Description

• Sarcoidosis is a noninfectious, multisystem granulomatous disease of unknown cause, commonly affecting young and middle-aged adults:
  • Frequently presents with hilar adenopathy, pulmonary infiltrates, ocular and 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/Lymphatic; Endocrine; Renal; Neurologic; Dermatologic; Ophthalmologic; Musculoskeletal
• Synonym(s): Löfgren syndrome (erythema nodosum, hilar adenopathy, fever, arthralgias); Heerfordt's syndrome (uveitis, parotid enlargement, facial palsy, fever); Besnier-Boeck disease; Boeck sarcoid; Schaumann disease (1,2)[C]

Epidemiology

Incidence
Estimated 6/100 person-years

• Estimated 10–20/100,000 persons
• <15% of patients with active disease >60 years of age
• Rare in children (3)

Risk Factors

Exact etiology and pathogenesis remain unknown (3).

• Reports of familial clustering
• 3–4× more common in African Americans
• Although worldwide in distribution, there is increased prevalence in Scandinavians, Japanese, African Americans, and women (3).

General Prevention

None

Pathophysiology

• 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/undergo fibrosis.
• “Immune paradox” with affected organs showing an intense immune response and yet anergy exists elsewhere (4).

Etiology

Unknown

Commonly Associated Conditions

None

History

• Patients may be asymptomatic.
• Patients may have nonspecific complaints, such as:
  • Nonproductive cough
  • Shortness of breath
  • Fever
  • Night sweats
  • Weight loss
  • General fatigue
  • Eye pain
  • Chest pain/palpitations
  • Skin lesions
  • Polyarthritis
  • Renal calculi (4)
  • Facial droop due to Bell palsy
  • Encephalopathy, seizures, hydrocephalus (rare)
  • Patients >70 years more likely to have systemic symptoms

Physical Exam

• Many patients have a normal physical exam.
• Lungs may reveal wheezing/fine interstitial crackles in advanced disease.
• ~30% of patients have extrapulmonary manifestations (1), which may include:
  • Uveitis
  • Other eye findings: Conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema
  • Cranial nerve palsies
  • Salivary gland swelling
  • Lymphadenopathy
  • Arrhythmias
  • Hepatosplenomegaly
  • Polyarthritis
  • Rashes (5):
    • Maculopapular of nares, eyelids, forehead, base of neck at hairline, and previous trauma sites
    • Waxy nodular of face, trunk, extensor surfaces of extremities
    • Plaques (lupus pernio) of nose, cheeks, chin, ears
    • Erythema nodosum (component of Lofgren syndrome)
    • Atypical lesions

Diagnostic Tests and 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

• CBC: Anemia/Leukopenia ± eosinophilia can be seen.
• Hypergammaglobulinemia can exist.
• LFTs: Abnormal liver function and increased alkaline phosphatase can be encountered with hepatic involvement.
• Calcium: Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent.
• Serum ACE inhibitors 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 and diabetes will increase serum ACE level.

• CXR or CT scan may reveal granulomas/hilar adenopathy. Routine CXRs are staged using Scadding classification (6):
  • Stage 0 = Normal
  • Stage 1 = Bilateral hilar adenopathy alone
  • Stage 2 = Bilateral hilar adenopathy + parenchymal infiltrates
  • Stage 3 = Parenchymal infiltrates alone (primarily upper lobes)
  • Stage 4 = Pulmonary fibrosis
• Chest CT scan may enhance appreciation of lymph nodes.
• High-resolution chest CT scan may reveal peribronchial disease.
• Gallium scan will be positive in areas of acute disease/inflammation, but is not specific.
• 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

• Pulmonary function tests (PFTs) may reveal restrictive pattern with decreased carbon monoxide diffusing capacity (DLCO).
• Characteristically in active disease, bronchioalveolar lavage fluid has an increased CD4-to-CD8 ratio.
• 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 ultrasound (EBUS)-guided transbronchial needle aspiration may potentially have a better diagnostic yield (7)[B].

ALERT
If signs indicate Löfgren syndrome, it is not necessary to perform a biopsy because prognosis is good with observation alone, and biopsy would not change management.

Pathological Findings
Noncaseating epithelioid granulomas without evidence of fungal/mycobacterial infection

Differential Diagnosis

• Infectious granulomatous disease, such as tuberculosis and fungal infections
• Hypersensitivity pneumonitis
• Lymphoma
• Other malignancies associated with lymphadenopathy
• Berylliosis

Medication (Drugs)

Systemic therapy is clearly indicated for hypercalcemia, cardiac disease, neurologic disease, and eye disease not responding to topical therapy.

• Systemic corticosteroids in the symptomatic individual:
  • The optimal dose of glucocorticoids is not known.
  • Usually prednisone initially, 0.3–0.6 mg/kg ideal body weight (20–40 mg/d) × 4–6 weeks.
  • If stable, taper by 5 mg/wk to 10–20 mg/d over the next 6 weeks.
  • If no relapse, 10–20 mg/d × 8–12 months
  • Relapse is common.
  • Higher doses may be warranted in patients with cardiac, neurologic, or ocular disease.
• In patients with skin disease, topical steroids may be effective.
• Inhaled steroids (budesonide 800–1,600 mcg b.i.d.) may be of some clinical benefit in early disease with mild pulmonary symptoms:
  • Contraindications: Patients with known problems with corticosteroids
  • Precautions: Careful monitoring in patients with diabetes mellitus and/or hypertension
  • Significant possible interactions: Refer to the manufacturer’s profile of each drug.

• All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection.
• Methotrexate: initially 7.5 mg/wk, increasing gradually to 10–15 mg/wk
• Azathioprine: 50–100 mg/d
• Leflunomide: 20 mg/d
• Use of immunosuppressants, such as methotrexate or azathioprine, will require regular monitoring of CBC and LFTs.
• Antimalarial agents, such as chloroquine or hydroxychloroquine
• Tumor necrosis factor antagonists, such as Infliximab, have been useful in refractory cases.

Additional Treatment

Issue for Referral
May be followed by a pulmonologist, with referrals to other specialists as dictated by involvement of other organ systems

Complementary and Alternative Therapies

None known to be effective

Surgery/Other Procedures

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

Follow-Up Recommendations

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

• Patients on prednisone for symptoms should be seen every 1–2 months while on therapy.
• Patients not requiring therapy should be seen regularly (every 3 months) for at least the 1st 2 years after diagnosis, obtaining a thorough history and physical exam, laboratory testing tailored to sites of disease activity, PFTs, and ambulatory pulse oximetry.
• If active disease:
  • Every 6 months, obtain ophthalmologic exam if on hydroxychloroquine.
  • Annually, CBC, creatinine, calcium, LFTs, ECG, 25-hydroxy vitamin D and 1,25 dihydroxy vitamin D, CXR, and ophthalmologic exam if not on hydroxychloroquine
• 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, EKG, ophthalmologic exam.

Diet

No special diet

Patient Education

• The American Lung Association at http://www.lungusa.org/lung-disease/sarcoidosis/...
• Sarcoidosis by Medline Plus at http://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 African 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. Cardiac, ocular, and CNS involvement usually manifests early on in patients with these complications of the disease.

ICD-9

135 Sarcoidosis

ICD-10

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

SNOMED

• 31541009 Sarcoidosis (disorder)
• 24369008 Pulmonary sarcoidosis (disorder)
• 234526006 Ocular sarcoidosis (disorder)
• 55941000 cutaneous sarcoidosis (disorder)
• 193251003 Sarcoid myopathy
• 64757003 lymph node sarcoidosis (disorder)
• 75403004 Cardiac sarcoidosis