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sIL-2R levels predict the spontaneous remission in sarcoidosis

  • Author Footnotes
    1 These authors contributed equally to this work.
    Ying Zhou
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Respiratory Medicine and Clinical Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Yuan Zhang
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    1 These authors contributed equally to this work.
    Affiliations
    Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Mengmeng Zhao
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Qiuhong Li
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    1 These authors contributed equally to this work.
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    Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
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  • Huiping Li
    Correspondence
    Corresponding author. Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Shanghai, 200433, China.
    Affiliations
    Department of Respiratory Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Open ArchivePublished:August 16, 2020DOI:https://doi.org/10.1016/j.rmed.2020.106115

      Highlights

      • It is important to identify patients with spontaneous remission in sarcoidosis.
      • sIL-2R level was an independent predictor of spontaneous remission in sarcoidosis.
      • CD8+ T cell and CD4/CD8 should be studied in larger populations to assess the prognostic roles.

      Abstract

      Background

      Sarcoidosis is associated with a wide range of disease outcomes including spontaneous remission and progressive courses. It is necessary to identify patients with spontaneous remission without corticosteroid treatment. This study aimed to identify the markers for predicting spontaneous remission in patients with sarcoidosis.

      Methods

      453 patients diagnosed with sarcoidosis at the Shanghai Pulmonary Hospital between Jan 2013 and Aug 2017 and were followed-up for more than 2 years were enrolled. Patients were divided into spontaneous remission group and non-remission group. Differences of variables between groups were analyzed by chi-square test or unpaired Student's t-test. The cumulative spontaneous remission rate was analyzed using the Kaplan-Meier method.

      Results

      Of the 173 patients (stage I/II/III/IV, 53/110/6/4) without medication, 117 (67.6%) achieved spontaneous remission. The serum level of soluble interleukin-2 (IL-2) receptor (sIL-2R) and the ratio of CD4/CD8 was significantly lower and CD8+ T cell was significantly higher in spontaneous remission group when compared with non-remission group (P < 0.001, P = 0.042 and P = 0.048). Multivariate logistic regression model showed sIL-2R level was an independent predictor of spontaneous remission (P = 0.021). In stage I subgroup, a cut-off value of 1129.5U/ml was obtained from the ROC curve, which yielded a sensitivity of 50% and a specificity of 94.4%. In stage II subgroup, a cut-off value of 1026.5U/ml was obtained with a sensitivity of 66.7% and a specificity of 68.7%.

      Conclusion

      This study provided useful information that sIL-2R level could be used as a maker for spontaneous remission in determining the treatment strategies for patients with pulmonary sarcoidosis.

      Keywords

      1. Introduction

      Sarcoidosis is a multisystem granulomatous disease of unknown etiology, and is characterized by an accumulation of activated, proliferating T lymphocytes and mononuclear phagocytes in the involved organs, predominantly the lungs and mediastinal lymph nodes. The most widely accepted immunologic hypothesis is that a T-helper cell/macrophage alveolitis in pulmonary sarcoidosis is caused by an unknown stimulus, which activates alveolar macrophages (AM) and lymphocytes to release mediators such as tumor necrosis factor-α (TNF-α) [
      • Muller-Quernheim J.
      • et al.
      Lung-restricted activation of the alveolar macrophage/monocyte system in pulmonary sarcoidosis.
      ] and interleukin-2 (IL-2) [
      • Muller-Quernheim J.
      • et al.
      Compartmentalized activation of the interleukin 2 gene by lung T lymphocytes in active pulmonary sarcoidosis.
      ] and subsequently recruits and activates other inflammatory cells. Clinical presentation of sarcoidosis can be quite variable, ranging from spontaneous remission to chronic progressive illness affecting various organs. Although several serum markers of sarcoidosis such as serum angiotensin-converting enzyme (SACE), neopterin and soluble IL-2 receptor (sIL-2R) exist and are used as staging parameters, no sufficient evidence is available about which of them are suitable for predicting the prognosis.
      The prognosis in sarcoidosis is relatively good, and a spontaneous remission can be observed in approximately 60% of patients [
      • Hunninghake G.W.
      • et al.
      Outcome of the treatment for sarcoidosis.
      ]. Despite improved knowledge of the pathogenesis of sarcoidosis, its natural disease course is still unpredictable in an individual patient. Therefore, prognostic parameters would be very helpful for predicting spontaneous remission in patients with sarcoidosis.
      Corticosteroids are highly effective for pulmonary sarcoidosis and widely used first-line drugs as a systemic therapy, but these often cause significant side effects [
      • James W.E.
      • Judson M.A.
      Therapeutic strategies for pulmonary sarcoidosis.
      ].
      Although sarcoidosis therapy might improve the metrics of lung function, the patients might still feel worsened or even die or lose organ functioning in the extreme cases due to treatment-related toxicities. Therefore, it is important for clinicians to identify the part of patients who have the tendency of spontaneous remission without corticosteroid treatment. The aim of the present study was to assess the value of several factors in predicting spontaneous remission in patients who were newly diagnosed with pulmonary sarcoidosis at the Shanghai Pulmonary Hospital.

      2. Material and methods

      2.1 Study subjects

      All Patients (n = 453) who were newly diagnosed with sarcoidosis at the Shanghai Pulmonary Hospital between Jan 2013 and Aug 2017 and were followed-up for more than 2 years were enrolled in this study. Three pulmonologists, 3 radiologists, and 3 pathologists independently reviewed each patient's clinical presentations, imaging examination results, pathological features, and laboratory test results. The diagnosis of sarcoidosis was established based on clinical symptoms, radiological features compatible with sarcoidosis, and biopsy evidence of noncaseating epithelioid cell granulomas with other known causes of granulomatosis excluded (evidence of acid-fast bacilli, fungi, etc.) [
      Statement on sarcoidosis. Joint statement of the American thoracic society (ATS), the European respiratory society (ERS) and the world association of sarcoidosis and other granulomatous disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee.
      ]. But histopathological confirmation is not required for pulmonary sarcoidosis patients with stage I, and requires only radiographic evidence of symmetric bilateral hilar adenopathy with or without mediastinal lymphadenopathy, even if there were no symptoms or identifiable causes in patients. Cases who were diagnosed as sarcoidosis before hospitalization at Shanghai Pulmonary Hospital were not included. All patients were followed-up by telephone or clinic visit. This study was approved by the Ethics Committee of Shanghai Pulmonary Hospital, Tongji University School of Medicine (k-15189).
      Patients without treatment were selected to study the spontaneous remission of sarcoidosis, and then cases who were lost to follow-up after 2 years or lacked sufficient information were excluded. Finally, a total of 173 patients without treatment was analyzed. They were divided into spontaneous remission group and non-remission group according to the follow-up records. (I) Spontaneous remission was defined as complete or incomplete disappearance of lesion at chest CT scan, in combination with improvement of clinical symptoms without medical treatment. (II) Non-remission group included patients who were not treated with corticosteroids at diagnosis but with progress or persistence of disease.

      2.2 Study parameters

      Demographic variables captured for analysis included date of diagnosis, age at diagnosis, sex, follow-up time, smoking status and date of the last follow-up. In addition, clinical data collected at diagnosis included Scadding chest radiograph stage, organ involvement, and pulmonary function parameters. Blood samples were obtained at the initial diagnosis and biochemical indicators (routine blood test, blood biochemical examination, the ratio of CD4/CD8, serum interleukins, serum immunoglobulin electrophoresis, rheumatoid factor, and other autoimmune antibody tests) were analyzed. The classification of the Scadding scoring system is based on the posteroanterior chest radiogram only, and stage 0 describes no visible intrathoracic findings. Stage I is bilateral hilar lymphadenopathy, which may be accompanied by paratracheal adenopathy. Stage II is bilateral hilar adenopathy accompanied by parenchymal infiltration. Stage III is parenchymal infiltration without hilar adenopathy. Stage IV consists of advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts, and emphysema [
      • Scadding J.G.
      Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years' observation.
      ]. Phenotypic organ involvement was confirmed for each patient by using the revised WASOG criteria described in 2014 [
      • Judson M.A.
      • et al.
      The WASOG Sarcoidosis Organ Assessment Instrument: an update of a previous clinical tool.
      ]. Study starting point was the date of diagnosis. The primary end point was the occurrence of spontaneous remission. The deadline date of follow-up was Aug 31, 2019.

      2.3 Analysis

      Differences of gender distribution, smoking history, organ involvement, radiologic stage between spontaneous remission group and non-remission group were analyzed by chi-square test, other variables were compared using unpaired Student's t-test. The cumulative spontaneous remission rate was analyzed using the Kaplan–Meier method. Predicting factors were studied using multivariate logistic regression model with stepwise selection. Variables with P < 0.05 were included in the model. ORs with 95% CIs were calculated for various factors. And then receiver operating characteristic (ROC) curve was plotted and area under curve (AUC) was calculated to elucidate diagnostic roles of the predicting factor. Statistical analysis was performed using SPSS 22.0 package software (IBM), with P < 0 0.05 considered statistically significant. Results of continuous variables are presented as mean ± standard deviation (SD).

      3. Result

      3.1 Characteristics of study subjects

      A total of 453 patients were newly diagnosed with pulmonary sarcoidosis at the Shanghai Pulmonary Hospital between Jan 2013 and Aug 2017. As shown in Fig. 1, 180 of the 453 patients were treated during their clinical courses. Of the 273 patients with sarcoidosis who received no treatment, 100 patients were excluded from the final analysis because of insufficient information or a follow-up time of less than two years. Finally, a total of 173 patients were included in the study.
      Fig. 1
      Fig. 1Flow diagram of sarcoidosis patients studied.
      Characteristics of all 453 sarcoidosis patients (including the sex, smoking history, and organ involvement) was shown in Table 1. Although lung was the most commonly involved organ, many patients exhibited extrapulmonary manifestations. In addition, 184 (40.6%) patients had non-thoracic lymph node involvement. Ninety-nine (21.6%) patients had abnormal calcium metabolism. Patients with parotid, renal, bone marrow and ENT involvement were not included in Table 1 because the number of them was less than five.
      Table 1Characteristics of 453 patients with sarcoidosis.
      CharacteristicsNumber of patientsPercentages (%)
      Sex (female)31268.9
      Smoking history5512.1
      Organ involvement
      Lung453100
      Non-thoracic lymph node18340.4
      Calcium9921.9
      Skin408.8
      Spleen255.9
      Eye245.3
      Liver122.6
      Bone/joint81.8
      Neurologic71.5
      Muscle51.2
      Biopsy
      VATS w/o medias25856.9
      EBUS13630.0
      TBLB276.0
      Subcutaneous nodular biopsy163.5
      Lymph node biopsy388.4
      Stage
      I11124.5
      II31369.1
      III81.8
      IV214.6

      3.2 Spontaneous remission

      Of the 173 patients without treatment, 117 (67.6%) achieved spontaneous remission. Thus, of the 453 newly diagnosed sarcoidosis cases meeting the inclusion criteria, at least 117 (25.8%) had spontaneous remission. The mean observation period from diagnosis of sarcoidosis was 34.4 ± 12.4 months in the spontaneous remission group and 29.9 ± 8.5 months in the non-remission group (P < 0.05). Since the duration of follow-up was different among patients, we used the Kaplan–Meier method to evaluate spontaneous remission rates. As shown in Fig. 2, the cumulative spontaneous remission rates, were 34.1% and 42.8% at 12 and 24 months, respectively, from onset. The mean time from onset to remission was 15.2 ± 13.4 months.
      Fig. 2
      Fig. 2Kaplan-Meier analysis of the cumulative spontaneous remission rates in patients with sarcoidosis.
      The 117 patients with spontaneous remission were compared with the remaining 56 patients in terms of sex, age, smoking history, Löfgren syndrome, organ involvement, radiologic stage, biochemical indicators and pulmonary function (Table 2). There was no significant difference in the age, sex, smoking history, and organ involvement between spontaneous remission and non-remission groups. Thirty-eight out of 53 patients with radiologic stage I (71.7%) have spontaneous remission, while 77 out of 110 patients with stage II (70.0%) have spontaneous remission, there was no significant difference of the remission rate between patients with stage I and II (P = 0.447, Fig. 3). In view of the limited number of patients, patients with neither stage III nor IV were included in this analysis. The patients with spontaneous remission had longer observation time from diagnosis than non-remission patients (P = 0.03, Table 2). Among the biochemical indicators, the level of sIL-2R was significantly lower and CD8+ T cell was significantly higher in spontaneous remission group when compared with non-remission group (P < 0.001 and P = 0.048, Table 2), and also the ratio of CD4/CD8 was lower in spontaneous remission patients (P = 0.042, Table 2). There was no significant difference in pulmonary functions.
      Table 2Comparisons of clinical characteristics between spontaneous remission group and non-remission group.
      CharacteristicsRemission (n = 117)Non-remission (n = 56)P value*
      Age, median (range), y51 (25–72)52 (27–70)0.079
      Gender (female/male)82/3535/210.318
      Smoking history, n (%)15 (12.8)11 (19.6)0.240
      Time from diagnosis34.4 ± 12.429.9 ± 8.50.003
      Organ involvement, n (%)
      Non-thoracic lymph node40 (34.2)24 (42.9)0.269
      Calcium14 (12.0)7 (12.5%)0.920
      Skin7 (6.0)5 (8.9)0.476
      Eye3 (2.6)3 (5.4)0.348
      Single/Multiple organ involvement60/5725/310.414
      Radiologic stage, n0.447
      I3815
      II7733
      III24
      IV04
      SACE65.9 ± 28.360.1 ± 28.70.996
      sIL-646.2 ± 139.464.0 ± 202.00.317
      sIL-2R882.0 ± 348.41389.6 ± 1145.8<0.001
      TNF-α55.8 ± 89.062.8 ± 106.70.650
      CD4+ T cell38.3 ± 9.836.7 ± 10.20.663
      CD8+ T cell19.1 ± 7.417.4 ± 9.20.048
      CD4/CD82.4 ± 1.42.9 ± 1.90.042
      FVC, % predicted90.2 ± 11.989.7 ± 13.30.216
      FEV1, %predicted84.9 ± 16.884.1 ± 11.40.438
      DLCO, %predicted95.1 ± 15.389.1 ± 11.90.206
      * Differences of gender distribution, smoking history, organ involvement, radiologic stage between spontaneous remission group and non-remission group were analyzed by chi-square test, other variables were compared using unpaired Student's t-test.
      Fig. 3
      Fig. 3The number of cases in different chest radiographic stage groups.

      3.3 Predictive factors of spontaneous remission rate

      The results of analyses using the multivariate logistic regression model for predictive factors of spontaneous remission was shown in Table 3. Only sIL-2R level was an independent predictor of spontaneous remission (P = 0.021, hazard ratio (HR) = 0.999, 95% confidence intervals (95% CI) = 0.998–1.000).
      Table 3Multivariate logistic regression model.
      VariablesP valueHazard ratio (HR)95% confidence intervals (95% CI)
      Time from diagnosisNSNSNS
      sIL-2R0.0210.9990.998–1.000
      CD8+ T cellNSNSNS
      CD4/CD8NSNSNS
      NS means not significant.
      As shown in Fig. 4a, sIL-2R level was significantly lower in spontaneous remission patients when compared with non-remission patients (P < 0.001). We also carried out a subgroup analysis based on chest radiograph stage, sIL-2R level was significantly lower in spontaneous remission group than that of non-remission group in both stage I and II subgroups (P < 0.001, Fig. 4b). There was no further analysis in either stage III or IV subgroups because of the limited number of patients.
      Fig. 4
      Fig. 4Serum soluble Interleukin-2 receptor (sIL-2R) level in different groups. (a) sIL-2R level in remission vs. non-remission groups. sIL-2R level was significantly lower in spontaneous remission patients than that of non-remission patients (P < 0.01); and (b) sIL-2R level in stage I vs. stage II subgroups. sIL-2R level was significantly lower in spontaneous remission patients than that of non-remission patients in both stage I and stage II subgroups (P < 0.01). sIL-2R level was a little bit higher in stage II group then that of stage I group without there being any statistical difference (P > 0.05). *means P < 0.01. ns = no statistical difference.
      ROC curve was plotted in sarcoidosis patients with stage I and II to assess the diagnostic value of sIL-2R levels in spontaneous remission. In stage I subgroup, a cut-off value of 1129.5 U/ml was obtained from the ROC curve, which yielded a sensitivity of 50% and a specificity of 94.4%, and the AUC value of the ROC curve is 0.7361 (Fig. 5a). In stage II subgroup, a cut-off value of 1026.5U/ml was obtained from the ROC curve, which yielded a sensitivity of 66.7% and a specificity of 68.7%, and the AUC value is 0.6271 (Fig. 5b).
      Fig. 5
      Fig. 5The diagnostic value of sIL-2R in stage I and II subgroups respectively. (a) A cut-off value of 1129.5 U/ml was obtained from ROC curve in stage I subgroup, and this cut-off value yielded a sensitivity of 50% and a specificity of 94.4%. The area under curve (AUC) value of the ROC curve is 0.7361; and (b) A cut-off value of 1026.5U/ml was obtained from ROC curve in stage II subgroup, and this cut-off value yielded a sensitivity of 66.7% and a specificity of 68.7%. The AUC value of the ROC curve is 0.6271.

      4. Discussion

      Pulmonary manifestations and prognosis of sarcoidosis can be quite variable, ranging from asymptomatic cases and spontaneous remission to chronic progressive disease affecting various organ systems and requiring systemic therapy [
      • Aryal S.
      • Nathan S.D.
      Contemporary optimized practice in the management of pulmonary sarcoidosis.
      ]. To date, there are no tools that assist us in reliably predicting the propensity of pulmonary sarcoidosis for spontaneous remission, wherein only long-term monitoring can reveal the trajectory of a disease in an individual, enabling the physician to develop a proper management plan. As a significant portion of patients had spontaneous remission, an apparent treatment effect might simply mirror the natural course of the disease, causing an obvious side effect with corticosteroid therapy. The best strategy is to observe the newly diagnosed patients who have a high probability of spontaneous remission, and to decide a treatment strategy when the disease progresses in the lung. Our study may provide a potential marker for predicting spontaneous remission in patients with sarcoidosis.
      Spontaneous remissions occur in 55–90% of patients with stage I disease; in 40–70% of patients with stage II disease; in 10–20% of patients with stage III disease; and in 0% of patients with stage IV disease [
      Statement on sarcoidosis. Joint statement of the American thoracic society (ATS), the European respiratory society (ERS) and the world association of sarcoidosis and other granulomatous disorders (WASOG) adopted by the ATS board of directors and by the ERS executive committee.
      ]. In our study, Spontaneous remissions occur in 71.7% of patients with stage I, in 70.0% of patients with sage II, in 33% of patients with stage III, and in 0% of patients with stage IV. It was consistent with the reported data.
      Interleukin (IL)-2 is secreted by T-helper 1 cells and is thought to play a key role in sarcoidosis as it stimulates T-cell proliferation and activates T-cells [
      • Muller-Quernheim J.
      Sarcoidosis: immunopathogenetic concepts and their clinical application.
      ,
      • Hunninghake G.W.
      • et al.
      Role of interleukin-2 release by lung T-cells in active pulmonary sarcoidosis.
      ]. Activation of T lymphocytes generates a soluble form of interleukin (IL)-2 receptor called soluble interleukin (IL)-2 receptor (sIL-2R), which was found to be increased in serum and bronchoalveolar lavage (BAL) fluid of patients with sarcoidosis [
      • Keicho N.
      • et al.
      Serum concentration of soluble interleukin-2 receptor as a sensitive parameter of disease activity in sarcoidosis.
      ,
      • Belli F.
      • et al.
      Cytokines assay in peripheral blood and bronchoalveolar lavage in the diagnosis and staging of pulmonary granulomatous diseases.
      ,
      • Lawrence E.C.
      • et al.
      Elevated concentrations of soluble interleukin-2 receptors in serum samples and bronchoalveolar lavage fluids in active sarcoidosis.
      ,
      • Tsutsumi T.
      • et al.
      Soluble interleukin-2 receptor in blood from patients with sarcoidosis and idiopathic pulmonary fibrosis.
      ]. sIL-2R is a marker for T-cell activation, and sIL-2R is also known to be a marker of pulmonary disease activity and multiple organ involvement in patients with sarcoidosis [
      • Grutters J.C.
      • et al.
      Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation.
      ,
      • Prasse A.
      • et al.
      Phenotyping sarcoidosis from a pulmonary perspective.
      ,
      • Gundlach E.
      • et al.
      Interleukin-2 receptor and angiotensin-converting enzyme as markers for ocular sarcoidosis.
      ,
      • Thi H.N.C.
      • et al.
      Serum soluble interleukin-2 receptor level is more sensitive than angiotensin-converting enzyme or lysozyme for diagnosis of sarcoidosis and may be a marker of multiple organ involvement.
      ]. Pelin Uysal et al. found that among the markers of disease activity, the level of sIL-2R was increased in sarcoidosis, so it had very good diagnostic value in differentiating between the sarcoidosis patients and controls, and was a promising marker for monitoring sarcoidosis disease activity [
      • Uysal P.
      • et al.
      YKL-40, soluble IL-2 receptor, angiotensin converting enzyme and C-reactive protein: comparison of markers of sarcoidosis activity.
      ]. Furthermore, it was shown that a serum sIL-2R concentration>4000 pg/mL was found to predict relapse after discontinuation of infliximab therapy and that sIL-2R is a suitable prognostic marker for disease progression [
      • Vorselaars A.D.
      • et al.
      Prediction of relapse after discontinuation of infliximab therapy in severe sarcoidosis.
      ,
      • Ziegenhagen M.W.
      • et al.
      Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers.
      ]. Moreover, serum sIL-2R levels were found to correlate with parenchymal infiltration in pulmonary sarcoidosis at disease presentation and might function as prognostic markers at diagnosis [
      • Ziegenhagen M.W.
      • et al.
      Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers.
      ,
      • Miyoshi S.
      • et al.
      Comparative evaluation of serum markers in pulmonary sarcoidosis.
      ].
      The clinical role of serum sIL-2R in spontaneous remission of sarcoidosis is still uncertain. In the present retrospective study, we assessed serum sIL-2R in a group of patients with sarcoidosis. On the basis of our data, we can claim that sIL-2R is a useful marker for predicting the spontaneous remission in patients with sarcoidosis. The highest level of sIL-2R was seen in a case with three organ involvements (lung, non-thoracic lymph node, calcium) (5805 pg/mL). Grutters et al. demonstrated a negative correlation between sIL-2R and peripheral blood lymphocytes, and a positive correlation between sIL-2R and BAL lymphocytes. They explained this by the fact that sIL-2R is produced when the disease is active and then released to blood circulation [
      • Grutters J.C.
      • et al.
      Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation.
      ].
      The results of our multivariate analyses also show that sIL-2R remains the most powerful parameter for predicting spontaneous remission of disease. Especially, when sIL-2R values are above 1129.5IU/mL in stage I subgroup or above 1026.5IU/mL in stage II subgroup, the risk of non-spontaneous remission increases, which is a significant finding. Nevertheless, we believe that other parameters, especially CD4/CD8, should be studied in larger populations to assess the risk of non-spontaneous remission to achieve promising results.
      Recent studies [
      • Bargagli E.
      • Prasse A.
      Sarcoidosis: a review for the internist.
      ,
      • Bargagli E.
      • et al.
      Chitotriosidase activity in patients with interstitial lung diseases.
      ,
      • Arger N.K.
      • et al.
      Serum CXCL11 correlates with pulmonary outcomes and disease burden in sarcoidosis.
      ,
      • Cameli P.
      • et al.
      The role of urinary calcium and chitotriosidase in a cohort of chronic sarcoidosis patients.
      ] also focused on some important biomarker including chitotriosidase, urinary calcium and chitotriosidase. Elena Bargagli et al. found that serum chitotriosidase is a potential marker of sarcoidosis severity and it is related to radiological stage and degree of lung infiltration [
      • Bargagli E.
      • et al.
      Chitotriosidase activity in patients with interstitial lung diseases.
      ]. Serum CXCL11 was another biomarker of sarcoidosis [
      • Arger N.K.
      • et al.
      Serum CXCL11 correlates with pulmonary outcomes and disease burden in sarcoidosis.
      ]. It was significantly elevated in sarcoidosis patients compared to healthy controls and had positive correlations with organs involved. Another study showed urinary calcium was correlated with clinical status, DLCO, and serum CTO activity, suggesting its potential role as a biomarker of the activity and severity of sarcoidosis [
      • Cameli P.
      • et al.
      The role of urinary calcium and chitotriosidase in a cohort of chronic sarcoidosis patients.
      ]. Compared with these markers, our data supported that the main value of sIL-2R is to predict the spontaneous remission in patients with sarcoidosis rather than suggest disease activity or diagnosis.
      This study is limited due to its retrospective nature and relatively smaller population size. Therefore, our cohort may not be representative of other sarcoidosis cohorts and larger studies are warranted to obtain the sensitivity and specificity of sIL-2R in spontaneous remission of sarcoidosis. Meanwhile, the sensitivity and specificity of sIL-2R are relatively low, so it has limited value when applied to the prediction of spontaneous remission of sarcoidosis and was inadequate to be used clinically. Further studies may combine other important biomarkers to improve the sensitivity and specificity.

      5. Conclusion

      In conclusion, our results indicate that sIL-2R may be a useful marker for predicting the spontaneous remission in patients with sarcoidosis. Larger-scale prospective studies and long-term follow-up are needed to prove its predictivity.

      Credit author statement

      Huiping Li: Project design and administration, Supervision; Ying Zhou: Project administration, Data acquisition and analysis, Writing the manuscript; Yuan Zhang: Data acquisition and analysis, Writing the manuscript; Mengmeng Zhao: Data acquisition and analysis, Writing the manuscript; Qiuhong Li: Writing the manuscript. All authors read and approved the final manuscript.

      Declaration of competing interest

      The authors declared that they have no conflicts of interest to this work.
      We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

      Acknowledgements

      The study was supported by grants from the National Science Foundation of Shanghai, China (Grant ID: 18ZR1431400 ).

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