Sarcoidosis - Cleveland Clinic Center for Continuing Education

Sarcoidosis around the world: 

Past, Present, Future 

Ulrich Costabel 

Dept Pneumology/Allergology 

Ruhrlandklinik – University Hospital 

Essen, Germany 

WASOG Cleveland 2012

Sarcoidosis: 


• Changing definition 

• Changing suspected aetiologic agents 

• Changing pathogenesis 

• Changing diagnostic procedures 

• Changing treatment modalities

Historical development of sarcoidosis 

• The disease, known as sarcoidosis, and originally 

named after Besnier, Boeck and Schaumann, had a 

complicated historical development since the first 

cases were described. 

• This development can be divided into three periods: 

I Early observations (1877-1915) 

II Description of the systemic disease (1915-1953) 

III Description of the stages and activity of the 

disease (since 1953)

Jonathan Hutchinson 

1828-1913

Sarcoidosis of the skin, 

described by Hutchinson in 1877

• About 1895, Hutchinson summarized all cases 

(including a new case called Mortimer) as follows: 

”I have to describe a form of skin disease, which 

has, I believe, hitherto escaped special recognition. 

It may not improbably be a tuberculous affection and 

one of the Lupus family, but if so it differs widely 

from all other forms of lupus, both in its features and 

its course.” 

• “The disease is characterised by the formation of 

multiple, raised, dusky-red patches which have no 

tendency to inflame or ulcerate. They are very 

persistent, and extend but slowly.” 

• “…I prefer to recognise it, by the name of one of its 

subjects, as Mortimer‟s Malady.”

Sarcoidosis milestones (1) 

• 1869 J. Hutchinson: first account of skin lesions 

• 1888 E. Besnier: coined term lupus pernio, described 

histology 

• 1897 C. Boeck: coined term „multiple benign sarcoid“ 

• 1902 R. Kienbock / K. Kreibich / O. Jüngling: described 

bone changes 

• 1909- H. Schumacher / Ch. Heerfordt / F. Bering: 

1910 recognised uveitis 

• 1915 J. Schaumann: emphasised multisystemic disorder 

• 1915 E. Kuznitsky / A. Bittorf: described lung lesions and 

other affected internal organs

Caesar Boeck 

1845-1917

In 1899 Caesar Boeck published his work: 

„Multiple Benign Sarcoid of the skin“ 

“The histology is unique. The areas of new growth might be described as 

perivascular sarcomatoid tissue built up by excessively rapid proliferation of 

epitheloid connective-tissue cells in perivascular lymph-spaces, with little 

addition of other varieties….true giant cells of sarcomatous type were found“. 

„As a preliminary name for the clinical and histological type here described the 

term „Multiple Benign Sarcoid” perhaps will be found suitable”. 

Caesar Boeck 

1845-1917

Robert Kienböck (1871-1953) and his observation from 1902

Otto Jüngling 

(1884-1944) 

Published in 1920 bone lesions as 

„ostitis tuberculosa multiplex cystica“

Christian Heerfordt 

(1872-1953) 

Described in 1909 a number of 

cases with Fever, Iridocyclitis, 

Neutitis optica, Parotitis, Pareses 

and affection of the joints, later 

known as 

„Uveo-parotitis of Heerfordt“

Sarcoidosis milestones (2) 

1941 A. Kveim: introduced Kveim test 

1946 S. Löfgren: described Löfgren´s syndrome 

1951 Sones et al: first use of corticosteroids 

1958 K. Wurm: first proposal for radiographic staging 

1958 1st International Conference on Sarcoidosis: London,UK 

1961 1st USA conference: Washington, DC, USA 

1979 H. Reynolds: bronchoalveolar lavage 

1984 G. Rizzato: starts journal Sarcoidosis (now called 

Sarcoidosis, Vasculitis and Diffuse Lung Disease) 

1987 G.Rizzato: founds World Association of Sarcoidosis and 

Other Granulomatous Disorders (WASOG) 

D.G. James elected the first president

Sven Löfgren 

(1910-1978) 

Published in 1953 his work on 

„Primary pulmonary 

sarcoidosis“

The participants to the 1st International Conference on Sarcoidosis, London 1958.

Karl Wurm 

WASOG 

Meeting 

Essen 

1997

International Conferences on Sarcoidosis (1) 

Year City Organizer 

1958 London D. Geraint James 

1960 Washington Martin Cummings 

1963 Stockholm Sven Löfgren 

1966 Paris Jude Turiaf 

1969 Prague Ladislav Levinsky 

1972 Tokyo Yutaka Hosoda 

1975 New York Louis Siltzbach & Al Teirstein 

1978 Cardiff W. Jones Williams 

1981 Paris Jacques Chretien 

1984 Baltimore Carol Johns 

1987 Milan Gianfranco Rizzato

10th 

International 

Conference 1984 

Baltimore

Hot topics of the 10th International 

Conference 1984, Baltimore 

• Basis mechanisms: macrophage mediators, 

activated T cells, CD4/CD8, Interleukin 1 and 2 

• BAL as research and clinical tool 

• Significance of Ga lung scans in sarcoidosis 

• Sarcoidosis activity 

• Cinical trials of corticosteroid therapy

International Conferences on Sarcoidosis (2) 

WASOG Meetings 

Year City Organizer 

1989 Lisbon Manuel Freitas E.Costa 

1991 Kyoto Takateru Izumi 

1993 Los Angeles Om P. Sharma 

1995 London Ron Dubois 

1997 Essen Ulrich Costabel 

1999 Kumamoto Masayuki Ando 

2002 Stockholm A. Eklund & O.Selroos 

2005 Denver R. Baughman & L. Newman 

2008 Athens Stavros Constantopoulos 

2011 Maastricht Marjolein Drent

Om P. Sharma 

Chairman

Hot topics of the 3rd WASOG Meeting 1993, 

Los Angeles 

• Basic mechanisms: IL-6, IL-8, ICAM-1, role of CD14 

cells, role of mycobacteria and retroviruses (HIV) 

• Immunology of beryllium granuloma 

• Biomarkers in sarcoidosis: ACE et al. 

• HRCT, MRI and FDG-PET in sarcoidosis 

• Methotrexate in sarcoidosis

5th 

WASOG 

Meeting 

Essen 

1997

M. Ando, Chairman of WASOG Meeting 1999 in Kumamoto

9th WASOG Meeting & 

11th BAL Congress, 

Athens 2008

Hot Topics of the 10th WASOG Meeting & 

12th BAL Conference, Maastricht 2011 

• Genetics in sarcoidosis: phenotype/genotype 

• Usefulness of PET/CT scan in sarcoidosis 

• Fatigue in sarcoidosis: diagnosis and treatment 

• New therapeutic options: biologicals and more 

• Pulmonary hypertension, lung transplantation 

• Impact of Sarcoidosis for patients' lives 

• Sarcoidosis: ready for personalized medicine?

To assess health status and quality of life, 

patients completed the Sickness Impact Profile (SIP) 

Eur Respir J 1997; 10: 1450-5.

The founder 

Gianfranco Rizzato

Contents of SARCOIDOSIS 

Vol. 1, No. 1, September 1984 

• Gianfranco Rizzato: The Sarcoidosis Movement 

• Om P. Sharma: Sarcoidosis - A Worldwide Phenomenon 

• W. Jones Williams: All that Glitters is not Sarcoidosis 

• Gianpietro Semenzato and D. Geraint James: 

The Immunological Approach to the Enigma 

• Harold L. Israel: Sarcoidosis has no Boundaries 

• Gianfranco Rizzato and Franco Spinelli: 

Ga Lung Scan has come to stay 

• Olof B. Selroos: Value of Biochemical Markers in Serum for 

Determination of Disease Activity in Sarcoidosis 

• Yutaka Hosoda: International Trial of Prednisone in 

Pulmonary Sarcoidosis

Semenzato G. & James G. Sarcoidosis 1984,1: 24-35.








1991 Descriptive Definition of Sarcoidosis 

Sarcoidosis is a multisystem disorder of unknown 

cause(s). It commonly affects young and middleaged 

adults and frequently presents with bilateral 

hilar lymph-adenopathy, pulmonary infiltration, 

ocular and skin lesions. Liver, spleen, lymph 

nodes, salivary glands, heart, nervous system, 

muscles, bones and other organs may also be 

involved.... 

In: Proc. XII World Congress Sarcoidosis 1991 

Sarcoidosis 9 (Suppl.1), p34, 1992

1991 Definition of sarcoidosis included: 

1) Multisystem disease 

2) Granulomas 

3) Immunological features 

4) Course and prognosis 

5) Treatment response

ATS / ERS / WASOG 

Statement on Sarcoidosis 

Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149 

Copublished in: 

Am J Respir Crit Care Med 1999; 160: 736 

The 1991 definition was revised: 

Th1 immune response instead of CD4/CD8 

Elevated markers section was deleted 

Corticosteroid section was deleted

Definition of sarcoidosis 

• Sarcoidosis is a multisystemic disorder of 

unknown aetiology characterized by a 

heightened helper T cell type 1 (Th1) immune 

response at sites of disease activity and by the 

presence of noncaseating granulomas. 

– Occurs in all age groups, preferably in young and 

middle-aged adults, peaking in those 20 ~ 29 yr old 

– The prevalence varies from < 1 ~ 40 / 100,000

Incidence and prevalence of Sarcoidosis 

Country Incidence/100,000 

mean (range) 

Prevalence/100,000 

mean (range) 

Europe 8.5 (3-19) 20 (5-64) 

Northern Europe and UK 

- Denmark 

- Finland 

- Sweden 

- Norway 

- UK 

Southern and continental Europe 

- Italy 

- Spain 

- Portugal 

- Germany 

- Moravia 

- Poland 

America (US) 

- Africans-Americans 

- Caucasians 

12 (9-19) 

9 (5-14) 

10 (8-11) 

19 

14 

9 (3-15) 

5 (1-9) 

5 (1-9) 

1 

1 

9 

4 

- 

19 (1- 82) 

36 

11 

27 

- 

7 (5-8) 

59.5 (55-64) 

27 

18 (8-33) 

Japan 4 (1-18) 6 

13 

12 

- 

- 

14 

- 

11 

- 

- 

- 

From Sarcoidosis, Baughman 2006

Comparison Finland vs Hokkaido, Japan 

Finland 

N (437) 

% 

Japan (Hokkaido) 

N (457) 

% 

Female/Male 58/42 51/49 

Age (mean) 42 28 

Stage I 

Stage II 

Stage III 

Stage IV 

44 

43 

13 

0 

Erythema nodosum 23 0 

Extrapulm (excl EN) 

- Eye 

- Heart 

45 

7 

0.4 

Symptom-free patients 49 57 

68 

27 

5 

0 

53 

47 

5 

Pietinalho et al, Sarc Vasc Diff Lung Dis 2000

Comparison Finland vs Hokkaido, Japan 

Finland 

N (437) 

% 

Japan (Hokkaido) 

N (457) 

% 

Female/Male 58/42 51/49 

Age (mean) 42 28 

Stage I 

Stage II 

Stage III 

Stage IV 

44 

43 

13 

0 

Erythema nodosum 23 0 

Extrapulm (excl EN) 

- Eye 

- Heart 

45 

7 

0.4 

Symptom-free patients 49 57 

68 

27 

5 

0 

53 

47 

5 


Normalisation of chest x ray over 5 years in 

Percent normal CXR 

Finnish and Hokkaido patients 

years 

Hokkaido, Japan 

Finland 


What is new in Epidemiology? 

• ACCESS study (Baughman et al, AJRCCM 2001) 

(a case control etiologic study of sarcoidosis) 

-enrolled 736 patients within 6 months of diagnosis at 10 ctrs in the US 

-same number of age, sex, race matched controls 

-follow-up of first 240 patients for 2 years 

• Peak age 35-45 yr, one third >55 yr, women older 

• Blacks: more extrathoracic, more severe lung disease 

• Women: higher incidence for EN, ocular, neurological disease 

• Occupational and environmental exposure with increased risk: 

-musty odors, insecticides, air conditioning, raising birds 

-employment in agriculture, teaching, and others 

-smoking: strong negative predictor








Sarcoidosis Aetiology 

Genetically susceptible 

individual 

(sarcoidosis genotype or 

sarcoid constitution) 

Sarcoidosis 

clinical phenotype 

Exposure to specific 

environmental agents

HLA-types and Sarcoidosis 

“Protective” alleles “Susceptible” alleles 

DR1 DR3 DR17 

DR4 DR18 

DR8 only in 

DR9 Japanese 

Ina et al, Chest 1989; 

Martinetti et al, AJRCCM 1995; 

Berlin et al, AJRCCM 1997

Acute sarcoidosis 

(Löfgren’s syndrome) 

• Bihilar lymphadenopathy 

• Arthritis 

• Erythema nodosum (more frequent in women) 

• Frequently fever, myalgia, malaise 

• 85% resolution after 2 years 

• DRB1*0301/DQB1*0201-pos: 99% resolution 

DRB1*0301/DQB1*0201-neg: 55% resolution 

Grunewald, AJRCCM 2007

Resolved (%) 

Resolution of Löfgren’s Syndrome 

2 years after onset 

100 

80 

60 

40 

20 

0 

84% 

All 

99% 

55% 

n = 144 104 

40 

(+) (-) 

DRB1*0301/DQB1*0201 

Grunewald J, et al. AJRCCM 2007; 175: 40

Heerfordt´s syndrome 

• Heerfordt´s syndrome (HS) is an unusual 

manifestation of sarcoidosis 

• HS was originally described by Christian 

Heerfordt in 1909 and termed „Febris uveoparotidea 

subchronica“ 

• Patients present with uveitis, parotid swelling, 

cranial nerve palsy and fever; an incomplete HS 

is also described 

• HS is more common in Japan than in Scandinavia 

Darlington et al, Eur Respir J 2011

Percent of patients 

Heerfordt´s syndrome: genetic 

association with HLA DRB1*04 

Frequency of HLA DRB1*04 

Patients with HS 

Darlington et al, Eur Respir J 2011

Genes strongly associated with sarcoidosis 

on short arm of chromosome 6 

• DRB1 (Martinetti 1995, Foley 2001, Rossman 2003) 

• BTNL2 (Valentonyte 2005, Rybicki 2005) 

• RAGE (Campo 2007) 

receptor for advanced glycation 

end products

What are potential 

causative agents of 

sarcoidosis?

Examples of agents suggested to be 

involved in the aetiology of sarcoidosis 

Infectious agents 

Viruses (herpes, Epstein-Barr, retrovirus, coxsackie B virus, 

cytomegalovirus) 

Borrelia burgdorferi 

Propionibacterium acnes 

M. tuberculosis and other mycobacteria 

Mycoplasma 

Rickettsia 

Inorganic agents 

Aluminum 

Zirconium 

Talc 

Organic agents 

Pine tree pollen 

Clay

Etiological triggers 

• Role of mycobacterial organisms 

• Role of Propionibacterium acnes 

• Non-infectious agents: 

beryllium, man-made mineral 

fibres, World Trade Center dust 

• Therapeutic agents: 

Interferons

P. acnes DNA in Lymph Nodes 

Sarcoidosis Tuberculosis 

Controls 

Japan 35 (81%) 2 (7%) 8 (20%) 

Italy 16 (94%) 5 (29%) 3 (19%) 

Germany 27 (82%) 1 (20%) 5 (33%) 

England 15 (100%) 5 (33%) 9 (60%) 

Eishi Y. J Clin Microbiol 2002; 40: 198

Spot forming cells/million PBMC 

T-cell Response 

to M. tuberculosis Peptides 

KatG peptide 13 ESAT-6 peptide 14 

Control PPD+ Sarcoid Control PPD+ Sarcoid 

Drake WP. Infect Immun 2007; 75: 527

Mechanism of Granuloma Formation 

Grunewald J. Proc ATS 2007; 4: 461








Milestones in the Immunology 

of Sarcoidosis 

• Boeck 1899 Noncaseating granuloma 

• Boeck 1916 Cutaneous anergy to tuberculin 

• Kveim 1941 Kveim skin test 

• Hirschhorn 1964 Spontaneous lymphoblastic 

transformation of blood cells 

• Voisin 1977 BAL lymphocytes increased 

• Hunninghake 1980 Spontaneous lymphokine 

production by BAL cells 

• Adams & Sharma Hypercalcemia caused by 

1983 calcitriol production from AM 

• Moller 1996 Th1 immune response

Hypercalcemia in Sarcoidosis 

• 1939 Harrel G: first description 

• 1979 Papapoulos SE: increased serum 

calcitriol (active Vit D3) is associated 

with hypercalcemia 

• 1981 Barbour G: site for overproduction of 

calcitriol must be extrarenal 

• 1983 Adams JS & Sharma OP puzzle solved: 

cultured AM in sarcoidosis are able to 

produce calcitriol

Changing Dogmas: 

Before BAL - 

Sarcoidosis an immune deficiency disorder 

In 1962, Good et al. grouped together as 

immunological deficiency diseases: 

• Agammaglobulinaemia 

• Hypogammaglobulinaemia 

• Hodgkin„s disease 

• Sarcoidosis

Immunology of sarcoidosis: 

Discrepant data before BAL era 

Cutaneous anergy 

Histologically granuloma as in immunological 

type-IV-reaction 

T-lymphocytopenia,-anergia in peripheral blood 

Increase in „activated„„ T-Lymphocytes in peripheral 

blood 

Serum-immunglobulin levels increased 

Decreased antibody formation by B cells after 

stimulation in vitro

IL-12, IL-18 

TNF-α

Compartmentalized Immune 

Response in Sarcoidosis 

• Involved organ: Th1 type 

IL-2, IFN-gamma, IL-12, IL-18 

• Peripheral blood: Anergy to tuberculosis 

Reduced T cells

Granuloma Evolution 

IL-10, IL-12, IL-18, 

Regulatory T cells 

Resolution 

TNF-alpha, IL-4, IL-13, 

Deficit of 

Immune Regulation 

Fibrosis 

(Chronic Disease) 

Facco M, et al. In Diffuse Parenchymal Lung Disease 2007; 36: 87








Diagnostic Problems 

• There is no single diagnostic test for 

sarcoidosis 

• Noncaseating granulomas in a single 

organ, such as skin, do not establish a 

diagnosis of sarcoidosis 

• Such granulomas are not specific for 

sarcoidosis

Diagnostic approach 

The diagnosis of sarcoidosis is based on 

• Compatible clinical or radiological picture 

• Histological demonstration of noncaseating 

granulomas 

• Exclusion of other diseases capable of producing 

a similar histologic or clinical picture 

ATS/ERS/WASOG Statement on Sarcoidosis 1999

Diagnostic approach 

Clinical picture Chest radiograph/CT 

Suggests Sarcoidosis 

Choose appropriate biopsy site: 

•easy accessible: skin, lip, nasal mucosa, conjunctiva, 

periphereal LN 

•Bronchoscopy 

TBB, mucosa, BAL, TBNA

Sarcoidosis: a systemic disease 

• Sarcoidosis is a complex multiorgan disease 

with multiple non-specific symptoms and 

organ involvement which go beyond the 

usual experience of chest physicians.

Systemic / constitutional symptoms 

• Fatigue (up to 70% of patients) 

• Fever (usually low-grade, but up to 40°C 

possible) 

• Weight loss (2-6 kg during 10-12 weeks) 

Fever of unknown origin: consider sarcoidosis!

Fatigue: a major problem 

Four types of fatigue -- Sharma 1999 

• Early morning fatigue 

- not able to arise or feeling of inadequate sleep 

• Intermittent fatigue 

- wakes up normally, but tired and exhausted after a few 

hours of activity 

• Afternoon fatigue 

- exhausted and sleepy, like “having a flu-like syndrome”, 

goes to bed early 

• Post-sarcoidosis chronic fatigue syndrome 

- many synonyms, like fibromyalgia, fatigue, myalgia and 

depression

Sarcoidosis without/with fatigue 

M.Drent et al. ERJ 1999

Measurements: systemic response 

• Quality of life 

• Fatigue – Score 

• Biomarkers in serum/BAL?

Fatigue assessment scale in sarcoidosis 

Controls 


FAS Score 

De Vries et al, Br J Health Psychol 2004;9:279

The changing tools for diagnosing sarcoidosis 

• Skin biopsy 

since 1890’s 

• X-ray stages 


• Mediastinoscopy 


• Transbronchial biopsy 

• BAL 

• HRCT 

since 1974 

• EBUS-TBNA 

European groups 1980’s 


since 2007

Chest-radiographic stages 

50% 15% 

25% 5-10%

Mediastinoscopy in patients with 

presumptive stage I sarcoidosis: 

A risk/benefit, cost/benefit analysis 

J.M. Reich et al, Chest 1998; 113: 147-153

Estimates based on US incidence rates 

obtained from MEDLINE search 

If 33,000 persons with asymptomatic BHL 

underwent mediastinocopy, there would be 

found 

• 32,982 (99.95%) with sarcoidosis I 

• 8 with tuberculosis 

• 9 with Hodgkin´s disease 

• 1 with non-Hodgkin´s lymphoma

33,000 Mediastinoscopies for BHL 

Complications 

- 407 would require hospitalization 

- 204 would experience major morbidity 

Costs 

- 100 to 200 million US$ 

Benefit 

- Avoidance of 2 additional deaths due to 

delayed diagnosis of malignant lymphoma

Diagnostic value of BAL CD4/CD8 

ratio for sarcoidosis 

CD4/CD8 Sensitivity Specificity Author 

> 3.5 59% 92% Costabel, 

Milan 1987 

> 4.0 59% 96% Winterbauer 

Chest 1993 

> 4.0 55% 94% Thomeer 

WASOG 1997

BAL Profile in Sarcoidosis 

• Lymphocytes in 90% of patients 

• Clinically active disease: 

Lymphocytes range 20~80%, mean ~40% 

• Clinically inactive disease: 

Lymphocytes lower, mean ~30%, but 

broad overlap 

• Neutrophils may be increased in late or 

advanced disease

International BAL Conferences 

• 1979 Lille, France Chretien / Voisin 

• 1984 Columbia, MD, USA Crystal / Reynolds 

• 1991 Vienna, Austria Klech 

• 1993 Umea, Sweden Bjermer / Sandström 

• 1995 Dublin, Ireland Burke / Poulter 

• 1998 Corfu, Greece Constantopoulos 

• 2000 Krakow, Poland Pirozynski 

• 2002 Turin, Italy Albera 

• 2004 Barcelona, Spain 

Diaz-Jimenez 

• 2006 Coimbra, Portugal Robalo Cordeiro 

• 2008 Athens, Greece Costantinopoulos 

• 2011 Maastricht, NL Drent

J. Chrétien 

C. Voisin 

Lille, France

R. G. Crystal 

H.Y. Reynolds 

Columbia, MD 

USA

L. Bjermer 

T Sandström

Happy Return from Wild-Water Rafting in Umea

C. Burke 

L. Poulter

Len Poulter 

Chairman and Bandleader...

... and his fans

M. Pirozynski

Krakow 7th International BAL Conference 

and European Soccer Cup 2000 

France - Portugal

Krakow 7th International BAL Conference 

and European Soccer Cup 2000 

France - Portugal

Carlos 

Robalo Cordeiro

From H. Reynolds









• BAL 

• HRCT 

since 1974 

• EBUS-TBNA 



since 2007

Positive FDG PET scan of the lymph 

nodes and subcutaneous tissues 

Teirstein A et al, CHEST 2007; 132: 1949-1953









• BAL 

• HRCT 

since 1974 

• EBUS-TBNA 



since 2007

Transbronchial Needle Aspiration 

(TBNA) Cytology in Sarcoidosis 

Multinucleated giant cell 

of Langhans type 

Scattered epithelioid cells 

and lymphocytes 

Smojver-Jezek S, et al. Cytopathology 2007; 18: 3

TBNA for Diagnosing Sarcoidosis 

Author Year 

Yield (%) 

Stage I Stage II 

Morales 1994 53 48 

Bilaceroglu 1999 61 42 

Trisolini 2004 82 47

Linear Real-time Endobronchial Ultrasoundguided 

Transbronchial Needle Aspiration Scope 

(BF-UC160F-OL8; Olympus Medical Systems, Tokyo, Japan) 

Herth FJF. Eur Respir J 2006

Endobronchial Ultrasound 

in Sarcoidosis 

Right paratracheal LN Vena cava superior 

Wong M et al. Eur Respir J 2007; 29: 1182

Endobronchial Ultrasound 

in Sarcoidosis 

Needle 

Wong M et al. Eur Respir J 2007; 29: 1182

Diagnostic effectiveness of EBUS-TBNA in 

sarcoidosis 

Author N Se Sp PPV NPV Prevalence 

Wong 2007 65 92 100 88 44 98 

Oki 2007 15 93 100 100 50 93 

Garwood 2007 50 85 100 100 12,5 98 

Tremblay 2009 50 83 100 n.a n.a. 92 

Nakajima 2009* 38 91 100 100 50 92 

*Retrospective study; all other prospective

The spectrum of Bx sites in 736 cases of 

sarcoidosis participating in ACCESS 

Biopsy site Number of Biopsies 

INTRATHORACIC 

Lung 329 

Lymph node 181 

Trachea/Bronchi 57 

EXTRATHORACIC 

Skin 74 

Lymph node 61 

Liver 19 

Kveim site 11 

Nasopharynx 8 

Parotid/Salivary 6 

Spleen 6 

Other 21 

TOTAL 776 

Teirstein, 2005

Per cent biopsy of involved organ 

# Cases # Biopsied % Biopsied 

Intrathoracic 699 567 81 

Skin 117 74 63 

Peripheral lymph node 112 61 54 

Otolaryngeal 22 11 50 

Liver 85 19 22 

Teirstein, 2005

Organ involvement: new aspects 

• Cardiac MRT instead of Thallium 

• PET in some instances 

• Pulmonary hypertension (6-50%), 

correlates with advanced disease

Clinical Course 

• ACCESS study: 

-80% showed improvement in CXR or PFT 

after 2 years (including treated and untreated) 

-Blacks tend to show less improvement and to 

develop new organ involvement

Follow-up for sarcoidosis 

in clinical routine 

• Clinical examination (Symptoms) 

• Chest radiograph 

• Lung function tests (Spirometry) 

• (Serum ACE) 

• (HR-CT) 

• (BAL)


in research 

• Lung function (FVC, FEV1, DLCO) 

• Changes on chest x-ray and HRCT 

using standardised radiographic scores 

• Symptom scores / QoL / FAS 

• 6 min walk 

• Sarcoidosis severity score 

• Biomarkers


in clinical routine 

• Stage I disease: every 6 months 

• Other stages: every 3 to 6 months 

• Follow-up for a minimum of 3 years after 

therapy is discontinued 

• If radiograph has normalized for 3 years, 

subsequent follow-up is not routinely required 

• Note: Follow-up needs to be more vigilant after 

corticosteroid-induced remissions than after 

spontaneous remissions 

ATS/ERS/WASOG Statement 1999








Treatment of pulmonary sarcoidosis- 

a house divided (De Remee 1977) 

• “I would treat no asymptomatic patient for 

pulmonary sarcoidosis of stage I or II“, 

H. Israel, 6th Intern. Sarc Conf. Tokyo 1972 

• “It is important to treat every patient with 

sarcoidosis early, as soon as the diagnosis 

has been made“, J. Brun, 1972

Treatment for Sarcoidosis 

• Which patient ? 

• Which drug ? 

• Which dose ? 

• Which tapering ? 

• Which duration ? 

• Which assessment ?

Natural history of sarcoidosis 

• Spontaneous remission: 60 - 70% 

• Chronic or progressive course: 10 - 30% 

• Serious extrapulmonary involvement 

at presentation: 4 - 7% 

• Permanent sequelae: 10 - 20% 

• Mortality: 1 - 5% 

(respiratory, central nervous, cardiac)

Goal of Treatment 

• Reduce symptoms 

• Improve/preserve organ function

Treatment indications for extrapulmonary organ 

involvement 

• Heart (arrhythmia, insufficiency) 

• Eye 

• Neurosarcoidosis 

• Hypercalcaemia and hypercalciuria 

• Disfiguring skin lesions

Indication for treatment of pulmonary 

sarcoidosis 

• Symptoms 

• Severe or progressive functional 

impairment 

• Progressive radiographic infiltration?

Recommended treatment of pulmonary 

sarcoidosis 

• Initial dosage: prednisone 20 - 40 mg / day 

for 1 - 3 months 

• After evaluation of response: taper slowly to the 

maintenance dose of 5 - 10 mg / day 

• Continue for a minimum of 12 months 

• After discontinuation: close follow-up for relapse 

(occurs in 16 - 74%) 

ATS/ERS/WASOG Statement 1999

Alternative drugs for sarcoidosis 

• Azathioprine 100 - 150 mg daily 

• Methotrexate 10 - 20 mg/wk 

• Hydrochloroquine 400 mg daily

Number of Patients 

70 

60 

50 

40 

30 

20 

10 

0 

Response rate to MTX in various organs 

Lung Skin Eye Neurologic 

Response Non Response 

Lung 15 % VC 

Other organs : 

> 50%resolution of 

target lesions 

or 

reduction of 

prednisone below 10 

mg 

Lower, Baughman 1995, 1999

Biological Agents with anti-TNF Activity 

Drug 

Etanercept 

Infliximab 

Mechanism 

of action 

Soluble 

TNF 

receptor 

Chimeric 

Monoclonal 

antibody 

Adalimumab Humanized 

Monoclonal 

antibody 

Administration 

Rheumatoid 

Arthritis 

Effectiveness 

Crohn’s 

Disease 

Psoriasis 


Subcutaneous Yes No Yes No 

Intravenous Yes Yes Yes Yes 

Subcutaneous Yes Yes Yes 

Insufficient 

Information 

(from Baughman et al, Sarc Vasc Diff Lung Dis 2008)

Before and After two weeks after first dose of 

Infliximab (Remicade) 

Baughman and Lower, Sarcoidosis 2001; 18: 70-74.

Lupus Pernio after 4th dose Infliximab

A Multicenter, Randomized, Double-blind, 

Placebo-controlled Trial Evaluating the Safety and 

Efficacy of Infliximab (REMICADE ® ) in Subjects with 

Chronic Sarcoidosis with Pulmonary Involvement 

031005 Schlenker-Herceg T48 topline main 147 

Centocor Sarcoidosis Trial 

Baughman et al 

Am J Respir Crit Care Med 2006; 174:795-802

6 months therapy with Infliximab 

posthoc analysis 

* 

* 

Baughman Rossman

What is on the horizon? 

• A phase 2, multicenter, randomized, doubleblind, 

placebo-controlled study evaluating the 

safety and efficacy of treatment with 

Ustekinumab or Golimumab in chronic 

sarcoidosis. 

• Ustekinumab: a human mAb that binds to the 

shared p40 subunit of human IL-12 and IL-23 

• Golimumab: a human mAb that binds to 

TNFalpha 

• Number of patients:180 

• Duration of study: 44 weeks 

• Sponsor: Centocor

Active recruiting studies for sarcoidosis 

• *CC-10004 (Phosphodiesterase-Inhibitor) – Skin sarcoidosis 

• *R-modafinil (Dopamin-Reuptake Inhibitor) - Fatigue 

• *Atorvastatine – Lung sarcoidosis 

• *PDA001 (Human Placenta derived cells) - sarcoidosis III and IV 

• *N-Acetylcysteine (Antioxidant) – Lung sarcoidosis 

• *AIN457 (Sekukinumab: anti IL17A-Ak) - Uveitis 

• *Tadalafil – Pulmonary hypertension in sarcoidosis 

*only in USA !!!

After 1999 – what is new since the first 

ATS/ERS statement? 

• Gene predicts outcome in Löfgren‟s 

syndrome 

• Genes define other phenotypes 

• Less invasise diagnosis: HRCT, TBNA, 

cardiac MRI 

• Quality of life, fatigue measurements 

• New biological drugs

Areas of Future Research 

• Discovery of further genes associated with 

sarcoidosis: beyond BTNL2 and RAGE? 

• Relation of gene polymorphisms and 

expression with well defined clinical 

phenotypes: more than Löfgren's syndrome? 

• Regulatory mechanisms in persistent disease: 

only T reg cells? 

• Switch to fibrosis: why? 

• Antigenic peptides as causative factors: how 

many?

Research in Sarcoidosis: 

is like Fashion (?)

Physiology 

Future scenario for sarcoidosis 

Genetics 

Proteomics 

Epigenetics 

Transcriptomics 

Metabolomics 

Breathomics 

Degradomics

What causes 

sarcoidosis?

WASOG 

Family

Sarcoidosis - Cleveland Clinic Center for Continuing Education

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