Sarcoidosis

Aka: Sarcoidosis, Lupus Pernio, Lofgren's Syndrome, Lofgren Syndrome, Lofgrens syndrome, Heerfordt Syndrome, Uveoparotid Fever

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II. Epidemiology

  1. Affects young adults most commonly ages 20 to 40 years old
    1. Second peak onset 50 to 65 years old
    2. Rarely affects children
  2. Prevalence in United States
    1. Most common in U.S. Black patients, African-Caribbean, Danes and Swedes
    2. Overall Prevalence: 60 to 100,000
  3. Race
    1. Black patients have as much as an 8 fold higher risk
    2. Lowest Incidence in asian countries
  4. Gender
    1. Females twice as likely as males to develop Sarcoidosis
  5. Geographic region
    1. Western U.S. has significantly fewer cases than the rest of the country

III. History

  1. First described by Hutchinson in 1877

IV. Pathophysiology

  1. Noncaseating Granuloma formation within the lungs, Lymph Nodes and many other systems
    1. Activated T Cells and Macrophages secrete Cytokines and TNFa
    2. Remission occurs if the Antigen trigger is cleared
  2. Idiopathic
    1. Underlying genetic predisposition
      1. First-degree relative with Sarcoidosis: 4-10% of patients
    2. Precipitated by trigger
      1. Infection (e.g. Mycobacteria, Borrelia Burgdorferi, Propionibacterium acnes, mold)
      2. Environmental exposure (e.g. Beryllium, Aluminum, silica, Insecticides)

V. Presentations: Common involvement sites (affects all organ systems)

  1. Lungs (>90%)
    1. Interstitial Lung Disease
    2. Pulmonary Hypertension
  2. Lymphadenopathy
    1. Hilar adnenopathy and mediastinal Lymphadenopathy (>95%)
    2. Cervical Lymphadenopathy (and Supraclavicular Lymphadenopathy)
  3. Liver (50-80%)
    1. Hepatic Granulomas (86%)
    2. Hepatomegaly (20%)
    3. Mild Liver Function Test Abnormality
      1. Increased Alkaline Phosphatase
  4. Spleen (40-80%)
  5. Skin lesions (25%)
    1. Lupus Pernio
    2. Dactylitis
    3. Erythema Nodosum (See Lofgren Syndrome below)
  6. Eyes (20-50%)
    1. Anterior Uveitis (18%, also in Spondyloarthropathy)
    2. Posterior Uveitis (7%, Behcet's Disease)
    3. Lacrimal gland hypertrophy
    4. Conjunctival Nodules
    5. Keratoconjunctivitis (also in Sjogren's Syndrome)
    6. Proptosis (also in Wegener's Granulomatosis)
  7. Heart (5%)
    1. Tachyarrhythmias (including Ventricular Tachycardia)
    2. Cardiomyopathy
    3. Congestive Heart Failure
  8. Kidney (uncommon)
    1. Membranous Glomerulonephritis
    2. Nephrocalcinosis
    3. Nephrolithiasis
    4. Renal Insufficiency
  9. Bone Marrow (4-40%)
    1. Leukopenia (28%)
    2. Eosinophilia (34%)
  10. Gastrointestinal
    1. Pancreas (6%)
    2. Stomach or Esophagus
  11. Parotid Gland (5%, also seen in Sjogren's Syndrome)
    1. May be associated with Heerfordt Syndrome
  12. Skeletal Muscle (4%, also seen in Polymyositis)
    1. Proximal Muscle Weakness
  13. Upper airway (3%, also in Wegener's Granulomatosis)
    1. Saddle-nose deformity
  14. Nervous System or Neurosarcoidosis (10%)
    1. Atypical central effects (e.g. acute Aphasia)
    2. Peripheral Neuropathy (esp. small fiber)
    3. Cranial Nerve palsy (especially CN 7, Bell's Palsy)
    4. Optic Neuritis
    5. Hypopituitarism (from pituitary and Hypothalamus involvement)
    6. Seizures (due to CNS Lesions)
  15. Hypercalcemia (<10%)
    1. Results from Vitamin D activation with increased intestinal Calcium absorption
    2. Nephrocalcinosis
    3. Nephrolithiasis
    4. Renal Failure

VI. Symptoms

  1. Asymptomatic initially in many patients
    1. Often diagnosed by Hilar Adenopathy on Chest XRay
  2. Pulmonary (presenting symptom in 40-45%)
    1. Dry cough
    2. Dyspnea
    3. Chest Pain (non-specific)
    4. Hemoptysis (rare initially)
  3. Constitutional symptoms (presenting symptom in 25%)
    1. Fever (associated with hepatic Granulomas)
    2. Weight loss
    3. Fatigue
    4. Malaise

VII. Signs: Arthritis (occurs in 10-15% of cases)

  1. Early joint disease (first 6 months)
    1. Duration: weeks to 3 months
    2. Common joints involved
      1. Onset in ankles
      2. Spreads to knees
    3. Involves other joints
      1. Proximal interphalangeal joint
      2. Metacarpophalangeal joint
      3. Wrist
      4. Elbow
    4. Spares axial skeleton
    5. Associated with Erythema Nodosum
    6. No XRay changes
  2. Late joint disease (onset after 6 months)
    1. Common joints involved
      1. Knees
      2. Ankles
      3. Proximal interphalangeal joints
    2. Associated with chronic cutaneous Sarcoidosis
    3. XRay changes (see below)

VIII. Signs: Skin changes (Lupus Pernio)

  1. Initial Characteristics
    1. Papular lesions (most common)
    2. Reddish-brown to purple color (violaceous Plaques)
    3. Scaling may occur
    4. Diameter: 1 to 3 cm
  2. Later Characteristics
    1. Lesions coalesce into Annular Lesions or Plaques
    2. Chronic form may show scarring and disfigurement
  3. Distribution (most commonly involves face)
    1. Periorbital area
    2. Nasolabial folds
    3. Mucous membranes
    4. Ears
    5. Fingers and Toes
  4. Diagnostics
    1. Diascopy (lesion blanches under pressure)
      1. Skin lesions yellow-orange
    2. Dermoscopy
      1. Branching vessels over a translucent yellow-orange globular lesion
  5. Other skin changes
    1. Dactylitis (Sausage Digits)
      1. Associated with chronic Arthritis

IX. Signs: Lymphadenopathy

  1. Mediastinal Lymph Node involvement most common
  2. Peripheral Lymphadenopathy (non-tender, <5 cm)
    1. Cervical Lymphadenopathy
    2. Axillary Lymphadenopathy
    3. Inguinal Lymphadenopathy
    4. Epitrochlear Lymphadenopathy

X. Staging

  1. Based on Chest XRay (see below)

XI. Imaging: Chest XRay (abnormal in 90% of cases)

  1. Stage 0: No abnormality (<10% of cases)
  2. Stage I: Lymphadenopathy alone (43% of cases)
    1. Bilateral hilar Lymphadenopathy
    2. Mediastinal Lymphadenopathy
    3. Right paratracheal Lymphadenopathy
  3. Stage II: Adenopathy and Infiltrates (24% of cases)
    1. Lymphadenopathy as in Type I Chest XRay findings
    2. Parenchymal infiltrates
    3. Symptomatic respiratory disease presentation
  4. Stage III: Infiltrates alone (13% of cases)
    1. Parenchymal infiltrates
  5. Stage IV: Pulmonary Fibrosis

XII. Imaging: Joint and Bone XRay in Arthritis

  1. Acute Arthritis not associated with XRay changes
  2. Chronic Arthritis uncommonly with XRay changes
    1. Middle and distal phalanx bone destruction or cysts
    2. Trabecular changes to bone (honeycombing)

XIII. Imaging: Diagnosis

  1. Advanced Imaging
    1. High Resolution CT Chest
      1. Upper lobe lymphatic and peribronchovascular Nodules
      2. Hilar Adenopathy and subcarinal adenopathy
      3. Quantifies pulmonary fibrosis
      4. Evaluates differential diagnosis of Interstitial Lung Disease, pulmonary fibrosis, Hilar Adenopathy
    2. F-fluorodeoxyglucose Positron Emission Tomography (F-FDG PET)
      1. Identifies activity distribution as well as biopsy sites, cardiac Sarcoidosis
    3. MRI Brain
      1. CNS Lesions
    4. MRI Heart
      1. Intramyocardial inflammation
      2. Delayed gadolinium enhancement is a risk for ventricular Arrhythmia
    5. Cardiac thallium scan
      1. Decreased uptake from sarcoid lesions does not follow Coronary Artery distribution
  2. Gallium scan
    1. Lambda pattern or sign
      1. Bilateral hilar and right paratracheal nodal uptake
    2. Panda pattern or sign
      1. Parotid and lacrimal gland uptake

XIV. Labs: Diagnosis

  1. See Imaging as above
  2. Biopsy or Cytology (Gold standard)
    1. Protocol
      1. Skin lesion biopsy or peripheral Lymph Node biopsy are less invasive options
      2. Samples typically obtained via flexible bronchoscopy with biopsy
    2. Finding
      1. Discrete noncaseating epithelioid Granuloma
      2. Collections of epithelioid histiocytes, mature Macrophages and giant cells
      3. Lymphocytes are primarily CD4 T Cells
    3. Biopsy sites
      1. Transbronchial lung biopsy (preferred site if no skin or peripheral node involvement)
        1. Transbronchial needle aspiration (TBNA)
        2. Ultrasound may guide TBNA
      2. Bronchoalveolar lavage (CD4-CD8 ratio >3.5)
      3. Skin biopsy of lesion
      4. Palpable peripheral Lymph Node biopsy
      5. Salivary Gland biopsy
  3. Pulmonary Function Testing (PFT)
    1. Findings consistent with Interstitial Lung Disease
    2. PFTs may demonstrate decreased DLCO, as well as restrictive or obstructive lung findings
    3. May be normal in 80% of patients despite significant involvement on CT Chest
  4. Serum Angiotensin-converting enzyme (Serum ACE)
    1. Not typically recommended (low Test Specificity, variable across patients)
    2. Increased in 50-80% of Sarcoidosis patients

XV. Labs: Baseline for Sarcoidosis monitoring

  1. General
    1. Complete Blood Count
    2. Serum Comprehensive Metabolic Panel
      1. Serum Calcium
        1. Hypercalcemia occurs in 2-10% of patients
        2. Granuloma associated Macrophages drive an increase in serum 1,25 Dihydroxyvitamin D
      2. Renal Function tests
      3. Liver Function Tests
    3. Urinalysis
  2. Differential Diagnosis Evaluation
    1. HIV Test
    2. Fungal Culture
    3. Tuberculosis Screening
      1. Tuberculosis Antigen-Specific Interferon-Gamma Release Assay (e.g. Quantiferon-TB) - preferred
      2. Tuberculin Skin Test (PPD)
  3. Cardiovascular Evaluation
    1. Electrocardiogram
      1. All patients with Sarcoidosis at time of diagnosis
      2. Abnormal findings (e.g. second degree AV Block, Right Bundle Branch Block, Arrhythmias)
        1. Evaluate with Cardiac MRI or Fluorodeoxyglucose PET/CT
    2. Other testing to consider
      1. Echocardiogram
      2. Holter Monitor (e.g. zio monitor)
  4. Eye Involvement
    1. Ophthalmology evaluation at baseline in all new Sarcoidosis patients
  5. Neurologic Involvement (neurosarcoidosis)
    1. Brain MRI
    2. Lumbar Puncture (CSF with inflammatory changes)

XVI. Associated Conditions: Pathognomonic for Sarcoid

  1. Lupus Pernio
    1. Pathognomonic for Sarcoidosis
    2. Associated with lung involvement and worse prognosis
  2. Lofgren Syndrome
    1. Erythema Nodosum (typically presenting complaint, suggests better prognosis)
    2. Bilateral hilar Lymphadenopathy
    3. Fever
    4. Polyarthritis (not typically chronic)
    5. Uveitis
  3. Heerfordt Syndrome (Uveoparotid Fever)
    1. Uveitis
    2. Parotitis
    3. Fever
    4. Facial Nerve Palsy (variably present)

XVII. Differential Diagnosis: Pulmonary

  1. See Interstitial Lung Disease
  2. See Hilar Adenopathy
  3. Infections
    1. Tuberculosis
    2. Coccidioidomycosis
    3. Blastomycosis
    4. Aspergillosis
    5. Histoplasmosis
    6. Pneumocystis jiroveci (Pneumocystis carinii)
    7. Brucellosis
  4. Exposures or toxins
    1. See Interstitial Lung Disease
    2. Drug induced Hypersensitivity (e.g. Monoclonal AntibodyDMARDs, Methotrexate)
    3. Hypersensitivity pneumonitis
  5. Malignancy
    1. Lymphoma
  6. Vasculitis
    1. Churg-Strauss Syndrome
    2. Granulomatosis with Polyangiitis (previously known as Wegener's Granulomatosis)

XVIII. Differential Diagnosis: Extra-pulmonary

  1. Arthritic Conditions
    1. Rheumatoid Arthritis
    2. Rheumatic Fever
    3. Systemic Lupus Erythematosus
    4. Gonococcal Arthritis
    5. Spondyloarthropathy
  2. Skin Involvement
    1. See Annular Lesion
    2. See Erythema Nodosum
    3. Papular lesions similar to Sarcoidosis
      1. Granulomatous Rosacea
      2. Acne Vulgaris
    4. Plaque-type lesions similar to Sarcoidosis
      1. Psoriasis
      2. Lichen Planus
      3. Nummular Eczema
      4. Discoid Lupus Erythematosus
      5. Granuloma Annulare
      6. Cutaneous T-Cell Lymphoma
      7. Kaposi's Sarcoma
      8. Secondary Syphilis
    5. References
      1. Katta (2002) Am Fam Physician 65(8):1581-84 [PubMed]
  3. CNS Involvement (Neurosarcoidosis)
    1. See CNS Lesion
    2. See Encephalitis
    3. Bacterial Infection (Tuberculosis, Brucellosis)
    4. Fungal infection (Aspergillosis, Coccidioidomycosis, Cryptococcosis)
    5. Parasitic Infection (Amoebiasis, Toxoplasmosis, Schistosomiasis, Echinococcus, Neurocysticercosis)
    6. Viral Infection (Varicella Zoster Virus. HSV Encephalitis)
    7. Lymphoid Granulomatosis
    8. Granulomatosis with Polyangiitis
    9. Rheumatoid Nodules
    10. Rosai-Dorfman Disease
    11. Histiocytosis
  4. Ocular Involvement
    1. Inflammatory Bowel Disease
    2. ANCA Vasculitis
    3. Blau syndrome
    4. Vogt-Koyanagi-Harada Disease
    5. Bacterial Infection (Tuberculosis, Syphilis)
    6. Parinaud octoglandular syndrome (Bartonella, Francisella)
    7. Parasite infection (Toxoplasmosis)
    8. Viral Infection (CMV, VZV)

XIX. Diagnosis: Criteria

  1. Clinical and imaging findings are consistent with Sarcoidosis AND
  2. Other conditions on differential diagnosis are excluded AND
  3. Noncaseating Granulomas on pathology
    1. Biopsy not required in classic Lupus Pernio, Lofgren Syndrome or Heerfordt Syndrome (pathognomonic)
    2. Early disease (asymptomatic Stage I Sarcoidosis) as management is not affected

XX. Management: Pulmonary Sarcoid

  1. Indications
    1. Dyspnea
    2. Persistent cough
    3. Widespread debilitating disease
  2. First-line: Systemic Corticosteroids (e.g. Prednisone)
    1. Indications
      1. Stage 2 or 3 lung changes
    2. Efficacy
      1. Short term benefit in moderate lung disease
      2. Unclear whether disease-modifying effect
      3. Do not appear to decrease mortality, pulmonary function or disease progression
    3. Protocol
      1. Start Prednisone at 20 to 40 mg (or 0.5 to 1 mg/kg) per day
      2. Evaluate at 1-3 months for response
        1. No response
          1. Taper off over 4-6 weeks
        2. Response
          1. Slowly taper Prednisone to 5-10 mg/day
          2. Continue Prednisone for total of 12 months
      3. Monitoring tools (obtain at 1-3 months, and repeat every 3-6 months while on Prednisone)
        1. Symptom history
          1. Pulmonary symptoms (e.g. cough, Dyspnea)
          2. Prednisone adverse effects
        2. Pulmonary Function Tests
        3. Chest XRay
      4. Osteoporosis Prevention for longstanding Corticosteroid use
        1. See Corticosteroid Associated Osteoporosis
    4. Reference
      1. Paramothayan (2002) JAMA 287:1301-7 [PubMed]
      2. (1999) Am J Respir Crit Care Med 160:736-55 [PubMed]
  3. Other management options
    1. Agents used as alternative or as adjunct to Prednisone
    2. Indications
      1. Corticosteroid refractory disease (10-15 mg/day Prednisone)
      2. Significant Corticosteroid adverse effects
      3. Frequent Sarcoidosis exacerbation
    3. Cytotoxic agents
      1. Methotrexate (Rheumatrex) 10-25 mg weekly
        1. Typically first-line after Corticosteroids
      2. Azathioprine (Imuran)
      3. Leflunamide (Arava)
    4. Immunomodulators
      1. Chloroquine
      2. Hydroxychloroquine (Plaquenil)
    5. Monoclonal Antibodies (indicated in cases refractory to Corticosteroids and Immunosuppressants)
      1. Inlfliximab (Remicade)
      2. Adalimumab (Humira)
    6. Thoracic surgery indications
      1. Life-threatening Hemoptysis (lung resection)
      2. End-stage pulmonary Sarcoidosis (lung transplant)
        1. Sarcoidosis may recur in transplanted lung (but does not affect mortality)

XXI. Management: Extrapulmonary Sarcoid

  1. Ophthalmologic Sarcoidosis: Uveitis
    1. First line: Topical Corticosteroids
    2. Refractory cases
      1. Prednisone (preferred)
      2. Methotrexate
  2. Cutaneous Sarcoidosis
    1. Erythema Nodosum lesions: NSAIDs
    2. Sarcoid lesions
      1. Topical Corticosteroids
      2. Intralesional Corticosteroids (e.g. Kenalog 5/ml)
        1. Inject lesions q2-3 weeks
      3. Other agents
        1. Doxycycline
        2. Minocycline
        3. Antimycobacterial agents
        4. Other Immunosuppressants (e.g. Methotrexate, Hydroxychloroquine, Biologic Agents)
    3. Oral Corticosteroid indications
      1. Lupus Pernio
      2. Severe or disfiguring lesions
  3. Cardiac Sarcoidosis
    1. Manage Left Ventricular Dysfunction
    2. Corticosteroids and Methotrexate may improve outcomes
    3. Other measures may be needed (e.g. AICD or Pacemaker placement, catheter ablation, Heart Transplant)
  4. Neurosarcoidosis: Cranial or Peripheral Neuropathy
    1. First-line: Oral Corticosteroids (e.g. Prednisone)
    2. Second-line agents
      1. See other management options above under pulmonary Sarcoidosis
      2. Methotrexate
      3. Alternatives include Cyclosporine and Azathioprine
    3. Third-line agents
      1. Infliximab

XXII. Monitoring

  1. Monitoring tools at visits
    1. History and physical
    2. Chest XRay
    3. Spirometry
    4. Specific testing when indicated
  2. Stage I Sarcoidosis
    1. Start with evaluations every 6 months
    2. May space visits to every 12 months if stable
    3. No follow-up if off therapy and stable for 3 years
  3. Stage II to IV Sarcoidosis
    1. Start with evaluations every 3-6 months
    2. Continue visits indefinately
  4. Consultations
    1. Ophthalmology exam annually

XXIII. Prognosis

  1. Remission within 2 years
    1. Stage I: 55-90% remission rate
    2. Stage II: 40-70% remission rate
    3. Stage III: 10-20% remission rate
    4. Stage IV: <5% remission rate
  2. Factors suggestive of worse prognosis
    1. Onset after age 40 year
      1. Progression risk at 3 years is linearly associated with advancing age
      2. Progression risk 20% in patients age >50 years
      3. Risk is 4%/year after diagnosis)
    2. Black race (esp. women)
    3. Chronic Hypercalcemia
    4. High risk pulmonary findings increasing mortality
      1. Progressive pulmonary fibrosis >20% (high resolution CT Chest)
      2. Stage 4 pulmonary disease on Chest XRay
      3. Pulmonary Hypertension
    5. Other Specific higher risk organ involvement
      1. Neurologic involvement
      2. Skin involvement (Lupus Pernio)
      3. Cardiac involvement
      4. Eye involvement (Chronic Uveitis)
      5. Renal involvement (Nephrocalcinosis)
      6. Cystic bone lesions
      7. Involvement of nasal mucosa
  3. Overall mortality: 1-5%
    1. Cause of death in U.S.: Respiratory Failure or CHF

XXIV. Resources

  1. EMedicine: Sarcoidosis
    1. http://emedicine.medscape.com/article/301914-overview#showall
  2. Stop Sarcoidosis Organization
    1. https://www.stopsarcoidosis.org/

XXV. References

  1. Klippel (1997) Primer Rheumatic Diseases, AF, p. 325-7
  2. Wilson (1991) Harrison's IM, McGraw-Hill, p.1463-9
  3. Belfer (1998) Am Fam Physician 58(9):2041-50 [PubMed]
  4. Hsu (2001) Am Fam Physician 64(2):289-96 [PubMed]
  5. Partin (2024) Am Fam Physician 109(1): 19-29 [PubMed]
  6. Soto-Gomez (2016) Am Fam Physician 93(10): 840-8 [PubMed]
  7. Wu (2004) Am Fam Physician 70:312-22 [PubMed]

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