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Sarcoidosis
Donnah Mathews, MD, FACP
image BASICS
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 syndrome (uveitis, parotid enlargement, facial palsy, fever); Besnier-Boeck disease; Boeck sarcoid; Schaumann disease (1,2,3)[C]
EPIDEMIOLOGY
Incidence
Estimated 6/100 person-years (4)
Prevalence
  • Estimated 10 to 20/100,000 persons
  • <15% of patients with active disease >60 years of age
  • Rare in children (4)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Despite extensive research, mostly 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 (1,5)[C].
Genetics
  • Reports of familial clustering, with genetic linkage to a section within MHC on short arm of chromosome 6
  • 3 to 4 times more common in African Americans
  • Although worldwide in distribution, increased prevalence in Scandinavians, Japanese, African Americans, and women (4)
RISK FACTORS
Exact etiology and pathogenesis remain unknown.
GENERAL PREVENTION
None
COMMONLY ASSOCIATED CONDITIONS
None
image DIAGNOSIS
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 (2), which may include the following:
    • Uveitis
    • Other eye findings: conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema
    • Cranial nerve palsies
    • Salivary gland swelling
    • Lymphadenopathy
    • Arrhythmias
    • Hepatosplenomegaly
    • Polyarthritis
    • Rashes (6)[A]
      • 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
      • Erythema nodosum (component of Löfgren syndrome)
      • Atypical lesions
DIFFERENTIAL DIAGNOSIS
  • Infectious granulomatous disease, such as tuberculosis and fungal infections
  • Hypersensitivity pneumonitis
  • Lymphoma
  • Other malignancies associated with lymphadenopathy
  • Berylliosis (1)[A]
DIAGNOSTIC TEST & 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 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.
    • 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 (7)
  • 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 (8)[B].
Diagnostic Procedures/Other
  • 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 US (EBUS)-guided transbronchial needle aspiration may potentially 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
image TREATMENT
  • Many patients undergo spontaneous remission. It is difficult to assess disease activity and severity, however, making it challenging to develop guidelines.
  • No treatment may be necessary in asymptomatic individuals, but treatment may be needed for specific indications, such as cardiac, CNS, renal, or ocular involvement.
  • No treatment is indicated for asymptomatic patients with stage I-III radiographic changes with normal/mildly abnormal lung function, although close follow-up is recommended.
  • P.939

  • Treatment of pulmonary and skin manifestations is done on the basis of impairment. The symptoms that necessitate systemic therapy remain controversial.
    • Worsening pulmonary symptoms
    • Deteriorating lung function
    • Worsening radiographic findings
MEDICATION
Systemic therapy is clearly indicated for hypercalcemia, cardiac disease, neurologic disease, and eye disease not responding to topical therapy. Most patients with pulmonary sarcoidosis do not require treatment with medications, as many are asymptomatic or have a spontaneous remission.
First Line
  • Systemic corticosteroids in the symptomatic individual (dyspnea, cough, hemoptysis) or in the individual with worsening lung function or radiographic findings
    • The optimal dose of glucocorticoids is not known.
    • Usually prednisone initially, 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, cardiac, neurologic, or ocular disease.
  • In patients with skin disease, topical steroids may be effective.
  • Inhaled steroids (budesonide 800 to 1,600 &mgr;g BID) 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.
Second Line
  • All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection.
  • Methotrexate: initially 7.5 mg/week, increasing gradually to 10 to 15 mg/week
  • Azathioprine: 50 to 100 mg/day
  • Leflunomide: 20 mg/day
  • 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 (9)[C].
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; longterm outcomes are unknown.
COMPLEMENTARY & ALTERNATIVE MEDICINE
None known to be effective
image ONGOING CARE
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 regularly (q3mo) for at least the first 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 to 12 months, obtain ophthalmologic exam if on hydroxychloroquine.
    • Annually, CBC, creatinine, calcium, LFTs, ECG, 25-hydroxy vitamin D and 1,25 dihydroxy vitamin 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, EKG, ophthalmologic exam.
DIET
No special diet
PATIENT EDUCATION
  • The American Lung Association at www.lungusa.org/lung-disease/sarcoidosis/?gclid=CPX6zuipm6MCFQxW2godISFepQ
  • Sarcoidosis by Medline Plus at 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%
REFERENCES
1. Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med. 2011;183(5):573-581.
2. Holmes J, Lazarus A. Sarcoidosis: extrathoracic manifestations. Dis Mon. 2009;55(11):675-692.
3. King CS, Kelly W. Treatment of sarcoidosis. Dis Mon. 2009;55(11):704-718.
4. Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001;164(11):2085-2091.
5. Dempsey OJ, Paterson EW, Kerr KM, et al. Sarcoidosis. BMJ. 2009;339:b3206.
6. Lodha S, Sanchez M, Prystowsky S. Sarcoidosis of the skin: a review for the pulmonologist. Chest. 2009;136(2):583-596.
7. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med. 1999;160(2): 736-755.
8. Tremblay A, Stather DR, Maceachern P, et al. A randomized controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis. Chest. 2009;136(2):340-346.
9. Iannuzzi MC, Fontana JR. Sarcoidosis: clinical presentation, immunopathogenesis, and therapeutics. JAMA. 2011;305(4):391-399.
Additional Reading
&NA;
  • Hoang DQ, Nguyen ET. Sarcoidosis. Semin Roentgenol. 2010;45(1):36-42.
  • Polychronopoulos VS, Prakash UB. Airway involvement in sarcoidosis. Chest. 2009;136(5):1371-1380.
Codes
&NA;
ICD10
  • D86.9 Sarcoidosis, unspecified
  • D86.0 Sarcoidosis of lung
  • D86.86 Sarcoid arthropathy
Clinical Pearls
&NA;
  • Sarcoidosis is a noninfectious, multisystem granulomatous disease of unknown cause, typically affecting young and middle-aged adults.
  • Any organ can be affected.
  • Diagnosis is based on clinical findings, exclusion of other disorders, and pathologic detection of noncaseating granulomas.
  • Most patients do not need systemic treatment and the disease resolves spontaneously; a few will have life-threatening progressive organ dysfunction.