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.

When pulmonary sarcoidosis is suspected and EBUS-TBNA is nondiagnostic, bronchoscopic transbronchial lung biopsy with bronchoalveolar lavage (BAL) can be used. It can also be used in patients without any lung parenchymal infiltrates because diagnostic yield for transbronchial lung biopsy in stage I sarcoidosis is about 50%. 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 occult 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 (eg, silica, beryllium), environmental (eg, 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 (eg, 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 caused by the fungi Coccidioides immitis and C. posadasii; it usually occurs as an acute, benign, asymptomatic or self-limited respiratory infection. The... 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

Imaging is often needed to detect extrapulmonary sarcoidosis. 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. 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). Whole-body gallium scanning has been largely replaced by PET scanning. If available, gallium scanning 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) strongly suggest sarcoidosis. A negative result in patients taking prednisone is unreliable.

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 can 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 include palpitations, fatigue, weight loss, heat intolerance, anxiety, and tremor... read more , diabetes Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... 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 ). 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 should be done along with bronchoscopic biopsy to rule out suspected infections (eg, when findings with less invasive means such as imaging are not typical of sarcoidosis) and to 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. The findings on BAL vary considerably, but lymphocytosis (lymphocytes > 15%), 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.

Symptom management begins with corticosteroids. The presence of chest imaging 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 severe neurologic and cardiac disease. Response usually occurs within 6 to 12 weeks, so symptoms, other disease-severity markers, 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. An inhaled bronchodilator can be added in patients with obstructive airway disease.

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

Prophylaxis against Pneumocystis jirovecii pneumonia is recommended 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 in people at risk (eg, older patients). 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 used when

Prior to adding other immunosuppressants, possible reasons for lack of clinical improvement, such as noncompliance, comorbid disease (eg, asthma, heart failure, anemia), 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. Before starting methotrexate, patients should be tested for infection with hepatitis B virus and hepatitis C virus. 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 2 to 4 weeks initially and then every 6 to 12 weeks once a stable dose is achieved. Folate (1 mg by mouth once a day) is recommended for patients treated with methotrexate to reduce the risk of adverse effects.

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 is usually used as a 3rd-line medication to treat refractory sarcoidosis and to treat patients who are intolerant to both corticosteroid and the above-mentioned immunosuppressants. Before beginning therapy, patients should have a purified protein derivative (PPD) or interferon gamma release assay to screen for latent tuberculosis. 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. Infliximab is usually combined with low-dose methotrexate or azathioprine to prevent antibody formation against it.

Adalimumab can be considered for patients with ocular or cutaneus sarcoidosis and in patients who have been treated successfully with infliximab but have developed antibodies or infusion reactions. Adalimumab 40 to 80 mg subcutaneously is given every 1 to 2 weeks.

Patients who have heart block or ventricular arrhythmias due to cardiac involvement should receive 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 as well as drug therapy.

No available drugs have consistently prevented pulmonary fibrosis.

Treatment of sarcoidosis-associated pulmonary arterial hypertension (SPAH) is supportive with diuresis and supplemental oxygen. The role of pulmonary vasodilators in treating SPAH has not been well established; a few small studies have suggested efficacy, but larger studies are needed to confirm it (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.

Patients with sarcoidosis and moderate or severe impairment of pulmonary or cardiac function are at increased risk of developing severe forms of COVID-19 infection COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more and mortality. As in patients with other inflammatory lung diseases during the COVID-19 pandemic, immunosuppressants should be used judiciously. SARS-CoV-2 vaccination COVID-19 Vaccine COVID-19 vaccines provide protection against COVID-19, the disease caused by infection with the SARS-CoV-2 virus. Vaccination is the most effective strategy to prevent severe illness and death... read more is strongly recommended in patients with sarcoidosis because it could reduce the mortality and severity of illness due to COVID-19 infection. An ongoing clinical trial aims to better assess the efficacy of SARS-CoV-2 vaccination in patients with sarcoidosis and in patients taking immunosuppressants.