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Sarcoidosis
“The Great Mimicker”
Richard F. Duff III, MD
Pulmonary/Critical Care Medicine
Sarcoidosis of Boeck
• First recognized as a skin lesion by Jonathan
Hutchinson in 1869
• First recognized in lymph nodes by Ziegler in 1881
• Besnier 1889 “lupus pernio”
• Boeck published 1899
• Generalized disease
• Affects skin, bones, organs
• Resembled sarcoma
– “multiple benign sarcoid of the skin”
Sarcoidosis of Boeck
• Initially thought infectious process
– Related to tuberculosis
• Schaumann first real description as
generalized disease 1914
– “lymphogranulomatosis benigna”
Sarcoidosis
• Affects people of all racial groups
• All ages
– Usually develops before age 50
– Peak incidence ages 20-39
– 0.06/100000 children < 4 yrs old
• Highest annual incidence in Northern European countries
followed by Japan
• Blacks 3x > Whites
• tends to occur later in life (4th decade)
• More likely to be chronic and/or fatal
Sarcoidosis
• Bimodal distribution in females
• 20’s and 60’s
• Socioeconomic status does not affect risk
• Lower incomes associated with more severe disease
• Great Mimicker
• Affects any organ, most commonly lung, eyes, skin
• Environmental? (airborne antigens)
– Wood burning stoves, Tree pollen, Insecticides, Inorganic
particles, Metal workers, Military, Firefighters 2001 WTC
bombing, molds, mycobacterium
Sarcoidosis
• No formal twin study completed
– Appears to be higher in monozygotes
• Siblings born to parents with sarcoid at risk
– Ocular or hepatic involvement (3%)
• Genes
– Class I HLA-B8
– Class II HLA-DRB1, DQB1
Sarcoidosis genes
Known To Date
Chromosome 6p
Chromosome 3p
White Germans
Chromosome 5p, 5q
Chromosome 3p, 5q11.2
Black Americans
Chromosome 5p15.2
Protective
Chromosome 1p36
Radiographic resolution
Chromosome 18q22
Cardiac/Renal involvement
Pathophysiology of Sarcoidosis
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Biochemistry
Organ involvement
Immune pathophysiology
Aggravating/Alleviating factors
Immunopathogenesis
• Granulomas are fundamental abnormality
– Organized collections of macrophages and
epithelial cells surrounded by lymphocytes
– Multinucleated giant cells
– Increased CD4:CD8
• IL-2, INF-Y, TNF-a
– Immune paradox; anergy
• CD25
Organ involvement
• Granulomas can involve ANY organ
– 90% intrathoracic lymph nodes
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Lung
Skin
Eye
combo
Organ involvement
• Lung
– Dyspnea
– Wheezing
– Vague chest discomfort
• Scadding stages are degrees of radiographic
involvement and do not correlate with
changes in PFT’s
Organ involvement
• Lung
– Fibrosis
– Abscess/mycetoma
– Bronchiectasis
– Hemoptysis
– Pulmonary hypertension
• 20% at rest, 40% with exertion
Organ involvement
• Pulmonary fibrosis 20-25% patients
– MMP 8 and 9 increased in BAL
– Lower metalloproteinase 1 levels
– TH2  IL 4, 10, 13, fibronectin, and CCL18
Sarcoidosis scadding stage IV
Sarcoidosis with mycetoma
Organ involvement
• Skin/Bone
– Not life threatening, but morbidity can be high…
• Emotionally devastating
• Nape of neck, back, extremities, face
• 25% pts
• Singular lesions or crops
– Lupus pernio
• Nose, cheeks, lips, ears
• Erodes cartilage
• May have bone involvement
• Women > men
• Usually extrapulmonary disease and chronic
Organ involvement
• Skin/bone
– Erythema nodosum
• 10%
• Lasts 3 weeks
• Septal panniculitis if biopsied
– Neither confirms nor negates diagnosis of sarcoidosis
Organ involvement
• Liver and Spleen
– 10%
– Cholestatic syndrome (infrequent)
– Blacks twice more likely than whites
– Cirrhosis, portal hypertension, hepatic failure < 1%
Organ involvement
• CNS
• 25% at autopsy, 10% with symptoms
– Cranial nerve palsies
– Headache
– Ataxia
– Cognitive dysfunction
– Weakness
– Seizures
• Precede diagnosis in up to 74%
• Solitary manifestation 10-15%
Organ involvement
• Ophthalmologic
– Eye and Adnexa involved 20-80%
– Anterior uveitis most common manifestation; 65%
• Glaucoma, Vision loss (chronic)
– Posterior uveitis 30%
• Usually accompanied by CNS involvement
Organ involvement
• Cardiovascular
– Cardiac granulomas 25% autopsy, 5% symptoms
• LV free wall followed by IV septum
– Conduction system
– Manifested as cardiomyopathy,
tachy/bradyarrythmias
• Palpitations, syncope, death
– Endomyocardial biopsy yield < 20%
Organ involvement
• Renal
– Hypercalciuria 40%
– Hypercalcemia 10%
– Nephrolithiasis 10%
• Sarcoid granulomas contain 25-hydroxyvitamin D-1ahydroxylase1,25 hydroxyvitamin D
• Renal failure more likely due to intrarenal calcinosis
than granulomatous nephritis
Organ involvement
• Bone and Joints
– Lesions scattered throughout skeleton
– Confused with metastasis
– Lupus pernio
– Arthralgias more common than frank arthritis
Diagnosis of Sarcoidosis
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Clinical Presentation
Laboratory
Radiology
Histology
PFT’s
Clinical findings
• CXR during routine screening exam
• Fatigue, night sweats, weight loss
• Lofgrens syndrome
– Arthritis (usually medium joint), erythema
nodosum, hilar lymphadenopathy
– Good prognosis
Diagnosis
• Clinical, radiographic findings, and histology
– Non-caseating granulomas in the absence of
organisms or particles (AFB, Fungi, Berylium)
• Unless Lofgrens syndrome
• Bronchoscopic TBBx ~85% yield
• EBUS TBNA ~82% yield
• Kviem Siltzbach preparation (not used anymore)
True positives > 50%, false positives near 0
• Response to CS does not = Sarcoidosis
Radiology
• CXR is usually suggestive
– Scadding stages do not reflect chronology of disease
• CT not always needed, unless D/DX or road map
for biopsy
– PET CT esp if without lung involvement
Radiology
• Gadolinium cardiac MRI
• PET CT
Laboratory values
• ACE controversy
– Produced by granulomas
– Elevated in 60% pts
– Lacks sensitivity and specificity
• PPV 84%, NPV 74%
– Poor therapeutic guide
Laboratory values
• CSF
– Non-specific lymphocytosis
– 1/3 oligoclonal immunoglobulin bands
• Difficult to differentiate from MS!
Laboratory values
• 24 hour urine excretion for calcium
– Normal is 100-300mg/day (for normal diet)
• If high, consider checking 1,25 vit D levels and iCA
• Thiazide diuretics lower urine calcium levels
PFT’s
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65% Restrictive pattern with reduced FVC
50% concomitant obstruction
83% airway hyperreactivity
80% return to normal after two years
ECG
Treatment of Sarcoidosis
• Organ involvement and derangement
• Options for therapy
Treatment
• None at all unless organ function threatened
or deranged
• Prednisone 20-40 mg/day
– Evaluate response in 1-3 months
• + Reduce dose 5-15mg/day for 9-12 months
• - Non-adherence, fibrosis, inadequate dose
Treatment
Treatment
• Immunosuppressive/Cytotoxic drugs
– Anecdotal or small sample size
– MTX is best steroid sparring alternative
– Hydroxychloroquine for hypercalcemia, skin, or
neurologic involvement
– Minocycline for skin
Treatment
• MTX
– Structurally similar to folic acid, inhibits DHFR
• Decreased synthesis of thymidylate, purine nucleotides,
amino acids
– Does not penetrate CNS
• Can be given intrathecally
– Myelosuppression, hemorrhagic enteritis,
neurotoxicity, pneumonitis, hepatotoxicity, alopecia
• Toxic effects reduced by co-administration of folinic acid
Treatment
• Thalidomide, pentoxyfylline, Infliximab,
Etanercept
– Suppress TNF-a
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case reports for refractory disease
Hypersensitivity rxn’s, headache, serum sickness
Sepsis
Development of malignancy
Treatment
• Hydroxychloroquine
– Removes excess Fe stores from liver
• Decreases DNA and RNA synthesis
– Decreases leukocyte chemotaxis
– Decreases T-lymphs response to mitogens
– Dermatitis, myopathy, ***Irreversible retinal
degeneration
– Ophthalmology eval Q 6 months
Treatment
• Transplant
– 3% of all lung
– 1% of all heart and liver
– Sarcoidosis can re-occur in allografts
Sarcoidosis Prognosis
• 2/3 remission within a decade of diagnosis
• 50% remission within three years
• 1/3 unrelenting disease with organ
impairment
• Relapse after one or more years of remission
is uncommon
• <5% Die
– Respiratory failure, cardiac, neurologic
involvement
Sarcoidosis Management
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Screening
Complications of disease
Complications of therapy
When to refer