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Serum autotaxin levels in chronic disease and acute exacerbation of fibrosing interstitial lung disease

Takuma Isshiki, Hiroshige Shimizu, Susumu Sakamoto, Akira Yamasaki, Shion Miyoshi, Yasuhiko Nakamura, Sakae Homma, Kazuma Kishi
ERJ Open Research 2022 8: 00683-2021; DOI: 10.1183/23120541.00683-2021
Takuma Isshiki
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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  • ORCID record for Takuma Isshiki
  • For correspondence: takuma.isshiki@med.toho-u.ac.jp
Hiroshige Shimizu
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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Susumu Sakamoto
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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Akira Yamasaki
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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Shion Miyoshi
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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Yasuhiko Nakamura
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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Sakae Homma
2Dept of Advanced and Integrated Interstitial Lung Diseases Research, School of Medicine, Toho University, Tokyo, Japan
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Kazuma Kishi
1Dept of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan
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  • FIGURE 1
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    FIGURE 1

    Autotaxin (ATX) levels in patients with fibrosing interstitial lung disease (ILD) and healthy controls (HC). Fibrosing ILD patients showed significantly increased ATX levels in a) male patients (0.743±0.160 mg ·L−1 versus 0.626±0.092 mg ·L−1; p=0.008) and b) female patients (0.975±0.236 mg· L−1 versus 0.786±0.133 mg· L−1; p=0.001).

  • FIGURE 2
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    FIGURE 2

    Survival curve of fibrosing interstitial lung disease (ILD) patients according to serum autotaxin (ATX) levels. a) Male patients with high ATX levels (>0.721 mg· L−1) showed significantly better outcome than patients with low ATX levels (log rank p=0.003). b) No such difference outcome was observed between high (>0.946 mg ·L−1) and low ATX levels in female patients (log rank p=0.478).

  • FIGURE 3
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    FIGURE 3

    Autotaxin (ATX) levels in male patients with chronic idiopathic pulmonary fibrosis (IPF) and acute exacerbation of IPF (AE-IPF). ATX levels were significantly decreased after the onset of AE-IPF compared with stable IPF (0.746±0.163 mg· L−1 versus 0.564±0.199 mg· L−1; p=0.006).

Tables

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  • TABLE 1

    Baseline characteristics of patients with stable fibrosing interstitial lung disease (ILD)

    PatientsHealthy controls
    Subjects, n11938
    Age years70±952±11
    Sex (male), n (%)69 (58)16 (42)
    Smoking history (yes), n (%)73 (61)11 (29)
    Diagnosis of fibrosing ILD, n
     IPF78
     NSIP11
     Unclassifiable ILD10
     PPFE8
     CTD-ILD12
    Treatment at the time of analysis, n
     Corticosteroids25
     Pirfenidone19
     Nintedanib15
    Laboratory data
     LDH U· L−1252±54
     KL-6 U m·L−11029±680
     SP-D ng· mL−1215±148
    Pulmonary function
     FVC mL2133±743
     %FVC75.9±20.4
     DLCO %59.8±20.9

    Data are presented as mean±sd, unless otherwise stated. IPF: idiopathic pulmonary fibrosis; NSIP: nonspecific interstitial pneumonia; CTD-ILD: connective tissue disease-associated ILD; PPFE: pleuroparenchymal fibroelastosis; LDH: lactate dehydrogenase; SP-D: surfactant protein-D; KL-6: Krebs von den Lungen-6; FVC: forced vital capacity; DLCO: diffusing capacity of the lung for carbon monoxide.

    • TABLE 2

      Autotaxin (ATX) activity by sex in fibrosing interstitial lung disease (ILD) patients without corticosteroid therapy at the time of blood sampling

      Diagnosis of ILDIPFNSIPUnclassifiable ILDPPFECTD-ILD
      Male
       Subjects, n533140
       ATX activity mg· L−10.746±0.1630.793±0.2210.6610.683±0.988
      Female
       Subjects, n164346
       ATX activity mg· L−11.003±0.2580.933±0.1051.217±0.3760.869±0.1950.876±0.101

      Data are presented as mean±sd, unless otherwise stated. IPF: idiopathic pulmonary fibrosis; NSIP: nonspecific interstitial pneumonia; PPFE: pleuroparenchymal fibroelastosis; CTD-ILD: connective tissue disease-associated ILD.

      • TABLE 3

        Correlation between autotaxin levels and clinical parameters

        rp-value
        Male (n=61)
         KL-6−0.1170.370
         SP-D0.0400.757
         %FVC−0.0930.481
         DLCO %−0.1910.146
         Δ1 year %FVC (n=28)0.1420.472
        Female (n=33)
         KL-6−0.0090.957
         SP-D0.2180.223
         %FVC0.0510.784
         DLCO %−0.1350.471
         Δ1 year %FVC (n=13)−0.6760.014

        KL-6: Krebs von den Lungen-6; SP-D: surfactant protein-D; FVC: forced vital capacity; DLCO : diffusing capacity of the lung for carbon monoxide.

        • TABLE 4

          Receiver operating characteristic (ROC) curve analysis to determine the optimal cut-off value of autotaxin for predicting the worse outcome of fibrosing interstitial lung disease

          Cut-off value mg ·dL−1AUCSensitivity %Specificity %
          Male (n=61)0.7210.76692.961.7
          Female (n=33)0.9460.60862.564.0

          AUC: area under curve.

          • TABLE 5

            Multivariate analysis using Cox proportional hazards model for predicting independent predictors of worse outcome in male patients with fibrosing interstitial lung disease (n=61)

            Hazard ratio95% CIp-value
            Age years1.0050.943–1.0720.868
            Smoking history (yes)1.2570.156–10.1000.830
            KL-60.9990.998–1.0010.228
            %FVC0.9640.930–0.9990.043
            ATX >0.721 mg ·L−18.2951.049–65.5580.045

            KL-6: Krebs von den Lungen-6; FVC: forced vital capacity; ATX: autotaxin.

            • TABLE 6

              Baseline characteristics of male patients with acute exacerbation of idiopathic pulmonary fibrosis (n=6)

              Age years71±6
              PaO2/FIO2315±52
              LDH U·L−1332±43
              KL-6 U·mL−11808±990
              SP-D ng·mL−1318±137
              CRP mg ·dL−19.3±10.9

              Data are presented as mean±sd. PaO2: arterial oxygen tension; FIO2: inspiratory oxygen fraction; LDH: lactate dehydrogenase; KL-6: Krebs von den Lungen-6; SP-D: surfactant protein-D; CRP: C-reactive protein.

              Supplementary Materials

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                Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.

                Supplementary material 00683-2021.SUPPLEMENT

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              Serum autotaxin levels in chronic disease and acute exacerbation of fibrosing interstitial lung disease
              Takuma Isshiki, Hiroshige Shimizu, Susumu Sakamoto, Akira Yamasaki, Shion Miyoshi, Yasuhiko Nakamura, Sakae Homma, Kazuma Kishi
              ERJ Open Research Apr 2022, 8 (2) 00683-2021; DOI: 10.1183/23120541.00683-2021

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              Serum autotaxin levels in chronic disease and acute exacerbation of fibrosing interstitial lung disease
              Takuma Isshiki, Hiroshige Shimizu, Susumu Sakamoto, Akira Yamasaki, Shion Miyoshi, Yasuhiko Nakamura, Sakae Homma, Kazuma Kishi
              ERJ Open Research Apr 2022, 8 (2) 00683-2021; DOI: 10.1183/23120541.00683-2021
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