Serum YKL-40 level is associated with severity of interstitial lung disease and poor prognosis in dermatomyositis with anti-MDA5 antibody
We aimed to investigate the clinical value of checking serum chitinase-3-like-1 protein (YKL-40) levels in anti-MDA5 antibody-positive dermatomyositis (anti-MDA5+DM) patients.
One hundred and five consecutive anti-MDA5+DM patients and 44 healthy controls were enrolled in this study. Baseline and follow-up serum YKL-40 were detected by ELISA. We evaluated the association of YKL-40 with rapidly progressive interstitial lung disease (RPILD), severity of interstitial lung disease (ILD), and ILD-related survival.
Forty-one out of 105 anti-MDA5+DM patients had RPILD at the time of serum sample collection (39.0%). Serum YKL-40 levels were significantly higher in anti-MDA5+DM patients with RPILD compared with those without (p = 0.011). One month after treatment, patients with aggravated ILD had increased YKL-40 levels, while those with stable/improved ILD had decreased YKL-40 levels. Higher serum levels of ferritin and YKL-40, as well as lower peripheral CD3+T cell counts, were independently associated with poorer prognosis. Kaplan–Meier survival curve showed that the 6 months survival rate in patients with high serum YKL-40 level (> 80 ng/ml) was significantly lower than that in patients with low YKL-40 level (≤ 80 ng/ml) (67% vs 89%, p < 0.01).
YKL-40 can be useful as an indicator for the occurrence of RPILD and correlates with severity of ILD and poor prognosis in anti-MDA5+DM patients. Closely monitoring and intensive treatment are suggested in anti-MDA5+DM patients showing high level of YKL-40, especially levels > 80 ng/ml.
KeywordsAnti-melanoma differentiation-associated protein 5 antibody Dermatomyositis Rapidly progressive interstitial lung disease (RPILD) YKL-40
The authors thank Xin Lu, He Chen, Lin Liang, Yamei Zhang, Lifang Ye, Yawen Shen, Hongxia Yang, and Hanbo Yang from the Department of Rheumatology, China-Japan Friendship Hospital, Beijing, China, for their assistance.
This work was supported by Beijing Municipal Science and Technology Commission (Z181100001718063), the National Natural Science Foundation of China (81571603, 81701615), and the Capital Foundation of Medical Developments (2016-2-4063).
Compliance with ethical standards
The authors declare that manuscript has been read and approved by all authors. We have obtained the approval from the Research Review Committee (RRC) and the Ethical Review Committee (ERC) of the China-Japan Friendship Hospital. All the samples were obtained after the patients had provided written informed consent. This study was approved by the Research Review Committee and the Ethical Review Committee of the China-Japan Friendship Hospital (approval number 2016–117).
- 1.Chen F, Wang D, Shu X, Nakashima R, Wang G (2012) Anti-MDA5 antibody is associated with a/SIP and decreased T cells in peripheral blood and predicts poor prognosis of ILD in Chinese patients with dermatomyositis. Rheumatol Int 32(12):3909–3915. https://doi.org/10.1007/s00296-011-2323-y CrossRefGoogle Scholar
- 2.Sato S, Kuwana M, Fujita T, Suzuki Y (2013) Anti-CADM-140/MDA5 autoantibody titer correlates with disease activity and predicts disease outcome in patients with dermatomyositis and rapidly progressive interstitial lung disease. Mod Rheumatol 23(3):496–502. https://doi.org/10.1007/s10165-012-0663-4 CrossRefGoogle Scholar
- 3.Koga T, Fujikawa K, Horai Y, Okada A, Kawashiri SY, Iwamoto N, Suzuki T, Nakashima Y, Tamai M, Arima K, Yamasaki S, Nakamura H, Origuchi T, Hamaguchi Y, Fujimoto M, Ishimatsu Y, Mukae H, Kuwana M, Kohno S, Eguchi K, Aoyagi K, Kawakami A (2012) The diagnostic utility of anti-melanoma differentiation-associated gene 5 antibody testing for predicting the prognosis of Japanese patients with DM. Rheumatology (Oxford, England) 51(7):1278–1284. https://doi.org/10.1093/rheumatology/ker518 CrossRefGoogle Scholar
- 4.Hakala BE, White C, Recklies AD (1993) Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 268(34):25803–25810Google Scholar
- 5.Lee CG, Da Silva CA, Dela Cruz CS, Ahangari F, Ma B, Kang MJ, He CH, Takyar S, Elias JA (2011) Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. Annu Rev Physiol 73:479–501. https://doi.org/10.1146/annurev-physiol-012110-142250 CrossRefGoogle Scholar
- 6.De Ceuninck F, Gaufillier S, Bonnaud A, Sabatini M, Lesur C, Pastoureau P (2001) YKL-40 (cartilage gp-39) induces proliferative events in cultured chondrocytes and synoviocytes and increases glycosaminoglycan synthesis in chondrocytes. Biochem Biophys Res Commun 285(4):926–931. https://doi.org/10.1006/bbrc.2001.5253 CrossRefGoogle Scholar
- 7.Wang Y, Ripa RS, Johansen JS, Gabrielsen A, Steinbruchel DA, Friis T, Bindslev L, Haack-Sorensen M, Jorgensen E, Kastrup J (2008) YKL-40 a new biomarker in patients with acute coronary syndrome or stable coronary artery disease. Scand Cardiovasc J 42(5):295–302. https://doi.org/10.1080/14017430802220567 CrossRefGoogle Scholar
- 8.Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C (2017) Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev 33(2). https://doi.org/10.1002/dmrr.2841
- 10.Furuhashi K, Suda T, Nakamura Y, Inui N, Hashimoto D, Miwa S, Hayakawa H, Kusagaya H, Nakano Y, Nakamura H, Chida K (2010) Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir Med 104(8):1204–1210. https://doi.org/10.1016/j.rmed.2010.02.026 CrossRefGoogle Scholar
- 11.Hozumi H, Fujisawa T, Enomoto N, Nakashima R, Enomoto Y, Suzuki Y, Kono M, Karayama M, Furuhashi K, Murakami A, Inui N, Nakamura Y, Mimori T, Suda T (2017) Clinical utility of YKL-40 in polymyositis/dermatomyositis-associated interstitial lung disease. J Rheumatol 44(9):1394–1401. https://doi.org/10.3899/jrheum.170373 CrossRefGoogle Scholar
- 16.Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183(6):788–824. https://doi.org/10.1164/rccm.2009-040GL CrossRefGoogle Scholar
- 18.Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, Dziura JD, Reed J, Coyle AJ, Kiener P, Cullen M, Grandsaigne M, Dombret MC, Aubier M, Pretolani M, Elias JA (2007) A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 357(20):2016–2027. https://doi.org/10.1056/NEJMoa073600 CrossRefGoogle Scholar
- 19.Mora AL, Torres-Gonzalez E, Rojas M, Corredor C, Ritzenthaler J, Xu J, Roman J, Brigham K, Stecenko A (2006) Activation of alveolar macrophages via the alternative pathway in herpesvirus-induced lung fibrosis. Am J Respir Cell Mol Biol 35(4):466–473. https://doi.org/10.1165/rcmb.2006-0121OC CrossRefGoogle Scholar
- 21.Mathai SK, Gulati M, Peng X, Russell TR, Shaw AC, Rubinowitz AN, Murray LA, Siner JM, Antin-Ozerkis DE, Montgomery RR, Reilkoff RA, Bucala RJ, Herzog EL (2010) Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype. Lab Invest 90(6):812–823. https://doi.org/10.1038/labinvest.2010.73
- 22.Christmann RB, Sampaio-Barros P, Stifano G, Borges CL, de Carvalho CR, Kairalla R, Parra ER, Spira A, Simms R, Capellozzi VL, Lafyatis R (2014) Association of interferon- and transforming growth factor beta-regulated genes and macrophage activation with systemic sclerosis-related progressive lung fibrosis. Arthritis Rheum 66(3):714–725. https://doi.org/10.1002/art.38288 CrossRefGoogle Scholar
- 24.Enomoto Y, Suzuki Y, Hozumi H, Mori K, Kono M, Karayama M, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suzuki D, Ogawa N, Nakashima R, Mimori T, Iwashita T, Suda T (2017) Clinical significance of soluble CD163 in polymyositis-related or dermatomyositis-related interstitial lung disease. Arthritis Res Ther 19(1):9. https://doi.org/10.1186/s13075-016-1214-8 CrossRefGoogle Scholar
- 25.Chino H, Sekine A, Baba T, Iwasawa T, Okudela K, Takemura T, Itoh H, Sato S, Suzuki Y, Ogura T (2016) Radiological and pathological correlation in anti-MDA5 antibody-positive interstitial lung disease: rapidly progressive perilobular opacities and diffuse alveolar damage. Intern Med (Tokyo, Japan) 55(16):2241–2246. https://doi.org/10.2169/internalmedicine.55.5774 CrossRefGoogle Scholar
- 27.Matsushita T, Mizumaki K, Kano M, Yagi N, Tennichi M, Takeuchi A, Okamoto Y, Hamaguchi Y, Murakami A, Hasegawa M, Kuwana M, Fujimoto M, Takehara K (2017) Antimelanoma differentiation-associated protein 5 antibody level is a novel tool for monitoring disease activity in rapidly progressive interstitial lung disease with dermatomyositis. Br J Dermatol 176(2):395–402. https://doi.org/10.1111/bjd.14882 CrossRefGoogle Scholar
- 28.Fujiki Y, Kotani T, Isoda K, Ishida T, Shoda T, Yoshida S, Takeuchi T, Makino S (2018) Evaluation of clinical prognostic factors for interstitial pneumonia in anti-MDA5 antibody-positive dermatomyositis patients. Mod Rheumatol 28(1):133–140. https://doi.org/10.1080/14397595.2017.1318468 CrossRefGoogle Scholar
- 29.Gono T, Sato S, Kawaguchi Y, Kuwana M, Hanaoka M, Katsumata Y, Takagi K, Baba S, Okamoto Y, Ota Y, Yamanaka H (2012) Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford, England) 51(9):1563–1570. https://doi.org/10.1093/rheumatology/kes102 CrossRefGoogle Scholar
- 30.Isoda K, Kotani T, Takeuchi T, Kiboshi T, Hata K, Ishida T, Otani K, Kamimori T, Fujiwara H, Shoda T, Makino S (2017) Comparison of long-term prognosis and relapse of dermatomyositis complicated with interstitial pneumonia according to autoantibodies: anti-aminoacyl tRNA synthetase antibodies versus anti-melanoma differentiation-associated gene 5 antibody. Rheumatol Int 37(8):1335–1340. https://doi.org/10.1007/s00296-017-3729-y CrossRefGoogle Scholar
- 32.Nara M, Komatsuda A, Omokawa A, Togashi M, Okuyama S, Sawada K, Wakui H (2014) Serum interleukin 6 levels as a useful prognostic predictor of clinically amyopathic dermatomyositis with rapidly progressive interstitial lung disease. Mod Rheumatol 24 (4):633–636. doi: https://doi.org/10.3109/14397595.2013.844390
- 33.Kawasumi H, Gono T, Kawaguchi Y, Kaneko H, Katsumata Y, Hanaoka M, Kataoka S, Yamanaka H (2014) IL-6, IL-8, and IL-10 are associated with hyperferritinemia in rapidly progressive interstitial lung disease with polymyositis/dermatomyositis. Biomed Res Int 2014:815245–815246. https://doi.org/10.1155/2014/815245 CrossRefGoogle Scholar
- 34.Kobayashi N, Takezaki S, Kobayashi I, Iwata N, Mori M, Nagai K, Nakano N, Miyoshi M, Kinjo N, Murata T, Masunaga K, Umebayashi H, Imagawa T, Agematsu K, Sato S, Kuwana M, Yamada M, Takei S, Yokota S, Koike K, Ariga T (2015) Clinical and laboratory features of fatal rapidly progressive interstitial lung disease associated with juvenile dermatomyositis. Rheumatology (Oxford, England) 54(5):784–791. https://doi.org/10.1093/rheumatology/keu385 CrossRefGoogle Scholar
- 35.Gono T, Kawaguchi Y, Ozeki E, Ota Y, Satoh T, Kuwana M, Hara M, Yamanaka H (2011) Serum ferritin correlates with activity of anti-MDA5 antibody-associated acute interstitial lung disease as a complication of dermatomyositis. Mod Rheumatol 21(2):223–227. https://doi.org/10.1007/s10165-010-0371-x CrossRefGoogle Scholar