Description

• Sarcoidosis is a noninfectious, multisystem, granulomatous disease of unknown cause.
  • 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).
• 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); lupus pernio; Besnier-Boeck disease; Boeck sarcoid; Scheuermann disease (1)

Epidemiology

Incidence
Estimated 6/100 person-years

Prevalence

• Estimated 10 to 20 cases per 100,000 persons, although recent evidence suggests it could be more prevalent
• 11/100,000 annual incidence rate for women (1)
• Usually occurs in younger persons, with the peak age of incidence for women aged 50 to 69 years and for men aged 40 to 59 years; rare in children

Etiology and Pathophysiology

Despite extensive research, etiology is unknown; thought to be due to exaggerated cell-mediated immune response to unknown antigen(s)

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

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/arrhythmias
  • Skin lesions
  • Polyarthritis
  • Encephalopathy, seizures, hydrocephalus (rare)
  • Patients >70 years old are 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, retinitis, or other eye findings: conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema
  • Cranial nerve palsies, especially 7th nerve
  • 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

• Infectious granulomatous disease, such as tuberculosis, nontuberculous mycobacteria, and fungal infections
  • Bacterial pneumonia, such as Brucella, Tropheryma whipplei, Francisella tularensis, Bartonella henselae, Coxiella burnetii
  • Viral, such as herpes zoster
  • Parasitic, such as Toxoplasma gondii, schistosomiasis, leishmaniasis
• Lymphoma
• Autoimmune such as vasculitides, Langerhans cell histocytosis, inflammatory bowel disease
• Hypersensitivity pneumonitis

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 (not always required)

Initial Tests (lab, imaging)

• Screening for extrapulmonary disease:
  • CBC, HIV
  • Creatinine (renal sarcoidosis)
  • Alkaline phosphatase (hepatic sarcoidosis) +/− transaminase testing
  • Calcium
  • 25- and 1,25-OH vitamin D levels to determine if replacement needed
• Baseline eye exam
• Baseline ECG
• Serum ACE elevated in >75% of patients but is not diagnostic or exclusionary and testing not recommended
• 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.
• For patients with extracardiac disease, cardiac MRI is recommended over cardiac PET scan. If cardiac MRI is not available, dedicated PET scan may be used.
• For patients with suspected pulmonary hypertension, transthoracic echocardiogram is suggested and may lead to right heart catheterization if indicated.

Follow-Up Tests & Special Considerations
Patients with asymptomatic bilateral hilar lymphadenopathy

• If high clinical suspicion for sarcoidosis (i.e., Lofgren syndrome, lupus pernio, Heerfordt syndrome), biopsy not needed
• If tissue sampling determined to be necessary, endobronchial ultrasound (EBUS)-guided lymph node sampling preferred over mediastinoscopy

Diagnostic Procedures/Other

• Pulmonary function tests (PFTs) may reveal restrictive pattern with decreased carbon monoxide diffusing capacity (DLCO).
• 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. EBUS–guided transbronchial needle aspiration may have a better diagnostic yield.

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

Medication

Systemic therapy is indicated for hypercalcemia or cardiac, neurologic, or eye disease.

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 (2).

Second Line

• All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection. Prior to using these medications, assess for adherence to steroid therapy, comorbid disease, or other complicating factors contributing to steroid failure. Referral to specialist is recommended.
• Alternative immunosuppressants:
  • Methotrexate: initially 7.5 mg/week, increasing gradually to 10 to 15 mg/week; cannot be used with underlying liver disease
  • Other immunosuppressants include azathioprine, leflunomide, or mycophenolate.
  • If tolerated, continue low dose prednisone (<20 mg/day)
  • Use of immunosuppressants requires 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.

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

Surgery/Other Procedures

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

Follow-up Recommendations

Patient Monitoring

• Approximately 23% of patients with sarcoidosis will develop a new disease manifestation within 3 years of baseline evaluation.
• Monitor serum calcium, creatinine, and alkaline phosphatase annually.
• Patients on prednisone for symptoms should be seen every 1 to 2 months while on therapy.
• Patients not requiring therapy should be seen every 3 months 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 on hydroxychloroquine, obtain ophthalmologic exam every 6 to 12 months
• Other testing per individual patient’s symptoms, including HRCT, echocardiogram, Holter monitoring, urinalysis (UA), thyroid-stimulating hormone (TSH), bone density, MRI of brain, ophthalmologic exam

Patient Education

• American Lung Association: https://www.lung.org/lung-health-diseases/lung-disease-lookup/sarcoidosis
• MedlinePlus: https://medlineplus.gov/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%; however, subset analysis suggests that Black American women have a higher mortality.

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 Sarcoidosis
• 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
• D86.8 Sarcoidosis of other sites
• 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

SNOMED

• 111936002 Cerebral sarcoidosis
• 111937006 Sarcoidosis, nodular type
• 17363001 Splenic sarcoidosis
• 192673008 Sarcoid meningitis
• 203042003 Myositis in sarcoidosis
• 232368009 Nasal sarcoidosis
• 232458003 Laryngeal sarcoidosis
• 234526006 Ocular sarcoidosis
• 234528007 Nasopharyngeal sarcoidosis
• 238679001 Sarcoidosis in scar
• 24369008 Pulmonary sarcoidosis
• 31541009 Sarcoidosis
• 402369000 Atrophic sarcoidosis
• 402370004 Ulcerative sarcoidosis
• 55941000 Cutaneous sarcoidosis
• 64757003 Lymph node sarcoidosis
• 735433009 Sarcoidosis of digestive system
• 75403004 Cardiac sarcoidosis
• 80941006 Subcutaneous sarcoidosis