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Randomized controlled trials (RCTs) are the gold standard for evaluating the efficacy and safety of both pharmacological and non-pharmacological interventions. However, while they are designed to control confounders and ensure internal validity, their usually stringent inclusion and exclusion criteria often limit the generalizability of findings to broader patient populations. Moreover, RCTs are resource-intensive, frequently underpowered to detect rare adverse events, and sometimes narrowly focused due to their highly controlled environments. In contrast, real-world data (RWD), typically derived from electronic health records (EHRs) and claims databases, offers a valuable counterpart for answering research questions that may be impractical to address through RCTs. Recognizing this, the US Food and Drug Administration (FDA) has increasingly relied on real-world evidence (RWE) from RWD to support regulatory decisions and post-market surveillance. Platforms like TriNetX, that leverage large-scale RWD, facilitate collaborations between academia, industry, and healthcare organizations, and constitute an in-depth tool for retrieval and analysis of RWD. TriNetX’s federated network architecture allows real-time, privacy-compliant data access, significantly enhancing the ability to conduct retrospective studies and refine clinical trial designs. With access to currently over 150 million EHRs, TriNetX has proven particularly effective in filling gaps left by RCTs, especially in the context of rare diseases, rare endpoints, and diverse patient populations. As the role of RWD in healthcare continues to expand, TriNetX stands out as a critical tool that complements traditional clinical trials, bridging the gap between controlled research environments and real-world practice. This review provides a comprehensive analysis of the methodologies and applications of the TriNetX platform, highlighting its potential contribution to advance patient care and outcomes.

Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions share mechanistic overlaps with AD in their pathophysiology, i.e., are linked to type 2 inflammation. Most recently, dupilumab was approved by the U.S. Food and Drug Administration for prurigo nodularis (PN). Given its relatively good safety profile, effective off-label use of dupilumab has been reported for a multitude of dermatologic diseases and several clinical trials for dermatologic skin conditions are currently ongoing. We conducted a systematic review of applications of dupilumab in dermatology other than AD and PN by searching the databases PubMed/Medline, Scopus, Web of Science and Cochrane Library as well as the clinical trial registry ClinicalTrials.gov. We found several reports for effective treatment of bullous autoimmune diseases, eczema, prurigo, alopecia areata, chronic spontaneous urticaria, Netherton syndrome and a variety of other chronic inflammatory skin diseases.

Autoimmune blistering disorders (AIBDs) are a heterogeneous group of approximately a dozen entities comprising pemphigus and pemphigoid disorders and dermatitis herpetiformis. The exact diagnosis of AIBDs is critical for both prognosis and treatment and is based on the clinical appearance combined with the detection of tissue-bound and circulating autoantibodies. While blisters and erosions on the skin and/or inspectable mucosal surfaces are typical, lesions may be highly variable with erythematous, urticarial, prurigo-like, or eczematous manifestations. While direct immunofluorescence microscopy (IFM) of a perilesional biopsy is still the diagnostic gold standard, the molecular identification of the major target antigens opened novel therapeutic avenues. At present, most AIBDs can be diagnosed by the detection of autoantigen-specific serum antibodies by enzyme-linked immunosorbent assay (ELISA) or indirect IFM when the clinical picture is known. This is achieved by easily available and highly specific and sensitive assays employing recombinant immunodominant fragments of the major target antigens, i.e., desmoglein 1 (for pemphigus foliaceus), desmoglein 3 (for pemphigus vulgaris), envoplakin (for paraneoplastic pemphigus), BP180/type XVII collagen (for bullous pemphigoid, pemphigoid gestationis, and mucous membrane pemphigoid), laminin 332 (for mucous membrane pemphigoid), laminin β4 (for anti-p200 pemphigoid), type VII collagen (for epidermolysis bullosa acquisita and mucous membrane pemphigoid), and transglutaminase 3 (for dermatitis herpetiformis). Indirect IFM on tissue substrates and in-house ELISA and immunoblot tests are required to detect autoantibodies in some AIBD patients including those with linear IgA disease. Here, a straightforward modern approach to diagnosing AIBDs is presented including diagnostic criteria according to national and international guidelines supplemented by long-term in-house expertise.

Oral lichen planus (OLP) is a chronic inflammatory condition with malignant potential for oral squamous cell carcinoma (OSCC). Differential risks of pharmacological treatments, particularly long-term use, remain unclear. We aimed to quantify OSCC risk across treatment modalities and assess potential benefit of combining immunosuppressive and anti-inflammatory agents to inform safer strategies. We conducted a large, retrospective cohort study with propensity score matching to balance demographic and clinical covariates. Patients with OLP treated with either systemic or topical glucocorticoids, calcineurin inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or combinations were followed. OSCC incidence rates were compared between treatment groups, controlling for confounders and stratifying by route and duration of therapy. Compared with glucocorticoid regimens, calcineurin inhibitors were associated with higher OSCC risk (glucocorticoids: HR 1.85, 95% CI 1.48-2.32; calcineurin inhibitors: HR 3.17, 1.48-6.76). The lowest risk was seen with topical glucocorticoids. Concomitant NSAIDs, particularly ketorolac and diclofenac, with topical glucocorticoids or calcineurin inhibitors, reduced OSCC risk (topical glucocorticoids: HR 0.73, 0.58-0.91; plus ketorolac: HR 0.63, 0.38-1.04; topical calcineurin inhibitors alone: HR 1.53, 1.03-2.28; plus ketorolac: HR 0.28, 0.15-0.54). Owing to retrospective design and reliance on ICD-10 coding, residual confounding and misclassification cannot be excluded. Calcineurin inhibitors carry high risk for malignant transformation in OLP, while topical glucocorticoids, especially NSAID/glucocorticoid combinations, offer safer profiles. These findings call for re-evaluation of treatment guidelines and prospective trials assessing novel or combination therapeutics that optimize long-term safety and symptom control in OLP.

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.

Mucous membrane pemphigoid (MMP) is an autoimmune disease affecting the oral mucosa, conjunctivae and other mucous membranes. The mainstay treatment options are local and systemic corticosteroids and immunomodulatory therapies. Current research on cancer risk in MMP is scarce and has yielded conflicting results. The aim of this study was to investigate the risk of developing skin cancer in patients with MMP by performing a large-scale, retrospective matched cohort study utilizing data from over 117 million US individuals. The risk of skin cancer in patients with MMP was observed within a 5-year follow-up period, along with three temporal difference analyses and stratification for disease severity. MMP was associated with an increased risk of several types of skin cancers within the first 5 years of follow-up, particularly squamous cell carcinoma, basal cell carcinoma, and non-melanoma skin cancer. Stratification by disease severity showed significantly elevated risks in severe cases. These findings underscore the importance of regular skin cancer screening and risk-based monitoring in MMP patients, particularly those with severe disease. Integrating dermatologic surveillance into routine care could facilitate early detection and timely intervention. Additionally, these results highlight the need for further research into cancer risks in other autoimmune blistering diseases, helping to refine long-term management strategies.

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation.

The association between atopic dermatitis (AD) and lymphoma risk remains inconclusive. Dupilumab, approved for moderate-to-severe AD, has been linked to an increased lymphoma risk, raising significant concerns. The objective of the study was to clarify the association between AD and lymphoma risk and extend to non-dermatological type 2 inflammatory diseases (T2IDs). This study also aimed to assess the impact of dupilumab on lymphoma risk in AD and non-dermatological T2IDs. A retrospective cohort study was conducted using the TriNetX database. Propensity-score matching allowed for better comparability, and sensitivity analyses ensured robustness. Among 801,508 cases and controls, AD was associated with an increased risk of lymphoma, e.g., cutaneous T-cell lymphoma (CTCL) and non-Hodgkin lymphoma (NHL). Among 14.4 million cases and controls, non-dermatological T2IDs also conferred an increased lymphoma risk. In the comparison of AD patients treated with dupilumab versus other systemic treatments (  = 7,840 per group), dupilumab exposure did not alter the risk for lymphomas but tended toward reduced risks. This decreased risk association was most evident in non-dermatological T2IDs (  = 16,908 per group). Retrospective data analysis, data quality, possible false registration of ICD-10-codes. T2IDs, including AD, are associated with a significantly increased risk for lymphoma. Treatment with dupilumab partially ameliorates this risk association, especially for NHL.

Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14 , CD169 , and CD34 cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4 T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4 T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.

[This corrects the article DOI: 10.1371/journal.ppat.1008560.].