Description

• Sarcoidosis is a noninfectious, multisystem, granulomatous disease of unknown cause, affecting young and middle-aged adults.
  • Frequently presents with bilateral hilar adenopathy, pulmonary infiltrates, ocular or skin lesions
  • In ~50% of cases, it is diagnosed in asymptomatic patients with abnormal chest x-rays (CXRs).
  • Almost any organ may be involved.
• System(s) affected: primarily pulmonary but also cardiovascular, gastrointestinal, hematologic, endocrine, renal, neurologic, dermatologic, ophthalmologic, musculoskeletal
• Synonym(s): Löfgren syndrome (erythema nodosum [EN], hilar adenopathy, fever, arthralgias); Heerfordt syndrome (uveitis, parotid enlargement, facial palsy, fever); Besnier-Boeck disease; Boeck sarcoid; Scheuermann disease (1),(2)

Epidemiology

Incidence
Estimated 6/100 person-years (1)

Prevalence

• Estimated 10 to 20/100,000 persons
• 11/100,000 annual incidence rate for women (2)
• Usually occurs in younger persons, with the peak age of incidence for women 50 to 69 years and for men 40 to 59 years. Rare in children

Etiology and Pathophysiology

• Despite extensive research, etiology unknown. Thought to be due to exaggerated cell-mediated immune response to unknown antigen(s)
• In the lungs, the initial lesion is CD4+ T-cell alveolitis, causing noncaseating granulomata, which may resolve or may undergo fibrosis. “Immune paradox” with affected organs showing an intense immune response and yet anergy exists elsewhere

Genetics

• Reports of familial clustering, with genetic linkage to a section within MHC on short arm of chromosome 6
• Although worldwide in distribution, increased prevalence in Scandinavians, Japanese, Black Americans, and women
• In Northern Europe, 5 to 40 cases per 100,000 persons. In Black Americans, 35 cases per 100,000 persons; in Caucasian Americans, 11 cases per 100,000 persons (1)

Risk Factors

Exact etiology and pathogenesis remain unknown.

History

• Patients may be asymptomatic.
• Patients may have nonspecific complaints, such as the following:
  • Nonproductive cough or shortness of breath
  • Fever or night sweats
  • Weight loss
  • General fatigue
  • Eye pain
  • Chest pain/palpitations
  • Skin lesions
  • Polyarthritis
  • Encephalopathy, seizures, hydrocephalus (rare)
  • Patients >70 years old more likely to have systemic symptoms

Physical Exam

• Many patients have a normal physical exam.
• Lungs may reveal wheezing/fine interstitial crackles
• ~30% of patients have extrapulmonary manifestations, including the following:
  • Uveitis or other eye findings: conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema
  • Cranial nerve palsies
  • Salivary gland swelling or lymphadenopathy
  • Arrhythmias
  • Hepatosplenomegaly
  • Polyarthritis
  • Rashes
    • Maculopapular of nares, eyelids, forehead, base of neck at hairline, and previous trauma sites
    • Waxy nodular of face, trunk, and extensor surfaces of extremities
    • Plaques (lupus pernio) of nose, cheeks, chin, and ears
    • EN (component of Löfgren syndrome)

Differential Diagnosis

• Sarcoidosis is a diagnosis of exclusion.
• Infectious granulomatous disease, such as tuberculosis and fungal infections
• Hypersensitivity pneumonitis
• Lymphoma or other malignancies
• Berylliosis

Diagnostic Tests & Interpretation

No definitive test for diagnosis, but diagnosis is suggested by the following:

• Clinical and radiographic manifestations
• Exclusion of other diagnoses
• Histopathologic detection of noncaseating granulomas

Initial Tests (lab, imaging)

• CBC: anemia/leukopenia ± eosinophilia
• Hypergammaglobulinemia
• Abnormal liver function and increased alkaline phosphatase with hepatic involvement.
• Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent.
• Serum ACE elevated in >75% of patients but is not diagnostic or exclusionary
  • Drugs may alter lab results: Prednisone will lower serum ACE and normalize gallium scan. ACE inhibitors will lower serum ACE level.
  • Disorders may alter lab results: Hyperthyroidism, diabetes, tuberculosis, other cancers may also increase serum ACE level.
• CXR or CT scan may reveal granulomas/hilar adenopathy. CXRs are staged using Scadding classification.
  • Stage 0 = normal
  • Stage 1 = bilateral hilar adenopathy alone
  • Stage 2 = bilateral hilar adenopathy + parenchymal infiltrates (primarily upper lobes)
  • Stage 3 = parenchymal infiltrates with shrinking hilar adenopathy
  • Stage 4 = parenchymal infiltrates with volume loss, bronchiectasis, calcification, or cyst formation
• High-resolution chest CT scan may reveal peribronchial disease.
• Positron emission tomography (PET) scan can indicate areas of disease activity in lungs, lymph nodes, and other areas of the body but does not differentiate between malignancy and sarcoidosis. Cardiac PET scan may detect cardiac sarcoidosis (1)[C].
• Serum amyloid A and adenosine deaminase has been found to be elevated with sarcoidosis but are not clinically used due to low sensitivity and specificity.

Diagnostic Procedures/Other

• Pulmonary function tests (PFTs) may reveal restrictive pattern with decreased carbon monoxide diffusing capacity (DLCO).
• In active disease, bronchoalveolar lavage fluid has an increased CD4-to-CD8 ratio. Ongoing research on whether the presence of D-dimer in BAL supports diagnosis of sarcoidosis.
• Ophthalmologic examination may reveal uveitis, retinal vasculitis, or conjunctivitis.
• ECG
• Tuberculin skin test
• Biopsy of lesions should reveal noncaseating granulomas.
• If lungs are affected, bronchoscopy with biopsy of central and peripheral airways is helpful. Endobronchial US (EBUS)–guided transbronchial needle aspiration may have a better diagnostic yield.
• Kveim test (ongoing research): Suspension of sterilized splenic cells from a patient with sarcoidosis is injected in an intradermal skin test to evoke a sarcoid granulomatous response over 3 weeks, similar to a tuberculin skin test.

Test Interpretation
Noncaseating epithelioid granulomas without evidence of fungal/mycobacterial infection

Medication

Systemic therapy is indicated for hypercalcemia or cardiac, neurologic, or eye disease. Most patients with pulmonary sarcoidosis do not require treatment with medications as many are asymptomatic or have a spontaneous remission.

First Line

• No FDA-approved treatment for sarcoidosis.
• Systemic corticosteroids in the symptomatic individual or with worsening lung function or radiographic findings
  • Optimal dose of glucocorticoids is not known. Prior to initiating glucocorticoids, must exclude tuberculosis.
  • Usually prednisone, 0.3 to 0.6 mg/kg ideal body weight (20 to 40 mg/day) for 4 to 6 weeks
  • If stable, taper by 5 mg/week to 10 to 20 mg/day over the next 6 weeks.
  • If no relapse, 10 to 20 mg/day for 8 to 12 months. Relapse is common.
  • Higher doses (80 to 100 mg/day) may be warranted in patients with acute respiratory failure and cardiac, neurologic, or ocular disease.
• In patients with skin disease, topical steroids may be effective.
• Inhaled steroids (budesonide 800 to 1,600 μg BID) may be of some clinical benefit in early disease with mild pulmonary symptoms.
  • Contraindications and significant possible interactions: Refer to the manufacturer’s profile of each drug (1),(3).

Second Line

• All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection. Prior to utilizing these medications, assess for steroid compliance, comorbid disease, or other complicating factors contributing to steroid failure. Referral to specialist is recommended.
• Methotrexate: initially 7.5 mg/week, increasing gradually to 10 to 15 mg/week. Cannot be used with underlying liver disease
• Azathioprine: generally a supplement to prednisone in an attempt to lower steroid doses
• Use of immunosuppressants, such as methotrexate or azathioprine, will require regular monitoring of CBC and LFTs.
• Antimalarial agents have been trialed without clear benefit, such as chloroquine or hydroxychloroquine.
• Tumor necrosis factor antagonists, such as infliximab, have been useful in refractory cases (1).

Issues For Referral

May be followed by a pulmonologist, with referrals to other specialists as dictated by involvement of other organ systems; if requiring a second-line therapy, should be followed by a specialist.

Surgery/Other Procedures

Lung transplantation in severe, refractory cases; long-term outcomes are unknown.

Follow-up Recommendations

There is limited data on indications for the specific tests and optimal frequency of monitoring of disease activity. Suggestions follow.

Patient Monitoring

• Patients on prednisone for symptoms should be seen q1–2mo while on therapy.
• Patients not requiring therapy should be seen q3mo for at least the first 2 years after diagnosis, obtaining a history and physical exam, laboratory testing tailored to sites of disease activity, PFTs, and ambulatory pulse oximetry.
• If active disease
  • Every 6 to 12 months, obtain ophthalmologic exam if on hydroxychloroquine.
  • Annually, CBC, creatinine, calcium, LFTs, ECG, 25-hydroxy vitamin D and 1,25 dihydroxyvitamin D, CXR, ophthalmologic examination
• Other testing per individual patient’s symptoms, including HRCT, echocardiogram, Holter monitoring, urinalysis (UA), thyroid-stimulating hormone (TSH), bone density, MRI of brain
• The serum ACE level is used by some physicians to follow the disease activity. In patients with an initially elevated ACE level, it should fall toward normal while on the therapy or when the disease resolves.
• If inactive disease, follow annually with history and physical exam, PFTs, ambulatory pulse oximetry, CBC, creatinine, calcium, liver enzymes, 1,25 dihydroxy vitamin D, ECG, and ophthalmologic exam.

Patient Education

• The American Lung Association: https://www.lung.org/lung-health-diseases/lung-disease-lookup/sarcoidosis
• Sarcoidosis by MedlinePlus: www.nlm.nih.gov/medlineplus/sarcoidosis.html

Prognosis

• 50% of patients will have spontaneous resolution within 2 years.
• 25% of patients will have significant fibrosis, but no further worsening of the disease after 2 years.
• 25% of patients (higher in some populations, including Black Americans) will have chronic disease.
• Patients on corticosteroids for >6 months have a greater chance of having chronic disease.
• Overall death rate: <5%

Complications

• Patients may develop significant respiratory involvement, including cor pulmonale. Pulmonary hemorrhage from infection with aspergillosis in the damaged lung is possible.
• Other organs, especially the heart (congestive heart failure, arrhythmias), eyes (rarely blindness), and CNS, can be involved with serious consequences.

ICD-10

• D86.0 Sarcoidosis of lung
• D86.1 Sarcoidosis of lymph nodes
• D86.2 Sarcoidosis of lung with sarcoidosis of lymph nodes
• D86.3 Sarcoidosis of skin
• D86.81 Sarcoid meningitis
• D86.82 Multiple cranial nerve palsies in sarcoidosis
• D86.83 Sarcoid iridocyclitis
• D86.84 Sarcoid pyelonephritis
• D86.85 Sarcoid myocarditis
• D86.86 Sarcoid arthropathy
• D86.87 Sarcoid myositis
• D86.89 Sarcoidosis of other sites
• D86.9 Sarcoidosis, unspecified

ICD-9

• 135 Sarcoidosis
• 517.8 Lung involvement in other diseases classified elsewhere
• 713.7 Other general diseases with articular involvement

SNOMED

• 193251003 Sarcoid myopathy
• 234526006 Ocular sarcoidosis (disorder)
• 238675007 Sarcoidosis-induced erythema nodosum (disorder)
• 24369008 Pulmonary sarcoidosis (disorder)
• 31541009 Sarcoidosis (disorder)
• 361198004 Sarcoid arthritis (disorder)
• 55941000 cutaneous sarcoidosis (disorder)
• 64757003 lymph node sarcoidosis (disorder)
• 75403004 Cardiac sarcoidosis