Rheumatol Int DOI 10.1007/s00296-016-3438-y

Rheumatology INTERNATIONAL

BIOMARKERS

Computed tomography of pulmonary changes in rheumatoid arthritis: carcinoembryonic antigen (CEA) as a marker of airway disease Milene Caroline Koch1 · Ivânio Alves Pereira2 · Luiz Felipe Souza Nobre3 · Fabricio Souza Neves3,4 

Received: 13 October 2015 / Accepted: 2 February 2016 © Springer-Verlag Berlin Heidelberg 2016

Abstract  Rheumatoid arthritis (RA) classically affects the joints, but can present extra-articular manifestations, including pulmonary disease. The present study aimed to identify possible risk factors or laboratory markers for lung involvement in RA, particularly the presence of rheumatoid factor (RF), anti-citrullinated peptide antibodies (ACPA), and tumor markers, by correlating them with changes observed on chest high-resolution computerized tomography (HRCT). This cross-sectional study involved RA patients who were examined and questioned by a specialist physician and later subjected to chest HRCT and blood collection for measurement of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), ACPA (anti-vimentin and/or anti-CCP3), and the tumor markers carcinoembryonic antigen (CEA), CA 125, CA 15-3, and CA 19-9. A total of 96 patients underwent chest HRCT. The most frequent findings were bronchial thickening (27/28.1 %) and bronchiectasis (25/26 %). RF was present in 63.2 % of patients (55/87), and ACPA (antivimentin or anti-CCP3) was present in 72.7 % of patients (64/88). CEA levels were high in 14 non-smokers (37.8 %) and 23 smokers (62.2 %). CA-19-9 levels were high in 6 of 86 patients (7.0 %), CA 15-3 levels were high in 3 of

* Fabricio Souza Neves [email protected] 1

Radiology Unit, Hospital Universitario Polydoro Ernani de São Thiago, Universidade Federal de Santa Catarina (HUUFSC), Florianópolis, Brazil

2

Rheumatology Unit, HU-UFSC, Florianópolis, Brazil

3

Internal Medicine Department, UFSC, Florianópolis, Brazil

4

Departamento de Clínica Médica, Hospital Universitário, Universidade Federal de Santa Catarina, 3 Andar, Trindade, Florianópolis, SC 88040‑900, Brazil





85 patients (3.5 %), and CA 125 levels were high in 4 of 75 patients (5.3 %). Multivariate analysis indicated a statistically significant association between high CEA levels and the presence of airway changes in patients with RA (p  = 0.048). CEA can serve as a predictor of lung disease in RA and can help identify individuals who require more detailed examination for the presence of respiratory disorders. Keywords  Rheumatoid arthritis · Computed tomography · Pulmonary changes · Anti-citrullinated peptide antibodies · Tumor markers

Introduction Rheumatoid arthritis (RA) is the most common autoimmune disease of connective tissue; it affects approximately 0.5–1.0 % of the population, predominantly women, with a ratio of 2–3 women for every man affected. It classically manifests as destructive chronic symmetric polyarthritis. Most RA patients have circulating autoantibodies, including rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Among the latter, anti-cyclic citrullinated peptide antibody (anti-CCP) and antimutated citrullinated vimentin (anti-MCV) [1] are frequently present In addition to the articular manifestations of RA, approximately 30–40 % of RA patients present extra-articular systemic inflammatory manifestations during the course of the disease, and pulmonary involvement is common [2]. RA can affect all anatomical compartments of the lung (airways, interstitium, vasculature, and pleura). According to some authors, airway involvement is the most prevalent lung manifestation of RA, whereas other authors report a higher prevalence of interstitial lung disease (ILD) [3].

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Pulmonary involvement in RA is associated with increased morbidity and mortality [4, 5]. The frequency of pulmonary involvement in RA is variable, and it depends on the diagnostic method used. Highresolution computed tomography (HRCT) has proven useful in the detection and characterization of pulmonary morphological changes in RA, and it has been shown to reflect pathological findings [6]. Bilgici et al. [7] evaluated 52 RA patients using HRCT and observed lung abnormalities in 67.3 % of cases. Skare et al. [8] observed similar changes in 55 % of RA patients; the most common manifestations were ground-glass opacity, parenchymal bands, traction bronchiectasis, and honeycombing [8]. Other tomographic studies of RA reported a prevalence of ILD ranging from 19 to 67 % [7, 9, 10] and bronchial dilation of up to 41.3 %, as reported by Mori et al. [11]. Several risk factors for lung disease in RA have been reported. These include genetic factors, smoking, duration and severity of disease, and the presence and concentration of autoantibodies, including RF and ACPA. Conflicting reports on the roles of many of these factors in RA are found in the literature, resulting in a continued search for clinical or laboratory predictors of pulmonary involvement in RA. In idiopathic pulmonary fibrosis and pneumonitis secondary to various diseases of the connective tissue, an increase in the traditional tumor markers CA 19-9 and CA 15-3 has been demonstrated [12, 13]. In addition, an increase in the concentration of tumor markers in RA without correlation with cancer has been observed [14]. Wang et al. [15] in a recent study of clinical features of RA demonstrated an increase in CA 15-3 e CA 125 in patients with ILD. The present study aimed to identify possible risk factors or laboratory markers for pulmonary disease in RA and to correlate clinical and laboratory data, particularly the presence of RF, ACPA, and tumor markers, with changes observed on HRCT. Second, this study aimed to describe the main clinical, laboratory, and tomographic findings of RA patients with pulmonary involvement and compare them with results reported in the literature.

Materials and methods Study design and population A cross-sectional study of RA patients was conducted between September 2012 and January 2014. The study was designed and conducted according to the RA diagnosis criteria established by the ACR/EULAR collaboration in 2010 [15]. The patients evaluated were treated consecutively in a specialized clinic of the Hospital Universitario Polydoro Ernani de São Thiago (HU) of the Universidade Federal de

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Rheumatol Int

Santa Catarina (UFSC) and later underwent laboratory testing and HRCT. Patients with chronic obstructive pulmonary disease (COPD) or pneumoconiosis or a previous history of tuberculosis, cancer, thoracic surgery, or irradiation were excluded. This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by our institution’s Research Ethics Committee under protocol No. 118.891. A free and informed consent form was signed by all participants. Clinical and laboratory data Patients were examined and questioned by a rheumatologist (I.A.P. or F.S.N.) regarding their age, RA duration, RA activity (Disease Activity Score of 28 joints—DAS28) [16], smoking, pulmonary symptoms, extra-articular manifestations (presence of rheumatoid nodules, vasculitis, or secondary Sjögren’s syndrome), and former and current use of medications. Using DAS28 score, the patients with an index ≤2.6 were considered in remission, those with an index >2.6 and ≤3.2 were considered to have low disease activity, those with a score >3.2 and ≤5.1 were considered to have moderate disease activity, and those with a score ≥5.1 were considered to have high disease activity [16]. For laboratory tests, blood samples were collected by venipuncture and the following parameters were analyzed: C-reactive protein (CRP) using nephelometry (Behring 100; Behring, Marburg, Germany; normal values less than 5 mg/L); erythrocyte sedimentation rate (ESR) using the Westergren method adjusted for gender and age [17]; rheumatoid factor (RF) using an ELISA kit (QUANTA Lite®, San Diego, CA, USA) with a sensitivity of 91.6 % and a specificity of 91.3 % and considered positive when the obtained value was >15 IU/mL and strongly positive when the obtained value was >113 IU/mL; ACPA (antiMCV using an ELISA kit, Orgentec®, Mainz, Germany, with a sensitivity of 81.2 % and a specificity of 98 % and/ or anti-CCP3 IgG using an ELISA kit—QUANTA Lite® with a sensitivity of 74 % and a specificity of 96 %) both considered positive when the obtained value was >20 U and strongly positive when the obtained value was >60 U; and the tumor markers carcinoembryonic antigen (CEA), CA 125, CA 15-3, and CA 19-9 using a chemiluminescence method by IMMULITE 2000® equipment (Siemens, Berlin, Germany). The overall reference value for CEA was 2.5 ng/mL; CEA corrected for gender and smoking presented normal limits of

Computed tomography of pulmonary changes in rheumatoid arthritis: carcinoembryonic antigen (CEA) as a marker of airway disease.

Rheumatoid arthritis (RA) classically affects the joints, but can present extra-articular manifestations, including pulmonary disease. The present stu...
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