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

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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

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Non-hispanic Males: Numbers of Deaths and Age-adjusted Mortality Rates per 1,000,000 Men

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Deaths: Non- hispanic White Males

Deaths: Non- hispanic Black Males

Mortality Rates: Non- hispanic White Males

Mortality Rates: Non- hispanic Black Males

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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

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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

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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

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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

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90

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Days from Catheterization

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viva

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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

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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!