Sarcoidosis

Useful references: 



Immunopathogenesis: Please see under https://ci-and-pulmonary-disease

  • The underlying immunologic events include: (1) exposure to one or more (unknown) antigens, (2) activation of antigen-presenting cells (macrophages and dendritic cells), (3) a T cell response in an effort to eliminate the antigen, and (4) granuloma formation.

  • Exaggerated immune response to far unidentified antigens most likely pathogen-associated molecular patterns of killed and partly degraded mycobacteria and propionibacteria
  • Innate and Adaptive Immune mechanisms are involved in pathogenesis. 
    • Innate Immune System
      • Epithelial cells :
      • Phagocytic defects: 

        Mycobacteria and propionibacteria persist in macrophage phagosomes because their high lipid content in membranes makes them acid-fast, and many of their glycolipoproteins are not very soluble and resist degradation. 

      • Cell Signaling: Antigen-associated molecular pattern trigger
        • 4 types: 
          • 2 Membrane-bound 
            • TLR (7 types)  TLR2 and TLR9
              • Also, alveolar macrophage in response to antigen via TLR 4 signal pathway leads to TNF alpha production
            • CLR (5 types) C-Type Lectin
          • 2 Cytoplasmic 
            • NLR (6 Types) NOD Like Receptors
            • RIG - 1 Helicase receptors (2 Types)
      • Complement (Alternate and Lectin Pathways)
    • Adaptive Immune System 
      • T-Cell
        • T-Cell Development
        • T-Cell Maturation
        • T-Cell Activation and antigen presentation or Functioning: Macrophage activation and phagocyte defects lead to T-cell activation. TNF alpha through e.  
          • Th1: There is also the influx of Th1 cells in organs with sarcoid manifestation. In-situ activation of T-Lymphocytes causes the production of interferon γ, TNF alpha, IL 2
            • These Th1 cytokines in turn, activate more antigen-presenting macrophages 
          • Th2: IL4, TGF Beta
          • Th17: Even though there is increased IL17 in sarcoidosis, the role of the Th17 pathway is still undefined. 
      • B-Cell
        • Impaired Development
          • Why some patients have spontaneous resolution of sarcoidosis and others have persistent disease is not clear. In progressive disease, the antigen is postulated to persist, thereby inducing a chronic immune response. However, in patient with spontaneous resolution, there is increased release of IMMUNOSPPRESSIVE cytokine TGF Beta 
        • Impaired Functioning 
          • T-cell mediated
          • T-cel independent 
    • Regulatory Immune System
      • Innate System Regulation
      • Adaptive System Regulation
        • Absence of negative immunological feedback signals delivered. ie. Tregs leads to further exaggerated Th1 response
    • Summary of pathogenesis: Increased inflammation by TNF alpha. Suppression by TGF Beta leads to spontaneous resolution. 

Clinical Features: Lancet 2014

Most common clinical presentations are : 
  • persistent cough, 
  • localization of disease in the skin, 
  • eye, and 
  • peripheral lymph nodes, 
  • erythema nodosum, 
  • fatigue, and 
  • incidental abnormal chest radiograph 

DDx
  • infections, particularly tuberculosis; 
  • occupationally induced, environmentally induced, and drug-induced granulomatosis; chronic pulmonary berylliosis is dependent on a focused questionnaire and on beryllium hypersensitivity
  • common variable immune deficiency. Diagnosis of common variable immune deficiency relies on hypogammaglobulinaemia,
  • Blau’s syndrome; 
  • sarcoid-like reactions in cancers and lymphomas, and 
  • other idiopathic granulomatosis.  

Diagnosis: Lancet 2014

Three most important advancement in diagnosis has been:
  • PET scan
  • Rapid on-site assessment by the well trained cytologists 
  • EUS guided Needle aspirations
Diagnosis is based on the following. The weight of each of them depends on the clinical scenarios. 
  • Clinical Picture and Radiological Picture
  • Caseating granulomas, and 
  • evidence of no alternative findings 
Most common diagnostic signs are 
  • bilateral intrathoracic hilar lymphadenopathy or diffuse micronodular pulmonary infiltration at chest radiograph, 
  • associated with a typical lymphatic distribution or a galaxy sign on CT  and 
  • the presence of some extrapulmonary localisations of disease—eg, in the eye and skin 

Sarcoidosis Lancet 2014


Sarcoidosis Lancet 2014


Additional Clinical Features: Sarcoidosis NEJM 2007
  • Constitutional symptoms such as fatigue may predominate.
  • Cardiac sarcoidosis is much more common than reported previously and may cause loss of ventricular function and sudden death.
  • Cardiac and neurologic sarcoidosis may occur without apparent disease activity in other organs. 
  • Chest radiographic patterns (stages 1, 2, and 3) do not reflect the chronology of the disease. 
  • A response to corticosteroid therapy does not establish the diagnosis of sarcoidosis.
  • Measurement of the serum angiotensin-converting–enzyme level is an insensitive and nonspecific diagnostic test and a poor therapeutic guide.
  • For patients without apparent lung involvement, 18FDG PET is useful in identifying sites for diagnostic biopsy.
  • 18FDG PET and MRI with gadolinium detect cardiac and neurologic involvement. 
  • CT imaging is unnecessary for most patients with sarcoidosis. CT is indicated when the chest radiograph is atypical for sarcoidosis or when hemoptysis occurs. 
Clinical Course
  • Acute  : ≤2 years
  • Chronic : ≥3–5 years
  • Refractory : progressing despite treatment 
References:
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