Methotrexate for inflammatory skin disease in pediatric patients: Consensus treatment guidelines.

Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.

TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations. OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients. METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment. RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2. CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.

Systemic Lupus Erythematosus, Evans Syndrome, and Neurofibromatosis: An Unusual Combination in Pediatric Patient.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems. Patients can have hematologic manifestations, including Evans syndrome (ES), which is characterized by immune-mediated thrombocytopenia and anemia. The association of neurofibromatosis 1 (NF1) with autoimmune disorders is rarely reported. We will review the literature for this combination of disorders and describe a case of a 16-year-old girl who presents with immune-mediated cytopenias and is diagnosed with SLE, ES, and NF1. There are 7 reported cases of SLE and NF1 and only 2 are pediatric cases. There are no reports of the combination of SLE, ES, and NF1.

Laboratory Studies in Autoimmune Diseases.

Autoimmune diseases (AID) are a great percentage of the patients needing to be seen by Rheumatologists. Their initial work-up by their primary care physician (PCP) can be helpful in determining who needs to be seen in consultation. If interpreted properly, initial laboratory studies can help the PCP know when to initiate a consultation. The following laboratory studies as outlined will provide the PCP with the necessary information to determine if a further AID work-up is indicated.

Laboratory Evaluation in Pediatric Autoimmune Diseases.

Pediatric autoimmune diseases are chronic lifelong disorders associated with potential disability and increased morbidity and mortality if not properly recognized and treated. On the basis of largely expert opinion in addition to observational studies, children with suspected autoimmune disease should undergo general laboratory and autoantibody screening. (1)(2)(4)(6)(7)(11) There can be many causes of positive antinuclear antibody test results, including, but not limited to, autoimmune disease. On the basis of expert opinion and observational studies, a thorough history and physical examination as well as laboratory evaluation is recommended (often in consultation with a pediatric rheumatologist) to elucidate the cause for a positive test result. (4) (6)(11)

Spectrum of SARS-CoV-2-Related Clinical Syndromes in Children: A Year in the Life.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a wide pediatric clinical spectrum. Initial reports suggested that children had milder symptoms compared with adults; then diagnosis of multisystem inflammatory syndrome in children (MIS-C) emerged. We performed a retrospective cohort study of hospitalized patients at a children's hospital over 1 year. Our objectives were to study the demographic and clinical profile of pediatric SARS-CoV-2-associated diagnoses. Based on the clinical syndrome, patients were classified into coronavirus disease 2019 (COVID-19; non-MIS-C) and MIS-C cohorts. Among those who tested positive, 67% were symptomatic. MIS-C was diagnosed in 24 patients. Both diagnoses were more frequent in Caucasians. Both cohorts had different symptom profiles. Inflammatory markers were several-fold higher in MIS-C patients. These patients had critical care needs and longer hospital stays. More COVID-19 patients had respiratory complications, while MIS-C cohort saw cardiovascular involvement. Health care awareness of both syndromes is important for early recognition, diagnosis, and prompt treatment.

14-3-3η Protein as a Potential Biomarker in Juvenile Idiopathic Arthritis.

The 14-3-3η (eta) protein was evaluated as a biomarker in a cohort of patients with juvenile idiopathic arthritis (JIA), as well as disease- and healthy-controls, to determine its potential clinical utility. In this case-control study, levels of 14-3-3η protein were evaluated in archival specimens from patients with JIA, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), as well as healthy pediatric controls. Just over 200 patients were evaluated, using specimens banked between 1990 and 2011. Comparisons were made to complete blood cell count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, and anti-nuclear antibody (ANA) positivity. 14-3-3η at levels 0.2 ng/mL or higher was considered positive. Fisher's exact tests, odds ratios, 95% confidence intervals, and p-values were reported. 14-3-3η positivity was seen in all included JIA subtypes. The rate of positivity was the highest in RF-positive (pos) polyarticular JIA. In the disease and healthy controls, lower rates of positivity were observed. The frequency of 14-3-3η positivity among RF-positive and RF-negative (neg) polyarticular JIA patients, especially at values ≥0.5 ng/mL (associated with poor outcomes in adults), was also highest. Several JIA patients with 14-3-3η positivity developed RF and anti-CCP positivity later in their disease. Significant levels of 14-3-3η can be found in approximately 30% of RF-pos and RF-neg patients with polyarticular JIA. This protein may represent a new biomarker for polyarticular JIA, particularly RF-neg polyarticular JIA.