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Flashcards in 31 Sarcoidosis Deck (17)
1

Epidemiology

  • Sarcoidosis 
  • Prevalence and incidence in the differential diagnosis
  • Geographic and racial differences 
  • Racial differences 

  • Sarcoidosis
    • A multisystem granulomatous disease of unknown etiology
    • Frequently affects intrathoracic organs
    • Associated with characteristic abnormalities of the cellular and humoral immune systems
  • Prevalence and incidence in the differential diagnosis
    • Sarcoidosis: 5-80 / 100,000 / year
    • Lymphoma: 10 / 100,000 / year
    • Tuberculosis: 5-45 / 100,000 / year
  • Geographic and racial differences
    • May in part reflect health care delivery systems, access, and utilization
    • More common the further away from the equator
  • Racial differences
    • Might reflect geographical differences, issues of access, utilization, and disease reporting
    • African Americans are affected ~10x more often than Caucasians in the US, but not in Europe or Asia

2

Epidemiology

  • Examples of “clustering” of the disease in families or unrelated individuals residing in the same location
  • Presentation of acute, symptomatic disease appears to be greatest from...
  • The disease is slightly more common in...
  • Smoking
  • Age 
  • Gender

  • Examples of “clustering” of the disease in families or unrelated individuals residing in the same location
    • Isle of Man in the mid-1980’s
    • Families where the percentage of members affected is much higher than predicted based on local prevalence figures (range from 0.7 to 4.6%)
    • Health care workers in whom the prevalence has been reported to be 3 times higher than expected
  • Presentation of acute, symptomatic disease appears to be greatest from...
    • Early spring to early summer (March to June)
  • The disease is slightly more common in...
    • Farm workers exposed to grains
  • Smoking
    • Heavy smokers appear to have a lower prevalence
    • Cigarette smoke may be suppressing the lung’s immune system and inflammatory response, thereby limiting the severity of the disease
    • Heavy smokers come from lower socio-economic strata where access to health care and screening is less available
  • Age
    • Peak incidence between the ages of 25 and 40
    • Becomes less common with increasing or decreasing age
    • Very uncommon before the age of 15
  • Gender
    • Women and men are affected nearly equally

3

Frequency of organ involvement (highest to lowest % affected)

  • Lung >90%
  • Liver 50-80%
  • Eyes 11-80%
  • Hilar Lymph Nodes 72%
  • Skin 25%
  • Kidney 20%
  • Erythema Nodosum 15%
  • Spleen 10%
  • Central Nervous System 10%
  • Sinuses and URT 6%
  • Heart 5%

4

Pathogenesis

  • Immune system of affected individuals 
  • T-helper cells
  • Macrophages 
  • B cells 
  • Common in subjects with active disease

  • Immune system of affected individuals
    • Activation is highly compartmentalized to areas of disease activity
  • T-helper cells
    • Predominant type of lymphocyte activated
    • Demonstrate high affinity IL-2 receptors, MHC Class II antigens, and the marker CD45RO+ indicating the cells are primed to specific antigens
    • Also markers indicating the cells are actively proliferating
  • Macrophages
    • Also express the activation phenotype with high levels of MHC II and adhesion molecules
  • B cells
    • Also activated, probably because of increased levels of help from the activated T cells
  • Common in subjects with active disease
    • Polyclonal hypergammaglobulinemia

5

Pathogenesis

  • TH1 cells 
  • Macrophages
  • Ineffective removal of antigen(s) leads to...
  • Impaired TH2 response may lead to...
  • Specific antigens unique to sarcoidosis ("sarcoidosis antigens") are responsible for...

  • TH1 cells
    • The predominant phenotype for the T cells
    • When activated, they spontaneously produce IL-2, IL-12, IL-15 and INF-gamma in vitro
  • Macrophages
    • Spontaneously produceof IL-12, which acts as a T cell growth factor
  • Ineffective removal of antigen(s) leads to...
    • Positive feedback between INF-gamma and IL-12
    • Low to undetectable production of IL-4 and IL-5
  • Impaired TH2 response may lead to...
    • Slower clearing of the putative antigens
    • Increased severity and duration of disease
  • Specific antigens unique to sarcoidosis ("sarcoidosis antigens") are responsible for...
    • The activation of the immune system in sites of disease

6

Pathogenesis

  • T cell activation takes place through....
  • The antigen-MHC complex then...
  • TCR’s are comprised of...
  • Antigen specificity 
  • Activation of antigen specific cells

  • T cell activation takes place through....
    • Presentation of antigen peptides in the groove of the MHC II molecule on the surface of antigen presenting cells (macrophages and B-cells)
  • The antigen-MHC complex then...
    • Interacts with the antigen specific T cell receptor (TCR)
  • TCR’s are comprised of...
    • Either alpha-beta or gamma-delta chains, with the former being much more common
  • Antigen specificity
    • Occurs in the variable region of the chains where an enormous number of specificities are possible due to rearrangement of germ line genes for the variable, diversity and junctional regions of the TCR
    • Theoretically, there can be over 25,000,000 distinct TCR specificities

7

Pathogenesis:
Activation of antigen specific cells

  • Leads to...
  • Preferences for the V-beta 2,3,6,8,12 regions along with V-alpha 2,3
  • Preferences for gamma-delta chains

  • Leads to clonal expansion of cells with a limited array of V-alpha and V-beta regions
  • Preferences for the V-beta 2,3,6,8,12 regions along with V-alpha 2,3
    • The latter seems to occur in subjects who express HLA DR3, DQ2 haplotype
  • Preferences for gamma-delta chains
    • Do not require MHC II presentation of antigen
    • This type of TCR is thought to be important in the recognition of Mycobacterium tuberculosis, another disease characterized by granulomata formation due to an immunological response to this obligate intracellular pathogen

8

Pathogenesis

  • MHC Class II molecules on antigen producing cells
  • Possible antigens
  • Differences in pro and anti-inflammatory gene expression related to single nucleotide polymorphism (SNP) 

  • MHC Class II molecules on antigen producing cells
    • Haplotypes containing HLA-DR3/DQB1*0201 are associated with remission of disease
    • Haplotypes with DQB1*0602/DRB1*1501 are associated with progression and severe disease
  • Possible antigens
    • Bacterial antigens specific to mycobacteria
  • Differences in pro and anti-inflammatory gene expression related to single nucleotide polymorphism (SNP)
    • The frequency of SNP’s for TNF-alpha, TGF-beta, complement receptors and Ig light chains differ in patients with sarcoidosis compared to normals with no evidence of disease

9

Radiographic staging of pulmonary sarcoidosis:
Stage I

  • The findings of this stage 
  • What % of subjects with sarcoidosis present with Stage I disease
  • Extrathoracic disease 
  • The prognosis of subjects presenting with Stage I disease 
  • Severe pulmonary fibrosis 

  • The findings of this stage
    • Hilar and/or mediastinal adenopathy in the absence of radiographic pulmonary infiltrates
    • A right paratracheal node is often present and quite prominent
    • Often enlargement of nodes in the aorto-pulmonary window
  • What % of subjects with sarcoidosis present with Stage I disease
    • Between 40 and 60%
  • Extrathoracic disease
    • Detected in fewer than 10% of these individuals
  • The prognosis of subjects presenting with Stage I disease
    • Very good
    • Remits spontaneously over 1-2 years in 2/3 of such individuals
    • Progression to a higher radiographic stage occurs in 10-15%, but most of these subjects will eventually go into remission without treatment
  • Severe pulmonary fibrosis
    • An unusual outcome
    • Involvement of other organs such as the eye and kidney may lead to disability

10

Radiographic staging of pulmonary sarcoidosis:
Stage I

  • Löfgren’s Syndrome 
  • Typically, individuals experience...
  • A chest radiograph will usually reveal...

  • Löfgren’s Syndrome
    • Constellation of findings in patients with acute sarcoidosis
    • Presentation is almost pathognemonic for this form of sarcoidosis
  • Typically, individuals experience...
    • The acute onset of systemic symptoms such as fatigue, fever, chills and night sweats
    • Severe arthralgias or frank arthritis affecting multiple joints
    • Painful red nodular swelling over their tibia, which is called erythema nodosum
    • Dry or painful eyes and conjunctival injection and episcleritis
  • A chest radiograph will usually reveal...
    • Bilateral hilar adenopathy with or without paratracheal adenopathy
  • Prognosis
    • Although these individuals feel miserable, their prognosis is actually quite good
    • The arthritis, arthralgias and systemic symptoms are well controlled with NSAIDs
    • More severe cases respond to a short course of oral corticosteroids

11

Radiographic staging of pulmonary sarcoidosis:
Stage II

  • Findings of this stage
  • How many subjects will present with Stage Ii disease
  • The type of infiltrates 
  • Quite frequently the volume of the affected lungs...
  • There is often marked disparity between...

  • Findings of this stage
    • A combination of adenopathy and pulmonary infiltrates
  • How many subjects will present with Stage Ii disease
    • About 1/3 of subjects
  • The type of infiltrates
    • Highly variable
    • Typically, the interstitial markings are accentuated
    • In other cases, the infiltrates are nodular suggesting metastatic malignancy
    • In a few instances, they fill the airspaces creating pneumonic infiltrates that often have shaggy borders
  • Quite frequently the volume of the affected lungs...
    • Appears normal or only minimally decreased
  • There is often marked disparity between...
    • The symptoms of shortness of breath and the measured decline in pulmonary function and the extent of the infiltrates
    • Subjects with impressive infiltrates, may have minimal or no shortness of breath on exertion

12

Radiographic staging of pulmonary sarcoidosis:
Stage II

  • The prognosis of subjects presenting with Radiographic Stage II disease 
  • Typical CT findings of Stage II radiographic disease

  • The prognosis of subjects presenting with Radiographic Stage II disease
    • Generally favorable
    • The disease eventually goes into remission in slightly more than half
    • Another 1/4 will have a tendency to relapse over many years
    • The remainder will progress to some degree of pulmonary fibrosis, which may lead to pulmonary disability
  • Typical CT findings of Stage II radiographic disease
    • Prominence of the “bronchovascular bundles” which usually show “beading”
    • May be airspace disease as well
    • Fibrosis at this stage is very unusual

13

Radiographic staging of pulmonary sarcoidosis:
Stage III

  • The findings in this stage
  • How many individuals present in this stage
  • There is a good correlation between...
  • Prognosis

  • The findings in this stage
    • Here the striking finding is absence of hilar or mediastinal adenopathy
    • The infiltrates may take many forms but typically, the upper lobes are more involved than the lower lobes
  • How many individuals present in this stage
    • Very few individuals present in this stage, at most 15%
  • There is a good correlation between...
    • The severity of the radiographic disease and respiratory symptoms
    • Clinically evident extrathoracic disease is almost the rule
  • Prognosis
    • Relatively poor
    • Although such patients may not present with a high grade of pulmonary disability, they often progress despite therapy to end stage lung disease in 5-10 years

14

Radiographic staging of pulmonary sarcoidosis:
Stage IV

  • The typical appearance of a Stage IV radiograph
  • The difference between Stage III and IV 
  • Patients with stage IV radiographs often have...
  • Pulmonary function studies demonstrate...
  • Prognosis
  • The cystic disease may be the source of...

  • The typical appearance of a Stage IV radiograph
    • Diffuse infiltrates without notable adenopathy
  • The difference between Stage III and IV 
    • The volume loss in the upper lobes, which indicates scarring
    • There are often cystic changes adjacent to the areas of dense scarring
    • Lung markings are usually diminished in the lung bases suggesting emphysema
  • Patients with stage IV radiographs often have...
    • Significant respiratory symptoms such as shortness of breath on exertion, cough and sputum production and even hemoptysis
    • Pulmonary hypertension that further limits their exercise tolerance
  • Pulmonary function studies demonstrate...
    • Moderate to severe restrictive disease
  • Prognosis
    • Overall they have the poorest prognosis
  • The cystic disease may be the source of...
    • Mycetomas
    • Most mycetomas are due to Aspergillus fumigatus
    • They frequently cause hemoptysis, which has the potential to be life threatening
    • Pain in the chest wall over the affected area can be troublesome

15

Diagnosis

  • Cause of sarcoidosis 
  • The rigorous approach to diagnosis involves...
  • Other diseases in the differential diagnosis

  • Cause of sarcoidosis
    • Remains unknown
    • No specific cellular or biochemical marker for this disease
  • The rigorous approach to diagnosis involves...
    • Doing a biopsy of affected tissue
    • Demonstrating the presence of granulomatous inflammation
    • Eliminating all other causes of this form of inflammation
    • Thus, the diagnosis of sarcoidosis is a diagnosis by exclusion
    • A clinical diagnosis not based on the results of a biopsy may be made, but this approach must be employed with discretion
  • Other diseases in the differential diagnosis
    • I.e. infection and cancer
    • May go untreated if the diagnosis of sarcoidosis is incorrect

16

Treatment

  • General
  • Corticosteroids are often used to treat this disease
  • The course of untreated disease 
  • Immunosuppressive drugs
  • The most widely employed steroid-sparing agent 
  • Other examples of steroid-sparing agents

  • General
    • No specific therapy
  • Corticosteroids are often used to treat this disease
    • No evidence suggesting that they “cure” sarcoidosis or affect the long-term outcome
    • Occasionally a small dose of corticosteroid is required to maintain a clinical remission, but in some patients, corticosteroids can be stopped without the patient having a severe relapse
  • The course of untreated disease
    • Can be highly variable, with patients experiencing complete remission, relapsing disease, or chronic activity ending in fibrosis
  • Immunosuppressive drugs
    • Added when the side effects of corticosteroids require a reduction in dose
  • The most widely employed steroid-sparing agent
    • Methotrexate
  • Other examples of steroid-sparing agents
    • Leflunamide
    • Azathioprine
    • Tmour necrosis factor inhibitors
    • Infliximab

17

Mortality

  • Mortality rate 
    • Overall
    • African Americans
    • Caucasians
  • The causes of death 
  • Transplantation 
    • Has the potential to affect...
    • The outcome
    • What frequently develops

  • Mortality rate
    • Overall: ~5%
    • African Americans: ~10% 
    • Caucasians: ~1-3%
  • The causes of death
    • Respiratory failure
    • Massive hemoptysis from a mycetoma
    • Right heart failure from pulmonary hypertension
    • Left ventricular failure from cardiac involvement
    • Renal failure
  • Transplantation
    • Has the potential to affect mortality since it is effective palliative therapy for patients with advanced pulmonary, cardiac and renal involvement
    • The outcome after pulmonary transplantation is similar to that for other diseases
    • Granulomatous inflammation frequently develops in the lung allograft but rarely causes impaired function

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