Clin Rheumatol DOI 10.1007/s10067-017-3707-5
ORIGINAL ARTICLE
Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis Jorge Rojas-Serrano 1,2 & Denisse Herrera-Bringas 1 & Diana I. Pérez-Román 1 & Renzo Pérez-Dorame 1 & Heidegger Mateos-Toledo 1 & Mayra Mejía 1
Received: 10 November 2016 / Revised: 10 April 2017 / Accepted: 25 May 2017 # International League of Associations for Rheumatology (ILAR) 2017
Abstract Interstitial lung disease (ILD) is a severe rheumatoid arthritis (RA) manifestation. The worst survival has been associated with usual interstitial pneumonia (UIP) definitive pattern in high-resolution chest tomography (HRCT) scans. Moreover, the use of methotrexate in RA-ILD is controversial. Our aim was to evaluate prognostic factors including methotrexate in an RA-ILD cohort and their association with survival. RA-ILD patients referred for medical evaluation and treatment at a single center were included. At the baseline, pulmonary function tests were carried out and a HRCT was obtained. A radiologist evaluated the ILD tomographic pattern and the extent of lung disease. Patients were considered as receiving methotrexate therapy if this drug was specifically prescribed for the treatment of RA-ILD at the beginning of follow up. Seventy-eight patients were included. UIP definite pattern in HRCT was not associated to worse survival. Variables associated with mortality reflected the severity of lung disease. Treatment with methotrexate was associated with survival (HR 0.13, 95% CI 0.02–0.64); older patients had worse prognosis (HR 1.04, 95% CI 1.003–1.09). After adjusting for confounding variables, methotrexate was strongly associated with survival. Methotrexate treatment during follow up was associated with survival. The severity of lung disease and not the
* Jorge Rojas-Serrano
[email protected]
1
Interstitial Lung Disease and Rheumatology Unit, Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Calzada de Tlalpan 4502, Sección XVI, CP 14080 México DF., Tlalpan, Mexico
2
Programa de Maestría y Doctorado en Ciencias Médicas, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
tomographic pattern is associated with mortality; older patients had worse prognosis. Keywords Interstitial lung disease . Methotrexate . Rheumatoid arthritis . Rheumatoid arthritis-related interstitial lung disease . Usual interstitial pneumonia
Introduction Rheumatoid arthritis-related interstitial lung disease (RAILD) is a severe rheumatoid arthritis systemic manifestation, with a prevalence of 19% in studies using high-resolution computed tomography (HRCT) as gold standard [1]. RAILD is an important cause of mortality in RA [2]. Patients may have a median survival of just 2.6 years after RA-ILD diagnosis [3, 4], and survival is associated with the extent and pattern of ILD, [5–7] with definitive usual interstitial pneumonia (UIP) pattern on HRCT carrying the worst prognosis compared to non-specific interstitial pneumonia (NSIP) pattern on HRCT or indeterminate UIP/NSIP pattern on HRCT [7, 8]. The prognosis of RA has improved dramatically and nowadays, the aim of RA treatment is remission of disease activity, to avoid structural damage and to improve long-term function [9]. Currently, there is solid evidence that medical treatment with methotrexate improves survival [10–12], indeed methotrexate is the cornerstone drug of RA treatment [9]. Nevertheless, in RA-ILD, there is no consensus on treatment and methotrexate and other therapies have not been recommended in the treatment of RA-ILD patients [13]. In this manuscript, we present the survival function of a cohort of RA-ILD patients, treated at a single center with broad experience in the clinical management of ILD. Our aim was to evaluate prognostic factors in an RA-ILD cohort,
Clin Rheumatol
including the tomographic pattern of ILD, the extent of lung disease and methotrexate and their association with survival.
Patients and methods This is a retrospective study of patients with RA according to the ACR 87 or ACR/EULAR 2010 criteria, evaluated and managed at the interstitial lung diseases and rheumatology unit (ILD&RU), at the Instituto Nacional de Enfermedades Respiratorias, Ismael Cosio Villegas. The ILD&RU is a national referral center, located in Mexico City, for the evaluation and management of ILD patients. To be attended at the ILD&RU, patients must be referred by their attending physicians for the evaluation and management of ILD. At the baseline, all patients are evaluated clinically by one of three pulmonologists and a rheumatologist seasoned in the evaluation of patients with ILD. Patients are also evaluated with pulmonary function tests, which include diffusing capacity of the lungs for carbon monoxide (DLCO), spirometry, and plethysmography. We reviewed all medical records of patients attended in the period from March 2004 to December 2015, and included patients with RA-ILD, all with evidence of ILD according to HRCT. We registered the baseline demographic data such as age and sex of the patient, smoking history and other environmental expositional factors, as well as RA disease duration and rheumatoid factor positivity, extra articular manifestations of RA such as sicca syndrome, vasculitis, and rheumatoid nodules. Anti–citrullinated peptide antibody (ACPA) was not available in our institution until 2010 so we have limited data regarding ACPA. Patients were evaluated twice a year by a pulmonologist and twice a year by a rheumatologist. Patients may also have had interim visits according to disease severity.
Patients’ medical treatment We have described elsewhere how patients with RA-ILD are treated at the ILD&RU [14]. Briefly, RA-ILD patients are treated with prednisone or equivalent at a dose of 1 mg/kg/ day for 6 weeks, followed by a taper over 6–8 months to reach a final dose of 10 mg/day. Patients receive a modifier anti rheumatic drug (DMARD) according to the criteria of the attending physicians (the rheumatologist in consensus with the pulmonologists), such as methotrexate, leflunomide, azathioprine, or a combination of such DMARDs. With this combination therapy, an improvement in the forced vital capacity was observed, with the greatest improvement in patients with lowest fibrosis observed in HRCT scans at the baseline evaluation [14]. Patients were considered as being methotrexate-treated patients if this drug was specifically prescribed for the treatment
of RA-ILD in the ILD&RU, as part of the first option of RAILD treatment. Patients started treatment immediately after the evaluation of the ILD&RU medical staff. Furthermore, to be considered as methotrexate-treated patients, they must have continued with this drug throughout censoring time or until time of death. Some patients had periods of non-compliance of the prescribed therapy; these patients were considered as methotrexate-treated patients if the period of non-compliance was no longer than 2 months and they resumed methotrexate therapy until censoring time or death. Patients who began therapy at our center with azathioprine, but later during follow up were changed to methotrexate, were excluded. We also excluded patients who were prescribed with methotrexate at our institution but were changed to other therapy somewhere else. The local institutional review board, named comité de ciencia y bioética en investigación, from the INER reviewed and approved the study protocol (ethics approval number C20-14).
High-resolution computed tomography evaluation HRCT was performed at the baseline evaluation with a 1.0 or 1.5-mm-thick axial section taken at 1 cm intervals throughout the thorax and was reconstructed using a high-spatial frequency algorithm. Between 20 and 25 CT scan images were acquired for each patient. HRCT scans were evaluated by one expert blinded to clinical data (Mejia, M). Each HRCT was graded according the Kazerooni score in its fibrotic component and in the extent of ground glass opacities [15]. HRCT patterns were classified according to the American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of Idiopathic Interstitial Pneumonias [16] as definite UIP pattern. Patients with HRCT characteristics associated with non-specific pneumonia (NSIP) pattern, organized pneumonia (OP) pattern, or lymphoid interstitial pneumonia (LIP) pattern are also reported. Some HRCT scans had overlapping patterns of interstitial pneumonias and were classified as overlapping patterns.
Statistical analysis Time to death was obtained from the medical records and the censoring time was defined as the last medical visit or the end of the study at December 1, 2015. In case of discontinuation of follow up, patients were called to establish survival status. The survival function was estimated with the Kaplan Meier method. The beginning of follow up was defined as the time that patients began medical treatment at the ILD&RU. Differences in the survival function in the evaluated groups were compared with the log rank test. A univariate Cox regression analysis was carried out to estimate the hazard ratio (HR) with a
Clin Rheumatol
95% confidence interval (CI) of the independent variables evaluated, to assess its association with time to death (dependent variable). To adjust for confounding, a multivariable Cox regression model was build including all variables that in the univariable analysis had a P value
