Genetic susceptibility is the foundation for disease development. Specific HLA alleles (such as HLA-DRB1*03, *07, DRB3/4/5, DPB1, DPA1, DQA1) are significantly associated with different clinical manifestations and prognoses (8). Polymorphisms in non-HLA genes (e.g., BTNL2, TNF-α genes) also elevate disease risk (9, 10). Environmental exposure is a critical trigger. Inhaled agents such as metal dusts, silica dust (11), and microbial antigens (e.g., Propionibacterium acnes, mycobacterial components) are considered potential antigen sources, which may disrupt immune tolerance through molecular mimicry or persistent antigen stimulation (12). Additionally, immune checkpoint inhibitors can also induce sarcoid-like reactions (13).

The classical immunological mechanism involves the polarization of CD4+ T cells into Th1/Th17 cells, which secrete large quantities of key cytokines such as IFN-γ, TNF-α, and IL-17, driving macrophage activation and the formation of non-necrotizing granulomas (5). Recent studies have significantly deepened this understanding. On the innate immunity front, metabolic reprogramming in macrophages–particularly the activation of the mTORC1–HIF-1α axis–has been established as a core driver of granuloma formation and maintenance (14, 15). In adaptive immunity, the research focus has shifted from classical Th1 cells to Th17.1 cells, which are recognized as the primary source of IFN-γ in the pulmonary microenvironment and are closely associated with disease chronicity and glucocorticoid resistance (16). Furthermore, B cells participate in in situ immune responses through the formation of tertiary lymphoid structures, revealing a new dimension of localized adaptive immune activation (17). The chronic nature of the disease and its progression to fibrosis are closely related to regulatory T cell (Treg) dysfunction and the persistent activation of pro-inflammatory signaling pathways (e.g., the OX40/OX40L pathway) (18, 19).

The diagnosis of pulmonary sarcoidosis requires a combination of clinical, imaging, and pathological findings, but assessing its immune activity is crucial for clinical decision-making, treatment evaluation, and prognosis. The core of this diagnostic strategy is the use of specific biomarkers to evaluate the immune status. Over the past decades, serum angiotensin-converting enzyme (SACE) has been routinely used in the clinical management of sarcoidosis. It is secreted by monocytes, macrophages, and epithelioid cells, and contributes to the regulation of granuloma formation in sarcoidosis. However, given its relatively low sensitivity and high specificity, SACE alone appears insufficient to establish a diagnosis of sarcoidosis based solely on this biomarker (20). In serological testing, the serum soluble IL-2 receptor (sIL-2R), serving as a quantitative marker of T-cell activation with sensitivity superior to SACE, is the preferred serological indicator for monitoring treatment response and predicting relapse (21). For the assessment of the local immune microenvironment, bronchoalveolar lavage fluid (BALF) immunophenotyping is essential; notably, a CD4+/CD8+ ratio > 3.5 is highly suggestive of sarcoidosis (specificity 93%–96%), directly reflects a local Th1 immune bias in the lungs, and constitutes important evidence supporting the diagnosis, while the expression of activated T-cell markers (such as CD38) aids in differentiation from other interstitial lung diseases (22). Key differentiating features is shown in Table 1.

In recent years, chitotriosidase (CHIT), a novel serum biomarker secreted by activated macrophages, has shown promising value in the diagnosis of sarcoidosis. Its activity is significantly elevated in patients, with diagnostic sensitivity and specificity exceeding 86% and 93%, respectively (23). Furthermore, CHIT levels decrease following treatment, supporting its utility in monitoring therapeutic efficacy (23). CHIT demonstrates superior diagnostic performance compared to the conventional biomarker angiotensin-converting enzyme (ACE). Notably, the “double product” (ACE × CHIT), derived from the multiplication of both markers, further enhances diagnostic accuracy and outperforms either biomarker alone (24). Additionally, the diagnostic efficacy of CHIT is comparable to that of BALF CD4+/CD8+ ratio, offering a reliable non-invasive assessment tool (25).

Imaging plays a pivotal role in the diagnosis, staging, and assessment of pulmonary sarcoidosis. Chest X-ray typically shows symmetrically enlarged bilateral hilar lymph nodes, with or without pulmonary infiltrates, serving as a common tool for initial screening and staging. High-resolution computed tomography (HRCT) is the cornerstone of imaging evaluation, providing superior visualization of subtle changes in lymph nodes and lung parenchyma. Typical HRCT findings include symmetrically enlarged bilateral hilar and mediastinal lymph nodes. On contrast-enhanced CT, these nodes frequently demonstrate moderate to marked homogeneous enhancement without fusion, aiding in differentiation from conditions such as lymphoma (which may show mild enhancement) or tuberculosis (which can present with rim enhancement) (26, 27). Furthermore, HRCT can reveal intrapulmonary micronodules distributed along lymphatic pathways, reticulation, traction bronchiectasis, and other fibrotic changes, offering significant value in assessing disease activity and the extent of fibrosis.

Furthermore, FDG-PET/CT functional imaging non-invasively assesses granulomatous metabolic activity and is of significant diagnostic value for pulmonary sarcoidosis (28). The images of chest X-ray and 18F-FDG PET/CT chest X-ray are shown in Figure 1. This technique is particularly valuable in clinical practice for several key applications. Primarily, it serves to accurately evaluate systemic disease activity and monitor treatment response. A reduction in the maximum standardized uptake value (SUVmax) post-treatment strongly correlates with improvements in pulmonary function parameters, such as forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) (29). Secondly, PET/CT offers unique advantages in detecting occult extrapulmonary involvement (e.g., cardiac, neural, or bone marrow), thereby aiding in comprehensive staging (30). Thirdly, it can guide biopsy site selection by identifying the most metabolically active lesions, thereby increasing diagnostic yield (31). It is therefore mainly recommended for cases with diagnostic uncertainty, suspected multi-organ involvement, or treatment refractoriness.

A meta-analysis provides high-level evidence for its diagnostic performance: the pooled sensitivity reached 0.971 (95% CI 0.909–1.000), meaning this technique can identify 97.1% of true cases with a very low missed diagnosis rate; the pooled specificity was 0.873 (95% CI 0.845–0.920), indicating it can accurately exclude 87.3% of non-sarcoidosis lesions, demonstrating good differential diagnostic capability (30). Notably, FDG-PET/CT is advancing from qualitative assessment to quantitative prognostic prediction. Volume-based metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), comprehensively quantify the systemic granulomatous burden. Higher baseline MTV or TLG independently correlates with accelerated lung function decline and increased disease progression risk (32), providing a key tool for risk stratification and personalized management in pulmonary sarcoidosis.

The measurement of 24-h urinary calcium has transcended its traditional role in monitoring calcium metabolism in pulmonary sarcoidosis, emerging as a significant biomarker that reflects systemic granulomatous immune activity and aids in the differentiation of fibrotic phenotypes. Elevated levels correlate positively with macrophage activation markers (e.g., chitotriosidase) and are associated with a decline in diffusing capacity, indicating its utility in assessing disease activity and severity (33, 34). Crucially, in the challenging differential diagnosis between stage IV fibrotic sarcoidosis and idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, 24-h urinary calcium demonstrates high specificity (approximately 89.7%) and good discriminatory power (AUC 0.77), outperforming serum calcium (35). Therefore, this simple, non-invasive test provides valuable evidence for the precise diagnosis and evaluation of sarcoidosis, particularly its fibrotic subtype.

Uveitis is a common and important extrapulmonary manifestation of pulmonary sarcoidosis. Comprehensive fundus examination holds critical diagnostic value in screening. Clinical practice has confirmed that systemic inflammation in sarcoidosis can directly coincide with or accompany uveitis. For example, Kawali et al. reported a case of biopsy-confirmed pulmonary sarcoidosis that was concurrently diagnosed with Fuchs uveitis presenting atypical signs during the disease course (36). This suggests that systematic ophthalmic screening is essential for sarcoidosis patients to promptly detect granulomatous inflammation or specific comorbidities. Additionally, another case demonstrated that a patient initially suspected of tuberculosis was found to have optic disk granuloma and periphlebitis upon fundus examination, ultimately leading to a revised diagnosis of systemic sarcoidosis (37). This further illustrates the indicative role of fundus findings in systemic diagnosis and their value in differential diagnosis. These fundus features are also included in the International Workshop on Ocular Sarcoidosis (IWOS) diagnostic criteria (38).

In addition to assessing immune activity, directly identifying antigens is a key advancement toward etiological diagnosis. For example, specific immunohistochemical staining for Propionibacterium acnes (using PAB antibody) can visualize this microorganism within granulomas and help distinguish sarcoidosis from other granulomatous diseases (39). This immunohistochemical approach provides a potential method for disease subtyping from an etiological perspective, supplementing immune biomarkers. It should be noted, however, that this finding originates from a relatively small-scale study, and the technique has not yet been incorporated into current diagnostic guidelines, remaining a primarily research tool.

Oral prednisone is the first-line choice for patients who are symptomatic or at risk of organ function impairment. Its efficacy stems from the broad suppression of pro-inflammatory cytokine gene transcription, including that of TNF-α and IFN-γ (40). For patients with pulmonary sarcoidosis, the recommended starting dose is 20–40 mg/day for 4–6 weeks (41). The European Respiratory Society (ERS) guideline recommends 20 mg/day as the standard starting dose (42). The SARCORT trial provided key evidence for personalized dosing, confirming that 20 mg/day is as effective as 40 mg/day but with fewer side effects, which supports using a lower starting dose in most patients (43). The specific dose selection should be individualized based on the degree of lung function impairment, symptom severity, and imaging findings, a point also emphasized in expert consensus (41). After an effective response, the dose should be tapered slowly over 6–18 months to a maintenance dose of 5–10 mg/day. If the maintenance dose cannot be reduced below 10 mg/day, a second-line drug should be added (44). The total course of treatment is typically at least 12 months; chronic or relapsing patients may require longer treatment to prevent recurrence (41).

These are primarily used for patients who fail to taper steroids, have an ineffective response, are intolerant, or require long-term treatment. Methotrexate (MTX) is the preferred second-line drug, at a common dose of 10–15 mg/week (42). In a recent published trial, its potential as a first-line agent has been evaluated (45). This study directly compared methotrexate (starting dose 40 mg/week) with prednisone (20 mg/day), finding that the initial high-dose methotrexate regimen did not show superior clinical efficacy and was associated with adverse reactions. However, the same trial protocol, which titrated methotrexate to a target dose, suggests that if MTX is used as first-line treatment, a weekly dose of 15–20 mg should be tolerated for optimal effect (46). For MTX-intolerant patients, Azathioprine (AZA) at 50–200 mg/day has been shown in a retrospective study to be as effective as MTX in its steroid-sparing effect and in preserving FVC, making it a viable alternative (47). Meanwhile, Leflunomide (10–20 mg/day) is a valuable option for patients intolerant to MTX (48). Mycophenolate mofetil represents another alternative, though evidence remains limited (49).

Mainly used for refractory, severe, or progressive disease. Tumor necrosis factor-alpha (TNF-α) therapy targets this core cytokine pivotal to granuloma formation and maintenance. Among these agents, infliximab is the most extensively studied and demonstrates well-established efficacy, administered via a recommended regimen of 5 mg/kg intravenously at weeks 0, 2, and 6, followed by maintenance infusions every 4–8 weeks (50). Adalimumab (40 mg subcutaneously every 1–2 weeks) can be used as an alternative. B-cell targeted therapy represents another approach, wherein rituximab, an anti-CD20 monoclonal antibody, functions by depleting B cells. Although supporting evidence from large randomized controlled trials remains limited, case series have indicated its potential to improve lung function (e.g., FVC) and exercise tolerance (as measured by the 6-min walk test) in certain refractory patients (51).

For patients presenting with a progressive pulmonary fibrosis phenotype, combination with anti-fibrotic drugs may be considered. A subgroup analysis of the INBUILD trial (Efficacy and Safety of Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Diseases) indicated that nintedanib can slow the decline in lung function in patients with various progressive fibrosing interstitial lung diseases, including sarcoidosis (52, 53). Recent clinical studies show that the presence of circulating CD34+ fibrocytes and EPCs in peripheral blood is related to the severity of pulmonary fibrosis, especially in patients with idiopathic pulmonary fibrosis (IPF) (54). Furthermore, in a study by Heukels et al. (55), fibrocytes constituted 2.6% of total CD45+ cells in IPF lungs, a statistically significant increase compared to control lungs, suggesting fibrocytes as a possible diagnostic marker and therapeutic target.

Emerging therapeutic strategies, including both disease-modifying agents and traditional Chinese medicine (TCM), are currently being evaluated. Studies show nicotine can modulate the immune system by activating the α7 nicotinic acetylcholine receptor (α7nAChR), down-regulating TNF-α, and enhancing Treg function. Clinical studies indicate that transdermal nicotine patches can improve lung function and are well-tolerated, suggesting that targeting the cholinergic anti-inflammatory pathway may be a novel non-immunosuppressive treatment approach (56–58). Meanwhile, Jiawei Yanghe Decoction (JWYHD) has been shown to effectively inhibit Th17 cell differentiation and the production of related cytokines (IL-17A, TNF-α) by up-regulating the expression of nuclear receptors NR1D1/2. Its effect was comparable to prednisolone in animal models (59).

Given the potential role of microbial antigens like P. acnes in the pathogenesis, antimicrobial therapy is considered an exploratory treatment strategy. The rationale is based on molecular studies that have detected various mycobacterial genes (e.g., gyrA, ropB) in sarcoidosis granulomas. The enzymes encoded by these genes are targets for existing antimicrobial drugs (like fluoroquinolones and rifampin), suggesting that targeting these enzymes with antibiotics could be an innovative strategy (60). Clinical studies have shown tetracyclines (e.g., minocycline) are effective for cutaneous sarcoidosis (61). However, the Phase II CLEAR trial (levofloxacin, ethambutol, azithromycin, and rifabutin) for pulmonary sarcoidosis, while reducing the ESAT-6 immune response, failed to improve physiological indicators such as FVC (62). Therefore, although etiology-targeted antimicrobial therapy is theoretically promising, its clinical application still requires more evidence and is an important direction for future research.