Sarcoidosis — Systemic Manifestations

Sarcoidosis is a multisystem inflammatory disorder of unknown etiology characterized by the formation of non-caseating granulomas in affected organs, most commonly the lungs and mediastinal lymph nodes, but with significant extrapulmonary manifestations in 25-35% of patients. The systemic manifestations of sarcoidosis are clinically important because they often determine morbidity and mortality, may be the presenting symptom before pulmonary involvement is evident, and can involve nearly every organ system including the musculoskeletal, rheumatologic, neurologic, cardiac, and ophthalmologic systems. The disease has a worldwide distribution with an estimated incidence of 10-20 per 100,000 in Northern Europe and North America; it predominantly affects adults between 20-40 years of age with a higher prevalence and more aggressive course in African Americans compared to Caucasians. Recognition of systemic manifestations is essential for clinical practice because they may require specific therapeutic intervention, represent prognostic indicators, and often coexist with pulmonary disease, creating diagnostic and therapeutic complexity. Understanding the musculoskeletal and rheumatologic manifestations is particularly important for medical students and residents because these presentations frequently prompt initial evaluation and are commonly tested in board examinations.

The pathophysiology of sarcoidosis involves a complex interplay of genetic predisposition, environmental triggers, and dysregulated immune responses that culminate in granuloma formation and organ dysfunction.

The fundamental pathophysiologic mechanism involves aberrant cellular and humoral immune responses to an unknown antigen (presumed environmental or infectious agent) in genetically susceptible individuals. Upon antigen exposure, antigen-presenting cells (APCs), particularly dendritic cells and macrophages, process and present the putative antigen via MHC-II molecules to CD4+ T helper cells. This interaction triggers polarization toward Th1 and Th17 immune responses, with accumulation of activated macrophages and CD4+ T lymphocytes at sites of inflammation. The activated macrophages produce excessive amounts of proinflammatory cytokines including TNF-α, IL-6, IL-8, and IL-23, while CD4+ T cells produce IFN-γ and IL-17. These cytokines recruit additional inflammatory cells and promote the differentiation of macrophages into epithelioid cells, which cluster together with giant cells (both langhans and foreign body types) and fibroblasts to form the characteristic non-caseating granuloma. Unlike tuberculous granulomas, sarcoid granulomas lack central necrosis, reflecting a different immune balance. The persistence of granulomas is sustained by chronic macrophage activation and altered apoptosis regulation, allowing prolonged antigen presentation and T cell activation. This pathophysiology explains the chronic course of sarcoidosis and the rationale for anti-TNF-α therapy in severe cases.

Sarcoid macrophages uniquely possess the ability to produce 1,25-dihydroxyvitamin D3 (the active metabolite of vitamin D) in an unregulated, non-renal fashion, independent of parathyroid hormone control. This extrarenal production occurs through expression of the enzyme CYP27B1 (1α-hydroxylase) within activated granulomatous macrophages, bypassing normal regulatory mechanisms. The result is increased intestinal calcium absorption and enhanced bone resorption, leading to hypercalcemia (5-10% of patients) and hypercalciuria (much more common, occurring in 20-40% of patients). Hypercalciuria predisposes to nephrolithiasis and can cause progressive renal dysfunction through crystal-induced tubular injury. This mechanism is distinct from primary hyperparathyroidism and explains why sarcoid-related hypercalcemia may not suppress PTH levels normally. Additionally, sarcoid macrophages produce FGF23 (fibroblast growth factor 23), which promotes renal phosphate wasting and can cause hypophosphatemia, contributing to bone disease and explaining why some sarcoidosis patients develop "sarcoid bone disease" with mixed osteolytic and osteosclerotic lesions.

Chronic granulomatous inflammation can progress to pulmonary fibrosis and other organ fibrosis through TGF-β activation and epithelial-mesenchymal transition (EMT). Activated macrophages within granulomas produce transforming growth factor-beta (TGF-β), which drives fibroblast proliferation, differentiation into myofibroblasts, and excessive collagen deposition. In the lungs, this progression from granulomatous inflammation to pulmonary fibrosis occurs in approximately 20-25% of patients with pulmonary sarcoidosis and represents a critical transition point in disease severity. Similar fibrotic progression can occur in other organs such as the heart (restrictive cardiomyopathy), nervous system, and liver. The fibrotic phase typically occurs after years of disease and is generally less responsive to immunosuppressive therapy than the granulomatous phase, making early recognition and treatment of active inflammation important for prevention of irreversible organ damage.

Sarcoidosis demonstrates clear genetic predisposition, with familial clustering in approximately 3-5% of cases and higher concordance in monozygotic twins than dizygotic twins. Genome-wide association studies (GWAS) have identified multiple susceptibility loci including FASNC (fatty acid synthase complex), ANXA11 (annexin A11), and FAP (familial amyloidosis precursor), though these genes individually confer modest increased risk. HLA alleles, particularly HLA-DRB1 and HLA-DQB1, show strong associations with disease susceptibility and phenotype; certain HLA alleles are associated with acute presentation (HLA-B8 and HLA-DRB3) while others predict more chronic disease. Environmental triggers remain incompletely understood but are presumed to include organic or inorganic antigens; proposed candidates include beryllium (which can cause chronic beryllium disease mimicking sarcoidosis), metals, dusts, and infectious pathogens (including mycobacteria and proprionibacteria). The two-hit hypothesis suggests that genetic susceptibility predisposes to aberrant immune responses when exposed to environmental triggers, explaining the variable penetrance and phenotypic heterogeneity of sarcoidosis.

While sarcoidosis is fundamentally a Th1/Th17-driven inflammatory disease, paradoxically, there is evidence of impaired regulatory T cell (Treg) function and dysregulated immune tolerance. Tregs, which normally suppress excessive immune responses through IL-10 and TGF-β production, are reduced in number or function in sarcoidosis patients, contributing to failure of immune downregulation. Additionally, sarcoid patients exhibit reduced IL-10 and increased IL-6 production, reflecting skewed toward pro-inflammatory responses. This helps explain the chronic, progressive nature of the disease and the difficulty in achieving sustained remission without immunosuppressive therapy.

While sarcoidosis is classified as an idiopathic disease (meaning the primary cause is unknown), several epidemiologic and biologic factors influence disease susceptibility, phenotype, and progression:

Familial sarcoidosis, accounting for 3-5% of cases, suggests autosomal dominant inheritance with variable penetrance, though complex multigenic inheritance is more likely. Individuals with a first-degree relative with sarcoidosis have approximately 5-fold increased risk of developing the disease. Specific HLA alleles confer both increased susceptibility and influence disease presentation; HLA-B8 and HLA-DRB3 are associated with acute, self-limited presentation (erythema nodosum, arthralgia, hilar lymphadenopathy), while **HLA-DRB1*03** and other alleles are associated with more chronic, progressive disease. Non-HLA genetic loci identified in GWAS studies contribute smaller effect sizes individually but collectively explain approximately 50% of disease heritability.

While definitive environmental triggers remain elusive, proposed exposures include inorganic dusts (beryllium, aluminum, titanium, zirconium), organic antigens from mold and bacteria, and possibly infectious pathogens. Beryllium exposure deserves special mention because chronic beryllium disease (CBD) can mimic sarcoidosis histologically and must be differentiated through beryllium lymphocyte proliferation test (BeLPT); beryllium-exposed individuals with a positive BeLPT and sarcoid-like granulomas have CBD rather than sarcoidosis. Occupational exposures to metals, construction dust, and agricultural exposures have been associated with higher sarcoidosis prevalence in some cohorts, though causality is difficult to establish.

African Americans have 10-15-fold higher incidence and prevalence of sarcoidosis compared to Caucasians, develop disease at younger ages, have more severe systemic manifestations, and experience worse outcomes with higher mortality rates. Women are affected slightly more frequently than men (slight female predominance), and the disease typically manifests between ages 20-40 years. Northern European ancestry (Scandinavian, Irish) also shows increased prevalence. Sarcoidosis is rare in children and the elderly, with bimodal age distribution showing rare pediatric cases and rare new-onset disease in patients over age 65.

Some evidence suggests that prior mycobacterial infections (including tuberculosis exposure) or specific pathogenic agents may trigger sarcoidosis development in susceptible individuals, though causation is not proven. Conversely, sarcoidosis patients have lower TB prevalence than the general population in endemic areas, suggesting that the immune dysregulation in sarcoidosis may actually protect against tuberculosis infection. No specific infectious agent has been definitively implicated as causal, though Propionibacterium acnes has been detected in sarcoid granulomas in some studies.

The systemic and musculoskeletal manifestations of sarcoidosis are protean and can affect virtually any organ system. Clinical presentation varies from asymptomatic incidental radiographic findings to acute multisystem disease to progressive organ dysfunction.

Acute polyarthritis is the most common rheumatologic manifestation of sarcoidosis, occurring in 3-13% of patients and more frequently in women. This typically presents as symmetric arthralgia or arthritis affecting the ankles, knees, wrists, and proximal interphalangeal (PIP) joints, mimicking rheumatoid arthritis or other inflammatory arthropathies. The arthritis is characteristically non-erosive, distinguishing it from seronegative spondyloarthropathies or rheumatoid arthritis; radiographs show soft tissue swelling without bony erosions or joint space narrowing. The arthritis is typically self-limited, lasting weeks to months, and frequently occurs as part of Löfgren syndrome, the acute systemic presentation of sarcoidosis characterized by the classic triad of erythema nodosum, polyarthralgia/polyarthritis, and bilateral hilar lymphadenopathy with or without pulmonary infiltrates. Löfgren syndrome is more common in women, has an excellent prognosis with spontaneous resolution in >90% of cases, and often requires only NSAIDs for symptom management.

Chronic arthralgia or polyarthritis occurs in a minority of sarcoidosis patients (1-5%) and typically involves larger joints including knees, ankles, hips, and shoulders. Unlike acute sarcoid arthritis, chronic arthropathy may be persistent, disabling, and require immunosuppressive therapy. In rare cases, sarcoid arthritis can be associated with bone cysts (lytic lesions in phalanges and long bones), representing another distinctive manifestation sometimes called "sarcoid dactylitis" when involving fingers. The chronic form may be asymmetric and oligoarticular, presenting diagnostic challenges in differentiating from other chronic inflammatory arthritides.

Erythema nodosum is the most common skin manifestation of sarcoidosis (20-30% of cutaneous involvement) and appears as painful, tender, erythematous subcutaneous nodules, typically on the anterior shins and less commonly on the knees, ankles, forearms, and buttocks. Erythema nodosum is part of the Löfgren syndrome triad and indicates a favorable prognosis. Histologically, erythema nodosum shows septal panniculitis (inflammation of subcutaneous adipose tissue septa) without vasculitis. The nodules are tender on palpation, warm, and may ulcerate but typically resolve without scarring. Erythema nodosum in the context of hilar lymphadenopathy is virtually diagnostic of sarcoidosis (in regions where TB is endemic, TB must be excluded first). Interestingly, erythema nodosum indicates a hyperergic (Th1) immune response and is associated with better prognosis than other skin manifestations.

Many sarcoidosis patients present with nonspecific constitutional symptoms including fatigue, malaise, weight loss, fever, and night sweats, particularly in acute presentations. These symptoms reflect the burden of systemic inflammation and cytokine production (especially TNF-α, IL-6, and IL-8). Fatigue is often more severe and persistent than would be expected from organ involvement alone and may reflect the systemic inflammatory burden. Some patients describe profound fatigue disproportionate to findings on examination, which is termed "sarcoidosis-related fatigue" and is increasingly recognized as an important component of disease burden affecting quality of life.

While technically not musculoskeletal, pulmonary involvement is the defining feature of sarcoidosis in 90% of patients and frequently accompanies systemic manifestations. Patients present with dyspnea on exertion, cough (usually nonproductive), and sometimes chest discomfort. Pulmonary manifestations range from asymptomatic hilar lymphadenopathy discovered on incidental chest radiography to progressive pulmonary fibrosis with severe restrictive physiology. Löfgren syndrome patients often have normal or near-normal pulmonary function despite radiographic findings, whereas non-Löfgren chronic disease frequently progresses to fibrosis. Acute cough, dyspnea, and constitutional symptoms in the context of hilar lymphadenopathy, arthralgia, and erythema nodosum form the classic presentation.

Patients with sarcoid-induced hypercalcemia may present with nonspecific symptoms including polyuria, polydipsia, nocturia, nephrolithiasis, cognitive dysfunction, muscle weakness, and constipation. Hypercalciuria (much more common than hypercalcemia) frequently causes nephrolithiasis, presenting with flank pain, hematuria, and urinary symptoms; approximately 10-20% of sarcoidosis patients develop kidney stones. Chronic hypercalciuria and nephrolithiasis can lead to progressive renal insufficiency and chronic kidney disease. Symptoms of hypercalcemia and hypercalciuria should prompt measurement of serum and urine calcium in all sarcoidosis patients.

Cardiac sarcoidosis occurs in approximately 5% of patients clinically but autopsy studies suggest pathologic involvement in 20-25% of patients, indicating significant underdiagnosis. Cardiac involvement can manifest as palpitations, syncope, dyspnea, angina-like chest pain, or sudden cardiac death. Arrhythmias (particularly ventricular tachycardia) are the most common presenting symptom and occur due to sarcoid granulomas creating areas of scar tissue that serve as reentrant circuits. Granulomatous infiltration of the myocardium can lead to dilated cardiomyopathy with systolic dysfunction, restrictive cardiomyopathy from fibrosis, or conduction abnormalities including heart block. Some patients present with sudden cardiac death as the first manifestation of sarcoidosis, representing the most life-threatening systemic manifestation. Cardiac sarcoidosis should be suspected in young to middle-aged patients presenting with unexplained cardiomyopathy, unexplained arrhythmias, or conduction abnormalities.

Neurosarcoidosis occurs in 5-10% of sarcoidosis patients and can involve the central nervous system, peripheral nervous system, or both. The most common presentation is cranial nerve involvement (particularly cranial nerve VII, the facial nerve, causing Bell's palsy), which may be bilateral and distinguishes sarcoid-related facial palsy from idiopathic Bell's palsy. Other manifestations include meningitis (both aseptic meningitis with CSF pleocytosis and chronic meningitis), **hypothalamic

Sarcoidosis is a diagnosis of exclusion requiring three elements per the ATS/ERS/WASOG framework endorsed in the ATS 2020 clinical practice guideline: a compatible clinical/radiographic picture, histologic non-caseating granulomas, and exclusion of alternative granulomatous disease.

Therapy is driven by organ dysfunction or intolerable symptoms, not by radiographic findings alone; the ERS clinical practice guideline on sarcoidosis treatment frames the decision as risk of mortality or permanent organ damage versus toxicity of immunosuppression.