Rapid and sustained response to JAK inhibition in a child with severe MDA5 + juvenile dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (jDM) is the most common idiopathic inflammatory myopathy of childhood. Amyopathic or hypomyopathic courses have been described. CASE PRESENTATION: We present the case of a 4-year-old patient with MDA5 antibody positive jDM and interstitial lung disease. In our patient, typical symptoms of jDM with classical skin lesions, arthritis, proximal muscle weakness, and ulcerative calcifications were observed. Due to the severity of the disease and the pulmonary changes, therapy with the Janus kinase (JAK) inhibitor ruxolitinib was added to the therapy with corticosteroids, intravenous immunoglobulins (IVIG) and hydroxychloroquine leading to a fast and sustained remission. CONCLUSION: While there is growing evidence that JAK inhibition is a promising therapeutic option in jDM our case report shows that this approach may also be effective in MDA5-positive jDM with high risk features.

First-year follow-up of children with chronic nonbacterial osteomyelitis-an analysis of the German National Pediatric Rheumatologic Database from 2009 to 2018.

OBJECTIVE: To assess the first-year features of patients with chronic nonbacterial osteomyelitis (CNO). METHODS: Patients with a diagnosis of CNO, disease duration of under 13 months, and first registration in the German National Pediatric Rheumatologic Database (NPRD) between 2009 and 2018 were included in this cross-sectional analysis. RESULTS: Of 774 documented patients, 62.8% were female, and all patients had a median age of 11 years. The most affected clinical sites were the tibia (29.7%), pelvis (28.0%), and femur (27.8%). HLA-B27 was positive in 48 of 314 analyzed patients (15.3%). In 406 patients, an X-ray was performed at the first visit; X-ray results showed osteosclerosis/-lysis in 34.0% and hyperostosis in 14.5% of the patients. MRI scans (focal and whole-body scans) were performed in 648 patients, and 81.5% showed a positive TIRM/STIR signal. A total of 84.7% of the patients were administered nonsteroidal anti-inflammatory drugs, 9.6% were administered oral glucocorticoids, 10.8% were administered disease-modifying anti-rheumatic drugs (DMARDs), and 6.1% were administered bisphosphonates. An evaluation of the patient's questionnaire showed an overall well-being (NRS 0-10) of 2.0. The PedCNO disease "activity" score revealed a 70% improvement in variables in 43% of patients in the initial 1-year follow-up. Copresentation with diagnostic criteria of pediatric enthesitis-related arthritis was rare. CONCLUSION: To our knowledge, the NPRD cohort seemed to be the largest cohort of children and adolescents suffering from CNO worldwide. Most patients were treated effectively with NSAIDs, and only a small group of patients was administered additional medication. The patient-defined measures of disease activity had a moderate impact on patients' daily lives. TRIAL REGISTRATION: Not applicable.

Establishing core domain sets for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO): A report from the OMERACT 2020 special interest group.

OBJECTIVE: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. METHODS: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. RESULTS: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). CONCLUSION: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

Orbital inflammation and colitis in pediatric IgG4-related disease: A case report and review of the literature.

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-ß2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.

High-dose intravenous methylprednisolone in juvenile non-infectious uveitis: A retrospective analysis.

Non-infectious uveitis is associated with visual impairment and blindness. Non-biologic treatment for non-infectious uveitis is not based on strong evidence. A retrospective chart review was conducted to investigate treatment response to high-dose intravenous methylprednisolone (IVMP) in children with non-infectious uveitis. Fifty-six patients (93 eyes affected) were included. In 29% uveitis was associated with juvenile idiopathic arthritis. Uveitis predominately affected the anterior segment, was bilateral and recurrent. Complications were common and included visual loss, synechiae, cataract and/or retinal lesions. Patients received up to 5 IVMP at monthly intervals. Visual acuity improved at 3 and 6 months. Anterior chamber cells, synechiae, keratic precipitates, papillary and/or macular edema improved at 3 months. Children treated with ≥3 IVMP (vs 1 IVMP) experienced trends towards fewer relapses, fewer cataracts and less frequently required treatment with biologic agents. High-dose IVMP induce rapid improvement in children with non-infectious uveitis. Prospective randomized trials are required to confirm results.

Kawasaki Disease.

Kawasaki disease (KD) is an acute-onset systemic vasculitis of medium-sized vessels that mostly affects infants and toddlers. Globally, it is the most common form of childhood primary vasculitis. Delayed diagnosis and treatment results in coronary artery aneurysms in up to 25% of all affected individuals. Thus, KD is the most common acquired heart disease in developed countries. Here, the current understanding of clinical presentations, pathophysiological concepts, disease-associated complications, and available pharmaceutical treatment is provided and discussed in the context of available literature.

Childhood Vasculitis.

The term vasculitis covers heterogeneous disorders that share the presence of inflammation of blood vessel walls. Immune cell infiltrates can vary significantly and involve granulocytes or mononuclear cells. Vasculitis can be a symptom of other underlying disorders or the underlying cause of organ specific or systemic disease. Classification of childhood vasculitis is based on clinic, the size of predominantly affected vessels, and the histopathology of inflammatory infiltrates. Timely and accurate diagnosis and (where necessary) treatment initiation determine disease progression and outcomes. In light of new developments and the identification of autoinflammatory conditions with vasculitis, new classification tools may be discussed.

Treatment Response and Longterm Outcomes in Children with Chronic Nonbacterial Osteomyelitis.

OBJECTIVE: The autoinflammatory bone disorder chronic nonbacterial osteomyelitis (CNO) covers a wide clinical spectrum, ranging from mild self-limited presentations to chronically active or recurrent courses, which are then referred to as chronic recurrent multifocal osteomyelitis (CRMO). Little is known about treatment options and longterm outcomes. We investigated treatment responses and outcomes in children with CNO. METHODS: A retrospective chart review was conducted in a tertiary referral center, covering 2004-2015. Disease activity was measured at 0, 3, 6, 12, and 24 months after treatment initiation, and at the last recorded visit. RESULTS: Fifty-six patients with CNO were identified; 44 had multifocal CNO. Fifty percent of patients relapsed after a median of 2.4 years, and as few as 40% remained relapse-free after 5 years. Nonsteroidal antiinflammatory drugs were used as first-line treatment in 55 patients, inducing remission after 3 months in all individuals with relapse rates of 50% after 2 years. Further treatment included corticosteroids (n = 23), tumor necrosis factor-α (TNF-α) inhibitors (n = 7), and bisphosphonates (n = 8). While 47% of patients with CNO relapsed within 1 year after corticosteroid therapy, favorable outcomes were achieved with TNF-α inhibitors or bisphosphonates (pamidronate). CONCLUSION: CNO is a chronic disease with favorable outcomes within the first year, but high relapse rates in longterm followup. Particularly, patients with CRMO with long-lasting, uncontrolled inflammation were at risk for the development of arthritis. Our findings underscore the importance of a timely diagnosis and treatment initiation. Prospective studies are warranted to establish evidence-based diagnostic and therapeutic approaches to CNO.

Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies.

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. The exact molecular pathophysiology of CNO remains largely unknown. Provided familial clusters and the association with inflammatory disorders of the skin and intestine suggest a genetic predisposition. Recently, profound dysregulation of cytokine responses was demonstrated in CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1ß release. In IL-10-deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1ß was linked to bone inflammation. Further, alterations to the gut microbiome were suggested in contributing to IL-1ß release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. Here, we summarize clinical presentation and treatment options in CNO/CRMO, current pathophysiological concepts, available mouse models, and promising future scientific directions.

Current understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches.

Because of its distinct clinical and laboratory features, reflecting systemic inflammation, sJIA can be distinguished from other forms of JIA which usually present as a milder phenotype. The exact pathophysiology of sJIA, however, remains unknown. Profound dysregulation of innate pro- and anti-inflammatory cytokines, and rapid clinical response to cytokine blocking strategies in sJIA patients suggest impaired control mechanisms in innate immune cells contributing to sJIA pathogenesis. Endogenous TLR ligands, such as S100 protein complexes, enhance the pro-inflammatory phenotype. Associations with polymorphisms in cytokine genes and their receptors suggest a genetic component. Furthermore, genetic associations that have been reported in familial hemophagocytic lympohistiocytosis also exist in patients with sJIA-associated macrophage activation syndrome, a severe complication of sJIA. Reported mutations in single genes, however, are too weak to confer sJIA, suggesting a multi-factorial mode of inheritance. We provide an overview of current pathophysiological concepts, state-of-the-art treatment regimens, and unanswered questions in sJIA.

Bridging bronchus--a rare cause of recurrent wheezy bronchitis.

BACKGROUND: Wheezing is a common symptom in infants and toddlers. Usually it occurs due to viral infection of the lower airways and no further diagnostic procedures are necessary. However in rare cases, other reasons such as anatomical malformation have to be considered. CASE PRESENTATION: We report about an infant with recurrent episodes of wheezy bronchitis, which persisted despite adequate therapy. Bronchoscopy and computed tomography of the lung with three-dimensional reconstruction revealed a rare bronchial branching anomaly - the so called "bridging bronchus". In contrast to previous case reports, this infant showed no additional malformations, which seems to be important for the prognosis. CONCLUSION: To the best of our knowledge this is the first report about a patient with a bridging bronchus in its "original form" without associated anomalies of the trachea-bronchial system or other organs.