Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

Juvenile eosinophilic fasciitis: a single center case series.

BACKGROUND: Eosinophilic fasciitis (EF) is a rare disease characterized by skin induration and musculoskeletal abnormalities. Diagnostic criteria for EF are based on adult populations. There is a need to expand the literature on EF in children due to limited reported cases and potential differences compared to adults. METHODS: We conducted a retrospective review of medical records for six pediatric patients diagnosed with EF at our institution between November 2011 and April 2023. Inclusion criteria required patients to be under 18 years of age at the time of diagnosis and to have confirmed diagnosis through clinical history, imaging, and histology. RESULTS: Most of our cohort were female (83%) and non-Hispanic white (50%). Age at diagnosis ranged from 4 to 16 years. Duration of symptoms before diagnosis varied from 1 to 12 months. Follow-up periods ranged from 14 to 123 months. Concurrent medical conditions included localized scleroderma, acquired thrombophilia, and juvenile idiopathic arthritis. Patients presented with progressive painful swelling, severe joint limitations, and positive prayer sign. Initial regimens involved corticosteroids and methotrexate. Hydroxychloroquine, immunoglobulin, mycophenolate mofetil, rituximab, and tocilizumab were also used depending on the patient's disease severity and course. CONCLUSIONS: Juvenile EF may manifest as swelling and progressive induration without apparent skin abnormalities. Unlike adult populations, no underlying malignancies or associations with trauma were observed in our cohort. Our cases did not exhibit systemic involvement observed in previous studies on juvenile EF. While non-specific, the prayer sign may aid in early recognition of juvenile EF and help prevent long-term disability.

Imaging findings of COPA Syndrome.

BACKGROUND: Autosomal dominant mutations in the coatomer-associated protein alpha (COPA) gene cause an immune dysregulation disorder associated with pulmonary hemorrhage, lymphoid hyperplasia, arthritis, and glomerulonephritis. OBJECTIVE: To describe the thoracic, musculoskeletal, and renal imaging findings of COPA syndrome with a focus on the evolution of the pulmonary findings. MATERIALS AND METHODS: With approval of the Institutional Review Board, consensus retrospective review of findings on chest radiography and computed tomography (CT), musculoskeletal radiography and magnetic resonance imaging (MRI), and renal ultrasound (US) was performed for pediatric COPA syndrome patients. COPA syndrome patients < 18 years of age presenting between 1992 and 2019 were identified from an institutional rheumatology registry. RESULTS: Twelve pediatric COPA syndrome patients (mean age of 6.5 years at first imaging exam; 6 females) were identified. Imaging exams available for review included 45 chest CT exams on 12 patients, 37 musculoskeletal exams on 4 patients, and 10 renal US exams on 5 patients. All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12). Nine had at least one follow-up chest CT, which showed improvement in nodules (7/9), ground-glass opacities (4/9), and lymphadenopathy (9/9), but worsening of septal thickening (3/9), cyst formation (3/9), and fibrosis (3/9). Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4). Five had at least one renal US, revealing renal size abnormalities (4/5) and cortical hyperechogenicity (3/5). CONCLUSION: The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis. Other imaging findings manifesting later in childhood or adolescence relate to arthritis and glomerulonephritis.

Risk factors associated with Pneumocystis jirovecii pneumonia in juvenile myositis in North America.

OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is associated with significant morbidity and mortality in adult myositis patients; however, there are few studies examining PJP in juvenile myositis [juvenile idiopathic inflammatory myopathy (JIIM)]. The purpose of this study was to determine the risk factors and clinical phenotypes associated with PJP in JIIM. METHODS: An research electronic data capture (REDCap) questionnaire regarding myositis features, disease course, medications and PJP infection characteristics was completed by treating physicians for 13 JIIM patients who developed PJP (PJP+) from the USA and Canada. Myositis features and medications were compared with 147 JIIM patients without PJP (PJP-) from similar geographic regions who enrolled in National Institutes of Health natural history studies. RESULTS: PJP+ patients were more often of Asian ancestry than PJP- patients [odds ratio (OR) 8.7; 95% CI 1.3, 57.9]. Anti- melanoma differentiation associated protein 5 (MDA5) autoantibodies (OR 12.5; 95% CI 3.0, 52.4), digital infarcts (OR 43.8; 95% CI 4.2, 460.2), skin ulcerations (OR 12.0; 95% CI 3.5, 41.2) and interstitial lung disease (OR 10.6; 95% CI 2.1, 53.9) were more frequent in PJP+ patients. Before PJP diagnosis, patients more frequently received pulse steroids, rituximab and more immunosuppressive therapy compared with PJP- patients. Seven PJP+ patients were admitted to the intensive care unit and four patients died due to PJP or its complications. CONCLUSIONS: PJP is a severe infection in JIIM that can be associated with mortality. Having PJP was associated with more immunosuppressive therapy, anti-MDA5 autoantibodies, Asian race and certain clinical features, including digital infarcts, cutaneous ulcerations and interstitial lung disease. Prophylaxis for PJP should be considered in juvenile myositis patients with these features.

Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases.

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

Clinical presentation and outcomes of childhood-onset membranous lupus nephritis.

BACKGROUND: Best practices for managing childhood-onset membranous lupus nephritis (MLN) are not yet established. Most studies involve primarily or exclusively adult cohorts or pediatric cohorts with combinations of pure or mixed membranous and proliferative nephritis. METHODS: We performed a single-center cohort study of consecutively diagnosed children with pure MLN from 1990 and 2016. Patients received care in Houston, Texas, one of the most diverse metropolitan areas in North America. Renal outcomes were obtained using consensus definitions from the Childhood Arthritis and Rheumatology Research Alliance (CARRA). Logistic regression was used to detect predictors of complete renal response. RESULTS: A total of 56 children with MLN were identified (82% females, 44% black, 35% Hispanic) with a median follow-up time of 4.1 years. The mean age of MLN onset was 13.7 ± 3.4 years. On initial presentation 69% had nephrotic syndrome and 11% had acute kidney injury. Glucocorticoids were prescribed in 96% of patients and anti-malarials in 88%. Mycophenolate mofetil was the most common non-steroid immunosuppressive agent (69%), followed by rituximab (25%), cyclophosphamide (18%), and azathioprine (9%). Renin-angiotensin aldosterone system blocking agents were prescribed in 78% of patients. Of 37 patients with ≥2 years of follow-up, 74% achieved complete renal response at 24 months. No predictor variable of complete renal response was identified in this small cohort. Renal flares occurred in 48% of patients (86% proteinuric, 14% nephritic). On subsequent renal biopsy, 13% patients had developed proliferative nephritis. CONCLUSIONS: This single-center cohort of childhood-onset MLN showed favorable outcomes. Utilizing pediatric renal outcomes definitions, we found that response rates were high, as were rates of renal flare.

Diffuse Alveolar Hemorrhage as a Manifestation of Childhood-Onset Systemic Lupus Erythematosus.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a devastating clinical syndrome characterized by a falling hematocrit, respiratory insufficiency, and radiographic evidence of pulmonary infiltrates. Literature regarding management of DAH in childhood-onset SLE (cSLE) is limited. METHODS: We reviewed the presentation, management, and outcome of DAH in a pediatric tertiary medical center with one of the largest cSLE cohorts in North America. During a 10 year period 7 of 410 children with cSLE had DAH. RESULTS: The majority of cSLE patients with DAH were male (71%) and Hispanic (57%). The median age at the time of DAH diagnosis was 14 years (range 3 -15 years). DAH was the presenting manifestation of cSLE in 29% of children; 71% presented with DAH within 3 months of their diagnosis. All patients had cough, 86% had dyspnea, and 29% had hemoptysis. All patients had anemia and 71% had thrombocytopenia. Eighty-six percent had hematuria/proteinuria, and a positive anti-double stranded DNA antibody. Chest imaging showed diffuse ground glass opacities in all events. All patients developed respiratory insufficiency (29% supplemental oxygenation and 71% mechanical ventilation). Transfusions were required in 57% of cases. All patients received corticosteroids and additional immunomodulation to achieve disease control. Eighty-six percent of our DAH/cSLE cohort survived their initial event (median follow-up 2.5 years). No survivor required supplemental oxygen or had a DAH recurrence. CONCLUSIONS: SLE should be in the hospitalist's differential diagnosis for any child with respiratory insufficiency, cytopenias, and/or urinary abnormalities. Once cSLE is identified, initiation of aggressive immune suppression with multiple agents may enhance outcomes.

A 2-year-old with 4 weeks of daily fever.

A 2-year-old female presents for evaluation of 4 weeks of daily fevers. When the fevers began, she had mild upper respiratory tract symptoms, which quickly resolved. The fevers persisted, however, with a maximum of 40°C. The child's review of symptoms was significant for a 1-kg weight loss over the past month. Ten months before presentation, she had moved from Saudi Arabia with her family. One week before the onset of symptoms, she had visited a petting zoo. During episodes of fever, the patient was ill-appearing and had an elevated heart rate and respiratory rate. On examination, she was found to be thin, febrile, tachycardic, and with scattered lymphadenopathy. Results of laboratory tests were remarkable for an elevated white blood cell count of 16,100 cells per uL with a neutrophilic predominance. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated at 99 mm/h and 27 mg/dL, respectively. A chest radiograph indicated a small amount of fluid in the interlobar fissures. Our expert panel examines her case, offers a definition of fever of unknown origin, and makes diagnostic considerations.

Wrist and ankle MRI of patients with juvenile idiopathic arthritis: identification of unsuspected multicompartmental tenosynovitis and arthritis.

OBJECTIVE: The purpose of this study was to characterize the extent of joint and tendon involvement in patients with juvenile idiopathic arthritis referred for MRI of the wrist or ankle. MATERIALS AND METHODS: Forty-five patients (32 female and 13 male patients; mean age, 10 years; age range, 1-19 years) with an established diagnosis of juvenile idiopathic arthritis were referred for MRI of the wrist or ankle between January 2000 and August 2012 (39 wrists and 33 ankles). All MRI examinations and clinical notes were reviewed, and joint and tendon involvement was recorded. RESULTS: Tenosynovitis was present in 50% (36/72) of examinations. Tenosynovitis was not documented in clinical notes before MRI. When tenosynovitis was present, an average of 3.5 tendons were involved (range, 1-12 tendons). For the wrist, 59% (23/39) had tenosynovitis, and the extensor digitorum tendon (23% [9/39]) was most commonly involved. For the ankle, 39% (13/33) had tenosynovitis, and the tibialis posterior tendon (33.3% [11/33]) was most commonly involved. For the wrist, 89.7% (35/39) had active joint inflammation with an average of 3.1 joints involved (range, 0-6 joints), and the intercarpal joint was most commonly involved (69% [27/39]). For the ankle, 69.7% (23/33) had active joint inflammation, with an average of 2.4 joints involved (range, 0-5 joints), and the tibiotalar joint (52% [17/33]) was most commonly involved. CONCLUSION: Multicompartmental tenosynovitis and arthritis involvement is common in patients with juvenile idiopathic arthritis referred for MRI of the wrist or ankle and is underappreciated on clinical examination. International League of Associations for Rheumatology subclassification and targeted intraarticular steroid injections guided by clinical examination alone may lead to undertreatment or incorrect treatment of active disease.

Distal extremity necrosis as a manifestation of cutaneous polyarteritis nodosa: case report and review of the acute management of a pediatric patient.

We present the case of an 8-year-old girl who presented with distal extremity necrosis of the hands, feet, nose, and ears as an acute manifestation of cutaneous polyarteritis nodosa (CPAN). She was emergently managed with intravenous steroids, nifedipine, sildenafil, pentoxifylline, nitroglycerin paste, aspirin, low-molecular-weight heparin, and intravenous gamma globulin. The necrosis was controlled, and reperfusion was attained to salvage the extremities. It is important for clinicians to be aware that acute distal extremity necrosis can be a manifestation of CPAN in children. Etiology is often not clear on presentation, but once infection is excluded, acute management with systemic steroids and systemic vasodilators is indicated regardless of the cause. Iloprost and bosentan may represent options for adjunctive vasodilators. More studies are needed to create guidelines for the acute and long-term management of these children. Close follow-up of children with CPAN, especially with a history of vaso-occlusive symptoms, is important to allow prompt intervention in the event of distal extremity infarction.