Abstract and Introduction
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.
Introduction
This article reviews the major biomarkers in serum, bronchoalveolar lavage fluid (BALF), and other sources, with diagnostic and prognostic value in interstitial lung disease (ILD) associated with connective tissue disease (CTD). ILD often complicates the course of CTD.[1–4] The heterogeneous group of CTDs includes rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), primary Sjögren syndrome (SS), mixed CTD (MCTD), and undifferentiated CTD (UCTD).[4,5] Although the majority of patients with CTD-ILD experience stable or slowly progressive ILD, a small yet significant group exhibits a more severe and progressive course.[4] The paradigmatic example of this interstitial lung involvement in CTDs is SSc, where postmortem examination gives evidence that nearly every patient develops pulmonary fibrosis, even though of very different extent. High-resolution computed tomography (HRCT) shows interstitial lung involvement in about two-thirds of the cases.[2] Severe pulmonary fibrosis is the leading cause of death in SSc, as demonstrated by Steen and Medsger in the Pittsburgh cohort.[6] EUSTAR database recently confirmed these data.[7] In PM/DM, ILD is the most common pulmonary manifestation and its presence is associated with increased morbidity and mortality. In RA, SLE, and SS, clinically significant ILD is less common and estimated to occur in approximately 10 to 30% of patients.[8] Beside these considerations, a consistent proportion of patients with idiopathic ILD presents with positive autoantibodies reflective of an autoimmune process.[9] Therefore, it is important to screen routinely ILD patients without clinical evidence of CTD for autoantibodies.[1,3,9,10]
Considering all the aforementioned aspects, the discovery and validation of biomarkers for the diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials on CTD-ILD patients could be of great clinical importance. Even if a single less invasive, reliable, and cheap biomarker would be optimal, the future will more likely offer a panel of disease-specific biomarkers. One example of that is the multi-biomarker disease activity score for RA,[11,12] a quantitative serum-based assay based on 12 biomarkers consistently associated with clinical disease activity levels and damage progression over time as measured by radiography.[11]
Many attempts have been made to find out a candidate biomarker for CTD-related ILDs, but most data come from retrospective single-center studies. The final step for biomarkers' validation implicates prospective well-designed multicenter studies in heterogeneous populations. Factors able to influence the levels of these biomarkers, such as covariates and genetic assets, and the dependence on baseline disease severity have to be taken into account as covariates.[13] Specific single nucleotide polymorphisms (SNPs), for example, can cause inter-ethnic and inter-individual variability in serum concentrations of biomarkers: well-known examples are angiotensin-converting enzyme II polymorphisms in sarcoidosis[14] and Krebs von den Lungen-6 (KL-6) mucin 1 (MUC 1) in fibrotic lung diseases.[15–17] Whether microRNAs (miRNAs) may play a clinical role as biomarkers in the future remains to be proven.
This review will focus on noninvasive biomarkers. In comparison to BALF or lung function, peripheral blood biomarkers can be easily obtained and measured longitudinally, and thus have the greatest potential to be applied in the clinical routine.
Semin Respir Crit Care Med. 2014;35(1):181-200. © 2014 Thieme Medical Publishers
