sarcoidosis

Introduction

Sarcoidosis is a granulomatous disease with variable clinical manifestations & an unpredictable course. 2/3 of patients who present with sarcoidosis will show clinical or radiographic evidence of improvement over a period of several years. Chronic disease develops in only a minority of patients.

Etiology

• unknown
• cellular autoimmunity
• some patients may develop sarcoidosis after smoking cessation

Epidemiology

• common disorder
• slight predilection for females
• in the US, sarcoidosis affects mostly blacks 10-17:1 over whites
• in Europe, sarcoidosis affects mostly whites
• disease rare among Canadian Indians & Southeast Asians
• onset of disease at any age, most commonly age 20-40
• sarcoidosis occurs more frequently in non-smokers

Pathology

• mononuclear cell-mediated inflammation of affected organs
• formation of epithelioid non-caseating granulomas
  • multinucleated giant cells
  • rim of T-helper cells
  • granulomas infiltrate tissue of almost any organ
• organ dysfunction results from distortion of architecture of affected tissues by inflammatory cells
• the disease involves most organs; however organ function is not uniformly affected
• interstitial lung disease involving alveoli, small bronchi & blood vessels
• decreased number of T-cells with proliferation of B-cells
• increased 25-hydroxyvitamin D-1-alpha hydroxylase activity by granuloma-associated macrophages resulting in increased serum 1,25-dihydroxyvitamin D & hypervitaminosis D

Genetics

• association with HLA-DR4
• susceptibility to sarcoidosis type 2 associated with polymorphism(s) in BTNL2

Clinical manifestations

• acute form
  • constitutional symptoms
    • fever
    • fatigue/anergy
    • malaise
    • anorexia
    • weight loss
    • night sweats
  • pulmonary symptoms
    • dry cough
    • dyspnea
    • chest pain/discomfort
  • polyarthritis (including Lofgren's syndrome)
• insidious form
  • most patients asymptomatic (disease is detected by abnormal chest X-ray)
  • develops over months
  • no constitutional symptoms
  • pulmonary symptoms
  • patients with insidious onset most commonly develop chronic sarcoidosis
• pulmonary (>90%)
  • dyspnea, especially with exercise
  • dry cough
  • hemoptysis is rare
  • pleural effusion, unilateral (1-5%)
  • pulmonary fibrosis, predominantly uppper lobe (5-15%)
  • pulmonary infiltrates
  • pulmonary nodules
  • pulmonary cystic changes including aspergillomas
  • may present as diffuse parenchymal lung disease
  • often asymptomatic
• lymphadenopathy is common
  • bilateral hilar lymphadenopathy, often with mediastinal lymphadenopathy (75-90%)
  • peripheral or generalized lymphadenopathy very common
    • non painful
    • rarely a problem
• skin (25%) (images)
  • erythema nodosum (including Lofgren's syndrome)
  • papules, plaques (image)
    • symmetric, brown-purple, round-oval
    • most commonly on extremities, face, scalp, buttocks
    • papular rash across chest
  • maculopapular eruptions
  • subcutaneous nodules
  • lupus pernio (image)
  • violaceous papules, nodules & plaques commonly occur around the nose, periorbital & around the mouth & at sites of trauma, including surgical scars & tattoos
  • nail changes (rare) include clubbing, discoloration, dystrophy, subungual hyperkeratosis, splinter hemorrhages, and onychorrhexis
• eye (25%)
  • eye pain, burning
  • blurred vision
  • photophobia
  • anterior & posterior uveitis
    • Heerfordt syndrome
    • common presentation for sarcoidosis
  • keratoconjunctivitis sicca (lacrimal gland inflammation)
  • may lead to blindness
• upper respiratory tract
  • nasal mucosa: stuffiness (20%)
  • larynx involvement (5%),
    • dyspnea
    • wheezing
    • stridor
    • complete obstruction rare
• bone marrow (40%)
  • mild abnormalities: anemia, neutropenia, thrombocytopenia, eosinophilia
• spleen involvement (50-60%), splenomegaly (5-10%)
• liver
  • hepatomegaly (20-30%)
  • elevated transaminases
  • not clinically significant
• kidney
  • nephrocalcinosis & nephrolithiasis (see management section)
• nervous system (5%)
  • unilateral facial paralysis (7th nerve)
    • most common
    • onset sudden
    • transient
    • Heerfordt syndrome
  • optic nerve dysfunction
  • papilledema
  • hypothalamic & pituitary abnormalities
  • chronic meningitis
  • psychiatric disturbances
  • seizures
  • peripheral neuropathy
  • brain lesions
  • myelopathy
• musculoskeletal
  • bone involvement (5%)
    • cysts within expanded bone
    • punched-out lesions
    • lytic lesions of bones of hands & feet most common, especially in terminal phalanges
    • may be painful
  • joints (25-50%)
    • arthralgias & arthritis in large joints
      • oligoarthritis or polyarthritis
      • polyarthritis in severe sarcoidosis may affect shoulders, wrists, knees, ankles & digits
    • may be migratory
    • usually transient
    • asymmetric joint swelling
    • may be chronic & deforming
    • tenosynovitis
    • dactylitis
  • muscle dysfunction rare:
    • polymyositis/dermatomyositis
    • chronic myopathy
• heart (5%)
  • granulomas involve the heart in 25% of patients
    • generally subclinical
  • left ventricular wall involvement common
  • arrhythmias
    • AV block, complete heart block, bundle branch block
    • ventricular arrhythmias, sudden death
      • monomorphic ventricular tachycardia
  • cardiomyopathy
    • myocarditis
    • LV systolic dysfunction
      • dilated cardiomyopathy
    • restrictive cardiomyopathy is rare
  • papillary muscle dysfunction
  • pericarditis
  • congestive heart failure
  • cor pulmonale secondary to pulmonary fibrosis is rare
• endocrine:
  • hypothalamus & pituitary most commonly involved
    • central adrenal insufficiency
    • pituitary hypothyroidism
    • hypogonadism of central origin
    • central diabetes insipidus
    • hypercalcemia, hypervitaminosis D
• exocrine glands:
  • parotitis, bilateral parotid gland enlargement (common)
    • Heerfordt syndrome
  • xerostomia
• gastrointestinal involvement rarely clinically significant

Diagnostic criteria

• diagnosis of exclusion
• multisystem involvement
• non-caseating granuloma
• biopsy needed except in case of classic Lofgren's syndrome

Laboratory

• complete blood count (CBC)
  • lymphocytopenia
  • eosinophilia may be present
• rheumatoid factor (RF) may be positive
• antinuclear antibodies (ANA) may be positive
• serum globulins or serum protein electrophoresis (hypergammaglobulinemia)
• serum calcium baseline & annually
  • hypercalcemia may be present (case report of 12.1 mg/dL)
  • serum phosphate may be simultaneously increased
  • serum PTH low for high serum calcium (hypercalcemia) & high urine calcium (hypercalciuria)
• serum creatinine & serum alkaline phosphatase baseline & annually
• serum 1,25-dihydroxyvitamin D may be elevated
  • measure both serum 25-hydroxyvitamin D & serum 1,25-dihydroxyvitamin D
  • patients with hypercalcemia, hypercalciuria & nephrolithiasis
• urinalysis
  • sterile pyuria may be noted
  • urine calcium: hypercalciuria may be present
  • urine protein: mild proteinuria may be present
  • urine osmolality:
    • urine may be inappropriately dilute (concentrating impairment)
• erythrocyte sedimentation rate (ESR) is generally normal
• serology: high serum antiviral titers
  • Epstein-Barr virus
  • rubella
  • parainfluenza
  • Herpes simplex
• flow cytometry: CD4/CD8 ratio increased
• serum angiotensin-converting enzyme: elevated ACE
  • of no benefit for diagnosis or management
• elevated interleukin 2 receptor soluble in serum/plasma (> 600 U/mL)
• see ARUP consult

Diagnostic procedures

• fiberoptic bronchoscopy
  • endobronchial ultrasound-guided transbronchial FNA
• bronchoalveolar lavage
  • increased lymphocytes
  • alveolar macrophages
  • a few neutrophils with pulmonary fibrosis
  • non-specific findings
• biopsy
  • bronchoscopic lung biopsy
    • endobronchial biopsy
    • transbronchial biopsy
      • mediastinal lymph nodes
      • hilar lymph nodes
    • US-guided endobronchial biopsy preferred vs mediastinocopy
  • biopsy of skin nodule, scalene nodes, conjunctival lesions
  • cardiac biopsy shows non-caseating granuloma in 20%
  • tissue stain & culture biopsy specimens to exclude infectious cause of non-caseating granuloma
  • rule-out tuberculosis & fungal infection
  • lacrimal gland biopsy if lacrimal gland enlargement
  • presentations that do NOT require tissue biopsy (lymph node biopsy)
    • asymptomatic bilateral hilar lymphadenopathy
    • Lofgren's syndrome
    • Heerfordt syndrome
    • lupus pernia
• suppression of delayed-type hypersensitivity (skin testing) in 60% of patients
• pulmonary function testing:
  • normal, restrictive or restrictive/obstructive pattern
  • DLCO is generally diminished
• ophthalmology slit-lamp exam on all patients
• baseline electrocardiogram rule out heart block on all patients
  • HOLTER not recommended
• upper GI endoscopy to evaluate for esophageal varices for suspected hepatic sarcoidosis

Radiology

• chest X-ray (images)
  • 90% have abnormal chest X-ray at some time
  • bilateral hilar lymphadenopathy without parenchymal changes (type 1)
  • bilateral hilar adenopathy with parenchymal changes (type 2)
  • diffuse parenchymal abnormalities without hilar adenopathy (type 3)
  • egg shell calcification of hilar nodes
  • predominantly upper lobe interstitial infiltrates
  • reticular opacities
  • pleural effusion
  • pneumothorax
  • cardiomegaly
  • 50% develop permanent pulmonary abnormalities
  • findings can help predict probability of spontaneous resolution
• high-resolution computed tomography of chest
  • identify hilar adenopathy suggested on chest E-ray
  • may identify early fibrosis
  • nodules along bronchovascular bundles
• gallium 67 lung scan: diffuse uptake
• X-ray of hands may show erosions & cystic changes of the phalanges*
• renal ultrasound in patients with hypercalcemia/hypercalciuria
• MRI for neurosarcoidosis
• cardiac MRI for suspected cardiac sarcoidosis
  • dilated cardiomyopathy
  • suspected restrictive cardiomyopathy
    • delayed gadolinium hyperenhancement generally of the mid myocardial wall or epicardium
    • findings indicative of inflammation in distribution atypical for coronary artery disease
    • also useful for excluding constrictive pericarditis
  • 18F fluorodeoxyglucose PET scan if MRI is negative & suspicion is high
• echocardiography for suspected pulmonary hypertension
  • right heart catheterization if confirmed

* image

Staging

• based on chest X-ray findings which roughly, but not necessarily, parallel clinical disease severity.
• no evidence that disease progresses from one phase to the next

• 0: normal chest X-ray with granulomas at other sites
• 1: bilateral hilar lymphadenopathy & paratracheal lymphadenopathy
• 2: pulmonary infiltrates with hilar lymphadenopathy
• 3: pulmonary infiltrates without lymphadenopathy
• 4: end-stage pulmonary fibrosis with bullous changes

• 1: > 90% with spontaneous resolution*
• 2 or 3: ~20% with spontaneous improvement*

* without treatment

Complications

• respiratory failure (rare)
• aspergilloma
• blindness
• cardiomypathy, congestive heart failure
  • dilated cardiomyopathy
  • restrictive cardiomyopathy
• cor pulmonale
• cardiac conduction system abnormalities
  • ventricular arrhythmias, including sudden death
• nephrocalcinosis & nephrolithiasis (see management section)

Differential diagnosis

• berylliosis
• multiple myeloma distinguished by paraproteinemia

Management

• do not treat asymptomatic sarcoidosis
• pharmacologic agents
  • NSAIDs for erythema nodosum or Lofgren's syndrome
  • glucocorticoids
    • uncertain benefit
    • topical glucocorticoid for skin lesions, anterior uveitis
    • inhaled glucocorticoid for nasal polyp, cough
    • oral glucocorticoids for
      • ophthalmologic disease
      • symptomatic pulmonary sarcoidosis
      • neurologic sarcoidosis
      • hypercalcemia
      • significant dysfunction of other vital organ (heart, kidney)
    • prednisone 30-40 mg/day for 4-8 weeks
    • if favorable response to glucocorticoids
      • taper dose to lowest dose that maintains remission
      • maintenance usually > 15 mg qod
      • maintain therapy for 1 year before discontinuing
    • 20-50% relapse rate after discontinuation of glucocorticoids
  • immunosuppressive agents, cytotoxic agents & antimalarials
    • consider for patients refractory to or unable to tolerate glucocorticoids
    • chloroquine
    • hydroxychloroquine
    • methotrexate
  • pentoxifylline has been used as a steroid-sparing agent
• surgery:
  • lung transplantation for severe pulmonary pathology despite appropriate medical therapy
• prognosis
  • most patients with acute presentation recover without significant sequellae
  • Lofgren syndrome has an 80% rate of spontaneous remission & resolution
  • chronic or recurrent disease in 15-20%
  • avoid vitamin D & calcium supplements
  • death attributed to sarcoidosis in 10% of total

More general terms

• autoimmune disease
• granulomatous disease

More specific terms

• cardiac sarcoidosis
• Lofgren's syndrome
• neurosarcoidosis
• sarcoidosis early onset

Patient information

sarcoidosis patient information

Database

• OMIM: https://mirror.omim.org/entry/181000
• OMIM: https://mirror.omim.org/entry/612387]