Editorial: Sarcoidosis Diagnosis and Treatment Based on Etiology

Abstract

Sarcoidosis is a heterogeneous granulomatous disease with variable organ involvement, clinical course, and treatment response. Because etiology is often uncertain at the point of care, clinicians must work with probabilistic, testable "working" etiological hypothesesexplicitly ranking plausible triggers/exposures and updating them as new data accrue-to refine diagnosis, exclude mimics, and choose therapy. This Research Topic, "Sarcoidosis Diagnosis and Treatment Based on Etiology," brings together ten contributions that collectively support an etiology-informed precision-management pipeline summarized in Figure 1.Operationalizing a "working" etiological hypothesis means translating mechanistic uncertainty into a structured bedside workflow. When direct evidence of a trigger (e.g., Cutibacterium acnes or tattoo particles) is absent, clinicians can: (i) systematically document exposure and treatment history (including tattoos/implants, occupational or environmental metal exposure such as beryllium, drugs and immune checkpoint inhibitors, and travel/zoonotic risks); (ii) seek supportive-but imperfect-signals from phenotype and tests (organ distribution, radiologic patterns, bronchoalveolar lavage profiles, histologic context, targeted microbiology, and, where available, immunohistochemistry/PCR for candidate antigens); and (iii) iteratively revise the hypothesis after high-consequence mimics are excluded and longitudinal response is observed. In this sense, "etiology" functions like a Bayesian prior that is refined by pathology, imaging, and activity markers rather than a binary label.Beyond its clinical heterogeneity, sarcoidosis can be conceptually understood as an antigen-driven, immune-mediated syndrome that occupies a distinct position between classical infection and autoimmunity, arising from failure of antigen-specific immune tolerance to persistent antigens rather than uncontrolled pathogen proliferation or primary autoimmunity. The collection was designed to (i) highlight putative triggers and host immune dysregulation, (ii) strengthen multimodal diagnostic refinement through pathology and imaging while rigorously excluding major mimics (notably tuberculosis and malignancy), and (iii) connect clinical phenotyping to tailored therapeutic strategies and activity markers. Two reviews set the conceptual foundation: A review of sarcoidosis etiology, diagnosis and treatment synthesizes current knowledge across etiological hypotheses, diagnostics, and management, while Diagnosis and Treatment of Sarcoidosis Based on Immunological Etiology and Mechanisms focuses on immunological endotypes that may underlie clinical heterogeneity. Mechanism-to-therapy translation is further developed in Latent microbial reactivation and immune dysregulation in sarcoidosis: bridging pathogenesis and precision therapeutics, which frames microbial/antigen hypotheses and immune dysregulation as actionable clinical context for treatment decisions. Etiologyoriented case evidence is provided by Case Report: Tattoo sarcoidosis with epithelioid cell granuloma positive for Propionibacterium acnes, supporting the relevance of Cutibacterium (formerly Propionibacterium) as a candidate antigen in susceptible hosts, and by Case Report: The immune architecture of immunotherapy-induced cutaneous sarcoidosis resembles peritumoral inflammation, illustrating treatment-associated triggers and immune perturbation. The pipeline's diagnostic core integrates histology (non-caseating granuloma), imaging (including CT and FDG-PET where appropriate), and systematic exclusion of sarcoidosis mimics. Pathological diversity of pulmonary sarcoidosis details the spectrum of histopathological patterns that can inform clinically meaningful phenotyping, while Case Report: Sarcoidosis or tuberculosis? A continuous challenge emphasizes the enduring necessity of differential diagnosis-particularly TB exclusion-before immunosuppression. Beyond the mimics discussed in this Research Topic (e.g., tuberculosis and malignancy), clinicians should also remain vigilant for other clinically important granulomatous mimics such as chronic beryllium disease (CBD) and common variable immunodeficiency (CVID)-associated granulomatous disease (e.g., granulomatous-lymphocytic interstitial lung disease), both of which can present with non-caseating granulomas and multisystem involvement. These entities are best addressed by a targeted exposure and infection history and focused testing when appropriate (e.g., beryllium sensitization testing such as the BeLPT, and serum immunoglobulin evaluation), to avoid misclassification and to align treatment with underlying pathobiology. Precision management depends on linking phenotype (e.g., pulmonary, cardiac, cutaneous) with treatment intensity and monitoring. Clinical characteristics of patients with pulmonary sarcoidosis treated with systemic steroids in Japan provides practiceoriented data on steroid-treated cohorts, and Phenotyping sarcoidosis: a single institution retrospective analysis illustrates how structured phenotyping can stratify patients with differing trajectories. Upregulation of HSP90α in the lungs and circulation in sarcoidosis adds biomarker-oriented insights that may complement clinical activity assessment and guide follow-up. In routine monitoring, serum ACE levels and soluble IL-2 receptors (sIL-2R) remain widely used indicators of granulomatous activity, but both have recognized limitations in specificity and can be influenced by host factors and comorbidities. Although not the primary focus of the included HSP90α study, HSP90α may represent a complementary axis of immune/stress activation, and a pragmatic nearterm approach is to integrate it (where available) as an add-on marker alongside symptoms, pulmonary function, imaging, and established serological tests-pending further validation and assay standardization. Across the collection, a consistent message emerges: "etiology" should be treated as a testable clinical hypothesis, iteratively refined by pathology, imaging, and exposure/treatment history, then operationalized through phenotype-guided therapy and biomarkers. Prospective studies that couple standardized phenotyping with etiologyinformed treatment strategies, and that validate activity markers, will be essential to advance individualized care. In summary, this Research Topic provides a coherent precision-management pipeline-from putative triggers to diagnosis, phenotyping, therapy, and monitoring-to support better decision-making for patients with sarcoidosis.From a conceptual standpoint, future progress will depend on clarifying how persistent antigens, host immune tolerance failure, and tissue-specific immune architecture interact to generate distinct sarcoidosis phenotypes.