Body site distribution of pediatric-onset morphea and association with extracutaneous manifestations.

BACKGROUND: The distribution of pediatric-onset morphea and site-based likelihood for extracutaneous complications has not been well characterized. OBJECTIVE: To characterize the lesional distribution of pediatric-onset morphea and to determine the sites with the highest association of extracutaneous manifestations. METHODS: A retrospective cross-sectional study was performed. Using clinical photographs, morphea lesions were mapped onto body diagrams using customized software. RESULTS: A total of 823 patients with 2522 lesions were included. Lesions were more frequent on the superior (vs inferior) anterior aspect of the head and extensor (vs flexor) extremities. Linear morphea lesions were more likely on the head and neck, whereas plaque and generalized morphea lesions were more likely on the trunk. Musculoskeletal complications were more likely with lesions on the extensor (vs flexor) extremity (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.4), whereas neurologic manifestations were more likely with lesions on the anterior (vs posterior) (OR, 2.8; 95% CI, 1.7-4.6) and superior (vs inferior) aspect of the head (OR, 2.3; 95% CI, 1.6-3.4). LIMITATIONS: Retrospective nature and the inclusion of only patients with clinical photographs. CONCLUSION: The distribution of pediatric-onset morphea is not random and varies with body site and within individual body sites. The risk stratification of extracutaneous manifestations by body site may inform decisions about screening for extracutaneous manifestations, although prospective studies are needed.

Clinical characteristics and management of clinically amyopathic juvenile dermatomyositis across four academic centers.

BACKGROUND/OBJECTIVES: Clinically amyopathic juvenile dermatomyositis (CAJDM) is an uncommon but important subset of patients with juvenile dermatomyositis, characterized by pathognomonic cutaneous findings without clinically evident muscle weakness. With limited data available and lack of standardized management guidelines for CAJDM, we sought to describe common features, including early indicators that may be associated with progression of muscle disease, and review the course and treatment of these patients. METHODS: A retrospective chart review of patients with CAJDM was conducted at four North American academic centers between the years 2000 and 2015. RESULTS: Twenty-nine patients were included, of whom 21 (72%) were female. After a median follow-up of 4 years (IQR 1.8-5.8 years), 5 of the 29 (17%) patients with CAJDM evolved into classic juvenile dermatomyositis. Median time to develop weakness was 12 months (IQR 8-19 months) after diagnosis. The skin disease of CAJDM patients who did not develop weakness was often found to be recalcitrant with 58% of them requiring multiple systemic therapies to control their cutaneous disease. CONCLUSION: These results highlight the need for long-term monitoring for the development of myositis in CAJDM and for prospective studies on treatment of recalcitrant skin disease.

Acral Changes in pediatric patients during COVID 19 pandemic: Registry report from the COVID 19 response task force of the society of pediatric dermatology (SPD) and pediatric dermatology research alliance (PeDRA).

BACKGROUND/OBJECTIVE: In spring 2020, high numbers of children presented with acral pernio-like skin rashes, concurrent with the coronavirus disease 2019 (COVID-19) pandemic. Understanding their clinical characteristics/ infection status may provide prognostic information and facilitate decisions about management. METHODS: A pediatric-specific dermatology registry was created by the Pediatric Dermatology COVID-19 Response Task Force of the Society for Pediatric Dermatology (SPD) and Pediatric Dermatology Research Alliance (PeDRA) and was managed by Children's Hospital of Philadelphia using REDCap. RESULTS: Data from 378 children 0-18 years entered into the registry between April 13 and July 17, 2020 were analyzed. Data were drawn from a standardized questionnaire completed by clinicians which asked for demographics, description of acral lesions, symptoms before and after acral changes, COVID-19 positive contacts, treatment, duration of skin changes, laboratory testing including SARS-CoV-2 PCR and antibody testing, as well as histopathology. 229 (60.6%) were male with mean age of 13.0 years (± 3.6 years). Six (1.6%) tested positive for SARS-CoV-2. Pedal lesions (often with pruritus and/or pain) were present in 96%. 30% (114/378) had COVID-19 symptoms during the 30 days prior to presentation. Most (69%) had no other symptoms and an uneventful course with complete recovery. CONCLUSIONS AND RELEVANCE: Children with acral pernio-like changes were healthy and all recovered with no short-term sequelae. We believe these acral changes are not just a temporal epiphenomenon of shelter in place during the spring months of the first wave of the COVID-19 pandemic and may be a late phase reaction that needs further study.

The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.

Muramyl dipeptide (MDP), a product of bacterial cell-wall peptidoglycan, activates innate immune cells by stimulating nucleotide-binding oligomerization domain containing 2 (NOD2) -dependent activation of the transcription factor NFkappaB and transcription of proinflammatory genes. A20 is a ubiquitin-modifying enzyme that restricts tumor necrosis factor (TNF) receptor and Toll-like receptor (TLR) -induced signals. We now show that MDP induces ubiquitylation of receptor- interacting protein 2 (RIP2) in primary macrophages. A20-deficient cells exhibit dramatically amplified responses to MDP, including increased RIP2 ubiquitylation, prolonged NFkappaB signaling, and increased production of proinflammatory cytokines. In addition, in vivo responses to MDP are exaggerated in A20-deficient mice and in chimeric mice bearing A20-deficient hematopoietic cells. These exaggerated responses occur independently of the TLR adaptors MyD88 and TRIF as well as TNF signals. These findings indicate that A20 directly restricts NOD2 induced signals in vitro and in vivo, and provide new insights into how these signals are physiologically restricted.

A survey of epidermolysis bullosa care in the United States and Canada.

Epidermolysis bullosa (EB) is a group of rare, inherited, blistering diseases that typically present in infancy. EB is not curable, and treatment is entirely supportive. There is a paucity of standardized recommendations to guide management. To assess the current state of EB care, an original online survey was conducted targeting attending physicians experienced with the care of EB. Members of the Society for Pediatric Dermatology residing in the United States and Canada served as the source pool. Parameters assessed included clinic visits, availability of subspecialists, and performance of surveillance studies. Fifty-six completed surveys were analyzed. Most providers saw between 1 and 10 individuals with EB per year in a general dermatology clinic. For each EB type there was considerable variation in the frequency of clinic visits, availability and use of specialists, and use of laboratory and imaging studies. Some agreement was observed in the frequency of follow-up for infants with more severe EB types, as well as for the components of a history, physical, and routine laboratory studies. These findings describe variations in the current state of EB care that pediatric dermatologists provide. The development and acceptance of evidence-based guidelines and outcome measures may lead to greater uniformity in EB care.

Cytokines elicited by T cell epitopes from a synovial autoantigen: altered peptide ligands can reduce interferon-gamma and interleukin-10 production.

OBJECTIVE: To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp-39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs). METHODS: Draining lymph node cells were harvested from HLA-DR*0401 transgenic mice that had been immunized with HC gp-39. Cytokine responses to 5 previously identified HLA-DR*0401-restricted HC gp-39 T cell epitopes were studied in vitro. The anchor and T cell receptor (TCR) contact residues of peptide 322-337 were identified, and this information was used to design alanine-substituted APLs. T cells were primed in vivo with wild-type peptide 322-337, restimulated with wild-type peptide or APLs, and the cytokine profiles were compared. RESULTS: Restimulation with individual peptides elicited distinct cytokine profiles. HC gp-39 (peptide 322-337) elicited a dominant interferon-gamma (IFNgamma) response. Residues within the core (positions P1-P9) 322-337 peptide sequence were critical for T cell recognition. Surprisingly, the N-terminal flanking region was also important for recognition by 6 of 10 specific T cell hybridomas. Substitutions of charged TCR contact residues in the 322-337 core epitope (E332A and K335A) were associated with a significant reduction in the IFNgamma and interleukin-10 (IL-10) stimulation indices. Restimulation with peptides W325A and V326A was also associated with a trend toward reduced IFNgamma and IL-10 secretion. In contrast, restimulation with peptide D330N elicited cytokine profiles more comparable with those resulting from restimulation with wild-type peptide. CONCLUSION: This study indicates that APLs of a proinflammatory HC gp-39 T cell epitope may be used to alter the cytokine response from a memory T cell population.

The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses.

A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)-induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor-induced activity of the transcription factor NF-kappaB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.