Improved Diagnostic Option for Confirmation of Sarcoidosis in Acute Uveitis

The 2 commonly utilized laboratory biomarkers, lysozyme and angiotensin-converting enzyme, lack sufficient sensitivity and specificity.

According to findings published in JAMA Ophthalmology, serum-soluble interleukin 2 receptor (sIL-2R) levels, particularly when combined with chest radiography, were superior to angiotensin-converting enzyme (ACE) levels as diagnostic biomarkers for sarcoidosis in patients with uveitis, a finding contrary to the current biomarker used in some clinical protocols.

The two commonly utilized laboratory biomarkers, lysozyme and ACE, lack sufficient sensitivity and specificity, prompting a team of researchers from The Netherlands to explore better diagnostic options for the confirmation of sarcoidosis in acute uveitis.

Accurately diagnosing sarcoidosis in these patients can have an impact on therapeutic management, vision outcomes, and medication choices. Undetected, sarcoidosis poses serious risks of ocular and systemic morbidity. The lack of published evidence concerning the use of sIL-2R in this scenario made determination of its diagnostic value a priority.

This cross-sectional retrospective study analyzed data from 249 clinic patients with uveitis using samples collected between April 2013 and November 2015. Diagnostic utility was assessed for ACE or sIL-2R alone, as well as for each in combination with chest radiography. The Youden index (YI) helped determine cutoff levels for the two measures: ≥4000 pg/mL for sIL-2R, and ≥51 U/L for ACE. The YI was more elevated for sIL-2R (0.45) vs ACE (0.23).

The mean (SD) age of participants was 51 (16); 64.7% were women (n=161) and 76.7% were white (n=191). While mean (SD) serum levels of sIL-2R and ACE were highest in subjects with sarcoidosis-related uveitis at 6047 (2533) ρg/mL and 61 (38) U/L, respectively, sIL-2R was also elevated in patients with varicella-zoster virus (5386 [1778] pg/mL) and HLA-B27 (4460 [2465] pg/mL; P =.08) uveitis. As expected, ACE and sIL-2R levels were highly correlated (Pearson correlation coefficient, 0.205; P =.001). There was no association between either sIL-2R (Spearman correlation coefficient [p], 0.070; P = .27) or ACE (p, –0.071; P =.27) and active uveitis.

When analyzed alone using the above cutoff value, sIL-2R demonstrated 81% sensitivity (95% CI, 74%-89%) and 64% specificity (95% CI, 56%-72%), YI 0.45, and positive and negative predictive values (PPV/NPV) of 0.28/0.95. ACE alone exhibited 54% (95% CI, 37%-71%) sensitivity and 70% (95% CI, 63%-76%) specificity, offering a PPV/NPV of 0.24/0.90, with a YI of 0.23.

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Combined, sIL-2R and chest radiography together resulted in 92% sensitivity, 58% specificity, 0.50 YI, and 0.32/0.97 PPV/NPV. For comparison, ACE plus chest radiography produced 70% sensitivity, 79% specificity, respectively, YI 0.49, and PPV/NPV 0.42/0.92. Using a cutoff value of 6000 pg/mL for sIL-2R in the combined measure yielded 77% sensitivity, 73% specificity, 0.50 YI, and 0.38/0.94 PPV/NPV.

The investigators recognized several study limitations. Active uveitis was not always present during sampling, which may have resulted in lower ACE and sIL-2R levels. As measures of overall disease activity, serum factors may have inaccurately reflected pathophysiology exclusive to the eyes. PPV was likely inflated because chest radiography was not always performed soon after onset of active ocular disease. ACE and sIL-2R fluctuate with sarcoidosis activity and do not necessarily reflect pathologic changes with the same precision as chest radiography over time. And the standard deviation for the entire cohort was probably increased by high individual patient variability in groups not related to sarcoidosis.

Although it was only slightly better diagnostically than ACE, sIL-2R was revealed as a useful tool for differentiating sarcoidosis- and nonsarcoidosis-associated uveal ocular disease. However, because high sIL-2R levels were also observed in patients who did not have sarcoidosis, clinicians are reminded that this is likely an indication of extensive T-cell-mediated disease in the collective uveitis population. Therefore, practitioners should remember to adjust diagnostic cutoffs when dealing with a diverse populace.

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Groen-Hakan F, Eurelings L, ten Berge JC, et al. Diagnostic value of serum-soluble interleukin 2 receptor levels vs angiotensin-converting enzyme in patients with sarcoidosis-associated uveitis. JAMA Ophthalmol. 2017;135(12):1352-1358.