Biomarkers in Connective Tissue Disease-Associated Interstitial Lung Disease

Abstract

This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies.

Monitoring of Lung Involvement in Rheumatologic Disease

“…Biomarkers of various kinds have an important theoretical role in this regard, both in initial evaluation and in monitoring. However, candidate serum, bronchoalveolar lavage and imaging biomarkers in CTD-ILD have mostly been studied only at a single point in time [34], including surfactant protein A and B (SP-A, SP-B) [35,36,37], Krebs von den Lungen (KL)-6 [35,38,39,40,41], other lung epithelium-derived proteins, as well as chemokines, cytokines, matrix metalloproteinases and interleukins [34,42,43,44,45,46,47,48]. Serial biomarker trends have the potential to refine prognostic evaluation with exciting possibilities with the introduction of a therapy, and short-term biomarker changes might provide invaluable information on longer-term efficacy.…”

Biomarkers in the Management of Difficult Asthma

“…The CC16/IL-8 ratio measured in sputum is a potentially valuable biomarker for non-invasive assessment of small airway remodeling in smokers as there was a striking negative correlation between CC16/IL-8 levels and whole airway thickness at morphometry [116]. Promising biomarkers in lung fibrosis are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]) [117]. All these markers deserve to be considered and validated in remodeled asthma.…”

Serum Krebs Von Den Lungen-6 as a Biomarker for Early Detection of Bronchiolitis Obliterans Syndrome in Children Undergoing Allogeneic Stem Cell Transplantation

“…This disruption, along with potential SCT-related lung injury because of chemotherapy and/or radiation, infections in the early post-SCT period, and later donor lymphocytes infiltrating the host's lungs because of infections or as part of acute or chronic GVHD, may together contribute to the sequence of events leading to the damaging and fibrotic result demonstrated at BOS diagnosis. KL-6 as a serum biomarker has been shown to be an important diagnostic and prognostic factor in many pediatric and adult interstitial lung diseases, including connective tissue diseases associated with interstitial lung disease where there is auto-immune mediated inflammation [25][26][27][28]. Lung inflammation post-SCT is somewhat similar; however, it is an allo-immune rather than auto-immune event.…”