Sarcoidosis
Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by the formation of non-caseating granulomas—small clusters of immune cells—in various organs, most commonly the lungs and intrathoracic lymph nodes, though it can affect nearly any part of the body including the skin, eyes, heart, liver, and nervous system.[1] These granulomas result from an abnormal immune response that leads to inflammation and potential tissue damage, often resolving spontaneously but sometimes causing chronic issues or fibrosis.[2] The disease typically presents between the ages of 20 and 60, with a higher incidence in women, individuals of African or Northern European descent, and those with occupational exposure to dust or chemicals.[3] The incidence of sarcoidosis varies widely by region and ethnicity, ranging from less than 1 to over 40 cases per 100,000 people annually, with higher rates in Northern European countries (e.g., 11.5 per 100,000 in Sweden as of 2016) and among African Americans in the United States (approximately 18 per 100,000 as of recent estimates).[4][5] The exact cause of sarcoidosis remains elusive, but it is believed to arise from a combination of genetic susceptibility and environmental triggers, such as infections (e.g., mycobacteria or propionibacteria), airborne irritants, or occupational exposures that provoke an exaggerated immune reaction in predisposed individuals.[2] Genetic factors play a role, as evidenced by familial clustering and associations with specific human leukocyte antigen (HLA) genes like HLA-DRB1, while environmental influences are suggested by higher rates in urban settings and among firefighters or agricultural workers.[1] Unlike infectious granulomatous diseases, sarcoidosis granulomas are non-infectious and non-caseating, meaning they lack central necrosis, distinguishing them histologically from conditions like tuberculosis.[3] Symptoms of sarcoidosis vary widely depending on the organs involved and disease stage, but pulmonary manifestations affect over 90% of patients and often include persistent dry cough, shortness of breath, and chest pain due to granuloma formation in the lung tissue or lymph nodes.[2] Common systemic symptoms encompass fatigue, fever, weight loss, and night sweats, while extrapulmonary involvement may cause skin lesions like erythema nodosum (affecting 20-30% of cases), ocular inflammation leading to uveitis (in over 40%), or cardiac arrhythmias from heart granulomas.[1] In many cases (up to 50%), the disease is asymptomatic and discovered incidentally on imaging, but severe complications such as pulmonary fibrosis, vision loss, kidney dysfunction, or neurological deficits can occur in chronic or advanced stages, potentially requiring long-term management.[3]Clinical presentation
General symptoms
Sarcoidosis often presents with nonspecific constitutional symptoms that reflect its systemic inflammatory nature. Fatigue is one of the most prevalent symptoms, affecting nearly 70% of patients and often persisting despite adequate rest.[6] Fever occurs in approximately one-third of cases, typically low-grade and intermittent.[7] Unintentional weight loss is similarly common, reported in about one-third of individuals, while night sweats affect a smaller subset, contributing to overall discomfort.[7][8] Anorexia and malaise frequently serve as early indicators of disease activity, with malaise noted in roughly one-third of patients alongside other constitutional features.[9] These symptoms can precede more localized manifestations, such as those involving the lungs, and underscore the multisystem impact of sarcoidosis.[10] A significant proportion of sarcoidosis cases, estimated at 30% to 50%, are asymptomatic at presentation and are incidentally detected through routine chest imaging showing bilateral hilar lymphadenopathy. When symptoms do occur, their duration and pattern vary widely; acute onset is characterized by sudden appearance and potential spontaneous resolution within months to years, whereas chronic forms develop insidiously and may persist for years, leading to prolonged fatigue and malaise.[2][10]Pulmonary involvement
Pulmonary involvement is the most common manifestation of sarcoidosis, affecting more than 90% of patients.[11] The primary respiratory symptoms include a persistent dry cough, dyspnea on exertion, and chest pain, which occur in 27–53%, 18–51%, and 9–23% of cases, respectively.[6] Wheezing may also be present due to airway involvement.[2] Hemoptysis is rare, reported in only about 4% of patients and typically associated with advanced disease.[12] Pulmonary sarcoidosis is classified into four radiographic stages, known as the Scadding stages, based on chest X-ray findings, which correlate with disease progression and prognosis.[13]- Stage I: Bilateral hilar lymphadenopathy without parenchymal involvement, often asymptomatic or associated with mild symptoms, and showing spontaneous resolution in many cases.[13]
- Stage II: Bilateral hilar lymphadenopathy with parenchymal infiltrates, commonly presenting with cough and dyspnea.[13]
- Stage III: Parenchymal infiltrates without hilar lymphadenopathy, indicating more advanced involvement and potential for persistent symptoms.[13]
- Stage IV: Fibrotic changes with evidence of pulmonary fibrosis, volume loss, and bullae formation, leading to severe respiratory impairment.[13]
Extrapulmonary manifestations
Sarcoidosis frequently involves organs beyond the lungs, with extrapulmonary manifestations occurring in up to 30% of patients and highlighting the disease's multisystem character.[16] These symptoms can vary widely in severity and may represent the initial presentation or develop alongside pulmonary involvement.[17] Skin involvement affects 20%-35% of patients and includes several distinct lesions. Erythema nodosum presents as painful, tender nodules typically on the anterior lower legs and is self-limiting, often associated with acute sarcoidosis and a favorable prognosis.[16] In contrast, lupus pernio manifests as chronic, violaceous, indurated plaques on the face, ears, or nose, which can be disfiguring and correlate with more aggressive systemic disease, particularly in women.[16] Maculopapular eruptions appear as red-brown papules on the trunk or neck and are generally linked to milder disease courses.[16] Ocular manifestations occur in 10%-25% of cases, with anterior uveitis being the most common form, affecting up to 25% of patients and causing symptoms such as eye pain, redness, photophobia, and blurred vision.[17] This inflammation is often bilateral and more prevalent in women and individuals of African descent.[16] Posterior segment involvement can lead to complications like glaucoma or, in severe cases, blindness if untreated.[16] Cardiac sarcoidosis complicates 5% of clinically evident cases, though autopsy studies reveal involvement in 20%-30%, and it carries a risk of sudden death due to granulomatous infiltration of the myocardium.[16] Common symptoms include arrhythmias, such as ventricular tachycardia, atrioventricular heart block, palpitations, and syncope, which may progress to dilated cardiomyopathy or heart failure.[17] Neurologic involvement, known as neurosarcoidosis, affects approximately 5% of patients and can be a presenting feature.[16] Cranial nerve palsies are the most frequent, with the facial nerve (seventh cranial nerve) being predominantly impacted, leading to facial weakness or paralysis.[17] Other manifestations include aseptic meningitis, which presents with headache and neck stiffness, and peripheral neuropathy, often manifesting as sensory loss or pain due to axonal damage.[16] Musculoskeletal symptoms arise in 5%-15% of cases and encompass arthralgias, which are joint pains commonly affecting the ankles and knees, either acutely as part of Löfgren syndrome or chronically.[17] Myositis involves muscle inflammation and weakness in less than 5% clinically, while bone lesions, seen in 3%-13%, include cystic or lytic changes, particularly in the phalanges of the hands and feet.[16] Other extrapulmonary sites include the liver and spleen, where hepatosplenomegaly occurs due to granulomatous infiltration, with liver involvement in 50%-80% at autopsy but symptomatic enlargement in only 5%-15% of patients, potentially causing abdominal discomfort or fatigue.[16] Salivary and lacrimal gland enlargement affects 5%-16%, leading to dry mouth or eye symptoms resembling Sjögren syndrome.[16] Hypercalcemia, present in 10%-20% of cases from dysregulated vitamin D metabolism, results in symptoms such as polyuria, polydipsia, fatigue, and renal complications including nephrolithiasis or impaired kidney function.[16]Etiology
Genetic factors
Sarcoidosis exhibits a genetic predisposition, evidenced by familial clustering where approximately 5-10% of patients report a family history of the disease, compared to about 1% in the general population.[18] This clustering is further highlighted by twin studies showing higher concordance rates in monozygotic twins (probandwise concordance of 14.8%) than in dizygotic twins (1.2%), with heritability estimates ranging from 39% to 66% based on twin studies, though SNP-based estimates are lower at approximately 9% as of 2025.[19][20] These findings indicate that inherited factors significantly contribute to disease susceptibility, though genetic risk interacts with environmental triggers to initiate the condition.[21] Associations with human leukocyte antigen (HLA) genes, particularly in the major histocompatibility complex (MHC) class II region, represent the strongest genetic links to sarcoidosis. The HLA-DRB11101 allele increases risk across populations, with odds ratios of approximately 2.0 in both Black and White individuals, and a population attributable risk of 8-17%.[22] Similarly, the HLA-DQB10201 allele, often in haplotype with DRB1*0301, elevates susceptibility, particularly in association with Löfgren's syndrome, where odds ratios can reach up to 5 in European cohorts.[23] These alleles likely influence antigen presentation and T-cell activation, contributing to granuloma formation. Beyond HLA genes, non-HLA variants also play key roles in immune regulation and disease risk. The BTNL2 gene, encoding butyrophilin-like 2, harbors the rs2076530 polymorphism; the A allele (in heterozygous AG) confers an odds ratio of about 2.6, while the homozygous AA variant increases risk up to 5-fold by impairing T-cell suppression.[24] ANXA11, involved in calcium signaling and immune cell function, shows associations via rs1049550, with specific variants linked to increased susceptibility in genome-wide association studies, particularly in African American populations.[21] A 2025 genome-wide association study (GWAS) in 9,755 cases identified 17 novel risk loci, including C1orf141-IL23R (OR 1.59 per C allele), CCDC88B (linked to T-cell maturation), and TYK2 (with high deleterious impact), implicating Th17/IL-23 pathways and JAK signaling in etiology and suggesting therapeutic targets like JAK inhibitors.[20] Ethnic variations underscore the heterogeneity of genetic risk, with stronger HLA associations observed in Scandinavian populations, where high disease incidence correlates with elevated frequencies of risk alleles like DRB11101 and DQB10201.[24] In contrast, African Americans exhibit distinct profiles, including race-specific ANXA11 variants and different HLA effects, such as protective influences from DRB1*0301.[21] These differences highlight the need for population-tailored genetic research in sarcoidosis.Environmental and infectious triggers
Sarcoidosis is hypothesized to arise from the interaction of environmental exposures with genetic susceptibility in predisposed individuals, though no single trigger has been definitively identified. Occupational exposures have been linked to increased disease risk, particularly in professions involving inorganic dusts. For instance, exposure to beryllium, often in metalworking or aerospace industries, can lead to chronic beryllium disease, which closely mimics sarcoidosis histologically and clinically, with non-caseating granulomas forming in response to the metal antigen. A 2025 analysis confirms frequent associations between particle exposures (e.g., metals, silica) and pulmonary sarcoidosis, supporting diagnostic consideration without exclusion.[25] Similarly, silica dust exposure, common in mining, construction, and stonework, has been associated with a higher incidence of sarcoidosis among men aged 20 to 65, potentially through induction of pulmonary inflammation and granuloma formation.[26] Agricultural workers, including farmers, face elevated risks due to dust and bioaerosol inhalation, with studies reporting an odds ratio of approximately 1.5 for sarcoidosis in those engaged in agricultural employment.[27] Infectious agents have long been proposed as potential initiators of sarcoidosis, though evidence remains associative rather than causal, with no pathogen consistently isolated from all cases. Propionibacterium acnes (now classified as Cutibacterium acnes), a commensal skin bacterium, has been detected via polymerase chain reaction (PCR) in sarcoid granulomas at higher frequencies than in controls, suggesting it may translocate to tissues and provoke an aberrant immune response in susceptible hosts. Emerging evidence also implicates the gut microbiome, with dysbiosis potentially contributing to immune activation (as of 2024).[28][29] Likewise, Mycobacterium species, including atypical strains, have been implicated through PCR and culture studies showing mycobacterial DNA or cell wall components in granulomatous tissue, though meta-analyses indicate inconsistent replication across studies and no definitive proof of active infection.[30] Dual analyses for both propionibacteria and mycobacteria in lymph nodes reinforce the possibility of microbial persistence contributing to granuloma persistence, but the absence of cultivable organisms underscores the challenge in establishing causality.[31] Other environmental factors, such as organic antigens, may also play a role in triggering acute presentations. Exposure to mold or musty odors has been clustered with increased sarcoidosis risk, potentially via inhalation of fungal spores leading to hypersensitivity reactions.[32] Bird proteins, encountered in pigeon breeders or pet owners, have been associated with early-stage disease, mirroring patterns seen in hypersensitivity pneumonitis.[33] Seasonal variations further support environmental influences, with acute sarcoidosis cases showing peaks in spring in regions like Spain, Japan, and Greece, possibly linked to pollen or allergen surges.[33] Despite these associations, sarcoidosis lacks direct transmissibility between individuals, aligning with a multifactorial model where external triggers amplify underlying genetic vulnerabilities without a singular infectious or environmental cause.[34]Immune dysregulation
Sarcoidosis involves aberrant immune processes that contribute to its onset, characterized by dysregulated adaptive immunity following potential environmental or infectious exposures in genetically susceptible individuals.[35] This dysregulation manifests as an exaggerated T-cell mediated response, alongside B-cell hyperactivity and impaired immune regulation, leading to persistent inflammation without a purely autoimmune etiology.[36] The immune response in sarcoidosis is predominantly T-cell driven, with CD4+ T-helper 1 (Th1) cells playing a central role through polarization toward Th1 and Th17 phenotypes.[37] These cells exhibit elevated production of interferon-gamma (IFN-γ) and interleukin-2 (IL-2), which amplify the inflammatory cascade and promote tissue involvement.[38] Th17 cells, in particular, contribute to this skewing by secreting IL-17, further sustaining the pro-inflammatory environment observed in affected tissues.[39] B-cell involvement is evident through polyclonal B-cell activation, resulting in hypergammaglobulinemia, a common serological finding in sarcoidosis patients.[35] Additionally, autoantibodies such as anti-Ro/SSA can occur in some cases, particularly those with overlapping autoimmune features, though their pathogenic role remains unclear.[40] Sarcoidosis shows autoimmune overlap, with patients at increased risk for comorbid conditions like Sjögren's syndrome and autoimmune thyroiditis, as demonstrated in large cohort studies. However, sarcoidosis is not classified as a purely autoimmune disease, given the absence of consistent disease-specific autoantibodies and its distinct granulomatous pathology.[36] Dysfunction of regulatory T cells (Tregs), marked by reduced FoxP3 expression and diminished suppressive capacity, fails to counteract the Th1/Th17 dominance, thereby perpetuating chronic inflammation.[41] This Treg impairment contributes to the unchecked immune activation central to sarcoidosis pathogenesis.[35]Pathophysiology
Granuloma formation
Granuloma formation represents the hallmark pathological process in sarcoidosis, characterized by the development of noncaseating granulomas composed primarily of immune cells responding to an unidentified antigen. The process begins with the recruitment of circulating monocytes to the site of inflammation, where they differentiate into macrophages. These macrophages further transform into epithelioid cells, which aggregate tightly and fuse to form multinucleated giant cells, such as Langhans-type giant cells, creating the central core of the granuloma.[42][43][44] This cellular orchestration is driven by a Th1-dominated immune response, where CD4+ T cells surround the granuloma periphery, providing ongoing stimulation.[43] Cytokines play a pivotal role in orchestrating this aggregation and maintenance of granulomas. Tumor necrosis factor-alpha (TNF-α) is central, promoting macrophage activation, differentiation into giant cells, and the recruitment of additional immune cells to sustain the structure.[42][44] Interleukin-12 (IL-12) and interleukin-18 (IL-18), often secreted by antigen-presenting cells, act synergistically to induce interferon-gamma (IFN-γ) production from T cells, further enhancing macrophage fusion and granuloma consolidation.[43][42] Genetic factors, such as polymorphisms in HLA-DRB1 alleles, may modulate susceptibility to this dysregulated granulomatous response.[42] The persistence of granulomas in sarcoidosis often results from a failure in programmed cell death mechanisms, leading to chronic inflammation rather than resolution. In typical granulomatous diseases, apoptosis clears the antigen and resolves the lesion; however, in sarcoidosis, macrophages exhibit resistance to apoptosis, partly due to IFN-γ-mediated upregulation of anti-apoptotic proteins like p21/WAF1.[42][44] This imbalance allows granulomas to endure, potentially progressing to fibrosis if unresolved.[43] Within these granulomas, characteristic inclusions such as asteroid bodies—star-shaped cytoplasmic inclusions in giant cells—and Schaumann bodies—concentric calcified structures—may appear, though they are neither specific nor diagnostic for sarcoidosis.[42][43][44] These features highlight the disorganized yet organized nature of the granulomatous response in the disease.Immune mechanisms
In sarcoidosis, alveolar macrophages exhibit heightened activation, characterized by increased cytokine secretion such as TNF-α and IL-1β, which drives the recruitment and proliferation of T cells and contributes to sustained granulomatous inflammation.[45] Despite this activation, defects in antigen presentation have been identified, particularly an impaired ability of bronchoalveolar lavage (BAL) cells to present HLA-DR-bound peptides effectively, leading to dysregulated T-cell responses and failure to clear persistent antigens.[46] This dysfunction, combined with enhanced overall antigen uptake and processing via upregulated vacuolar H+-ATPase, perpetuates the immune response and granuloma persistence in the lungs.[47] The fibrotic cascade in chronic sarcoidosis involves TGF-β signaling, where elevated TGF-β1 levels promote the transition from acute inflammation to progressive scarring, primarily through activation of Smad3 pathways that induce myofibroblast differentiation and extracellular matrix deposition.[48] This process is exacerbated by a shift toward a Th2-biased environment and M2 macrophage polarization, both of which amplify TGF-β production and contribute to pulmonary fibrosis in 10-20% of patients with advanced disease. Regulatory failure in sarcoidosis manifests as impaired function of FoxP3+ regulatory T cells (Tregs), which accumulate at sites of inflammation but exhibit reduced suppressive capacity, failing to adequately inhibit effector T-cell proliferation and cytokine release.[49] Similarly, diminished IL-10 production by these Tregs and regulatory B cells allows unchecked Th1/Th17 responses, correlating with disease chronicity and relapse after treatment withdrawal. Systemic immune effects include polyclonal B-cell activation, driven by elevated B-cell activating factor (BAFF) and interactions with T follicular helper cells, leading to increased transitional B cells and hypergammaglobulinemia (polyclonal gammopathy) observed in many patients.[50] This activation results in the formation of immune complexes containing microbial antigens, which deposit in tissues and amplify multisystem inflammation.[51]Histopathological features
The histopathological hallmark of sarcoidosis is the presence of discrete, compact, noncaseating epithelioid granulomas composed primarily of transformed macrophages (epithelioid cells) and multinucleated giant cells, often surrounded by a sparse rim of lymphocytes, forming so-called "naked" granulomas without significant caseation or necrosis.[9] These granulomas typically measure less than 1 mm in diameter and appear as small, grayish or yellowish-white lesions on gross examination, reflecting the accumulation of mononuclear phagocytes in response to persistent antigenic stimulation.[52] Although focal areas of coagulative necrosis may occasionally be observed, the absence of extensive necrosis distinguishes sarcoid granulomas from those seen in infectious processes like tuberculosis.[9] The distribution of these granulomas varies by organ, adapting to local tissue architecture while maintaining their noncaseating character. In the lungs, the most commonly affected site, granulomas are predominantly peribronchiolar or located in subpleural and perilobular regions, often leading to lymphatic involvement along bronchovascular bundles.[9] Cutaneous sarcoidosis features dermal granulomas, which may present in a nodular, diffuse, or angiocentric pattern within the superficial or deep dermis, sometimes extending to the subcutis.[53] In the heart, granulomas are typically interstitial within the myocardium, particularly affecting the basal septum and left ventricular free wall, contributing to conduction abnormalities.[9] Multinucleated giant cells within these granulomas are a prominent feature and include both Langhans-type (with nuclei arranged in a horseshoe pattern) and foreign body-type cells, which may contain characteristic cytoplasmic inclusions such as asteroid bodies (star-shaped inclusions) or Schaumann bodies (concentric calcified structures).[9] These inclusions, while not pathognomonic, support the diagnosis when present. To exclude alternative etiologies like infection or malignancy, histopathological evaluation routinely employs special stains, such as Ziehl-Neelsen for acid-fast bacilli (typically negative in sarcoidosis) and Gomori methenamine silver for fungi, alongside immunohistochemistry to rule out neoplastic processes.[9]Diagnosis
The diagnosis of sarcoidosis is established by compatible clinical and radiologic findings, histologic evidence of noncaseating granulomas, and exclusion of alternative causes, as per ATS guidelines.[54]Clinical evaluation
The clinical evaluation of sarcoidosis begins with a thorough history and physical examination to establish clinical suspicion, particularly in young or middle-aged adults presenting with unexplained symptoms, while excluding alternative diagnoses such as tuberculosis or malignancy.[7][54] During history taking, patients often report an insidious onset of constitutional symptoms including fatigue, fever, weight loss, and arthralgias, alongside pulmonary complaints such as dry cough and exertional dyspnea, which occur in approximately 50% of cases.[55] The history should probe for potential environmental exposures, occupational risks, or travel to endemic areas to differentiate from infectious etiologies, with bilateral hilar involvement suggested by respiratory symptoms or incidental findings prompting further suspicion.[7] Exclusion of tuberculosis requires assessing for risk factors like immunosuppression or contact history, while malignancy concerns arise in cases with unexplained lymphadenopathy or systemic symptoms mimicking lymphoma.[54] On physical examination, peripheral lymphadenopathy, particularly in cervical, axillary, or supraclavicular regions, is a common finding in up to 30% of patients and supports diagnostic consideration.[7] Cutaneous manifestations, observed in about 25% of cases, include nonspecific lesions like tender erythema nodosum on the lower extremities or specific lesions such as indurated plaques of lupus pernio on the face, ears, or nose, which are highly suggestive of sarcoidosis.[55] Ocular involvement, affecting approximately 25% of patients, may present with signs of anterior uveitis including conjunctival redness, photophobia, or blurred vision, necessitating referral to ophthalmology.[54] Hepatic involvement occurs in approximately 12% of patients and splenic involvement in 5-15%, with palpable hepatosplenomegaly present in a subset (typically 5-20%) of these cases, often without overt symptoms.[54][55] Symptom clustering aids in distinguishing acute from chronic forms; the acute presentation of Löfgren syndrome, characterized by fever, bilateral ankle arthritis, erythema nodosum, and uveitis, typically occurs within weeks and carries an excellent prognosis with high rates of spontaneous remission.[54] In contrast, the more common insidious chronic form evolves over months to years, often involving progressive pulmonary or multisystem symptoms without the dramatic acute features.[7] Red flags warranting urgent evaluation include neurological symptoms such as cranial nerve deficits, seizures, or peripheral neuropathy, seen in 5-10% of cases and indicating potential neurosarcoidosis.[55] Cardiac symptoms like palpitations, syncope, chest pain, or arrhythmias, present in up to 5% of symptomatic patients, signal high-risk involvement and require immediate specialist assessment to prevent life-threatening complications.[7]Imaging modalities
Chest radiography remains the initial imaging modality for evaluating suspected pulmonary sarcoidosis, often revealing bilateral hilar lymphadenopathy in up to 85% of cases.[56] The Scadding staging system, introduced in 1961, classifies thoracic involvement based on radiographic patterns and provides prognostic insights, with higher stages associated with lower rates of spontaneous remission.[57]| Stage | Description | Frequency at Presentation | Prognosis (5-Year Remission Rate) |
|---|---|---|---|
| 0 | Normal chest radiograph | 5-15% | >90% |
| I | Bilateral hilar lymphadenopathy without parenchymal infiltrates | 50-60% | ~80-90% |
| II | Bilateral hilar lymphadenopathy with pulmonary infiltrates | 25-30% | ~50-60% |
| III | Pulmonary infiltrates without hilar lymphadenopathy | 10-15% | ~20-30% |
| IV | Advanced fibrosis with volume loss, reticulation, and bullae | 5-10% | <10% |
Biopsy and laboratory findings
Biopsy procedures are essential for confirming sarcoidosis through the identification of non-caseating granulomas and excluding alternative etiologies such as infections or malignancies. The selection of biopsy site is guided by clinical accessibility and involvement. Skin lesions, occurring in approximately 25% of cases, provide the easiest and least invasive option due to their superficial location, allowing for simple excisional or punch biopsy with minimal risk.[59] Peripheral lymph nodes, enlarged in up to 15% of patients, can be sampled via fine-needle aspiration or core biopsy, offering a diagnostic yield of around 40-70% when accessible.[60] For patients with pulmonary involvement, which affects over 90%, transbronchial lung biopsy (TBLB) performed via flexible bronchoscopy is a standard approach, often guided by imaging such as fluoroscopy or endobronchial ultrasound to target affected areas. Diagnostic yields for TBLB in sarcoidosis range from 40% to 90%, varying by disease stage, with higher rates (50-85%) in early stages featuring prominent hilar lymphadenopathy and lower yields in advanced fibrotic disease. Intrathoracic lymph node sampling, typically via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), achieves diagnostic yields of 80-90%, making it particularly valuable for mediastinal involvement.[61][62][54][63] Laboratory findings aid in supporting the diagnosis, assessing organ function, and monitoring disease activity, though no single test is pathognomonic. Serum angiotensin-converting enzyme (ACE) levels are elevated in approximately 60% of patients at diagnosis, reflecting granulomatous activity, but exhibit limited sensitivity (around 60%) and specificity due to elevations in other conditions like tuberculosis or hyperthyroidism. Hypercalcemia, resulting from excess 1,25-dihydroxyvitamin D production by macrophages, affects 10-20% of patients and may lead to nephrolithiasis or renal impairment if severe. Peripheral lymphopenia, particularly of CD4+ T cells, is observed in up to 50% of cases and correlates with disease severity.[64][65][66] Serum biomarkers provide additional utility for evaluating disease activity beyond routine tests. Soluble interleukin-2 receptor (sIL-2R), a marker of T-cell activation, is elevated in active sarcoidosis and correlates with granuloma burden, aiding in diagnosis and response to therapy assessment. Chitotriosidase, secreted by activated macrophages, serves as a reliable indicator of disease severity and activity, with levels decreasing upon treatment and remission. Exclusion of mimics requires negative microbiologic cultures from biopsy specimens for bacteria, fungi, mycobacteria, and other pathogens, often confirmed via standard and molecular methods. Serologic testing for antineutrophil cytoplasmic antibodies (ANCA) and antinuclear antibodies (ANA) is performed to rule out vasculitides and autoimmune disorders, typically yielding negative results in sarcoidosis.[67][68][69]Staging and classification
Sarcoidosis staging primarily relies on the Scadding radiographic classification system for pulmonary disease, which categorizes chest X-ray findings into five stages to assess disease extent and guide prognosis. Stage 0 denotes a normal chest radiograph, observed in 5-15% of cases at presentation. Stage I features bilateral hilar lymphadenopathy without parenchymal involvement, seen in 45-65% of patients and associated with a high spontaneous resolution rate of 50-90% without treatment. Stage II includes bilateral hilar lymphadenopathy plus parenchymal infiltrates, occurring in 30-40% of cases with 30-70% resolution. Stage III shows parenchymal infiltrates without lymphadenopathy, affecting 10-15% and resolving in only 10-20%. Stage IV indicates advanced pulmonary fibrosis with honeycombing, hilar retraction, or architectural distortion, present in about 5% of cases and carrying a 0% spontaneous resolution rate.[70] Higher Scadding stages correlate with reduced likelihood of remission, increased chronicity, and poorer long-term outcomes, such as progressive fibrosis and impaired lung function.[35] Biopsy confirmation of noncaseating granulomas supports staging accuracy.[54]| Stage | Radiographic Features | Prevalence at Presentation | Spontaneous Resolution Rate |
|---|---|---|---|
| 0 | Normal | 5-15% | N/A |
| I | Bilateral hilar lymphadenopathy only | 45-65% | 50-90% |
| II | Bilateral hilar lymphadenopathy + parenchymal infiltrates | 30-40% | 30-70% |
| III | Parenchymal infiltrates without lymphadenopathy | 10-15% | 10-20% |
| IV | Advanced fibrosis | 5% | 0% |