Induced sputum compared to bronchoalveolar lavage for evaluating patients with sarcoidosis and non-granulomatous interstitial lung disease. *Respir Med,* Vol. 93,

Bronchoalveolar lavage cell counts as a predictor of short term outcome in

Pforte, A. (2000). Diagnosing sarcoidosis using endosonography-guided fine-needle

Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis. *Chest,*

determine the optimal number of biopsies. *Am Rev Respir Dis*, Vol.122, pp. 721-724,

analysis in differentiating pulmonary tuberculosis and sarcoidosis. *Eur Respir J,*

sarcoidosis: alterations in bronchoalveolar lymphocytes and T cell subsets. *Thorax*,

Patterson G.A. (1999). The current role of mediastinoscopy in the evaluation of thoracic disease. *J Thorac Cardiovasc Surg*, Vol.118, pp. 894-899, ISSN 0022-5223 Harber, P. (1981). The optimal number of trans-bronchoscopic biopsies for diagnosing

Bronchoalveolar Lavage and Sampling in Pulmonary Sarcoidosis 119

Porte, H.; Roumilhac, D.; Eraldi, L.; Cordonnier, C.; Puech, P. & Wurtz, A. (1998). The role of

Poulter, L.W.; Rossi, G.A.; Bjermer, L.; Costabel, U.; Israel-Biet, D.; Klech, H.; Pohl, W. &

Reich, J.M.; Brouns, M.C.; O'Connor, E.A. & Edwards, M.J. *(*1998*)* Mediastinoscopy in

Reich, J.M. (2010). Endobronchial ultrasonography-guided transbronchial needle aspiration

Remy-Jardin, M.; Beuscart, R.; Sault, M.C.; Marquette, C.H. & Remy, J. (1990). Subpleural

Rennard, S.I.; Bauer, W. & Eckert H. (1992). Bronchoalveolar lavage: ethical considerations.

Reynolds, H.Y. (1992). Bronchoalveolar lavage has extended the usefulness of

Roethe, R.A.; Fuller, P.B.; Byrd, R.B. & Hafermann, D.R. (1980). Transbronchoscopic lung

Rosen, Y.; Amorosa, J.K.; Moon, S.; Cohen, J. & Lyons, H.A. (1977). Occurrence of lung

Rosen, Y.; Athanassiades, T.J.; Moon, S. & Lyons, H.A. (1978). Nongranulomatous interstitial pneumonitis in sarcoidosis. *Chest*, Vol.74, pp. 122-125, ISSN 0012-3692 Rothkrantz-Kos, S.; van Dieijen-Visser, M.P.; Mulder, P.G.H. & Drent, M. (2003). Potential

Schulte, W. & Costabel, U. (1998). Biopsies and bronchoalveolar lavage in interstitial lung

Segawa, Y.; Takigawa, N.; Okahara, M.; Maeda, Y.; Takata, I.; Fujii, M.; Mogami, H.; Mandai,

Semenzato, G.; Bortoli, M.; Brunetta, E. & Agostini, C. (2005). Immunology and

Shorr A.F.; Torrington, K.G. & Hnatiuk, O.W. (2001). Endobronchial biopsy for sarcoidosis: a

pathophysiology. *Eur Respir Mon, Vol.*32, pp. 49-63, ISSN 1025-448x

prospective study. *Chest*, Vol.120, pp. 109-114, ISSN 0012-3692

bronchoscopy. *Eur Respir Rev*, Vol.2, pp. 48-53, ISSN 0905-9180

in sarcoidosis. *Clin Chem*, Vol.49, pp. 1510-1517, ISSN 0009-9147

diseases. *Eur Respir Mon*, Vol.9, pp. 171-180, ISSN 1025-448x

prognosis of sarcoidosis. *Eur Respir Rev*, Vol.2, pp. 75-82, ISSN 0905-9180 Puar, H.S.; Young Jr, R.C. & Armstrong, E.M. (1985). Bronchial and transbronchial lung

*Cardiothorac Surg*, Vol.13, pp. 196-199, ISSN 1010-7940

*Chest, Vol.*113, pp. 147-153, ISSN 0012-3692

scans. *Radiology*, Vol.177, pp. 133-139, ISSN 0033-8419

*Eur Respir Rev*, Vol.2, pp. 125-127, ISSN 0905-9180

400-402, ISSN 0012-3692

1085, ISSN 1546-3141

731, ISSN 0918-2918

3692

mediastinoscopy in the diagnosis of mediastinal lymphadenopathy. *Eur J*

Semenzato, G. (1992). The value of bronchoalveolar lavage in the diagnosis and

biopsy without fluoroscopy in sarcoidosis. *Chest, Vol.*87, pp. 3 303-306, ISSN 0012-

patients with presumptive stage I sarcoidosis: a risk/benefit, cost/benefit analysis*.*

in patients with suspected sarcoidosis. *Chest, Vol.*137, pp. 1 235-236, ISSN 0012-3692

micronodules in diffuse infiltrative lung diseases: evaluation with thin-section CT

biopsy in sarcoidosis. Optimal number and sites for diagnosis. *Chest, Vol.*77, pp. 3

granulomas in patients with stage I sarcoidosis. *Am J Roentgenol,* Vol.129, pp. 1083-

usefulness of inflammatory markers to monitor respiratory functional impairment

K. & Kataoka, M. (1996). Primary lung cancer associated with diffuse granulomatous lesions in the pulmonary parenchyma. *Inter Med,* Vol.35, pp. 728-

Laviolette, M.; Forge, J.L.; Tennina, S. & Boulet, L.P. (1991). Prognostic value of

Lemaire, A.; Nikolic, I.; Petersen, T.; Haney, J.C.; Toloza, E.M.; Harpole Jr, D.H.; D'Amico,

Leonard, C.; Tormey, V.J.; O'Keane, C. & Burke, C.M. Bronchoscopic diagnosis of sarcoidosis. (1997). *Eur Respir J, Vol.*10, pp. 2722-2724, ISSN 0903-1936 Leonard, C.; Tormey, V.J.; Lennon, A. & Burke, C.M. (1997). Utility of Wang transbronchial

Leslie, K.O.; Helmers, R.A.; Lanza, L.A. & Colby, T.V. (2000). Processing and evaluation of lung biopsy specimens. *Eur Respir Mon*, Vol.14, pp. 55-62, ISSN 1025-448x Lin, Y.H.; Haslam, P.L. & Turner-Warwick, M. (1985). Chronic pulmonary sarcoidosis:

standard lung function tests. *Thorax, Vol.40, pp.* 501-507, ISSN 0040-6376 Maxeiner, H. (2001). Lethal hemoptysis caused by biopsy injury of an abnormal bronchial

McDougall, J.C. & Cortese, D.A. (1997). Bronchoscopic lung biopsy, In: *Bronchoscopy,* U.B.S.

Midthun, D.E. & Cortese, D.A. (1997). Bronchoscopic needle aspiration and biopsy,

Mitchell, D.M.; Mitchell, D.N.; Collins, J.V. & Emerson, C.J. (1980). Transbronchial lung

Müller-Quernheim, J. (1998). Sarcoidosis: clinical manifestations, staging and therapy (part

Müller-Quernheim, J. (1998). Sarcoidosis: immunopathogenetic concepts and their clinical

Nunes, H.; Soler, P. & Valeyre, D. (2005). Pulmonary sarcoidosis. *Allergy,* Vol.60, pp. 565-

Ohara, K.; Okubo, A.; Kamata, K.; Sasaki, H.; Kobayashi, J. & Kitamura, S. (1993).

Oki, M.; Saka, H.; Kitagawa C.; Tanaka, S.; Shimokata, T.; Kawata, Y.; Mori, K.; Kajikawa, S.;

Polychronopoulos, V.S. & Prakash, U.B.S. (2009). Airway involvement in sarcoidosis. *Chest,*

Popper, H.H. (1999). Epithelioid cell granulomatosis of the lung: new insights and concepts.

*Sarcoidosis Vasc Diffuse Lung Dis*, Vol.16, pp. 32-46, ISSN 1460-2725

Transbronchial lung biopsy in the diagnosis of suspected ocular sarcoidosis.

Ichihara, S. & Moritani, S. (2007). Real-time endobronchial ultrasound-guided transbronchial needle aspiration is useful for diagnosing sarcoidosis. *Respirology,*

sarcoidosis. *Chest, Vol.*100, pp. 2 380-384, ISSN 0012-3692

needle biopsy in sarcoidosis. *Irish J Med Sci,* Vol.166, pp. 41-43,

artery. *Chest, Vol.*119, pp. 5 1612-1615, ISSN 0012-3692

II). *Respir Med*, Vol.92, pp. 140-149, ISSN 0954-6111

*Arch Ophthalmol,* Vol.111, pp. 642-644,

*Vol.*136, pp. 5 1371-1380, ISSN 0012-3692

application. *Eur Respir J,* Vol.12, pp. 716-738, ISSN 0903-1936

pp. 1185-1190, ISSN 0003- 4975

USA

582,

0095-7, Philadelphia, USA

Vol.280, pp. 679-681,

Vol.12, pp. 863-868,

bronchoalveolar lavage lymphocyte count in recently diagnosed pulmonary

T.A. & Burfeind, W.R. (2006). Nine-year single center experience with cervical mediastinoscopy: complications and false negative rate. *Ann Thorac Surg*, Vol.82,

relationship between lung lavage cell counts, chest radiograph, and results of

Prakash, (Ed.), 141-146, Lippincott-Raven Publ., ISBN 0-7817-0095-7, Philadelphia,

*Bronchoscopy,* U.B.S. Prakash, (Ed.), 147-154, Lippincott-Raven Publ., ISBN 0-7817-

biopsy through fibreoptic bronchoscope in diagnosis of sarcoidosis. *Br Med J*,

Bronchoalveolar Lavage and Sampling in Pulmonary Sarcoidosis 121

van der Werf, T.S.; Timmer, A. & Zijlstra, J.G. (1999). Fatal haemorrhage from Dieulafoy's

Varela-Lema, L.; Fernández-Villar, A. & Ruano-Ravina, A. (2009). Effectiveness and safety of

Venissac, N.; Alifano, M. & Mouroux, J. (2003). Video-assisted mediastinoscopy: experience from 240 consecutive cases. *Ann Thorac Surg*, Vol.76, pp. 208-212, ISSN 0003- 4975 Verstraeten, A.; Demedts, M.; Verwilghen, J.; van den Eeckhout, A .; Mariën, G.; Lacquet,

Wang, K.P.; Fuenning, C.; Johns, C.J. & Terry P.B. (1989). Flexible transbronchial needle

Ward, K.; O'Connor, C.; Odlum, C. & Fitzgerald, M.X. (1989). Prognostic value of

Welker, L.; Jorres, R.A.; Costabel, U. & Magnussen, H. (2004). Predictive value of BAL cell

Wells, A.U. & Hirani, N. (2008). Interstitial lung disease guideline: the British Thoracic

the Irish Thoracic society. *Thorax*, Vol.63 (Suppl. 5), pp. 1-58, ISSN 0040-6376 Wildi, S.M.; Judson, M.A.; Fraig, M.; Fickling, W.E.; Schmulewitz, N.; Varadarajulu, S.;

Williams, W.J. & Williams, D. (1967). 'Residual bodies' in sarcoid and sarcoid-like

Winterbauer, R.H.; Lammert, J.; Selland, M.; Wu, R.; Corley, D. & Springmeyer, S.C. (1993).

Winterbauer, R.H.; Wu, R. & Springmeyer, S.C. (1993). Fractional analysis of the 120-ml

Wong, M.; Yasufuku, K.; Nakajima, T.; Herth, F.J.F.; Sekine, Y.; Shibuya, K.; Iizasa, T.;

Zavala, DC. (1978). Transbronchial biopsy in diffuse lung disease. *Chest*, Vol.73 (Suppl. 5),

as we think? *Thorax, Vol.*59, pp. 794-799, ISSN 0040-6376

sarcoidosis. *Chest, Vol.*104, pp. 2 344-351, ISSN 0012-3692

granulomas. *J Clin Pathol*, Vol.20, pp. 574-577, ISSN 0021-9746

disease of the bronchus. *Thorax, Vol.*54, pp. 184-185, ISSN 0040-6376

pulmonary sarcoidosis. *Chest, Vol.*98, pp. 3 560-567, ISSN 0012-3692

*Eur Respir J, Vol.*33, pp. 1156-1164, ISSN 0903-1936

pp.516-524, ISSN 0040-6376

300, ISSN 0096-8056

1000-1006, ISSN 0903-1936

*Thorax*, Vol.44, pp. 6-12, ISSN 0040-6376

Vol.104, pp. 352-361, ISSN 0012-3692

pp. 727-733, ISSN 0012-3692

0903-1936

clinical manifestations, alveolitis, and evolution of the disease. *Thorax, Vol.*43,

endobronchial ultrasound–transbronchial needle aspiration: a systematic review.

L.M. & Ceuppens, J.L. (1990). Predictive value of bronchoalveolar lavage in

aspiration for the diagnosis of sarcoidosis. *Ann Otol Rhinol Laryngol*, Vol.98, pp. 298-

bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation.

differentials in the diagnosis of interstitial lung diseases. *Eur Respir J*, Vol.24, pp.

society in collaboration with Thoracic society of Australia and New Zealand and

Roberts, S.S.; Prasad, P.; Hawes, R.H.; Wallace, M.B. & Hoffman, B.J. (2004). Is endosonography guided fine needle aspiration (EUS-FNA) for sarcoidosis as good

Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. *Chest,*

bronchoalveolar lavage. Determination of the best specimen for diagnosis of

Hiroshima, K.; Lam, W.K. & rFujisawa T. (2007). Endobronchial ultrasound: new insight for the diagnosis of sarcoidosis. *Eur Respir J*, Vol.29, pp. 1182-1186, ISSN

Shorr A.F.; Torrington, K.G. & Hnatiuk, O.W. (2001). Endobronchial involvement and

Sibille, A.; van Bleyenbergh, P.; Lagrou, K.; Verstraeten, A. & Wuyts, W. (2011). Three colleagues with sarcoidosis? *Eur Respir J*, Vol.37, pp. 962-964, ISSN 0903-1936 Spagnolo, P.; Richeldi, L. & Raghu G. (2009). The role of bronchoalveolar lavage cellular

Stoopen, E.; Baquera-Heredia, J.; Cortes, D. & Green, L. (2001). Dieulafoy's disease of the

Sweerts, M.; Nicholson, A.G.; Goldstraw, P. & Corrin, B. (1995). Dieulafoy's disease of the

Takahashi, T.; Azuma, A.; Abe, S.; Kawanami, O.; Ohara, K. & Kudoh, S. (2001). Significance

Thomas, A. & Lenox, R. (2008). Pulmonary lymphangitic carcinomatosis as a primary

Thomas, K.W. & Hunninghake, G.W. (2003). Sarcoidosis. *JAMA*, Vol.289, pp. 3300–3303,

Thomeer, M. & Demedts, M. (1997). Predictive value of CD4/CD8 ratio in bronchoalveolar

Tomimaru, Y.; Higashiyama, M.; Okami, J.; Oda, K.; Takami, K.; Kodama, K. & Tsukamoto,

Tournoy, K.G.; Bolly, A.; Aerts, J.G.; Pierard, P.; De Pauw, R.; Leduc, D.; Leloup, A.; Pieters,

Trisolini, R.; Agli, L.L.; Cancellieri, A.; Poletti, V.; Tinelli, C.; Baruzzi, G. & Patelli, M. (2003).

Trisolini, R.; Tinelli, C.; Cancellieri, A.; Paioli, D.; Alifano, M.; Boaron, M. & Patelli M. (2008).

aspirate. *J Thorac Cardiovasc Surg,* Vol.135, pp. 837-842, ISSN 0022-5223 Valeyre, D.; Soler, P.; Clerici, C.; Pré, J.; Battesti, J.P.; Georges, R. & Hance A.J. (1988).

bronchus. *Thorax, Vol.*50, pp. 697-698, ISSN 0040-6376

nodes. *Jpn J Clin Oncol*, Vol.37, pp. 90-95, ISSN 0368-2811

sarcoidosis *Chest, Vol.*124, pp. 6 2126-2130, ISSN 0012-3692

*Respir J*, Vol.18, pp. 515-521, ISSN 0903-1936

Vol.14 (Suppl. 1), p. 36, ISSN 1460-2725

*Vol.*136, pp. 2 340-346, ISSN 0012-3692

ISSN 0012-3692

46, ISSN 1025-448x

0820-3946

ISSN 0098-7484

292-294, ISSN 0012-3692

airway hyperreactivity in patients with sarcoidosis. *Chest*, Vol.120, pp. 3 881-886,

analysis in the diagnosis of interstitial lung diseases. *Eur Respir Mon, Vol.*46, pp. 36-

bronchus in association with a paravertebral neurilemoma. *Chest*, Vol.119, pp. 1

of lymphocytosis in bronchoalveolar lavage in suspected ocular sarcoidosis. *Eur*

manifestation of colon cancer in a young adult. *CMAJ*, Vol.179, pp. 338-339, ISSN

lavage in the diagnosis of sarcoidosis. (abstract). *Sarcoidosis Vasc Diffuse Lung Dis,*

Y. (2007). Surgical results of lung cancer with sarcoid reaction in regional lymph

T.; Slabbynck, H.; Janssens, A.; Carron, K.; Schrevens, L.; Pat, K.; De Keukeleire, T. & Dooms, C. (2010). The value of endoscopic ultrasound after bronchoscopy to diagnose thoracic sarcoidosis. *Eur Respir J, Vol.*35, pp. 1329-1335, ISSN 0903-1936 Tremblay, A.; Stather, D.R.; MacEachern, P.; Khalil, M. & Field, S.K. (2009). A randomized

controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis. *Chest,*

The value of flexible transbronchial needle aspiration in the diagnosis of stage I

Transbronchial needle aspiration in sarcoidosis: Yield and predictors of a positive

Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence,

clinical manifestations, alveolitis, and evolution of the disease. *Thorax, Vol.*43, pp.516-524, ISSN 0040-6376

**Part 3**

**Management**

## **Part 3**

**Management**

122 Sarcoidosis Diagnosis and Management

Ziegenhagen, M.W.; Rothe, M.E.; Schlaak, M. & Müller-Quernheim, J. (2003).

Ziora, M.; Grzanka, P.; Mazur, B.; Niepsuj, G.; Dworniczak, S.; Oklek, K. & Shani, J. (2001).

Zissel, G. & Müller-Quernheim, J. (1998). Sarcoidosis: historical perspective and immunopathogenesis (part I). *Respir Med*. Vol.92, pp. 126-139, ISSN 0954-6111

*Eur Respir J*, Vol.21, pp. 407-413, ISSN 0903-1936

6586

Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis.

Evaluation of alveolitis by bronchoalveolar lavage and high-resolution computed tomography in patients with sarcoidosis. *J Bronchol*. Vol.8, pp. 260–266, ISSN 1944-

**7**

*Spain*

**Updated Guidelines for the Treatment of**

Sarcoidosis is a systemic granulomatous disease that affects the lungs in 90% of cases. The stage of the disease is determined by the level of pulmonary damage as assessed by a chest x-ray. This pulmonary damage varies widely between stages I, when lymph node damage has no repercussions on lung functioning, and stage IV, in which interstitial pulmonary

Systemic corticosteroids are the drugs of choice for the treatment of sarcoidosis, although no clear consensus exists regarding when to start treatment, the correct doses, or how long treatment should be maintained. We must keep in mind that the progression of this disease is often unpredictable, with frequent cases of spontaneous remission, above all in stage I patients. However, systemic steroids have side effects and the decision to start treatment is determined by the intensity of the symptoms, especially exercise-induced dyspnoea, and the

Sarcoidosis can affect both the upper and lower airways. Endobronchial damage occurs in 40% of stage I patients and approximately 70% of stage III and IV patients. Endobronchial granulomas have been described along with stenosis of the airway due to peribronchial damage. Clinically relevant airway stenosis is uncommon but difficult to treat. In the upper airway, granulomas can appear in the submucosa of the larynx, pharynx, and paranasal sinuses. Sleep apnoea has been described as a result of involvement of the epiglottis. This damage to the airway is occasionally manifested as the presence of persistent cough, with no findings in the pulmonary parenchyma. In up to 50% of cases, spirometry reveals obstructive phenomena, especially in patients with endobronchial damage due to the

The treatment of choice for pulmonary sarcoidosis is oral corticosteroids. Other alternative treatments have been described, such as immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, leflunomide, cyclosporine, and chlorambucil), cytokine inhibitors (thalidomide and pentoxifylline), and immunomodulatory agents (TNF-alpha antagonists, infliximab, adalimumab, and antimalarial agents such as chloroquine) (Table 1). Currently, no clear evidence exists showing the usefulness of these drugs, and they are only indicated when the sarcoidosis does not respond to conventional treatment with oral

damage and the development of fibrosis has clear repercussions on lung functioning.

**1. Introduction**

sarcoidosis.

level of lung functioning deterioration.

**Pulmonary Sarcoidosis**

*Medical-Surgical Unit of Respiratory Diseases,*

 *University Hospital Virgen del Rocio,*

Luis Jara-Palomares, Candela Caballero-Eraso,

Alicia Díaz-Baquero and Jose Antonio Rodríguez-Portal

## **Updated Guidelines for the Treatment of Pulmonary Sarcoidosis**

Luis Jara-Palomares, Candela Caballero-Eraso, Alicia Díaz-Baquero and Jose Antonio Rodríguez-Portal *Medical-Surgical Unit of Respiratory Diseases, University Hospital Virgen del Rocio, Spain*

#### **1. Introduction**

Sarcoidosis is a systemic granulomatous disease that affects the lungs in 90% of cases. The stage of the disease is determined by the level of pulmonary damage as assessed by a chest x-ray. This pulmonary damage varies widely between stages I, when lymph node damage has no repercussions on lung functioning, and stage IV, in which interstitial pulmonary damage and the development of fibrosis has clear repercussions on lung functioning.

Systemic corticosteroids are the drugs of choice for the treatment of sarcoidosis, although no clear consensus exists regarding when to start treatment, the correct doses, or how long treatment should be maintained. We must keep in mind that the progression of this disease is often unpredictable, with frequent cases of spontaneous remission, above all in stage I patients. However, systemic steroids have side effects and the decision to start treatment is determined by the intensity of the symptoms, especially exercise-induced dyspnoea, and the level of lung functioning deterioration.

Sarcoidosis can affect both the upper and lower airways. Endobronchial damage occurs in 40% of stage I patients and approximately 70% of stage III and IV patients. Endobronchial granulomas have been described along with stenosis of the airway due to peribronchial damage. Clinically relevant airway stenosis is uncommon but difficult to treat. In the upper airway, granulomas can appear in the submucosa of the larynx, pharynx, and paranasal sinuses. Sleep apnoea has been described as a result of involvement of the epiglottis. This damage to the airway is occasionally manifested as the presence of persistent cough, with no findings in the pulmonary parenchyma. In up to 50% of cases, spirometry reveals obstructive phenomena, especially in patients with endobronchial damage due to the sarcoidosis.

The treatment of choice for pulmonary sarcoidosis is oral corticosteroids. Other alternative treatments have been described, such as immunosuppressive agents (methotrexate, azathioprine, cyclophosphamide, leflunomide, cyclosporine, and chlorambucil), cytokine inhibitors (thalidomide and pentoxifylline), and immunomodulatory agents (TNF-alpha antagonists, infliximab, adalimumab, and antimalarial agents such as chloroquine) (Table 1). Currently, no clear evidence exists showing the usefulness of these drugs, and they are only indicated when the sarcoidosis does not respond to conventional treatment with oral

Updated Guidelines for the Treatment of Pulmonary Sarcoidosis 127

up. DuBois et al (DuBois et al., 1999) compared the administration of 2mg/day of fluticasone with a placebo in stage II-III sarcoidosis patients for 6 months, with no followup. Erkkila et al (Erkkila et al., 1988) compared the treatment of stage I-II sarcoidosis patients with 0.8mg budesonide twice/ day with a placebo for 10 weeks. None of these studies demonstrated improvement in lung function or radiological parameters in the treatment group compared to the placebo group. Only the study by Alberts et al (Albert et al., 1995) found that the group treated with budesonide at high doses improved in the global clinical index, including symptoms. In all other studies regarding treatment with inhaled corticosteroids, symptoms were not improved when compared to the placebo group. One study did demonstrate that inhaled fluticasone could help to reduce coughing in cases of

It has been reported that treatment with inhaled steroids may reduce the need for systemic steroids, and thus considerably reduce the adverse effects from this type of treatment. Milman et al (Milman et al., 1994) studied the use of budesonide at 1.2-2mg/day and oral steroids in 8 patients with stage I-II sarcoidosis. The study lasted 12 months, with 18 months of follow-up. They found no beneficial effect from the use of inhaled budesonide. Pietinalho et al (Pietinalho et al., 1999) compared a group of patients initially treated with 10-20mg prednisolone during 3 months, followed by inhaled budesonide at 1.6mg/day during 15 months, with a control group that received a placebo. After 3 months of treatment, a radiological improvement was observed in the treatment group compared to the control group. At 6 months of treatment, these differences were still significant, but from that time on, there were no differences between the two groups. In patients that started the study in stage I of the disease, neither FVC nor DLCO changed during the study, since they were at normal levels at the start of the treatment. In patients that started the study in stage II, FVC did not change during the treatment period. In this group, those patients that were treated for 18 months did show significant differences in FVC and DLCO. These difference were greater in patients with initial values of FVC<80% and DLCO<75%. The authors concluded that, in stage II sarcoidosis patients, treatment change from initial oral steroids to inhaled steroids is a good option to avoid the long-term administration of oral corticosteroids. However, based on the information that is currently available (Paramothayan & Lasserson, 2008), we can conclude that insufficient evidence exists based on randomised clinical trials that could establish the efficacy and/or usefulness of inhaled corticosteroids in the

The US guidelines and the recently updated BTS guidelines substantially updated the treatment options for pulmonary sarcoidosis (American Thoracic Society [ATS], 1999; Bradley et al., 2008). Dempsey OJ et al. later summarised and published a treatment update based on both guidelines (Dempsey et al., 2009). One of the main recommendations that they made was to carefully assess the decision to start treatment with corticosteroids (the most frequently used treatment), comparing the benefits with potential risks. In general, treatment should be considered when organ function is affected. The primary conclusions obtained from conferences and consensus documents developed by experts are summarised

acute sarcoidosis (Baughman et al., 2002).

treatment of sarcoidosis.

**2.2 Oral corticosteroids 2.2.1 Introduction**

in Table 2 (Bradley et al., 2008).

corticosteroids, in patients with intolerance to corticosteroids (poorly controlled diabetes, myopathy, osteoporosis), or in order to reduce the dosage of corticosteroids (King, 2010). However, these drugs require close monitoring as they can cause severe adverse effects. Here, we will review the different treatment options for patients with pulmonary sarcoidosis.

Table 1. Drugs used for the treatment of sarcoidosis

#### **2. Treatment options in patients with pulmonary sarcoidosis**

#### **2.1 Inhaled corticosteroids**

The mild ocular and cutaneous manifestations of sarcoidosis can be treated using topical corticosteroids. For the treatment of pulmonary damage, an alternative to the use of systemic corticosteroids is inhaled corticosteroids, which can be useful in selected groups of patients. This treatment has been used in two types of patients: a) those with an affected airway, with chronic coughing as the primary symptom, and b) as a treatment used for suspending or at least reducing the need for systemic corticosteroids.

Several randomised studies have compared the efficacy of inhaled corticosteroids with that of a placebo. The characteristics of both patient groups were similar with regard to radiological findings, lung function (FEV1), DLCO (%), and symptoms. Alberts et al (Albert et al., 1995) compared the administration of 1.2mg budesonide with a placebo in a group of stage I-III sarcoidosis patients during 6 months of treatment and another 6 months of follow-

corticosteroids, in patients with intolerance to corticosteroids (poorly controlled diabetes, myopathy, osteoporosis), or in order to reduce the dosage of corticosteroids (King, 2010). However, these drugs require close monitoring as they can cause severe adverse effects. Here, we will review the different treatment options for patients with pulmonary

sarcoidosis.

INHALED CORTICOSTEROIDS

IMMUNOSUPPRESSIVE AGENTS

IMMUNOMODULATORY AGENTS

• Etanercept b. Monoclonal antibodies • Infliximab • Adalimumab

ANTIMALARIAL AGENTS

**2.1 Inhaled corticosteroids**

c. Thalidomide d. Pentoxifylline

a. Tumour necrosis factor (TNF) antagonists

a. Chloroquine and hydroxychloroquine

Table 1. Drugs used for the treatment of sarcoidosis

**2. Treatment options in patients with pulmonary sarcoidosis**

suspending or at least reducing the need for systemic corticosteroids.

The mild ocular and cutaneous manifestations of sarcoidosis can be treated using topical corticosteroids. For the treatment of pulmonary damage, an alternative to the use of systemic corticosteroids is inhaled corticosteroids, which can be useful in selected groups of patients. This treatment has been used in two types of patients: a) those with an affected airway, with chronic coughing as the primary symptom, and b) as a treatment used for

Several randomised studies have compared the efficacy of inhaled corticosteroids with that of a placebo. The characteristics of both patient groups were similar with regard to radiological findings, lung function (FEV1), DLCO (%), and symptoms. Alberts et al (Albert et al., 1995) compared the administration of 1.2mg budesonide with a placebo in a group of stage I-III sarcoidosis patients during 6 months of treatment and another 6 months of follow-

ORAL CORTICOSTEROIDS

a. Methotrexate b. Azathioprine c. Cyclophosphamide d. Chlorambucil e. Cyclosporine f. Leflunomide

up. DuBois et al (DuBois et al., 1999) compared the administration of 2mg/day of fluticasone with a placebo in stage II-III sarcoidosis patients for 6 months, with no followup. Erkkila et al (Erkkila et al., 1988) compared the treatment of stage I-II sarcoidosis patients with 0.8mg budesonide twice/ day with a placebo for 10 weeks. None of these studies demonstrated improvement in lung function or radiological parameters in the treatment group compared to the placebo group. Only the study by Alberts et al (Albert et al., 1995) found that the group treated with budesonide at high doses improved in the global clinical index, including symptoms. In all other studies regarding treatment with inhaled corticosteroids, symptoms were not improved when compared to the placebo group. One study did demonstrate that inhaled fluticasone could help to reduce coughing in cases of acute sarcoidosis (Baughman et al., 2002).

It has been reported that treatment with inhaled steroids may reduce the need for systemic steroids, and thus considerably reduce the adverse effects from this type of treatment. Milman et al (Milman et al., 1994) studied the use of budesonide at 1.2-2mg/day and oral steroids in 8 patients with stage I-II sarcoidosis. The study lasted 12 months, with 18 months of follow-up. They found no beneficial effect from the use of inhaled budesonide. Pietinalho et al (Pietinalho et al., 1999) compared a group of patients initially treated with 10-20mg prednisolone during 3 months, followed by inhaled budesonide at 1.6mg/day during 15 months, with a control group that received a placebo. After 3 months of treatment, a radiological improvement was observed in the treatment group compared to the control group. At 6 months of treatment, these differences were still significant, but from that time on, there were no differences between the two groups. In patients that started the study in stage I of the disease, neither FVC nor DLCO changed during the study, since they were at normal levels at the start of the treatment. In patients that started the study in stage II, FVC did not change during the treatment period. In this group, those patients that were treated for 18 months did show significant differences in FVC and DLCO. These difference were greater in patients with initial values of FVC<80% and DLCO<75%. The authors concluded that, in stage II sarcoidosis patients, treatment change from initial oral steroids to inhaled steroids is a good option to avoid the long-term administration of oral corticosteroids. However, based on the information that is currently available (Paramothayan & Lasserson, 2008), we can conclude that insufficient evidence exists based on randomised clinical trials that could establish the efficacy and/or usefulness of inhaled corticosteroids in the treatment of sarcoidosis.

#### **2.2 Oral corticosteroids**

#### **2.2.1 Introduction**

The US guidelines and the recently updated BTS guidelines substantially updated the treatment options for pulmonary sarcoidosis (American Thoracic Society [ATS], 1999; Bradley et al., 2008). Dempsey OJ et al. later summarised and published a treatment update based on both guidelines (Dempsey et al., 2009). One of the main recommendations that they made was to carefully assess the decision to start treatment with corticosteroids (the most frequently used treatment), comparing the benefits with potential risks. In general, treatment should be considered when organ function is affected. The primary conclusions obtained from conferences and consensus documents developed by experts are summarised in Table 2 (Bradley et al., 2008).

Updated Guidelines for the Treatment of Pulmonary Sarcoidosis 129

In this respect, McKinzie et al. (McKinzie et al., 2010) performed a retrospective study of patients with pulmonary sarcoidosis that were treated with ≤20mg of oral prednisone during exacerbations, and clinical evolution and changes in spirometry values were assessed after two weeks. This study demonstrated that these patients improved in clinical symptoms and spirometry values, although it did have some limitations: 1) the study was retrospective, implying a patient selection bias; 2) it did not follow up on long-term patient progression, and therefore, we cannot comment on the evolution of the disease; 3) the study was not designed specifically to measure the adverse effects of corticosteroid treatment; 4) it lacked a control group; 5) the two-week follow-up period was not maintained in all patients (median: 21 days). Even so, it did show that the treatment of acute exacerbations of pulmonary sarcoidosis using 20mg of prednisone for a median 21 days significantly improves symptoms and lung function test results. This low dosage with a short duration of treatment has the potential to minimise the side effects of corticosteroids. This study opened the possibility of performing prospective studies that compare long- and short-term treatment plans, low and high doses, and the side

Even so, it is clear that there is no standardisation in the treatment of pulmonary sarcoidosis, and this is due to the lack of clinical trials. The majority of published studies are not blinded, randomised, or controlled, and involve a very small number of patients, using different

For these reasons, Schutt et al. (Schutt et al., 2010) used the Delphi research technique. The Delphi method uses an expert panel with a voting system in order to reach a consensus in special situations in which insufficient data exists in order to come to an objective conclusion. The aim of this study was to gather a panel of experts in the treatment of pulmonary sarcoidosis to formulate a consensus whenever possible, using rigorous Delphi methods including interactive questions and feedback for previous responses. The conclusions from this study of expert opinions were the following: 1) oral corticosteroids are the initial treatment recommended for pulmonary sarcoidosis; 2) it is not recommended to start concomitant treatment using inhaled corticosteroids as a general practice; 3) treating pulmonary sarcoidosis with dosages >40mg of prednisolone or equivalent does not provide any additional benefit; 4) regarding the treatment of chronic pulmonary sarcoidosis, the dosage should be decreased to a minimum maintenance dose of 10mg of prednisone or equivalent. The final conclusion was that methotrexate was the preferred agent for replacing or reducing the dosage of corticosteroids. Several different controversies arose in various subjects that could aid in developing future studies, as no consensus was reached 1) regarding the dosage of corticosteroids to be administered in *de novo* pulmonary sarcoidosis; 2) regarding the decision to treat or observe patients with mild sarcoidosis based on

This study also had several limitations. First, the use of multiple-choice questions can limit or potentially affect the responses. Second, there were experts that did not answer all questions. Third, it was not established whether all participants in the study were in fact

*Mechanism of action*: Methotrexate is an immunosuppressive and anti-inflammatory agent. After corticosteroids, this is the most commonly used drug for the treatment of sarcoidosis. It is also used in other pathologies such as rheumatoid arthritis, Crohn's disease, and psoriasis. Several studies have evaluated the efficacy of this treatment in systemic sarcoidosis (cutaneous, ocular, pulmonary, and neurological sarcoidosis) (Baughman & Lower, 1999;

pulmonary sarcoidosis experts. Fourth, the majority of experts worked in the USA.

effects and recurrence of the disease for each method of treatment.

symptoms, lung function, and chest x-ray results.

**2.3 Immunosuppressive agents**

**2.3.1 Methotrexate**

doses or lengths of treatment and different endpoints (McKinzie et al., 2010).

	- Asymptomatic stage I disease
	- Stable stage II asymptomatic disease
	- Stage III disease with slightly altered lung function
	- In stage II or III with moderate, severe, or progressive symptoms
	- With changes observed in chest x-rays

Table 2. Primary conclusions obtained from conferences and consensus documents developed by experts (Baughman et al. 2003)

#### **2.2.2 Treatment plan**

The UK guidelines indicate that treatment should start with prednisolone at 0.5mg/kg/day for 4 weeks (Bradley et al., 2008). The dosage should then be gradually reduced over the next 6 months, with an ideal dose of ≤10mg/day. In order to avoid bone loss caused by the corticosteroids, patients must also start treatment with oral biphosphonates along with bone densitometry tests. The duration of treatment can vary, but frequently ranges between 6 months and 2 years. Some patients need more than 10mg/day of prednisolone in order to control the disease. In these circumstances, another drug may be added in order to further decrease the dosage of corticosteroids (steroid-sparing), thus achieving a final dosage of ≤10mg/day of prednisone.

A systematic review of randomised placebo-controlled clinical trials on patients with pulmonary damage that started treatment with oral or inhaled corticosteroids concluded that oral corticosteroids improved chest x-ray results and overall score in symptoms, spirometry, and radiological tests between 3 and 24 months of treatment. However, little evidence pointed towards improved lung function, and data were scarce regarding the impact of oral corticosteroids in the long-term progression of the disease (Paramothayan et al., 2000).

However, there are no clear guidelines for the initiation of corticosteroid treatment, when to decide that treatment has failed or consider a therapeutic alternative for pulmonary sarcoidosis. As such, the use of corticosteroids in pulmonary sarcoidosis continues to be discussed, and a final conclusion has yet to be made regarding the optimal duration of treatment. With the medical literature currently available, we do not know if oral corticosteroids can alter the final result of this disease. However, the benefits of this type of treatment do now outweigh the side effects. Some retrospective studies have suggested that patients with sarcoidosis and do not take corticosteroids (Gottlieb et al., 1997) or only at low doses (Rizzato et al., 1998) have a lower rate of relapse. These data suggest that, when making a decision to treat acute pulmonary sarcoidosis with oral corticosteroids, the lowest dosage possible must be used.

• Erythema nodosum can be painful, and treatment should be paracetamol or NSAID

• Many patients do not require treatment and the disease can regress spontaneously.

on a short-term, on-demand basis.

• Asymptomatic stage I disease • Stable stage II asymptomatic disease

developed by experts (Baughman et al. 2003)

• With changes observed in chest x-rays • Absolute indications for oral steroids include:

• Ocular involvement (only when topical treatment fails)

• Oral steroids can benefit patients:

• Hypercalcaemia • Neurological involvement • Cardiac involvement

**2.2.2 Treatment plan**

≤10mg/day of prednisone.

dosage possible must be used.

• Stage III disease with slightly altered lung function

• In stage II or III with moderate, severe, or progressive symptoms

Table 2. Primary conclusions obtained from conferences and consensus documents

The UK guidelines indicate that treatment should start with prednisolone at 0.5mg/kg/day for 4 weeks (Bradley et al., 2008). The dosage should then be gradually reduced over the next 6 months, with an ideal dose of ≤10mg/day. In order to avoid bone loss caused by the corticosteroids, patients must also start treatment with oral biphosphonates along with bone densitometry tests. The duration of treatment can vary, but frequently ranges between 6 months and 2 years. Some patients need more than 10mg/day of prednisolone in order to control the disease. In these circumstances, another drug may be added in order to further decrease the dosage of corticosteroids (steroid-sparing), thus achieving a final dosage of

A systematic review of randomised placebo-controlled clinical trials on patients with pulmonary damage that started treatment with oral or inhaled corticosteroids concluded that oral corticosteroids improved chest x-ray results and overall score in symptoms, spirometry, and radiological tests between 3 and 24 months of treatment. However, little evidence pointed towards improved lung function, and data were scarce regarding the impact of oral

However, there are no clear guidelines for the initiation of corticosteroid treatment, when to decide that treatment has failed or consider a therapeutic alternative for pulmonary sarcoidosis. As such, the use of corticosteroids in pulmonary sarcoidosis continues to be discussed, and a final conclusion has yet to be made regarding the optimal duration of treatment. With the medical literature currently available, we do not know if oral corticosteroids can alter the final result of this disease. However, the benefits of this type of treatment do now outweigh the side effects. Some retrospective studies have suggested that patients with sarcoidosis and do not take corticosteroids (Gottlieb et al., 1997) or only at low doses (Rizzato et al., 1998) have a lower rate of relapse. These data suggest that, when making a decision to treat acute pulmonary sarcoidosis with oral corticosteroids, the lowest

corticosteroids in the long-term progression of the disease (Paramothayan et al., 2000).

• Treatment is not indicated in:

In this respect, McKinzie et al. (McKinzie et al., 2010) performed a retrospective study of patients with pulmonary sarcoidosis that were treated with ≤20mg of oral prednisone during exacerbations, and clinical evolution and changes in spirometry values were assessed after two weeks. This study demonstrated that these patients improved in clinical symptoms and spirometry values, although it did have some limitations: 1) the study was retrospective, implying a patient selection bias; 2) it did not follow up on long-term patient progression, and therefore, we cannot comment on the evolution of the disease; 3) the study was not designed specifically to measure the adverse effects of corticosteroid treatment; 4) it lacked a control group; 5) the two-week follow-up period was not maintained in all patients (median: 21 days). Even so, it did show that the treatment of acute exacerbations of pulmonary sarcoidosis using 20mg of prednisone for a median 21 days significantly improves symptoms and lung function test results. This low dosage with a short duration of treatment has the potential to minimise the side effects of corticosteroids. This study opened the possibility of performing prospective studies that compare long- and short-term treatment plans, low and high doses, and the side effects and recurrence of the disease for each method of treatment.

Even so, it is clear that there is no standardisation in the treatment of pulmonary sarcoidosis, and this is due to the lack of clinical trials. The majority of published studies are not blinded, randomised, or controlled, and involve a very small number of patients, using different doses or lengths of treatment and different endpoints (McKinzie et al., 2010).

For these reasons, Schutt et al. (Schutt et al., 2010) used the Delphi research technique. The Delphi method uses an expert panel with a voting system in order to reach a consensus in special situations in which insufficient data exists in order to come to an objective conclusion. The aim of this study was to gather a panel of experts in the treatment of pulmonary sarcoidosis to formulate a consensus whenever possible, using rigorous Delphi methods including interactive questions and feedback for previous responses. The conclusions from this study of expert opinions were the following: 1) oral corticosteroids are the initial treatment recommended for pulmonary sarcoidosis; 2) it is not recommended to start concomitant treatment using inhaled corticosteroids as a general practice; 3) treating pulmonary sarcoidosis with dosages >40mg of prednisolone or equivalent does not provide any additional benefit; 4) regarding the treatment of chronic pulmonary sarcoidosis, the dosage should be decreased to a minimum maintenance dose of 10mg of prednisone or equivalent. The final conclusion was that methotrexate was the preferred agent for replacing or reducing the dosage of corticosteroids. Several different controversies arose in various subjects that could aid in developing future studies, as no consensus was reached 1) regarding the dosage of corticosteroids to be administered in *de novo* pulmonary sarcoidosis; 2) regarding the decision to treat or observe patients with mild sarcoidosis based on symptoms, lung function, and chest x-ray results.

This study also had several limitations. First, the use of multiple-choice questions can limit or potentially affect the responses. Second, there were experts that did not answer all questions. Third, it was not established whether all participants in the study were in fact pulmonary sarcoidosis experts. Fourth, the majority of experts worked in the USA.

#### **2.3 Immunosuppressive agents**

#### **2.3.1 Methotrexate**

*Mechanism of action*: Methotrexate is an immunosuppressive and anti-inflammatory agent. After corticosteroids, this is the most commonly used drug for the treatment of sarcoidosis. It is also used in other pathologies such as rheumatoid arthritis, Crohn's disease, and psoriasis. Several studies have evaluated the efficacy of this treatment in systemic sarcoidosis

(cutaneous, ocular, pulmonary, and neurological sarcoidosis) (Baughman & Lower, 1999;

Updated Guidelines for the Treatment of Pulmonary Sarcoidosis 131

This third-line drug is not frequently used as a corticosteroid saver in the treatment of

*Administration route and dosage*: Treatment with this drug starts at 25mg-50mg/day orally, with a progressive increase until reaching white blood cell counts of 4000mm3-7000mm3, with twice-weekly monitoring during the first 3 months, and once per month afterwards. It

*Adverse effects*: The most important adverse effect is the appearance of pancytopaenia, which requires an immediate adjustment of the dosage. Other side effects are: gastrointestinal discomfort, infertility, haemorrhagic cystitis, and it has even been related to the appearance

The use of chlorambucil is very limited in the treatment of pulmonary sarcoidosis. Its mechanism of action is similar to that of cyclophosphamide, as inhibits the immune response by reducing the number of lymphocytes and other bone marrow cells. Given the relative efficacy of this drug as a corticosteroid saver (Kataria, 1980) and the important side effects (Sahgal & Sharma, 1984), it is not commonly recommended in the treatment of this disease.

Cyclosporine is an immunosuppressive drug that is widely used in organ transplants in order to reduce the risk of rejection. It is also used in diseases that involve T-cells, such as uveitis and rheumatoid arthritis. Its use is very limited in pulmonary sarcoidosis due to the

*Mechanism of action*: Leflunomide is a cytotoxic agent used alone or in combination with methotrexate for the treatment of rheumatoid arthritis, but little experience has been gained in its use for treating pulmonary sarcoidosis. In a study published in 2004 (Baughman & Lower, 2004) that treated 32 patients using leflunomide (15 of them also were administered methotrexate), good tolerance was observed to leflunomide with a response at least as efficient as methotrexate and with lower toxicity. Its use was then recommended in patients with chronic sarcoidosis and intolerance to methotrexate, or in combination with methotrexate in patients with chronic pulmonary sarcoidosis refractory to other second-line

*Administration route and dosage*: 20mg/day orally, starting with 10mg and increasing dosage

*Adverse effects*: Gastrointestinal symptoms, rash, peripheral neuropathy, and hepatotoxicity (Emery et al., 2000; Savage et al., 2006; Utz et al., 2003), which increases in the case of

Utz et al started a clinical trial in which etanercept was used for the treatment of stage II-II sarcoidosis. This study was suspended due to a lack of results from the treatment, defined as progression of the disease, need for other immunosuppressive agents, or intolerance to treatment (Utz et al., 2003). Its use is not currently indicated in the treatment of sarcoidosis.

previous hepatopathy or concomitant treatment with hepatotoxic treatments.

sarcoidosis due to its adverse effects (Salomon et al., 1975).

lack of experience and its severe side effects (Wyser et al., 1997).

has been rarely administered intravenously.

of bladder carcinomas.

**2.3.4 Chlorambucil**

**2.3.5 Cyclosporine**

**2.3.6 Leflunomide**

drugs (Baughman et al., 2001).

in the presence of good tolerance.

**2.4 Immunomodulatory agents**

• Etanercept

**2.4.1 Tumour necrosis factor (TNF) antagonists**

Lacher, 1968; Lower & Baughman, 1990, 1995). In 2000, Baughman focused on the efficacy of methotrexate as a corticosteroid saver, performing a prospective randomised study in which one group of patients took prednisone with methotrexate and the control group took a placebo. This study demonstrated that patients treated with methotrexate required smaller amounts of prednisone after 6 months than those that took the placebo (Baughman et al., 2000).

*Administration route and dosage*: This medication can be administered orally or intramuscularly, using the second option as an alternative in the case of oral intolerance or a lack of response after 3-6 months of treatment. The initial dosage is 7.5mg once per week, with progressive increases until reaching 10-15mg per week. In order to decrease the level of myelosuppression associated with methotrexate, folic acid must also be administered, and liver function must be periodically checked. This drug is contraindicated in patients with chronic liver disease or chronic infection by HBV or HCV, creatinine clearance <30ml/h, or alcoholism (Saag et al., 2008)

*Side effects:* The most frequent side effects are leukopaenia, hepatic fibrosis, and interstitial pneumonitis (Baughman et al., 2008). In a study of 100 liver biopsies from 68 patients with sarcoidosis, 14 had changes from the use of methotrexate (Baughman et al., 2003). Other, less frequent side effects have also been described, such as baldness, cutaneous rashes, and lymphoproliferative syndrome that occasionally regresses after treatment suspension (Hoshida et al., 2007; Niitsu et al., 2010).

#### **2.3.2 Azathioprine**

*Mechanism of action*: Azathioprine acts on RNA synthesis from DNA and inhibits the proliferation of lymphocytes, but its mechanism of action in sarcoidosis is unclear.

Second-line drug. In 1985, Pacheco assessed the efficacy of azathioprine in 10 patients with sarcoidosis refractory to corticosteroids. Patients were treated for 6 months with 150mg azathioprine per day, and 70% of cases had clinical and radiological improvements (Pacheco et al., 1985). Currently, this drug is primarily indicated in association with corticosteroids (Baughman, 2004; Bradley et al., 2008). In a study involving 11 patients with chronic sarcoidosis, the efficacy of treatment using azathioprine as a corticosteroid saver was evaluated. Patients underwent a combined treatment for 20 months with 0.1mg/kg prednisolone along with 2mg/kg azathioprine per day, producing clinical and radiological improvements with no evidence of relevant adverse effects (abdominal pain + transitory increase in lipase levels in 1 case) (Mueller-Quernheim et al., 1999).

*Administration route and dosage*: Orally administered, 25mg/day, with progressive increase until reaching 2mg/kg (maximum: 200mg/day). The toxicity of azathioprine is linked to the existence of thiopurine-S-methyltransferase polymorphisms (Bakker et al., 2007).

*Adverse effects*: The most frequent adverse effects are: gastrointestinal discomfort, cutaneous rash, and fever. Another less frequent but more serious side effect is pancytopaenia (difficult to distinguish from suppressed bone marrow, which can occur in sarcoidosis). The patient's blood cell levels must be checked weekly while the dosage is being increased, and every 8- 12 weeks during the first few months of treatment. The frequency can be decreased for longterm treatment in patients with normal levels from previous measurements.

#### **2.3.3 Cyclophosphamide**

*Mechanism of action:* Cyclophosphamide acts by reducing the number and function of lymphocytes, with an added anti-inflammatory effect.

This third-line drug is not frequently used as a corticosteroid saver in the treatment of sarcoidosis due to its adverse effects (Salomon et al., 1975).

*Administration route and dosage*: Treatment with this drug starts at 25mg-50mg/day orally, with a progressive increase until reaching white blood cell counts of 4000mm3-7000mm3, with twice-weekly monitoring during the first 3 months, and once per month afterwards. It has been rarely administered intravenously.

*Adverse effects*: The most important adverse effect is the appearance of pancytopaenia, which requires an immediate adjustment of the dosage. Other side effects are: gastrointestinal discomfort, infertility, haemorrhagic cystitis, and it has even been related to the appearance of bladder carcinomas.

#### **2.3.4 Chlorambucil**

130 Sarcoidosis Diagnosis and Management

Lacher, 1968; Lower & Baughman, 1990, 1995). In 2000, Baughman focused on the efficacy of methotrexate as a corticosteroid saver, performing a prospective randomised study in which one group of patients took prednisone with methotrexate and the control group took a placebo. This study demonstrated that patients treated with methotrexate required smaller amounts of prednisone after 6 months than those that took the placebo (Baughman et al.,

*Administration route and dosage*: This medication can be administered orally or intramuscularly, using the second option as an alternative in the case of oral intolerance or a lack of response after 3-6 months of treatment. The initial dosage is 7.5mg once per week, with progressive increases until reaching 10-15mg per week. In order to decrease the level of myelosuppression associated with methotrexate, folic acid must also be administered, and liver function must be periodically checked. This drug is contraindicated in patients with chronic liver disease or chronic infection by HBV or HCV, creatinine clearance <30ml/h, or

*Side effects:* The most frequent side effects are leukopaenia, hepatic fibrosis, and interstitial pneumonitis (Baughman et al., 2008). In a study of 100 liver biopsies from 68 patients with sarcoidosis, 14 had changes from the use of methotrexate (Baughman et al., 2003). Other, less frequent side effects have also been described, such as baldness, cutaneous rashes, and lymphoproliferative syndrome that occasionally regresses after treatment suspension

*Mechanism of action*: Azathioprine acts on RNA synthesis from DNA and inhibits the

Second-line drug. In 1985, Pacheco assessed the efficacy of azathioprine in 10 patients with sarcoidosis refractory to corticosteroids. Patients were treated for 6 months with 150mg azathioprine per day, and 70% of cases had clinical and radiological improvements (Pacheco et al., 1985). Currently, this drug is primarily indicated in association with corticosteroids (Baughman, 2004; Bradley et al., 2008). In a study involving 11 patients with chronic sarcoidosis, the efficacy of treatment using azathioprine as a corticosteroid saver was evaluated. Patients underwent a combined treatment for 20 months with 0.1mg/kg prednisolone along with 2mg/kg azathioprine per day, producing clinical and radiological improvements with no evidence of relevant adverse effects (abdominal pain + transitory

*Administration route and dosage*: Orally administered, 25mg/day, with progressive increase until reaching 2mg/kg (maximum: 200mg/day). The toxicity of azathioprine is linked to the

*Adverse effects*: The most frequent adverse effects are: gastrointestinal discomfort, cutaneous rash, and fever. Another less frequent but more serious side effect is pancytopaenia (difficult to distinguish from suppressed bone marrow, which can occur in sarcoidosis). The patient's blood cell levels must be checked weekly while the dosage is being increased, and every 8- 12 weeks during the first few months of treatment. The frequency can be decreased for long-

*Mechanism of action:* Cyclophosphamide acts by reducing the number and function of

existence of thiopurine-S-methyltransferase polymorphisms (Bakker et al., 2007).

term treatment in patients with normal levels from previous measurements.

lymphocytes, with an added anti-inflammatory effect.

proliferation of lymphocytes, but its mechanism of action in sarcoidosis is unclear.

increase in lipase levels in 1 case) (Mueller-Quernheim et al., 1999).

2000).

alcoholism (Saag et al., 2008)

**2.3.2 Azathioprine**

**2.3.3 Cyclophosphamide**

(Hoshida et al., 2007; Niitsu et al., 2010).

The use of chlorambucil is very limited in the treatment of pulmonary sarcoidosis. Its mechanism of action is similar to that of cyclophosphamide, as inhibits the immune response by reducing the number of lymphocytes and other bone marrow cells. Given the relative efficacy of this drug as a corticosteroid saver (Kataria, 1980) and the important side effects (Sahgal & Sharma, 1984), it is not commonly recommended in the treatment of this disease.

#### **2.3.5 Cyclosporine**

Cyclosporine is an immunosuppressive drug that is widely used in organ transplants in order to reduce the risk of rejection. It is also used in diseases that involve T-cells, such as uveitis and rheumatoid arthritis. Its use is very limited in pulmonary sarcoidosis due to the lack of experience and its severe side effects (Wyser et al., 1997).

#### **2.3.6 Leflunomide**

*Mechanism of action*: Leflunomide is a cytotoxic agent used alone or in combination with methotrexate for the treatment of rheumatoid arthritis, but little experience has been gained in its use for treating pulmonary sarcoidosis. In a study published in 2004 (Baughman & Lower, 2004) that treated 32 patients using leflunomide (15 of them also were administered methotrexate), good tolerance was observed to leflunomide with a response at least as efficient as methotrexate and with lower toxicity. Its use was then recommended in patients with chronic sarcoidosis and intolerance to methotrexate, or in combination with methotrexate in patients with chronic pulmonary sarcoidosis refractory to other second-line drugs (Baughman et al., 2001).

*Administration route and dosage*: 20mg/day orally, starting with 10mg and increasing dosage in the presence of good tolerance.

*Adverse effects*: Gastrointestinal symptoms, rash, peripheral neuropathy, and hepatotoxicity (Emery et al., 2000; Savage et al., 2006; Utz et al., 2003), which increases in the case of previous hepatopathy or concomitant treatment with hepatotoxic treatments.

#### **2.4 Immunomodulatory agents**

#### **2.4.1 Tumour necrosis factor (TNF) antagonists**

#### • Etanercept

Utz et al started a clinical trial in which etanercept was used for the treatment of stage II-II sarcoidosis. This study was suspended due to a lack of results from the treatment, defined as progression of the disease, need for other immunosuppressive agents, or intolerance to treatment (Utz et al., 2003). Its use is not currently indicated in the treatment of sarcoidosis.

Updated Guidelines for the Treatment of Pulmonary Sarcoidosis 133

In patients with chronic pulmonary sarcoidosis in which treatment with corticosteroids has not been sufficient, or when the patient has intolerance to the drug or it is causing severe adverse effects, intensification of the therapy is indicated using methotrexate, azathioprine, or leflunomide (stage IIB). The first choice drug is methotrexate due to the greater experience gained in the treatment of pulmonary sarcoidosis using this drug. If the patient has intolerance or it does not produce a positive response, the use of leflunomide or azathioprine is recommended, and can occasionally lead to a reduced need or even cessation

Given that all of the previously mentioned drugs imply severe side effects such as myelosuppression with predisposition to opportunistic infections and hepatotoxicity, their use must be evaluated on an individual basis. Before starting treatment with methotrexate, azathioprine, and leflunomide, the patient must undergo liver function, haemogram, and creatinine tests. Also, hepatitis B and C tests must be performed before starting treatment

In patients in which treatment with immunosuppressive agents with or without corticosteroids is insufficient, two different second-line drugs may be combined, or administered along with a TNF antagonist, which should be decided upon according to

Before starting treatment with a TNF antagonist, the patient must also be screened for

Because of their mechanisms of action, many of the drugs proposed for the treatment of chronic sarcoidosis are not commonly used due to their secondary side effects (colchicine,

Patients with sarcoidosis must have a periodical follow-up regimen with a specialist. The lung is the primary organ affected by the disease, and so a pneumologist must be involved in the follow-up process. The BTS recommends a multi-disciplinary follow-up by clinics that specialise in interstitial lung diseases (Bradley et al., 2008). Check-ups must be performed initially every 3-6 months, or more frequently if drug treatment is started. Patients with clinically stable disease can be seen less frequently. Patients with stage II-IV must continue with an indefinite follow-up period, whereas patients with mild levels of the disease (stage 0 or I) can be discharged from the follow-up after 2 years. In these check-ups, the patient should undergo clinical (signs and symptoms), radiological (chest x-ray as the primary tool), and functional (respiratory function) tests. The follow-up protocol may also require laboratory analyses (especially if the patient had a previous case of hypercalcaemia, renal or liver involvement, or if tests show some type of alteration in serum angiotensin-converting enzyme). Patients rarely develop progressive pulmonary sarcoidosis with failed

pharmacological treatment. In this case, the next step would be a lung transplant.

Alberts C, Van der Mark TW, & Jansen HM. (1995). Inhaled budesonide in pulmonary

American Thoracic Society. Statement on sarcoidosis. (1999). *Am J Resp Crit Care Med,* Vol.

sarcoidosis: a double-blind, placebo-controlled study. *Eur Respir J*, Vol. 8, pp. 682–

chlorambucil, cyclophosphamide, cyclosporine, and pentoxifylline).

**2.6 Conclusions**

of treatment with corticosteroids.

with methotrexate and leflunomide.

tuberculosis, hepatitis B, and hepatitis C.

patient characteristics.

**3. Follow-up**

**4. References**

68, ISSN 7656936

160, pp. 736-755.

#### **2.4.2 Monoclonal antibodies**

#### • Infliximab

Infliximab is a monoclonal antibody with important anti-inflammatory activity. Several different studies have proven its efficacy in the treatment of pulmonary and extrapulmonary sarcoidosis refractory to corticosteroids (Baughman et al., 2006; Pritchard & Nadarajah, 2004). In a double-blind study which divided 138 patients with chronic pulmonary sarcoidosis into three groups: one treated with low doses of infliximab, other treated with placebo, and the third treated with high doses of infliximab at the start of treatment and at weeks 2, 6, 12, and 24, forced vital capacity improved during weeks 24-54, compared to initial values . There were no significant differences regarding the adverse effects produced in the three groups (Baughman et al., 2006). According to a study published in 2010 (Crouser et al., 2010), patients with decreased CD4+ T-cell count and resistance to conventional immunosuppressive treatment have a better response to this drug.

Although its long-term toxicity is still unclear, some severe complications have been associated with its use, such as the appearance of tuberculosis (Kean et al., 2001).

• Adalimumab

The experience with this drug has been limited to extrapulmonary chronic sarcoidosis (Heffernan & Smith, 2006; Patel, 2009).

#### **2.4.3 Thalidomide**

Just as in the case of the previous drug, the use of thalidomide has only been described in the treatment of extrapulmonary sarcoidosis, mainly the cutaneous form (Baughman et al., 2002). Its use in pulmonary sarcoidosis appears to provide no benefit, as was observed in a study by Judson et al. published in 2006, in which no clinical improvements were documented, and dosage had to be reduced in 9 out of the 10 patients due to adverse effects produced, including excessive somnolence and peripheral neuropathy (Judson et al., 2006).

#### **2.4.4 Pentoxifylline**

In a clinical trial by Zabel et al., they observed a positive response to treatment with pentoxifylline in patients with acute pulmonary sarcoidosis (Zabel et al., 1997) although no studies currently exist testing its use in chronic sarcoidosis.

#### **2.5 Antimalarial agents**

#### **2.5.1 Chloroquine and hydroxychloroquine**

These drugs have been used for the treatment of chronic sarcoidosis for many years (British Tuberculosis Association, 1967). They have a low level of toxicity, and have proven effective in treating cutaneous sarcoidosis (Siltzbach & Teirstein, 1964). Some studies also exist in which these drugs have been used to treat pulmonary sarcoidosis (Chloroquine in pulmonary sarcoidosis, 1968). Bazan et al. (Baltzan et al., 1999) studied the use of chloroquine to treat chronic sarcoidosis. After treating 18 patients for 6 months, treatment was continued with a group of patients with a slower decrease in FEV1 and diffusion capacity, but no changes in forced vital capacity were registered, although important adverse effects were produced in 13% of cases.

*Administration route and dosage*: The commonly used dosage is 250mg-750mg/day, taken orally for 6 months or 9 months.

*Side effects*: The most severe side effect is irreversible retinopathy and blindness, therefore, ophthalmologic follow-up is necessary at the start of treatment and after 6 months.

#### **2.6 Conclusions**

132 Sarcoidosis Diagnosis and Management

Infliximab is a monoclonal antibody with important anti-inflammatory activity. Several different studies have proven its efficacy in the treatment of pulmonary and extrapulmonary sarcoidosis refractory to corticosteroids (Baughman et al., 2006; Pritchard & Nadarajah, 2004). In a double-blind study which divided 138 patients with chronic pulmonary sarcoidosis into three groups: one treated with low doses of infliximab, other treated with placebo, and the third treated with high doses of infliximab at the start of treatment and at weeks 2, 6, 12, and 24, forced vital capacity improved during weeks 24-54, compared to initial values . There were no significant differences regarding the adverse effects produced in the three groups (Baughman et al., 2006). According to a study published in 2010 (Crouser et al., 2010), patients with decreased CD4+ T-cell count and resistance to conventional immunosuppressive treatment have a better response to this

Although its long-term toxicity is still unclear, some severe complications have been

The experience with this drug has been limited to extrapulmonary chronic sarcoidosis

Just as in the case of the previous drug, the use of thalidomide has only been described in the treatment of extrapulmonary sarcoidosis, mainly the cutaneous form (Baughman et al., 2002). Its use in pulmonary sarcoidosis appears to provide no benefit, as was observed in a study by Judson et al. published in 2006, in which no clinical improvements were documented, and dosage had to be reduced in 9 out of the 10 patients due to adverse effects produced, including excessive somnolence and peripheral neuropathy (Judson et al., 2006).

In a clinical trial by Zabel et al., they observed a positive response to treatment with pentoxifylline in patients with acute pulmonary sarcoidosis (Zabel et al., 1997) although no

These drugs have been used for the treatment of chronic sarcoidosis for many years (British Tuberculosis Association, 1967). They have a low level of toxicity, and have proven effective in treating cutaneous sarcoidosis (Siltzbach & Teirstein, 1964). Some studies also exist in which these drugs have been used to treat pulmonary sarcoidosis (Chloroquine in pulmonary sarcoidosis, 1968). Bazan et al. (Baltzan et al., 1999) studied the use of chloroquine to treat chronic sarcoidosis. After treating 18 patients for 6 months, treatment was continued with a group of patients with a slower decrease in FEV1 and diffusion capacity, but no changes in forced vital capacity were registered, although important

*Administration route and dosage*: The commonly used dosage is 250mg-750mg/day, taken

*Side effects*: The most severe side effect is irreversible retinopathy and blindness, therefore,

ophthalmologic follow-up is necessary at the start of treatment and after 6 months.

associated with its use, such as the appearance of tuberculosis (Kean et al., 2001).

**2.4.2 Monoclonal antibodies**

• Infliximab

drug.

• Adalimumab

**2.4.3 Thalidomide**

**2.4.4 Pentoxifylline**

**2.5 Antimalarial agents**

(Heffernan & Smith, 2006; Patel, 2009).

studies currently exist testing its use in chronic sarcoidosis.

**2.5.1 Chloroquine and hydroxychloroquine**

adverse effects were produced in 13% of cases.

orally for 6 months or 9 months.

In patients with chronic pulmonary sarcoidosis in which treatment with corticosteroids has not been sufficient, or when the patient has intolerance to the drug or it is causing severe adverse effects, intensification of the therapy is indicated using methotrexate, azathioprine, or leflunomide (stage IIB). The first choice drug is methotrexate due to the greater experience gained in the treatment of pulmonary sarcoidosis using this drug. If the patient has intolerance or it does not produce a positive response, the use of leflunomide or azathioprine is recommended, and can occasionally lead to a reduced need or even cessation of treatment with corticosteroids.

Given that all of the previously mentioned drugs imply severe side effects such as myelosuppression with predisposition to opportunistic infections and hepatotoxicity, their use must be evaluated on an individual basis. Before starting treatment with methotrexate, azathioprine, and leflunomide, the patient must undergo liver function, haemogram, and creatinine tests. Also, hepatitis B and C tests must be performed before starting treatment with methotrexate and leflunomide.

In patients in which treatment with immunosuppressive agents with or without corticosteroids is insufficient, two different second-line drugs may be combined, or administered along with a TNF antagonist, which should be decided upon according to patient characteristics.

Before starting treatment with a TNF antagonist, the patient must also be screened for tuberculosis, hepatitis B, and hepatitis C.

Because of their mechanisms of action, many of the drugs proposed for the treatment of chronic sarcoidosis are not commonly used due to their secondary side effects (colchicine, chlorambucil, cyclophosphamide, cyclosporine, and pentoxifylline).

#### **3. Follow-up**

Patients with sarcoidosis must have a periodical follow-up regimen with a specialist. The lung is the primary organ affected by the disease, and so a pneumologist must be involved in the follow-up process. The BTS recommends a multi-disciplinary follow-up by clinics that specialise in interstitial lung diseases (Bradley et al., 2008). Check-ups must be performed initially every 3-6 months, or more frequently if drug treatment is started. Patients with clinically stable disease can be seen less frequently. Patients with stage II-IV must continue with an indefinite follow-up period, whereas patients with mild levels of the disease (stage 0 or I) can be discharged from the follow-up after 2 years. In these check-ups, the patient should undergo clinical (signs and symptoms), radiological (chest x-ray as the primary tool), and functional (respiratory function) tests. The follow-up protocol may also require laboratory analyses (especially if the patient had a previous case of hypercalcaemia, renal or liver involvement, or if tests show some type of alteration in serum angiotensin-converting enzyme). Patients rarely develop progressive pulmonary sarcoidosis with failed pharmacological treatment. In this case, the next step would be a lung transplant.

#### **4. References**

Updated Guidelines for the Treatment of Pulmonary Sarcoidosis 135

DuBois RM, Greenhalgh PM, Southcott AM, Johnson NM, & Harris TA. (1999). Randomized

Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, & Gömör B. (2000). A

Gottlieb JE, Israel HL, Steiner RM, Triolo J, & Patrick H. (1997). Outcome in sarcoidosis. The

Heffernan MP, & Smith DI. (2006). Adalimumab for Treatment of Cutaneous Sarcoidosis.

Hoshida Y, Xu JX, Fujita S, Nakamichi I, Ikeda J, Tomita Y, Nakatsuka S, Tamaru J, Iizuka A,

Judson MA, Silvestri J, Hartung C, Byars T, & Cox CE. (2006). The effect of thalidomide on

Kataria YP. (1980). Chlorambucil in sarcoidosis. *Chest*, Vol. 78, No. 1, pp. 36-43, ISSN

Kean J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, &

Lacher MJ. (1968). Spontaneous remission response to methotrexate in sarcoidosis. *Ann*

Lower EE, & Baughman RP. (1990). The use of low dose methotrexate in refractory

Lower EE, & Baughman RP. (1995). Prolonged use of methotrexate for sarcoidosis. *Arch*

McKinzie BP, Bullington WM, Mazur JE, & Judson MA. (2010). Efficacy of short-course, low-

Milman N, Graudal N, Grode G, & Munch E. (1994). No effect of high-dose inhaled

Mueller-Quernheim J, Kienast K, Held M, Pfeifer S, & Costabel U. (1999). Treatment of

Niitsu N, Okamoto M, Nakamine H, & Hirano M. (2010). Clinicopathologic correlations of

methotrexate. *Cancer Sci.*, Vol. 101, No. 5, pp. 1309-1313, ISSN 20210795 Pacheco Y, Marechal C, Marechal F, Biot N, & Perrin Fayolle M. (1985). Azathioprine

dose corticosteroid therapy for acute pulmonary sarcoidosis exacerbations. *Am J*

corticosteroids in pulmonary sarcoidosis: a doubleblind, placebo- controlled study.

chronic sarcoidosis with an azathioprine/prednisolone regimen. *Eur Respir J*., Vol.

diffuse large B-cell lymphoma in rheumatoid arthritis patients treated with

treatment of chronic pulmonary sarcoidosis*. Sarcoidosis.*, Vol. 2, No.2, pp. 107-113,

sarcoidosis. *Am J Med Sci*., Vol. 299, pp. 153–157, ISSN 2316559

medication*. J Rheumatol.*, Vol. 34, No. 2, pp. 322-331, ISSN 17117491

pilot study. *Eur Respir J*., Vol. 13, pp. 1345–1350, ISSN 10445610

*Arch Dermatol.*, Vol. 142, pp. 17-19, ISSN 16415380

*Intern Med*., Vol. 69, pp. 1247–1248, ISSN 5725738

*Intern Med.*; Vol. 155, pp. 846–851. ISSN 7717793

*Med Sci.,* Vol. 339, No. 1, pp. 1-4, ISSN 19996733

*J Intern Med* , Vol. 236, pp. 285–290, ISSN 8077885

14, pp. 1117-1122. ISSN 10596700

Vol 23, No. 1, pp. 51-57. ISSN 16933470

9118698

7471842

*Up To Date*.

ISSN 3031790

trial of inhaled fluticasone proprionate in chronic stable pulmonary sarcoidosis: a

comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. *Rheumatology*., Vol. 39, pp. 655-665, ISSN 10888712 Erkkila S, Froseth B, Hellstrom PE, Kaltiokallio K, Taskinen E, Viljanen A, Viljanen B, &

Selroos O. (1988). Inhaled budesonide influences cellular and biochemical abnormalities in pulmonary sarcoidosis*. Sarcoidosis*, Vol. 5, pp. 106–110, ISSN 2852389

relationship of relapse to corticosteroid therapy. *Chest*, Vol. 111, pp. 623–631, ISSN

Takeuchi T, & Aozasa K. (2007). Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate

corticosteroid-dependent pulmonary sarcoidosis. *Sarcoidosis Vasc Diffuse Lung Dis.*,

Braun MM. (2001). Tuberculosis associated with infliximab, a tumor necrosis factoralpha neutralizing agent. *N Engl J Med*, Vol. 345, pp. 1098–1104, ISSN 11596589 King TE. (2010). Treatment of pulmonary sarcoidosis with alternatives to glucocorticoids.

Bakker JA, Drent M, & Bierau J. (2007). Relevance of pharmacogenetic aspects of

Baltzan M, Mehta S, Kirkham TH, Cosio MG. (1999). Randomized trial of prolonged

Baughman RP, & Lower EE. (1999). A clinical approach to the use of methotrexate for

Baughman RP, Winget DB, & Lower EE. (2000). Methotrexate is steroid sparing in acute

Baughman RP, Ohmichi M, & Lower EE. (2001). Combination therapy for sarcoidosis. *Sarcoidosis Vasc Diffuse Lung Dis.*, Vol. 18, No 2, pp. 133-137, ISSN 11436533 Baughman RP, Iannuzzi MC, Lower EE, Moller DR, Balkissoon RC, Winget DB, & Judson

Baughman RP. (2004). Pulmonary sarcoidosis. *Clin Chest Med*., Vol. 25; 521–530, ISSN

Baughman RP, & Lower EE. (2004). Leflunomide for chronic sarcoidosis*. Sarcoidosis Vasc*

Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, Albera C, Brutsche

Baughman R, Costabel U, & Bois R. (2008). Treatment of Sarcoidosis. *Clinics in Chest*

Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, Hirani N, Hubbard

British Tuberculosis Association: Chloroquine in the treatment of sarcoidosis. (1967).

Crouser ED, Lozanski G, Fox CC, Hauswirth DW, Raveendran R, & Julian MW. (2010). The

Dempsey OJ, Paterson EW, Kerr KM, & Denison AR. (2009). Sarcoidosis. *BMJ* , Vol. 339, pp.

CD4+ lymphopenic sarcoidosis phenotype is highly responsive to anti-tumor necrosis factor-{alpha} therapy. *Chest.*, Vol. 137, No. 6, pp. 1432-1435, ISSN 20525654

Chloroquine in pulmonary sarcoidosis. (1968). *Lancet*; Vol. 1, pp. 736, ISSN 4170972

*Pulm Med.,* Vol. 13, No. 5, pp. 458-463, ISSN 17940494

sarcoidosis. *Thorax*, Vol. 54, pp. 742-6, ISSN 10413729

*Intern Med*., Vol. 163, pp. 615–620, ISSN 12622609

*Diffuse Lung Dis.*, Vol. 21, No. 1, pp. 43-48, ISSN 15127974

*Resp Crit Care Med*., Vol. 174, pp. 795-802, ISSN 16840744

*Medicine,* Vol. 29, No. 3, pp. 533-548, ISSN 18539243

*Tubercle*, Vol. 48, pp. 257–272, ISSN 4872114

Vol. 160, pp. 192–197, ISSN 10390399

*Dis*, Vol. 17, pp. 60-66, ISSN 10746262

15331189

18757459

3206, ISSN 20534676

mercaptopurine metabolism in the treatment of interstitial lung disease*. Curr Opin*

chloroquine therapy in advanced pulmonary sarcoidosis. *Am J Respir Crit Care Med*,

sarcoidosis: results of a double blind, randomized trial. *Sarcoidosis Vasc Diffuse Lung*

MA. (2002). Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis., Vol. 19, No. 3, pp. 198-204, ISSN 12405489 Baughman RP, Judson MA, Teirstein AS, Moller DR, & Lower EE. (2002). Thalidomide for chronic sarcoidosis*. Chest.*, Vol. 122, No. 1, pp. 227-232, ISSN 12114363 Baughman RP, Koehler A, Bejarano PA, Lower EE, & Weber FL Jr. (2003). Role of liver

function tests in detecting methotrexate-induced liver damage in sarcoidosis. *Arch*

M, Davis G, Donohue JF, Müller-Quernheim J, Schlenker-Herceg R, Flavin S, Lo KH, Oemar B, & Barnathan ES; Sarcoidosis Investigators. (2006). Infliximab Therapy in Patients with Chronic Sarcoidosis and Pulmonary Involvement. *Am J*

R, Lake F, Millar AB, Wallace WA, Wells AU, Whyte MK, & Wilsher ML; British Thoracic Society Interstitial Lung Disease Guideline Group, British Thoracic Society Standards of Care Committee; Thoracic Society of Australia; New Zealand Thoracic Society; Irish Thoracic Society. (2008). Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. *Thorax*, Vol. 63, Suppl. 5, pp. 1-58, ISSN

**8**

*Poland*

Wojciech J. Piotrowski

*Medical University of Lodz,*

**Prognostic Factors in Sarcoidosis**

*Division of Pneumology and Allergy, Department of Internal Medicine,*

Sarcoidosis is a multisystem disorder of unknown etiology. Inflammation mediated by lymphocytes of Th1 phenotype leads to formation of non-caseating granulomas, consisting of epithelioid and multinucleated giant cells. In the majority of patients it affects intrathoracic lymph nodes and lungs, but all organs may be involved (ATS, ERS, WASOG Statement on Sarcoidosis). The overall prognosis is good, and in about 60 % of all cases the disease regresses spontaneously. In the rest of patients, sarcoidosis is a chronic disease, sometimes showing up with relapses, which often follow withdrawal or dose reduction of steroids (Gottlieb et al., 1997; Neville et al., 1983; Scadding, 1961). In about 10-15 % it slowly progresses to lung fibrosis, which is the major cause of death, affecting less than 1 % of patients in Europe and up to 5% in North America. The immunopathological concepts on sarcoidosis describe mechanisms leading to induction of granuloma formation, mechanisms responsible for prolongation and sustaining of inflammation, and mechanisms responsible for fibrosis (the latter are the worse recognized). Although the etiology of sarcoidosis is unknown, it is generally acknowledged that the disease develops in genetically predisposed subjects who were exposed to unidentified (presumably inhaled) antigen(s). This unidentified "sarcoid factor" has the ability to persist in the intracellular milieu of macrophages, which results in the production of cytokines responsible for transformation of Th0 to Th1 cells. In response, lymphocytes produce a variety of cytokines which conversely stimulate macrophages and induce their transformation to granuloma cells. There is premise to speculate that the ability to eliminate the antigen from the intracellular environment is *sine qua non* of complete and definitive remission (Grunewald, 2002). Although mechanisms regulating these processes are not known, this knowledge seems to be critical for

understanding the pathogenesis of persistent and progressive sarcoidosis.

treat to achieve the best final cost/effect ratio.

Selection of patients at higher risk of lung fibrosis or other unfavorable outcomes at the early stages of disease is a hard task for a physician. There are no objective tests which would be helpful in this matter. Some prognostic factors important for a certain ethnic group may be useless in another. The most important question is whom to treat, and how to

Statement on Sarcoidosis, a document published by ATS, ERS and WASOG in 1999, lists a number of clinical factors of prognostic significance. These factors include: lupus pernio, chronic uveitis, age of onset >40 yr, chronic hypercalcemia, nephrocalcinosis, black race, progressive pulmonary sarcoidosis, nasal mucosal involvement, cystic bone lesions, neurosarcoidosis, myocardial involvement and chronic respiratory insufficiency. Different prognostic factors of real or potential clinical relevance will be discussed in this chapter.

**1. Introduction**

## **Prognostic Factors in Sarcoidosis**

Wojciech J. Piotrowski

*Division of Pneumology and Allergy, Department of Internal Medicine, Medical University of Lodz, Poland*

#### **1. Introduction**

136 Sarcoidosis Diagnosis and Management

Paramothayan NS, Lasserson TJ, & Jones PW. (2005). Corticosteroids for pulmonary

Paramothayan S, & Lasserson T. (2008). Treatments for pulmonary sarcoidosis. *Respiratory*

Patel SR. (2009). Systemic sarcoidosis with bone marrow involvement responding to therapy with adalimumab: a case report. *Journal of Medical*, Vol. 3, pp. 8573. ISSN 19830230 Pietinalho A, Tukiainen P, Haahtela T, Persson T, & Selroos O. (1999). Oral prednisolone

Pritchard C, & Nadarajah K. (2004). Tumour necrosis factor a inhibitor treatment for

Rizzato G, Montemurro L, & Colombo P. (1998). The late follow-up of chronic sarcoid

Saag KG, Teng GC, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A,

Sahgal SM, & Sharma OP. (1984). Fatal herpes simplex infection during chlorambucil therapy for sarcoidosis*. J R Soc Med*, Vol. 77, No. 2, pp. 144–146, ISSN 6737398 Salomon MI, Poon TP, Hsu KC, King EJ, & Tchertkoff V. (1975). Membranous

Savage RL, Highton J, Boyd IW, & Chapman P. (2006). Pneumonitis associated with

Siltzbach LE, & Teirstein AS. (1964). Chloroquine therapy in 43 patients with intrathoracic

Schutt AC, Bullington WM, & Judson MA. (2010). Pharmacotherapy for pulmonary

Utz JP, Limper AH, Sanjay Kalra, et al. (2003). Etanercept for the Treatment of Stage II and III Progressive Pulmonary Sarcoidosis. *Chest*, Vol. 124, pp. 177-185, ISSN 20089389 Wyser CP, Schalwyk EM, Berthold A, Bardin PG, & Joubert JR. (1997). Treatment of

Zabel P, Entzian P, Dalhoff K, & Schlaak M. (1997). Pentoxifylline in treatment of sarcoidosis. *Am J Respir Crit Care Med*., Vol. 155, pp. 1665–1669, ISSN 9154873

followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis. A double-blind, placebo-controlled multicentre study. *Chest*, Vol. 116, pp. 424–431,

sarcoidosis refractory to conventional treatments: a report of five patients. *Ann*

patients previously treated with corticosteroids. *Sarcoidosis Vasc Diffuse Lung Dis*.;

Pisu M, Elkins-Melton M, Outman R, Allison JJ, Suarez Almazor M, Bridges SL Jr, Chatham WW, Hochberg M, MacLean C, Mikuls T, Moreland LW, O'Dell J, Turkiewicz AM, & Furst DE; American College of Rheumatology. (2008). American College of Rheumatology 2008 recommendations for the use of non-biologic and biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis. *Arthritis*

glomerulopathy in a patient with sarcoidosis*. Arch Pathol.*,; Vol. 99, No. 9, pp. 479-

leflunomide: a profile of New Zealand and Australian reports. *Internal Medicine*

and cutaneous sarcoidosis. *Acta Medica Scandinavica*; Vol. 176, pp. 302-308, ISSN

sarcoidosis: a Delphi consensus study. Respir Med., Vol. 104, No. 5, pp. 717-723, ISSN

Progressive Pulmonary Sarcoidosis with Cyclosporin A. *Am. J. Respir. Crit. Care*

sarcoidosis. *Cochrane Database Syst Rev.*, Vol. 2, CD001114

*Medicine*, Vol. 102, pp. 1–9, ISSN 17954027

*Rheum Dis*, Vol. 63, pp. 318–320, ISSN 14962969

Vol. 15, pp. 52–58. ISSN 9572002

*Rheum*., Vol. 59, pp. 762, ISSN 18512708

*Journal*., Vol. 36, pp. 162–169, ISSN 16503951

*Med.*, Vol. 156, No. 5, pp. 1371-1376, ISSN 9372647

ISSN 10453872

483, ISSN 1100020

5884512

Sarcoidosis is a multisystem disorder of unknown etiology. Inflammation mediated by lymphocytes of Th1 phenotype leads to formation of non-caseating granulomas, consisting of epithelioid and multinucleated giant cells. In the majority of patients it affects intrathoracic lymph nodes and lungs, but all organs may be involved (ATS, ERS, WASOG Statement on Sarcoidosis). The overall prognosis is good, and in about 60 % of all cases the disease regresses spontaneously. In the rest of patients, sarcoidosis is a chronic disease, sometimes showing up with relapses, which often follow withdrawal or dose reduction of steroids (Gottlieb et al., 1997; Neville et al., 1983; Scadding, 1961). In about 10-15 % it slowly progresses to lung fibrosis, which is the major cause of death, affecting less than 1 % of patients in Europe and up to 5% in North America. The immunopathological concepts on sarcoidosis describe mechanisms leading to induction of granuloma formation, mechanisms responsible for prolongation and sustaining of inflammation, and mechanisms responsible for fibrosis (the latter are the worse recognized). Although the etiology of sarcoidosis is unknown, it is generally acknowledged that the disease develops in genetically predisposed subjects who were exposed to unidentified (presumably inhaled) antigen(s). This unidentified "sarcoid factor" has the ability to persist in the intracellular milieu of macrophages, which results in the production of cytokines responsible for transformation of Th0 to Th1 cells. In response, lymphocytes produce a variety of cytokines which conversely stimulate macrophages and induce their transformation to granuloma cells. There is premise to speculate that the ability to eliminate the antigen from the intracellular environment is *sine qua non* of complete and definitive remission (Grunewald, 2002). Although mechanisms regulating these processes are not known, this knowledge seems to be critical for understanding the pathogenesis of persistent and progressive sarcoidosis.

Selection of patients at higher risk of lung fibrosis or other unfavorable outcomes at the early stages of disease is a hard task for a physician. There are no objective tests which would be helpful in this matter. Some prognostic factors important for a certain ethnic group may be useless in another. The most important question is whom to treat, and how to treat to achieve the best final cost/effect ratio.

Statement on Sarcoidosis, a document published by ATS, ERS and WASOG in 1999, lists a number of clinical factors of prognostic significance. These factors include: lupus pernio, chronic uveitis, age of onset >40 yr, chronic hypercalcemia, nephrocalcinosis, black race, progressive pulmonary sarcoidosis, nasal mucosal involvement, cystic bone lesions, neurosarcoidosis, myocardial involvement and chronic respiratory insufficiency. Different prognostic factors of real or potential clinical relevance will be discussed in this chapter.

Prognostic Factors in Sarcoidosis 139

HRCT scores were more likely to have worse lung function parameters and abnormal gas exchange. They found HRCT superior to chest X-ray in depicting respiratory disability. Thickening of bronchovascular bundle and septal/nonseptal lines were especially linked to worse spirometric values and gas exchange parameters. Interestingly, "clear" lung parenchyma did not rule out abnormal gas exchange. Other authors confirmed that patients with extensive bronchovascular bundle thickening are at increased risk of developing irreversible bronchial obstruction (Handa et al., 2006). Another group of authors evaluated HRCT initially and after a mean follow-up period of 7.4 years in 40 patients and concluded that predominant small and multiple large nodules in the majority of cases disappeared or decreased in size, whereas ground-glass opacities and consolidations evolved into honeycombing. In addition, significant functional and respiratory impairment accompanied this evolution (Akira et al, 2005). Abehsera et al (2000) defined three CT signs of definitive lung fibrosis in patients suffering from stage IV disease: bronchial distortion, honeycombing and linear patterns. Emphysematous pattern is rare, but should be added to the list of possible irreversible radiologic changes in stage IV sarcoidosis (Akira et al, 2005). These and other reports (Malaisamy et al, 2009) indicate that small disseminated nodules (the most frequent finding in lung parenchyma of sarcoidosis patients) and also confluent nodes are potentially reversible, whereas others may represent fibrosis at different stages of evolution. Therefore, HRCT scans may be useful in predicting the outcomes of patients with

**3. Lung function tests and other measures of functional disability**

The risk of lung function impairment is greater in patients with a more advanced radiological stage. However, the disparity between radiological signs of parenchymal involvement and lung function tests results is quite common in sarcoidosis. It has been estimated that normal spirometry (vital capacity) may be seen in up to 80% of patients with stage I and 35% of patients with stage II and III (Winterbauer & Hutchinson, 1980]. A restrictive pattern of ventilatory impairment occurs in about 30-50% of all sarcoidosis patients. Atypical to other interstitial lung diseases, a significant proportion of patients present with bronchial obstruction. In one series from Japan, the percentage of patients with FEV1/FVC <70% was 8.8, and was associated with radiographic stage IV, higher age, smoking, and thickened bronchovascular bundles on CT (Handa et al., 2006). Other authors reported a much higher incidence of bronchial obstruction (Kieszko et al., 2004; Sharma & Johnson, 1988). Harrison et al. estimated that bronchial obstruction at different levels of the bronchial tree is the most common functional abnormality in sarcoidosis (Harrison et al., 1999). Bronchial obstruction may be independent of the parenchymal involvement, and results from the predilection to peribronchial and endobronchial formation of granulomas (Kieszko et al., 2004; Sharma & Johnson, 1988). Its frequency increases with the increasing

Initial lung function impairment has an obvious impact on long-term prognosis. In one study (Viscum & Vestbo, 1993) patients with FEV1 <50% of predicted had an increased mortality risk of 4.2, compared to patients with FEV1 >80%. Bronchial obstruction (FEV1/FVC<70%) increased the mortality risk to 1.9. Also, patients with lung restriction defined as TLC<80% of predicted value had an increased mortality risk (RR=2.6). Other authors in a long-term follow-up study (Mañá et al., 1996) found that initial FVC<80% of

predicted value is a strong predictor of persistent disease (RR=2.17).

pulmonary sarcoidosis.

**3.1 Lung function tests**

radiological stage (Lamberto, 1985).

#### **2. Radiology**

#### **2.1 Chest X-ray**

In the 50's, two radiologists, Nitter and Wurm (DeRemee, 1983; Nitter, 1953; Wurm et al, 1958) proposed a three-stage classification system based on chest X-ray (1-enlarged lymphnodes alone; 2- enlarged lymph-nodes plus parenchymal changes; 3- parenchymal changes without signs of intrathoracic lymph-nodes involvement). Today, a five-stage radiological classification is in use. It is ascribed to Scadding, who added stage 0 (for patients with normal chest X-ray) and stage IV (for patients with signs of irreversible lung fibrosis) (Scadding, 1961).

Scadding was one of the first to report on the influence of radiological stage on the longterm prognosis. He found that after > 5-years follow-up, 84% of patients with initial radiological stage I experienced complete radiological remission and even in the situation when hilar enlargement persisted, patients presented only with mild symptoms or were asymptomatic. In stage II, radiological remissions were observed in 58% of patients, and in stage III (clearly separated from stage IV) this percentage was as high as 43% (in later studies the chance of spontaneous remission in this stage was estimated at 10-20%). Of note, there were no remissions in the group with radiological signs of fibrosis (stage IV), and only in this group did sarcoidosis-related deaths occur. Many authors further confirmed the adverse relationship between III/IV radiological stage and worse long-term prognosis. Reich, in his meta-analysis (Reich, 2002), estimated that sarcoidosis mortality is 4.8% in referral centers and 0.5% in population-based settings, and is attributed to stage III/IV radiological stage. Viskum and Vestbo (1993) reported on their results of a 27-year follow-up study of 254 sarcoidosis patients, showing that radiological stage III was related to excess mortality. The authors also proved that early clearance of chest X-ray is a good prognostic factor.

Staging based on the chest X-ray remains the main clinico-radiological classification of sarcoidosis, but limitations are evident, and include: low sensitivity in determining small lymph nodes and tiny parenchymal shadows, problems with differentiation between parenchymal granulomatous infiltrations from signs of fibrosis, and relatively low levels of agreement between examiners (Baughman et al, 2009). Advantages of chest X-ray-based classification are: low costs, low radiation dose per one examination, general availability of a chest X-ray, and paradoxically, low sensitivity (what allows a clinician a first-glance diagnosis).

#### **2.2 Computed tomography**

Contrast-enhanced CT scans may be helpful in diagnosis of hilar/mediastinal lymphadenopathy, differentiating lymph nodes from vessels, and in all cases where there is a threat of malignancy. However, the presence of adenopathy, in contrast to parenchymal changes, is not an adverse risk factor for unfavorable outcome. Therefore, high resolution computed tomography (HRCT), which enables a precise estimation of the extent of pulmonary involvement and a detailed qualitative description of parenchymal changes, may be more useful as a tool for disease severity evaluation. Drent et al (2003) proposed a simple classification of HRCT signs based on the presence and extent of the most frequent findings in sarcoidosis patients: thickening or irregularity of the bronchovascular bundle, intra-parenchymal nodules, septal and nonseptal lines, and parenchymal consolidation, including ground-glass opacifications. The authors found that patients with higher total

In the 50's, two radiologists, Nitter and Wurm (DeRemee, 1983; Nitter, 1953; Wurm et al, 1958) proposed a three-stage classification system based on chest X-ray (1-enlarged lymphnodes alone; 2- enlarged lymph-nodes plus parenchymal changes; 3- parenchymal changes without signs of intrathoracic lymph-nodes involvement). Today, a five-stage radiological classification is in use. It is ascribed to Scadding, who added stage 0 (for patients with normal chest X-ray) and stage IV (for patients with signs of irreversible lung fibrosis)

Scadding was one of the first to report on the influence of radiological stage on the longterm prognosis. He found that after > 5-years follow-up, 84% of patients with initial radiological stage I experienced complete radiological remission and even in the situation when hilar enlargement persisted, patients presented only with mild symptoms or were asymptomatic. In stage II, radiological remissions were observed in 58% of patients, and in stage III (clearly separated from stage IV) this percentage was as high as 43% (in later studies the chance of spontaneous remission in this stage was estimated at 10-20%). Of note, there were no remissions in the group with radiological signs of fibrosis (stage IV), and only in this group did sarcoidosis-related deaths occur. Many authors further confirmed the adverse relationship between III/IV radiological stage and worse long-term prognosis. Reich, in his meta-analysis (Reich, 2002), estimated that sarcoidosis mortality is 4.8% in referral centers and 0.5% in population-based settings, and is attributed to stage III/IV radiological stage. Viskum and Vestbo (1993) reported on their results of a 27-year follow-up study of 254 sarcoidosis patients, showing that radiological stage III was related to excess mortality. The authors also proved that early clearance of chest X-ray is a good prognostic

Staging based on the chest X-ray remains the main clinico-radiological classification of sarcoidosis, but limitations are evident, and include: low sensitivity in determining small lymph nodes and tiny parenchymal shadows, problems with differentiation between parenchymal granulomatous infiltrations from signs of fibrosis, and relatively low levels of agreement between examiners (Baughman et al, 2009). Advantages of chest X-ray-based classification are: low costs, low radiation dose per one examination, general availability of a chest X-ray, and paradoxically, low sensitivity (what allows a clinician a first-glance

Contrast-enhanced CT scans may be helpful in diagnosis of hilar/mediastinal lymphadenopathy, differentiating lymph nodes from vessels, and in all cases where there is a threat of malignancy. However, the presence of adenopathy, in contrast to parenchymal changes, is not an adverse risk factor for unfavorable outcome. Therefore, high resolution computed tomography (HRCT), which enables a precise estimation of the extent of pulmonary involvement and a detailed qualitative description of parenchymal changes, may be more useful as a tool for disease severity evaluation. Drent et al (2003) proposed a simple classification of HRCT signs based on the presence and extent of the most frequent findings in sarcoidosis patients: thickening or irregularity of the bronchovascular bundle, intra-parenchymal nodules, septal and nonseptal lines, and parenchymal consolidation, including ground-glass opacifications. The authors found that patients with higher total

**2. Radiology 2.1 Chest X-ray**

(Scadding, 1961).

factor.

diagnosis).

**2.2 Computed tomography**

HRCT scores were more likely to have worse lung function parameters and abnormal gas exchange. They found HRCT superior to chest X-ray in depicting respiratory disability. Thickening of bronchovascular bundle and septal/nonseptal lines were especially linked to worse spirometric values and gas exchange parameters. Interestingly, "clear" lung parenchyma did not rule out abnormal gas exchange. Other authors confirmed that patients with extensive bronchovascular bundle thickening are at increased risk of developing irreversible bronchial obstruction (Handa et al., 2006). Another group of authors evaluated HRCT initially and after a mean follow-up period of 7.4 years in 40 patients and concluded that predominant small and multiple large nodules in the majority of cases disappeared or decreased in size, whereas ground-glass opacities and consolidations evolved into honeycombing. In addition, significant functional and respiratory impairment accompanied this evolution (Akira et al, 2005). Abehsera et al (2000) defined three CT signs of definitive lung fibrosis in patients suffering from stage IV disease: bronchial distortion, honeycombing and linear patterns. Emphysematous pattern is rare, but should be added to the list of possible irreversible radiologic changes in stage IV sarcoidosis (Akira et al, 2005). These and other reports (Malaisamy et al, 2009) indicate that small disseminated nodules (the most frequent finding in lung parenchyma of sarcoidosis patients) and also confluent nodes are potentially reversible, whereas others may represent fibrosis at different stages of evolution. Therefore, HRCT scans may be useful in predicting the outcomes of patients with pulmonary sarcoidosis.

#### **3. Lung function tests and other measures of functional disability**

#### **3.1 Lung function tests**

The risk of lung function impairment is greater in patients with a more advanced radiological stage. However, the disparity between radiological signs of parenchymal involvement and lung function tests results is quite common in sarcoidosis. It has been estimated that normal spirometry (vital capacity) may be seen in up to 80% of patients with stage I and 35% of patients with stage II and III (Winterbauer & Hutchinson, 1980]. A restrictive pattern of ventilatory impairment occurs in about 30-50% of all sarcoidosis patients. Atypical to other interstitial lung diseases, a significant proportion of patients present with bronchial obstruction. In one series from Japan, the percentage of patients with FEV1/FVC <70% was 8.8, and was associated with radiographic stage IV, higher age, smoking, and thickened bronchovascular bundles on CT (Handa et al., 2006). Other authors reported a much higher incidence of bronchial obstruction (Kieszko et al., 2004; Sharma & Johnson, 1988). Harrison et al. estimated that bronchial obstruction at different levels of the bronchial tree is the most common functional abnormality in sarcoidosis (Harrison et al., 1999). Bronchial obstruction may be independent of the parenchymal involvement, and results from the predilection to peribronchial and endobronchial formation of granulomas (Kieszko et al., 2004; Sharma & Johnson, 1988). Its frequency increases with the increasing radiological stage (Lamberto, 1985).

Initial lung function impairment has an obvious impact on long-term prognosis. In one study (Viscum & Vestbo, 1993) patients with FEV1 <50% of predicted had an increased mortality risk of 4.2, compared to patients with FEV1 >80%. Bronchial obstruction (FEV1/FVC<70%) increased the mortality risk to 1.9. Also, patients with lung restriction defined as TLC<80% of predicted value had an increased mortality risk (RR=2.6). Other authors in a long-term follow-up study (Mañá et al., 1996) found that initial FVC<80% of predicted value is a strong predictor of persistent disease (RR=2.17).

Prognostic Factors in Sarcoidosis 141

dyspnea score, lung fibrosis on HRCT, pulmonary hypertension and systemic therapy (Alhamad et al., 2010). The impaired exercise tolerance in sarcoidosis may be explained at least in part by reduced peripheral muscle strength (Marcellis et al., 2011). Patients with sarcoidosis-associated pulmonary hypertension walk shorter distances and desaturate during the 6MWT. Desaturation <90% during the test was shown to be a very strong predictor of sarcoidosis-associated pulmonary hypertension (Bourbonnais & Samavati,

Alveolar-arterial oxygen pressure gradient (P(A-a)O2) during exercise may be useful in selection of patients demanding immunosuppressive treatment. Of note, impaired gas exchange during exercise also occurred in some patients with normal spirometry and

The typical finding in sarcoidosis is an increase of BAL lymphocyte count, displayed by 80- 90% of patients at the time of initial diagnosis. The lymphocyte percentage is an activity marker, and an average increase in active disease reaches 30-60%, but higher percentages are also observed. About 60% of patients have a CD4/CD8 ratio above 3.5, which is highly specific for sarcoidosis. Sensitivity of both high BAL lymphocyte percentage and CD4/CD8

It was shown that lymphocytic alveolitis is an unstable feature, because in 75% of initial high intensity alveolitis the lymphocyte BAL content spontaneously dropped and in 12% of patients with initial low-grade alveolitis it spontaneously reverted to high intensity alveolitis after approximately 6-month follow-up observation. In the latter case, the increase of BAL lymphocyte percentage was frequently followed by the deterioration in at least one lung function parameter at the next 6-month follow-up examination (Keogh et al., 1983). According to the majority of authors, high BAL lymphocytes are not connected with worse long-term prognosis, and may even determine a subpopulation of patients with evidently better prognosis (Tahanovich et al., 2003). BAL lymphocytes >35 % predicted a good response to treatment, as indicated by an increase in FVC value in >90% of patients, whereas patients with low-intensity alveolitis deteriorated in 50% of cases, regardless of the treatment (Hollinger et al., 1985). Many authors did not find any differences in BAL lymphocytes content between subgroups of different prognosis as defined by radiological stage, chronicity or other factors (Vidal Serrano et al., 2005; Ziegenhagen et al., 2003); whereas some authors report higher intensity alveolitis in patients with stage I comparing to stage III (Danila et al., 2008; Verstraeten et al., 1990). Follow-up studies clearly show the lack of negative prognostic value of high lymphocyte content in BAL. The recovery of lymphocytes in lavage fluid had no prognostic value for persistent disease in the over two-

High content of CD4 lymphocytes or high CD4/CD8 ratio in BAL are more relevant markers of activity comparing to total lymphocyte BAL percentage (Costabel, 1998). Patients who improved radiologically had higher numbers of CD4 cells and higher CD4/CD8 ratio comparing to patients who deteriorated or remained unchanged (Verstraeten et al., 1990). Also, patients with higher CD4/CD8 at initial diagnosis responded better to treatment

The detailed characterization of BAL lymphocyte subpopulations by flow cytometry may be promising in description of patients with worse prognosis. For instance, lymphocytes with

DLCO. Good correlation was observed with radiological staging (Kollert et al., 2011).

**4. Bronchoalveolar lavage (BAL) cells**

ratio is however, unacceptably low (Costabel, 1998).

year follow-up studies (Bjermer et al., 1988; Verstraeten et al., 1990).

(Baughman et al., 1984; Płodziszewska et al., 2000).

2008).

Regardless of the evident negative prognostic value of impaired lung function test results at the initial evaluation, it was shown by many authors that in some patients these abnormalities are potentially reversible after long term observation. Approximately 80% of subjects had an improved or stable FVC and FEV1 after two years follow-up. Interestingly, changes in FVC alone were found unreliable as descriptors of pulmonary status, as they did not fully correspond to radiological changes or symptoms (Judson et al., 2003). Although bronchial obstruction (FEV1/FVC <70%) is a strong predictor of unfavorable outcome, it was shown that when it is attributed merely to bronchial sarcoid granulomas, it may be completely or partially reversible with immunosuppressive treatment in >70% of patients (Lavergne et al., 1999). Bronchial obstruction related to other mechanisms like bronchial scarring, airway distortion secondary to interstitial fibrosis, or other mechanisms may be burdened with a much worse prognosis.

#### **3.2 Diffusion capacity**

Diffusion capacity for carbon monoxide (DLCO) is a measure frequently used to estimate the severity of lung parenchymal involvement. DLCO disturbances may result from deprivation of gas exchange area, increase of barrier thickness or ventilation-perfusion mismatching. According to general understanding, DLCO is a very sensitive marker and its decrease may herald the development of irreversible fibrosis. It may be especially useful in monitoring of disease progression or regression (spontaneous or resulting from treatment). It was shown to be a good predictor of gas exchange abnormalities at exercise; moreover, from the two components of DLCO (alveolar membrane diffusing capacity and pulmonary capillary blood volume), the effect was rather related to the "membrane" component (Lamberto, 1985). However, the vascular component may also be important, as DLCO<60% predicted was proven to be a strong predictor of pulmonary hypertension in sarcoidosis (Bourbonnais & Samavati., 2008). Unfortunately, DLCO also has some limitations. DLCO may represent transient gas transfer impairment, especially in patients with stage I or II with low grade parenchymal lung disease, where gas exchange may be altered by reversible mechanisms. Dunn et al. reported that DLCO of idiopathic pulmonary fibrosis (IPF) patients was significantly lower comparing to sarcoidosis patients; regardless the comparison was performed in patients with the same level of lung volume impairment. This observation suggests that diffusing capacity may not be a sensitive indicator of pulmonary pathology in sarcoidosis since lung volume can be altered independently of abnormalities in the diffusing capacity (Dunn et al., 1988).

#### **3.3 Six-minute walk test**

The six-minute walk test (6MWT) is a simple test used to assess the exercise capacity in patients suffering from different respiratory and heart diseases. Changes in exercise capacity may be due to such factors as lung function, cardiac status, respiratory and skeletal muscle strength. Its role in the clinical assessment of sarcoidosis is still growing. In one series of patients, six-minute walk distance (6MWD) <400 m was documented in >50% of patients (Baughman et al., 2007). Several factors were associated with reduced results of the test, including FVC, oxygen saturation with exercise and self-reported respiratory health (Baughman et al., 2007). Some authors suggest that distance-saturation product (DSP), which is a result of the 6MWD multiplied by the lowest oxygen saturation, better reflects the functional status in patients with sarcoidosis, and it was shown to correlate with female gender, pulmonary function parameters (especially FEV1), partial pressure of oxygen, Borg

Regardless of the evident negative prognostic value of impaired lung function test results at the initial evaluation, it was shown by many authors that in some patients these abnormalities are potentially reversible after long term observation. Approximately 80% of subjects had an improved or stable FVC and FEV1 after two years follow-up. Interestingly, changes in FVC alone were found unreliable as descriptors of pulmonary status, as they did not fully correspond to radiological changes or symptoms (Judson et al., 2003). Although bronchial obstruction (FEV1/FVC <70%) is a strong predictor of unfavorable outcome, it was shown that when it is attributed merely to bronchial sarcoid granulomas, it may be completely or partially reversible with immunosuppressive treatment in >70% of patients (Lavergne et al., 1999). Bronchial obstruction related to other mechanisms like bronchial scarring, airway distortion secondary to interstitial fibrosis, or other mechanisms may be

Diffusion capacity for carbon monoxide (DLCO) is a measure frequently used to estimate the severity of lung parenchymal involvement. DLCO disturbances may result from deprivation of gas exchange area, increase of barrier thickness or ventilation-perfusion mismatching. According to general understanding, DLCO is a very sensitive marker and its decrease may herald the development of irreversible fibrosis. It may be especially useful in monitoring of disease progression or regression (spontaneous or resulting from treatment). It was shown to be a good predictor of gas exchange abnormalities at exercise; moreover, from the two components of DLCO (alveolar membrane diffusing capacity and pulmonary capillary blood volume), the effect was rather related to the "membrane" component (Lamberto, 1985). However, the vascular component may also be important, as DLCO<60% predicted was proven to be a strong predictor of pulmonary hypertension in sarcoidosis (Bourbonnais & Samavati., 2008). Unfortunately, DLCO also has some limitations. DLCO may represent transient gas transfer impairment, especially in patients with stage I or II with low grade parenchymal lung disease, where gas exchange may be altered by reversible mechanisms. Dunn et al. reported that DLCO of idiopathic pulmonary fibrosis (IPF) patients was significantly lower comparing to sarcoidosis patients; regardless the comparison was performed in patients with the same level of lung volume impairment. This observation suggests that diffusing capacity may not be a sensitive indicator of pulmonary pathology in sarcoidosis since lung volume can be altered independently of abnormalities in the diffusing

The six-minute walk test (6MWT) is a simple test used to assess the exercise capacity in patients suffering from different respiratory and heart diseases. Changes in exercise capacity may be due to such factors as lung function, cardiac status, respiratory and skeletal muscle strength. Its role in the clinical assessment of sarcoidosis is still growing. In one series of patients, six-minute walk distance (6MWD) <400 m was documented in >50% of patients (Baughman et al., 2007). Several factors were associated with reduced results of the test, including FVC, oxygen saturation with exercise and self-reported respiratory health (Baughman et al., 2007). Some authors suggest that distance-saturation product (DSP), which is a result of the 6MWD multiplied by the lowest oxygen saturation, better reflects the functional status in patients with sarcoidosis, and it was shown to correlate with female gender, pulmonary function parameters (especially FEV1), partial pressure of oxygen, Borg

burdened with a much worse prognosis.

**3.2 Diffusion capacity**

capacity (Dunn et al., 1988).

**3.3 Six-minute walk test**

dyspnea score, lung fibrosis on HRCT, pulmonary hypertension and systemic therapy (Alhamad et al., 2010). The impaired exercise tolerance in sarcoidosis may be explained at least in part by reduced peripheral muscle strength (Marcellis et al., 2011). Patients with sarcoidosis-associated pulmonary hypertension walk shorter distances and desaturate during the 6MWT. Desaturation <90% during the test was shown to be a very strong predictor of sarcoidosis-associated pulmonary hypertension (Bourbonnais & Samavati, 2008).

Alveolar-arterial oxygen pressure gradient (P(A-a)O2) during exercise may be useful in selection of patients demanding immunosuppressive treatment. Of note, impaired gas exchange during exercise also occurred in some patients with normal spirometry and DLCO. Good correlation was observed with radiological staging (Kollert et al., 2011).

#### **4. Bronchoalveolar lavage (BAL) cells**

The typical finding in sarcoidosis is an increase of BAL lymphocyte count, displayed by 80- 90% of patients at the time of initial diagnosis. The lymphocyte percentage is an activity marker, and an average increase in active disease reaches 30-60%, but higher percentages are also observed. About 60% of patients have a CD4/CD8 ratio above 3.5, which is highly specific for sarcoidosis. Sensitivity of both high BAL lymphocyte percentage and CD4/CD8 ratio is however, unacceptably low (Costabel, 1998).

It was shown that lymphocytic alveolitis is an unstable feature, because in 75% of initial high intensity alveolitis the lymphocyte BAL content spontaneously dropped and in 12% of patients with initial low-grade alveolitis it spontaneously reverted to high intensity alveolitis after approximately 6-month follow-up observation. In the latter case, the increase of BAL lymphocyte percentage was frequently followed by the deterioration in at least one lung function parameter at the next 6-month follow-up examination (Keogh et al., 1983). According to the majority of authors, high BAL lymphocytes are not connected with worse long-term prognosis, and may even determine a subpopulation of patients with evidently better prognosis (Tahanovich et al., 2003). BAL lymphocytes >35 % predicted a good response to treatment, as indicated by an increase in FVC value in >90% of patients, whereas patients with low-intensity alveolitis deteriorated in 50% of cases, regardless of the treatment (Hollinger et al., 1985). Many authors did not find any differences in BAL lymphocytes content between subgroups of different prognosis as defined by radiological stage, chronicity or other factors (Vidal Serrano et al., 2005; Ziegenhagen et al., 2003); whereas some authors report higher intensity alveolitis in patients with stage I comparing to stage III (Danila et al., 2008; Verstraeten et al., 1990). Follow-up studies clearly show the lack of negative prognostic value of high lymphocyte content in BAL. The recovery of lymphocytes in lavage fluid had no prognostic value for persistent disease in the over twoyear follow-up studies (Bjermer et al., 1988; Verstraeten et al., 1990).

High content of CD4 lymphocytes or high CD4/CD8 ratio in BAL are more relevant markers of activity comparing to total lymphocyte BAL percentage (Costabel, 1998). Patients who improved radiologically had higher numbers of CD4 cells and higher CD4/CD8 ratio comparing to patients who deteriorated or remained unchanged (Verstraeten et al., 1990). Also, patients with higher CD4/CD8 at initial diagnosis responded better to treatment (Baughman et al., 1984; Płodziszewska et al., 2000).

The detailed characterization of BAL lymphocyte subpopulations by flow cytometry may be promising in description of patients with worse prognosis. For instance, lymphocytes with

Prognostic Factors in Sarcoidosis 143

patients with the same radiological stage and elevated SACE concentrations (DeRemee & Rohrbach, 1984; Krychniak-Soszka & Kuś, 2002). According to some authors, SACE may help to differentiate patients with stable and persistent or progressive disease (Mañá et al., 1996), but other authors do not confirm this observation (Rust et al., 1985; Ziegenhagen et al., 2003). Therefore, it may be concluded that the role of SACE in predicting the course of

25-hydroxyvitamin D undergoes 1α-hydroxylation to form more active 1,25 dihydroxyvitamin D, and granuloma cells possess high amounts of 25-hydroxyvitamin D-1α-hydroxylase, responsible for this conversion (Bell et al., 1979). Elevated serum calcium concentrations may be found in about 11% of patients with sarcoidosis, abnormal urinary calcium loss in about 40 % of patients, and nephrocalcinosis in about 10 % [Ianuzzi et al., 2007]. Severe abnormalities in calcium metabolism, like persistent hypercalcemia, may bear serious and sometimes life-threatening consequences and constitute an independent indication to treatment (ATS, ERS, WASOG Statement on Sarcoidosis, 1999). Therefore, hypercalcemia *per se* is a factor which may potentially worsen the prognosis. Altered calcium metabolism is more frequent in patients with more advanced and chronic lung sarcoidosis and in those with extrapulmonary disease (Neville et al., 1983). Also, chronic nephrocalcinosis in the course of sarcoidosis is usually linked to a chronic course and often

Serum C-reactive protein (CRP) is elevated in almost all patients with Löfgren syndrome and is frequently normal in asymptomatic patients and those with more advanced disease (Rothkrantz-Kos et al., 2003; Mert et al., 2007). Therefore it may not be linked to worse prognosis in the crude population of sarcoidosis patients. In chronic sarcoidosis, however, elevated CRP may identify a subpopulation of patients with more extensive and severe disease. It may also be helpful in identifying patients with better response to treatment with

Serum amyloid A (SAA) is another acute phase reactant which is related to HDL-cholesterol. Its diagnostic value in sarcoidosis is similar to CRP (Rothkrantz-Kos et al., 2003), but recent data show its potential role in the pathogenesis of sarcoidosis, as it was shown to be deposited in granuloma cells. This molecule is capable of triggering the release of cytokines through an interaction with toll-like receptor 2 (Chen et al., 2010). This may be one of mechanisms responsible for chronicity of inflammation, but the clinical value of SAA in predicting the chronic course of sarcoidosis is unknown. Patients suffering from sarcoidosis-related fatigue

The level of immunoglobulins is elevated in serum (and BAL) in above 50 % of patients (Bergmann et al., 1997). Circulating immune complement binding complexes are detected in 67% of patients (Schoenfeld et al. 1994). Hyperglobulinemia was shown to influence the

Neopterin is a product of macrophages, and its serum concentration may reflect the level of macrophage stimulation. The exact biological role of this pro-inflammatory mediator is

did not have higher concentrations of CRP and SAA in serum (de Vries et al., 2004).

persistence of activity over time in one study (Maña et al., 1996).

**5.4 Other immunological markers**

sarcoidosis is limited.

**5.2 Altered calcium metabolism**

an unfavorable outcome (Neville et al., 1983).

the anti-TNF agent, infliximab (Sweiss et al., 2010).

**5.3 Acute phase reactants**

higher expression of CD95, an apoptotic molecule (Fas), were found in unexpectedly high amount on the surface of BAL lymphocytes from patients with progressive sarcoidosis (Ozdemir et al., 2007). Increased number of Th17 cells may be predictive for progressive sarcoidosis and may help in selecting patients under increased risk of lung fibrosis (Facco et al., 2011). As yet, lymphocytes subpopulations other than CD4 and CD8 are not in everyday use in clinical practice.

Several authors report on the possible prognostic value of BAL neutrophils. Patients with stage 3 had higher concentrations of BAL neutrophil elastase than patients with stage 1 or 2 (Danila et al., 2008; Peros-Golubcić et al., 2001). The length of disease duration correlated with the lung lavage neutrophil counts (Peros-Golubcić et al., 2001). It was shown that patients with lower neutrophil count in BAL have a greater chance to recover spontaneously (Drent et al., 1999). Ziegenhagen et al reported on significantly elevated percentage of BALF neutrophils in patients with progressive disease, and found that increased percentage of neutrophils in BAL >3% may predict the future necessity of treatment (Ziegenhagen et al., 2003).

Some authors reported on possible prognostic value of increased BALF eosinophils (Danila et al., 2008; Ziegenhagen et al., 2003) and mast cells (Bjermer et al., 1988). Patients with high percentage of neutrophils and eosinophils in BAL fluid more frequently have gas exchange impairment on exercise (Kollert et al., 2011).

#### **5. Laboratory markers**

A huge number of biochemical and immunological markers have been evaluated so far in the context of diagnosis, estimation of activity or prognosis. The most frequently used biological materials are serum and BAL fluid, but some new possibilities emerged recently, for instance, exhaled breath condensate (EBC) analysis (Piotrowski et al., 2007; Psathakis et al., 2004). These markers include substances that are directly produced by granuloma cells (angiotensin converting enzyme, ACE) or that result from their metabolic activity (increased serum and urinary calcium due to increased rate of hydroxylation of vitamin D), or acute phase reactants (CRP), or various immunological markers involved in initiation and propagation of granulomatous inflammation (cytokines, soluble receptors, lipid peroxidation products, other mediators).

#### **5.1 Angiotensin converting enzyme (ACE)**

Angiotensin converting enzyme is a product of active granuloma cells. It has been the most widely used laboratory marker in sarcoidosis, as it was shown to correlate with the total volume of granulomas within an organism. Unfortunately, it is neither specific nor sensitive. Its serum concentration is elevated only in about 60% of patients with active sarcoidosis (Gupta et al., 1979), and high concentrations were reported in patients with lung diseases other than sarcoidosis (Farber et al., 1980; Studdy et al., 1978). Moreover, its levels may be influenced by polymorphism of the ACE gene (Arbustini et al., 1996). SACE concentrations were proven to correlate with the extent of lung parenchymal infiltrations (Studdy et al., 1980). It was also shown to normalize in response to treatment and to follow spontaneous remissions (Pietinalho et al., 1999; Planck et al., 2003; Studdy et al., 1978; Studdy et al., 1980). It correlates with BAL lymphocytes, although it was shown to be inferior comparing to BAL lymphocyte count in differentiating active from inactive disease (Rossman et al., 1982). Patients with stage I sarcoidosis and low SACE levels seem to have better prognosis than

higher expression of CD95, an apoptotic molecule (Fas), were found in unexpectedly high amount on the surface of BAL lymphocytes from patients with progressive sarcoidosis (Ozdemir et al., 2007). Increased number of Th17 cells may be predictive for progressive sarcoidosis and may help in selecting patients under increased risk of lung fibrosis (Facco et al., 2011). As yet, lymphocytes subpopulations other than CD4 and CD8 are not in everyday

Several authors report on the possible prognostic value of BAL neutrophils. Patients with stage 3 had higher concentrations of BAL neutrophil elastase than patients with stage 1 or 2 (Danila et al., 2008; Peros-Golubcić et al., 2001). The length of disease duration correlated with the lung lavage neutrophil counts (Peros-Golubcić et al., 2001). It was shown that patients with lower neutrophil count in BAL have a greater chance to recover spontaneously (Drent et al., 1999). Ziegenhagen et al reported on significantly elevated percentage of BALF neutrophils in patients with progressive disease, and found that increased percentage of neutrophils in BAL >3% may predict the future necessity of treatment (Ziegenhagen et al.,

Some authors reported on possible prognostic value of increased BALF eosinophils (Danila et al., 2008; Ziegenhagen et al., 2003) and mast cells (Bjermer et al., 1988). Patients with high percentage of neutrophils and eosinophils in BAL fluid more frequently have gas exchange