Predictive value of serum markers for pulmonary involvement in ocular sarcoidosis (2013)

Sarcoidosis is a systemic disease and an important cause of uveitis with variable clinical presentation (Jabs & Johns 1986). The diagnosis has to be supported by laboratory testing or pathology of tissue specimen. Mostly, the definitive diagnosis relies on nonocular involvement, mainly the pulmonary manifestation. Confirmation by ophthalmic pathology is rarely possible with <1% of ocular manifestation in conjunctiva or tear gland (Heiligenhaus et al. 2011). The most commonly used serological marker is angiotensin-converting enzyme (ACE). We tested the additional markers lysozyme and soluble interleukin-2 receptor (sIL-2R), both associated with sarcoidosis (Bargagli et al. 2008), and compared their single and combined values to predict pulmonary involvement. Angiotensin-converting enzyme (normal range, nr: 8–52 U/l), sIL-2R (nr: 223–710 kU/l) and lysozyme (nr: 4–17 mg/ml) levels have been determined in the serum of one hundred and sixty-six consecutive patients with idiopathic noninfectious uveitis (anterior: n = 63, intermediate: n = 51, posterior: n = 30, panuveitis: n = 14 and retinal vasculitis: n = 8), and thirty-five patients with elevation of at least one parameter (Fig. 1) were enrolled in this study (anterior: n = 17, intermediate: n = 10, posterior: n = 4, panuveitis: n = 3 and retinal vasculitis: n = 1). Uveitis was compatible with sarcoidosis but not always typical for it. In line with this, eleven of thirty-five enrolled patients met the diagnostic criteria from the International Workshop on Ocular Sarcoidosis, Tokyo, 2006 (Herbort et al. 2009). Other specific causes of uveitis were excluded. All one hundred and sixty-six patients were screened for pulmonary involvement by chest X-ray examination. The definitive diagnosis of pulmonary sarcoidosis was only made by confirmation of suspected chest X-ray findings by bronchoscopic biopsy or lavage. Based on these findings, all patients were retrospectively subdivided into groups with (n = 11, all confirmed by biopsy or lavage of the lung) or without pulmonary involvement (n = 24, two with negative bronchoscopy, other patients with normal chest X-ray findings and normal functional tests of the lungs). None of the patient had the diagnosis of sarcoidosis established before testing, and all patients had active uveitis requiring treatment. Patients on ACE inhibitors or systemic steroids were excluded. The mean ± SD age of the patients was 56 years ± 19 (range, 13–84 years), similar in the pulmonary (59 years) versus nonpulmonary group (55 years). Except for one Indian and one African patient, all patients were Caucasians. Sensitivity, specificity and Youden index (a measure combining sensitivity and specificity: y = sensitivity + specificity-1) have been calculated to predict pulmonary sarcoidosis of single and combined serological values. Combinations of markers have been calculated following the ‘believe-the-negative rule’ or BN rule (Shen 2008). Therefore, a combination has been considered positive when both of two markers or all three markers were elevated above the normal range. Angiotensin-converting enzyme as a single parameter revealed a lower sensitivity (0.55) than sIL-2R (0.91) or lysozyme (0.82), whereas the specificity was higher in ACE alone (0.88) than in sIL-2R (0.54) or lysozyme (0.50). Following the BN rule, the combination of ACE and sIL-2R demonstrated the highest Youden index (0.50) with a sensitivity of 0.55 and a specificity of 0.96, followed by the combination of ACE, sIL-2R and lysozyme (Youden index 0.45, sensitivity 0.45, specificity 1.00). Lysozyme combined with sIL-2R showed a Youden index of 0.44, a sensitivity of 0.73 and a specificity of 0.71, better than the single values of ACE or lysozyme and with higher specificity than s-IL-2R alone (Table 1). In this small sample, the combination of ACE and sIL-2R was the most reliable predictor of pulmonary involvement in ocular sarcoidosis. In patients who take ACE inhibitors, ACE should be replaced by lysozyme. Certainly, there will be no combination of these markers to diagnose sarcoidosis by itself. The ideal combination of markers, however, could support diagnosis and help to decide whether invasive procedures such as bronchoscopy should be considered or not. To our knowledge, this is the first study that compares these three markers in the same uveitis patients (Fig. 1). In our opinion, these results warrant further multicentric international studies to establish the diagnostic value of different combinations of these markers in various organ manifestations (e.g. lung, skin, tear gland, liver or joints) and at different disease stages and various ethnicities with or without ocular involvement. Also, uveitis known to be of other causes would be a valuable additional control and possibly novel markers such as chitotriosidase (Bargagli et al. 2008).