Disease Course, Treatments, and Outcomes of Children With Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease.

OBJECTIVE: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes. METHODS: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD. RESULTS: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time. CONCLUSION: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.

B lymphocytes in treatment-naive paediatric patients with lupus are epigenetically distinct from healthy children.

BACKGROUND: SLE is likely triggered by gene-environment interactions. We have shown that most SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in lymphocytes, suggesting genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in paediatric SLE (pSLE). We aim to identify differences in epigenetically regulated chromatin architecture in treatment-naive patients with pSLE compared with healthy children. METHODS: Using the assay for transposase-accessible chromatin with sequencing (ATACseq), we surveyed open chromatin in 10 treatment-naive patients with pSLE, with at least moderate disease severity, and 5 healthy children. We investigated whether regions of open chromatin unique to patients with pSLE demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of <0.05. Further analyses for histone modification enrichment and variant calling were performed using bioinformatics packages in R and Linux. RESULTS: We identified 30 139 differentially accessible regions (DAR) unique to pSLE B cells; 64.3% are more accessible in pSLE than healthy children. Many DAR are found in distal, intergenic regions and enriched for enhancer histone marks (p=0.027). B cells from adult patients with SLE contain more regions of inaccessible chromatin than those in pSLE. In pSLE B cells, 65.2% of the DAR are located within or near known SLE haplotypes. Further analysis revealed enrichment of transcription factor binding motifs within these DAR that may regulate genes involved in pro-inflammatory responses and cellular adhesion. CONCLUSIONS: We demonstrate an epigenetically distinct profile in pSLE B cells when compared with healthy children and adults with lupus, indicating that pSLE B cells are predisposed for disease onset/development. Increased chromatin accessibility in non-coding genomic regions controlling activation of inflammation suggest that transcriptional dysregulation by regulatory elements controlling B cell activation plays an important role in pSLE pathogenesis.

The safety of COVID-19 vaccination in immunocompromised children and young adults with immune-mediated inflammatory disease.

AIM: To assess safety of COVID-19 vaccination in paediatric patients with immune-mediated inflammatory disease (IMID). METHODS: Subjects of 5-21 years of age with IMID who received at least one COVID-19 vaccine completed electronic surveys after each vaccine to assess side effects within 1 week of vaccination, current medications and COVID-19 testing after vaccination. Charts were reviewed for COVID-19 polymerase chain reaction and IgG response to SARS-CoV-2 spike protein results and for disease flare during the study period. RESULTS: Among 190 enrolled subjects, 71% were female, with median age 17 (range 6-21) years. The most common diagnosis was juvenile idiopathic arthritis/rheumatoid arthritis (55%). 78% of subjects were taking immunosuppressive medication. At least one side effect was reported in 65% of subjects after any dose of the vaccine; with side effects in 38%, 53% and 55% of subjects after the first, second and third vaccine doses, respectively. The most common side effects were injection site pain (59%), fatigue (54%) and headache (39%). No anaphylaxis or myocarditis was reported. Three subjects (2%) experienced disease flare. CONCLUSION: In our cohort of paediatric patients with IMID, observed side effects were found to be mild and disease flare rates were found to be low following COVID-19 vaccination.

Pilot Study of the Juvenile Dermatomyositis Consensus Treatment Plans: A CARRA Registry Study.

OBJECTIVES: To determine the feasibility of comparing the Childhood Arthritis and Rheumatology ResearchAlliance (CARRA) consensus treatment plans (CTP) in treating moderate new-onset juvenile dermatomyositis (JDM) using the CARRA registry, and to establish appropriate analytic methods to control for confounding by indication and missing data. METHODS: A pilot cohort of 39 patients with JDM from the CARRA registry was studied. Patients were assigned by the treating physician, considering patient/family preferences, to 1 of 3 CTP: methotrexate (MTX) and prednisone (MP); intravenous (IV) methylprednisolone, MTX, and prednisone (MMP); or IV methylprednisolone, MTX, prednisone, and IV immunoglobulin (MMPI). The primary outcome was the proportion of patients achieving moderate improvement at 6 months under each CTP. Statistical methods including multiple imputation and inverse probability of treatment weighting were used to handle missing data and confounding by indication. RESULTS: Patients received MP (n = 13), MMP (n = 18) and MMPI (n = 8). Patients in all CTP had significant improvement in disease activity. Of the 36 patients who remained in our pilot study at 6 months, 16 (44%) of them successfully achieved moderate improvement at 6 months (6/13, 46% for MP; 7/15, 47% for MMP; 3/8, 38% for MMPI). After correcting for confounding, there were no statistically significant pairwise differences between the CTP (P = 0.328-0.88). CONCLUSION: We gained valuable experience and insight from our pilot study that can be used to guide the design and analysis of comparative effectiveness studies using the CARRA registry CTP approach. Our analytical methods can be adopted for future comparative effectiveness studies and applied to other rare disease observational studies.

Performance and psychometric properties of lupus impact tracker in assessing patient-reported outcomes in pediatric lupus: Report from a pilot study.

OBJECTIVE: To evaluate the reliability, validity, feasibility and psychometric performance of the Lupus Impact Tracker (LIT) as a patient reported outcome (PRO) measure tool in pediatric systemic lupus erythematosus (pSLE). METHODS: This is a prospective, observational, pilot study where patients aged between 12 and 25 years, fulfilling the 1997 ACR classification criteria for SLE, were enrolled. Over 3 consecutive, routine, clinical visits, the patients completed the LIT alongside the Patient-Reported Outcomes Measurement Information System-Short Forms (PROMIS-SFs), Childhood Health Assessment Questionnaire (CHAQ). Rheumatologists completed the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC-ACR) Damage Index. Demographic, clinical and laboratory data were also collected. RESULTS: Of 46 patients enrolled, 38 patients completed 2 visits and 31 completed all 3 visits. Seventy-eight percent were female, 33% African American, 28% Asian, 15% Caucasian and 17% Hispanic. The mean (SD) age was 17.2 (2.7) years, with a mean (SD) disease duration of 4.6 (3.1) years. The mean (SD) SLEDAI-2K at enrollment was 3.54 (2.96). In the 38 patients who completed two or more visits, intra-class correlation coefficient and Cronbach alpha were calculated to be 0.70 and 0.91 respectively, signifying good reliability of LIT. The LIT showed positive correlation with CHAQ-Disability Index and majority of the PROMIS-SFs parameters. Construct validity was established against clinical disease activity (SLEDAI-2K). CONCLUSION: The preliminary results indicate that the LIT is a reliable and valid instrument to capture PRO in p-SLE. Prospective validation with a larger, multicenter cohort is the next step.

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV. METHODS: Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months. RESULTS: In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months. CONCLUSION: This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Validation of the Lupus Nephritis Clinical Indices in Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: To validate clinical indices of lupus nephritis activity and damage when used in children against the criterion standard of kidney biopsy findings. METHODS: In 83 children requiring kidney biopsy, the Systemic Lupus Erythematosus Disease Activity Index renal domain (SLEDAI-R), British Isles Lupus Assessment Group index renal domain (BILAG-R), Systemic Lupus International Collaborating Clinics (SLICC) renal activity score (SLICC-RAS), and SLICC Damage Index renal domain (SDI-R) were measured. Fixed effects and logistic models were calculated to predict International Society of Nephrology/Renal Pathology Society (ISN/RPS) class; low-to-moderate versus high lupus nephritis activity (National Institutes of Health [NIH] activity index [AI]) score: ≤10 versus >10; tubulointerstitial activity index (TIAI) score: ≤5 versus >5; or the absence versus presence of lupus nephritis chronicity (NIH chronicity index) score: 0 versus ≥1. RESULTS: There were 10, 50, and 23 patients with ISN/RPS class I/II, III/IV, and V, respectively. Scores of the clinical indices did not differentiate among patients by ISN/RPS class. The SLEDAI-R and SLICC-RAS but not the BILAG-R differed with lupus nephritis activity status defined by NIH-AI scores, while only the SLEDAI-R scores differed between lupus nephritis activity status based on TIAI scores. The sensitivity and specificity of the SDI-R to capture lupus nephritis chronicity was 23.5% and 91.7%, respectively. Despite being designed to measure lupus nephritis activity, SLICC-RAS and SLEDAI-R scores significantly differed with lupus nephritis chronicity status. CONCLUSION: Current clinical indices of lupus nephritis fail to discriminate ISN/RPS class in children. Despite its shortcomings, the SLEDAI-R appears best for measuring lupus nephritis activity in a clinical setting. The SDI-R is a poor correlate of lupus nephritis chronicity.

Flares in pediatric systemic lupus erythematosus.

OBJECTIVE: To determine the flare rate and the change in Safety of Estrogens in Lupus Erythematosus: National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA SLEDAI) score with disease flare in pediatric systemic lupus erythematosus (pSLE). METHODS: A retrospective chart review of 62 patients with pSLE (ages 5-20 yrs). A flare was defined as the start of, or increase in, the dose of corticosteroids and/or the addition of an immunosuppressive medication. All pre-flare, flare, and post-flare visits were recorded with a SELENA SLEDAI score calculated for each visit. The flare rate was calculated by dividing the total number of flares in the cohort by the total followup years. RESULTS: Sixty-two patients were eligible. Forty-seven patients had 112 flares. The average number of flares/patient was 1.8 +/- 2.0 and the mean inter-flare time was 15.4 +/- 17.9 months. The flare rate in pSLE was 0.46 flares/patient-year of followup. The median time to first flare from the date of diagnosis was 14.3 months. Patients with cytopenia, pleuritis, or pericarditis, or a positive antibody to Smith nuclear antigen at the time of diagnosis had a significantly higher flare rate than those who did not. The average SELENA SLEDAI score at presentation was 12.5 +/- 5.4, at the pre-flare visit 6.3 +/- 3.5, and during a flare 7.9 +/- 5.1. CONCLUSION: This is the first large study to report a flare rate (0.46 flares/patient-year of followup) in pSLE. The flare rate was similar to what has been reported in pSLE previously but significantly lower than that reported in adults with lupus. The average change in the SELENA SLEDAI score with disease flare is 2 points.

Comparison of the intraarticular effectiveness of triamcinolone hexacetonide and triamcinolone acetonide in treatment of juvenile rheumatoid arthritis.

OBJECTIVE: To compare patients with juvenile rheumatoid arthritis (JRA) injected with triamcinolone hexacetonide (TH) or triamcinolone acetonide (TA) with respect to time to relapse. METHODS: This was a retrospective chart review of 85 patients: 51 patients with JRA who had received a joint injection with TH during the period June 2000-April 2001 and 48 patients who had received a joint injection with TA during the period May 2001-March 2002 who were followed for a minimum of 15 months, after an intraarticular steroid injection. RESULTS: The primary endpoint variable for the study was the time to relapse of the arthritis in the affected joint following an intraarticular injection. A total of 227 joints were injected, 114 with TH and 113 with TA. In the TH group the mean time to relapse (+/- SE) was 10.14 +/- 0.49 months compared to the TA group at 7.75 +/- 0.49 months (p < 0.0001) using the log-rank test. A proportional hazards (Cox) regression analysis revealed no statistical association between sex, duration of illness, or type of arthritis and relapse time. An analysis was performed on the first intraarticular injection for each patient, with the average time to relapse for all joints injected of 10.36 +/- 0.72 months for TH compared to 8.45 +/- 0.78 months for TA (p < 0.02). A further analysis of the first knee injections showed a relapse time in the TH group of 11.11 +/- 0.81 months compared to 7.95 +/- 0.95 months for TA (p < 0.008). CONCLUSION: TH offers an advantage to TA, as there is a longer duration of action leading to an improved prolonged response rate in weight-bearing joints, particularly the knees. The results suggest that TH should be the intraarticular steroid of choice, particularly for the knee joint, in patients with JRA.