Continuing Education Activity
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that primarily affects the lungs and lymphoid organs, with the potential for significant extrapulmonary involvement, including cardiac, ocular, neurologic, and cutaneous manifestations. Despite its clinical complexity, sarcoidosis remains underrecognized and is frequently misdiagnosed due to its variable presentation and overlap with other granulomatous conditions. Clinicians demonstrate inconsistent application of diagnostic criteria, radiographic staging, and evidence-based treatment strategies, contributing to delayed diagnosis and preventable organ damage. This activity provides a comprehensive review of sarcoidosis, including its pathophysiology, histopathologic features, staging, and interdisciplinary management. Participants develop improved competence in diagnostic evaluation, risk stratification, selection of corticosteroid and corticosteroid-sparing therapies, prevention of complications, and coordination of interprofessional care to optimize patient outcomes throughout the disease course.
Objectives:
Identify the major etiologic, genetic, and environmental risk factors associated with sarcoidosis and explain their role in the pathogenesis of noncaseating granuloma formation and clinical heterogeneity.
Assess patients with suspected sarcoidosis using a systematic diagnostic approach that includes laboratory evaluation, pulmonary function testing, radiographic staging, and biopsy interpretation to confirm the diagnosis and determine disease extent.
Select evidence-based pharmacologic treatment strategies for sarcoidosis, including appropriate initiation, tapering, and discontinuation of corticosteroids, and determine when corticosteroid-sparing agents or biologic therapies are indicated.
Collaborate with an interdisciplinary team including pulmonology, cardiology, neurology, ophthalmology, nursing, respiratory therapy, and pharmacy to coordinate comprehensive, patient-centered care and improve outcomes for patients with sarcoidosis.
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Introduction
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that primarily affects the lungs and lymphoid organs. Additional organs may become involved over time. Sarcoidosis was first reported in 1877 and remains a concern for clinicians and pathologists. The disease may remain silent, and most patients remain asymptomatic for a prolonged period. Patients may later present with nonspecific symptoms or organ failure. Sarcoidosis is a challenging diagnosis for clinicians, and histopathology remains the gold standard for diagnosis.
Etiology
Sarcoidosis is a chronic inflammatory disease of unknown etiology; however, it has been associated with genetic factors, certain antigens, and immune dysregulation, and usually occurs in individuals with genetic susceptibility after exposure to specific environmental agents. Etiologic agents can evoke the histologic hallmarks of sarcoidosis and are responsible for its clinical heterogeneity and immunologic features. Genetic factors that predispose patients to sarcoidosis include the following risk loci: butyrophilin-like 2 (BTNL2), human leukocyte antigen B (HLA-B), human leukocyte antigen DP β1 chain (HLA-DPB1), annexin A11 (ANXA11), interleukin 23 receptor (IL23R), SH2B adaptor protein 3 (SH2B3), ataxin 2 (ATXN2), interleukin 12B p40 subunit (IL12B), nuclear factor κB subunit 1 (NFKB1)/ mannosidase β A (MANBA), and family with sequence similarity 177 member B (FAM177B). Environmental agents, such as aluminum, zirconium, talc, pine tree pollen, clay, and insecticides, have been implicated. Mycobacteria species are the infectious agents most strongly associated with sarcoidosis, followed by Leptospira species, Mycoplasma species, Chlamydia pneumoniae, and Borrelia burgdorferi.
Epidemiology
People of all age groups, most commonly those aged 20 to 39 years, are affected by sarcoidosis, regardless of race and ethnicity. The disease has a higher incidence among Black individuals, with an annual incidence of 17 to 35 per 100,000 population. The male-to-female ratio is 2:1. Extrathoracic manifestations include erythema nodosum in Europeans, chronic uveitis in Black individuals in the United States, and lupus pernio in Puerto Ricans. Cardiac involvement is the most common cause of death in sarcoidosis, followed by respiratory failure. The mortality rate due to sarcoidosis ranges from 1% to 5%.[1]
Pathophysiology
The pathogenesis of sarcoidosis is poorly understood. Environmental exposures, genetic factors, and dysregulated immune systems have been associated with an exaggerated T helper 1 cell immune response, which contributes to the pathogenesis of sarcoidosis. T cells are often associated with an inverted CD4/CD8 ratio and play a key role in the development of sarcoidosis by promoting cellular immune responses. The noncaseating granuloma characterizes Sarcoidosis. Tumor necrosis factor is elevated in this disease.
In addition to the role of T cells, polymorphisms in human leukocyte antigen genes and the butyrophilin-like 2 receptor gene (BTNL2, a costimulatory molecule within the MHC locus) have been associated with sarcoidosis. There is an association of the annexin A11 gene on chromosome 10q22.3. The function of annexin is to regulate calcium signaling, cell division, and apoptosis.[2] Sarcoidosis is also associated with the DR subtypes of class II antigens. HLA-DRB1*03, HLA-DRB1*11, HLA-DRB1*12, HLA-DRB1*14, and HLA-DRB1*15 increase the risk of sarcoidosis. Lofgren syndrome is an acute form of sarcoidosis that is self-limited and shows a triad of lymphadenopathy, erythema nodosum, and arthritis. HLA-DRB1*03 is associated with sarcoidosis.[3]
Histopathology
Lymph node biopsy reveals discrete or confluent noncaseating granulomas comprising epithelioid cells and multinucleated giant cells. The granuloma is surrounded by sparse lymphocytes with minimal or no central necrosis. Cells with cytoplasmic inclusions, such as asteroid bodies, Schaumann bodies, and Hamazaki-Wesenberg bodies, as well as calcium oxalate crystals, are present.[4]
History and Physical
Symptoms are variable; typically, patients present with a persistent dry cough, fatigue, and shortness of breath. Other manifestations include painful, red lumps on the skin; uveitis with blurred vision; hoarseness; palpable lymph nodes at multiple sites (including the axilla and neck); painful, swollen joints; hearing loss; seizures; and psychiatric disorders. Cardiomyopathy, conduction defects, nephrolithiasis, and hepatomegaly are observed in a few cases.
A wide range of cutaneous manifestations may be observed, including papular, maculopapular, nodular, subcutaneous, hypopigmented, and plaque sarcoidosis. The most common lesions in cutaneous sarcoidosis are papular nodules on the upper half of the face, the back of the neck, and at sites of previous trauma, including scars and tattoos. Lupus pernio is a cutaneous sarcoidosis variant that mainly involves the central facial skin and presents with violaceous or erythematous papules, plaques, or nodules.
Other well-described skin manifestations of sarcoidosis include nodular sarcoidosis. Plaque-like lesions and subcutaneous nontender nodules are also commonly observed. Erythema nodosum is seen in a variety of other conditions, including sarcoidosis, and usually presents with painful nodules on the shins. This panniculitis is a characteristic feature of Löfgren syndrome. Skin lesions can appear up to 10 or more years after the initial injury or tattoo.[5]
Ocular manifestations are observed in approximately 50% of patients, with uveitis being the most common clinical feature. The CD4:CD8 ratio of vitreous lymphocytes has prognostic value in this condition. Additionally, conductive heart block and sudden cardiac death have also been reported in patients with sarcoidosis. Prophylactic insertion of an implantable cardioverter-defibrillator is recommended in patients with cardiac sarcoidosis. Furthermore, central nervous system manifestations include diabetes insipidus followed by hyperprolactinemia. Patients with central nervous system symptoms often have a poor quality of life and may present with psychiatric disorders such as anxiety and depression.[6]
Evaluation
The diagnosis of sarcoidosis involves laboratory, radiologic, and histologic confirmation.
Laboratory Examination
Complete blood count and differential (for anemia, leukopenia, and thrombocytopenia), liver function tests, blood urea nitrogen, creatinine, blood glucose, electrolyte levels, and serum calcium (to detect hypercalcemia) should be obtained. Erythrocyte sedimentation rate and C-reactive protein levels are nonspecific tests that are often elevated.
Elevated serum alkaline phosphatase levels suggest diffuse granulomatous hepatic involvement.
Serologic testing, including serum angiotensin-converting enzyme, adenosine deaminase, serum amyloid A, and soluble interleukin-2 receptor levels, can be considered.
The Kveim test is similar to the tuberculin skin test and elicits a granulomatous sarcoid response; however, its significance is limited.
Imaging Studies
Radiographic Stages
Stage I: Presence of bilateral hilar adenopathy
Stage II: Bilateral hilar adenopathy and reticular opacities
Stage III: Reticular opacities with shrinking hilar nodes (mainly infiltrates)
Stage IV: Reticular opacities with fibrosis
In a patient with unexplained dyspnea or cough and a normal chest radiograph, high-resolution chest computed tomography should be considered.[9]
Histopathology
Sarcoidosis histopathology characteristically shows noncaseating granulomas with aggregates of epithelioid histiocytes, giant cells, and mature macrophages. If these results are positive, pulmonary function testing, electrocardiogram, echocardiography, urinalysis, and tuberculin skin testing should be considered to exclude systemic disease; pulmonary disease can be monitored.
A biopsy is often required to confirm the diagnosis, and a transbronchial biopsy has a high yield. Mediastinoscopy is required to perform a lymph node biopsy if the transbronchial biopsy results are negative. The key feature of a biopsy is the absence of Mycobacteria spp and fungi in noncaseating granulomas.
Treatment / Management
Pulmonary sarcoidosis is often an asymptomatic, nonprogressive disease and requires no treatment because most patients undergo spontaneous remission. Close monitoring of symptoms, chest radiography, and pulmonary function testing at 3- to 6-month intervals should be considered in asymptomatic patients. For patients with worsening pulmonary sarcoidosis with stage II to III radiographic findings, oral glucocorticoids at 0.3 to 0.6 mg/kg for 4 to 6 weeks should be considered.
If there is no improvement in symptoms, radiographic abnormalities, and pulmonary function test results, glucocorticoid treatment may be continued for an additional 4 to 6 weeks. Maintenance glucocorticoids are not needed; tapering to a dose of 0.25 to 0.5 mg/kg per day (usually 10 to 20 mg) should be considered over at least 6 to 8 months. Methotrexate, azathioprine, infliximab, leflunomide, and antimalarial agents may be considered corticosteroid-sparing agents for patients unable to tolerate corticosteroids.[10] A lung transplant is an option for patients with end-stage lung disease. However, the transplant is also associated with risks and the need for life-long immunosuppressive therapy.
Differential Diagnosis
The differential diagnosis of sarcoidosis includes the following:
Prognosis
Patients without symptoms do not require treatment and often remain stable for many years. However, patients with symptomatic lung or extrapulmonary disease tend to have a guarded prognosis. Symptom relapse is common, and many patients with advanced disease develop dyspnea and pulmonary hypertension. The overall mortality rate for untreated patients is approximately 5%. Prolonged use of corticosteroids is associated with multiple adverse effects.
Complications
Complications of sarcoidosis include pulmonary hypertension and end-stage lung disease.
Deterrence and Patient Education
There are no established measures to prevent sarcoidosis; therefore, prevention focuses on early detection, disease progression, and treatment-related complications. Patients should be educated about the variable and potentially chronic course of the disease and the importance of regular follow-up, even during periods of remission. Patients should be instructed to promptly report symptoms suggestive of organ involvement, including worsening dyspnea, chest pain, palpitations, syncope, visual disturbances, neurologic symptoms, or persistent fatigue.
The early recognition of cardiac, ocular, neurologic, and progressive pulmonary sarcoidosis is essential to prevent irreversible organ damage. Smoking cessation and avoidance of environmental or occupational lung irritants should be encouraged. Patients should be counseled regarding the risk of hypercalcemia and advised to avoid unnecessary vitamin D or calcium supplementation unless directed by a clinician.
Education should emphasize medication adherence, awareness of potential adverse effects, and, when appropriate, the need for gradual tapering for patients receiving systemic corticosteroids or immunosuppressive therapy. Preventive measures should be implemented, such as reducing the risk of infection and reviewing vaccinations. Patient education and shared decision-making improve adherence, reduce complications, and support long-term disease management.
Enhancing Healthcare Team Outcomes
Sarcoidosis has no known cause; therefore, it cannot be prevented. The disorder often resolves spontaneously, and treatment is not always required. However, severe cases require ongoing monitoring. Treating patients with sarcoidosis is best managed in an interdisciplinary manner by a team of healthcare professionals, including clinicians in cardiology, neurology, radiology, and pulmonology, as well as nursing, respiratory therapy, and pharmacy professionals. Patients need regular chest radiography because it is a marker of disease progression. Some patients may benefit from pulmonary rehabilitation and bronchodilators. A regular eye examination is important if the disease is advanced.
Patients with symptoms may require drug therapy, and the pharmacist should emphasize the importance of adherence and the need for follow-up because most drugs have adverse effects. Patients who do not respond to corticosteroids may require potent biologic agents. Patients with end-stage lung disease may need to be seen by a transplant nurse to determine their eligibility. Patients with eye symptoms should be referred to an ophthalmologist.
The nurse should ensure that patients undergo a routine 12-lead electrocardiogram at each clinic visit, as conduction abnormalities are common. The pharmacist and nurse should educate patients on the importance of smoking cessation and alcohol abstinence. Finally, all team members should educate patients treated with corticosteroids about the drug’s adverse effects. Only through such an interdisciplinary team approach can the outcomes of sarcoidosis be improved.[11][12]
Outcomes
No treatment is required for many patients with sarcoidosis, and in most, the disorder resolves spontaneously. However, in some individuals, the disease may take a fulminant course with severe symptoms. Factors that indicate a poor prognosis include significant chest imaging findings, extrapulmonary involvement, and pulmonary hypertension.
Results from many studies indicate that a chest radiograph is an excellent marker for disease prognosis. In severe cases, patients may require oxygen and experience conductive heart block and respiratory failure.[13] Mortality data are unavailable because long-term follow-up is often lacking. Approximately one-fifth of patients develop functional impairment, and the mortality rate in untreated patients ranges from 1% to 5%. The highest mortality rates are observed in Black women after the fifth decade of life.
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Disclosure: Syed Rizwan Bokhari declares no relevant financial relationships with ineligible companies.
Disclosure: Ahlam Safdar declares no relevant financial relationships with ineligible companies.
Disclosure: Preeti Rout declares no relevant financial relationships with ineligible companies.
