A Practical Approach to
Sarcoidosis
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Kamyar Afshar, DO
Director, USC Center for Advanced Lung Disease
Disclosures
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• I have no financial or industry related conflicts of
interests to disclose related to this presentation
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Objectives
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Case Example
Pathophysiology & Epidemiology
Clinical Presentation
Diagnostic evaluation
Patient Monitoring
Treatment Options
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Sarcoidosis
Case Example
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Symptoms
Person
Physiological
Parameter
Imaging
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Case Example
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• 62 y/o Caucasian Male c/o 3 month history of DOE
and chest pressure with strenuous activity
• He was treated briefly (6 weeks) with oral
Prednisone with some symptomatic improvement.
He experienced adverse events with insomnia and
irritability
• After discontinuation of the prednisone, his DOE
recurred and images worsened
• He was patient wants a second opinion from you
PFTs
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FVC
84%
FEV
85%
FEV1/FV
C
79
FEF 25-
83%
75%
TLC
88%
RV
92%
DLCO
62%
Is the stage important?
What are your treatment
recommendation?
Helpful Radiographic Patterns
Differential Diagnosis of ILD
Upper zone predominance
Granulomatous disease
Sarcoidosis
Eosinophilic granuloma
Chronic hypersensitivity pneumonitis
Chronic infectious diseases (e.g., tuberculosis, histoplasmosis)
Pneumoconiosis
Silicosis
Berylliosis
Coal miners’ pneumoconiosis
Hard metal disease
Miscellaneous
Rheumatoid arthritis (necrotic nodular form)
Ankylosing spondylitis
Radiation fibrosis
Drug-induced (amiodarone, gold)
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Duration of Illness
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Acute (days to weeks)
< 3 WKS
Acute idiopathic interstitial pneumonia (AIP, “Hamman-Rich syndrome”)
Eosinophilic pneumonia
Hypersensitivity pneumonitis
Bronchiolitis obliterans with organizing pneumonia
Subacute (weeks to months) 3-12 WKS
Sarcoidosis
Some drug-induced ILDs
Alveolar hemorrhage syndromes
Idiopathic bronchiolitis obliterans with organizing pneumonia
Connective tissue disease (systemic lupus erythematosus or
polymyositis)
Chronic (months to years) >12 WKS
Idiopathic pulmonary fibrosis
Sarcoidosis
Eosinophilic Granuloma
Case Cont’d
FVC
84%
FEV
85%
FEV1/FV
C
79
FEF 25-
83%
75%
TLC
88%
RV
92%
DLCO
62%
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Differential Diagnosis
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Hilar adenopathy:
Non-caseating granuloma:
• Granulomatous infections • Granulomatous infections
– Tuberculosis
– Coccidioidomycosis
– Histoplasmosis
– Tuberculosis
– Coccidioidomycosis
– Histoplasmosis
• Auto-immune Disorder
• Berylliosis
• Malignancy
• Hypersensitivity pneumonitis
– Lymphoma
– Lung cancer
• Malignancy
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Questions to be answered in
deciding on diagnosis & therapy
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1. Is the patient symptomatic? (duration)
2. What is the likely culprit?
3. Does the patient exhibit life- or organ-threatening
disease?
a. Is the patient experiencing or is likely to experience, chronic
disease?
b. Does the patient have a relative or absolute contraindication to any
specific therapy?
4. What is the progression on his/her disease?
Eur Respir Mon, 2005, 32, 301-315 Printed in UK – all rights reserved. Copyright ERS Journals Ltd 2005; Europena Respiratory Monograph;
ISSN 1025-448x. ISBN 1-904097-22-7
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Sarcoidosis
Pathophysiology & Epidemiology
Sarcoidosis
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• It is a multi-system granulomatous disorder of
unknown etiology characterized by the activation of
T-lymphocytes and mononuclear phagocytes at the
sites of disease
– activated (CD4+) T lymphocytes and macrophages with
Th1 cytokine pattern
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Sarcoidosis
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• Develops in genetically predetermined hosts who
are exposed to certain environmental agents that
trigger an exaggerated inflammatory immune
response leading to granuloma formation
– Genetic susceptibility based on the data from
monozygotic twins who do not live in the same
environment
– Not a single gene noted
• Multiple subset genes that are protective or harmful
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Sarcoidosis
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• MHC Class I
– HLA B7 (high prevalence with African-Americans)
• MHC Class II
– HLA DR5, -DR8, - DR9
– HLA-DR5
– HLA-DR3
– HLA-DR14, -DR15
Japanese
Germans (chronic dz)
Germans (acute dz)
Scandanavian (acute)
Scandanavian (chronic)
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Fibrosis may result if Th2
reaction becomes more
dominant than the initial
Th1 reaction leading to
more prominent fibrosis
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Iannuzzi MC. Sarcoidosis. NEJM 2007;357:2153-2165
Epidemiology
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• More predominant in women
– Incidence 6.3 cases per 100,000 persons
• Annual incidence in the U.S. is 10/100,000 among
whites and 36/100,000 among African Americans
• Affects siblings of first- or second- degree relatives
in 15% of patients with sarcoidosis
– Familial cases described in 17% of African Americans,
but only 6% of whites.
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Sarcoidosis
Clinical Presentation
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Site Involved
Frequency (%)
Signs and Symptoms
Lung
90
Cough, dyspnea, CXR changes
Liver/Spleen
50-80
Hepatosplenomegaly, abnl LFTs
Eyes
50
Ueitis, irits, dry eyes
Bone & bone
marrow
40
Osteopenia/porosis, osteolytic lesions,
leucopenia, anemia
Skin
25
Indurated purple plaques, erythema
nodosum
Cardiac, Neuro
5-10
Arrythmias, CHF, encephalopathy, facial
nerve palsies
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Clinical Presentation
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• 30-50% of patients are asymptomatic and are
diagnosed on routine CXR
• One third have non-specific symptoms of fever,
fatigue, weight loss and malaise
– Onset of sarcoidosis in white patients is usually
asymptomatic
– African Americans tend to present with an earlier onset
and a more aggressive and severe clinical course
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Clinical Presentation
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• Spontaneous remission in two-thirds of patients
within 2 years of presentation
• 10%-30% experience chronic disease causing
progressive organ damage
• Leads to death in 4% of patients, usually those
with pulmonary, cardiac, or CNS involvement
• Patients who present with pulmonary parenchymal,
skin lesions (other than erythema nodosum), bone
lesions, cardiac disease, neurologic disease, or
renal disease are at increased risk for chronic
disease
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Sarcoidosis
Diagnostic Approach & Helpful Hints
Diagnosis of Sarcoidosis
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Established on the basis of :
• Clinical & Radiologic findings
• Supported by histologic evidence in one or more organs of
non-caseating epithelioid-cell granulomas
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How to establish Sarcoidosis diagnosis
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The diagnosis of a specific ILD is based on:
1.
Patient’s history and physical
2.
Radiograph appearance and laboratory
findings
3.
Bronchoalveolar lavage
4.
Transbronchial biopsy vs. Open lung biopsy
5.
Biopsy of extrathoracic tissues
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Classification
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Interstitial Lung Diseases
*Sarcoidosis
Hypersensitivity Pneumonitis
UIP/IPF
Fibrosis
AIP
1970s
“IPF”
“IPF”
LIP
2005
COP
Asbestosis
LAM
etc
IPs=Interstitial pneumonias
LAM=lymphangioleiomyomatosis
Adapted from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101.
Adapted from ATS/ERS. Am J Respir Crit Care Med. 2002;165:277-304.
Cellular
NSIP
DIP
Fibrotic
RBILD
Inflammation
Interstitial Lung Diseases
5 most common
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Usual interstitial pneumonia
Nonspecific interstitial pneumonia
Collagen Vascular Disease
Hypersensitivity Pneumonitis
Sarcoidosis
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Sarcoidosis
Thoracic Manifestations
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• Pulmonary Parenchyma
• Endobronchial involvement
• Pulmonary Vasculature
• Pleural involvement
• Lymphadenopathy
– Bilateral hilar, paratracheal (71% of patients) subcarinal
– Very uncommon:
• Isolated anterior mediatinal, isolated posterior mediastinal
• Unilateral hilar adenopathy
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Symptoms and Signs
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Symptoms
• Dyspnea of exertion
• Non-productive cough
• Fatigue, malaise
• Anorexia, weight loss
Signs
• Bilateral inspiratory crackles
• Extrapulmonary systemic findings: skin, joints
• Clubbing: IPF, asbestos, malignancy
• Exertional hypoxemia
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Uncommon Symptoms
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• Wheezing:
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Chronic eosinophilic pneumonia
Churg-Strauss syndrome
Lymphangitic carcinomatosis
Sarcoidosis
• Chest pain:
– Sarcoidosis
– Pleuritic pain seen in RA and SLE
• Hemoptysis:
– Granulomatous vasculitides, LAM, DAH, PVOD, mitral
stenosis, mycetoma
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PFTs in “ILD”
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• Generally restrictive physiology with a low DLco
except in:
– Sarcoidosis
– LAM/TSC
– IPF + COPD
In Sarcoidosis:
Bronchial mucosa often involved
40% in stage I
70% in stages II and III
Nodular elevation of mucosa
2-3 mm diameter
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Indication for lung biopsy
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to assess disease activity
to exclude neoplasm or infection
to identify a more treatable condition
to establish a definitive Dx before starting a
treatment with serious side effects
• to provide a specific diagnosis in patients with:
– atypically or progressive pattern
– a normal or atypical chest x-ray features
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Probability of obtaining histological
diagnosis
Transbronchial Biopsy
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Surgical biopsy
Granulomatous diseases
Malignant
tumors/lymphangitic
DAD (any cause)
Certain infections
Often
Alveolar proteinosis
Eosinophilic pneumonia
Vasculitis
Amyloidosis
EG/HX/PLCH
Sometimes
LAM
RB/RBILD/DIP
UIP/NSIP/LIP COP
Never
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Normal lung on pathology
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HP vs Sarcoidosis
What is the difference in the granuloma?
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• Sarcoidosis: well-formed
granulomas without
necrosis; present at the
bifurcation of a bronchiole
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Diagnosis
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Established on the basis of :
• Clinical & Radiologic findings
• Supported by histologic evidence in one or more organs of
non-caseating epithelioid-cell granulomas in the absence of
organisms or particles
– transbronchial biopsy has a diagnostic yield of at least
85% when multiple lung segments are sampled
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Sarcoidosis
Patient Monitoring &
Prognostic Indicators
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Stage
Remission Rate
I
Bilateral hilar lymphadenopathy and paratracheal
adenopathy
55-90%
II
Mediastinal adenopathy with pulmonary
parenchymal involvements
40-70%
III
Pulmonary parenchymal without adenopathy
10-20%
IV
Pulmonary fibrosis with honeycombing
0-5%
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Management of Sarcoidosis
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• Major goal of therapy
– Identify & aggressively treat the inflammatory process
– Removal of the offending agent
• No accurate or specific method available to stage
the intensity of the alveolitis in a serial fashion
• Followed by HRCT & PFT
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Monitoring
Quarterly visits
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• Subjective
– Symptoms: determine progression of disease, acute
exacerbations
– Monitor for infections
• FVC & DLCO, SpO2
• 6MWD, (desaturation study as indicated)
• Imaging – No need for HRCT unless scenario
mandates
• Labs
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Sarcoidosis
Treatments
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Treatment
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• Not all patients require therapy
• General: treat clinically significant, progressive dz
• All therapeutic regimens require monitoring
• Glucocorticoids may be the mainstay
• Steroid-sparing / immune-suppressing /
immunomodulatory / cytotoxic agents
• Nuance
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Case Example
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• 62 y/o Caucasian Male c/o 3 month history of DOE
and chest pressure with strenuous activity
• He was treated briefly (6 weeks) with oral
Prednisone with some symptomatic improvement.
He experienced adverse events with insomnia and
irritability
• After discontinuation of the prednisone, his DOE
recurred and images worsened
• He was patient wants a second opinion from you
Questions to be answered in
deciding on therapy
1. Is the patient symptomatic?
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YES
2. Does the patient exhibit life- or organ-threatening
disease?
YES
3. Is the patient experiencing or is likely to
experience, chronic disease?
PERHAPS
4. Does the patient have a relative or absolute
contraindication to any specific therapy?
NO
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Sarcoidosis and therapy
Factors taken into consideration
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• Spontaneous remission common
• Progressive fibrosis may occur
• Mortality (<5%)
• Short term responses to treatment common
• Relapses occur
– Relapse, Acute Pulmonary Exacerbation of Sarcoidosis
• Long term benefit of therapy unclear
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Why the differing opinions to treat?
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• Steroids may not alter the course of sarcoidosis
– Treatment should be reserved to alleviate symptoms
– Large number of individuals will have remission or follow
a benign course
• Steroids should be given to prevent irreversible
fibrosis (irrespective of symptomology)
– Should we treat based PFT, imaging or ACE level?
– Sarcoid activity: ACE, PET scan, Gallium scan
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If treating, then why the variable
treatment recommendations?
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1. Variation in disease outcomes
– Even within the same individual, different tissues
involved in sarcoidosis inflammation respond differently
to different medications
2. Controlling symptoms; no treatment cures
sarcoidosis
3. Patient and physician preferences
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Who should be treated?
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• Stage I & asymptomatic – no treatment, repeat
CXR in 6 months
• Stage II + NO symptoms – PET scan; if highly
active then treat; otherwise no treatment and follow
up in 3-6 months
• Stage II + symptoms – treat
– Monitor lung function, CXR, ACE level
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Who should be treated?
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• Stage III
– Asymptomatic with normal or mild lung function should
be monitored
– Asymptomatic with lung function deterioration and/or
positive PET scan should be treated for possible
reversible alveolitis
– Symptomatic – Always treat
• Stage IV – PET scan to assess activity to treat
– Treating the co-existing active alveolitis
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6 Phases of Steroid Therapy
Pulmonary Sarcoidosis
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The dose to induce
remission is higher than the
dose to maintain remission
20% 50%
Over a 6 month period
Judson MA. An approach to the treatment of pulmonary sarcoidosis with corticosteroids: The six phases of treatment. Chest
1999;115:1158-1165
Acute Pulmonary Exacerbation
of Sarcoidosis (APES)
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• Worsening of pulmonary symptoms for a minimum of 1 month and not explained
by another cause
• Patients can develop APES while receiving corticosteroids or alternative
therapies
Balancing cellular immunity to reduce
relapse rates with reducing complications
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• If the Ag is still present, the granulomatous process might resume
once therapy is withdrawn or tapered, resulting in APES
• APES may be more closely related to the duration of the initial
therapy than the use of a specific agent and/or doses
Panselinas E, Judson MA. Acute Pulmonary Exacerbation of Sarcoidosis. Chest 2012;142:827-836
Risk factors for sarcoidosis
relapse and APES
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Clinical factors of prognostic value
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Adverse prognostic factors:
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African-American
HLA-DR17 negative
Lupus pernio
chronic uveitis
age at onset > 40 years
hypercalcemia, nephrocalcinosis
cystic bone lesions
myocardial involvement
neurosarcoidosis
chronic respiratory insufficiency
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What if steroids are not enough or the
patient develops an adverse drug
event?
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THANK YOU FOR THE INVITATION!
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