Anti-NMDAR Encephalitis Clinical Practice Guideline: Improving Time to Diagnosis, Treatment, and Hospital Length of Stay.

Background and Objectives: A clinical practice guideline (CPG) was created to standardize evaluation and treatment for patients with suspected anti-methyl-d-aspartate receptor (NMDAR) autoimmune encephalitis (AE), the most common AE in children. The objective of this study was to evaluate the CPG effect on time to diagnosis, treatment, and hospital length of stay (LOS). Methods: Patients with an inpatient consult to pediatric rheumatology for AE during a 4-year period (period 2) after CPG implementation were identified. Data were extracted and compared with data over the preceding 4-year period (period 1). Results: During period 1, fewer patients underwent diagnostic testing than during period 2 (34 vs 80). Number of patients diagnosed with AE did not differ from period 1 to that from period 2 (NMDAR AE 9 vs 8; seronegative AE 4 vs 5). The average time to diagnostic evaluation with lumbar puncture decreased from 5.4 to 1.5 days (p = 0.0082), and time to treatment decreased from 7.6 to 3.9 days (p = 0.018). LOS showed a trend toward improvement (40.4-29.2 days (p = 0.23)). Discussion: Creation of a CPG for patients with suspected AE was associated with an improved time to diagnostic evaluation and treatment. With the CPG, more patients underwent AE testing, though total diagnoses remained the same.

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.

Chronic Recurrent Multifocal Osteomyelitis: A Review of the Noninfectious Inflammatory Bone Disease and Lessons for More Timely Diagnosis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic autoinflammatory disease of the bone that typically occurs in children and adolescents. CRMO is characterized by recurrent periods of exacerbation and remission of symptomatic, osteolytic/sclerotic sterile bone lesions and is often a diagnosis of exclusion. Treatment consists of multimodal anti-inflammatory medication management by rheumatology and rarely involves surgery. This review summarizes the clinical presentation, pathophysiology, diagnosis, and management of this disease and highlights the role of the orthopedic surgeon. With increased familiarity with CRMO, clinicians will be able to diagnose and treat the condition in a more timely manner. [Orthopedics. 2023;46(3):e149-e155.].

Juvenile Fibromyalgia in Patients With Juvenile Idiopathic Arthritis: Utility of the Pain and Symptom Assessment Tool.

OBJECTIVE: To evaluate the proportion of children with juvenile idiopathic arthritis (JIA) who met criteria for comorbid juvenile fibromyalgia (FM) using the Pain and Symptom Assessment Tool (PSAT), and to identify clinical and demographic differences among JIA patients with and without juvenile FM. METHODS: Patients ages 11-17 years with JIA were recruited from 4 North American pediatric rheumatology centers. Each patient completed the PSAT. Additional clinical and disease activity measures included pain visual analog scale, patient global assessment of disease activity (PtGA) and physician global assessment of disease activity (PhGA), the Functional Disability Inventory (FDI), and the Pain Catastrophizing Scale in children. RESULTS: Of 129 patients, 11 met criteria for juvenile FM. FDI scores were markedly higher in patients who tested positive for juvenile FM, with a mean of 24.8 compared to 6.9 in patients without juvenile FM (P < 0.001). Pain catastrophizing scores were also significantly higher, by ~14 points, in patients with juvenile FM. There was a significant tendency for patients to give higher disease activity scores than physicians, which was more marked among patients with juvenile FM. In patients with juvenile FM, PtGA scores exceeded PhGA scores by a mean of 3.7, compared to a mean of 0.7 among patients without juvenile FM (P < 0.001). CONCLUSION: A minority of JIA patients (8.5%) met criteria for juvenile FM. This group demonstrated markedly more functional impairment. PtGA scores were strikingly higher than PhGA scores among patients with JIA who met juvenile FM criteria, suggesting that providers might consider a more expansive approach to chronic pain and non-musculoskeletal symptom assessment and treatment in JIA patients.

Efficacy and Safety of Abatacept, Adalimumab, and Etanercept in Pediatric Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: The lack of randomized controlled trials comparing biologics for the treatment of juvenile idiopathic arthritis (JIA) has led to wide variation in treatment approaches. The objective of this study is to compare the efficacy and safety of abatacept, adalimumab, and etanercept in JIA patients treated at a tertiary pediatric institution. METHODS: This was a single-center, retrospective chart review of patients initiated on abatacept, adalimumab, or etanercept from December 1, 2015, to August 31, 2018, at Monroe Carell Jr. Children's Hospital at Vanderbilt (VCH). The primary outcome was the change in the Physician Global Assessment (PGA) score after 4 to 6 months of biologic therapy. Secondary outcomes included change in laboratory markers of JIA disease activity, change in the number of joints with active disease or limitation of motion, reduction in corticosteroid dose, adverse effects, adherence among patients who have their medications filled at the institution's specialty pharmacy, and reason for discontinuation of therapy. RESULTS: A total of 139 patients were included, with a median age of 13 years. Most patients, 80.6%, experienced a reduction in their PGA score after starting biologic therapy. There was not a statistically significant difference among the agents (p = 0.64). Adverse effects were reported in only 26.6% of patients, with the most frequent being injection site reactions or pain (n = 35). Ultimately, 32% of patients discontinued biologic therapy with a lack of efficacy being the most common reason. CONCLUSIONS: Abatacept, adalimumab, and etanercept were not significantly different in efficacy and safety for the treatment of JIA at this single institution.

T2 relaxation time changes in distal femoral articular cartilage in children with juvenile idiopathic arthritis: a 3-year longitudinal study.

OBJECTIVE: Increased cartilage T2 relaxation time is thought to be an early marker of disease progression in juvenile idiopathic arthritis, because it can identify microstructural changes before damage becomes visible. The purpose of this study was to investigate longitudinal changes in T2 relaxation time mapping (i.e., T2 map) in children with early juvenile idiopathic arthritis and to compare with changes in clinical assessments. SUBJECTS AND METHODS: Twenty children (age range, 6.4-16 years) with early juvenile idiopathic arthritis completed at least four evaluations with T2 maps and clinical assessments: at enrollment, at 3 months, and at 1, 2, and 3 years. Sagittal T2 maps of distal femoral cartilage were generated, a region of interest was selected, and a T2 relaxation time profile was generated. The area under the curve from the T2 profile (i.e., T2 value) was correlated with patient age and sex and the following clinical assessments: total knee score, Childhood Health Assessment Questionnaire, physician global assessment, parent global assessment, and total number of active joints. RESULTS: There was a significant increase in mean T2 values from 3 months to 2 years (p < 0.05). There was a significant decrease in mean Childhood Health Assessment Questionnaire values between enrollment and 2 years (p < 0.05) and a significant decrease in parent global assessment, physician global assessment, total number of active joints, and total knee score values between enrollment and 1 year (p < 0.05). There were no statistically significant correlations between T2 values and patient age, sex, or clinical assessments. CONCLUSION: In patients with early juvenile idiopathic arthritis, T2 maps showed increased T2 values from the 3-month to 2-year follow-up, during which time the clinical assessments improved. This increase likely represents progressive microstructural changes, even though clinical symptoms improved with treatment.

Depression, coping, and functional disability in juvenile primary fibromyalgia syndrome.

This study describes pain characteristics, coping, depression, and functional disability in children with juvenile primary fibromyalgia syndrome (JPFS) and compares them with a group of children with nonmalignant chronic back pain (CBP). Subjects were 18 female subjects (9 to 19 years of age) diagnosed with JPFS and 18 matched control subjects with CBP. Visual Analog Pain Rating Scales, the Pain Coping Questionnaire, the Children's Depression Inventory, and Functional Disability Inventory were administered. Results indicated that both JPFS and CBP groups reported significant disruption in functional abilities and school attendance as a result of chronic pain. Both groups reported mildly elevated symptoms of depression overall, but there was a subgroup of JPFS subjects who reported severe levels of depression. The JPFS group had suffered from pain for significantly longer than the CBP group before being referred for specialty care. However, pain duration was not significantly related to depression, functional disability, or pain coping efficacy. The levels of functional disability were similar in both groups, but the JPFS group reported somewhat more school absences. The longer time to receive specialty care and identification of a subgroup of depressed subjects at risk for long-term psychosocial consequences are of particular concern in JPFS.

Kawasaki disease without fever.

Kawasaki disease (KD) characteristically presents with prolonged, remittent fever in addition to other clinical findings. We report the case of a 3-month-old boy who developed characteristic manifestations of KD and coronary aneurysms in the absence of fever. This case report underlines the difficulty to diagnose KD in young infants.

The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis.

OBJECTIVE: Macrophage activation syndrome is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Levels of soluble interleukin-2 receptor alpha (sIL-2Ralpha) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages, respectively. This study was undertaken to assess the value of serum sIL-2Ralpha and sCD163 in diagnosing acute macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (JIA). METHODS: Enzyme-linked immunosorbent assay was used to assess sIL-2Ralpha and sCD163 levels in sera from 7 patients with acute macrophage activation syndrome complicating systemic JIA and 16 patients with untreated new-onset systemic JIA. The results were correlated with clinical features of established macrophage activation syndrome, including ferritin levels. RESULTS: The median level of sIL-2Ralpha in the patients with macrophage activation syndrome was 19,646 pg/ml (interquartile range [IQR] 18,128), compared with 3,787 pg/ml (IQR 3,762) in patients with systemic JIA (P = 0.003). Similarly, the median level of sCD163 in patients with macrophage activation syndrome was 23,000 ng/ml (IQR 14,191), compared with 5,480 ng/ml (IQR 2,635) in patients with systemic JIA (P = 0.017). In 5 of 16 patients with systemic JIA, serum levels of sIL-2Ralpha or sCD163 were comparable with those in patients with acute macrophage activation syndrome. These patients had high inflammatory activity associated with a trend toward lower hemoglobin levels (P = 0.11), lower platelet counts, and significantly higher ferritin levels (P = 0.02). Two of these 5 patients developed overt macrophage activation syndrome several months later. CONCLUSION: Levels of sIL-2Ralpha and sCD163 are promising diagnostic markers for macrophage activation syndrome. They may also help identify patients with subclinical macrophage activation syndrome.

Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome.

Macrophage activation syndrome (MAS) has been reported in association with many rheumatic diseases, most commonly in systemic juvenile rheumatoid arthritis (sJRA). Clinically, MAS is similar to hemophagocytic lymphohistiocytosis (HLH), a genetic disorder with absent or depressed natural killer (NK) function. We have previously reported that, as in HLH, patients with MAS have profoundly decreased NK activity, suggesting that this abnormality might be relevant to the pathogenesis of the syndrome. Here we examined the extent of NK dysfunction across the spectrum of diseases that comprise juvenile rheumatoid arthritis (JRA). Peripheral blood mononuclear cells (PBMC) were collected from patients with pauciarticular (n = 4), polyarticular (n = 16), and systemic (n = 20) forms of JRA. NK cytolytic activity was measured after co-incubation of PBMC with the NK-sensitive K562 cell line. NK cells (CD56+/T cell receptor [TCR]-alphabeta-), NK T cells (CD56+/TCR-alphabeta+), and CD8+ T cells were also assessed for perforin and granzyme B expression by flow cytometry. Overall, NK cytolytic activity was significantly lower in patients with sJRA than in other JRA patients and controls. In a subgroup of patients with predominantly sJRA, NK cell activity was profoundly decreased: in 10 of 20 patients with sJRA and in only 1 of 20 patients with other JRA, levels of NK activity were below two standard deviations of pediatric controls (P = 0.002). Some decrease in perforin expression in NK cells and cytotoxic T lymphocytes was seen in patients within each of the JRA groups with no statistically significant differences. There was a profound decrease in the proportion of circulating CD56bright NK cells in three sJRA patients, a pattern similar to that previously observed in MAS and HLH. In conclusion, a subgroup of patients with JRA who have not yet had an episode of MAS showed decreased NK function and an absence of circulating CD56bright population, similar to the abnormalities observed in patients with MAS and HLH. This phenomenon was particularly common in the systemic form of JRA, a clinical entity strongly associated with MAS.