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Respiratory Medicine 166 (2020) 105948
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: http://www.elsevier.com/locate/rmed
Increased serum soluble programmed death ligand 1(sPD-L1) is associated with the presence of interstitial lung disease in rheumatoid arthritis: A monocentric cross-sectional study Xinyu Wu a, 1, Li Xu a, b, 1, Qi Cheng a, Liuyan Nie a, Songzhao Zhang c, Yan Du a, *, Jing Xue a, ** a b c
Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China Department of Medical, Jiaxing University Affiliated Women and Children Hospital, Jiaxing, 314000, China Department of Clinical Laboratory, The Second Affiliated Hospital of Zhejiang University, School of Medicine, Hangzhou, 310009, China
A R T I C L E I N F O
A B S T R A C T
Keywords: Rheumatoid arthritis sPD-L1 Interstitial lung disease
Objective: This paper is to examine the relationship between serum soluble programmed death ligand 1(sPD-L1) levels and the development of interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Method: Serum sPD-L1 were measured by enzyme-linked immunosorbent assay. sPD-L1 levels in RA with ILD, RA without ILD and healthy controls were compared. Associations between ILD and various markers including sPDL1 and confounding factors were investigated by logistic regression analysis. Diagnostic values of sPD-L1 for the presence of ILD were investigated using receiver operating characteristics curve analysis. Results: Serum sPD-L1 levels were higher in RA patients with ILD than RA patients without ILD and healthy controls (23.7 � 9.8 vs. 18.0 � 7.7 pg/mL, P ¼ 0.01 and 23.7 � 9.8 vs. 2.9 � 1.5 pg/mL, P < 0.0001). sPD-L1 levels were positively correlated with RF titer (r ¼ 0.245, P ¼ 0.03), CRP (r ¼ 0.265,P ¼ 0.01), HRCT score (r ¼ 0.265, P ¼ 0.04) and Ferritin (r ¼ 0.442, P ¼ 0.01), but negatively associated with FVC% (r ¼ 0.359, P ¼ 0.01) and DLCO% (r ¼ 0.399, P ¼ 0.008). sPD-L1 and anti-CCP antibody status were independently associated with the presence of ILD during multivariate logistic regression analysis. Sensitivity and specificity of sPD-L1 levels for the detection of ILD in RA patients were 51.7% and 79.3%, respectively (area under the curve ¼ 0.661). Conclusion: Serum sPD-L1 levels were increased in RA patients with ILD. Increased sPD-L1 levels were associated with the presence of ILD.
1. Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease char­ acterized by synovial inflammation, which can lead to irreversible articular damage, a decrease in physical functioning, and radiologic progression [1,2]. RA-related interstitial lung disease (ILD) is observed in 4.5–7.7% of RA patients [3,4] and is characterized by dyspnea, dry cough and characteristic findings on chest imaging or pulmonary func­ tion tests [5]. Immune checkpoint PD-1 is one of the important inhibitory mole­ cules for controlling inflammatory response to injury the normal tissues. Programmed death protein (PD-1)/programmed death ligand 1(PD-L1) axis represents a relevant negative feedback loop for maintaining
immune homeostasis, but it is also of crucial importance for restricting tumor immunity [6,7]. Checkpoint inhibitor agents targeting PD-1/PD-L1 liberate antitumor T cells from the blockade enabling their further activation, proliferation and killing tumor cells. This cancer immunotherapy has revolutionized treatment and outcomes in several cancers. Both PD-1 and PD-L1 also have their soluble forms, the finding contributing to the complexity and multiplicity of the PD-1/PD-L1 immunomodulation pathway [8–10]. Abundant mouse and human data released recently clearly point that checkpoint regulatory mole­ cules are essential in some autoimmune diseases, not only in cancer [11, 12]. Recent study further indicates that, serum sPD-1/PD-L1 is easily detected in clinical practice and should be further evaluated as a
* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (Y. Du), [email protected] (J. Xue). 1 Xinyu Wu and Li Xu have equally contributed to this work. https://doi.org/10.1016/j.rmed.2020.105948 Received 19 September 2019; Received in revised form 8 February 2020; Accepted 26 March 2020 Available online 28 March 2020 0954-6111/© 2020 Elsevier Ltd. All rights reserved.
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Respiratory Medicine 166 (2020) 105948
potential prognostic or/and predictive biomarker in idiopathic pulmo­ nary fibrosis [13]. In this study we aimed to elucidate the possible dysregulation of the sPD-L1 in RA and to investigate the relationship with RA-ILD.
Table 1 Characteristics of rheumatoid arthritis (RA) patients with or without interstitial lung disease (ILD).
2. Methods and materials
sPD-L1 (pg/mL) Age (years) Female Disease duration (months) Smoking history DAS28-ESR Sharp/van der Heijde score Anti-CCP positive Anti-CCP titer RF positive RF titer ESR CRP Ferritin Use of biologics Use of MTX Use of GCs Dose of GCs (mg/day)
2.1. Human subjects Blood samples of 58 clinical diagnosed RA-ILD patients and 29 clinical diagnosed RA patients without a pulmonary complication were collected from the Department of Rheumatology, the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2014 to December 2018. The RA was diagnosed according to the Guideline of American College of Rheumatology (ACR) 1987 criteria for the diag­ nosis of RA [14]. Patients with ILD and IPF due to other causes, com­ plications and/or chronic pulmonary diseases and infectious diseases such as chronic obstructive pulmonary disease (COPD), pulmonary infection, tuberculosis, and tumors in the lung were excluded from this study. Patients with severe heart, lung and renal dysfunction were also excluded. All blood samples were collected in tubes with heparin, and serum were isolated and frozen in 100 μL aliquots at 80 � C until analyzed. There was no genetic relationship among these individuals. 45 healthy controls were recruited from healthy staff members of the hos­ pital. Prior to enrollment, all participants signed the informed consent to donate their blood samples and their clinical information was de-identified for research. Our study was approved by the ethics com­ mittee of the Second Affiliated Hospital of Zhejiang University School of Medicine.
RA-ILD
RA-non-ILD
(n ¼ 58)
(n ¼ 29)
P
23.7 � 9.8 65.7 � 9.4 36 (62.1) 60 (1–360) 15 (25.9) 4.8 � 1.5 18.4 � 22.2 54 (93.1) 696.9 � 531.4 51 (87.9) 615.8 � 1186.5 54.2 � 34.3 32.8 � 44.3 213.4 � 128.7 11 (18.9) 10 (17.2) 45 (77.6) 13.9 � 12.8
18.0 � 7.7 61.8 � 9.2 25 (86.2) 72 (6–360) 1 (3.4) 4.7 � 1.2 29.8 � 24.7 21 (75.0) 429.3 � 555.8 22 (75.9) 213.8 � 194.9 47.1 � 30.6 39.2 � 35.5 188.2 � 180.5 0 (0) 18 (62.1) 16 (55.2) 7.6 � 7.6
0.01 0.096 0.02 0.772 0.011 0.739 0.099 0.008 0.004 0.148 0.289 0.716 0.109 0.341 0.012 <0.0001 0.03 0.024
sPD-L1, soluble programmed death ligand 1; DAS28, 28-joint Disease Activity Score; CRP, C-reactive protein; MTX, methotrexate; GCs, glucocorticoids (in prednisolone equivalent); anti-CCP, anticitrullinated peptide antibody; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate. Continuous variables were compared using the Mann–Whitney U test and are expressed as mean � sd. Categorical variables were compared by the chi-squared test and are expressed as numbers (%) unless otherwise mentioned.
2.5. Statistical analysis
2.2. Clinical assessment of patients
Statistical analysis of data was performed using PRISM (version 5) (GraphPad Software, La Jolla, CA, USA) and/or SPSS for Windows (version 18.0) (SPSS Inc., Chicago, IL, USA). Differences between groups were analyzed by Student’s t-test. Comparisons of categorical variables were conducted using Pearson chi-square tests. For nonparametric data, results were expressed as median (range) values, and the differences between groups were analyzed by the Mann-Whitney U test. Spearman’s correlation coefficient was applied to detect the correlation between two groups. Univariate logistic regression analysis was performed to deter­ mine the factors associated with the presence of ILD. Multivariate lo­ gistic regression analysis was performed by including the confounding factors that were found to be significantly associated with the univariate analyses. The factors were selected in a stepwise manner owing to the small number of events in the logistic model. ROC curve was used to determine the best cut off value and validity of certain variable. Data was presented as mean � standard deviation (SD). A p value of less than 0.05 was considered statistically significant.
The demographic feature, serologic features, current treatment and clinical features, including medication history, the 28 joint Disease Ac­ tivity Score (DAS28), current medication at baseline, serum levels of rheumatoid factors (RF), anti-cyclic peptide containing citrulline (AntiCCP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Ferritin, respiratory manifestations and related measurement including the forced vital capacity (FVC) and diffusing capacity for carbon mon­ oxide (DLCO), were conducted for all patients. DLCO values of, 80% of predicted normal values and FVC values of, 80% of predicted normal values were considered abnormal. were also recorded. 2.3. Clinical assessment of patients and ILD diagnosis ILD was diagnosed according to high-resolution computed tomog­ raphy (HRCT) and pulmonary function tests. The HRCT findings were scored on a scale of 1–6, according to the classification method proposed by Kazuya et al. [15], with the variables as follows: (1) normal attenu­ ation, (2) ground glass attenuation (GGA) without traction bronchiec­ tasis or bronchiolectasis, (3) consolidation without traction bronchiectasis or bronchiolectasis, (4) GGA with traction bronchiectasis or bronchiolectasis, (5) consolidation with traction bronchiectasis or bronchiolectasis, and (6) honeycombing. An overall CT score was ob­ tained by adding the six averaged scores (three zones in each lung) assigned by a radiologist.
3. Results 3.1. Clinical and demographic features 87 RA patients (58 with ILD and 29 without ILD) and 45 healthy controls (HC) with matched age and gender were recruited in this study. The RA patients had median disease duration of 72 months ranging from 6 to 360. The mean DAS28-CRP score was 4.9 � 1.3. To study whether sPD-L1 levels are increased in RA patients with ILD, patients were divided into the RA with ILD group (n ¼ 58, RA-ILD) and the RA without ILD group (n ¼ 29, RA-non-ILD). Comparisons of the collected data for the RA-ILD and RA-non-ILD are shown in Table 1. Female frequency, smoking history, anti-CCP antibody titer, use of biologics, use of MTX, use of glucocorticoids and dose of glucocorticoids showed significant differences in the RA groups with and without ILD.
2.4. Detection of serum sPD-L1 by enzyme-linked immunosorbent assay (ELISA) The concentration of serum sPD-L1 was measured using commer­ cially available ELISA kit per manufacturer’s instruction. The ELISA kit for sPD-L1 was a product of Invitrogen (American). For detection of sPDL1 protein, the serum was directly detected with stock suspension, and its concentration was presented as pg/mL through a standard curve. 2
X. Wu et al.
Respiratory Medicine 166 (2020) 105948
Fig. 1. Concentrations of sPD-L1 in patients with rheumatoid arthritis (RA) and Healthy controls (HC) (A) and their relationship between rheumatoid factor (RF) (B) and C-reaction protein (CRP) (C).
Fig. 2. Correlation between the serum levels of sPD-1 levels with the high-resolution computed tomography score (HRCT score), serum ferritin, diffusing capacity for carbon monoxide percent predicted values (DLCO%) and forced vital capacity percent predicted values (FVC%) in RA-ILD.
3.2. Serum sPD-L1 was elevated in RA especially in RA-ILD patients
female, smoking history, anti-CCP antibody titer, use of MTX, use of glucocorticoids and dose of glucocorticoids were associated with the presence of ILD according to univariate analysis. On multivariate anal­ ysis, after selecting the factors in the multivariate model in a stepwise manner, sPD-L1, anti-CCP antibody status and use of MTX remained independent factors that were associated with the presence of ILD (Table 2).
Serum sPD-L1 levels were significantly higher in patients with RAILD (23.7 � 9.8 pg/mL) than RA without ILD (18.0 � 7.7 pg/mL, P ¼ 0.01, Fig. 1A) and healthy controls (2.9 � 1.5 pg/mL, P < 0.0001, Fig. 1A). The concentrations of serum sPD-L1 were identified to be weak positively correlated with RA serological marker RF (r ¼ 0.245, P ¼ 0.03, Fig. 1B). Further correlation analysis was performed for determi­ nation of the correlation coefficients of sPD-L1 with other clinical serological biomarkers, including ESR, CRP and anti-CCP. The correla­ tion coefficients between sPD-L1 and ESR, sPD-L1 and CRP, and sPD-L1 and anti-CCP were respective r ¼ 0.142 (P ¼ 0.19), r ¼ 0.265 (P ¼ 0.01) (Fig. 1C) and r ¼ 0.083 (P ¼ 0.45). In addition, we also find that serum sPD-L1 were positively associated with HRCT scores (r ¼ 0.265, P ¼ 0.04) and Ferritin levels (r ¼ 0.442, P ¼ 0.01), but negatively associated with FVC% (r ¼ 0.359, P ¼ 0.01) and DLCO% (r ¼ 0.399, P ¼ 0.008) (Fig. 2).
3.4. Serum sPD-L1 levels can be a disease marker for detection of RA with ILD To evaluate the significance of the sPD-L1 protein in clinical settings, we analyzed the sensitivities and specificities of these circulating factors in identified RA patients with ILD (Fig. 3). The area under the curve (AUC) was 0.661 (SE: 0.061; range: 0.542–0.780; sensitivity: 0.517; specificity: 0.793) for sPD-L1 protein. According to the cutoff value, RAILD were divided into sPD-L1 positive and negative groups. Comparisons of the collected data for the sPD-L1 positive and sPD-L1 negative are shown in Table 3. FVC% and DLCO% showed significant differences in the RA groups with sPD-L1 positive and sPD-L1 negative. These results thus imply that the serum sPD-L1 protein may be an independent biomarker for the identification of ILD in RA patients, which can be an
3.3. Serum sPD-L1 is associated with the presence of ILD in RA We performed univariate and multivariate logistic analyses to determine the factors associated with ILD in RA patients. sPD-L1, 3
X. Wu et al.
Respiratory Medicine 166 (2020) 105948
Table 2 Univariate and multivariate logistic regression analyses for factors associated with the presence of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. Univariate sPD-L1 (pg/mL) Age (years) Female Disease duration (months) Smoking history DAS28-ESR Sharp/van der Heijde score Anti-CCP titer Anti-CCP positive RF titer RF positive ESR CRP Ferritin Use of biologics Use of MTX Use of GCs Dose of GCs (mg/ day)
Multivariate
OR (95% CI)
P
OR (95% CI)
P
1.08 (1.02–1.15) 1.05 (0.99–1.10) 0.27 (0.08–0.88) 1.00 (0.95–1.06) 9.77 (1.22–78.14) 1.05 (0.77–1.44) 0.86 (0.69–1.07) 1.01 (1.01–1.03) 4.38 (1.16–16.45) 1.00 (0.99–1.01) 1.94 (0.59–6.41) 1.01 (0.99–1.02) 1.00 (0.99–1.01) 1.00 (0.99–1.01) 5.71 (0.70–47.01) 0.13 (0.05–0.34) 2.61 (1.01–6.73) 1.06 (1.01–1.12)
0.011
1.15 (0.91–1.11)
0.014
0.17 (0.01–5.02)
0.305
2.23 (0.04–128.01)
0.697
0.014
1.01 (1.00–1.01)
0.374
0.029
22.6 (1.08–473.2)
0.045
0.073 0.029 0.977 0.032 0.768 0.171
0.175 0.278 0.497
Fig. 3. Area under the curve (AUC) and sensitivity and specificity of sPD-1 levels in RA patients using receiver operating characteristics curve analysis for the detection of RA with ILD.
0.498 0.641
Table 3 Characteristic of RA-ILD patients according to sPD-L1 protein status.
0.105 <0.0001
0.04 (0.01–0.27)
0.001
0.05
5.55 (0.48–63.7)
0.169
0.021
1.00 (0.91–1.11)
0.939
Age (mean � SD) (years) Gender (female%) RA duration (months) Current/ever-smoker RF (IU/ml) Anti-CCP (þ) number ESR (mm/h) CRP (mg/dl) DAS28 score HRCT score FVC% DLCO% Cough Dyspnea Chest congestion Glucocorticoids MTX
sPD-L1, soluble programmed death ligand 1; DAS28, 28-joint Disease Activity Score; CRP, C-reactive protein; MTX, methotrexate; GCs, glucocorticoids (in prednisolone equivalent); anti-CCP, anticitrullinated peptide antibody; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate.
independent biomarker candidate for evaluating disease severity and progression of ILD in RA patients. 4. Discussion This is the first report on the association between serum sPD-L1 levels and the presence of ILD in RA patients. sPD-L1 levels were increased in the RA-ILD patients. Furthermore, sPD-L1 and anti-CCP antibody were found to be independent disease markers for the detec­ tion of ILD in RA patients. In the present study, we examined sPD-L1 in serum of RA-ILD pa­ tients, and identified that serum sPD-L1 had a strong association with ILD in RA patients. Interestingly, we also found that the increased serum sPD-L1 in RA-ILD patients was positively correlated with rheumatoid factor (RF) and HRCT score. Additionally, a higher level of serum sPD-L1 was negatively associated with FVC% and DLCO% in RA-ILD patients. Multivariate logistic regression analysis suggested that the sPD-L1 was clinically significant risk factors in RA-ILD. ROC curves further demonstrated that the capacity of serum sPD-L1 as a potential biomarker in RA-ILD. This study thus implies that the circulating sPD-L1 may be a valuable biomarker for identifying ILD in RA patients. Previous studies have demonstrated that aging, male, smoking [16, 17] and several serological markers are the predictors for the develop­ ment of ILD. For example, Krebs von den Lungen-6 (KL-6) is known as a
sPD-L1 positive (n ¼ 30)
sPD-L1 negative (n ¼ 28)
Pvalue
66.0 � 9.8
65.5 � 9.4
0.691
19 (63.3) 66 (6–360) 9 (30.0) 607.2 � 1220.3 27 (90.0) 50.6 � 29.5 41.7 � 51.3 4.7 � 1.5 6.2 � 3.4 79.8 � 20.1 54.2 � 15.0 20 (66.7) 7 (23.3) 13 (43.3) 22 (73.3) 6 (20.0)
18 (64.3) 60 (1–300) 5 (17.9) 465.7 � 863.5 27 (96.4) 50.9 � 36.6 24.2 � 34.6 4.8 � 1.6 5.4 � 3.3 95.3 � 14.7 68.8 � 17.6 11 (39.3) 2 (7.1) 7 (25.0) 22 (78.6) 3 (10.7)
0.940 0.377 0.280 0.301 0.334 0.72 0.06 0.674 0.259 0.004 0.006 0.037 0.147 0.142 0.641 0.473
sPD-L1, soluble programmed death ligand 1; DAS28, 28-joint Disease Activity Score; CRP, C-reactive protein; MTX, methotrexate; GCs, glucocorticoids (in prednisolone equivalent); anti-CCP, anticitrullinated peptide antibody; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate; HRCT: high-resolution computed tomography; FVC: forced vital capacity; DLCO: diffusing capacity for carbon monoxide.
classical marker for idiopathic and connective tissue disease (CTD)-as­ sociated ILD [18–20]. In addition, lactate dehydrogenase (LDH) [21], anti-cyclic citrullinated peptide (anti-CCP) antibody [3,22] and rheu­ matoid factor [23] have recently been reported to be markedly increased in patients with ILD. Except for sPD-L1, in this study we also found that anti-CCP antibody and smoking factory were also risk factors and female was a protective t factor for ILD in RA, which were consistent with previous reports [3,16,17,22]. A rare adverse effect of MTX is hypersensitivity pneumonitis, which is described in 0.43% patients [24]. This organ-specific hypersensitivity 4
X. Wu et al.
Respiratory Medicine 166 (2020) 105948
reaction has led to a creeping concern in routine practice that MTX may also be associated with an increased incidence or exacerbation of the interstitial lung disease (ILD) that is associated with RA and may be a reason to withhold MTX from RA patients with any lung disease. How­ ever, in our study, multivariate logistic regression analysis demonstrated that MTX treatment was not associated with an increased risk of RA-ILD diagnosis. On the contrary, evidence suggested that MTX may be a protective factor for RA-ILD and it was consistent with a recent report [25]. Ferritin was also reported to be associated with CTD-ILD [26]. In our study, although it showed no association with RA-ILD, maybe due to relatively small sample, the serum ferritin level was positively associ­ ated with sPD-L1, thus, association between ferritin and RA-ILD needs future study. There are several limitations in our current study. First, the sample size of this study was small, which may lead to potential analytical bias. Further studies with large cohorts are needed. Second, the subjects in our study were from a single institution, and these subjects were ho­ mogenous Han Chinese ethnic group. A multicenter study with various ethnic groups is needed to evaluate the generalizability of our results. Third, we only measured serum sPD-L1 expression without evaluating PD-1 and PD-L1 in patient’s lung tissue biopsies by immunohisto­ chemistry (IHC) and quantify PD-1 in Peripheral Blood Mononuclear Cells (PBMCs) by real time RT-PCR and correlating to blood leukocytes and DAS28 Scores. Finally, evidence from this study warrants further investigation with prospective study design to help draw more confident conclusions.
[4]
[5] [6] [7]
[8] [9]
[10] [11] [12] [13]
[14]
Declaration of competing interest
[15]
The authors declare no conflicts of interest regarding this work. The Corresponding Authors have the right to grant on behalf of all authors and do grant on behalf of all authors.
[16] [17]
CRediT authorship contribution statement
[18]
Xinyu Wu: Data curation, Methodology, Validation, Funding acquisition. Li Xu: Methodology, Resources, Formal analysis, Software. Qi Cheng: Methodology, Resources, Validation. Liuyan Nie: Method­ ology, Resources. Songzhao Zhang: Methodology, Validation. Yan Du: Conceptualization, Software, Investigation, Writing - original draft, Project administration, Funding acquisition, Visualization. Jing Xue: Conceptualization, Investigation, Writing - review & editing, Project administration, Supervision.
[19] [20]
[21]
Acknowledgements
[22]
This work was supported by the National Natural Science Foundation of China (No. 81501388), Zhejiang Provincial Public Technology Applied Research Project, China (No.2015C33177, No.2017C33032) and National Natural Science Foundation of Zhejiang Province, China (No.LY20H100007, LQ17H160007).
[23]
[24]
Referencess
[25]
[1] E.D. Harris Jr., Rheumatoid arthritis. Pathophysiology and implications for therapy, N. Engl. J. Med. 322 (18) (1990) 1277–1289. [2] K.W. Kim, H.R. Kim, Macrophage migration inhibitory factor: a potential therapeutic target for rheumatoid arthritis, Kor. J. Int. Med. 31 (4) (2016) 634–642. [3] C.A. Kelly, V. Saravanan, M. Nisar, S. Arthanari, F.A. Woodhead, A.N. Price-Forbes, J. Dawson, N. Sathi, Y. Ahmad, G. Koduri, A. Young, N. British Rheumatoid
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