The frequency and clinical features of sarcoidosis patients with extrapulmonary organ involvement.

1. The frequency and clinical features of sarcoidosis patients with extrapulmonary organ involvement. Muammer Bilir and Sevtap Sipahi Demirkok Istanbul University,Cerrahpasa Medical Faculty,Internal Medicine

2. Backgound • Sarcoidosis is a multisystemic granulomatous disease of unknown aetiology • Since sarcoidosis is a multiorgan disease,patients may complain of a variety of symptoms that may complicate diagnosis. • Extrapulmonary involvement is a major cause of morbidity

3. . • Extrapulmonary organ involvement is also an important criteria for therapy as well.

4. Objective We aimed (i) to investigate the organs most affected in a cohort of 212 sarcoidosis patients.(ii) to analyse the clinical,demographic and diagnostic features of sarcoidosis pts with extrapulmonary symptoms at onset.

5. Material and Methods • 109 sarcoidosis cases with extrapulmonary symptoms (1985-2005) at onset were included in the study. • The diagnosis of sarcoidosis was established by the presence of noncaseating granulomas on the histological examination of at least one tissue specimen. • The demographic features, presenting clinical features, initial diagnostic methods for each patient were analyzed.

6. Results The study population included 83 female and 26 male patients with the mean age of 42.48±12.10 yrs. • 8.3% of patients with extrapulmonary symptoms had a normal chest x-ray • 54.1% presented with bilateral hilar adenopathy • 33% with stage II • 4.6 % with stage III

7. The frequency of involvement of various organs • 51.4% erythema nodosum (EN) • 24.8% skin lesions other than EN, lupus pernio and subcutaneous nodul • 17.4% peripheral lymphadenopathy • 16.5% ocular involvement • 8% hepatomegaly • 5% miyaljia • 4.8% hipercalcemia

8. The frequency of involvement of various organs • 8.3% Lupus Pernio • 8.3% Subcutaneous nodular lesion • 3.6% lacrimal ve parotis gland involvement • 2.8% Skar infiltration

9. The frequency of involvement of various organs • 4.6% Neurologic involvement .1.8% Fasiyal Paralizi .0.9% Diabet İnsipidus .0.9% Empty cella .0.9% Leptomeningeal involvement

10. The frequency of involvement of various organs • 0.9% Glomerulonefritis • 0.9% Gastric ve omentum major involvement • 0.9% Nefrocalcinosis *The total number of observations is higher than the number of patients because some patients had more than one type of organ involvement

11. Initial diagnostic methods • Transbronchial biopsy (52.3%), • Mediastinoscopy (22% ) • Skin biopsy (27.5%) • Peripheral lymph node biopsy (27.5%) • Kveim biopsy(%7.3) • Liver biopsy(%5.5) • Nasal biopsy(%1.8) • Scalen lymph node biopsy (%1.8) • Bone marrow biopsy(%0.9) *The total number of observations is higher than the number of patients because some patients had more than one type of organ involvement

12. . • Extrapulmonary involvement during the course of systemic sarcoidosis is observed in 9-37% of the patients. Wu J,Schift Rashcouskay K. Sarcoidosis. American Family Phscian Vol:70,No:2,2004 Rizzato G. Extrapulmonary presentation of sarcoidosis. Cur Opin Pulm Med. 2001 Sep;7(5):295-7 Rizzato G, Palmieri G, Agrati AM, Zanussi C. The organ-specific extrapulmonary presentation of sarcoidosis: a frequent occurrence but a challenge to an early diagnosis. A 3-year-long prospective observational study. Sarcoidosis Vasc Diffuse Lung Dis. 2004 Jun;21(2):119-26

13. . • The frequency of extrapulmonary involvement was approximately 50% in our series. • Variations in the frequency of extrapulmonary involvement in sarcoidosis in the world literature might be due ethnicity,geophraphy,enviromental factors and difference in the number of asyptomatic patient.

14. . • Variations in the selection of patients into the study(retrospective/prospective) • Lack of a precise standard forms in the follow-up of sarcoidosis patients • No further evaluation of the organ involvement in asyptomatic patients. • Lack of a precise standard diagnostic algorithms

15. The mean age of sarcoidosis was reported as 40.2±12.8 years in Turkey. Sevtap Sipahi Demirkok, Metin Basaranoglu, Eylem Deniz Akinci and Tuncer Karayel. Analysis of 275 patients with sarcoidosis over a 38 year period; a single institution experience Respiratory Medicine,doi:10.1016/j.rmed.2006.11.013 (in press). Tabak L, Kılıçaslan Z,Kıyan E,Erelel M,Çuhadaroglu Ç,Arseven O,Erkan F,Ece T.147 Sarkoidoz hastasının klinik özellikleri. Solunum 3:80-85,2001 Baran A, Özşeker F,Güneylioğlu D,Bilgin S,Arslan S,Uyanusta Ç,Akkaya E.Sarkoidoz:Yedi yıllık deneyim. Toraks Dergisi, 2004 5(3): 160-5

16. . • In our cohort group, 49.6% of the patients were aged 20-40 years .22% of the patients were distributed between 41-50 years of age • While in our cohort groupthe female-male ratio was 3/1, this ratio was 4/1 in the subgroup • Extrapulmonary involvement did not show an effect on the clustering of gender and age

17. . • The most frequent skin lesion in our study was erythema nodosum ( 29.6 %) • The frequency of EN was 51.4% in the group with extrapulmonary involvement • The frequency of arthralgia was 18.4% in our cohort ,while the frequency arthralgia associated with EN was 45%

18. . • The highest incidence in EN and Löfgren syndrome was reported from north European and Spain(30% /40%) Mana J, Gomez-Vaquero C, Montero A et al. Löfgren’s syndrome revisited: a study of 186 patients. Am. J. Med. 1999; 107: 240–5. Mana J, Badrinas et al.Sarcoidosis in Spain.Sarcoidosi.1992;9:118-122 Veien NK, Stahl D, Brodthagen H: Cutaneous sarcoidosis in Caucasians, J Am Acad Dermatol, 16: 534-540, 1987.

19. . • The frequency of EN and Löfgren syndrome in the United States was reported in 8.3-25% of the patients. Baughman R, Teirstein A,, Judson A, Clinical Characteristics of Patients in a Case Control Study of SarcoidosisAm. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1885-1889

20. . • EN and Löfgren’s syndrome were rarely reported in south Asia, in east India and in Japon

21. . • The incidence of Löfgren’s syndrome was17% on avarage in a woldwide series which is as similar as our study series Teirstein AS, Lesser M. Worldwide distribution and epidemiology of sarcoidosis. In: James DG, editor. Sarcoidosis and other granulomatous diseases of the lung. New York: Marcel Dekker; 1983. p. 101-134. James DG, Neville E,SiltzbachLE. A worldwide review of sarcoidosis.Ann N Y Acad Sci1976:278:321-324 Demirkök Sipahi S,Basaranoglu M,Derviş E, Bal M,Karayel T. Analyzing of 87 patients with Löfgren's syndrome and the pattern of seasonality of subacute sarcoidosis.Respirology,Vol:11,No:4,456-461,July,2006

22. . • Cutaneous involvement except EN during the course of systemic sarcoidosis is observed in 9-37% of the patients (11% in Spain,42% in India,15.8% in USA, 30% in north European and nearly 3/1 of the patients in Turkey ) • This ratio was 24.8% in our study group • Veien NK, Stahl D, Brodthagen H: Cutaneous sarcoidosis in Caucasians, J Am Acad Dermatol, 16: 534-540, 1987. Mana J et al. Cutaneous involvement in sarcoidosis: Relationship to systemic disease. Arch Dermatol.1997:133:882-888. Sharma SK et al. Clinical characteristics and clinical outcome treated with prednisolone in 106 sarcoidosis patients.J Assoc Phsycians India 2001;49:691-704 Baughman R, Teirstein A,, Judson A, Clinical Characteristics of Patients in a Case Control Study of SarcoidosisAm. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1885-1889

23. . • Lupus Pernio which is more commonly seen with chronic type of sarcoidosis was most observed in north European (10%) in the world • Veien NK, Stahl D, Brodthagen H: Cutaneous sarcoidosis in Caucasians, J Am Acad Dermatol, 16: 534-540, 1987.

24. . • It was reported that subcutaneous nodular lesions were associated with either subacute or chronic sarcoidosis. • Granulomatous skin involvement in Spain was 19% The frequency of subcutaneos nodular lesions was 11.8% among them. • It was 8.3% in our series. Marcoval J, Mana J, Moreno A, Peyri J Subcutaneous sarcoidosis--clinicopathological study of 10 cases. Br J Dermatol. 2005 Oct;153(4):790- 4.

25. . • The incidence of ocular involvement varies between 20% and 30% in the world. • The frequency of ocular involvement was 8% in our cohort group James DG, Angime MR.Ocular sarcodosis.In:James DG,ed.Sarcoidosis and other granulamatous disorders.Newyork,MarcelDekker,1994,pp:275-284.

26. . The frequency of ocular involvement was 11% in USA and 20% in Japan Baughman R, Teirstein A,, Judson A, Clinical Characteristics of Patients in a Case Control Study of SarcoidosisAm. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1885-1889Goda C, Kotake S, Sasamoto Y, Yoshikawa K Okamoto T, Matsuda H. Clinical manifestations and diagnosis of patients with sarcoidosis Nippon Ganka Gakkai Zasshi. 1998 Feb;102(2):106-10.

27. . • In a study comparing the clinical features between the patients with sarcoidosis in Japon and in Finland showed that the frequency of ocular involvement was 41% vs 5% ,in Japon, and in Finland,respectively. Pietinalho A, Ohmichi M, The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finnish and 686 Japanese patients.Sarcoidosis Vasc Diffuse Lung Dis. 1996 Sep;13(2):159-66.

28. . • The frequency of ocular involvement was 3% in Italy. Rizzato G, Palmieri G, Agrati AM, Zanussi C. The organ-specific extrapulmonary presentation of sarcoidosis: a frequent occurrence but a challenge to an early diagnosis. A 3-year-long prospective observational study. Sarcoidosis Vasc Diffuse Lung Dis. 2004 Jun;21(2):119-26

29. . • A study followed-up sarcoidosis patients more than two years in Turkey demonstrated the frequency of ocular involvement was 10%. • Sevtap Sipahi Demirkok, Metin Basaranoglu, Eylem Deniz Akinci and Tuncer Karayel. Analysis of 275 patients with sarcoidosis over a 38 year period; a single institution experience Respiratory Medicine,doi:10.1016/j.rmed.2006.11.013 (in press).

30. . • The frequency of peripheral lymph node involvement was 5% in Japan and 8% in Italy. Goda C, Kotake S, Sasamoto Y, Yoshikawa K Okamoto T, Matsuda H. Clinical manifestations and diagnosis of patients with sarcoidosis Nippon Ganka Gakkai Zasshi. 1998 Feb;102(2):106-10. Rizzato G, Palmieri G, Agrati AM, Zanussi C. The organ-specific extrapulmonary presentation of sarcoidosis: a frequent occurrence but a challenge to an early diagnosis. A 3-year-long prospective observational study. Sarcoidosis Vasc Diffuse Lung Dis. 2004 Jun;21(2):119-26

31. . • The frequency of peripheral lymph node involvement in our study group (17.4%) was more relevant with the frequency reported in USA (15.8%) Baughman R, Teirstein A,, Judson A, Clinical Characteristics of Patients in a Case Control Study of SarcoidosisAm. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1885-1889

32. . • Neurosarcoidosis was observed in 3-15% of the patients in the world. • The frequency of neurosarcoidosis was 4.8% in USA. • In our study group the frequency of neurosarcoidosis was 4.6%. • Sipahi Demirkök S, Benbir G, Ertan S.Nörosarkoidoza genel bir bakış. Cerrahpaşa Tıp Dergisi , Cerrahpaşa Tıp Dergisi,2007:37;No:1,1-36

33. . • The frequency of hepatomegaly was 8% in our series . • The frequency of hepatomegaly was 11% in USA,40% in India. Baughman R, Teirstein A,, Judson A, Clinical Characteristics of Patients in a Case Control Study of SarcoidosisAm. J. Respir. Crit. Care Med., Volume 164, Number 10, November 2001, 1885-1889 Gupta SK.Sarcoidosis: a journey through 50 years. Indian J Chest Dis Allied Sci. 2002 Oct-Dec;44(4):247-53.

34. . • The frequency of cardiac involvement was 2.3% in USA and 1% in our study group. • The frequency of cardiac involvement presented as atrioventricolar block was 10% in Japon • Sipahi S,İlerigelen B,Bilir M,Tavşanoğlu S,Uçak D,Karayel T. Sarkoidozda sol ventrikül fonksiyonlarının ekokardiyogafi doppler yöntemiyle değerlendirilmesi. Türkiye Klinik Kardiyoloji(Türkish Klin Cardiol) 1999;12:123-126. Gurkan O U, Celik,Kumbasar O,Kaya A,Doganay A. Sarcoidosis in Turkey:1954-2004.Annals of Saudi Medicine 24(1):36-39 Jan-Feb 2004. Yoshida Y, Morimoto S, Hiramitsu S,Incidence of cardiac sarcoidosis in Japanese patients with high-degree atrioventricular block. Am Heart J. 1997 Sep;134(3):382-6.

35. Conclusions • Among skin lesions, EN was the most frequently observed manifestation in patients with extrapulmonary involvement. • Although the various diagnostic methods used in our study, transbronchial biopsy was the method most frequently used to diagnose sarcoidosis at onset.