sarcoidosis - namdrc.org culver saturday 3-16-19.pdfsarcoidosis arena, he has special interests in...
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SARCOIDOSIS DANIEL CULVER, DO DIRECTOR, INTERSTITIAL LUNG DISEASE PROGRAM CLEVELAND CLINIC CLEVELAND, OH
Daniel Culver received his BS from Ohio State University with degrees in Biology and English. He received his Doctor of Osteopathy from Heritage Ohio University College of Osteopathic Medicine, and then completed training at Southpointe Hospital and Cleveland Clinic for Internal Medicine and Pulmonary-Critical Care Medicine. He is the director of the Interstitial Lung Disease Program at Cleveland Clinic, Chair of the Scientific Advisory Board for the Foundation for Sarcoidosis Research, and the President-elect of the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG). He is the Research Officer for the Respiratory Institute at Cleveland Clinic. His interests include clinical trials, novel endpoint development, and newer therapies. In the sarcoidosis arena, he has special interests in cardiac sarcoidosis and small fiber neuropathy related to sarcoidosis. Outside of medicine, he stays busy with his wife and 3 children, and he is currently preparing for the Marine Corps Marathon at the time of this writing.
SATURDAY, MARCH 16, 2019 11:15 AM
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SARCOIDOSIS
Sarcoidosis disclosures
• Clinical trials/consulting– Celgene– aTyr– Mallinkrodt– Johnson & Johnson
• Research support– Foundation for Sarcoidosis Research– NHLBI– Ann Theodore Foundation– Mallinkrodt
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Which is false about the epidemiology of sarcoidosis?
1. More common in African-Americans
2. More common in females
3. Diagnosed before age 50 in most
4. Mortality rates are rising in the US
5. Prevalence is highest in the Southeast and lowest in the West
3
Mortality in Swedish sarcoidosis patients vs general population
Rossides M. Eur Respir J 2018
Rising sarcoidosis mortality in the US
Swigris JJ. AJRCCM 2011
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
Nu
mb
ers
of
De
ath
s
Mo
rta
lity
Rat
e p
er 1
,000
,00
0 P
op
ula
tio
n
Non-hispanic Males: Numbers of Deaths and Age-adjusted Mortality Rates per 1,000,000 Men
0
50
100
150
200
250
300
350
0
2
4
6
8
10
12
14
16
18
20
Deaths: Non- hispanic White Males
Deaths: Non- hispanic Black Males
Mortality Rates: Non- hispanic White Males
Mortality Rates: Non- hispanic Black Males
4
Sarcoidosis less common in the West
Baughman RP. Ann Am Thorac Soc 2016
Sarcoidosis in the US
2010-2013 Optum Database
Baughman RP. Ann Am Thorac Soc 2016
5
Female predilection
Most patients are >55 at the time of diagnosis now
Baughman RP. Ann Am Thorac Soc 2016
6
Mortality in Swedish sarcoidosis patients vs age
Rossides M. Eur Respir J 2018
Who is at risk for mortality in pulmonary sarcoidosis?
Walsh SLF. Lancet Respir Med 2015
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Validation cohort test performance
n=252
Fibrotic sarcoidosis is not UIP
8
Is mortality the best vantage point?
Complications of fibrosis
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Chest CT pattern correlates with exercise capacity
Lopes AJ. Lung 2011
Sarcoidosis burden in a US registry
Hospitalization
Large financial impact
n=2318
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Sarcoidosis penumbra
Lazar CA. SRCCM 2010
Cumulative risk of steroid complications
Other covariatesAge/yr 1.02 (1.00-1.04)
Pre-existing disease 2.27 (1.33-3.89)
HR: 2.37 (1.34-4.17)
Duration of steroids ( per month)1.023 (1.013-1.033)
Cumulative dose ( per gram)1.038 (1.019-1.056)
Khan NA. Respir Med 2017
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Which of the following is the least common cause of exercise limitation in sarcoidosis?
1. Airways hyper-reactivity
2. Cardiac sarcoidosis
3. Pulmonary hypertension
4. Large airways stenosis from endobronchial disease
5. Myopathy
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Multifaceted dyspnea of sarcoidosis
Dyspneic sarcoidosispatient
Anemia
Cardiac sarcoidosis
Diaphragm myopathy
Pulmonary HTN
Obesity
Deconditioning Airways stenosisBronchospasm
Asthmatic symptoms are common
• Endobronchial involvement in up to 75%
• Obstructive physiology in up to half
• Positive methacholine challenge test 21%
• May respond to inhaled corticosteroids and bronchodilators
• Proximal airway stenosis in 3-5 % RUL
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Unusual causes of dyspnea
Sarcoidosis Associated PAH—membership in WHO Group 5
LV diseaseHypoxia
Portopulmonary HTN
Elevated pulmonary pressure
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Granuloma distribution and pulmonary hypertension
Diaz-Guzman E. Clin Chest Med 2008
Pulmonary hypertension in sarcoidosis
0
10
20
30
40
50
60
70
80
Per
cent
wit
h P
ulm
onar
y
Hyp
erte
nsio
n
Kyoto Detroit Milan New York Cincinnati Transplant
All patients Only Dyspneic Patients
Baughman RP, Culver DA, Judson MA. AJRCCM 2011
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Pulmonary hypertension in a large international registry
Baughman RP. Resp Med 2018
n=176
Do clinical markers predict SAPH?
Baughman RP. Resp Med 2018
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Survival from time of RHC
Group123
0 500 1000 1500 2000 2500
100
90
80
70
60
50
40
30
Days from Catheterization
Sur
viva
l pro
babi
lity
(%)
Normal PAPH-LVDSAPAH
Baughman RP. Chest 2010
p<0.02
RCT of bosentan for SAPH
p=0.01
p=0.01
Baughman RP. Chest 2014
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Shlobin OA. In press
6MWT and FEV1/FVC ratio were the strongest predictors of survival
Respiratory muscle weakness in sarcoidosis
Kabitz HJ. Chest 2006
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Marcellis RG. ERJ 2011 Spruit MA. Thorax 2005
Muscle weakness relates to other variables affecting QOL
6MWD Hand grip Extensor Quadriceps PT
HPT Pimax
Men -0.25 -0.25 -0.29 -0.17 -0.36 0.24
Women -0.12 -0.21 -0.30 -0.04 -0.043 0.051
Spruit MA Thorax 2005
Steroids are associated with muscle weakness in sarcoidosis
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Which is true about cardiac sarcoidosis?
1. Most common presentation is ventricular dysrhythmias
2. Most common in black females
3. Cardiac FDG-PET is the diagnostic test of choice
4. Serum ACE level is usually normal
5. All are true
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Which is true about cardiac sarcoidosis?
1. Most common presentation is ventricular dysrhythmias
2. Most common in black females
3. Cardiac FDG-PET is the diagnostic test of choice
4. Serum ACE level is usually normal
5. All are true
Frequency of cardiac sarcoidosis
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Prevalence of cardiac abnormalities in various series
AV block 26-62%
Bundle branch block 12-61%
Cardiomyopathy 10-30%
Ventricular tachycardia 2-42%
Supraventricular tachycardia
0-15%
Kim JS. Am Heart J. 2009
I
MRI is the most specific test for evaluating possible CS
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Cardiac PET scan assesses scar and inflammation
Who is at higher risk for cardiac involvement
• White males—FSR registry– O.R. 1.4 for whites vs blacks
– O.R. 1.8 for males vs females
• Neurologic and ocular disease
• Multisystem disease
• Chronic disease
• Ocular-cutaneous-CNS-cardiac cluster
Lower EE. Arch Intern Med 1997 Rybicki BA. Genes Immun 2007Inoue Y. PlosOne 2015 Schupp JC. Eur Respir J 2018
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How can we arrive at a diagnosis?
“The diagnosis is established whenclinicoradiological findings are supportedby histological evidence of non-caseatingepithelioid cell granulomas. Granulomasof known causes and local sarcoidreactions must be excluded…..”
ATS Statement on Sarcoidosis. Am J Resp Crit Care Med 1999
Does bronchoscopy have a role in the diagnosis of extrapulmonary sarcoidosis?
17 patients with mediastinal LN <10 mm
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Typical chest CT features may be diagnostic
56%
76%
54%
• 66% of sarcoidosis diagnosed with high confidence (>75% certain)• 87% of sarcoidosis diagnosed as leading choice
Grenier P. Radiology 1991
FeatureRelative frequency in
sarcoidosisMajor differential considerations
Perilymphatic nodules predominating in the
mid‐to upper lung zones
+++Granulomatous infection (usually
unilateral)
Nodular thickening of the bronchovascular
bundles, interlobular septae, fissures
and/or pleura
+++
Lymphangitic tumor spread
Bilateral hilar lymph node enlargement ++++ Lymphoma, granulomatous infection,
heart failure, reactive lymphadenopathy
“Frosted” calcification pattern of lymph
nodes
+Early phase of fungal infection
Conglomerate bilateral perihilar masses +Silicosis/Coal workers pneumoconiosis
Symmetric peribronchial upper lobe
predominant architectural distortion
++ Silicosis/Coal workers pneumoconiosis,
Chronic hypersensitivity pneumonitis
Curvilinear upper lobe bronchial distortion +
CT features suggesting sarcoidosis
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Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA)
• Now the diagnostic procedure of choice
• Rapid on-site cytopathology 255 EBUS procedures in
625 LN stations– Concordance between ROSE
and cytopathology in 81.6%– 1.1% with false positive
ROSE
Rokadia HK. Ann Am Thorac Soc 2016
BAL lymphocyte percentage
Nagai S. Clin Chest Med 1997
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BAL CD4+/CD8+ ratio
Nagai S. Clin Chest Med 1997
ACE: diagnostic accuracy
Author Sarcoidosis/control
Sensitivity (%) Sensitivity (%)Active disease
Specificity (%)
Lieberman 1979 391/927 58 75 93
Studdy 1981 1941/1355 55 90.5
Ainslie 1985 128/211 58 92 84
Based on 2 S.D. above the mean reference value
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False positive ACE
Disease No. No. (%) elevated
Tuberculosis 140 5 (3.6)
Hypersensitivity pneumonitis
3 3 (14)
Leprosy 95 32 (34)
Cocccidiomycosis 13 1 (7)
Primary biliary cirrhosis 71 19 (27)
Hodgkin’s lymphoma 90 3 (3)
Berylliosis 4 3 (75)
Asbestosis 26 3 (11)
Silicosis 19 8 (42)
Lung cancer 315 2 (0.6)
COPD 209 1 (0.5)
Asthma 86 1 (1)
Diabetes 265 48 (18)
Alcoholic liver disease 151 43 (28)
Hyperthyroidism 21 17 (81)
Studdy PR. J Clin Pathol 1983
Conclusions
• Sarcoidosis affects approximately 200,000 Americans
• Although the mortality rate is low, it is rising
• The burden of the disease has been underestimated
• Pulmonary complications of sarcoidosis are protean
• Bronchoscopy is still the leading diagnostic tool; serologies are still not ready for prime time
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THANK YOU!