95% CI: 9.2, 34.5; p < .001) and blood GFAP was on average 3.2 pg/ml higher (95% CI: 1.9, 5.5; p < .001) for cases of active major NPSLE compared to SLE without active major NPSLE. In a subset of 6 patients sampled at multiple time points, blood NfL and GFAP decreased after immunotherapy. Conclusions: Blood NfL and GFAP levels are elevated in persons with SLE with active major NPSLE compared to disease matched controls and may lower after immunotherapy initiation. Larger and longitudinal studies are needed to ascertain their utility in a clinical setting.

To determine the relationship of blood neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in persons with systemic lupus erythematosus (SLE) with and without active major neuropsychiatric (NP) systemic lupus erythematosus (NPSLE)

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

ObjectiveWe compared the measurement properties of a traditional physician global assessment of disease activity (PhGA) 10‐cm visual analog scale (PhGA0–10) with that of the three‐point numeric scale (PhGA0–3) in childhood‐onset systemic lupus erythematosus (cSLE) as part of the childhood Lupus Low Disease Activity State (cLLDAS).MethodsWe used a secondary data analysis from a convenience sample of 100 patients with cSLE followed every three months for up to seven visits. Ratings of PhGA0–10, PhGA0–3, parent assessment of patient well‐being (ParGA) (range: 0= very poorly, 10 = very well), disease activity as measured by the SLE disease activity index 2000 (SLEDAI‐2k), Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI, and the British Isles International Lupus Activity Group index (BILAG; A = 9, B = 3, C = 1, D/E = 0) were compared. After linear transformation of PhGA0–10 to a 0 to 3 range (tPhGA0–10), the frequency of PhGA0–3 ≤1 was assessed to estimate the impact of scale type on the scoring of the cLLDAS.ResultsIn 600 visits, the median (range) scores of PhGA0–10, PhGA0–3, SLEDAI‐2k, SELENA‐SLEDAI, and BILAG were 2 (0–10), 1(0–3), 4 (0–28), 4 (0–32), and 2 (0–28), respectively. PhGA0–10 and PhGA0–3 ratings were strong to moderately correlated with (r = 0.73; P < 0.0001) and with more variability for PhGA0–3 ≥2. SELENA‐SLEDAI and SLEDAI‐2k scores were moderately correlated with PhGA0–10 (r = 0.56/0.54; P < 0.0001). ParGA values were weakly correlated with all other measures considered (all r = −0.19 to −0.34). There were 490 of 600 visits with PhGA0−3 ≤1 and 497 of 600 visits with tPhGA0−10 ≤1 (κ (SE) =0.59 (0.04), McNemar P = 0.4).ConclusionPhGA0–3 and PhGA0–10 have comparable measurement properties and yield almost identical cLLDAS rates when used in cSLE.

Chronic recurrent multifocal osteomyelitis is a rare, multisystemic inflammatory disease that affects children and adolescents. We present the case of an African-American adolescent male who presented with recurrent swelling of the temporal region with skull involvement on head imaging, which is atypical for chronic recurrent multifocal osteomyelitis. He had clinical and laboratory improvement after initiation of indomethacin and pamidronate.

Background Physician Global Assessment of Disease Activity (PhGA) are commonly used outcome measures in pediatric rheumatology. For childhood-onset systemic lupus erythematosus (cSLE), the traditional visual analog scale (range: 0 – 10; 0=inactive; 10=very active; PhGA0–10) but also the SELENA-SLEDAI (range: 0–3; 0= none, 1=mild, 2=moderate, 3=severe; PhGA0–3) are used to measure treatment response, flare, and Lupus Low Disease Activity Status (LLDAS) with PhGA0–3 ≤1. Thus, the purpose of this study was to compare the measurement properties of the PhGA0–10 and the PhGA0–3 in cSLE and with scores of the SLEDAI-2k, and the SELENA-SLEDAI. Methods Secondary data analysis from a convenience sample of 100 cSLE followed every 3 months for up to 7 visits.1 Ratings of PhGA0–10, PhGA0–3, parent assessment of patient well- being (ParGA; range: 0= very poorly, 10=very well), SLEDAI-2k and SELENA-SLEDAI were compared. After linear transformation of PhGA0–10 to a 0–3 range (tPhGA0–10) frequency of PhGA0–3≤1 were compared. Results In 601 visits, mean (SD)/median (range) of PhGA0–10, PhGA0–3, SLEDAI-2K and SELENA-SLEDAI were 2.13 (1.87)/2 (0–10), 0.79 (0.64)/1(0–3), 4.63 (4.14)/4 (0–28) and 4.51 (4.1)/4 (0–32) respectively. PhGA0–10 were moderately correlated with PhGA0–3 (r=0.73; p<0.0001; figure 1) with more variability for PhGA0–3 ≥2. ParGA was weakly correlated with PhGA0–10, PhGA0–3, SLEDAI-2k and SELENA-SLEDAI scores (r = -0.34, -0.30, -0.19 and -0.20). SELENA-SLEDAI and SLEDAI-2k scores were highly (r=0.98) correlated with each other. However, SLEDAI-2K/SELENA-SLEDAI scores were weakly correlated with PhGA0–3 (r=0.28/0.28; p <.001) and moderately correlated with PhGA0–10 (r= 0.56/0.54; p <.0001). There were 490/497 of 601 visits with PhGA0–3 ≤1/tPhGA0–10 ≤1 [Kappa (SE) =0.59 (0.04), McNemar p=0.4]. Conclusion Using the traditional PhGA0–10 in cSLE yields almost identical LLDAS rates compared to the PhGA0–3. Given its closer association with the scores of disease activity indices in cSLE, use of the PhGA0–10 may be preferable in pediatric populations. Reference Mina R, Klein-Gitelman MS, Nelson S, Eberhard BA, Higgins G, Singer NG, Onel K, Tucker L, O'Neil KM, Punaro M, Levy DM, Haines K, Martini A, Ruperto N, Lovell D, Brunner HI. Validation of the systemic lupus erythematosus responder index for use in juvenile- onset systemic lupus erythematosus. Ann Rheum Dis. 2014 Feb;73(2):401–6. PMID: 23345596.

Objective Treat-to-target (T2T) strategies are advocated to improve prognosis in childhood-onset SLE (cSLE). Proposed T2T states include SLEDAI score of < 4 (SLEDAI-LD), limited corticosteroid use (low-CS), and lupus low disease activity state (LLDAS). We sought to compare T2T states for their association with cSLE prognosis under consideration of relevant disease characteristics such as pre-existing damage, race and lupus nephritis (LN). Methods Longitudinal data from 165 patients enrolled in the Cincinnati Lupus Registry were included. LN presence was based on renal biopsy, and patients were followed up until 18 years of age. Results The 165 patients (LN: 45, white: 95) entered the registry within a median of 0 (IQR: 0–1) year post diagnosis and were followed up for a median of 4 (IQR: 2–5) years during which 80%, 92% and 94% achieved LLDAS, low-CS and SLEDAI-LD. Patients with LN were significantly less likely to achieve any T2T state (all p < 0.03) and required a significantly longer time to reach them (all p<0.0001). Over the study period, patients maintained low-CS, SLEDAI-LD or LLDAS for a median of 76% (IQR: 48%–100%), 86% (IQR: 55%–100%) or 39% (IQR: 13%–64%) of their follow-up. Significant predictors of failure to maintain LLDAS included LN (p≤0.0062), pre-existing damage (p≤0.0271) and non-white race (p≤0.0013). There were 22%, 20% and 13% of patients who reached SLEDAI-LD, CS-low and LLDAS and nonetheless acquired new damage. Patients with LN had a higher risk of new damage than patients without LN even if achieving low-CS (p=0.009) or LLDAS (p=0.04). Conclusions Patients with LN and pre-existing damage are at higher risk of increased future damage acquisition, even if achieving a T2T state such as LLDAS. Among proposed common T2T states, the LLDAS is the hardest to achieve and maintain. The LLDAS may be considered the preferred T2T measure as it conveys the highest protection from acquiring additional disease damage.

Treatment guidelines provide strategies for managing specific disease conditions based on the best scientific evidence available. Pediatric rheumatologists manage predominantly rare autoimmune and autoinflammatory conditions. Although the availability of guidelines to inform treatment decisions in pediatric rheumatic diseases is desirable, only a few treatment guidelines exist. Furthermore, the rarity of these diseases limits the feasibility of conducting randomized controlled studies to inform guideline recommendations. Thus, there remains a need for stronger supporting evidence for recommendations, and treatment guidelines for rarer rheumatologic diseases. In this review, we give an overview of past and current guidelines in pediatric rheumatology.

Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. SLE disproportionately affects women and minorities. Childhood-onset SLE (cSLE) in particular tends to be more aggressive than adult-onset SLE. Despite substantial improvements in the treatment of cSLE, there is significant variability in treatment responses and long-term outcomes. Furthermore, there is a paucity of studies involving cSLE, and in particular, cSLE among different age groups. The aim of this study was to test the hypothesis that an early-onset cSLE cohort would demonstrate unique characteristics with distinctive clinical and laboratory features at disease onset. We specifically investigated whether clinical, epidemiological, or serological factors are differentially associated with early- and late-onset cSLE. This could have direct impact on clinical management with the goal of improving outcomes and quality of life for children with SLE. Methods: Our study was conducted at a large tertiary center. We included 213 subjects seen at our pediatric rheumatology clinic aged 4–17 years. Epidemiologic, clinical phenotype, disease severity, serology, treatment, and outcome data were compared between subjects with cSLE onset prior to 10 years of age (early-onset disease, n = 43) and those with cSLE onset greater than 10 years of age (peri-adolescent disease, n = 170). We compared clinical features between early- and peri-adolescent onset cSLE in order to investigate the association between age at disease onset of cSLE and clinical disease expression and outcomes. Results: Of the 213 subjects with cSLE in our study, 43 subjects had early-onset disease (age 2 to ≤9 years) and 170 patients had peri-adolescent onset disease. We found that early-onset cSLE was associated with a higher prevalence of positive anti-dsDNA antibody at cSLE diagnosis, higher anti-dsDNA antibody titer at cSLE diagnosis, rash, and azathioprine use (p < 0.001, p = 0.004, p = 0.011, and p = 0.008, respectively). In contrast, we found that peri-adolescent onset cSLE (≥10 years of age) was associated with worse disease activity (SLEDAI range 0–24) (p < 0.001), higher SLICC at diagnosis (p < 0.001), as well as a higher rate of mycophenolate mofetil and hydroxychloroquine use (p = 0.003 and p < 0.001, respectively). There were no significant differences in the prevalence of neuropsychiatric symptoms or the development of Class IV/Class V lupus nephritis between the early-onset and peri-adolescent groups.