Sarcoidosis

Appropriate biopsy sites may be obvious from physical examination and initial assessment; peripheral lymph nodes, skin lesions, and conjunctivae are all easily accessible. Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) of a mediastinal or hilar lymph node has a reported diagnostic yield of about 90% and is the diagnostic procedure of choice in patients with intrathoracic involvement.

Bronchoscopic transbronchial biopsy can be used when EBUS-TBNA is nondiagnostic; if the bronchoscopic transbronchial biopsy is nondiagnostic, it can be tried a second time.

If EBUS-TBNA and bronchoscopic transbronchial biopsies are nondiagnostic or if bronchoscopy cannot be tolerated, mediastinoscopy can be done to biopsy mediastinal or hilar lymph nodes, or video-assisted thoracoscopic (VAT) lung biopsy or open-lung biopsy can be done to obtain lung tissue. If sarcoidosis is strongly suspected but a biopsy site is not evident based on examination or imaging findings, positron emission tomography (PET) scanning can help identify active sites such as heart, bone, muscle, and brain.

Exclusion of other diagnoses is critical, especially when symptoms and x-ray signs are minimal, because many other disorders and processes can cause granulomatous inflammation (see table Differential Diagnosis of Sarcoidosis Differential Diagnosis of Sarcoidosis ). Biopsy tissue should be cultured for fungi and mycobacteria. Exposure history to occupational (silicates, beryllium), environmental (moldy hay, birds, and other antigenic triggers of hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis is a syndrome of cough, dyspnea, and fatigue caused by sensitization and subsequent hypersensitivity to environmental (frequently occupational or domestic) antigens... read more ), and infectious ( tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more , coccidioidomycosis Coccidioidomycosis Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute benign... read more , histoplasmosis Histoplasmosis Histoplasmosis is a pulmonary and hematogenous disease caused by Histoplasma capsulatum; it is often chronic and usually follows an asymptomatic primary infection. Symptoms are those... read more ) antigens should be explored. Purified protein derivative (PPD) skin testing or interferon gamma release assay should be done early in the assessment.

Severity is assessed according to organ involvement so, for example, with only pulmonary involvement

Pulmonary function test Overview of Tests of Pulmonary Function Pulmonary function tests provide measures of airflow, lung volumes, gas exchange, response to bronchodilators, and respiratory muscle function. Basic pulmonary function tests available in the... read more results are often normal in early stages but demonstrate restriction and reduced diffusing capacity for carbon monoxide (DLCO) in advanced disease. Airflow obstruction also occurs and may suggest involvement of the bronchial mucosae. Adding a 6-minute walk test may characterize functional impairment more comprehensively than the results of pulmonary function tests alone. Patients with extensive lung involvement may have normal oxygen saturation at rest but may show desaturation with exertion.

Recommended routine screening tests for extrapulmonary disease include

Cardiac magnetic resonance imaging (MRI) with and without gadolinium contrast may be appropriate in patients with cardiac symptoms. In patients with neurologic symptoms, brain or spine MRI with or without gadolinium may be needed, and bone scans and electromyography may be appropriate in patients with rheumatologic symptoms. PET scanning appears to be the most sensitive test for detecting bone and other extrapulmonary sarcoidosis and is used together with MRI in patients with cardiac involvement. Abdominal CT with radiopaque contrast agents is not routinely recommended but can provide evidence of hepatic or splenic involvement (eg, enlargement, hypolucent lesions).

Laboratory testing plays an adjunctive role in establishing the diagnosis and determining the extent of organ involvement. Complete blood count with differential may show anemia, eosinophilia, or leukopenia. Serum calcium should be measured to detect hypercalcemia. Blood urea nitrogen (BUN), creatinine, and liver test results may be elevated in renal and hepatic sarcoidosis. Total protein may be elevated because of hypergammaglobulinemia. Elevated erythrocyte sedimentation rate is common but nonspecific. Measurement of calcium in a urine specimen collected over 24 hours is recommended to exclude hypercalciuria, even in patients with normal serum calcium levels. Elevated serum angiotensin-converting enzyme (ACE) levels also suggest sarcoidosis but are nonspecific and may be elevated in patients with other conditions (eg, hyperthyroidism Hyperthyroidism Hyperthyroidism is characterized by hypermetabolism and elevated serum levels of free thyroid hormones. Symptoms are many and include tachycardia, fatigue, weight loss, nervousness, and tremor... read more , Gaucher disease Gaucher Disease Gaucher disease is a sphingolipidosis, an inherited disorder of metabolism, resulting from glucocerebrosidase deficiency, causing deposition of glucocerebroside and related compounds. Symptoms... read more , silicosis Silicosis Silicosis is caused by inhalation of unbound (free) crystalline silica dust and is characterized by nodular pulmonary fibrosis. Chronic silicosis initially causes no symptoms or only mild dyspnea... read more , mycobacterial disease, fungal infections, hypersensitivity pneumonitis Hypersensitivity Pneumonitis Hypersensitivity pneumonitis is a syndrome of cough, dyspnea, and fatigue caused by sensitization and subsequent hypersensitivity to environmental (frequently occupational or domestic) antigens... read more , lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more ). However, angiotensin-converting enzyme (ACE) levels, if elevated, may be useful for monitoring adherence with corticosteroid treatment. ACE levels plummet even when patients are taking low-dose corticosteroids.

Bronchoalveolar lavage (BAL) is used to help exclude other forms of interstitial lung disease Overview of Interstitial Lung Disease Interstitial lung diseases are a heterogeneous group of disorders characterized by alveolar septal thickening, fibroblast proliferation, collagen deposition, and, if the process remains unchecked... read more if the diagnosis of sarcoidosis is in doubt and to rule out infections. The findings on BAL vary considerably, but lymphocytosis (lymphocytes > 10%), a CD4+/CD8+ ratio of > 3.5 in the lavage fluid cell differential, or both suggest the diagnosis in the proper clinical context. However, absence of these findings does not exclude sarcoidosis.

Whole-body gallium scanning has been largely replaced by PET scanning. If gallium scanning is available, it may provide useful supportive evidence in the absence of tissue confirmation. Symmetric increased uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid, and salivary glands (panda sign) are patterns highly suggestive of sarcoidosis. A negative result in patients taking prednisone is unreliable.

Symptom management begins with corticosteroids. The presence of chest imagining abnormalities without significant symptoms or evidence of decline in organ function is not an indication for treatment. A standard protocol is prednisone 20 mg to 40 mg by mouth once a day, depending on symptoms and severity of findings. Alternate-day regimens may be used: eg, prednisone 40 mg by mouth once every other day. Although patients rarely require > 40 mg/day, higher doses may be needed to reduce complications in neurologic disease. Response usually occurs within 6 to 12 weeks, so symptoms and pulmonary function test results may be reassessed between 6 and 12 weeks. Chronic, insidious cases may respond more slowly. Corticosteroids are tapered to a maintenance dose (eg, prednisone 10 to 15 mg/day) after evidence of response and are continued for an additional 6 to 9 months if improvement occurs.

The optimal duration of treatment is unknown. Premature taper can result in relapse. The drug is slowly stopped if response is absent or equivocal. Corticosteroids can ultimately be stopped in most patients, but because relapse occurs up to 50% of the time, monitoring should be repeated, usually every 3 to 6 months. Corticosteroid treatment should be resumed for recurrence of symptoms and signs. Because angiotensin-converting enzyme (ACE) production is suppressed with low doses of corticosteroids, serial serum ACE levels may be useful in assessing adherence with corticosteroid treatment in patients who have elevated ACE levels.

Inhaled corticosteroids can relieve cough in patients with endobronchial involvement or with hyperreactive airways.

Topical corticosteroids may be useful in dermatologic, nasal sinus, and ocular disease.

Prophylaxis against Pneumocystis jirovecii pneumonia should be considered while patients are taking > 20 mg prednisone daily or its equivalent for more than a month and for those who are taking immunosuppressants.

Alendronate or another bisphosphonate may be the treatment of choice for prevention of corticosteroid-induced osteoporosis. Using supplemental calcium or vitamin D risks hypercalcemia due to endogenous production of active vitamin D (1, 25 dihydroxy vitamin D) by sarcoidal granulomas. Serum and 24-hour urinary calcium measurements should be normal before starting such supplements.

Immunosuppressants are often effective in refractory cases. For example, immunosuppressive drugs have been used when:

Prior to adding other immunosuppressants, possible reasons for lack of clinical improvement, such as noncompliance, comorbid disease, pulmonary hypertension, and end-stage fibrosis should be considered.

Methotrexate is the most commonly used immunosuppressant. Patients should be given a 6-month trial of methotrexate 10 to 15 mg/week. Patients should be tested for infection with hepatitis B virus and hepatitis C virus before methotrexate is started. Initially, methotrexate and corticosteroids are both given; over 6 to 8 weeks, the corticosteroid dose can be tapered and, in many cases, stopped. The maximal response to methotrexate, however, may take 6 to 12 months. In such cases, prednisone must be tapered more slowly. Serial blood counts and liver enzyme tests should be done every 1 to 2 weeks initially and then every 4 to 6 weeks once a stable dose is achieved. Folate (1 mg by mouth once a day) is recommended for patients treated with methotrexate.

Other immunosuppressants include azathioprine, mycophenolate, cyclophosphamide, leflunomide, and hydroxychloroquine. Hydroxychloroquine 400 mg by mouth once a day or 200 mg by mouth twice a day can be effective for treating hypercalcemia, arthralgia, skin sarcoidosis, or enlarged uncomfortable or disfiguring peripheral lymph nodes. Ophthalmologic evaluation should be done before hydroxychloroquine is started and every 6 to 12 months during treatment to monitor for its ocular toxicity.

Relapse is common after stopping an immunosuppressant.

Infliximab can be effective for treatment of chronic corticosteroid-dependent pulmonary sarcoidosis, refractory lupus pernio, and neurosarcoidosis. Patients should have a purified protein derivative (PPD) or interferon gamma release assay for tuberculosis before beginning therapy. Infliximab is given intravenously 3 to 5 mg/kg once, again 2 weeks later, then once per month. It may take 3 to 6 months for maximal response. Adalimumab can be considered for patients who have been treated successfully with infliximab but have developed antibodies or infusion reactions.

Patients who have heart block or ventricular arrhythmias due to cardiac involvement should have an implantable cardiac defibrillator and pacemaker Implantable Cardioverter-Defibrillators (ICD) The need for treatment of arrhythmias depends on the symptoms and the seriousness of the arrhythmia. Treatment is directed at causes. If necessary, direct antiarrhythmic therapy, including antiarrhythmic... read more placed as well as drug therapy.

No available drugs have consistently prevented pulmonary fibrosis.

Treatment of sarcoidosis-associated pulmonary arterial hypertension is supportive with diuresis and supplemental oxygen. So far therapy with pulmonary vasodilators has not been found to be beneficial ( 1 Treatment reference Sarcoidosis is an inflammatory disorder resulting in noncaseating granulomas in one or more organs and tissues; etiology is unknown. The lungs and lymphatic system are most often affected, but... read more ).

Organ transplantation is an option for patients with end-stage pulmonary, cardiac, or liver involvement, although disease may recur in the transplanted organ.

Moderate or severe impairment of pulmonary function may predict mortality in patients with sarcoidosis who are infected with SARS‑CoV‑2. As in patients with other inflammatory lung diseases, during the COVID-19 pandemic, immunosuppressants should be used judiciously.