Clinical endpoints in myositis: challenges and ways forward.

PURPOSE OF REVIEW: This review addresses the challenges and advances in clinical endpoints for myositis, with a particular focus on ensuring comprehensive assessment of both muscle and skin disease activity. The relevance of this review stems from recent developments in outcome measures and their implications for clinical trial design and patient inclusivity. While quality of life (QoL) and lung involvement are also important aspects of myositis, they are beyond the scope of this review and need to be addressed in future studies. RECENT FINDINGS: Traditional outcome measures like the Total Improvement Score (TIS) have limitations, especially for patients with skin-predominant dermatomyositis (DM). Recent studies highlight the importance of incorporating skin-specific measures such as the Cutaneous Disease Area and Severity Index (CDASI) and the novel composite measure, Dermatomyositis Outcomes for Muscle and Skin (DMOMS). These measures provide a more balanced assessment of disease activity. Clinical trial data analyzed using these measures have demonstrated significant benefits for patients with both classic and amyopathic DM, emphasizing the need for their broader adoption. SUMMARY: Advancements in outcome measures are crucial for inclusive and effective myositis clinical trials. Incorporating comprehensive tools like the DMOMS can enhance the assessment of both muscle and skin disease activities, potentially leading to better therapeutic strategies and improved patient outcomes. This shift is essential for addressing the needs of all Idiopathic inflammatory myopathy patients, including those with skin-predominant DM.

Keratinocyte derived extracellular vesicles mediated crosstalk between epidermis and dermis in UVB-induced skin inflammation.

BACKGROUND AND RATIONALE: Ultraviolet-B (UVB) light induces dermal inflammation, although it is mostly absorbed in the epidermis. Recent reports suggest extracellular vesicles (EVs) act as a mediator of photodamage signaling. Melatonin is reported to be a protective factor against UV-induced damage. We hypothesized that EVs derived from UVB-irradiated keratinocytes might trigger proinflammatory responses in dermal cells and tested whether melatonin can ameliorate UVB-induced inflammation. METHODS: We used UVB-irradiated HaCaT cells, primary keratinocytes and STING knock-out mice to model production of EVs under photodamaging conditions and performed immunoblotting and ELISA to measure their effect on dermal macrophages. RESULTS: UVB-irradiated keratinocytes produce an increased number of EVs that contain higher concentrations of DNA and protein compared with controls. KC-derived EVs (KEVs) induced a STING- and inflammasome-mediated proinflammatory response in macrophages in vitro, and a pronounced inflammatory infiltrate in mouse dermis in vivo. Melatonin ameliorated KEVs inflammatory effect both in vitro and in vivo. CONCLUSIONS: This data suggests EVs are mediators in a crosstalk that takes place between keratinocytes and their neighboring cells as a result of photodamage. Further studies exploring EVs induced by damaging doses of UVB, and their impact on other cells will provide insight into photodamage and may help develop targeted therapeutic approaches.

Extracellular Vesicles in the Pathogenesis, Clinical Characterization, and Management of Dermatomyositis: A Narrative Review.

Extracellular vesicles (EVs) are lipid-bilayer particles secreted from cells that primarily assist in cell-to-cell communication through the content of their cargo, such as proteins and RNA. EVs have been implicated in the pathogenesis of various autoimmune diseases, including dermatomyositis (DM), an inflammatory autoimmune disease characterized by distinct cutaneous manifestations, myopathy, and lung disease. We sought to review the role of EVs in DM and understand how they contribute to the pathogenesis and clinical characterization of the disease. We summarized the research progress on EVs in dermatomyositis based on recent publications. EV cargoes, such as double-stranded DNA, microRNA, and proteins, contribute to DM pathogenesis and mediate the proinflammatory response and cytokine release through signaling pathways such as the stimulator of interferon genes (STING) pathway. These nucleic acids and proteins have been proposed as disease-specific, stable biomarkers to monitor disease activity and responses to therapy. They also correlate with clinical parameters, inflammatory markers, and disease severity scores. Furthermore, some markers show an association with morbidities of DM, such as muscle weakness and interstitial lung disease. The continued study of EVs will help us to further elucidate our understanding of dermatomyositis.

Brief Teaching Intervention Improves Medical Students' Dermatology Diagnostic Skills and Comfort in Performing Dermatology Exams.

BACKGROUND: Skin disease is a significant contributor to the global disease burden, with dermatologic health disparities adding to this burden. Internists, general practitioners, and other medical professionals often manage skin disease with limited exposure to dermatologic education in medical school. OBJECTIVE: This study evaluated a brief educational intervention for medical students to improve dermatologic knowledge, diagnostic and communication skills, and comfort in performing dermatology-focused physical exams. A secondary focus of the intervention was to promote awareness of skin disease, detection, and prevention for patients with a variety of skin tones. METHODS: Sixty-five first through fourth-year students at Rutgers RWJMS participated in a pre-test-post-test within-subject study. Students described images using open-ended responses followed by multiple-choice identification questions. Students watched a one-hour self-paced module created by a licensed dermatologist and completed a follow-up assessment. RESULTS: At pre-test, descriptions were brief and often inaccurate but significantly improved post-intervention to include descriptors such as primary morphology and demarcation. Accuracy on diagnostic and management questions significantly improved and comfort in advising patients and performing dermatologic exams significantly increased. CONCLUSIONS: A low-cost, brief, self-paced module can augment dermatologic education for medical students while increasing exposure to multiple skin tone presentations of lesions.

Diet and acne: A systematic review.

Background: Acne vulgaris is a common cutaneous disorder. Diet and metabolism, specifically glycemic content and dairy, influence hormones such as insulin, insulin-like growth factor 1, and androgens, which affect acnegenesis. Objective: To systematically review high-quality evidence regarding the association of dietary glycemic and dairy intake with acnegenesis. Methods: A comprehensive literature search, without timeline restriction, of MEDLINE (completed between October and November 2021) for English-language papers that examined the association between diet and acne was conducted. The evidence quality was assessed using the Ottawa quality assessment scale. Results: The literature search yielded 410 articles, of which 34 articles met the inclusion criteria. The literature on whether dairy product intake is associated with acnegenesis is mixed and may be dependent on sex, ethnicity, and cultural dietary habits. High glycemic index and increased daily glycemic load intake were positively associated with acnegenesis and acne severity, an observation supported by randomized controlled trials. Conclusion: High glycemic index, increased glycemic load, and carbohydrate intake have a modest yet significant proacnegenic effect. Increased dairy consumption may have been proacnegenic in select populations, such as those in which a Western diet is prevalent. The impact of diet on acnegenesis is likely dependent on sex and ethnicity. Further randomized trials are necessary to fully characterize the potential associations.

Biliverdin reductase bridges focal adhesion kinase to Src to modulate synaptic signaling.

Synapses connect discrete neurons into vast networks that send, receive, and encode diverse forms of information. Synaptic function and plasticity, the neuronal process of adapting to diverse and variable inputs, depend on the dynamic nature of synaptic molecular components, which is mediated in part by cell adhesion signaling pathways. Here, we found that the enzyme biliverdin reductase (BVR) physically links together key focal adhesion signaling molecules at the synapse. BVR-null (BVR-/-) mice exhibited substantial deficits in learning and memory on neurocognitive tests, and hippocampal slices in which BVR was postsynaptically depleted showed deficits in electrophysiological responses to stimuli. RNA sequencing, biochemistry, and pathway analyses suggested that these deficits were mediated through the loss of focal adhesion signaling at both the transcriptional and biochemical level in the hippocampus. Independently of its catalytic function, BVR acted as a bridge between the primary focal adhesion signaling kinases FAK and Pyk2 and the effector kinase Src. Without BVR, FAK and Pyk2 did not bind to and stimulate Src, which then did not phosphorylate the N-methyl-d-aspartate (NMDA) receptor, a critical posttranslational modification for synaptic plasticity. Src itself is a molecular hub on which many signaling pathways converge to stimulate NMDAR-mediated neurotransmission, thus positioning BVR at a prominent intersection of synaptic signaling.

Identification of skin signs in human-trafficking survivors.

Human-trafficking survivors suffer significant physical, mental, and social health consequences, prompting them to seek health care services. Although there is research regarding identification protocols for human-trafficking victims, there is no framework outlining the dermatologic patterns of survivors of human trafficking. We sought to identify the dermatologic signs reported in human-trafficking victims to create a framework for dermatologists and the broader medical community to appropriately screen patients at risk. After screening 577 pertinent records in the PubMed and Google Scholar databases for information about the physical signs of human trafficking in health care, 10 final studies were selected. Significant findings of rashes and brandings, such as tattoos, were more likely in sex-trafficked patients, whereas burns, injuries, and deep cuts were more likely to be found in labor-trafficked patients. This review outlines important identification guidelines that dermatologists and the broader medical community can use to recognize victims and take appropriate action while also raising awareness of human trafficking as an emerging public health issue.

Bilirubin Links Heme Metabolism to Neuroprotection by Scavenging Superoxide.

Bilirubin is one of the most frequently measured metabolites in medicine, yet its physiologic roles remain unclear. Bilirubin can act as an antioxidant in vitro, but whether its redox activity is physiologically relevant is unclear because many other antioxidants are far more abundant in vivo. Here, we report that depleting endogenous bilirubin renders mice hypersensitive to oxidative stress. We find that mice lacking bilirubin are particularly vulnerable to superoxide (O2⋅-) over other tested reactive oxidants and electrophiles. Whereas major antioxidants such as glutathione and cysteine exhibit little to no reactivity toward O2⋅-, bilirubin readily scavenges O2⋅-. We find that bilirubin's redox activity is particularly important in the brain, where it prevents excitotoxicity and neuronal death by scavenging O2⋅- during NMDA neurotransmission. Bilirubin's unique redox activity toward O2⋅- may underlie a prominent physiologic role despite being significantly less abundant than other endogenous and exogenous antioxidants.