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      Serial measurements of KL-6 for monitoring activity and recurrence of interstitial pneumonia with anti-aminoacyl-tRNA synthetase antibody : A retrospective cohort study

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          Abstract

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          Abstract

          The aim of this study was to evaluate whether serial measurements of serum Krebs von den Lungen-6 (KL-6) could be used to monitor disease activity and to detect recurrence in patients with interstitial pneumonia (IP) with anti-aminoacyl-tRNA synthetase antibodies (ARS-IP).

          This retrospective cohort study included 44 patients with ARS-IP. Thirty-six patients had serial data of blood tests and pulmonary function tests. Baseline and longitudinal analyses were performed to investigate whether lung function parameters were associated with serum biomarkers (KL-6, lactate dehydrogenase [LDH], and C-reactive protein [CRP]) using Pearson correlation coefficient. Additionally, the diagnostic accuracy of changes in these biomarkers for detecting ARS-IP recurrence was analyzed by receiver operating characteristic curve analysis.

          Baseline levels of serum KL-6 were significantly associated with vital capacity (VC) and diffusion capacity for carbon monoxide (DLco) ( r = −0.40, P = .015, and r = −0.44, P = .010, respectively). Longitudinal changes in KL-6 were inversely correlated with changes in VC and DLco ( r = −0.57, P <.001 and r = −0.42, P <.001, respectively), whereas those in LDH and CRP were not. Moreover, longitudinal changes in serum KL-6 were significantly associated with recurrence of ARS-IP and could be used to detect ARS-IP recurrence; the area under the curve was 0.79 ( P = .002).

          The present study demonstrated that serial measurement of KL-6 is useful for monitoring disease activity and detecting recurrence of ARS-IP.

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          Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases.

          Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. Because injury and/or regeneration of type II pneumocytes are prominent histological features of ILDs, substances derived from type II pneumocytes have been the focus of research investigating potential biomarkers for ILD. One important biomarker for ILD is the high-molecular-weight glycoprotein, Krebs von den Lungen-6 (KL-6). KL-6 is now classified as a human MUC1 mucin protein, and regenerating type II pneumocytes are the primary cellular source of KL-6/MUC1 in the affected lungs of patients with ILD. KL-6/MUC1 is detectable in the serum of patients with ILD, and extensive investigations performed primarily in Japan have revealed that serum KL-6/MUC1 is elevated in 70-100% of patients with various ILDs, including idiopathic interstitial pneumonias, collagen vascular disease-associated interstitial pneumonia, hypersensitivity pneumonia, radiation pneumonitis, drug-induced ILDs, acute respiratory distress syndrome, pulmonary sarcoidosis, and pulmonary alveolar proteinosis. The results from these various studies have supported the utility of KL-6/MUC1 as a serum biomarker for detecting these various ILDs. Moreover, KL-6/MUC1 serum levels have been demonstrated to be useful for evaluating disease activity and predicting the clinical outcomes of various ILD types. Based on these observations, we believe that KL-6/MUC1 is currently one of the best and most reliable serum biomarkers available for ILD management. Copyright © 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
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            Common and Distinct Clinical Features in Adult Patients with Anti-Aminoacyl-tRNA Synthetase Antibodies: Heterogeneity within the Syndrome

            Objective To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs). Methods This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009. Results Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset. Conclusion Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.”
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              A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis siné myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies.

              Classical dermatomyositis (CDM) patients display the hallmark cutaneous manifestations of dermatomyositis (DM), proximal muscle weakness, and laboratory evidence of myositis. The epidemiology and management of both adult-onset and juvenile-onset CDM has been well characterized. However, the clinical significance of the hallmark inflammatory cutaneous manifestations of DM occurring in individuals who have no clinically significant muscle weakness and normal muscle enzymes for prolonged periods of time (ie, 6 months or longer) has not been clear. The term amyopathic DM (ADM) (synonymous with DM siné myositis) has been proposed to draw attention to such individuals. A related form of DM, "hypomyopathic DM" [HDM], is the presence of DM skin disease for 6 months or longer in individuals who have no muscle weakness but who are found to have some evidence of muscle inflammation upon testing (muscle enzyme levels, electromyogram, muscle biopsy, muscle magnetic resonance imaging [MRI]). Clinically amyopathic DM (CADM) is a designation that has been proposed for patients having either ADM or HDM. The clinically amyopathic component of this designation was coined to emphasize the fact that the only clinical problem being experienced by these patients at the time of diagnosis is their DM skin disease. Our personal experience suggests that the CADM subphenotype might be more prevalent in adults than has been thought previously. To test this hypothesis and address questions relating to the optimal management and prognosis of such patients, we have systematically reviewed the published literature in this area. We carried out a systematic review of the published literature on adult-onset CADM as defined in Table 1 through May 1, 2004. We identified 291 adult-onset CADM cases (18 years or older) reported from over 19 countries. The average duration of DM skin disease was 3.74 years (range, 6 months [by definition] to > 20 years), and 73% were female. Among 37 patients with HDM who were identified, the average duration of disease was 5.4 years, and none had developed clinically significant weakness at the time of the reports. Thirty-seven of the reported CADM patients developed muscle weakness greater than 6 months after onset of their skin disease (15 months to 6 years). For the sake of this discussion, such patients have been analyzed under the designation of "CADM --> CDM." Somewhat surprisingly, 36/291 (13%) of the identified published CADM patients developed interstitial lung disease. Incidental to our review, we also identified 10 published cases of individuals having DM skin disease and interstitial lung disease without muscle weakness, 7 of whom died from interstitial lung disease less than 6 months after onset of their DM skin disease (the term pre-myopathic DM coined by others has been used here to refer to such patients). In addition, an associated internal malignancy was found in 41/291 (14%) of the identified CADM cases. A positive antinuclear antibody was reported in 63% and myositis-specific autoantibodies (eg, Jo-1, Mi-2) in only 3.5% of the reported CADM patients in which such data were available. The results of this analysis suggests that the CADM subphenotype is more common than has been thought previously and that such patients may comprise a relatively high proportion of DM patients followed by dermatologists. Some CADM patients also have been observed to develop overt proximal muscle weakness years after onset of their DM skin disease. In addition, CADM patients appear to be at risk of developing the same potentially fatal disease associations/complications for which CDM patients are at risk (eg, interstitial lung disease and internal malignancy). Population-based studies of the epidemiology and optimal management of CADM patients, including efforts to identify risk factors associated with potentially fatal outcomes such as late-onset muscle weakness, interstitial lung disease, and malignancy, are needed. As an incidental finding to this literature review, we also identified a small number of reported cases of often-fatal interstitial lung disease occurring shortly after the onset of DM skin disease (< 6 months) in the complete absence of muscle weakness. This subphenotype, referred to as "pre-myopathic DM," is one with which dermatologists should be aware as early diagnosis and aggressive management can be lifesaving.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                December 2018
                10 December 2018
                : 97
                : 49
                : e13542
                Affiliations
                [a ]Department of Molecular and Internal Medicine
                [b ]Department of Emergency and Critical Care Medicine
                [c ]Department of Physical Analysis and Therapeutic Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University
                [d ]Hiroshima Cosmopolitan University, Hiroshima, Japan.
                Author notes
                []Correspondence: Hiroshi Iwamoto, Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1–2–3 Kasumi, Minami-ku, Hiroshima, 734–8551, Japan (e-mail: iwamotohiroshig@ 123456gmail.com ).
                Article
                MD-D-18-04033 13542
                10.1097/MD.0000000000013542
                6310603
                30544464
                fdb6a567-a2fa-4da0-8921-7e199556e753
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0

                History
                : 6 June 2018
                : 12 November 2018
                Categories
                6700
                Research Article
                Observational Study
                Custom metadata
                TRUE

                anti-aminoacyl-trna synthetase antibody,interstitial lung disease,kl-6,monitoring marker

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