Emerging evidence has suggested a link between new-onset psoriasis and both COVID-19 infection and vaccination, though findings have been limited by small case numbers and lack of adequate control groups. This retrospective cohort study used electronic health records from the US Collaborative Network of TriNetX from January 2020 to January 2025 to compare the risk of developing new-onset psoriasis in individuals with confirmed COVID-19 infection and no vaccination history vs those vaccinated without prior infection. Propensity score matching was applied to balance demographics, comorbidities, and psoriasis risk factors. The primary outcome was a new diagnosis of psoriasis (ICD10-CM: L40.0–5) within 3 months following infection or vaccination. Subgroup analyses assessed the specific codes L40.0-5 separately. Kaplan–Meier survival analysis and Cox proportional hazards models were used to compare outcomes. Patients with COVID-19 infection had a significantly higher risk of developing psoriasis compared with vaccinated individuals (HR 1.30; 95% CI, 1.14–1.49; p < 0.001). Increased risks were also observed for psoriatic arthritis and pustulosis palmaris et plantaris. These findings suggest a potential triggering role of infection in psoriasis pathogenesis and support the safety profile of vaccination. Further studies are needed to confirm causality and guide clinical decision-making.

Zusammenfassung Hintergrund und Zielsetzung Das bullöse Pemphigoid (BP) ist die häufigste blasenbildende Autoimmunerkrankung in der westlichen Welt. Während die Mehrheit der Patienten mit BP durch die langfristige Anwendung von Kortikosteroiden mit oder ohne Immunmodulatoren/Immunsuppressiva Remissionen erreicht, empfehlen nationale und internationale Leitlinien bei refraktären Erkrankungen die adjuvante Immunadsorption (IA). Ziel dieser Studie war es, die Sicherheit und Wirksamkeit der IA bei schwer betroffenen Patienten und/oder refraktärem BP zu untersuchen. Patienten und Methodik Zehn Patienten mit BP (3 Frauen, 7 Männer; Durchschnittsalter 69,7 Jahre; 52–81 Jahre) wurden an drei aufeinanderfolgenden Tagen mit IA (LigaSorb ® , Fresenius Medical Care) in Kombination mit oralem Prednisolon (0,5 mg/kg KG/Tag, ausschleichend), Dapson (1,5 mg/kg KG/Tag) und Mometasonfuroat‐Salbe behandelt. Ergebnisse Innerhalb von 2 und 6 Monaten nach IA zeigten 50% beziehungsweise 90% der Patienten eine vollständige Remission unter der Therapie. Bei allen Patienten sanken die Serum‐Anti‐BP180‐IgG‐Spiegel unmittelbar nach der dritten IA um durchschnittlich 89% und 4 Wochen später um 73%. Während der 12‐monatigen Nachbeobachtungszeit traten insgesamt 56 unerwünschte Ereignisse (UE) auf. Die Mehrzahl der unerwünschten Ereignisse hatte den Schweregrad 2 (50%), 15 unerwünschte Ereignisse wurden als schwerwiegend (Grad 3–4) eingestuft. Schlussfolgerungen Die IA kann als relativ sichere und wirksame adjuvante Therapie für Patienten mit schwerem oder refraktärem BP angesehen werden.

IntroductionDespite significantly improved therapies in recent years, long-term morbidity and mortality in ANCA-associated vasculitis (AAV) remain high. The leading causes of death within the first year after diagnosis are active vasculitis and in subsequent years cardiovascular diseases, malignancies, and infections. Population-based database and cohort analyses suggest an increased risk for major adverse cardiovascular events (MACE) in AAV.MethodsThis retrospective cohort study analyzed data samples from an electronic health records database of the US-based TriNetX network. Patients with the diagnostic codes granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and patients without vasculitis as a matched control cohort (1:1) were included. To optimize between-group comparability, propensity score matching was performed for demographic variables and comorbidity. Hazard ratios (HR) for death and cardiovascular outcomes were calculated using univariate Cox regression after analyzing the matched cohort using the Kaplan-Meier method.ResultsWe identified 20, 422 patients with GPA and 5, 907 with MPA. Mortality was more frequent in patients with GPA (17.87%) and MPA (25.85%) than in matched controls (GPA controls: 5.79%; MPA controls: 9.70%), corresponding to an increased hazard of death in both cohorts (GPA: HR 3.01; MPA: HR 3.01). The risk of cardiovascular events was increased in GPA and MPA compared to matched controls, particularly for MACE (GPA: HR: 1.94, MPA: HR: 2.24) and thromboembolic events (deep vein thrombosis: GPA HR: 2.82, MPA HR: 3.33; pulmonary embolism: GPA HR: 3.01, MPA HR: 3.00) and did not differ when adjusted according to sex, disease duration, and age. Compared with GPA patients, MPA patients had a higher risk of MACE (HR: 1.13) and peripheral arterial disease (HR: 1.17).ConclusionAAV was associated with an increased risk of death and cardiovascular events. Compared with GPA, MPA was associated with an increased risk for MACE and peripheral arterial disease.

BACKGROUND:Type 2 chronic inflammatory diseases (T2IDs) are highly prevalent among women of reproductive age. Dupilumab, a monoclonal antibody, is increasingly used to treat T2IDs. While dupilumab is not approved during pregnancy, smaller studies suggest no increased risk of pregnancy complications (adverse pregnancy outcomes (APOs)). Additional data are required to better assess the drug's safety during pregnancy. OBJECTIVES:To retrospectively assess the risk of APOs in dupilumab-treated pregnant women in a large real-world database. METHODS:Pregnant women with T2ID and dupilumab treatment during pregnancy were retrieved from the US Collaborative Network of TriNetX. Pregnant women with T2ID and without dupilumab treatment served as controls. Propensity score matching (PSM) for demographics, diagnoses, medications and putative APO risk factors was employed. Outcomes analysed included various maternal pregnancy complications, including premature obstetric labour, pregnancy-induced hypertension, gestational diabetes, puerperal infections and spontaneous abortion. Survival analyses were assessed using the Kaplan-Meier method, outcome differences the log-rank test and hazard ratios (HR) the Cox regression model. RESULTS:During pregnancy, 293 women were exposed to dupilumab. Following PSM, no increased risks for APOs were noted. Of note, reduced risks for premature obstetric labour (HR: 0.11, confidence interval (CI): 0.03-0.45, p = 0.0002) and 'any APO' (HR: 0.53, CI: 0.33-0.84, p = 0.0067) in the dupilumab-treated group were found. Furthermore, no difference in risks for any APO was noted between dupilumab-treated and untreated women up to 6 months before pregnancy or during the postpartum period. CONCLUSIONS:This large-scale propensity-matched retrospective cohort study suggests a favourable safety profile of dupilumab during pregnancy. Given the difficulties of prospective studies during pregnancy, it provides valuable insights, though further studies are needed to confirm these findings and explore causal relationships.

Cyclin-dependent kinases are involved in basic cellular processes like regulation of cell-cycle progression and transcription. However, recent data also indicate a specific role in terminally differentiated neutrophils by promoting reactive oxygen species (ROS) release, degranulation, neutrophil extracellular trap (NET) formation, or apoptosis. Thus, we investigated the effect of pharmacological CDK inhibition on IC-activated neutrophil functions. Inhibitors targeting CDK1, 2, 4/6, 7, 9, 11, and 12 showed effects on different neutrophil functions (surface activation marker expression, ROS release, adhesion, apoptosis) in vitro . To analyse the inhibitors in a more translational approach, we proceeded with the systemic application of the effective inhibitors in a murine antibody transfer-induced local EBA model. In this predominantly neutrophil-driven model, we observed a reduction of disease severity upon treatment with CDK7, 9, or 11 inhibitors. Inhibiting these CDKs with topical THZ2, MC180295, or OTS964 also improved the clinical phenotype. Therefore, the most efficient inhibitor, MC180295, was validated in two other IC-mediated models of autoimmune disease: Serum-transfer arthritis, which also, but not exclusively depends on neutrophils and ITP, which is considered neutrophil-independent. Here, an effect in STA was observed, but not in ITP. Hence, we show the therapeutic potential of CDK7, 11, and especially 9 inhibition in IC-driven neutrophil-mediated diseases such as RA and EBA. ### Competing Interest Statement The authors have declared no competing interest. Cluster of Excellence “Precision Medicine in Chronic Inflammation”, EXC 2167 Research Training Group “Defining and Targeting Autoimmune Pre-Disease”, GRK 2633 Collaborative Research Center “Pathomechanisms of Antibody-mediated Autoimmunity”, CRC 1526

Background: Chronic spontaneous urticaria (CSU), a common and debilitating disease, is widely held not to be life limiting, but the mortality of CSU has not been investigated. Objective: We sought to assess all-cause mortality in patients with CSU, risk for comorbidities that are leading causes of death, and impact of guideline-recommended urticaria treatments on mortality rates. Methods: This was a retrospective population-based cohort study of electronic health records of 272,190 adult patients with CSU and 12,728,913 controls without urticaria from the US collaborative network TriNetX. Results: The study included 264,680 propensity score-matched patients with CSU (mean [SD] age = 47.5 [19.8] years; 71.5% female) and a corresponding number of controls without urticaria. Patients with CSU had higher 3-month (hazard ratio [HR] 2.10, 95% CI 1.97-2.22), 1-year (HR 1.77, 95% CI 1.711.83), and 5-year (HR 1.69, 95% CI 1.65-1.73) all-cause mortality (all P < .0001). Compared with controls, patients with CSU exhibited higher risk and rates of the leading causes of death in the United States, including suicidal ideations/suicide attempts (HR 3.14, 95% CI 3.00-3.28) and malignant neoplasms (HR 2.09, 95% CI 2.02-2.16). The risk of mortality appeared to be more pronounced in White and younger patients with CSU. All-cause mortality rates at 5 years were significantly lower in patients treated with second-generation H1 antihistamines versus untreated patients (1.0% vs 2.3%; HR 1.84, P <.0001) and omalizumab-treated patients versus antihistamine-treated patients (0.7% vs 2.6%; HR 3.99, P = .0003). Conclusions: CSU is associated with increased mortality likely due to comorbidities, especially suicide, and effective CSU treatment may reduce mortality. These findings should be investigated in additional studies and in other populations. (J Allergy Clin Immunol 2025;155:1290-8.)

Background: Cardiovascular comorbidity increases morbidity and mortality in psoriasis. Systemic treatments, particularly biologics, are effective in alleviating skin and joint inflammation. Conversely, the impact of systemic therapy on cardiovascular disease risk and mortality in psoriasis remains uncertain. Methods: Impact of systemic treatments on all-cause mortality and cardiovascular disease risk in psoriasis patients' electronic health records (EHRs) from TriNetX was assessed. Treatment categories included apremilast, IL-17 inhibitors (IL-17i), IL23i, TNFi, and classic antipsoriatic drugs. Index event was the first prescription of each treatment, requiring a two-year continuous treatment with exclusion of other systemic antipsoriatic drugs. Propensity-score matching was used to improve comparability. Sensitivity analyses ensured study robustness. Findings: In descriptive analysis, all-cause mortality rates were 0.61% (classic antipsoriatics, n = 7929), 0.91% (apremilast, n = 1101), 0.00% (IL17i, n = 677), 0.81% (IL23i, n = 1242), and 0.20% (TNFi, n = 6468). Major adverse cardiac events (MACE) were documented in 8.49% (classic antipsoriatics), 5.14% (apremilast), 2.99% (IL17i), 2.09% (IL23i), and 3.74% (TNFi) EHRs. Propensity-score matching showed all-cause mortality rates of 0.23% for any biologic vs. 0.49% for classic antipsoriatics or apremilast, resulting in an HR of 2.21 (95% CI 1.21-3.71, p = 0.0073). MACE risk was also higher with classic antipsoriatics or apremilast (HR 1.66, CI 1.43-1.93, p < 0.0001). The majority of findings were consistent across all four sensitivity analyses. No significant differences in all-cause mortality or MACE risk were observed among biologics. Interpretation: Biological treatment, as opposed to classic antipsoriatic drugs or apremilast, reduces risk of death and cardiovascular disease in psoriasis. Prospective trials are required to validate these findings.

Objective:The global rise of autoimmune diseases presents a significant medical challenge, with inadequate treatment options, high morbidity risks, and escalating healthcare costs. While the underlying mechanisms of autoimmune disease development are not fully understood, both genetic predispositions and lifestyle factors, particularly sleep, play critical roles. Insomnia and circadian rhythm sleep disorders not only impair sleep but also disrupt multi-organ interactions by dysregulating sympathetic nervous system activity, altering immune responses, and influencing neuroendocrine function. These disruptions can contribute to immune system dysregulation, increasing the risk of autoimmune disease development. Methods:To assess the impact of impaired sleep on the risk of developing autoimmune diseases, a global population-based retrospective cohort study was conducted using electronic health records from the TriNetX US Global Collaborative Network, including 351,366 subjects in each propensity score matched group. Twenty autoimmune diseases were examined, and propensity score matching was employed to reduce bias. Three sensitivity analyses were conducted to test the robustness of the results. Results:The study identified significantly increased risks for several autoimmune diseases associated with impaired sleep, likely mediated by dysregulated neuroimmune and autonomic interactions. Specifically, cutaneous lupus erythematosus [hazard ratio (HR) = 2.119; confidence interval (CI) 1.674-2.682; p < 0.0001], rheumatoid arthritis (HR = 1.404; CI 1.313-1.501; p < 0.0001), Sjögren syndrome (HR = 1.84; CI 1.64-2.066; p < 0.0001), and autoimmune thyroiditis (HR = 1.348; CI 1.246-1.458; p < 0.0001) showed significantly increased risks. No diseases demonstrated reduced risks, and 4 out of 20 tested diseases did not show significant HR increases in any analysis. Conclusion:This study highlights the integral role of sleep in maintaining immune homeostasis through multi-organ interactions involving the autonomic nervous system, immune signalling pathways, and endocrine regulation. Disruptions in these systems due to chronic sleep impairment may predispose individuals to autoimmune diseases by altering inflammatory responses and immune tolerance. These findings underscore the necessity of recognizing and treating sleep disorders not only for general wellbeing but also as a potential strategy to mitigate the long-term risk of autoimmune disease development.

BackgroundOverweight and obesity are a global pandemic, contributing to death and disability-adjusted life-years. Obesity is a major factor in the onset of chronic inflammatory diseases (CIDs). Yet, several knowledge gaps remain: For several CIDs, inconsistent results have been reported, relating to their obesity-imposed risk, data on most rare CIDs remain unavailable, sex differences and racial disparities remain mostly unaddressed.MethodsA large-scale cohort study compared the risk of developing 46 CIDs in individuals with overweight/obesity (n=3,101,824) to an equal number of non-overweight/obese individuals. Propensity score matching optimized between-group comparability, and sensitivity analyses assessed study robustness.ResultsThe risk of developing any CID was 28.48% in overweight/obese individuals versus 17.55% in non-overweight/obese controls, with a hazard ratio (95%-confidence interval) of 1.52 (1.509-1.521, p<0.0001). This risk was consistent across all sensitivity, sex-, and race-stratified analyses. Overweight and obesity were associated with an increased risk for 24 of 46 CIDs in the primary analysis and all sensitivity analyses. For 12 diseases, increased risks were confirmed to one of the two sensitivity analyses, while for 10 diseases, results were discordant. No increased risk was observed for one disease. In sex-stratified analysis, overweight and obesity posed a more pronounced risk for four CIDs in female individuals. In race-stratified analysis, overweight and obesity were linked to a higher risk for seven CIDs in White individuals and to one CID in “Black or African American” individuals.ConclusionOverweight and obesity increase the risk for the majority of CIDs in a sex- and race-specific manner.

Epidermolysis bullosa acquisita (EBA) is a severe autoimmune blistering disease characterized by autoantibodies against type VII collagen (COL7). Neutrophils are the key effector cells of tissue destruction but regulatory T cells (Tregs) direct their recruitment and activation. In vitro experiments revealed a decrease of the effect of Tregs from EBA-diseased mice after transfer of anti-mCOL7 IgG in contrast to Treg from healthy mice on neutrophils and effector T cells. These findings suggest that Tregs may lose their function in EBA, similar to other autoimmune diseases. To deepen this understanding, we also performed RNA analysis of lesional skin and of Tregs isolated from lesional skin and lymph nodes of mice with experimental EBA. Whereas Tregs from lymph nodes showed no differences, Tregs isolated from lesional skin were significantly different in their gene expression profile compared to Tregs from healthy mice. In particular, gene expression related to T cell receptor, Th17 and Th1/Th2 differentiation was altered in Tregs from lesional skin showing the development of a possible instable phenotype of exhausted Tregs in EBA. To investigate a possible therapeutic impact of Tregs, adoptively transferred Tregs from healthy mice were administered prior disease induction utilizing the antibody transfer-induced mouse model of EBA. A significant reduction in clinical disease manifestation and reduction of neutrophils in the skin was observed by rescuing the Treg function in EBA. Supported by EXC 2167, SFB 1526, GRK 2633, all from the Deutsche Forschungsgemeinschaft. Basic Autoimmunity (BA)

BACKGROUND AND OBJECTIVES:Bullous pemphigoid (BP) is the most common autoimmune blistering disease in the Western world. While remission is achieved in the majority of BP patients by long-term use of corticosteroids with or without immunomodulants/immunosuppressants, national and international guidelines recommend adjuvant immunoadsorption (IA) in refractory patients. Here we investigated the safety and efficacy of IA in severe and/or refractory BP patients. PATIENTS AND METHODS:10 BP patients (3 women, 7 men; mean age 69.7 years; range 52-81 years) were treated with IA on three consecutive days (LigaSorb®, Fresenius Medical Care) combined with oral prednisolone (0.5 mg/kg BW per day, tapered), dapsone (1.5 mg/kg BW per day), and lesional mometasone furoate ointment. RESULTS:Within 2 and 6 months after IA, 50% and 90% of patients showed complete remission on therapy, respectively. In all patients, serum anti-BP180 IgG levels decreased significantly by an average of 89% and 73% immediately after the third IA and 4 weeks later, respectively. A total of 56 adverse events (AE) occurred during the 12-month follow-up. The majority of AE were of severity grade 2 (50%), 15 AE were classified as severe (grade 3-4). CONCLUSIONS:IA can be considered as a relatively safe and effective adjuvant therapy for patients with severe or refractory BP.

IntroductionChronic, non-communicable inflammatory diseases (CIDs) affect a large portion of the population, imposing a significant morbidity, encompassing a substantial mortality. Thus, they are a major medical burden with a high unmet need. CIDs develop over the span of several years, and the risk of developing CIDs has been linked to genetic and environmental factors. Thus, modification of environmental factors is a promising approach for the prevention of CIDs. Among modifiable environmental factors that have been linked to the CID risk is nicotine dependence. However, for only few CIDs, compelling evidence suggests that nicotine dependence increases (e.g., rheumatoid arthritis and asthma) or decreases (e.g., pemphigus) the CID risk. For most CIDs, there are inconsistent, scant, or no reports on the risk of CID associated with nicotine dependence.MethodsTo address this gap, we leveraged TriNetX, analyzing data from over 120 million electronic health records (EHRs). Using propensity score matching (PSM) to control for age, sex, ethnicity, and other CID risk factors, we contrasted the risk of developing any or any of the 38 CIDs in 881,192 EHRs from individuals with nicotine dependence to PSM-matched unexposed counterparts.ResultsThe analytical pipeline was validated by demonstrating an increased risk of individuals exposed to nicotine dependence for subsequent diagnosis of myocardial infarction, malignant neoplasm of the lung, and chronic obstructive pulmonary disease. Overall, 16.8% of individuals with nicotine dependence developed CIDs, compared to 9.6% of individuals not exposed to nicotine dependence (hazard ratio 2.12, confidence interval 2.10–2.14, p < 0.0001). Investigating single CIDs, nicotine dependence imposed increased risks for 23 of the 38 investigated diseases, i.e., dermatomyositis, granulomatosis with polyangiitis, pyoderma gangrenosum, and immune thrombocytopenic purpura. The sex-stratified analysis revealed few sex-specific differences in CID risk.DiscussionOur study emphasizes the importance of preventive measures targeting nicotine addiction to reduce the global burden of CIDs.

Pemphigoid diseases constitute a group of organ-specific autoimmune diseases characterized and caused by autoantibodies targeting autoantigens expressed in the skin and mucous membranes. Current therapeutic options are still based on unspecific immunosuppression that is associated with severe adverse events. Biologics, targeting the IL4-pathway or IgE are expected to change the treatment landscape of pemphigoid diseases. However, clinical studies demonstrated that targeting these pathways alone is most likely not sufficient to meet patient and healthcare partitioners expectations. Hence, model systems are needed to identify and validate novel therapeutic targets in pemphigoid diseases. These include pre-clinical animal models, in vitro and ex vivo model systems, hypothesis-driven drug repurposing, as well as exploitation of real-world-data. In this review, we will highlight the medical need for pemphigoid diseases, and in-depth discuss the advantages and disadvantages of the available pemphigoid disease model systems. Ultimately, we discuss how rapid translation can be achieved for the benefit of the patients.

Background:Chronic venous disorder (CVD), often overlooked as a significant medical burden, has recently been linked to severe health risks, especially deep vein thrombosis (DVT), and pulmonary embolism (PE). However, large-scale data are lacking. Specifically, the impact of CVD severity on the risk of thromboembolic events and the impact of procedural interventions on these risks are unknown. Methods:A retrospective cohort study of mortality and serious adverse events was conducted using electronic health records derived from the TriNetX database. Propensity-score matching and sensitivity analyses were performed to mitigate bias. Results:We included 463,313 patients with CVD. An increased risk of superficial vein thrombosis [SVT; hazard ratio (HR), 19.0, 95% confidence interval (CI) 17.1-21.0, p < 0.0001], DVT (3.3, 3.2-3.6), PE (2.1, 2-2.1), and mortality (1.8, 1.8-1.8) were observed. These results persisted in two sensitivity analyses. When stratifying CVD for disease severity into chronic venous disease and -insufficiency, elevated risks of thromboembolic events and all-cause mortality were observed in both groups. Comparing CVD patients with interventions to those without, the risk of DVT (0.9, 0.8-0.9), PE (0.6, 0.5-0.6) and all-cause mortality (0.5, 0.5-0.5) decreased. Conversely, the risk of SVT increased (1.8, 1.6-2.0). Discussion:Independently of disease severity, CVD entails an increased risk for venous thromboembolic events and all-cause mortality. In CVD patients, procedural interventions are associated with reduced risks for DVT, PE and all-cause mortality. Confirmation of these potentially clinically relevant findings necessitates prospective randomized trials.

A balanced immune system is essential to maintain adequate host defense and effective self-tolerance. While an immune system that fails to generate appropriate response will permit infections to develop, uncontrolled activation may lead to autoinflammatory or autoimmune diseases. To identify drug candidates capable of modulating immune cell functions, we screened 1200 small molecules from the Prestwick Chemical Library for their property to inhibit innate or adaptive immune responses. Our studies focused specifically on drug interactions with T cells, B cells, and polymorphonuclear leukocytes (PMNs). Candidate drugs that were validated in vitro were examined in preclinical models to determine their immunomodulatory impact in chronic inflammatory diseases, here investigated in chronic inflammatory skin diseases. Using this approach, we identified several candidate drugs that were highly effective in preclinical models of chronic inflammatory disease. For example, we found that administration of pyrvinium pamoate, an FDA-approved over-the-counter anthelmintic drug, suppressed B cell activation in vitro and halted the progression of B cell-dependent experimental pemphigoid by reducing numbers of autoantigen-specific B cell responses. In addition, in studies performed in gene-deleted mouse strains provided additional insight into the mechanisms underlying these effects, for example, the receptor-dependent actions of tamoxifen that inhibit immune-complex-mediated activation of PMNs. Collectively, our methods and findings provide a vast resource that can be used to identify drugs that may be repurposed and used to promote or inhibit cellular immune responses.