Systemic evaluation of a potential cutaneous sarcoidosis patient

Transcription

1 Clinics in Dermatology (2007) 25, Systemic evaluation of a potential cutaneous sarcoidosis patient Ulrich Costabel, MD a,, Josune Guzman, MD b, Robert P. Baughman, MD c a Department of Pneumology/Allergy, Ruhrlandklinik Essen, D Essen, Germany b General and Experimental Pathology, Ruhr University, Bochum, D Bochum, Germany c Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA Abstract The diagnosis of sarcoidosis cannot be established by the presence of granuloma in a single organ, such as the skin. Therefore, the patient with potential cutaneous sarcoidosis should undergo a systemic evaluation for two reasons: to help confirm the diagnosis, and to identify other potential problems. This article reviews the recommended testing in patients with suspected or known sarcoidosis. The evaluation leads to a wide number of organs being assessed by either history, physical examination or routine laboratory investigations. The major organs routinely assessed are the lungs, the eyes, the liver and the heart Elsevier Inc. All rights reserved. Introduction Sarcoidosis is defined as a multisystemic disorder of unknown etiology characterized by the formation of epithelioid cell granulomas. Therefore, by definition, the diagnosis of sarcoidosis cannot be established by the presence of granuloma in a single organ, such as the skin. The patient with potential cutaneous sarcoidosis should undergo a systemic evaluation. One reason for this systemic evaluation is to help confirm the diagnosis of sarcoidosis. Another reason for the systemic evaluation is to identify other potential problems of the sarcoidosis patient. These issues are interrelated. Sarcoidosis remains a diagnosis of exclusion. A skin biopsy demonstrating noncaseating granulomas is not sufficient for the diagnosis of sarcoidosis. For a specific diagnosis of sarcoidosis, the pathologic findings should be Corresponding author. Tel.: ; fax: address: erj.costabel@t-online.de (U. Costabel). supported by a compatible clinical picture. 1 This information can be obtained doing the recommended testing in patients with suspected or known sarcoidosis (Table 1). For example, Fig. 1A is the scalp lesion of a patient with patchy alopecia and hypopigmentation. The patient had a cough, and a chest roentgenogram was obtained (Fig. 1B). The presence of marked adenopathy and upper lobe fibrosis was highly suggestive of sarcoidosis. Clinical presentation The clinical picture of sarcoidosis is diverse. There is no single specific presentation for sarcoidosis. The spectrum can range from asymptomatic disease captured on an incidental chest radiograph to acute febrile illness with nonspecific constitutional symptoms to chronic insidious organ failure. The true number of asymptomatic patients cannot be reliably determined because many of them escape diagnosis. In various series, 30% to 50% of patients were found to be asymptomatic at the time of diagnosis X/$ see front matter 2007 Elsevier Inc. All rights reserved. doi: /j.clindermatol

2 304 Table 1 Recommended initial evaluation of patients with known or suspected sarcoidosis 1. History (including symptoms and occupational exposures) 2. Physical examination 3. Posterior anterior chest roentgenogram 4. Pulmonary function studies: spirometry and diffusion of carbon monoxide in the lung 5. Peripheral blood counts 6. Serum chemistries: calcium, liver function testing (alkaline phosphatase, alanine aminotransferase, aspirate aminotransferase, total bilirubin), creatinine, glucose 7. Routine ophthalmologic examination 8. Electrocardiogram 9. Urine analysisa 10. Tuberculin skin testa Adapted from Hunninghake et al.1 a Suggested if clinically indicated. Nonspecific constitutional symptoms, including fever (generally low grade, but up to 40 C has been observed), weight loss (usually limited to 2 to 6 kg during the 10 to 12 weeks before presentation), night sweats, and arthralgias, are present in about 20% to 30% of patients. Fatigue and weakness that can be disabling are more common; in one study, up to 70% of patients have been affected.5 These systemic symptoms can be explained by the release of proinflammatory cytokines, most importantly tumor necrosis factor, by alveolar macrophages.6 Sarcoidosis is an important and frequently overlooked cause of fever of unknown origin. A distinct subgroup of sarcoidosis patients is characterized by an acute onset, classically with Löfgren syndrome, which is defined by bilateral hilar lymphadenopathy, ankle arthritis, and erythema nodosum and is frequently associated with systemic symptoms including fever, myalgia, and malaise.7 The prognosis is good and spontaneous remission usually occurs within 2 years; but rarely, erythema nodosum may relapse after many years. Löfgren syndrome occurs more frequently in whites than in African Americans or in Asians. Erythema nodosum and fever usually remit spontaneously within 4 to 8 weeks, whereas the resolution of hilar lymphadenopathy may need 1 or more years. Chronic sarcoidosis has an insidious onset. Several risk factors have been associated with a chronic or progressive course, including lupus pernio, chronic uveitis, higher age at onset, chronic hypercalcemia and nephrocalcinosis, black race, progressive pulmonary sarcoidosis, nasal mucosal involvement, cystic bone lesions, neurosarcoidosis, and myocardial involvement.8,9 U. Costabel et al. symptoms.10 This can be seen in patients with a normal chest roentgenogram and/or normal lung function studies. 4 Dyspnea can be at rest but in most cases will only be with exercise. Dyspnea only with walking up a flight of stairs is considered mild to moderate disease. Dyspnea that occurs while walking on level ground is associated with a moderate to severe defect. The cough in sarcoidosis is usually nonproductive and often brought on by airway irritants such as cold air and cigarette smoke.11 It is sometimes associated with infiltration of the airway with sarcoid granulomas. 12 Hemoptysis is rare, and so is pleural involvement. In contrast to many other interstitial lung diseases, clubbing and crackles are not usually present.13 When they occur, crackles and clubbing suggest an underlying complication such as secondary bronchiectasis.13 The chest roentgenogram is discussed elsewhere in this issue. The presence of any abnormality of chest roentgenogram of a patient with skin disease raises the issue of a systemic disease. The finding of symmetrical adenopathy, Pulmonary assessment The history should ask about symptoms related to specific extracutaneous involvement. This includes questions about pulmonary symptoms of cough and dyspnea. At the time of diagnosis, most patients will have either or both of these Fig. 1 Patient with alopecia and cough. A, Her scalp lesion consisted of areas of erythema and hypopigmentation. Biopsy demonstrated noncaseating granulomas. B, A chest roentgenogram demonstrates marked hilar enlargement and upper lobe fibrosis.

3 Systemic evaluation of a potential cutaneous sarcoidosis patient Suspected complications of lung disease, such as bronchiectasis, aspergilloma, and traction emphysema 4. Suspicion of superimposed infection or malignancy Fig. 2 The chest roentgenogram stage 14 at presentation from 3 large series of sarcoidosis patients in the United States, 4 Germany and Switzerland, 3 Finland, 2 and Japan. 2 with or without parenchymal infiltrates, should always suggest sarcoidosis in a patient with skin lesions. The chest roentgenogram in sarcoidosis is described in 4 stages 14 : stage 1, adenopathy alone; stage 2, adenopathy plus infiltrates; stage 3, infiltrates alone; stage 4, fibrosis. Patients with a normal chest roentgenogram are considered stage 0. Fig. 2 summarizes the chest roentgenogram stages at presentation of 3 large series of sarcoidosis patients in the United States, Europe, or Japan. 3,4,15 These studies were performed by pulmonary groups; and therefore, this may have led to a smaller number of cases presenting with normal chest roentgenogram (stage 0). In addition, these studies were at the time of presentation; and therefore, more patients may develop stage 4 disease over time. Winterbauer et al proposed that the appearance of a characteristic stage 1 chest radiograph is characteristic enough to be considered diagnostic in an asymptomatic patient. 16 Therefore, histologic confirmation may not be needed in asymptomatic patients who have symmetrical bihilar lymphadenopathy. When the hilar lymphadenopathy is asymmetrical, massive, or associated with a large paratracheal enlargement, however, biopsy confirmation is strongly advised. It is important to ask for previous chest radiographs. If they show minor hilar changes, which may have been overlooked, and later show the characteristic development to stage II disease, such changes during the course may be sufficient to allow a diagnosis of sarcoidosis without biopsy confirmation. Chest computed tomographs (CT) are not routinely needed. In some patients (30% of patients according to the experience of the present authors), high-resolution CT is indicated for the following reasons: 1. Atypical clinical and/or chest radiographic findings 2. A normal chest radiograph but a high clinical suspicion of the disease The standard pulmonary function studies recommended in Table 1 are spirometry and diffusion of carbon monoxide in the lung. The spirometry measurement will give the clinician the forced vital capacity and the forced expiratory volume in 1 second. Airway obstruction leads to a reduced flow rate and a reduction in the forced expiratory volume in 1 second/forced vital capacity ratio to less than 80%. Restrictive disease is a reduction in all lung volumes, leading to a reduction in the forced vital capacity to less than 80%. In pure restrictive disease, the forced expiratory volume in 1 second/forced vital capacity ratio will remain greater than 80%. Although sarcoidosis classically is a restrictive disease, over a third of patients will have obstruction with a reduced forced expiratory volume in 1 second/forced vital capacity ratio. 10 The diffusion of carbon monoxide in the lung is a more sensitive test for early interstitial lung disease. 17 The test however is not as reproducible, and some centers prefer to follow just spirometry. Pulmonary function tests have only a modest correlation with the chest radiograph. All patients however should have a thorough baseline pulmonary function assessment even when the lungs are radiographically not involved. It is important to have such baseline data for detection of functional improvement or deterioration during the further course of the disease. Only 20% of patients with stage 1 disease show lung function abnormalities, compared with 40% to 70% in the other radiographic stages. The most sensitive tests are the carbon monoxide diffusion capacity and the vital capacity. The typical pattern in sarcoidosis is a Fig. 3 Comparison of liver function tests and the liver biopsy results in patients with known sarcoidosis. 26 The reference ranges for the alkaline phosphatase and aspirate aminotransferase are indicated in the boxes. Although the test results were higher for the patients with granulomas in their liver biopsies, elevated levels could be seen in patients with normal liver biopsies.

4 306 U. Costabel et al. Table 2 Criteria for organ involvement Organ Definite Probable Lungs 1. Chest roentgenogram with one of the 1. Lymphocytic alveolitis by BAL following: 2. Any pulmonary infiltrates Bilateral hilar adenopathy Diffuse infiltrates 3. Isolated reduced diffusion of carbon monoxide in the lung Upper lobe fibrosis 2. Restriction on PFTs 3. Biopsy Neurologic 1. Positive magnetic resonance imaging with uptake in meninges or brainstem 2. CSF with increased lymphocytes and/or protein 3. Diabetes insipidus 4. Bell palsy 5. Cranial nerve dysfunction 6. Biopsy 1. Other abnormalities on magnetic resonance imaging 2. Unexplained neuropathy 3. Positive EMG Nonthoracic lymph node 1. Biopsy 1. New palpable node above waist 2. Lymph node >2 cm by CT scan Renal 1. Treatment-responsive renal failure 1. Steroid-responsive renal failure in patient 2. Biopsy with diabetes and/or hypertension Cardiac 1. Treatment-responsive cardiomyopathy 1. No other cardiac problem and either: 2. EKG showing IVCD or nodal block Ventricular arrhythmias 3. Positive gallium scan of heart Cardiomyopathy 4. Biopsy 2. Positive magnetic resonance imaging 3. Positive thallium scan Skin 1. Lupus pernio 1. Macular papular 2. Anular lesion 2. New nodules 3. Erythema nodosum 4. Biopsy Eyes 1. Lacrimal gland swelling 1. Blindness 2. Uveitis 3. Optic neuritis 4. Biopsy Liver 1. LFTs >3 times normal 1. Compatible ultrasound or CT scan 2. Biopsy 2. Elevated alkaline phosphatase Bone marrow 1. Granulomas in bone marrow 2. Unexplained anemia 3. Marked leukopenia 4. Thrombocytopenia Spleen 1. Biopsy 1. Enlargement by: Exam Ultrasound or CT Radioisotope scan Bone/Joints 1. Granulomas in bone biopsy 1. Asymmetric, painful clubbing 2. Cystic changes on hand or feet phalanges (continued on next page)

5 Systemic evaluation of a potential cutaneous sarcoidosis patient 307 Table 2 (continued) Organ Definite Probable Ear/Nose/Throat 1. Biopsy 1. Unexplained hoarseness with examination consistent with granulomatous involvement Parotid/Salivary glands 1. Biopsy confirmation 2. Symmetrical parotitis without mumps 3. Positive gallium scan (Panda sign) Muscles 1. Granulomas in muscle 1. Increased CPK/aldolase 2. Increased CPK/aldolase that decreases with treatment Hypercalcemia/ Hypercalcuria/ Nephrolithiasis 1. Increased serum calcium with no other cause 1. Increased urine calcium 2. Nephrolithiasis analysis showing calcium Adapted from Judson et al. 35 Organ involvement in a patient with already established diagnosis of sarcoidosis, assuming no other cause identified for abnormality. Biopsy evidence in that organ is definite evidence for sarcoidosis. PFT indicates pulmonary function test; CSF, cerebrospinal fluid; EMG, electromyogram; EKG, electrocardiogram; IVCD, intraventricular conduction delay; LFT, liver function test; CPK, creatine phosphokinase. restriction, whereas an obstruction is seen in up to 30% of patients and bronchial hyperreactivity is present in up to 50%. 11,18 Interestingly, the involvement of the bronchial mucosa seems to be one factor for the bronchial hyperreactivity. Shorr et al 19 noted that all sarcoid cases with airway hyperreactivity demonstrated abnormal endobronchial findings compared with similar bronchoscopic findings in only 46% of patients without airway hyperreactivity. Changes in gas exchange with exercise, including arterial blood gas measurements at rest and with exercise, are the most sensitive indicators of lung impairment. Extrapulmonary assessment Ocular symptoms can range from none to blindness. 20 The most common manifestation is uveitis; however, glaucoma, retinal disease, and optic neuropathy can also be caused by sarcoidosis. 21 Patients with no symptoms may still have eye disease. 20 Therefore, a formal eye examination is recommended even in patients with no symptoms. 1 A minimal examination requires a measurement of the intraocular pressure and the use of a slit lamp. Other features of sarcoidosis should be searched for in all potential sarcoidosis patients. Calcium metabolism may be altered by the disease, either in the form of hypercalcemia or nephrolithiasis. In a patient with a history of renal stones, a 24-hour urine test for calcium is warranted to determine if hypercalcuria is present. Some groups routinely screen with a urinalysis. Nephrolithiasis due to sarcoidosis is strongly associated with chronic disease. 22 A patient with transient seventh cranial nerve paralysis may have been diagnosed as having Bell palsy (idiopathic seventh nerve paralysis) when this really was a manifestation of sarcoidosis. 23 Liver function testing is recommended as part of the initial evaluation in all patients. 1 Abnormalities of liver function tests are seen in approximately a third of cases. 24 The alkaline phosphatase is the most frequently elevated test. Other testing may also detect liver involvement. This would include ultrasound or CT scan of the liver, where a nodular pattern can be seen in the liver and spleen. 25 Liver biopsy is the most sensitive test for liver disease; however, the liver function tests may still be abnormal in a patient with a normal biopsy. Fig. 3 demonstrates how liver function tests are complimentary in sarcoidosis. This study compares the results of the liver biopsy to the liver function tests done at the time of the biopsy. 26 In addition to initial screening, liver function abnormalities may arise during therapy. Methotrexate is used for sarcoidosis and is associated with hepatotoxicity. 27 The baseline abnormalities from sarcoidosis make routine screening less effective in monitoring patients on chronic methotrexate. Routine liver biopsies have been used to monitor for toxicity. 26 A history of palpitations and or syncope should lead to investigations for possible cardiac sarcoidosis. Routine electrocardiography is the first step. 1 It is not however a sufficiently sensitive or specific test in a patient with symptoms. Because ventricular tachycardia can lead to sudden death, the symptomatic patient should be further evaluated. 28 Japanese investigators have demonstrated that 24-hour Holter monitoring was the most sensitive and specific test 29 ; however, there are still patients who may be missed by this method and may require longer monitoring. Another type of heart manifestation is cardiomegaly and cardiac failure. Doppler echocardiography may show cardiac dysfunction, especially diastolic dysfunction. Another specific noninvasive method to demonstrate structural and functional abnormalities of the heart in sarcoidosis is the cardiac magnetic resonance imaging. 30 Fatigue is a common feature of sarcoidosis. 5 Although a nonspecific feature of the disease, the clinician may be confronted by a patient who cannot function because of overwhelming fatigue. Corticosteroids and other agents may

6 308 U. Costabel et al. Fig. 4 Overall incidence of individual manifestations of sarcoidosis at time of presentation of sarcoidosis. 4 Cutaneous manifestations other than erythema nodosum are noted, but patients could have both patterns of skin involvement. Involvement was more common in African Americans vs whites in some cases (indicated by * ), or more common in whites (indicated by ** ). Female patients had more involvement of some organs (indicated by ), whereas male patients had more problems with calcium metabolism (indicated by ). In regard to age at time of diagnosis, those 40 years or older were more likely to have abnormal calcium metabolism (indicated by ), whereas younger patients were more likely to have extrathoracic lymph nodes (indicated by ). help with the fatigue, but are not always successful. Recent interest in agents that may treat the fatigue specifically are being investigated. 31 Occupational and family history An occupational history should ask specifically for features that mimic sarcoidosis. This would include exposure to beryllium. Chronic berylliosis can cause skin lesions and pulmonary lesions similar in appearance to sarcoidosis. 32 As discussed elsewhere in this series, there have been several occupational and environmental exposures associated with sarcoidosis. 33 None of these, however, have been found to be the sole cause of sarcoidosis. Also discussed elsewhere in this issue is a discussion of the genetics of sarcoidosis. In a recent case control study of sarcoidosis, it was pointed out that when evaluating a patient for possible sarcoidosis, the presence of a sibling with sarcoidosis was associated with an odds ratio of In this study, a family history of sarcoidosis was more frequent in African Americans than in white controls. Therefore, the odds ratio for a white patient was 18, whereas for an African- American patient, it was only 2.8. Multiple organ involvement For potential sarcoidosis patients, the more organ involvement that can be identified, the more comfortable one is with the diagnosis. A structured approach to defining organ involvement has been established. 35 Table 2 lists the criteria for confirming involvement in specific areas. Most manifestations of sarcoidosis can be summarized using this table. 4 Most of the criteria for organ involvement can be detected by a focused history and physical examination as well as the laboratory testing suggested in Table 1. Fig. 4 demonstrates the frequency of organ involvement at the time of diagnosis in a large cohort of patients with sarcoidosis. 4 In that study, erythema nodosum was collected as a separate organ manifestation. Patients could have more than one manifestation of their sarcoidosis. The effect of race, sex, and age on clinical presentation is noted. In a follow-up study of a third of these patients, 9 new organ involvement occurred in 23% of the patients. 9 The skin was the most frequent new organ involvement, with 6% of cases developing new involvement. This was more common in African Americans than in whites. There was no effect of age or sex on the risk for developing new organ involvement. Other testing The recommendations shown do not include testing that may aid in the diagnosis of sarcoidosis. These include serum markers, gallium scanning, positron emission testing (PET scan), and bronchoalveolar lavage. These tests have been used to supplement clinical information and help make the diagnosis of sarcoidosis. 36

7 Systemic evaluation of a potential cutaneous sarcoidosis patient 309 The angiotensin-converting enzyme (ACE) serum level is a useful diagnostic test. This is derived from the granuloma, and elevations of serum ACE are seen in 40% to 80% of patients in different series There are several diseases associated with mild elevation of ACE. These include diabetes and osteoarthritis. 39,40 Angiotensin-converting enzyme levels more than 50% of the upper limit of normal are usually due to sarcoidosis. There are however other conditions that can lead to high ACE levels, including other granulomatous diseases such as tuberculosis, fungal infections, or leprosy. 40 Gaucher disease, 41 chronic berylliosis, 42 and hyperthyroidism 43 also are associated with elevated ACE levels. Angiotensin-converting enzyme levels are also influenced by polymorphisms of the ACE gene. 44 The insertion/deletion polymorphism in intron 16 of the ACE gene has been shown to cause up to half of the variation of the normal serum ACE level. 45 This has led some authors to propose genotyping the patient and use different reference ranges for different polymorphisms. Such corrections increase the sensitivity of ACE by 25% 44 ; however, it is not clear if this increased expense is that useful. In addition, there are other polymorphisms of the ACE gene that can lead to extremely high levels. The value of ACE in monitoring disease activity is controversial. Although some have found it quite useful, 46 others have found it less useful. Corticosteroid therapy depresses the ACE level, and reducing the corticosteroid dosage will lead to a rise in the ACE level. This does not mean that the patient will always relapse. 47 Another serum marker has been the lysozyme level. This is derived from the macrophage, and increased levels have been found in approximately two thirds of cases. 2 Elevations of lysozyme and ACE are correlated. The ACE level however is more specific and is currently the preferred test. 48 The gallium scan and PET scan are useful in looking for inflammation throughout the body. The gallium scan has proven to be useful in detecting lung disease and can be used for estimating the amount of activity in the lung. 49 The test can also be useful in confirming the diagnosis in patients with uptake in the hilum of the chest (lambda sign) and parotids, salivary glands, and lacrimal glands (Panda sign) 50 ;however, corticosteroids rapidly downregulate the transferrin receptor, which leads to a negative gallium scan in most patients within a few months of systemic therapy. 51 The PET scan also can identify activity in the thorax and abdomen. 52 Thetestisnot routinely performed in sarcoidosis. For many patients, the PET scan is performed in someone with possible malignancy; and the PET scan is misinterpreted as metastatic disease. 53 Bronchoalveolar lavage (BAL) has been a tremendous research tool in sarcoidosis. 54 Its role in the diagnosis and management of sarcoidosis is more controversial. 55,56 In examining patients with possible sarcoidosis vs other interstitial lung diseases, BAL has provided additional useful information. 57,58 The BAL fluid analysis shows increase in lymphocytes in 90% of sarcoidosis patients at the time of diagnosis. This finding is nonspecific but supportive of the diagnosis in the appropriate clinical setting. The CD4/CD8 ratio in BAL may be of additional help because an elevated ratio has a high specificity of 95% for sarcoidosis, 56 although the sensitivity is low, reaching only 50% to 60%. In the setting of a patient with cutaneous granulomas, BAL probably does not provide sufficient further information unless there is a question of tuberculosis or fungal infection. In that setting, bronchoscopy with BAL has been a useful diagnostic test. 59 Assessment of activity The term activity is frequently used in sarcoidosis, but often misinterpreted. Activity implies an active ongoing disease or inflammation. It should not be confused with the disease extent, severity, or unfavorable prognosis. Disease extent and severity are best judged from the number of involved organs and the magnitude of functional impairment of those organs. Unfortunately, there is not a single test to indicate active disease. The presence of systemic symptoms; hypercalcemia; active uveitis; skin changes such as erythema nodosum, lupus pernio, or changing scars; myocardial disease; neurosarcoidosis; and progressive respiratory symptoms (dyspnea, cough) is indicative of active disease. A long list of laboratory and cell biological markers has been discussed as potential parameters of active disease, either in serum or in BAL fluid. In practice, only 2 of them have been assessed routinely. These are serum ACE, reflecting the granuloma burden, and the soluble interleukin 2 receptor in serum, reflecting the activity of the T-cell component. 46,60-62 Serum ACE may be useful in monitoring patients 46 ; however, an increased ACE activity will be reduced within a few weeks after the start of treatment. 47,63 At present, the best way to assess the activity of sarcoidosis is through traditional clinical investigations. It is however of more clinical relevance to depict disease extent and severity than the activity in an individual patient. Special cutaneous syndromes Patients with certain patterns from their sarcoidosis often have associated systemic disease. Patients with erythema nodosum often have hilar adenopathy and ankle arthritis. Sven Löfgren originally noted this connection, and Löfgren syndrome is usually associated with an excellent outcome. 7 Lupus pernio is associated with chronic disease. 8 Lupus pernio is also associated with bone cysts in the hands. In addition, sinus involvement was identified in over half of the cases of lupus pernio in one series. 64 Conclusions The evaluation of a patient with known or possible cutaneous sarcoidosis leads to a wide number of organs being assessed by either history, physical examination, or

8 310 U. Costabel et al. routine laboratory testing. The results of this initial evaluation will often help ensure the diagnosis of sarcoidosis or lead to an alternative diagnosis. In addition, other features may be identified that also require therapy. References 1. Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16: Pietinalho A, Ohmichi M, Lofroos AB, et al. The prognosis of sarcoidosis in Finland and Hokkaido, Japan. A comparative five-year study of biopsy-proven cases. Sarcoidosis Vasc Diffuse Lung Dis 2000;17: Loddenkemper R, Kloppenborg A, Schoenfeld N, et al. Clinical findings in 715 patients with newly detected pulmonary sarcoidosis results of a cooperative study in former West Germany and Switzerland. WATL Study Group. Wissenschaftliche Arbeitsgemeinschaft fur die Therapie von Lungenkrankheitan. Sarcoidosis Vasc Diffuse Lung Dis 1998;15: Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 2001;164: devries J, Rothkrantz-Kos S, Dieijen-Visser MP, et al. The relationship between fatigue and clinical parameters in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2004;21: Baughman RP, Strohofer SA, Buchsbaum J, et al. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115: Mana J, Gomez VC, Montero A, et al. Lofgren's syndrome revisited: a study of 186 patients. Am J Med 1999;107: Neville E, Walker AN, James DG. Prognostic factors predicting the outcome of sarcoidosis: an analysis of 818 patients. Q J Med 1983;208: Judson MA, Baughman RP, Thompson BW, et al. Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003;20: Yeager H, Rossman MD, Baughman RP, et al. Pulmonary and psychosocial findings at enrollment in the ACCESS study. Sarcoidosis Vasc Diffuse Lung Dis 2005;22: Baughman RP, Iannuzzi MC, Lower EE, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19: Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy for sarcoidosis: a prospective study. Chest 2001;120: Baughman RP, Shipley RT, Loudon RG, et al. Crackles in interstitial lung disease. Comparison of sarcoidosis and fibrosing alveolitis. Chest 1991;100: Scadding JG. Prognosis of intrathoracic sarcoidosis in England. Br Med J 1961;4: Pietinalho A, Ohmichi M, Hiraga Y, et al. The mode of presentation of sarcoidosis in Finland and Hokkaido, Japan. A comparative analysis of 571 Finnish and 686 Japanese patients. Sarcoidosis 1996;13: Winterbauer RH, Belic N, Moores KD. A clinical interpretation of bilateral hilar adenopathy. Ann Intern Med 1973;78: Subramanian I, Flaherty KR, Martinez FJ. Pulmonary function testing in sarcoidosis. In: Baughman RP, editor. Sarcoidosis. New York: Taylor and Francis; p Bechtel JJ, Starr TI, Dantzker DR, et al. Airway hyperreactivity in patients with sarcoidosis. Am Rev Respir Dis 1981;124: Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial involvement and airway hyperreactivity in patients with sarcoidosis. Chest 2001; 120: Ohara K, Judson MA, Baughman RP. Clinical aspects of ocular sarcoidosis. In: Drent M, Costabel U, editors. Sarcoidosis. Wakefield, UK: The Charlesworth Group; p Bradley DA, Baughman RP, Raymond L, et al. Ocular manifestations of sarcoidosis. Semin Respir Crit Care Med 2002;23: Rizzato G, Fraioli P, Montemurro L. Nephrolithiasis as a presenting feature of chronic sarcoidosis. Thorax 1995;50: Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurologic sarcoidosis. Arch Intern Med 1997;157: Judson MA. Hepatic, splenic, and gastrointestinal involvement with sarcoidosis. Semin Respir Crit Care Med 2002;23: Warshauer DM, Molina PL, Hamman SM, et al. Nodular sarcoidosis of the liver and spleen: analysis of 32 cases. Radiology 1995;195: Baughman RP, Koehler A, Bejarano PA, et al. Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis. Arch Intern Med 2003;163: Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155: Deng JC, Baughman RP, Lynch JPI. Cardiac involvement in sarcoidosis. Semin Respir Crit Care Med 2002;23: Suzuki T, Kanda T, Kubota S, et al. Holter monitoring as a noninvasive indicator of cardiac involvement in sarcoidosis. Chest 1994;106: Skold CM, Larsen FF, Rasmussen E, et al. Determination of cardiac involvement in sarcoidosis by magnetic resonance imaging and Doppler echocardiography. J Intern Med 2002;252: Wagner MT, Marion SD, Judson MA. The effects of fatigue and treatment with methylphenidate on sustained attention in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22: Glazer CS, Newman LS. Beryllium as a model for sarcoidosis. In: Baughman RP, editor. Sarcoidosis. New York: Taylor and Francis Group; p Newman LS, Rose CS, Bresnitz EA, et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med 2004;170: Rybicki BA, Iannuzzi MC, Frederick MM, et al. Familial aggregation of sarcoidosis: a case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164: Judson MA, Baughman RP, Teirstein AS, et al. Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999;16: Baughman RP, dubois RM, Lower EE. Sarcoidosis. Lancet 2003;361: Gronhagen-Riska C, Selroos O, Wagar G, et al. Angiotensin-converting enzyme. II. Serum activity in early and newly diagnosed sarcoidosis. Scand J Respir Dis 1979;60: Lieberman J. Elevation of serum angiotensin converting enzyme (ACE) level in sarcoidosis. Am J Med 1975;59: Baughman RP, Costabel U. Markers of sarcoidosis. In: Baughman RP, editor. Sarcoidosis. New York: Taylor and Francis Group; p Lieberman J, Nosal A, Schlessner A, et al. Serum angiotensinconverting enzyme for diagnosis and therapeutic evaluation of sarcoidosis. Am Rev Respir Dis 1979;120: Lieberman J. The specificity and nature of serum-angiotensinconverting enzyme (serum ACE) elevations in sarcoidosis. Ann N Y Acad Sci 1976;278: Newman LS, Orton R, Kreiss K. Serum angiotensin converting enzyme activity in chronic beryllium disease. Am Rev Respir Dis 1992;146: Silverstein E, Schussler GC, Friedland J. Elevated serum angiotensin-converting enzyme in hyperthyroidism. Am J Med 1983;75: Tomita H, Ina Y, Sugiura Y, et al. Polymorphism in the angiotensinconverting enzyme (ACE) gene and sarcoidosis. Am J Respir Crit Care Med 1997;156:255-9.

9 Systemic evaluation of a potential cutaneous sarcoidosis patient Rigat B, Hubert C, Alhenc-Gelas F, et al. An insertion/deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 1990;86: DeRemee RA, Rohrbach MS. Serum angiotensin-converting enzyme activity in evaluating the clinical course of sarcoidosis. Ann Intern Med 1980;92: Baughman RP, Ploysongsang Y, Roberts RD, et al. Effects of sarcoid and steroids on angiotensin-converting enzyme. Am Rev Respir Dis 1983;128: Romer FK, Ahlbom G, Jensen JU. Relationship between angiotensinconverting enzyme and lysozyme in sarcoidosis. Eur J Respir Dis 1982;63: Baughman RP, Fernandez M, Bosken CH, et al. Comparison of gallium-67 scanning, bronchoalveolar lavage, and serum angiotensinconverting enzyme levels in pulmonary sarcoidosis. Predicting response to therapy. Am Rev Respir Dis 1984;129: Sulica R, Teirstein AS, Kakarla S, et al. Distinctive clinical, radiographic, and functional characteristics of patients with sarcoidosis-related pulmonary hypertension. Chest 2005;128: Kohn H, Klech H, Mostbeck A, et al. 67Ga scanning for assessment of disease activity and therapy decisions in pulmonary sarcoidosis in comparison to chest radiography, serum ACE and blood T-lymphocytes. Eur J Nucl Med 1982;7: Taaleb K, Kaiser KP, Wieler H. Elevated uptake of F-18 FDG in PET scans in nonmalignant disease. Clin Nucl Med 2000;25: Hendrickx BW, van Herpen CM, Bonenkamp JJ, et al. Positive positron emission tomography scan in sarcoidosis and two challenging cases of metastatic cancer. CASE 1. Mediastinal sarcoidosis in a melanoma patient treated with interferon. J Clin Oncol 2005;23: Reynolds HY. Use of bronchoalveolar lavage in humans past necessity and future imperative. Lung 2000;178: Baughman RP, Drent M. Role of bronchoalveolar lavage in interstitial lung disease. Clin Chest Med 2001;22: Costabel U, Guzman J. Bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med 2001;7: Welker L, Jorres RA, Costabel U, et al. Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur Respir J 2004;24: Drent M, Jacobs JA, Cobben NA, et al. Computer program supporting the diagnostic accuracy of cellular BALF analysis: a new release. Respir Med 2001;95: Baughman RP, Dohn MN, Loudon RG, et al. Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungal infections. Chest 1991;99: Grutters JC, Fellrath JM, Mulder L, et al. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest 2003;124: Lawrence EC, Brousseau KP, Berger MB, et al. Elevated concentrations of soluble interleukin-2 receptors in serum samples and bronchoalveolar lavage fluids in active sarcoidosis. Am Rev Respir Dis 1988;137: Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNFalpha release from alveolar macrophages and serum level of sil-2r are prognostic markers. Am J Respir Crit Care Med 1997;156: Gronhagen-Riska C, Selroos O, Niemisto M. Angiotensin converting enzyme. V. Serum levels as monitors of disease activity in corticosteroid-treated sarcoidosis. Eur J Respir Dis 1980;61: Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest 2002;122:

10