Cutaneous Involvement in Systemic Lupus Erythematosus: A Review for the Rheumatologist.

The majority of patients with systemic lupus erythematosus (SLE) have cutaneous manifestations at some point in their disease course. The skin findings in SLE are classified as SLE-specific or SLE-nonspecific based on histopathologic findings. SLE-specific skin diseases include chronic cutaneous lupus erythematosus (CLE), subacute CLE, and acute CLE. There are subsets of skin lesions within each group and the likelihood of associated SLE varies among them. SLE-nonspecific lesions are more common in patients with SLE and tend to coincide with active systemic disease. SLE-nonspecific lesions may be seen as a feature of another disease process, including other connective tissue diseases. It is important for the rheumatologist to be familiar with the spectrum of cutaneous diseases in SLE to help prognosticate the likelihood of systemic disease and to ensure patients receive timely dermatologic care with the goal of controlling disease activity to prevent damage.

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.

Interventions for Cutaneous Disease in Systemic Lupus Erythematosus: Summary of a Cochrane Review.

CLINICAL QUESTION: What is the efficacy of interventions for cutaneous disease in systemic lupus erythematosus (SLE) in randomized clinical trials (RCTs)? BOTTOM LINE: Available RCT evidence on the management of cutaneous disease in SLE is sparse and of limited quality. Among traditional options, methotrexate and hydroxychloroquine have the strongest evidence compared with placebo in the end points of complete clinical response and number of clinical flares, respectively, while chloroquine appears noninferior to methotrexate in achieving complete clinical response.

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.

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.

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.

Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A Pediatric Normal Tissue Effects in the Clinic Normal Tissue Outcomes Comprehensive Review.

PURPOSE: Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. METHODS AND MATERIALS: A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. RESULTS: The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). CONCLUSIONS: Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

Multidimensional Immune Profiling of Cutaneous Lupus Erythematosus In Vivo Stratified by Patient Response to Antimalarials.

OBJECTIVE: The pathogenesis of cutaneous lupus erythematosus (CLE) is multifactorial, and CLE is difficult to treat due to the heterogeneity of inflammatory processes among patients. Antimalarials such as hydroxychloroquine (HCQ) and quinacrine (QC) have long been used as first-line systemic therapy; however, many patients do not respond to treatment with antimalarials and require systemic immunosuppressants that produce undesirable side effects. Given the complexity and the unpredictability of responses to antimalarial treatments in CLE patients, we sought to characterize the immunologic profile of patients with CLE stratified by subsequent treatment outcomes to identify potential biomarkers of inducible response. METHODS: We performed mass cytometry imaging of multiple immune cell types and inflammation markers in treatment-naive skin biopsy samples from 48 patients with CLE to identify baseline immunophenotypes that may predict the response to antimalarial therapy. Patients were stratified according to their response to treatment with antimalarials, as HCQ responders, QC responders, or nonresponders. RESULTS: HCQ responders demonstrated increased CD4+ T cells compared to the QC responder group. Patients in the nonresponder group were found to have decreased Treg cells compared to QC responders and increased central memory T cells compared to HCQ responders. QC responders expressed increased phosphorylated stimulator of interferon genes (pSTING) and interferon-κ (IFNκ) compared to HCQ responders. Phosphorylated STING and IFNκ were found to be localized to conventional dendritic cells (cDCs), and the intensity of pSTING and IFNκ staining was positively correlated with the number of cDCs on a tissue and cellular level. Neighborhood analysis revealed decreased regulatory cell interactions in nonresponder patients. Hierarchical clustering revealed that nonresponder patients could be further differentiated based on expression of pSTAT2, pSTAT3, pSTAT4, pSTAT5, phosphorylated interferon regulatory factor 3 (pIRF3), granzyme B, pJAK2, interleukin-4 (IL-4), IL-17, and IFNγ. CONCLUSION: These findings indicate differential immune cell compositions between patients with CLE, offering guidance for future research on precision-based medicine and treatment response.

Scalp and Cranium Radiation Therapy Using Modulation (SCRUM) and Bolus.

PURPOSE: A bolus is usually required to ensure radiation dose coverage of extensive superficial tumors of the scalp or skull. Oftentimes, these boluses are challenging to make and are nonreproducible, so an easier method was sought. METHODS AND MATERIALS: Thermoplastic sheets are widely available in radiation oncology clinics and can serve as bolus. Two template cutouts were designed for anterior and posterior halves to encompass the cranium of children and adults. RESULTS: The created bolus was imaged using computed tomography, which demonstrated good conformity and minimal air gaps. CONCLUSIONS: Although making a bolus for treating superficial tumors of the scalp or head and neck is challenging, the presented technique enables thermoplastic to be used as a bolus and is quick, easy, and reproducible.