Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests

OBJECTIVE: Methotrexate has a well-recognized side-effect of acute hypersensitivity pneumonitis. There is concern about whether chronic pulmonary toxicity can occur with methotrexate treatment. Our objective was to compare chest high-resolution computed tomography (HRCT) findings and serial pulmonary function tests in rheumatoid arthritis (RA) patients on methotrexate with findings for a control group of patients with RA who were not being treated with methotrexate. METHODS: Study patients had an initial chest radiograph, full pulmonary function tests and chest HRCT. Pulmonary function tests were then performed regularly over a 2-yr period. RESULTS: Fifty-five RA patients on methotrexate and 73 control patients with RA were enrolled for the study. Mean dose of methotrexate was 10.7 mg/week (S.D. 2.5 mg/week) and mean duration of treatment at entry into the study was 30 (20) months. Twenty per cent of patients with RA treated with methotrexate had pulmonary fibrosis (PF) on initial HRCT compared with 23% in the control group. When the patients with and without PF were compared, there was no statistical difference in the duration (mean difference -4.18 months, P=0.237) or dose (mean difference -0.8 mg/week P=0.52) of methotrexate therapy. Mean changes after 2 yr in forced expiratory volume, forced vital capacity, diffusion capacity for carbon monoxide and residual volumes were not different in the methotrexate group compared with the control group. CONCLUSION: There is no evidence to suggest clinically, from HRCT assessment or serial pulmonary function tests, that low-dose methotrexate is associated with chronic interstitial lung disease.     

Correlation of chest roentgenograms with pulmonary function and bronchoalveolar lavage in interstitial lung disease

We used the ILO classification for occupational lung disease to determine whether there was any correlation between the type and/or severity of pulmonary infiltration on chest roentgenograms and either pulmonary function tests or the types of inflammatory cells present in BAL fluid in patients with interstitial lung disease. Of the 62 patients evaluated (27 with sarcoidosis, 18 with IPF, and 17 with a CV disease and lung involvement), 49 had irregular linear opacities and 13 had normal chest x-rays. There were no significant correlations between the types of cells present in BAL fluid and the various categories of infiltrate or profusion of the infiltrates within each disease group. In patients with sarcoidosis, more extensive infiltration (profusion) was associated with lower FEV, (p less than 0.01). In patients with IPE, linear opacity type, profusion, and the presence or absence of honeycombing were not related to the severity of pulmonary function abnormalities. We conclude that the ILO classification for analysis of chest roentgenograms can be applied to patients with interstitial lung disease not associated with an occupational exposure and that this approach is useful, especially for communication. However, these data provide no information regarding the inflammatory process in the lung and limited information regarding abnormalities in pulmonary function.     

High‐resolution CT pulmonary findings in idiopathic ankylosing spondylitis: correlations with clinical assessment,plain chest X‐ray and pulmonary function tests

Aim: The aim of this study is to evaluate pulmonary manifestations of ankylosing spondylitis on high‐resolution computed tomography (CT) scan and to correlate these findings with clinical assessment, plain chest X‐ray and pulmonary function tests. Methods: The study comprised 32 patients (26 males [81.3%], 6 females [18.8%]) who met the modified New York criteria for diagnosis of idiopathic ankylosing spondylitis; in addition 10 normal subjects not complaining of any respiratory symptoms and matched for age and sex served as a control group. All patients were subjected to full history‐taking, full clinical examination, chest X‐ray, high‐resolution computed tomography (HRCT) chest and pulmonary function tests. Results: The abnormalities on HRCT included evidence of apical lung fibrosis in two patients (6.3%), interstitial lung disease in six (18.8%), minor interstitial abnormalities in eight (25%), bronchiectasis in four (12.5%), lung nodules in three (6.3%) and pleural thickening in five patients (6.3%). Nine patients (28.1%) showed negative findings by chest X‐ray which revealed positive findings on HRCT. Five patients (15.6%) showed positive findings on both HRCT and plain chest X‐ray, and 18 patients (56.3%) showed no findings on both HRCT and chest X‐ray. Four patients (12.5%) showed normal pulmonary function tests, 25 (78.13%) showed restrictive pattern, 17 (53.13%) had obstructive pattern and 26 patients (81.3%) had diffusion defects. Conclsuion: The identification of non‐apical minor basal interstitial lung disease in our study which was previously reported in other studies, raises a possible association to ankylosing spondylitis. High‐resolution CT scan is more sensitive than chest X‐rays in detection of such minor interstitial lung disease (ILD), and other parenchymal lung changes.     

Long-term outcome of idiopathic pulmonary hemosiderosis in children

We retrospectively analyzed the long-term outcome of idiopathic pulmonary hemosiderosis (IPH) in 15 children. IPH started at a mean age of 5 years, and the mean duration of follow-up was 17.2 years (range, 10-36 yr). Four patients developed immune disorders, 3 cases of rheumatoid polyarthritis or rheumatoid polyarthritis-like diseases and 1 case of celiac disease. Respiratory outcome showed that 3 patients had severe symptoms: 2 patients developed severe pulmonary fibrosis resulting in major chronic respiratory insufficiency, and 1 patient had severe asthma. Twelve patients (80%) had mild or no respiratory problems and were able to lead a normal life. According to chest X-ray and pulmonary function test data, 4 patients had normal chest X-ray and no evidence of restrictive syndrome, 6 patients had an interstitial pattern on chest X-ray and evidence of restrictive pattern, 1 patient had an interstitial pattern but normal lung function, and 1 patient had a normal chest X-ray but evidence of mixed obstructive and restrictive pattern. Our results show that long-term survival is possible in patients with IPH. Factors of poor prognosis seem to be the presence of antineutrophil cytoplasm antibodies (ANCA) or other autoantibodies. No other clinical or biological predictive factors for prolonged survival were found.     

Interstitial lung disease in polymyositis and dermatomyositis: analysis of six cases and review of the literature.

Interstitial pneumonitis may be the presenting manifestation of polymyositis-dermatomyositis, or may occur later in the evolution of the disease. The clinical picture is characterized by non-productive cough, dyspnea and hypoxemia. The chest radiograph demonstrates interstitial infiltrates with predilection for the lung bases, often with an alveolar pattern in addition. The histopathologic features are those of organizing and interstitial pneumonitis and pleuritis, with variable fibrosis. In the present series, the patients with mixed alveolar and interstitial infiltrates on chest radiograph and organizing pneumonia and bronchiolitis obliterans in addition to interstitial pneumonitis. In one patient evolution from pulmonary inflammation to interstitial fibrosis was demonstrated. The etiology of primary lung disease in PM-DM is not known, but cell-mediated autoimmunity to an unidentified component of lung tissue is suggested. Including the present series, 50 percent of patients have responded favorably to corticosteroids with decreased dyspnea, clearing of the chest radiograph and improved pulmonary function tests.     

51例特发性肺间质纤维化的临床研究

目的 总结特发性肺间质纤维化（IPF）的临床特点。方法 回顾我院51例IPF的临床资料。结果 我院IPF构成比呈上升趋势。临床以上进行性呼吸困难伴干咳、肺部听诊有爆裂音和杵状指为突出表现,胸片／胸部HRCT显示双下肺外带弥漫网状结节影,肺功能改变有限制性通气功能和弥散障碍,血气分析提示低氧血症Ⅰ型呼吸衰竭。4例肺组织活检病理诊断为普通型间质性肺炎（UIP）。本组病例中约1／5患于住院期间死亡,中位存活时间为18个月。结论 IPF的诊断依赖于临床表现、胸片／胸部HRCT、肺功能及血气分析的特征性表现,并除外其它ILD,确诊还需肺活检示UIP病变。     

HIGH DEFINITION COMPUTED TOMOGRAPHY IN RHEUMATOID ARTHRITIS ASSOCIATED PULMONARY DISEASE

Eighteen patients with rheumatoid arthritis (American RheumatismAssociation definition) were selected consecutively from a rheumatologyclinic. All patients were examined with plain chest radiographs,thin slice computed tomography, and pulmonary function tests.Four patients with normal chest radiographs, and normal pulmonaryfunction tests were found to have normal CT scans. In ten patients,abnormalities consistent with rheumatoid associated lung diseasewere demonstrated, including changes of interstitial fibrosisin seven cases. This fibrosis had a predominantly peripheralpattern on CT scan. Computed tomography was found to be moresensitive than plain radiographs in detecting abnormalitieshowever, all the patients in this series with CT lung changeshad abnormalities on pulmonary function testing. KEY WORDS: Computed tomography, Rheumatoid arthritis, Interstitial pulmonary fibrosis     

Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis

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 tomographic pattern is associated with mortality; older patients had worse prognosis.     

Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature

INTRODUCTION: Smoking can cause a variety of pulmonary interstitial diseases. Pulmonary fibrosis has traditionally been considered a non-smoking-related disease. Recently, however, evidence of smoking-induced fibrosis has emerged. SUBJECTS AND METHODS: A group of eight patients from the pulmonary clinic in Rabin Medical Center with a combine presentation of fibrosis and emphysema was identified retrospectively. All patients underwent chest computed tomography and pulmonary function tests. One patient underwent lung-heart transplantation and a complete review of his lung pathology was obtained. Transbronchial biopsy was performed in 3 additional patients and echocardiography was performed to evaluate the pulmonary vasculature. RESULTS: Upper-lobe emphysema with bulluos changes was found in all patients. In addition, a basal interstitial process was recognized, ranging from ground glass opacities to severe pulmonary fibrosis, with honeycombing. The radiological findings matched the pathological results of combined emphysema and usual interstitial pneumonia. Pulmonary function tests were also in accord, showing severe hypoxemia with mild obstruction, normal-to-mildly reduced lung volumes and a severe decrease in diffusion capacity. Most of the patients had moderate-to-severe pulmonary hypertension as well as diffuse coronary artery disease. CONCLUSION: Our findings are in line with emerging evidence that the spectrum of interstitial damage caused by smoke includes not only Langerhans cell hystiocytosis, respiratory bronchiolitis or desquamative interstitial pneumonia but also advanced usual interstitial pneumonitis as well. We believe that in some patients smoking plays a destructive role by a variety of mechanisms and can cause emphysema, lung fibrosis as well as pulmonary vasculopathy and hypertension. Future studies are needed to define the genetics and pathophysiology of this uncommonly reported clinical syndrome.     

Respiratory bronchiolitis causing interstitial lung disease. A clinicopathologic study of six cases

We describe 6 patients with chronic interstitial lung disease in whom open lung biopsies showed respiratory bronchiolitis. The patients ranged from 28 to 46 yr of age (mean, 36 yr) and included 5 men and 1 woman. All were heavy cigarette smokers. Five had respiratory symptoms, most commonly cough and dyspnea. Diffuse interstitial infiltrates were seen on chest radiographs in 5 and bibasilar atelectasis in 1. Pulmonary function tests showed mild to moderate restriction in 4 and decreased diffusing capacity in 4. The initial pathologic interpretation in 3 patients suggested a variant of idiopathic pulmonary fibrosis, and these patients received corticosteroids because of this diagnosis. All patients have remained stable or improved after a mean follow-up of 3.2 yr. Respiratory bronchiolitis should be recognized as an uncommon cause of chronic interstitial lung disease. It must be separated from the other diseases in this category because of marked differences in treatment and prognosis.     

Lack of evidence for an association between neurofibromatosis and pulmonary fibrosis

STUDY OBJECTIVES: To reassess the association between neurofibromatosis and pulmonary fibrosis. DESIGN: Retrospective single-center study with analysis of patients' chest radiographs, CT scans, and medical records. SETTING: Tertiary care, referral medical center. PATIENTS: One hundred fifty-six adult patients with neurofibromatosis seen over a 6-year period between 1997 and 2002. RESULTS: A review of chest radiographs revealed abnormal findings in 70 patients (44.9%). The most common radiographic abnormalities were extrapulmonary nodules or masses seen in 22 patients (14.1%), followed by skeletal abnormalities in 16 patients (10.3%). Bilateral interstitial infiltrates were noted in only three patients (1.9%), all of whom had potential causes other than neurofibromatosis for their lung infiltrates, including smoking-related interstitial lung disease, rheumatoid lung disease, recurrent pneumonias, and a history of ARDS. CT scans were available in two of these patients and revealed nonspecific patterns of abnormalities with no honeycombing. Six patients had bullae or cystic airspaces demonstrated on chest radiography or CT scan; all of these findings occurred in the context of smoking-related emphysema. Combined together, bilateral interstitial lung infiltrates or cystic airspaces were demonstrated in five patients (3.2%) by chest radiography, and in eight patients (5.1%) by chest radiography or CT scanning; one patient had both findings on the CT scan. CONCLUSIONS: We found little evidence to support an association between neurofibromatosis and pulmonary fibrosis or any other form of parenchymal lung disease. Interstitial lung disease and bullae described in association with neurofibromatosis in previous reports may have, in part, represented smoking-induced manifestations.     

Pulmonary interstitial fibrosis following near-drowning and exposure to short-term high oxygen concentrations.

Following near-drowning in fresh water, a 19-year-old man experienced severe adult respiratory distress syndrome, necessitating ventilatory support with positive end-expiratory pressure and high oxygen concentrations. Post-extubation, his course was highlighted by persistent hypoxemia and interrupted by a lung abscess which responded promptly to antibiotics. Pulmonary function tests were consistent with severe restrictive disease and chest radiograph revealed persistent bilateral alveolar and interstitial infiltrates. An open lung biopsy on the 26th hospital day showed interstitial fibrosis. Over the ensuing two months, the chest radiograph and pulmonary function tests returned towards normal. We attribute the pulmonary fibrosis to incomplete resolution of the alveolar interstitial pathology secondary to the near-drowning and exposure to high oxygen mixtures.     

Algorithm for diagnosing pulmonary fibrosis in tropical countries

An algorithm for diagnosis of pulmonary fibrosis in the tropical countries has been developed on the basis of the common causes of fibrosis, and the availability and feasibility of different diagnostic techniques in those countries. First, it is important to exclude common diseases such as the atypical or occult forms of bronchiectasis, pulmonary tuberculosis, and chronic bronchitis, which often overshadow interstitial pulmonary fibrosis. A good history and physical examination supplemented with chest radiography and simple lung function tests are generally enough to narrow down the list of causes of diffuse lung disease to interstitial pulmonary fibrosis. The real difficulty lies in identifying the idiopathic or "lone" forms from the secondary forms of pulmonary fibrosis. High-resolution CT is helpful in a large number of patients. Transbronchial lung biopsy is performed in a select population of patients. Open surgical or thoracoscopy guided biopsy is the gold standard, but is rarely required.     

强直性脊柱炎患者肺部表现的高分辨CT特征及临床

目的研究强直性脊柱炎(anky losing spondy litis,A S)患者肺部高分辨CT(HRCT)表现及其临床特征。方法43例确诊A S患者分别进行肺HRCT、肺部X线平片、肺功能检查,并结合临床特征对比分析。结果43例A S患者中28例(65%)发现有肺HRCT异常,最常见的表现为非特异性间质改变20/43(46.5%),4例(9.3%)为间质性肺病(ILD),3例(7.0%)为上叶纤维化,每例患者可有1种以上病变表现。肺功能有16/43(23.3%)表现轻度限制性通气功能障碍,无DLCO下降。肺HRCT异常与不同病程、骶髂关节炎严重度、肺功能均无统计学相关。结论A S病人的肺部表现不少见,通过肺HRCT可以早期发现。     

Bronchoalveolar lavage--a sensitive tool for early diagnosis of pulmonary involvement in rheumatoid arthritis

Bronchoalveolar lavage (BAL) was performed to assess the nature of pulmonary involvement in 12 asymptomatic nonsmoking patients with rheumatoid arthritis (RA). All 12 patients had normal lung function tests, including diffuse capacity for carbon monoxide and normal blood gases. Four patients (33%) had mild basilar interstitial changes on chest radiographs. In these 4 patients an elevated lymphocytic count in BAL fluid (30.7 +/- 8.3%) was found, as compared to the 8 patients with normal chest roentgenograms (7.2 +/- 1.9%; p less than 0.001). We suggest that BAL may be used as a sensitive tool for early diagnosis of pulmonary involvement in patients with RA.     

Pulmonary fibrosis in rheumatoid arthritis: a review of clinical features and therapy

During the past four decades there has been a growing appreciation of the frequency of pulmonary abnormalities associated with RA. Approximately 30% to 40% of patients with RA demonstrate either radiographic or pulmonary function abnormalities indicative of interstitial fibrosis or restrictive lung disease. The severity of pulmonary fibrosis is not associated with rheumatologic symptoms or the duration of the associated RA, nor is there any clear relation to the extraarticular features of RA or serologic findings. Survival rates in patients with coexisting RA and pulmonary fibrosis are similar to those of patients with idiopathic pulmonary fibrosis. However, the spectrum of disease activity is quite variable. The majority of patients with progressive pulmonary symptomatology, when treated with corticosteroids, will have equivocal results. Some patients appear to respond to immunosuppressive or cytotoxic medications. The role of macrophages may be central to the injury to lung. Recent studies suggest a potential treatment role for cyclosporine, which may be able to interrupt lymphocyte-stimulated macrophage activation, and thus, fibroblast-mediated fibrosis in patients with pulmonary interstitial fibrosis. Bronchoalveolar lavage studies may delineate subgroups of patients who are more likely to respond to immunosuppressive agents, especially when treatment is started early.     

类风湿性关节炎并发肺间质纤维化23例临床分析

目的探讨类风湿性关节炎（RA）并发肺间质纤维化的发生情况、临床特点、肺功能、影像学检查及相关因素。方法分析我院146例住院RA患者的临床资料,包括类风湿性因子（RF）、血气分析、胸部x线、肺高分辨CT（HRCT）、肺功能检查等,分析RA并发肺间质纤维化患者的特点。结果本组RA患者中并发肺间质纤维化23例;其中,RF强阳性17例,ESR增高21例,CRP增高18例,血小板增高14例,低氧血症17例,经过适当的治疗,病情一般能够控制,有2例死亡,占8．7％,死亡原因为I型呼吸衰竭。结论患者呼吸系统病患出现在关节炎之后,肺间质纤维化的发生与重症类风湿关节炎有关,但病情较轻,RA患者应尽早做肺HRCT及肺功能检查,尤其是RF强阳性的RA患者。     

Clinical characteristics affecting survival in patients with rheumatoid arthritis undergoing cervical spine surgery: a controlled study

A controlled study of the clinical characteristics affecting survival in patients with rheumatoid arthritis (RA) with cervical spine involvement treated surgically demonstrated a strong association between disease severity, the frequency of severe extraarticular manifestations, especially interstitial lung disease, and a decreased probability of survival. These probabilities at 1 and 5 years postoperatively were 74 and 54%, respectively. Death resulted most often from infection or comorbid conditions. All surgery patients with interstitial lung disease died within 28 months postoperatively. In patients with RA undergoing cervical spine surgery, fatality rates appear to be increased in patients with severe extraarticular manifestations, especially interstitial lung disease.     

Interstitial lung disease in polymyositis and dermatomyositis

PURPOSE OF REVIEW: The purpose of this review is to discuss current concepts regarding management of interstitial lung disease in polymyositis and dermatomyositis. RECENT FINDINGS: Interstitial lung disease seems to be a more frequent manifestation in patients with polymyositis and dermatomyositis than previously reported. Modern technology, including high-resolution computerized tomography in combination with pulmonary function tests provides sensitive tools to detect early signs of interstitial lung disease. By systematic use of these investigations in newly diagnosed polymyositis and dermatomyositis, up to two thirds of patients were discovered to have signs of interstitial lung disease in a recent study. Clinical symptoms such as cough and dyspnea may not be sensitive enough to detect interstitial lung disease. Awareness of this complication in patients with myositis is important, because early diagnosis and management of interstitial lung disease may prevent development of chronic pulmonary fibrosis and thereby prolong patient survival and improve quality of life. Treatment recommendations of interstitial lung disease in polymyositis and dermatomyositis are still limited by absence of controlled trials and could only be based on experiences from small case series and case reports. At least some patients with interstitial lung disease improve with immunosuppressive treatment, but data are limited, and longitudinal studies are needed. SUMMARY: Interstitial lung disease seems to be a common manifestation in patients with polymyositis and dermatomyositis already at diagnosis of the muscle disease. When present, interstitial lung disease has a major effect on morbidity and mortality and should be looked for in these patients using high-resolution computerized tomography and pulmonary function tests early in the disease course, because immunosuppressive treatment may change the course of the lung disease.     

Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low-dose methotrexate.

OBJECTIVES: To analyse pulmonary toxicity in psoriatic arthritis patients treated with weekly low-dose methotrexate. METHODS: A transversal study was carried out to analyse the findings on chest x-rays and high resolution computed tomography, and the results of pulmonary function tests in 27 Caucasian psoriatic arthritis patients treated with weekly low-dose methotrexate. None of them had previous recognized interstitial lung disease. RESULTS: The median age of the patient cohort was 50 years (range 24-70 years) and the sex ratio was 20M/7F. 17 patients had previously used other disease-modifying antirheumatic drugs. The mean weekly dose of methotrexate was 8.46 mg (range 5-15 mg), the average treatment period was 52 months (range 3-240 months), and the median cumulative dose was 2241 mg (range 300-6520 mg). High resolution computed tomography failed to show alveolar or interstitial involvement in any patient. Diffusing lung capacity for carbon monoxide was mildly altered only in 2 cases. Pulmonary function tests did not show differences between patients with and without recognized risk factors for developing methotrexate-associated lung toxicity identified in rheumatoid arthritis patients (old age, diabetes, hypoalbuminemia, previous use of disease modifying antirheumatic drugs). CONCLUSION: In this cohort of 27 psoriatic arthritis patients methotrexate was not associated with pulmonary fibrosis evaluated by means of sensitive imaging findings and pulmonary function tests.