Plasmacytoid Dendritic Cells Are Not Major Producers of Type 1 IFN in Cutaneous Lupus: An In-Depth Immunoprofile of Subacute and Discoid Lupus.

The immunologic drivers of cutaneous lupus erythematosus (CLE) and its clinical subtypes remain poorly understood. We sought to characterize the immune landscape of discoid lupus erythematosus and subacute CLE using multiplexed immunophenotyping. We found no significant differences in immune cell percentages between discoid lupus erythematosus and subacute CLE (P > .05) with the exception of an increase in TBK1 in discoid lupus erythematosus (P < .05). Unbiased clustering grouped subjects into 2 major clusters without respect to clinical subtype. Subjects with a history of smoking had increased percentages of neutrophils, disease activity, and endothelial granzyme B compared with nonsmokers. Despite previous assumptions, plasmacytoid dendritic cells (pDCs) did not stain for IFN-1. Skin-eluted and circulating pDCs from subjects with CLE expressed significantly less IFNα than healthy control pDCs upon toll-like receptor 7 stimulation ex vivo (P < .0001). These data suggest that discoid lupus erythematosus and subacute CLE have similar immune microenvironments in a multiplexed investigation. Our aggregated analysis of CLE revealed that smoking may modulate disease activity in CLE through neutrophils and endothelial granzyme B. Notably, our data suggest that pDCs are not the major producers of IFN-1 in CLE. Future in vitro studies to investigate the role of pDCs in CLE are needed.

Validation of Cutaneous Dermatomyositis Disease Area and Severity Index Activity Score and Other Efficacy Outcomes as Measures of Skin Disease in Dermatomyositis in the Lenabasum Phase 3 Trial.

In the past decade, there have been six industry-sponsored phase 3 trials in adult patients with dermatomyositis (DM), primarily focusing on improving muscle weakness. However, skin disease is a cardinal manifestation of DM. This study evaluated the sensitivity of Cutaneous Dermatomyositis Disease Area and Severity Index Activity score, Cutaneous Dermatomyositis Activity Investigator Global Assessment, Total Improvement Score, and other outcome measures used in DM clinical trials to detect improvement in DM skin disease activity. Data analyzed from the lenabasum phase 3 trial in DM showed that improvement in Cutaneous Dermatomyositis Disease Area and Severity Index Activity score increased proportionately with the degree of patient- or physician-reported improvement in skin disease, consistently measuring improvement when clinically meaningful improvement was reported at weeks 16-52. In contrast, Cutaneous Dermatomyositis Activity Investigator Global Assessment measured little change from baseline with reported no improvement in skin disease but also a similar change from baseline with slight improvement. No Skindex-29+3 subscale performed well at reflecting increasing degrees of improvement in skin disease. Extramuscular Global Assessment and Total Improvement Score generally showed increasing levels of improvement as the degree of patient- and physician-reported improvement in skin disease increased, but these are composite measures and are not specific to improvement in DM skin disease. To measure clinically meaningful improvement in skin disease in a DM trial, Cutaneous Dermatomyositis Disease Area and Severity Index Activity score is the more sensitive outcome measure across time points.

Effect of external eyelid weighting on eyelid and eyebrow position in normal and ptosis patients.

PURPOSE: This study aims to characterize the physiologic response of both eyelid and eyebrow position to increasing downward forces simulated by external weights. METHODS: In this prospective observational study, both normal individuals and patients affected by ptosis were tested. External eyelid weights were placed on one upper eyelid with incrementally increasing weight from 0.2 to 2.4 g. The eyelid carrying the weight was randomly selected for normal subjects and patients with bilateral ptosis, whereas for unilateral ptosis, the ptotic eyelid was utilized. Photographs were obtained at baseline and with increasing weight until MRD1 reached 0 on the weighted side or, until 2.4 g was reached. Eyelid and brow position on the weighted and unweighted sides were digitally measured in millimeter. Primary outcome measures were change in the margin to reflex distance (MRD1) and pupil to brow distance (PTB) with weight on the weighted and unweighted sides for normal and ptosis subjects. RESULTS: The weighted eyelid MRD1 decreased linearly with increasing weight. This was true for normal and ptosis subjects. The unweighted eyelid MRD1 increased linearly with increasing weight. This was also the case for both normal and ptosis subjects. With increasing weight, PTB increased linearly on the weighted side. No significant intergroup differences were noted. CONCLUSIONS: In normal and ptosis subjects, when external weight on the eyelid is incrementally increased, the weighted eyelid MRD1 decreases, the unweighted eyelid MRD1 increases, and both brows elevate in a linear fashion.

Bullous systemic lupus erythematosus in females.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering presentation of systemic lupus erythematosus, typically affecting women with the highest incidence in those of African descent. The key pathogenic insult includes the formation of autoantibodies against type VII collagen, which weaken the basement membrane zone and lead to the formation of subepidermal blisters. The acute vesiculobullous eruptions in BSLE generally tend to affect photo-distributed areas, although they can arise unrelated to sun exposure (eg, mucous membranes, axillae). The bullae can arise from erythematous macules, inflammatory plaques, or previously normal skin. Their appearance can range from small, grouped vesicles reminiscent of lesions in dermatitis herpetiformis to large, tense blisters, similar to bullous pemphigoid. Internal organ involvement occurs in up to 90% of those affected. This mostly includes lupus nephritis (classes III-V, lifetime prevalence of up to 90%), arthralgias/arthritis, and cytopenias, while serositis and neuropsychiatric involvement are rare. First-line management with dapsone should be considered in mild disease with stable underlying systemic lupus erythematosus. As discussed in this review, the off-label use of rituximab (an anti-CD20 B-cell depleting agent) has been shown to be safe and effective in several refractory cases of BSLE unresponsive to dapsone, glucocorticoids, or steroid-sparing immunosuppressants.

Emerging Therapies in Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can occur with or without underlying systemic lupus erythematosus (SLE) and often has a profoundly negative impact on patient quality of life. There is substantial need for new and more effective therapies to treat CLE. CLE has a multifactorial pathogenesis that involves several key immune cells and pathways, including abnormalities in innate (e.g., type 1 interferon pathways) and adaptive immune responses (e.g., B and T cell autoreactivity), presenting multiple opportunities for more targeted therapies that do not require immunosuppression. Here we review several emerging therapies and their efficacy in CLE. Anifrolumab and belimumab have both been approved for the treatment of SLE in recent years, and clinical trial evidence suggests some forms of CLE may improve with these agents. Therapies currently in development that are being evaluated with CLE-specific outcome measures include BIIB059 and VIB7734, which target plasmacytoid dendritic cells (pDCs), and iberdomide, a cereblon modulator. These novel therapies all have previously demonstrated clinical benefit in some forms of CLE. Other therapies which target molecules believed to play a role in CLE pathogenesis, such as Janus kinases (JAKs), spleen tyrosine kinase (SYK), interferon γ (IFNγ), IL-12, and IL-23, have been evaluated in lupus clinical trials with skin-specific outcomes but failed to meet their primary endpoints.

Autoimmune Skin Disease Exacerbations Following COVID-19 Vaccination.

Background: Vaccination against COVID-19 reduces the risk of severe COVID-19 disease and death. However, few studies have examined the safety of the COVID-19 vaccine in patients with autoimmune skin disease. Objectives: We sought to determine the incidence of disease exacerbation in this population following COVID-19 vaccination as well as the associated factors. Methods: We performed a chart review of all patients seen in the autoimmune skin disease clinic of the principal investigator during the study period. All patients included for analysis were systematically and prospectively asked about COVID-19 vaccination status, manufacturers, vaccine dates, autoimmune symptoms after the vaccine, and timing of symptom onset using a standardized template as part of their visit. Demographics and autoimmune disease diagnosis were also collected. Analysis used Chi-square and Fisher's exact tests. Results: 402 subjects were included for analysis. 85.6% of patients were fully vaccinated, with 12.9% unvaccinated and 1.5% partially vaccinated. 14.8% of fully vaccinated patients reported worsening autoimmune signs and symptoms after the vaccine. Fully vaccinated dermatomyositis patients were more likely to report worsening autoimmune signs and symptoms after the vaccine (22.7%) than fully vaccinated lupus erythematosus patients (8.6%) (p=0.009). Patients fully vaccinated with the Moderna vaccine trended towards an increased likelihood of reporting worsening autoimmune signs and symptoms after the vaccine (19.1%) than those with the Pfizer-BioNTech vaccine (12.0%) (p=0.076). Of the patients who had autoimmune symptoms after vaccination, 20% had symptoms after the 1st dose, 82% after the 2nd dose, and 4% after the 3rd dose with median onset (95% confidence interval) of 7 (2,14), 14 (14,21), and 18 (7,28) days later, respectively. Conclusions: More fully vaccinated dermatomyositis patients had exacerbation of autoimmune signs and symptoms after the vaccine than fully vaccinated lupus erythematosus patients. However, given the risks of COVID-19, clinicians should still promote vaccination in most patients with autoimmune skin disease.

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases.

An estimated 20-25% of the population is affected by chronic, non-communicable inflammatory skin diseases. Chronic skin inflammation has many causes. Among the most frequent chronic inflammatory skin diseases are atopic dermatitis, psoriasis, urticaria, lichen planus, and hidradenitis suppurativa, driven by a complex interplay of genetics and environmental factors. Autoimmunity is another important cause of chronic skin inflammation. The autoimmune response may be mainly T cell driven, such as in alopecia areata or vitiligo, or B cell driven in chronic spontaneous urticaria, pemphigus and pemphigoid diseases. Rare causes of chronic skin inflammation are autoinflammatory diseases, or rheumatic diseases, such as cutaneous lupus erythematosus or dermatomyositis. Whilst we have seen a significant improvement in diagnosis and treatment, several challenges remain. Especially for rarer causes of chronic skin inflammation, early diagnosis is often missed because of low awareness and lack of diagnostics. Systemic immunosuppression is the treatment of choice for almost all of these diseases. Adverse events due to immunosuppression, insufficient therapeutic responses and relapses remain a challenge. For atopic dermatitis and psoriasis, a broad spectrum of innovative treatments has been developed. However, treatment responses cannot be predicted so far. Hence, development of (bio)markers allowing selection of specific medications for individual patients is needed. Given the encouraging developments during the past years, we envision that many of these challenges in the diagnosis and treatment of chronic inflammatory skin diseases will be thoroughly addressed in the future.

Surgical Start Time Is Not Predictive of Microdiscectomy Outcomes.

STUDY DESIGN: Retrospective analysis of clinical data from a single institution. OBJECTIVE: The objective of this study was to assess the time of surgery as a possible predictor for outcomes, length of stay, and cost following microdiscectomy. SUMMARY OF BACKGROUND DATA: The volume of microdiscectomy procedures has increased year over year, heightening interest in surgical outcomes. Previous investigations have demonstrated an association between time of procedures and clinical outcomes in various surgeries, however, no study has evaluated its influence on microdiscectomy. METHODS: Demographic and outcome variables were collected from all patients that underwent a nonemergent microdiscectomy between 2008 and 2016. Patients were divided into 2 cohorts: those receiving surgery before 2 pm were assigned to the early group and those with procedures beginning after 2 pm were assigned to the late group. Outcomes and patient-level characteristics were compared using bivariate, multivariable logistic, and linear regression models. Adjusted length of stay and cost were coprimary outcomes. Secondary outcomes included operative complications, nonhome discharge, postoperative emergency department visits, or readmission rates. RESULTS: Of the 1261 consecutive patients who met the inclusion criteria, 792 were assigned to the late group and 469 were assigned to the early group. There were no significant differences in demographics or baseline characteristics between the 2 cohorts. In the unadjusted analysis, mean length of stay was 1.80 (SD=1.82) days for the early group and 2.00 (SD=1.70) days for the late group (P=0.054). Mean direct cost for the early cohort was $5088 (SD=$4212) and $4986 (SD=$2988) for the late cohort (P=0.65). There was no difference in adjusted length of stay or direct cost. No statistically significant differences were found in operative complications, nonhome discharge, postoperative emergency department visits, or readmission rates between the 2 cohorts. CONCLUSION: The study findings suggest that early compared with late surgery is not significantly predictive of surgical outcomes following microdiscectomy.

The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues. OBJECTIVE: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals. METHODS: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 µg/10 µL for skin and blood and RNA sequencing of the skin. RESULTS: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin. LIMITATIONS: Our analysis was limited to 354 proteins. CONCLUSIONS: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring.

Predictors of Success Following Müller's Muscle-Conjunctival Resection.

PURPOSE: This study aims to describe Müller's muscle-conjunctival resection surgery in terms of outcomes and potential factors that may predict final positions. METHODS: This cross-sectional cohort study included patients undergoing Müller's muscle-conjunctival resection surgery for involutional ptosis over a 15-year period. Success was defined in 2 ways: 1) final marginal reflex distance 1 (MRD1) ≥2.5 mm (MRD1 success) and 2) final difference in MRD1 ≤1 mm between eyelids (symmetry success). Percentages of patients achieving both outcomes were calculated. Predictors of outcome were assessed using bivariate analysis and multivariate models. RESULTS: The final sample included 315 eyes in 192 patients. The mean age (standard deviation) was 67.9 (11.9) years, and 60.0% were female. MRD1 ≥2.5 mm was achieved in 65.7% of the sample. Symmetry within 1 mm was achieved in 82.9% of the sample. Significant (p < 0.05) predictors of MRD1 success were female sex, concurrent lower eyelid blepharoplasty, and higher preoperative MRD1 in bivariate analysis; preoperative MRD1 and female sex in the multivariate model; and preoperative MRD1 in the a priori model. Significant (p < 0.05) predictors of symmetry success were female sex, previous lower eyelid blepharoplasty, concurrent lateral canthoplasty, preoperative symmetry, and older age in bivariate analysis; only female sex in the multivariate model. DISCUSSION: Müller's muscle-conjunctival resection is effective for elevating the eyelid in ptosis and may be more effective for achieving symmetry than absolute elevation over 2.5 mm. The results remain difficult to predict based clinical, surgical, or demographic factors.