Sarcoidosis

Definition, Etiology, PathogenesisTop

Sarcoidosis is a multisystem inflammatory disorder of unknown etiology. Although the lung is the most commonly involved organ, with physiologic and/or radiographic abnormalities found in >90% of patients, granulomatous infiltration can occur in any organ system and result in chronic progressive dysfunction. Lymphocytes and macrophages accumulate in sites of the active inflammatory process, forming noncaseating granulomas. The presumable antigenic stimulus that initiates the disease process and promotes disease progression remains elusive.

Clinical Features and Natural HistoryTop

Sarcoidosis is a worldwide disease, with the highest incidence noted in African Americans and Scandinavians. The disease can occur in both sexes, with a slight predominance in females. Seventy percent of patients are aged between 25 to 45 years.

1. Symptoms of organ involvement:

1) Dyspnea, cough, and chest pain (usually retrosternal, occasionally resembling angina).

2) Cutaneous changes: Erythema nodosum, lupus pernio (indurated, disfiguring infiltrations associated with discoloration of the skin of the nose, cheeks, lips, and ears), papular or maculopapular eruptions, subcutaneous nodules, fine ulcerations or areas of depigmentation or erythema, lesions similar to ichthyosis, alopecia.

3) Ocular involvement: Most frequently uveitis, conjunctivitis, and lacrimal gland involvement.

4) Enlarged, mobile, and painless peripheral lymph nodes (mostly cervical or supraclavicular).

5) Enlargement of the liver, less frequently of the spleen.

6) Arthralgia (hands and feet are classically most involved) and myalgia.

7) Central nervous involvement: Frequently cranial nerve involvement, in particular affecting the facial nerve, less frequently the optic or oculomotor nerves. It can also present with leptomeningitis, diabetes insipidus, hypopituitarism, spinal cord disease, polyneuropathy, and small fiber neuropathy.

8) Cardiac involvement: Symptoms of arrhythmias or conduction disturbances, or symptoms of heart failure.

9) Features of pulmonary hypertension are present in 5% to 15% of all patients and in 70% of patients awaiting lung transplant. Given its multifactorial nature, it is classified as group 5 pulmonary hypertension.

10) Head and neck disease: Nasal congestion, epistaxis, anosmia, hoarseness, stridor, and dysphagia.

11) Enlargement of one or both parotid glands, causing tenderness and edema (Heerfordt syndrome: parotid gland enlargement, fever, facial nerve palsy, and anterior uveitis).

12) Gastrointestinal involvement: Most often symptom-free but the esophagus, stomach, small intestine, and colon can be involved.

In many patients general symptoms are observed, including debilitating fatigue, weakness, loss of appetite, weight loss, and fever.

2. Natural history: In ~50% of patients spontaneous remission occurs within 2 years from the diagnosis and does so in many other cases within 5 years. After 5 years remission is much less likely, with many patients experiencing a chronic or progressive course. An acute onset with erythema nodosum, asymptomatic bilateral hilar lymph node enlargement, migratory polyarthralgia, and fever (Löfgren syndrome) is usually associated with a favorable prognosis. The course of the disease correlates with its onset: In >80% of patients with stage 1 radiographic changes (see Diagnostic Tests, below), the disease resolves without treatment. In stage 2 patients the lesions resolve in 40% of 70% of cases, and in stage 3 patients, in 10% to 20% of cases. Five-year mortality rates are reported to be between 1% and 7%. Most fatalities are related to advanced pulmonary fibrosis, central nervous system disease, or cardiac involvement. Pulmonary hypertension is the most robust predictor of mortality in patients who are candidates for lung transplant.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests may reveal anemia (usually mild), leukopenia, hypercalcemia and hypercalciuria, increased serum angiotensin-converting enzyme levels, hypergammaglobulinemia, and other abnormalities depending on organ involvement, for example, abnormal liver (alkaline phosphatase [ALP]) or kidney parameters.

2. Electrocardiography (ECG): In patients with cardiac involvement ECG may reveal arrhythmia and conduction disturbances. However, normal ECG does not entirely exclude cardiac sarcoidosis. Cardiac magnetic resonance imaging (MRI) is recommended in patients with suspected cardiac involvement. Holter monitoring can be considered in the presence of symptoms suggestive of arrhythmia.

3. Imaging studies: Chest radiographs most frequently reveal bilateral (hilar and paratracheal) lymph node enlargement; after several years lymph node calcifications may develop. Parenchymal lesions include nodular changes and reticular nodular changes, as well as upper-lobe volume loss and conglomerate mass formation in end-stage fibrosis. Disease staging on the basis of chest radiographs is as follows:

– Stage 0: Normal chest radiographs.

– Stage 1: Hilar and mediastinal lymph node enlargement.

– Stage 2: Hilar and mediastinal lymph node enlargement and parenchymal changes.

– Stage 3: Parenchymal changes, no lymph node enlargement.

– Stage 4: Pulmonary fibrosis.

The chest radiographic stages do not correspond to the chronologic progression of the disease but rather to the likelihood of future radiographic and symptomatic disease resolution.

High-resolution computed tomography (HRCT) of the chest reveals perilymphatic nodular lesions that are usually peribronchovascular, subpleural, and/or perifissural in distribution along with enlargement of hilar and mediastinal lymph nodes. Computed tomography (CT) is more sensitive and specific in evaluating parenchymal lung involvement than plain-film chest radiography.

4. Pulmonary function tests can identify different patterns of abnormalities, including a reduced carbon monoxide diffusing capacity of the lungs (DLCO), restriction with reduced vital capacity, and commonly evidence of airflow obstruction related to small airway/endobronchial disease.

5. Bronchoscopy is done with the aim of performing lymph node biopsy (preferably using endobronchial ultrasonography), biopsy of bronchial mucosa, transbronchial lung biopsy, or bronchoalveolar lavage (≥25% of lymphocytes or a CD4+:CD8+ cell ratio >3.5).

6. Histologic examination reveals noncaseating granulomas in biopsy specimens of the bronchial mucosa, lung, or lymph nodes.

7. Other tests include contrast-enhanced magnetic resonance imaging (MRI) to assess for meningeal, brain, optic nerve, spinal cord, or cranial nerve involvement. Examination of cerebrospinal fluid (CSF) in patients with suspected central nervous system involvement identifies increased lymphocyte counts and protein levels in 80% of patients. Cardiac MRI or positron emission tomography (PET)/CT with 18F-fluorodeoxyglucose (FDG) can be used to assess for evidence of active cardiac inflammation or cardiac fibrosis/scar indicative of chronic disease. The presence of cardiac involvement, based on imaging findings, should be confirmed by a multidisciplinary team. Right heart catheterization is suggested in patients in whom pulmonary hypertension is suspected based on echocardiography. PET/CT or whole-body gallium (67Ga) scintigraphy can also be used to assess for systemic disease activity. In patients presenting with fatigue, the Fatigue Assessment Scale (FAS) is suggested as a tool for quantification of this symptom.

8. All patients should be referred for ophthalmologic examination.

Diagnostic Criteria

The diagnosis of sarcoidosis requires:

1) A compatible clinical and radiologic presentation.

2) Evidence of noncaseating granulomas.

3) Exclusion of other diseases capable of producing a similar clinical picture.

Patients who present with Löfgren syndrome, lupus pernio, or Heerfordt syndrome do not require biopsy (ongoing serial surveillance is recommended). Outside of these syndromic presentations, the confirmation of noncaseating granulomatous inflammation is recommended in the majority of patients. This confirmation is critical, taking into account the long-term nature and adverse-effect profile of potential treatments. Endobronchial ultrasound (EBUS)–guided lymph node sampling rather than mediastinoscopy is recommended as the initial sampling procedure in patients with mediastinal and/or hilar lymphadenopathy in whom biopsy is necessary. A careful examination may disclose other extrapulmonary sites for biopsy, such as skin or superficial lymph nodes.

Differential Diagnosis

An essential component of the diagnosis of sarcoidosis is the exclusion of alternative possibilities, which can be difficult, given the heterogeneous presentation of individual patients:

1) Hilar and mediastinal lymph node enlargement: Lymphoid malignancies, metastatic neoplasm, and granulomatous inflammation as a result of inflammatory or infectious etiologies (tuberculosis is the leading differential diagnosis and needs to be closely evaluated for or excluded with appropriate staining and culture).

2) Disseminated lung changes: Berylliosis, silicosis, lymphangitic carcinomatosis, chronic hypersensitivity pneumonitis, and postprimary tuberculosis.

3) Diseases in which histologic examination may reveal granulomas: Tuberculosis, chronic beryllium disease, mycobacterial infections, fungal infections (including aspergillosis), hypersensitivity pneumonitis, granulomatosis with polyangiitis, lymphoma, a sarcoid-like reaction to adjacent malignancy, necrotizing sarcoid granulomatosis, lymphocytic interstitial pneumonia, and granulomatous-lymphocytic interstitial lung disease in patients with common variable immunodeficiency.

TreatmentTop

1. Indications for treatment: The decision to treat either immediately or in follow-up is guided by the risk of severe dysfunction or irreversible damage to major organs, risk of death, or the presence of incapacitating symptoms. Most treatment protocols incorporate a period of observation without treatment whenever possible. The main indications for urgent treatment are cardiac involvement, eye disease that has not responded to topical therapy, symptomatic hypercalcemia, neurologic involvement, or severe disfiguring skin lesions. Parenchymal lung disease with severe functional impairment on presentation (vital capacity and/or DLCO <50% predicted) and progressive pulmonary disease with functional deterioration in the last 6 to 12 months are considered by many experts to be treatment indications.

2. First-line treatment: Oral corticosteroids: Prednisone. Start with 0.5 mg/kg or 20 to 40 mg/d for 6 to 12 weeks with dose reduction thereafter to a maintenance dose of 5 to 10 mg/d over a period of 6 months. A minimum of 6 to 12 months of therapy is often advised to prevent relapse. Alternative immunosuppressive agents are considered in patients who fail to respond to corticosteroids or in whom a maintenance prednisone dose of >15 to 20 mg/d is required. Methotrexate is the first-choice add-on, with a target dose in the range of 15 to 20 mg/wk. Folic acid should be use in conjuncture with methotrexate to reduce the risk of toxicity and increase compliance. Agents such as azathioprine, mycophenolate mofetil, antimalarial drugs, and in severe refractory disease infliximab are considered if the initial second-line therapy fails. In patients with persistent cough, airflow obstruction, or both, consider inhaled corticosteroids. Patients presenting with fatigue should be offered a systematic approach to fatigue management.

3. Lung transplant is reserved for patients with advanced pulmonary fibrosis, especially in the presence of concomitant pulmonary hypertension.

Follow-UpTop

For the first 2 years from diagnosis perform follow-up studies to assess organs previously involved using the least invasive methods. For pulmonary involvement perform chest radiography, spirometry, and DLCO measurements every 3 to 6 months and then annually for ≥3 years from the discontinuation of treatment or induction of sustained remission. Monitor for new involvement of common target organs annually or sooner, depending on symptoms.

Complications Top

Complications depend on the organs involved and may include respiratory insufficiency, pulmonary hypertension, heart failure, sudden cardiac death, pulmonary aspergilloma, iris adhesions (leading to glaucoma, cataract, loss of vision), nephrocalcinosis, nephrolithiasis, renal failure, diabetes insipidus, hypothyroidism, and adrenal insufficiency. Close evaluation for adverse effects related to chronic corticosteroid and immunosuppressive therapy is also warranted (see Osteoporosis).