Comparing the risk of death, major adverse cardiac events, and relapse in bullous pemphigoid patients treated with systemic or topical corticosteroids.

BACKGROUND: According to current guidelines, systemic or topical corticosteroids are recommended as first-line treatments for bullous pemphigoid (BP). There is evidence suggesting that topical application may be associated with a lower risk of mortality. However, there is a lack of comprehensive large-scale data comparing mortality rates, as well as the risk of major adverse cardiac events (MACE), infections, and relapse, between systemic and topical corticosteroid treatments. OBJECTIVES: To evaluate the risk of death, MACE, infections, and relapse in BP patients treated with systemic or topical corticosteroids. METHODS: A population-based retrospective cohort study was performed in the TriNetX US Collaborative Network. As a measure against bias, propensity-score matching for age, sex, ten diseases and six medications, and three sensitivity analyses were conducted. RESULTS: All-time risk of death was increased in US BP patients exposed to any dose of systemic corticosteroids (n=2,917) compared to topical clobetasol propionate treated patients (n=2,932, hazard ratio [HR], 1.43, 95% confidence interval [CI] 1.28-1.58, p<0.0001). This was consistent in time-stratified analysis (1- and 3-year mortality rates), and in analysis contrasting prednisone (equivalent) does of 1-10 mg (low) or 30-100 mg (medium-high) systemic corticosteroid to topical treatment. The increased risk of death in US BP patients exposed to any dose of systemic corticosteroids compared to topical treatment was accompanied by increased risks for MACE (HR 1.33, CI 1.08-1.64, p=0.0075) and infections (HR 1.33, CI 1.15-1.54, p=0.0001). The risk of continued disease or relapse was decreased in patients treated with systemic as opposed to topical corticosteroid (HR 0.85, CI 0.77-0.94, p=0.0016). Results regarding mortality and continued disease or relapse persisted in three of three sensitivity analyses. Potential limitations are the retrospective data collection, bias for treatment selection and miscoding. CONCLUSION: Pending validation in prospective studies, where feasible, and despite the heightened risk of relapse, topical corticosteroid treatment may be advantageous compared to systemic corticosteroid treatment due to its significantly lower risk of death.

[Pemphigoid diseases in older adults]. / Pemphigoiderkrankungen bei älteren Menschen.

Pemphigoid diseases are a group of bullous autoimmune diseases characterized by autoantibodies against structural proteins of the dermal-epidermal junction. With a steadily growing aging population, pemphigoid diseases are emerging as a significant medical challenge, because they occur primarily in older individuals. The by far most common disease is bullous pemphigoid, which is clinically characterized by tense blisters, erosions, erythema or urticarial plaques, while severe pruritus is the leading subjective symptom. Mucous membrane pemphigoid predominantly affects surface-close mucous membranes with painful erosions and blisters as well as frequently scarring usually in the mouth, nose, and eyes. Anti-p200 pemphigoid clinically resembles bullous pemphigoid but is much less common. Diagnosis of these diseases involves the combination of clinical evaluation, lesional histopathology, direct immunofluorescence microscopy of a perilesional biopsy and serology. Topical and systemic corticosteroids are the mainstay of pemphigoid diseases treatment. Depending on the severity of the disease, various potentially corticosteroid-sparing therapies, such as dapsone, doxycycline, methotrexate, azathioprine and mycophenolate may be used. In severe courses, treatment with rituximab, cyclophosphamide, intravenous immunoglobulins or immunoadsorption are second- or third-line treatment options. Patients are best managed in centers experience with the management of pemphigoid diseases. Updated national and international guidelines for the diagnosis and treatment of bullous pemphigoid and mucous membrane pemphigoid have recently been published.

LPS-Induced Endotoxemia Evokes Epigenetic Alterations in Mitochondrial DNA That Impacts Inflammatory Response.

Mitochondrial DNA (mtDNA) plays a vital role as a damage-associated molecular pattern in sepsis being able to shape the immune response. Since pathogen recognition receptors of innate immune cells are activated by demethylated DNA only, we set out to investigate the amount of DNA methyltransferase 1 (DNMT1) in mitochondria and the extent of mtDNA methylation in a human endotoxin model. Peripheral blood mononuclear cells of 20 healthy individuals were isolated from whole blood and stimulated with lipopolysaccharide (LPS) for 48 h. Subsequently, DNMT1 protein abundance was assessed in whole cells and a mitochondrial fraction. At the same time, methylation levels of mtDNA were quantified, and cytokine expression in the supernatant was measured. Despite increased cellular expression of DNMT1 after LPS stimulation, the degree of mtDNA methylation slightly decreased. Strikingly the mitochondrial protein abundance of DNMT1 was reduced by 50% in line with the lower degree of mtDNA methylation. Although only modest alterations were seen in the degree of mtDNA methylation, these strongly correlated with IL-6 and IL-10 expression. Our data may hint at a protein import problem for DNMT1 into the mitochondria under LPS stimulation and suggest a role of demethylated mtDNA in the regulation of the inflammatory immune response.