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Comprehensive review of current diagnostic and treatment approaches to interstitial lung disease associated with rheumatoid arthritis.

Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease manifested by articular and extra-articular features. Pulmonary involvement is a common extra-articular manifestation occurring roughly in approximately 60%-80% of patients with RA. The pulmonary involvement in RA may vary, including interstitial lung disease (ILD), pleural disease, rheumatoid nodules, bronchiectasis, and vasculitis. ILD is one particular type of pulmonary involvement associated with significant morbidity and mortality (1-3). The management of RA-associated ILD (RA-ILD) depends on patients' clinical, functional, and radiologic findings. Several therapeutic agents have been suggested in the literature, but the optimal treatment has not been determined (4-6).

Risk factors

The mechanism behind ILD in RA is poorly understood, but there are certain risk factors believed to play an important role. Smoking is believed to play the major role, but male sex, high titers of the rheumatoid factor, and elevated anticyclic citrullinated protein antibodies are the prevailing factors.

Clinical features and diagnostic tools

In 2002, the American Thoracic Society/European Respiratory Society classification of acute and chronic parenchymal lung diseases (7) has also been adopted for the identification of ILD (Table 1). The clinical manifestations of RA-related ILD are dyspnea and dry cough. However, some patients may be asymptomatic, especially in early stages. Pleuritic chest pain, fever, hemoptysis, and tachypnea are other symptoms of the disease. The most frequent finding on physical examination were crepitant rallies in bilateral baselines in pulmonary auscultation. In the majority of patients, the pulmonary function test (PFT) has a low force vital capacity (FVC), low total lung capacity, low/normal carbon monoxide diffusion capacity (DLCO), and restrictive respiratory pattern with exercise or resting hypoxemia (8). Since the earliest functional disorder in patients with ILD is a DLCO decrease, DLCO is one of the important tests for the early diagnosis of ILD. FVC may not be affected until the late stage. The PFTs may also reveal a normal or high force vital capacity at 1 second/FVC (restrictive type lung disease finding) ratio. DLCO and FVC are the most commonly and most important used diagnostic markers in ILD. Generally, changes of 10% in FVC and 15% in DLCO are considered to be significant (8). X-ray has a low sensitivity in the ILD detection, and X-ray findings may be normal in early stages. Reticular and small nodular opacities can be seen in lower lung zones on plain chest X-ray. High-resolution computed tomography (HRCT) has been accepted as the gold standard noninvasive imaging method in the diagnosis of ILD in patients with RA (9). HRCT results were consistent with the results of open lung biopsy (10).

The most common HRCT findings in patients with RA-ILD are usual interstitial pneumonia (UIP) (Figure 1), nonspecific interstitial pneumonia (NSIP) (Figure 2), lymphocytic interstitial pneumonia, organizing pneumonia, diffuse alveolar damage, respiratory bronchiolitis, and desquamative interstitial pneumonia (11). Since there may be some alterations in bronchoalveolar lavage (BAL) fluid in the absence of ILD, BAL is not routinely used as a diagnostic tool to demonstrate the presence of ILD in RA. Neutrophil and macrophage predominance is a characteristic feature of RA-ILD. Although BAL may be useful in the exclusion of infection, it is not necessary for the diagnosis of RA-ILD. Surgical lung biopsy has been considered the gold standard in the histopathological diagnosis. However, due to the potential risks associated with the method, many patients are diagnosed without surgical biopsy and pathologic confirmation. Video-assisted thoracoscopic surgery is often preferred for open lung biopsy. Transbronchial biopsy in diagnosis is limited, and it is not required in patients with typical clinical and radiological findings.

Recent developments in diagnosis

Studies on biomarkers that can be used to confirm the diagnosis and evaluate the treatment response are still ongoing. In recent years, a serologic marker known as KL-6 (Krebsvon del Lungen-6, proliferating Type 2 pneumocytes and high-molecular-weight glycoprotein expressed in epithelial cells) has been investigated. Serum KL-6 levels were elevated in interstitial pneumonia, hypersensitivity pneumonitis, tuberculosis, sarcoidosis, and pulmonary alveolar proteinosis. It was also observed in patients with RA-ILD (11, 12). A significant increment in the serum KL-6 levels reflects the extensity of HRCT lesions. The grade of alveolitis and severity of pulmonary fibrosis, however, may not be very sensitive in early-stage pulmonary disease. It can also be helpful in the detection of active and progressive pulmonary disease in RA-ILD (12). Oyama et al. (13) reported that KL-6 was elevated in 88.9% of patients with active ILD, and in only 0.6% of patients without active ILD. Recently, studies indicating that transthoracic ultrasonography is a useful method in the diagnosis of early-stage ILD have been published. In a study involving patients with RA, systemic sclerosis, and systemic lupus erythematosus, a significant proportion of patients who showed ILD on HRCT also showed pathological changes in transthoracic ultrasonography (14).

The 18-flurodeoxyglucose positron emission tomography/computed tomography (18 FDG PET-CT) is an alternative method that can be used in the diagnosis of ILD. A recent study evaluating patients with connective tissue disease reported that deep-inspiration breath-hold 18F-FDG-PET/CT could be a useful method in the diagnosis of ILD (15).

Management

Treatment regimens must be tailored to the individual patient; both the supportive treatment and medical treatment should be emphasized. The promotion of smoking cessation comes at the beginning of supportive therapies, which is considered to play a pivotal role in the pathogenesis of RA, and also known to increases both joint symptoms and lung damage. Pneumococcal and influenza vaccines should be routinely administered. Oxygen should be administered to patients with low oxygen saturation (16, 17).

Treatment of RA-ILD is becoming more complicated and challenging, since almost all drugs used in the treatment of RA can cause ILD or have already mediated ILD. Hence, treatment depends on the severity of the disease and the clinical condition of the patient. At this point, radiological findings and functional capacity of the lungs are as important as the clinical condition of the patient. There are some cases where disease symptoms are absent (e.g., breathlessness and/or cough) that are incidentally detected with radiologic imaging of ILD findings, and these patients do not need additional treatment if they are functionally stable (18). It is recommended to follow these patients with the respiratory function test (PFT) every 3 months, and HRCT and PFT/DLCO every 6-12 months for the first 2 years, if the symptoms progress. Treatment of asymptomatic RA-associated patients with ILD without progressive disease should be continued as usual, and the use of any DMARD that controls joint symptoms is not contraindicated in those patients. During the follow-up period, patients in who progression is indicated according to clinical, radiological, or PFT findings should be given additional ILD treatment. Despite the lack of controlled studies in the RA-ILD treatment, corticosteroids are considered as the first-line therapy. The initial dose is usually 0.5-1 mg/kg prednisolone (usually 40-60 mg/daily). Once the response to corticosteroids is achieved, the dose is gradually reduced to the lowest possible dose. Some ILD subtypes, such as the NSIP and OP, have a better response to corticosteroids than other subtypes. When corticosteroids are reduced, additional immunosuppressive agents may be required. For this purpose, corticosteroids may be combined with azathioprine, cyclophosphamide, or mycophenolate mofetil (MMF) (19, 20). As there is a risk of respiratory failure, patients with a rapidly progressive ILD pattern should be approached aggressively.

Corticosteroids at high doses (prednisolone at 10 mg/kg/day) and intravenous pulse cyclophosphamide (6 cycles at 15 mg/kg) every 3-4 weeks are recommended in these patients. At the end of the cyclophosphamide treatment, MMF or azathioprine therapy are recommended as an indwelling therapy. Cyclophosphamide has been reported to be useful in active, rapidly progressing disease (19), although there are no randomized controlled trials of its use in RA-ILD, and limited efficacy has been reported. In a cohort of mixed connective tissue diseases involving a small number of patients with RA-ILD, it has been reported that mycophenolate mofetil contributes to symptomatic recovery and stabilization or improvement in PFTs, and it is also useful in reducing steroid doses (20, 21). Although few studies have shown positive effects on lung findings, since there is no curative effect on joint symptoms, the use of mycophenolate mofetil is limited.

Rituximab (RTX) has been one of the most commonly used drugs in the treatment of RA-ILD in recent years. It is a monoclonal antibody against the B-cell marker CD20 used to treat patients with RA who do not respond to anti-TNF therapy or who cannot use these drugs. After the demonstration of follicular B-cell hyperplasia and interstitial plasma cell infiltration in patients with RA-ILD, a potential role of B-cells in pathogenesis is suggested. This led to an increased interest in RTX for the treatment of RA-ILD (22, 23). In contrast to other biological therapies, there is a concern about the potential pulmonary RTX toxicity. The reported cases are largely due to lymphoproliferative diseases. However, there are several reports on the development or worsening of ILD in RA patients using rituximab (24-26). It has been shown that antitumor necrosis factor (anti-TNF) agents have great efficacy in the suppression of RA joint symptoms and improvement of the disease progression, and they have been used in many RA patients who have not responded to conventional DMARD therapy in recent years.

However, with the widespread use of these drugs, they have caused concerns about potential pulmonary toxicity. There have been reports of new-onset ILD or worsening of preexisting disease after starting an anti-TNF treatment (27-31). In a study by Ramos-Casals et al. (32), it was reported that ILD develops in 10% of 226 patients (83% of RA) who received anti-TNF therapy.

On the other hand, some studies show that there is no correlation between the use of anti-TNF and the development or exacerbation of ILD in RA. A report from the British Society for Rheumatology Biologics Register on patients with RA-ILD taking either anti-TNF agents or traditional DMARDs showed no difference in mortality rates. However, in the same report, the ILD mortality was 21% in patients treated with anti-TNF therapy compared to 7% in conventional DMARDs (33). In another study, Herrinton et al. (34) compared anti-TNF therapy with non-TNF biologic therapy in their study of more than 8.000 patients; there was no difference in the development of ILD.

However, anti-TNF drugs have been shown to have potentially positive effects in stabilizing or ameliorating pulmonary disease (35). Experimental studies indicate that TNF-alpha may have both profibrotic and antifibrotic effects; the imbalance between these two roles may trigger fibrosis or stable ILD in vulnerable individuals, but further studies are needed to confirm this hypothesis (36). Patients with preexisting RA-ILD should be followed closely during anti-TNF treatment. Since methotrexate has a potential risk of pulmonary toxicity, the combination of anti-TNF and methotrexate may have a greater risk of developing ILD or worsening the preexisting disease. Therefore, in patients with ILD, the combination of methotrexate and anti-TNF should not be preferred or should be closely monitored in case of necessity. Although the non-TNF biological agents such as tocilizumab and abatacept are reported to be beneficial in RA patients with ILD, there are some reports that suggest new ILD developments or worsening of the preexisting ILD under these agents (37-40). Lung transplantation is recommended as an option in case of progressive and severe pulmonary disease, despite medical treatment.

Prognosis

Patients with RA-associated ILD have an increased mortality compared to patients without ILD. The male sex, an advanced age, high seropositivity, and greater impairment of the pulmonary function at diagnosis have been associated with worse prognosis (30). Histopathologic and/or radiologic phenotype plays an important role in the prognosis of RA-associated ILD. The cases with the UIP pattern have a worse prognosis compared to those without the UIP pattern (3, 11).

Conclusion

Interstitial lung disease is a common extra-articular manifestation of RA, associated with increased morbidity and mortality. At baseline, an assessment of the severity and the extent of ILD using objective pulmonary parameters is required to make decisions with regard to therapy. The treatment of RA-associated ILD should be tailored for each patient. It should also be kept in mind that drugs used for RA may exacerbate ILD.

Peer-review: Externally peer-reviewed.

Conflict of Interest: The author has no conflict of interest to declare.

Financial Disclosure: The author declared that this study has received no financial support.

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Cemal Bes [iD]

ORCID ID of the author: C.B. 0000-0002-1730-2991.

Cite this article as: Bes C. Comprehensive review of current diagnostic and treatment approaches to interstitial lung disease associated with rheumatoid arthritis. Eur J Rheumatol 2019; 6(3): 146-9.

Department of Rheumatology, University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey

Address for Correspondence: Cemal Bes; Department of Rheumatology, University of Health Sciences, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey

E-mail: cemalbes@hotmail.com

Submitted: 16 February 2019

Accepted: 9 May 2019

DOI: 10.5152/eurjrheum.2019.19036
Table 1. American Thoracic Society/European Respiratory Society
Classification of Idiopathic Interstitial Pneumonia

Histologic Pattern         Clinical/Radiologic/Pathologic Diagnosis

Usual interstitial         Idiopathic pulmonary fibrosis/cryptogenic
pneumonia                  fibrosing alveolitis
Nonspecific interstitial   Nonspecific interstitial pneumonia
pneumonia
Organizing pneumonia       Cryptogenic organizing pneumonia
Diffuse alveolar damage    Acute interstitial pneumonia
Respiratory bronchiolitis  Respiratory bronchiolitis interstitial
                           lung disease
Desquamative interstitial  Desquamative interstitial pneumonia
pneumonia
Lymphoid interstitial      Lymphoid interstitial pneumonia
pneumonia
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Author:Bes, Cemal
Publication:European Journal of Rheumatology
Article Type:Disease/Disorder overview
Date:Sep 1, 2019
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