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Elevated serum levels of C-X-C motif chemokine ligand 10 can distinguish systemic lupus erythematosus patients from cutaneous lupus erythematosus patients

Published:April 17, 2021DOI:https://doi.org/10.1016/j.jaad.2021.04.032
      To the Editor: Serological biomarkers distinguishing cutaneous lupus erythematosus (CLE) from systemic lupus erythematosus (SLE) may help track CLE patients at risk of progression to SLE. Thus, we compared the CLE and SLE sera concentrations of C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, 2 chemokines previously demonstrated to be upregulated in patients with CLE and SLE,
      • Wenzel J.
      • Wörenkämper E.
      • Freutel S.
      • et al.
      Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.
      ,
      • Baechler E.C.
      • Batliwalla F.M.
      • Karypis G.
      • et al.
      Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.
      and assessed their ability to discriminate between patient groups.
      Serum samples from patients with CLE only (CLE+/SLE) (n = 48), both CLE and SLE (CLE+/SLE+) (n = 17), and SLE without CLE (CLE/SLE+) (n = 26) as well as from controls (n = 29) were collected at the University of Texas Southwestern Medical Center and Parkland Memorial Hospital (Table I). Patients who fulfilled ≥4 American College of Rheumatology SLE criteria were classified as having SLE. Patients with CLE-isolated disease were diagnosed based on a skin biopsy and fulfilled <4 American College of Rheumatology SLE criteria. Seventeen SLE patients had a concomitant diagnosis of CLE. The exclusion criteria included concomitant autoimmune disease, chronic infection, or active malignancy. The serum levels of the chemokines were measured using enzyme-linked immunosorbent assays (R&D Systems) and compared using the Mann-Whitney or Kruskal-Wallis test. The ability of the chemokines to discriminate between CLE and SLE patients was measured using the area under the receiver operating characteristics curve.
      Table IPatient demographics and clinical characteristics
      Demographics and clinical characteristicsCLE+/SLE (n = 48)CLE+/SLE+ (n = 17)CLE/SLE+ (n = 26)Controls (n = 29)
      Age, median (IQR)48 (39-58)41 (29.5-51)28 (25.6-34.4)44.1 (35.1-55.7)
      Sex, n (%)
       Female35 (73%)14 (82%)26 (100%)22 (76%)
       Male13 (27%)3 (18%)0 (0%)7 (24%)
      Race/ethnicity, n (%)
       African American30 (63%)14 (82%)7 (27%)18 (62%)
       Caucasian13 (27%)1 (6%)5 (19%)9 (31%)
       Hispanic4 (8%)2 (12%)12 (46%)1 (3%)
       Asian1 (2%)0 (0%)2 (8%)1 (3%)
      ACR SLE criteria, n (%)N/A
       Malar rash0 (0%)5 (29%)0 (0%)
       Discoid rash42 (88%)17 (100%)0 (0%)
       Photosensitivity32 (67%)15 (88%)9 (35%)
       Oral ulcers1 (2%)8 (47%)5 (19%)
       Arthritis0 (0%)11 (65%)10 (38%)
       Pleuritis/pericarditis0 (0%)3 (18%)5 (19%)
       Renal disorder0 (0%)9 (53%)26 (100%)
       Neurologic disorder0 (0%)0 (0%)2 (8%)
       Hematologic disorder11 (23%)7 (41%)10 (38%)
       Immunologic disorder2 (4%)14 (82%)21 (81%)
       Positive antinuclear antibody13 (27%)17 (100%)20 (77%)
      Predominant CLE subtype, n (%)
      One CLE+/SLE+ patient had a diagnosis of DLE per chart review, but information regarding the DLE subtype was not available.
      N/AN/A
       Localized DLE29 (60%)3 (18%)
       Generalized DLE13 (27%)13 (71%)
       SCLE6 (13%)0 (0%)
      Medications, n (%)N/A
       None16 (33%)0 (0%)2 (8%)
       Topical steroids15 (31%)0 (0%)0 (0%)
       Antimalarials13 (27%)4 (24%)4 (15%)
       Other immunosuppresants4 (8%)13 (76%)20 (77%)
      CLASI-A, median (IQR)4 (3-9)11 (6-21)
      CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.
      N/AN/A
      CLASI-D, median (IQR)8 (2-13)16 (11-28)
      CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.
      N/AN/A
      ACR, American College of Rheumatology; CLASI-A, cutaneous lupus erythematosus disease area and severity index – activity; CLASI-D, cutaneous lupus erythematosus disease area and severity index – damage; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; IQR, interquartile range; LE, lupus erythematosus; N/A, not available; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.
      CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.
      One CLE+/SLE+ patient had a diagnosis of DLE per chart review, but information regarding the DLE subtype was not available.
      The CLE+/SLE sera had elevated CXCL9 and CXCL10 levels compared with the control sera (CXCL9: median 50.91 pg/mL [interquartile range {IQR} 32.8-122.1 pg/mL] vs 20.54 pg/mL [IQR 12.7-34.4 pg/mL] [P < .0001], CXCL10: median 220.77 pg/mL [IQR 132-360.1 pg/mL] vs 124.12 pg/mL [89.5-149.4 pg/mL] [P = .002]). The serum levels of CXCL10 in CLE+/SLE+ patients (473.9 pg/mL [IQR 327.5-1978.8 pg/mL]) and CLE/SLE+ patients (642.3 pg/mL [IQR 398.5-1561.3 pg/mL]) were significantly elevated compared with the levels in CLE+/SLE patients (P < .003) and healthy controls (P < .0001). The CXCL9 levels were significantly higher in CLE+/SLE+ patients (88.5 pg/mL [IQR 77.0-138.0 pg/mL]) and CLE/SLE+ patients (57.7 pg/mL [IQR 24.1-107.5 pg/mL]) than in the controls (P < .0001) but not in CLE+/SLE patients (Fig 1, A and B). Receiver operating characteristic analysis was performed to distinguish CLE+/SLE+ patients from CLE+/SLE patients based on the CXCL9 and CXCL10 levels (Fig 1, C and D). CXCL10 levels in CLE+/SLE+ and CLE+/SLE patients yielded an area under the curve of 0.83 (95% confidence interval: 0.72-0.93) (P < .0001).
      Figure thumbnail gr1
      Fig 1CXCL9 and CXCL10 serum levels in SLE and CLE patients and healthy control patients. The serum levels of CXCL9 (A) and CXCL10 (B) were compared between healthy, CLE+/SLE, CLE+/SLE+, and CLE/SLE+ patients using the Kruskal-Wallis test. Data points corresponding to CLE patients classified as having DLE are indicated as open dots. ROC curves for CXCL9 (C) and CXCL10 (D) levels in CLE and SLE patients were generated. CLE, Cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; ROC, receiver operating characteristics; SLE, systemic lupus erythematosus. ∗P ≤ .01. P < .001. P < .0001.
      These results highlight the potential utility of CXCL10 as a biomarker to distinguish SLE patients from CLE patients. In CLE patients, CXCL10 induces helper T cell type 1-based inflammation, the recruitment of C-X-C chemokine receptor type 3+ T cells, and the release of interferon-associated cytokines into the skin, promoting tissue injury.
      • Wenzel J.
      • Wörenkämper E.
      • Freutel S.
      • et al.
      Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.
      Increasing sera levels of CXCL10 from controls to those of CLE+/SLE patients to those of CLE+/SLE+ and CLE/SLE+ patients demonstrated the potential spread of helper T cell type 1-induced inflammation from skin to systemic levels. Increased CXCL10 levels in SLE patients have been shown to come from both peripheral blood and other end organs.
      • Enghard P.
      • Humrich J.
      • Rudolph B.
      • et al.
      CXCR3+ CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients.
      Thus, we postulate that increases in the CXCL10 levels over time may help predict the onset of SLE in CLE patients. In contrast, CXCL9 does not help distinguish CLE patients from SLE patients. The lack of significant CXCL9 upregulation in end organs in human patients with lupus may explain the smaller difference in the CXCL9 levels between CLE and SLE patients.
      • Flier J.
      • Boorsma D.M.
      • van Beek P.J.
      • et al.
      Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation.
      ,
      • Wenzel J.
      • Zahn S.
      • Mikus S.
      • Wiechert A.
      • Bieber T.
      • Tüting T.
      The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets.
      While this study was limited by its cross-sectional single-center design and small sample size, larger, longitudinal studies are needed to confirm our hypothesis that CXCL10 is a biomarker that distinguishes CLE from SLE and track systemic disease spread for CLE patients.

      Conflicts of interest

      Dr Chong is an investigator for Pfizer Incorporated, Biogen Incorporated, Daavlin Corporation, and Amgen Incorporated and is a consultant for Viela Bio, Beacon Bioscience, Bristol Meyers Squibb, EMD Serono, and Principia Biopharma. Drs O'Brien and Saxena and author Zhu and Barber have no conflicts of interest to declare.
      We would like to acknowledge Rebecca Vasquez, MD, Andrew Kim, MD, Daniel Grabell, MD, Noelle Teske, MD, MSc, and Tina Vinoya, MD for recruiting patients. The authors would like to thank participants of the University of Texas Southwestern Medical Center's Cutaneous Lupus Erythematosus Registry for their contributions to lupus research.

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