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A. Characteristicsnavigator

  1. Syndrome Consists of:
    1. Bilateral Hilar Lymphadenopathy
    2. Pulmonary Infiltrates
    3. Skin or Eye Lesions
    4. Less common: central nervous system (CNS), liver, heart and/or salivary gland involvement
  2. Most commonly a disease of the lungs
    1. Early disease primarily affects hilar lymph nodes
    2. Progressive disease affects nodes and lung interstitium
    3. Non-pulmonary involvement may occur
  3. Patients
    1. Most patients present age 20-40; nearly always present prior to age 50
    2. Females 2:1 Males
    3. Highly variable depending on geography
    4. Affects ~20 persons per 100,000 in USA
    5. Annual incidence is 35 per 100,000 for blacks and 11 per 100,000 for whites in USA
    6. Thus, ~80% of patients in USA are non-white
    7. Highest incidence of sarcoidosis in northern Europena countries: 5-40/100,000/year

B. Pathology and Etiology navigator

  1. Non-caseating multisystem granulomatous disease
    1. Non-caseating appears non-"cheese-like" with minimal or no necrosis
    2. Other non-caseating granulomatous diseases: Crohn's, Primary Biliary Cirrhosis
    3. Note that many infectious agents are known to stimulate granulomatous reactions
    4. Unclear which pathogen(s), if any, are involved in sarcoidosis
  2. Sarcoidosis is believed to be an autoimmune disease initiated by a pathogen [1,4]
    1. Mycobacterial DNA sequences were found in some biopsy specimens
    2. Proprionobacterium acnes or P. granulosum DNA was found in all Japanese sarcoid specimens [4]
    3. Human Herpesvirus 8 (HHV 8) DNA has been found in many samples
    4. Role of HHV 8 is not understood
    5. Overall, no consistent association with any specific etiologic agent
  3. Weak Major Histocompatibility (HLA) Association [3]
    1. Association with MHC locus on human chromosome 6
    2. Susceptibility increased with HLA DR 11,12,14,15,17
    3. Protective alleles HLA DR1, 4, and possibly DQ*0202
    4. Some association between TNF alpha locus (-308 promoter polymorphism) and Lofgren's
    5. Increased risk of disease in twins
    6. Manifestations of disease differ in twins except for ocular and hepatic manifestations
  4. CD4+ T helper cells play prominant initial role [1]
    1. Granulmoma formation typically requires Th1 type cytokines
    2. Interleukin 12, 15, 18, TNFa, MIP and MCP-1 play early initiating role
    3. These stimulate production of IFN gamma and IL2
    4. CD4 stimulation of activated CD8+ cells occurs
    5. Th2 cells are also expanded, and can enhance granuloma and fibrosis formation
    6. Often have a reversal in serum CD4:CD8 T cell ratio, from normal of 2 to ~0.8
    7. Expansion of CD4+CD25(bright) regulatory T cells may account for observed anergy
  5. CD1d Restricted NK T Cells [5]
    1. Immunoregulatory group of T cells
    2. Also called Va24 invariant NKT cells
    3. CD1d restricted T cells express an invariant TCR which recognizes antigen+CD1d molecule
    4. These cells may regulate Th1 helper cells
    5. Deficiency of NKT cells found in patients with sarcoidosis (but not Lofgren's Syndrome)
  6. As granulomas mature, CD8+ T cells and B cells are found
  7. Macrophages
    1. Aggregate to form epitheliod and multinucleated giant cells (granulomas)
    2. Alveolar macrophages are highly activated (likely by T cell derived cytokines)

C. Symptoms and Signs [6]navigator

  1. Most common presentation is discovery with chest radiography without symptoms
  2. Pulmonary
    1. Shortness of breath (SOB) and cough are most common complaints
    2. Chest pain - may be pleuritic
    3. Sputum production may also occur
    4. Hemoptysis - less common with sarcoidosis than other destructive lung diseases
    5. Mycetoma (fungal infection) - often in setting of chronic immunosuppression
    6. Pulmonary Fibrosis - long term
    7. Cardiopulmonary: Right Heart Failure, Cor Pulmonale (usually with pulmonary fibrosis)
  3. Systemic Symptoms
    1. Found at presentation in ~30% of patients [7]
    2. Fatigue, malaise may be most prominent
    3. Fever [8]
    4. Weight loss
    5. Lymphadenopathy (mimics lymphoma) [9]
  4. Skin Lesions [1]
    1. Found in ~30% of cases
    2. Variable lesions, may be single or multiple
    3. Commonly involve nape of neck and uper back, extremities, and trunk
    4. Macules, papules and/or plaques can occur
    5. Indurated bumpy (papular) violaceous lesions of nose, cheeks, lips, ears called lupus pernio
    6. Lupus pernio more common in women than man, and may erode underlying carilage and bone
    7. Erythema nodosum (red, nodular lesions, ~10%) - inflammation of subcutaneous fat
    8. Erythema nodosum usually lasts <3 weeks
  5. Polyarthropathy
    1. Monoarticular or oligoarticular disease, often with periarthritis, most common
    2. Occurs in ~15% of patients
    3. Syndromic: Lofgren's Syndrome
  6. Lofgren's Syndrome [10]
    1. Sarcoidosis causing ankle arthritis / periarthritis
    2. Hilar lymphadenopathy
    3. Erythema nodosum
  7. Liver Disease - granulomatous hepatitis [6]
  8. Ocular Disease [1]
    1. Uveitis - most commonly anterior uveitis with red eye (iritis)
    2. Anterior or posterior uveitis (or both) may occur
    3. Granulomatous conjunctivitis, scleritis - biopsy may be performed
    4. Cranial Nerve palsy affecting vision
    5. CNS lesions (mass) affecting visual nerve tracts
  9. Neurologic Manifestations (~5%) [11]
    1. Headache
    2. Cranial nerve lesions - single or multiple nerves are commonly affected
    3. Aseptic Meningitis
    4. Hydrocephalus
    5. Hypothalamic and/or Pituitary Disease - neuroendocrine
    6. Multifocal white matter changes
    7. Spinal cord lesions [9,12]
    8. Peripheral neuropathies - may be due to spinal cord lesions
    9. Myopathy - uncommon
    10. CNS mass lesions - uncommon
  10. Cardiac Disease [13]
    1. Conduction Abnormalities - AV block, bradycardias, or ventricular arrhythymias [14]
    2. Dilative Cardiomyopathy - probably due to sarcoid myocarditis
    3. Infiltrative (Restrictive) Cardiomyopathy
    4. Gadolinium-Magnetic Resonance Imaging (Gad-MRI) for active cardiac inflammation [13]
    5. Endomyocardial biopsy is required to confirm the diagnosis

D. Staging of Lung Lesionsnavigator

  1. Stage 0: No evidence of pulmonary disease on chest radiograph (~25%)
  2. Stage I: Perihilar bilateral lymph node (LN) enlargement (~30%)
  3. Stage II: LN and lung parenchyma (~30%)
  4. Stage III: Lung parenchyma only without perihilar adenopathy (~10%)
  5. Stage IV: Complete lung destruction + fibrosis (End Stage Lung Disease, ~5% of patients)
  6. Note that chest radiographic patterns do not reflect chronology of disease

E. Diagnosisnavigator

  1. Biopsy of lesions are generally required for definitive diagnosis
    1. Skin lesions are easiest to biopsy
    2. Bronchoscopy or laparoscopic lung biopsy may be required for obtaining lung tissue
    3. FDG-PET imaging of lungs may be useful for targeting diagnostic biopsy
    4. Occasionally, conjunctivial biopsy will show granulomas
    5. Finding non-caseating granulomas increased likelihood of sarcoidosis
    6. Finding caseating granulomas rules out sarcoidosis
    7. Other causes of granulomas, particularly tuberculosis, should be ruled out
  2. Evaluation of Critical Organs
    1. Complete neurological exam
    2. Electrocardiogram (ECG)
    3. Complete ophthalmological examination
  3. Pulmonary
    1. Usually asymptomatic; findings on physical exam correspond to stage of disease
    2. Chest Radiographic Findings - as described above
    3. Chest computed tomography (CT) is generally not helpful in diagnosis
    4. Pulmonary function tests (PFT): all patients, usually restrictive pattern, reduced DLCO
    5. Reduction in DLCO is generally cuase for concern and often warrants treatment
    6. Bronchoalveolar lymphocytosis with CD4:CD8 ratio >3.5
    7. Right heart catheterization should follow echocardiographic evidence of pulmonary hypertension
  4. Ophthalmological Examinations
    1. Granulomatous conjunctivitis, scleritis - biopsy may be performed
    2. Anterior (or less commonly posterior) uveitis
    3. Examinations should be performed every 6 months to 2 years
  5. Neurologic Involvement
    1. Complete thorough neurologic exam should be done
    2. Gadolinium enhanced MRI to assess neurologic involvement
    3. Cerebrospinal fluid (CSF) may show leukocytosis (mainly mononuclear cells) [11]
  6. Cardiac Invovlement
    1. ECG in all patients
    2. Holter monitoring if arrhythmia suspected; electrophysiological study if indicated
    3. Echocardiography to assess anatomy, right ventricular function
    4. FDG-PET may be useful for assessing cardiac involvement if suspected
  7. Liver
    1. Liver function tests should be performed
    2. Increase in alkaline phosphatase ± increased bilirubin
    3. Gamma-glutamyl transferase or 5-nucleotidase can help confirm
    4. Transaminase increases are not typically seen
    5. Liver biopsy often less helpful because granulomatous hepatitis has large differential
  8. Laboratory Testing
    1. No sensitive or specific definitive tests for sarcoidosis are available
    2. Tissue biopsy showing noncaseating granulomas is highly suggestive (see below)
    3. ACE levels increased in ~50% of patients (non-specific; see below)
    4. Full electrolyte and renal function tests should be done with urine analysis
    5. Complete blood count
    6. Hypercalcemia may occur due to increase dihydroxyvitamin D production by granulomas
    7. Hypergammaglobulinemia ~40% of patients
    8. Abnormal blood CD4:CD8 T cell ratios are not helpful diagnostically
  9. Nuclear Medicine Scans
    1. Gallium-67 scanning is acceptable
    2. Assess for lymph node and lung uptake, as well as other areas
    3. Gallium-67 is nonspecifically taken up by liver and spleen and gut
    4. If Ga67 test is positive, can be used to follow disease activity and treatment response
  10. Tuberculin skin testing is generally recommended

F. Differential Diagnosis [6,7,9] navigator

  1. Tuberculosis
  2. Asbestosis
  3. Lymphoma
  4. Berylliosis
  5. Fungal Diseases: Coccidiomycosis, Histoplasmosis, etc.
  6. Primary Biliary Cirrhosis
  7. Silicosis
  8. Granulomatous Hepatitis
  9. Hypersensitivity Pneumonitis
  10. Bronchogenic Carcinoma
  11. Gaucher's Disease, Inflammatory Bowel Disease
  12. Leprosy
  13. Differential Diagnosis of Increased Serum ACE Levels
    1. Young persons otherwise healthy
    2. Sarcoidosis
    3. Hyperthyroidism
    4. Mycobacterial Disease: Tuberculosis, Leprosy
    5. Fungal Disease: Coccidiomycosis, Histoplasmosis
    6. Neoplastic Disease: Lymphoma, Multiple Myleloma, Histiocytosis
    7. Amyloidosis
    8. Primary Biliary Cirrhosis
    9. Whipple's Disease (Bacterial)
    10. Gaucher's Disease
  14. Tuberculosis (Miliary) Versus Sarcoidosis [7]
    1. Nonreactive PPD test: 25% of miliary TB and 95% of sarcoidosis
    2. Noncaseating Granulomas: 20% of miliary TB and 100% of sarcoidosis
    3. Normal ACE Level: 95% of miliary TB and 20-50% of sarcoidosis

G. Therapy [1] navigator

  1. Asymptomatic patients should generally not be treated
  2. Indications for Treatment [2,6]
    1. Patients with dyuspnea plus FEV1 or FVC <70% should receive oral glucocorticoids
    2. Symptomatic lung involvement with cough or wheezing - inhaled glucocorticoid
    3. Deforming skin lesions usally chronic and require prolonged therapy
    4. CNS sarcoid (independent of symptoms) - 500-1000mg iv methylprednisolone x 3 days
    5. Uveitis should be treated - topical and/or systemic glucocorticoids
    6. Liver disease is usually self-resolving and may not respond to glucocorticoids
    7. Muscle disease may respond to methotrexate
    8. Good prognosis including Lofgren syndrome may not require glucocorticoids
  3. Glucocorticoids [15]
    1. Prednisone, initially 20-40mg po qd for most patients with dyspnea or FEV1 or FVC <70%
    2. Generally taper prednisone to 5-10mg po qd after 1-2 months
    3. Most patients can be controlled <15mg prednisone qd with minimal side effects
    4. Many patients can reduce prednisone to alternating day (10-20mg po qod) or off
    5. Oral glucocorticoids clear radiographic, FVC, DLCO benefits in pulmonary sarcoid [15]
    6. Inhaled glucocorticoids may be used for progressive pulmonary dysfunction
    7. Predisone reduced or eliminated Gad-MRI enhancement in patients with cardiac sarcoid
    8. Arthritis or myositis treated with prednisone 20-40mg/day; NSAIDs for arthralgias
    9. Uveitis: anterior with topical glucocorticoid; posterior or optic neuritis with prednisone
    10. Cranial neuropathy (without other CNS) can be treated with 20-40mg/d prednisone
    11. Intracerebral disease: systemic glucocorticoids then azathioprine or hydroxychloroquine
    12. Spinal cord lesions treated with high dose methylprednisolone (see below)
    13. Cardiac disease (decreased left ventricular function): prednisone 20-40mg/day
    14. Kidney stones with hypercalciuria (hypercalcemia): prednisone 20-40mg/day
    15. Very slow taper of prednisone to reduce risk of relapse
    16. Prophylaxis for glucocorticoid associated side effects is essential
  4. Severe Disease
    1. CNS and/or severe ocular disease is usual indication for aggressive therapy
    2. High dose glucocorticoids (1000mg iv methylprednisolone qd x 3 days) with taper
    3. Cyclosporine or cyclophosphamide have been used in glucocorticoid resistant CNS disease
    4. Methotrexate (Rheumatrex®) 10-15mg/week po then adjust for responses
    5. Responses to methotrexate may take up to 6 months
    6. Infliximab (anti-tumor necrosis factor alpha antibody) may be useful in some patients
    7. CNS irradiation may also be used
    8. Lung transplantation may be required for endstage lung disease (~3% of lung transplants)
    9. Heart transplantation may be required for severe cardiac disease
  5. Glucocorticoid Sparing Agents [1]
    1. Methotrexate 7.5-20mg po q week - up to 6 months to become effective
    2. Azathioprine 2-4mg/kg po qd - less well studied than methotrexate
    3. Cyclophosphamide - 500-700mg iv initial dose, then every 2-4 weeks (adjusted dose)
    4. Cyclosporine - 25-200mg qd (adjust dose), particularly for resistant disease
    5. Infliximab (Remicade®) - 5mg/kg IV day 1, 14, then q4-8 weeks (little efficacy data)
  6. Skin Disease
    1. Lupus pernio should be treated aggressively with agents below
    2. Hydroxychloroquine (Plaquenil®) 200-400mg/d
    3. Thalidomide 100-150mg po qpm
    4. Methotrexate: 10-15mg/week
    5. Plaques and nodeuls treated with prednisone 20-40mg/day or hydroxychloroquine
    6. Topical glucocorticoids can be used for some skin lesions
    7. Erythema nodosum pain will respond to NSAIDs
  7. Prognosis [1]
    1. About 65% of patients have remission within a decade after symptoms
    2. Remission occurs in ~50% of patients within 3 years
    3. About 20% will develop significant pulmonary fibrosis over course of disease
    4. Mortality <3% over lifetime with disease
    5. Mortality is increased in women and in non-white patients
    6. Mortality also varies by geographic location

References navigator

  1. Iannuzzi MC, Rybicki BA, Teirstein AS. 2007. NEJM. 357(21):2153 abstract
  2. Weinberger SE. 2006. JAMA. 296(17):2133 (Case Discussion) abstract
  3. Baughman RP, Lower EE, du Bois RM. 2003. Lancet. 361(9363):1111 abstract
  4. Ishige I, Usui Y, Takemura T, Eishi Y. 1999. Lancet. 354(9173):120 abstract
  5. Ho LP, Urban BC, Thickett DR, et al. 2005. Lancet. 365(9464):1062 abstract
  6. Smith CC, Mandel J, Bush B. 2001. NEJM. 344(14):1079 (Clinical Problem Solving) abstract
  7. Kopelman RI, Wong JB, Pauker SG. 1999. NEJM. 341(6):435 (Case Review) abstract
  8. Mushlin SB, Drazen JM, Samuels MA, et al. 2002. NEJM. 347(17):1350 (Case Record) abstract
  9. Querfurth HW and Mark EJ. 1998. NEJM. 338(11):747 (Case Record)
  10. Bates PW and Mark EJ. 2001. NEJM. 344(6):443 (Case Record)
  11. LeCates WW. 2002. Am J Med. 113(1):70 (Case Review) abstract
  12. Gross PT and Mark EJ. 1998. NEJM. 339(21):1534 (Case Record)
  13. Shimada T, Shimada K, Sakane T, et al. 2001. Am J Med. 110(7):520 abstract
  14. Stevenson WG and Aretz HT. 2000. NEJM. 342(26):1979 (Case Record)
  15. Paramothayan S and Jones PW. 2002. JAMA. 287(10):1301 abstract