Sarcoidosis
Sarcoidosis is a systemic inflammatory disorder with manifestations ranging from abnormal
chest radiographic findings to severe multiorgan involvement. ACCESS trial evaluating 736
patients confirmed that 95% had thoracic involvement, 30-50% had also extrathoracic
involvement and only 2% had isolated extrathoracic sarcoidosis. ≈50% is detected
incidentally by X-ray. Sarcoidosis is the most prevalent cause of fibrotic lung interstitial
disease after IPF.
Epidemiology
60/100.000 (USA), 3-4x times more common in Black Americans. The average age of
diagnosis is 40-55yrs and onset is typically at a younger age in males (30–50yrs) compared to
females (50-60yrs) and the disease onset is ≈10 years earlier in Blacks than in Whites.
Risk factors
-Black race: the lifetime risk for Blacks is 2.4% vs. 0.85% for Whites. Blacks tend to be
affected more acutely and with more severe disease than Whites, who tend to present with
asymptomatic and chronic disease.
-Family history: positive family history has 4-5x risk. The absolute risk that a sibling or parent
of a sarcoidosis patient will develop sarcoidosis is 1%.
Causes
The ACCESS trial reported an increased risk in people with exposure to (1) water sources
that serve as reservoirs for aerosolized microbial antigens [agriculture and water-damaged
areas rich in molds], (2) metal industry [heavy metals and mycobacteria-contaminated metal
working fluids], (3) inorganic particulate matter [silicates], (4) insecticides. Interestingly,
multiple studies have shown that cigarette smoking decreases the risk.
Infectious: Mycobacterial and Propionibacterial nucleic acid have been recovered
from sarcoid granulomas. Recently, Mycobacterium tuberculosis DNA coding for a catalase-
peroxidase protein (mKatG) has been found in sarcoid biopsy specimens (38%). Additionally,
peripheral blood and lung T-cell responses as well as circulating IgG against mKatG are
increased in 50% of sarcoid patients. Kveim-Siltzbach reagent (homogenates of human
sarcoid tissue): 70% of patients with early sarcoidosis develop granulomatous inflammation
identical to sarcoidosis 4-6wks after the intradermal injection of this reagent. Vimentin is a
type III filament protein that is part of the cytoskeleton of human mesenchymal cells and
bacteria and a component of the Kveim-Siltzbach reagent.
Occupational: beryllium, zirconium and aluminum. World Trade Center case series,
sarcoidosis (https://www.mdpi.com/1660-4601/16/7/1291).
Genetics: 40% of sarcoidosis is due to genetics. Also HLA-DRB1*11 (and other).
Löfgren and non-Löfgren syndrome are associated with different loci. The novel gene BTNL2
has been associated with sarcoidosis in a GWAS analysis using a cohort of Caucasian
patients. Also the ANXA11 (annexin A11).
Respiratory (95%)
Any part from sinuses to lungs. Granulomas are found in peribronchovascular distribution
and can be necrotizing (non-caseating).
•asymptomatic hilar adenopathy (20-50%)
•ILD
•Fibrosis
•Hemoptysis is rare and occurs primarily in patients with fibrosis and cavitation filled with
aspergillomas
•Pulmonary hypertension (5-15%, mostly from pre-capillary PAH). Mostly IV stage.
, •Pleural involvement is unusual (<5%), but can result in lymphocytic exudative effusion,
chylothorax, hemothorax and pneumothorax.
•Upper respiratory: nose (even saddle-nose), sinuses, larynx.
Eye (25-50%)
Initial manifestation at 5%. Because the disease may be asymptomatic (30%), all patients
with sarcoidosis should have a baseline slit-lamp and fundoscopy with repeat examinations
annually or with development of symptoms. Any area of the eye may be involved! Acute
anterior uveitis is the most common presentation and is usually bilateral (as in Behçet, but
dx with SpAs [unilateral]). Other ophthalmologic manifestations include interstitial keratitis,
posterior uveitis, pars planitis (“snowballing” on slit-lamp), scleral plaques, lacrimal gland
enlargement (15-30%), optic neuropathy, retinal vasculitis and corneal/conjunctival nodules.
Along with Behçet, it causes panuveitis and retinal vasculitis (with anterior being the most
common). Posterior might be silent, so ophthalmologic check. Secondary glaucoma,
cataracts and impaired vision are potential late complications due to the underlying disease
or chronic GC therapy.
Skin (25%)
granulomatous inflammation on biopsy
-papular / nodular / maculopapular (2-5mm) on the face, neck and upper back.
-psoriasiform skin plaques
-annular lesions (associated with worse prognosis and chronicity)
-atrophic and ulcerative lesions
-Lupus pernio: predilection for Black and Puerto Rican women. It is the most characteristic
and specific skin manifestation (indurated and violaceous, primarily on the nose, cheeks,
ears, lips and fingers; they tend to be slowly progressive and disfiguring). It has significant
association with chronic upper respiratory tract involvement, pulmonary fibrosis and bony
lesions of the phalanges. It is less responsive to treatment than other sarcoidosis lesions.
Without treatment, the lesions progressively infiltrate and indurate, eventually resulting in
erosion into the underlying cartilage and bone.
non-specific lesions without granulomas on biopsy
-Erythema nodosum (10%): the most common of non-specifics (a panniculitis). Young white
females and it is usually associated with an acute presentation and benign course (=Löfgren).
Scars and tattoos can become infiltrated with sarcoidosis.
Cardiac
Sarcoidosis may affect any part of the heart except the valves. Symptomatic cardiac
involvement 5%, but cardiac lesions are considerably more common at autopsy (20% USA,
7% Japan). It frequently coexists with neurosarcoidosis. Myocardial biopsy findings are often
negative because cardiac sarcoid lesions tend to be heterogeneous and have a predilection
for the left ventricular free wall (we biopsy the right heart mostly).
-Pericarditis: common
-Sarcoid nodules
-Infiltrative cardiomyopathy
-Heart block: due to conduction irregularities. Cardiac sarcoidosis can cause sudden
death due to ventricular arrhythmias.
Nervous (5-10%)
Neurosarcoidosis has a predilection for the base of the brain and the hypothalamic/pituitary
regions and can occur without pulmonary or systemic features of sarcoidosis.
CNS
i. Cranial neuropathy (25-50%)
Sarcoidosis is a systemic inflammatory disorder with manifestations ranging from abnormal
chest radiographic findings to severe multiorgan involvement. ACCESS trial evaluating 736
patients confirmed that 95% had thoracic involvement, 30-50% had also extrathoracic
involvement and only 2% had isolated extrathoracic sarcoidosis. ≈50% is detected
incidentally by X-ray. Sarcoidosis is the most prevalent cause of fibrotic lung interstitial
disease after IPF.
Epidemiology
60/100.000 (USA), 3-4x times more common in Black Americans. The average age of
diagnosis is 40-55yrs and onset is typically at a younger age in males (30–50yrs) compared to
females (50-60yrs) and the disease onset is ≈10 years earlier in Blacks than in Whites.
Risk factors
-Black race: the lifetime risk for Blacks is 2.4% vs. 0.85% for Whites. Blacks tend to be
affected more acutely and with more severe disease than Whites, who tend to present with
asymptomatic and chronic disease.
-Family history: positive family history has 4-5x risk. The absolute risk that a sibling or parent
of a sarcoidosis patient will develop sarcoidosis is 1%.
Causes
The ACCESS trial reported an increased risk in people with exposure to (1) water sources
that serve as reservoirs for aerosolized microbial antigens [agriculture and water-damaged
areas rich in molds], (2) metal industry [heavy metals and mycobacteria-contaminated metal
working fluids], (3) inorganic particulate matter [silicates], (4) insecticides. Interestingly,
multiple studies have shown that cigarette smoking decreases the risk.
Infectious: Mycobacterial and Propionibacterial nucleic acid have been recovered
from sarcoid granulomas. Recently, Mycobacterium tuberculosis DNA coding for a catalase-
peroxidase protein (mKatG) has been found in sarcoid biopsy specimens (38%). Additionally,
peripheral blood and lung T-cell responses as well as circulating IgG against mKatG are
increased in 50% of sarcoid patients. Kveim-Siltzbach reagent (homogenates of human
sarcoid tissue): 70% of patients with early sarcoidosis develop granulomatous inflammation
identical to sarcoidosis 4-6wks after the intradermal injection of this reagent. Vimentin is a
type III filament protein that is part of the cytoskeleton of human mesenchymal cells and
bacteria and a component of the Kveim-Siltzbach reagent.
Occupational: beryllium, zirconium and aluminum. World Trade Center case series,
sarcoidosis (https://www.mdpi.com/1660-4601/16/7/1291).
Genetics: 40% of sarcoidosis is due to genetics. Also HLA-DRB1*11 (and other).
Löfgren and non-Löfgren syndrome are associated with different loci. The novel gene BTNL2
has been associated with sarcoidosis in a GWAS analysis using a cohort of Caucasian
patients. Also the ANXA11 (annexin A11).
Respiratory (95%)
Any part from sinuses to lungs. Granulomas are found in peribronchovascular distribution
and can be necrotizing (non-caseating).
•asymptomatic hilar adenopathy (20-50%)
•ILD
•Fibrosis
•Hemoptysis is rare and occurs primarily in patients with fibrosis and cavitation filled with
aspergillomas
•Pulmonary hypertension (5-15%, mostly from pre-capillary PAH). Mostly IV stage.
, •Pleural involvement is unusual (<5%), but can result in lymphocytic exudative effusion,
chylothorax, hemothorax and pneumothorax.
•Upper respiratory: nose (even saddle-nose), sinuses, larynx.
Eye (25-50%)
Initial manifestation at 5%. Because the disease may be asymptomatic (30%), all patients
with sarcoidosis should have a baseline slit-lamp and fundoscopy with repeat examinations
annually or with development of symptoms. Any area of the eye may be involved! Acute
anterior uveitis is the most common presentation and is usually bilateral (as in Behçet, but
dx with SpAs [unilateral]). Other ophthalmologic manifestations include interstitial keratitis,
posterior uveitis, pars planitis (“snowballing” on slit-lamp), scleral plaques, lacrimal gland
enlargement (15-30%), optic neuropathy, retinal vasculitis and corneal/conjunctival nodules.
Along with Behçet, it causes panuveitis and retinal vasculitis (with anterior being the most
common). Posterior might be silent, so ophthalmologic check. Secondary glaucoma,
cataracts and impaired vision are potential late complications due to the underlying disease
or chronic GC therapy.
Skin (25%)
granulomatous inflammation on biopsy
-papular / nodular / maculopapular (2-5mm) on the face, neck and upper back.
-psoriasiform skin plaques
-annular lesions (associated with worse prognosis and chronicity)
-atrophic and ulcerative lesions
-Lupus pernio: predilection for Black and Puerto Rican women. It is the most characteristic
and specific skin manifestation (indurated and violaceous, primarily on the nose, cheeks,
ears, lips and fingers; they tend to be slowly progressive and disfiguring). It has significant
association with chronic upper respiratory tract involvement, pulmonary fibrosis and bony
lesions of the phalanges. It is less responsive to treatment than other sarcoidosis lesions.
Without treatment, the lesions progressively infiltrate and indurate, eventually resulting in
erosion into the underlying cartilage and bone.
non-specific lesions without granulomas on biopsy
-Erythema nodosum (10%): the most common of non-specifics (a panniculitis). Young white
females and it is usually associated with an acute presentation and benign course (=Löfgren).
Scars and tattoos can become infiltrated with sarcoidosis.
Cardiac
Sarcoidosis may affect any part of the heart except the valves. Symptomatic cardiac
involvement 5%, but cardiac lesions are considerably more common at autopsy (20% USA,
7% Japan). It frequently coexists with neurosarcoidosis. Myocardial biopsy findings are often
negative because cardiac sarcoid lesions tend to be heterogeneous and have a predilection
for the left ventricular free wall (we biopsy the right heart mostly).
-Pericarditis: common
-Sarcoid nodules
-Infiltrative cardiomyopathy
-Heart block: due to conduction irregularities. Cardiac sarcoidosis can cause sudden
death due to ventricular arrhythmias.
Nervous (5-10%)
Neurosarcoidosis has a predilection for the base of the brain and the hypothalamic/pituitary
regions and can occur without pulmonary or systemic features of sarcoidosis.
CNS
i. Cranial neuropathy (25-50%)
