Sarcoidosis is a systemic granulomatous disease influenced by genetic and environmental factors, resulting in a wide range of phenotypic variation. Accordingly, it often represents a diagnostic and therapeutic challenge. In recent years, evidence has notably accelerated across both diagnostic and therapeutic domains. EBUS-guided cryobiopsy has shown promising diagnostic improvement supported by randomized controlled trial data, while quantitative FDG-PET/CT biomarkers, novel radiotracers targeting somatostatin receptors and vascular adhesion protein 1, and multiparametric cardiac MRI have expanded the precision and prognostic value of imaging. Preclinical proteomic signatures and electronic nose technology suggest a future of earlier, less invasive detection. The 2025 WASOG Position Paper marked a paradigm shift in corticosteroid use, arguing against the traditional corticosteroid-centered model of sarcoidosis treatment. The PREDMETH trial supports methotrexate as a first-line alternative to prednisone in pulmonary sarcoidosis. Emerging targeted therapies—JAK inhibitors, PDE-4 inhibitors, and SGLT-2 inhibitors in sarcoid cardiomyopathy—provide preliminary but promising evidence of efficacy. Collectively, these advances outline a trajectory toward more precise, less toxic, and increasingly personalized management of sarcoidosis.
Sarcoidosis is a systemic granulomatous disease influenced by genetic and environmental factors and characterized by the formation of noncaseating granulomas that can affect virtually any organ. The lungs and mediastinal lymph nodes are involved in more than 90% of cases, but cardiac, neurological, cutaneous, and ocular manifestations account for significant morbidity and mortality [1,2]. Epidemiological data show considerable variability by race, sex, and geography, with the highest incidence reported in Scandinavian populations and individuals of African descent (15–40 cases per 100000 population), and a bimodal age distribution peaking in the third and fifth decades of life [1].
The clinical course is highly heterogeneous: approximately one-third of patients experience spontaneous remission, while up to 30% develop chronic progressive disease leading to pulmonary fibrosis, cardiac arrhythmias, or end-organ failure [2,3]. Diagnostic delay remains problematic, particularly in cardiac sarcoidosis, where recent data suggest that disease phenotype—especially isolated cardiac presentation—may be a stronger determinant of outcomes than time to diagnosis [4]. The diagnostic approach continues to rely on a combination of clinical, radiological, and histological criteria in the absence of a validated gold standard test. Similarly, treatment has been largely empirical, anchored in systemic corticosteroids despite well-documented long-term toxicity [5,6].
However, recent years have witnessed a transformation in both domains: the identification of preclinical proteomic signatures [7], the emergence of cryobiopsy as a superior bronchoscopic technique [8], a WASOG-endorsed paradigm shift in corticosteroid use [5], and evidence for novel targeted therapies, including JAK inhibitors, efzofitimod, and SGLT-2 inhibitors in sarcoid cardiomyopathy [9–14]. This review summarizes the most clinically relevant advances in the diagnosis and treatment of sarcoidosis published over the past 2 years, aiming to provide an updated, integrated framework for practicing clinicians.
Advances in diagnosisBiomarkersSerum angiotensin-converting enzyme (ACE) and soluble interleukin 2 receptor (sIL-2R) remain the most widely used biomarkers in clinical practice for assessing disease activity and monitoring treatment response. Although both lack the sensitivity and specificity required for standalone diagnostic use, they retain clinical utility when interpreted alongside imaging findings and the clinical context [1]. Recent data have further refined their role: a retrospective Spanish single-center study by López-Martínez et al. confirmed the association between elevated ACE levels and multiorgan disease and additionally identified older age, White ethnicity, and skin involvement as independent predictors of normal ACE levels at diagnosis [15]. Complementing this, Mehta et al. showed in a prospective cohort that baseline serum ACE independently predicts corticosteroid response, potentially informing treatment decisions at diagnosis [16].
Beyond established markers, novel candidates targeting different pathophysiological pathways have emerged. Bozkürk et al. identified serum paraoxonase 1—an antioxidant enzyme reflecting systemic oxidative stress—as a marker of pulmonary dysfunction and disease activity in sarcoidosis, correlating with functional impairment and offering prognostic potential [17]. At the frontier of molecular diagnostics, Kraaijvanger et al. recently demonstrated that targeted proteomics in extracellular vesicles (EVs) can identify biomarkers predictive of therapeutic response in patients with pulmonary sarcoidosis. Increased baseline concentrations of chitinase-3-like protein 1 (CHI3L1) in serum EVs were associated with an improved treatment response in patients with pulmonary sarcoidosis treated with prednisone [18]. Increased chitinase activity in pulmonary sarcoidosis provides the rationale for the ongoing phase 2 trial in which a first-in-class chitinase inhibitor, OATD-01, is being studied as a novel treatment option for pulmonary sarcoidosis [19].
Similarly, in patients on methotrexate (MTX), increased baseline concentrations of carboxypeptidase A1 (CPA1) in serum EVs were associated with treatment response. Interestingly, CPA1 has been described as a potential prodrug-activating enzyme of MTX, capable of hydrolyzing stable MTX prodrugs [20].
Perhaps the most transformative recent contribution, however, comes from Arkema et al., who analyzed stored plasma samples from a Swedish population cohort and identified 44 inflammatory proteins—including interferon-related and myeloid activation markers—that were significantly elevated up to 2 decades before clinical diagnosis, with 27 remaining significant in samples obtained 10 years or more before diagnosis [7]. This landmark finding reframes sarcoidosis as a disease with a measurable preclinical phase and opens the door to early detection strategies. Collectively, these advances signal a paradigm shift from reactive monitoring toward predictive and phenotype-based biomarker strategies [21].
Advances in imagingHigh-resolution computed tomographyHigh-resolution computed tomography (HRCT) remains the cornerstone imaging modality for the initial assessment and staging of pulmonary sarcoidosis. The characteristic perilymphatic nodular pattern with bilateral hilar adenopathy is well established, but atypical presentations—including ground-glass opacity, consolidation, or honeycombing—pose significant diagnostic challenges (Fig. 1) [1,2,22]. A multinational Delphi consensus involving 146 experts identified 7 distinct HRCT phenotypes in pulmonary sarcoidosis, broadly categorized as nonfibrotic (micronodular, macronodular, and consolidation) or likely fibrotic (bronchocentric reticulation with or without cavitation, and large masses mimicking progressive massive fibrosis), each associated with distinct functional profiles. This framework represents a step toward a formal CT-based classification to guide disease stratification and assessment of treatment response [23].
Beyond sarcoidosis-specific applications, the broader field of radiomics in interstitial lung disease (ILD) is rapidly evolving, with quantitative CT features enhancing disease classification and prognostication [24]. Recent studies have shown that machine learning-based radiomic models can distinguish fibrotic from inflammatory ILD patterns and differentiate idiopathic pulmonary fibrosis from autoimmune-related ILD with high accuracy [25,26]. Once validated in multicenter prospective studies, these approaches may complement visual CT assessment in sarcoidosis by enabling objective phenotyping and quantification of disease burden.
PET/CTThe role of 18F-FDG PET/CT in sarcoidosis continues to evolve (Fig. 2). Donnelly et al. found near-chance interrater agreement on treatment decisions after PET/CT in pulmonary sarcoidosis (AC1=0.178), versus substantial agreement in cardiac cases (AC1=0.797), underscoring the need for standardized guidance in noncardiac disease [27]. Nonetheless, Zekri et al. showed that PET/CT detected active inflammation in 76% of patients, prompted diagnostic biopsy in 32%, and influenced treatment in 60% [28].
Beyond detection, Shao et al. demonstrated that volume-based PET parameters, rather than SUVmax, independently predicted disease progression, suggesting that total inflammatory burden better informs risk stratification [29]. In cardiac sarcoidosis, a 60-minute acquisition protocol proved diagnostically sufficient [30], while residual FDG uptake 1 month after corticosteroid initiation independently predicted adverse outcomes [31].
Among novel radiotracers, 68Ga-DOTANOC PET/CT showed diagnostic performance comparable to FDG-PET/CT for cardiac sarcoidosis without requiring dietary preparation [32,33], and a proof-of-concept study using [68Ga]Ga-DOTA-Siglec-9—targeting vascular adhesion protein 1 (VAP-1) on inflamed endothelium—demonstrated significantly higher uptake in affected lungs and lymph nodes compared with controls, supporting further investigation of more specific alternatives to 18F-FDG for granulomatous inflammation [34].
Cardiac MRICardiac MRI (CMR) is the reference modality for tissue characterization in cardiac sarcoidosis. Drew et al. demonstrated the complementary value of CMR and FDG-PET/CT, with CMR detecting fibrosis through late gadolinium enhancement and PET identifying active inflammation—supporting a multimodal imaging strategy, particularly when initial findings are equivocal or when distinguishing active disease from fibrosis is clinically relevant [35]. Emerging CMR-derived markers are expanding prognostic capabilities: Nita et al. showed that atrial phasic dysfunction assessed by feature-tracking CMR independently predicts new-onset atrial fibrillation in patients with cardiac sarcoidosis [36], while Giallafos et al. demonstrated that plasma aldosterone levels are independently associated with myocardial extracellular volume—a CMR-derived marker of diffuse fibrosis—in patients with sarcoidosis and preserved ejection fraction, even in the absence of late gadolinium enhancement or PET/CT-defined inflammation, suggesting that aldosterone may reflect early fibrotic remodeling through a pathway distinct from active granulomatous inflammation [37]. Finally, Mathijssen et al. found that CMR phenotyping showed greater discriminative accuracy than societal recommendations for predicting fatal or life-threatening ventricular arrhythmias, suggesting that it may be more effective for identifying candidates for primary prevention implantable cardioverter-defibrillator (ICD) placement [38].
Advances in bronchoscopyRecent scientific evidence supports a pivotal diagnostic role for EBUS-guided mediastinal cryobiopsy. Deng et al. published the first multicenter randomized controlled trial comparing EBUS-guided transbronchial mediastinal cryobiopsy (TBMC) with TBNA for nonmetastatic mediastinal lymphadenopathy, demonstrating a significantly superior diagnostic yield (97.1% vs 79.9%; P<.001)—with particularly high sensitivity for sarcoidosis (98.0% vs 82.7%)—and a comparable safety profile, positioning TBMC as a potential first-line diagnostic tool [39]. A second randomized clinical trial by the same group, conducted specifically in patients with suspected sarcoidosis, confirmed these findings, with cryobiopsy providing larger and better-preserved tissue samples that enabled confident granuloma identification and exclusion of alternative diagnoses [40]. Complementing the randomized clinical trial evidence, Terschluse et al. reported a retrospective analysis of 321 patients with sarcoidosis or chronic beryllium disease, showing that transbronchial lung cryobiopsy provided meaningful additional diagnostic value beyond EBUS-TBNA alone, particularly in parenchymal disease [41].
The combination of both techniques in a single bronchoscopic session has also been explored. Ota et al. demonstrated that a dual approach—EBUS-TBNA followed by transbronchial lung cryobiopsy—achieved high diagnostic yield with an acceptable complication rate, suggesting that this strategy may become the preferred bronchoscopic workup for complex or atypical presentations [42]. Together, these data support EBUS-guided cryobiopsy as a new standard of care in the bronchoscopic diagnosis of sarcoidosis, with direct implications for clinical practice guidelines.
Emerging diagnostic techniquesBeyond established modalities, a series of novel tools are reshaping the diagnostic horizon in sarcoidosis. De Crem and Wuyts provided a timely integrative overview of emerging techniques, positioning these advances within the broader challenge of noninvasive phenotyping and earlier detection. Among the most promising is electronic nose (eNose) technology, which analyzes volatile organic compound patterns in exhaled breath to generate disease-specific “breathprints.” [43].
Electronic nose technology has advanced toward clinical translation: van der Sar et al. previously demonstrated that exhaled breath profiling could distinguish sarcoidosis from other respiratory diseases in a single-center study, and Formsma et al. recently provided international multicenter external validation for differentiating fibrotic ILD subtypes, with AUCs of 0.75–0.95, supporting its potential as a noninvasive point-of-care tool [44,45].
Advances in treatment (Fig. 3)A paradigm shift in corticosteroid useFor more than 7 decades, systemic corticosteroids have been the undisputed cornerstone of sarcoidosis treatment. The year 2025 marked a decisive turning point. Wells, Lower, Baughman, Culver et al. published a WASOG Position Paper in The Lancet Respiratory Medicine that explicitly calls for oral corticosteroids to no longer be considered first-line therapy in all patients with sarcoidosis, characterizes long-term corticosteroid use as an “undesirable outcome,” and proposes that, when corticosteroids are required, they should serve only as bridging therapy for no longer than 3–4 months, with early withdrawal and replacement by steroid-sparing agents. The document provides a treatment algorithm stratified by disease severity and includes consensus statements approved unanimously by a multidisciplinary panel of sarcoidosis experts and patient-group leaders [5].
Therapeutic targets and treatment algorithm in sarcoidosis. Upper panel: key pathogenic pathways driving granuloma formation and their pharmacological targets. The non-caseating granuloma is composed of multinucleated giant cells (MNG) and epithelioid macrophages in the core, surrounded by activated macrophages with upregulated mTORC1 signaling, and an outer layer of CD4+ Th1/Th17 lymphocytes. Fibroblasts are present at the periphery. Green boxes indicate established treatments; amber boxes indicate emerging or investigational agents; purple box indicates agents targeting progressive pulmonary fibrosis (PPF); red box indicates therapy for sarcoid cardiomyopathy. Lower panel: treatment algorithm adapted from the 2025 WASOG Position Paper, stratifying therapy by disease severity and organ involvement. CS: corticosteroids; MTX: methotrexate; AZA: azathioprine; MMF: mycophenolate mofetil; LEF: leflunomide; NRP2: neuropilin-2; GM-CSF: granulocyte-macrophage colony-stimulating factor; JAK: Janus kinase; mTOR: mechanistic target of rapamycin; PDE-4: phosphodiesterase-4; PPF: progressive pulmonary fibrosis; MNG: multinucleated giant cell. Created with BioRender.com.
The clinical urgency behind this shift is well documented. Harper et al. conducted an international survey of nearly 2000 patients quantifying the burden of corticosteroid-related comorbidities in sarcoidosis, finding that ever-use of oral corticosteroids (OCS) was associated with significantly higher rates of diabetes, osteoporosis, weight gain, and infections—adverse effects that notably persisted even after steroid discontinuation [46].
Importantly, the SARCORT trial—the first randomized clinical trial comparing high-dose (40mg/d) versus low-dose (20mg/d) prednisolone—demonstrated no superiority of the higher dose, providing direct evidence that lower initial dosing is sufficient [47]. Logan et al. further argued that watchful waiting and early tapering may yield equivalent outcomes in non-life-threatening disease [48].
Second-line immunosuppressantsMethotrexate and azathioprine have long been used as corticosteroid-sparing agents in sarcoidosis, but robust comparative evidence has been lacking [49]. The PREDMETH trial provided the first randomized head-to-head comparison of methotrexate versus prednisone as initial therapy for symptomatic pulmonary sarcoidosis, demonstrating noninferior efficacy with a different side-effect profile—a finding with direct implications for first-line treatment algorithms [50].
Other second-line agents—azathioprine, leflunomide, and mycophenolate mofetil—offer steroid-sparing potential but are supported primarily by retrospective data. For refractory or organ-threatening disease, infliximab is the most validated third-line option, while adalimumab, repository corticotropin injection, sirolimus, and JAK inhibitors represent emerging alternatives with varying levels of evidence. There is a lack of robust randomized trial data across most therapeutic lines. This is one of the reasons individualized, patient-centered treatment decisions that balance disease control with minimization of treatment-related harm are paramount [49,51–53].
Targeted therapiesJAK inhibitorsIn a recent systematic review including 49 patients, complete or partial responses were observed in 94% of cases, with corticosteroid withdrawal or dose reduction in 74%. Nevertheless, the median follow-up was short (8 months), and the available evidence derived predominantly from case reports and small retrospective series, carrying a substantial risk of publication bias [14]. Despite these limitations, the convergence of a strong mechanistic rationale—targeting STAT1 upregulation and pleiotropic JAK-STAT–mediated cytokine signaling [54]—with consistently favorable clinical outcomes across heterogeneous phenotypes positions JAK inhibitors among the most promising emerging therapies in sarcoidosis, pending validation in adequately powered prospective studies [9,55–59].
EfzofitimodEfzofitimod is a novel immunomodulatory agent targeting the neuropilin 2 receptor [12]. It was evaluated in a phase 1b/2a randomized, placebo-controlled trial of 37 patients with pulmonary sarcoidosis, demonstrating dose-dependent steroid-sparing effects, nonsignificant improvements in FVC and DLCO, and significant improvements in patient-reported outcomes, including the Sarcoidosis Assessment Tool (SAT), King's Sarcoidosis Questionnaire (KSQ), Fatigue Assessment Scale (FAS), and general health scores at the 5-mg/kg dose [60]. The subsequent phase 3 EFZO-FIT trial failed to meet its primary end point of significant corticosteroid reduction at week 48, partly attributed to a higher-than-expected steroid tapering rate in the placebo arm; nevertheless, the 5-mg/kg dose showed significant improvement in KSQ-Lung scores and a significantly higher rate of complete steroid withdrawal with concomitant clinical improvement compared with placebo (29.5% vs 14.4%; P=.0199) according to preliminary data [61,62].
NamilumabNamilumab is a monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF), a key cytokine upregulated in patients with sarcoidosis [63–65]. In the RESOLVE-Lung trial, 107 patients with FDG-PET-defined active pulmonary sarcoidosis receiving prednisone, with or without immunosuppressive agents, were randomized 1:1 to namilumab or placebo, followed by mandatory steroid tapering and discontinuation of concomitant immunosuppressants. The trial did not meet its primary end point: rescue events occurred more frequently in the namilumab arm (38%) than in the placebo arm (24%), although sarcoidosis-specific relapses after 26 weeks were similar (21% vs 24%). Notably, most patients with active parenchymal disease were able to significantly reduce immunosuppressive therapy without clinical relapse, a finding with important implications for future trial design in sarcoidosis [66].
SGLT-2 inhibitors in sarcoid cardiomyopathyMahmoud et al. conducted a multicenter retrospective study evaluating SGLT-2 inhibitors in patients with sarcoidosis-associated cardiomyopathy, demonstrating improvements in functional class and reductions in heart failure hospitalization that appeared independent of glycemic effects [10]. In a large propensity-matched retrospective cohort study, Alam et al. found that the addition of SGLT-2 inhibitors to angiotensin receptor blocker therapy in patients with sarcoidosis was associated with significantly lower 5-year all-cause mortality (HR, 0.839; P=.016), providing preliminary evidence that the anti-inflammatory, antifibrotic, and RAAS-modulatory properties of SGLT-2 inhibitors may confer survival benefits in this population, although prospective validation is needed [67].
PDE-4 inhibitorsIn a retrospective single-center cohort of 51 patients with mixed phenotypes, roflumilast reduced the risk of significant FEV1 decline (OR, 0.20) and therapy escalation (OR, 0.45), with a numerically greater benefit in fibrotic disease, although gastrointestinal adverse effects led to discontinuation in 14% of patients. Its dual anti-inflammatory and antifibrotic mechanism warrants prospective validation [68].
mTOR inhibitorsThe mTORC1 pathway is dysregulated in sarcoidosis granuloma formation, providing a rationale for targeting it in refractory disease. In a single-center randomized trial, Redl et al. showed that systemic sirolimus for 4 months led to clinical and histological improvement in 70% of patients with persistent glucocorticoid-refractory cutaneous sarcoidosis, while topical application was ineffective. Remarkably, the therapeutic effect was sustained for up to 2 years after drug withdrawal without relapse, suggesting a disease-modulating mechanism [69]. Although the evidence remains limited to small studies, mTOR inhibitors represent a potential alternative for patients in whom conventional biologic therapies fail [53].
AntifibroticsThe 3 landmark trials evaluating antifibrotic therapy in non-IPF progressive fibrotic ILDs included very few or no patients with sarcoidosis. In the INBUILD trial, only 12 of 663 participants had sarcoidosis, yielding an underpowered subgroup analysis with no significant treatment effect (MD, −20.5mL/y; 95%CI, −337.1 to 296.1) [70,71]. The RELIEF trial excluded sarcoidosis from its eligibility criteria [72], and the FIBRONEER-ILD trial included only 17 patients with sarcoidosis among 1176 enrolled participants [73]. Collectively, these findings underscore that progressive pulmonary fibrosis (PPF) in sarcoidosis remains a major unmet therapeutic need (Tables 1 and 2).
Recent advances in the diagnosis of sarcoidosis.
| Diagnostic domain | Advance and key findings | Strengths and limitations | Ref. |
|---|---|---|---|
| Tissue acquisition | |||
| EBUS-guided mediastinal cryobiopsy | The addition of cryobiopsy to EBUS-TBNA increases diagnostic yield (93% vs 81%; P=.004), particularly for benign disorders, including sarcoidosis (94% vs 67%). In the RCT (n=271), all sarcoidosis and tuberculosis cases were diagnosed. | S: RCT-level evidence; superior tissue architecture; enables immunohistochemical and molecular studies. L: Higher rate of minor bleeding; requires expertise. | [8,78,79] |
| Advanced imaging | |||
| Multiparametric cardiac MRI | T2 mapping detects active inflammation, while T1 mapping and ECV quantify diffuse fibrosis beyond LGE. LGE extent predicts SCD and VT (HR, 1.83 per 10% increase). Endorsed in the 2024 AHA and 2024 ESC guidelines. | S: No radiation; differentiates inflammation from fibrosis; strong prognostic data. L: Gadolinium contraindicated in renal failure; MRI-incompatible devices; no consensus LGE threshold. | [80–82] |
| Quantitative FDG-PET/CT | SUVmax, metabolic volume, and total lesion glycolysis provide reproducible metrics for disease activity and treatment response. Meta-analysis confirms prognostic value for adverse cardiac events. | S: Whole-body assessment; objective quantification; guides immunosuppression. L: Prolonged fasting required; physiological myocardial uptake; radiation exposure; cost. | [81,83] |
| Novel PET radiotracers (68Ga-SSTR2, 68Ga-pentixafor, 18F-GE-180) | SSTR2 ligands target activated macrophages without dietary preparation. 68Ga-pentixafor (CXCR4) shows no myocardial background. 18F-GE-180 (TSPO) binds M1 macrophages. All are in early clinical investigation. | S: No fasting required; may distinguish inflammation from fibrosis. L: Very limited data; no comparative trials with FDG; restricted availability. | [32,33] |
| HRCT radiomics with machine learning | Quantitative radiomic features differentiate sarcoidosis from other ILDs and correlate with lung function. Machine learning algorithms identify phenotypes not apparent on visual assessment. | S: Automated and reproducible; potential for prognostic phenotyping. L: No prospective validation; requires standardized acquisition; risk of overfitting. | [84,85] |
| Molecular biomarkers and noninvasive diagnostics | |||
| Multiomics biomarker discovery | Prediagnostic inflammatory proteins are detectable years before clinical onset. | S: Treatment-specific predictive potential; noninvasive specimens. L: Exploratory; small cohorts; no validated clinical assays. | [7,18,21] |
| Novel markers: PON1, HSP90α, and alveolar nitric oxide | Serum paraoxonase 1 (PON1) has emerged as a novel biomarker for disease activity and monitoring. Heat shock protein 90α (HSP90α) and alveolar nitric oxide concentration (CANO) have emerged as complementary markers. | S: ROC analysis demonstrated that PON1 effectively differentiated patients from controls (AUC, 0.838; sensitivity, 75%; specificity, 82% at ≤210.53U/L). L: Very limited data. | [17,84] |
| Electronic nose breath analysis | VOC profiling distinguishes sarcoidosis from controls (AUC, 1.00) and from other ILDs (AUC, 0.87) in validated analyses (n=617). Machine learning classification achieves 87% accuracy. Findings correlate with soluble interleukin 2 receptor (sIL-2R) levels (AUC, 0.78). | S: Noninvasive, rapid, point-of-care potential; disease-specific signal. L: Cannot differentiate sarcoidosis subgroups. | [44,45] |
AHA, American Heart Association; AUC, area under the curve; CANO, alveolar nitric oxide concentration; CXCR4, C-X-C chemokine receptor type 4; EBUS, endobronchial ultrasound; ECV, extracellular volume; eNose, electronic nose; ESC, European Society of Cardiology; FDG, fluorodeoxyglucose; HR, hazard ratio; HRCT, high-resolution CT; HSP90α, heat shock protein 90α; ILD, interstitial lung disease; L, limitations; LGE, late gadolinium enhancement; MRI, magnetic resonance imaging; MTX, methotrexate; PET/CT, positron emission tomography/computed tomography; PON1, serum paraoxonase 1; RCT, randomized clinical trial; ROC, receiver operating characteristic; S, strengths; SCD, sudden cardiac death; sIL-2R, soluble interleukin 2 receptor; SSTR2, somatostatin receptor subtype 2; TBNA, transbronchial needle aspiration; TSPO, translocator protein; VOC, volatile organic compound; VT, ventricular tachycardia.
Recent advances in the treatment of sarcoidosis.
| Therapeutic domain | Advance and key findings | Strengths and limitations | Ref. |
|---|---|---|---|
| Corticosteroid paradigm shift | |||
| WASOG Position Paper on corticosteroid therapy | OCS should no longer be considered first-line therapy for all patients. The Position Paper proposes OCS as bridging therapy for 3 to 4 months or less, with early introduction of steroid-sparing agents. Long-term OCS use is defined as an undesirable outcome. | S: Consensus of international experts (WASOG/AASOG); addresses the central problem of chronic steroid toxicity. L: Based on expert opinion, not RCT evidence; implementation may vary across health care settings. | [5] |
| SARCORT trial: high-dose vs low-dose prednisolone | RCT (n=86): prednisolone 40mg/d vs 20mg/d, tapered over 6 months. Relapse at 18 months was similar (46.5% vs 44.2%; P=.75). No differences were observed in FVC, adverse effects, or HRQoL. | S: RCT evidence; directly challenges traditional high-dose regimens; supports dose minimization. L: Single-center; open-label; modest sample size; 6-month treatment duration only. | [47] |
| First-line steroid-sparing therapy | |||
| PREDMETH trial: MTX vs prednisone | RCT (n=138; 17 centers): MTX was noninferior to prednisone for change in FVC at 24 weeks (6.11% vs 6.75%; difference, −1.17, within the noninferiority margin). Different side-effect profiles support shared decision-making. | S: First RCT evidence supporting MTX as a first-line alternative; informs shared decision-making. L: Open-label; no placebo control; 24-week follow-up only; higher prednisolone and MTX target doses than recommended by the guidelines. | [50,86] |
| Targeted and biologic therapies | |||
| JAK inhibitors (tofacitinib, baricitinib, ruxolitinib) | Small open-label and observational studies suggest clinical benefit in cutaneous and multiorgan refractory sarcoidosis through IFN-γ/JAK-STAT pathway inhibition. Adequately powered RCTs are needed to define efficacy, safety, and optimal patient selection. | S: Mechanistically rational approach targeting IFN-γ; efficacy in refractory disease; oral administration. L: Small open-label studies; no RCTs; infection and thrombosis risk; no long-term safety data in sarcoidosis. | [9,11,14,55–58] |
| PDE-4 inhibitors (roflumilast) | Retrospective single-center cohort (n=51; mixed phenotypes): roflumilast reduced the risk of significant FEV1 decline (OR, 0.20) and therapy escalation (OR, 0.45), with a numerically greater benefit in fibrotic disease. Its dual anti-inflammatory and antifibrotic mechanism is mediated through intracellular cAMP elevation. | S: Pleiotropic anticytokine effect (TNF-α, IFN-γ, IL-17); oral administration; approved for COPD; acceptable long-term safety (mean treatment duration, 2.1 years). L: Retrospective, uncontrolled design; no significant effect on therapy de-escalation; GI adverse effects led to discontinuation in 14% of patients; requires prospective validation. | [68] |
| Anti-TNF-α biologics (infliximab, adalimumab) | Established biologic option for refractory sarcoidosis. Meta-analysis confirms efficacy across organ domains. The TNF-α G-308A polymorphism may predict response. | S: Most robust evidence base among biologics; effective in refractory multiorgan disease. L: Infection risk; infusion reactions with infliximab; high cost; limited RCT data specific to sarcoidosis. | [53,87] |
| Emerging approaches | |||
| SGLT-2 inhibitors in cardiac sarcoidosis | Synergistic RAAS modulation through AT2R-mediated anti-inflammatory signaling, plus NF-κB/NLRP3 suppression, may improve functional class, reduce heart failure hospitalizations, and improve survival. | S: Established cardiac benefit in heart failure; potential anti-inflammatory effects; oral administration; well tolerated. L: Retrospective data; no sarcoidosis-specific trials; theoretical rationale; evidence extrapolated from heart failure populations; prospective validation needed. | [10,67] |
| mTOR inhibitors (sirolimus) | The mTORC1 pathway is dysregulated in sarcoidosis. Efficacy has been reported in refractory cutaneous disease and after JAK inhibitor failure in severe pulmonary sarcoidosis. | S: Targets a specific dysregulated pathway; alternative after JAK inhibitor or anti-TNF failure. L: Mostly case reports only; immunosuppression risk. | [53,69,84,88] |
AASOG, Americas Association of Sarcoidosis and Other Granulomatous Disorders; AT2R, angiotensin II type 2 receptor; cAMP, cyclic adenosine monophosphate; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GI, gastrointestinal; HF, heart failure; HRQoL, health-related quality of life; IFN-γ, interferon gamma; IL, interleukin; JAK, Janus kinase; MTX, methotrexate; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor κB; NI, noninferiority; NLRP3, NLR family pyrin domain containing 3; OCS, oral corticosteroids; OR, odds ratio; PDE-4, phosphodiesterase 4; RAAS, renin-angiotensin-aldosterone system; RCT, randomized clinical trial; S, strengths; SGLT-2, sodium-glucose cotransporter 2; STAT, signal transducer and activator of transcription; TNF-α, tumor necrosis factor α; WASOG, World Association of Sarcoidosis and Other Granulomatous Disorders.
The field of targeted therapies in sarcoidosis is rapidly evolving, with both novel and repurposed agents under investigation. However, integrating pharmacogenetic approaches will be essential to optimize treatment selection and outcomes across the heterogeneous population of patients with sarcoidosis [74].
Cardiac sarcoidosis: device therapy and risk stratificationBeyond pharmacological treatment, cardiac sarcoidosis management has advanced through improved risk stratification and device therapy. Bhimani et al. emphasized that anti-inflammatory treatment, while improving atrioventricular (AV) conduction and ventricular function, does not reliably eliminate the risk of sudden cardiac death, and that CMR/PET-guided risk stratification with early implantable cardioverter-defibrillator (ICD) consideration remains essential [75].
Yeo et al. conducted the first propensity-matched comparison of cardiac resynchronization therapy (CRT) versus ICD-only implantation in patients with sarcoidosis and heart failure with reduced ejection fraction, finding no significant differences in 5-year all-cause mortality, hospitalization, or heart failure exacerbation between groups, although a nonsignificant trend toward greater LVEF recovery was observed in the CRT cohort [76].
At the frontier of risk prediction, Lai et al. developed MAARS-CS, a multimodal artificial intelligence model integrating raw LGE-CMR images with clinical and electrocardiographic covariates to predict sudden cardiac death in cardiac sarcoidosis, achieving an AUROC of 0.86—significantly outperforming LVEF-based criteria (AUROC, 0.59 for LVEF≤35%; P<.0001)—although external validation is still needed [77].
ConclusionsThe last few years have brought meaningful advances in the diagnosis and treatment of sarcoidosis, yet the field remains constrained by the same fundamental limitation: a shortage of high-quality randomized evidence. Promising diagnostic tools and therapeutic biomarker candidates continue to emerge, but translating them into clinical practice will require well-designed multicenter trials that stratify patients by phenotype and measure clinically meaningful end points. Whether the current momentum leads to genuinely personalized care will depend less on biological discovery than on the collective willingness to invest in the studies that turn promise into practice.
Artificial intelligence involvementArtificial intelligence tools [Claude (Anthropic, claude.ai)] were used to assist with language editing and formatting of the manuscript. All content was critically reviewed and approved by the authors.
FundingDr. Jacobo Sellares’ research is funded by Instituto de Salud Carlos III (ISCIII) through project PI23/00924 and cofunded by the European Union, Marató TV3 (61/C/2025), SEPAR, SOCAP, FUCAP, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). No funding was received for the publication of this article.
Conflicts of interestJS reports honoraria for lectures, educational events, and support for attending meetings from Roche, Boehringer Ingelheim, AstraZeneca, Aflofarm, Neuroxpharma, and Atyr. JS discloses consulting fees from Boehringer Ingelheim and Aflofarm, and grants from Roche and Boehringer Ingelheim, all outside the submitted work.
PS reports consulting fees from PPM Services; honoraria for lectures from Boehringer Ingelheim; honoraria for participation in advisory boards from AstraZeneca, BMS, CSL Behring, MSD, and Trevi; and research funding from Boehringer Ingelheim, Chiesi, PPM Services, and Roche. His wife is an employee of AstraZeneca.
FB reports consulting fees from Boehringer Ingelheim, Insmed, Avalyn, Vicore, Savara, Kyowa Kirin, Fujirebio, Tosoh, and Trevi, and honoraria for lectures from Boehringer Ingelheim, Vicore, and Sanofi, outside the submitted work.
MV reports consulting fees from Boehringer Ingelheim and Xentria, and honoraria for lectures from Boehringer Ingelheim and Chiesi.
