INTRODUCTION — Interstitial lung disease (ILD) is the most common manifestation of rheumatoid lung disease [1,2]. However, rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is not a single type of ILD, but rather is composed of a spectrum of histologic types with different associated patterns of clinical presentation, radiographic features, response to treatment, and clinical course.
ILD complicating rheumatoid arthritis (RA) will be reviewed here. Other pulmonary complications associated with rheumatoid arthritis and their management are discussed separately (table 1 and table 2). (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Drug-induced lung disease in rheumatoid arthritis".)
PATHOLOGIC TYPES OF RA-ILD — A spectrum of lung histopathology is seen in RA-ILD, and the histopathologic types of RA-ILD can generally be categorized according to the American Thoracic Society/European Respiratory Society's classification system for idiopathic interstitial pneumonia (IIP) (table 3). The most common histopathologic types are usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) [3-10]. It should be noted these classifications continue to evolve [11,12]. (See "Idiopathic interstitial pneumonias: Classification and pathology".)
Histopathologic patterns of ILD associated with RA include the following [3-9,13,14]:
●NSIP (picture 1 and picture 2) (see "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia")
●UIP (picture 3), which is the pattern associated with idiopathic pulmonary fibrosis (IPF) (see "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia')
●Organizing pneumonia (picture 4 and picture 5) (see "Cryptogenic organizing pneumonia")
●Lymphoid interstitial pneumonia (LIP) (picture 6) (see "Lymphoid interstitial pneumonia in adults")
●Desquamative interstitial pneumonia (DIP) (picture 7) (see "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Desquamative interstitial pneumonia')
●Diffuse alveolar damage (DAD), the pathologic correlate of acute interstitial pneumonia (picture 8 and picture 9) (see "Acute interstitial pneumonia (Hamman-Rich syndrome)")
●Pleuroparenchymal fibroelastosis (PPFE; rare)
In some patients, a combination of histopathologic types may be present, in which case a determination of the dominant type is made. Differences in the pathological picture of the idiopathic and RA-associated UIP picture have been noted, with fewer fibroblastic foci in RA [15].
DIP is most commonly associated with cigarette smoking, but rare cases of DIP have been reported in RA in the absence of smoking [7,16,17].
PPFE is characterized by bilateral subpleural fibrosis and pleural thickening, predominantly affecting the upper lobes, and is rare in RA [18-20]. The diagnosis is often a clinical one, made on the basis of definite or consistent features on high resolution computed tomography (HRCT). Other ILDs may be present such as UIP (eg, due to RA). (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Idiopathic pleuroparenchymal fibroelastosis'.)
It is not clear how many patients with RA-ILD may fall into the category of "unclassifiable interstitial pneumonia" where there is major discordance between clinical, radiologic, and pathologic investigations (table 3) [9].
EPIDEMIOLOGY — As RA-ILD is often asymptomatic, the reported frequency depends upon the type of investigation used and the severity of RA in the population studied [21-28]. The following observations illustrate the range of findings:
●In a database study that examined insurance claims from 2003 to 2014, the prevalence of RA-ILD ranged from 3.2 to 6.0 cases per 100,000, and the incidence ranged from 2.7 to 3.8 per 100,000 [29]. The prevalence increased over time, while the incidence remained stable. The median survival was 7.8 years (95% CI 7.1-8.3).
●Clinically significant RA-ILD occurs in nearly 10 percent of patients with RA [27,30] and is generally more common among men than women [27,31].
●Among patients with early rheumatoid disease (joint symptoms <2 years) who were surveyed with a range of investigations including pulmonary function tests (PFTs), chest radiographs, and bronchoalveolar lavage (BAL), 21 of 36 patients (58 percent) had abnormal findings on at least one modality that were consistent with ILD [23]. Among these patients, pulmonary involvement was clinically apparent in 14 percent and clinically silent in 44 percent.
●In an observational cohort of 5699 patients with RA followed for 2.5 years, 15 (<1 percent) developed new interstitial pneumonitis and 18 (<1 percent) developed methotrexate-induced pulmonary toxicity [32].
●In another series, the prevalence of changes characteristic of idiopathic pulmonary fibrosis (IPF) on high resolution computed tomography (HRCT), regardless of pulmonary symptoms, abnormal lung function, or the duration of the rheumatoid disease, was nearly 20 percent [24].
●An autopsy study of 81 patients with longstanding RA noted that 28 (35 percent) had evidence of ILD and in 7 (9 percent) the cause of death was respiratory failure related to ILD [21].
Disease-modifying antirheumatic drugs (DMARDs) and biologic therapies have reduced the extra-articular manifestations of RA, but their impact on RA-ILD is not clear. Case reports, series, and data from registries demonstrate a spectrum of pulmonary effects, including development of new ILD, worsening of pre-existing ILD, and resolution of ILD. In an analysis of data from the British Society for Rheumatology Biologics Register, outcomes of anti-tumor necrosis factor-alpha (TNF-alpha) therapy were compared with DMARDs in patients with known RA-ILD [33]. After adjustment for age, sex, and other potential confounders, the adjusted mortality rate ratio (aMRR) was 0.81 (95% CI 0.38-1.73) for the anti-TNF-alpha cohort compared with the DMARD cohort, suggesting that anti-TNF-alpha agents did not increase mortality. However, RA-ILD was a more common cause of death in the anti-TNF cohort. At this stage, it is not clear what the overall impact of biologic agents is on morbidity or mortality from ILD [33-35].
RISK FACTORS AND GENETIC PREDISPOSITION — Risk factors for RA-ILD include more severe RA, high C-reactive protein, male sex, older age, obesity, cigarette smoking, and exposure to fine particulate matter [10,32,36-38]. The principal preventable risk factor for ILD is cigarette smoking [25,39]. One study of 336 patients with RA found that those with a >25 pack-year smoking history were significantly more likely to have radiographic evidence of ILD (odds ratio [OR] 3.76, 95% CI 1.59-8.88) [39].
●Serologic features – Serologic studies, such as a high titer of rheumatoid factor (RF) (eg, ≥90 international units/mL), may identify patients at higher risk of ILD [28,36]. While a higher titer of anti-cyclic citrullinated peptide (anti-CCP) antibodies is also a risk factor for ILD, the presence of these antibodies more strongly predicts RA-associated airway disease, although specific subtypes of anti-CCP antibodies (Hsp90) may be important for interstitial disease [40].
●Cigarette smoking and environmental exposures – It is thought that lung injury from cigarette smoking and other stimuli may contribute to the post-translational modification (citrullination) of proteins, which then creates new epitopes and subsequent autoimmune responses [41]. Higher levels of a variety of specific anti-citrullinated peptide antibodies and an expanded repertoire of these antibodies were present in patients with RA-ILD with lung function abnormalities [42]. RA-associated antibodies have been found in the sputum of patients at risk of RA well before joint disease developed [43,44]. Further research is needed to clarify the role of autoantibodies to citrullinated proteins in RA-ILD [44,45]. (See "Pathogenesis of rheumatoid arthritis".)
●Genetic risk factors – The gain-of-function MUC5B promoter variant rs35705950 is the strongest risk factor for development of idiopathic pulmonary fibrosis (IPF); this variant is associated with an increased risk for RA-ILD among patients with RA (adjusted OR 3.1; 95% CI 1.8-5.4; p = 7.4×10−5) [46,47]. Additionally, in patients with RA-ILD, the MUC5B variant is associated with features of usual interstitial pneumonia (UIP) on high resolution computed tomography (HRCT). The exact role of MUC5B protein in the pathogenesis of fibrotic lung disease is not known, but accumulation of MUC5B may disrupt repair mechanisms or interfere with ciliary clearance. This MUC5B variant has not been associated with ILD in systemic sclerosis or inflammatory myositis, underscoring the similarity of RA-ILD to IPF. In IPF, presence of the MUC5B variant has been associated with significantly better survival [48]. By contrast, the MUC5B promoter variant did not affect transplant-free survival in 261 patients with RA-ILD [49]. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'MUC5B'.)
CLINICAL FEATURES — In RA-ILD, the onset of symptoms is typically around 50 to 60 years of age [3,31,50]. Men are two to three times more likely to acquire ILD than women. While RA-ILD is often associated with erosive joint disease and postdates the onset of joint symptoms by up to five years, it can occasionally precede joint disease [10].
The exact clinical presentation of RA-associated ILD depends on the underlying lung pathology. Most often, symptoms develop insidiously and include dyspnea on exertion and a nonproductive cough. Recognition of exertional dyspnea may be delayed due to the exercise limitation associated with joint disease. Patients with the pathologic pattern of usual interstitial pneumonia (UIP), typically become symptomatic late in its course when widespread fibrosis is present. By contrast, a fulminant onset has been described in a few cases of rapidly fatal Hamman-Rich type syndrome, which has the pathologic pattern of acute interstitial pneumonia. Less common manifestations include fever and chest pain. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Classification' and "Acute interstitial pneumonia (Hamman-Rich syndrome)".)
Physical signs may be absent in early RA-ILD disease. Bibasilar crackles are present in over 75 percent, while signs of pulmonary hypertension and respiratory failure may develop late in the course of disease [3,50]. Clubbing is frequently noted in patients with the UIP pattern of RA-ILD (>75 percent), but is much less common among those with other patterns of RA-ILD [51].
EVALUATION — RA-ILD is usually suspected when a patient with RA develops dyspnea, cough, auscultatory crackles, or abnormalities on pulmonary function tests (PFTs) or chest radiograph. The evaluation of suspected RA-ILD typically includes a combination of laboratory testing, PFTs, imaging, and sometimes bronchoalveolar lavage (BAL), but uncommonly a lung biopsy. These tests are designed to characterize the presence, pattern, and severity of ILD, and also to exclude alternative diagnoses. (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)
All of the histopathologic types of idiopathic ILD can occur in the context of RA (table 3). For patients with a known diagnosis of RA, if there is a compatible high resolution computed tomography (HRCT) scan showing ILD, further identification of usual interstitial pneumonia (UIP) or non-UIP lung disease is not pursued as the therapeutic approach for UIP and non-UIP fibrotic lung disease is the same in RA-ILD. In addition, patterns suggesting organizing pneumonia, nonfibrotic nonspecific interstitial pneumonia (NSIP), or lymphoid interstitial pneumonia (LIP) may be treated without pathologic confirmation.
In a minority of cases, when the clinical and HRCT features are not typical for a given type of ILD and the patient is symptomatic and fit for surgery, and the biopsy would change the therapeutic approach (eg, avoid glucocorticoids in UIP pattern), characterization of the ILD by lung biopsy is appropriate [52].
It is important to determine whether the patient is experiencing a first presentation of new ILD, an exacerbation of previously unknown ILD (usually UIP pattern), or one of these possibilities combined with a superimposed comorbid disease not directly due to RA. Investigations evaluating the various pulmonary manifestations of RA [2] are designed to exclude the possibility that another lung disease or extrapulmonary process is etiologic or coexistent, such as:
●Infection (especially in an immunosuppressed host)
●Drug-induced lung disease (eg, methotrexate, rituximab, anti-tumor necrosis factor-alpha [TNF-alpha]) (see "Methotrexate-induced lung injury" and "Drug-induced lung disease in rheumatoid arthritis")
●Hypersensitivity pneumonitis due to inhalational agent (see "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis")
●A new or intercurrent ILD, such as acute interstitial pneumonitis or vasculitis, if symptoms are rapidly progressive
●Heart failure, pulmonary embolism, cancer, or recurrent gastroesophageal aspiration
Laboratory testing — For patients with (or without) RA who present with diffuse lung disease, we generally obtain a complete cell count and differential to look for leukocytosis (infection), leukopenia (immune suppression due to medication), or eosinophilia (possible drug reaction). A serum natriuretic peptide level is measured to screen for heart failure or pulmonary hypertension. Most patients have already had serologic testing for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, but full assessment of other autoantibodies should be performed, including antinuclear antibodies and anti-double-stranded DNA (deoxyribonucleic acid) antibodies, and also cryoglobulins to assess for coexistent rheumatic disease that may be contributory in the appropriate clinical setting, such as when purpura, Raynaud phenomenon, skin ulcers, or renal disease are present.
RF may be present in high titer in patients with ILD [36]. Anti-citrullinated peptide antibody (ACPA) positivity also correlates with the presence of RA-ILD and higher titers may be associated with more severe ILD [36,42,53,54].
While the sedimentation rate (ESR) and C-reactive protein (CRP) correlate with activity of RA joint disease, their role in the evaluation of lung disease is unclear.
Pulmonary function tests — Complete lung function testing (spirometry, lung volumes, diffusing capacity) and pulse oximetry are obtained in all patients with suspected ILD to assess the pattern, severity, and progression of respiratory impairment.
Abnormalities associated with ILD include reductions in lung volumes and diffusing capacity for carbon monoxide (DLCO, also known as transfer factor), oxygen desaturation during exercise, and in late disease, resting hypoxemia. In a study of 81 patients with recent onset rheumatoid arthritis, for example, 33 percent had a DLCO <80 percent of predicted, while only 14 percent had symptoms [23]. When assessing changes over time, changes that are considered clinically important include a decrease in forced vital capacity (FVC) of ≥10 percent or a decrease in DLCO of ≥15 percent [52]. (See "Overview of pulmonary function testing in adults" and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Pulmonary function testing'.)
Among patients with RA, restrictive abnormalities on pulmonary function tests (PFTs) are common even in the absence of symptoms and may reflect poor muscle strength or kyphosis due to osteoporosis rather than ILD. The association of restrictive abnormalities and evidence of abnormal gas exchange (eg, reduced DLCO, low pulse oxygen saturation) favor the diagnosis of ILD.
Breathlessness and hypoxemia are usually more evident on exertion than at rest. Thus, measuring oximetry during a six-minute walk test may provide more information regarding abnormal gas exchange, than an arterial blood gas obtained at rest. Arterial blood gases and cardiopulmonary exercise testing are occasionally required to corroborate abnormal pulse oxygen saturation or DLCO findings.
Imaging studies — In patients with RA, a chest radiograph is typically obtained to assess complaints of dyspnea or abnormal findings on lung examination. Further imaging depends on the chest radiograph findings and severity of symptoms.
●Chest radiograph – The chest radiograph may be normal in patients with early or mild RA-ILD. When abnormal, potential findings include bibasilar ground-glass opacities, reticular and nodular opacities, and honeycombing. Late in the course of the disease, changes suggestive of pulmonary hypertension (eg, enlargement of central pulmonary arteries, attenuation of peripheral vessels) may be detectable. (See "Evaluation of diffuse lung disease by conventional chest radiography" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Imaging'.)
●High resolution computed tomography – HRCT is obtained in almost all patients with symptoms, PFT findings, or chest radiograph abnormalities suggestive of diffuse parenchymal disease. Both prone and supine views are obtained to avoid misinterpretation of gravity-induced opacities in dependent areas. HRCT detects abnormalities earlier than chest radiography and may reveal a range of parenchymal abnormalities [7,55]. In one study of 20 nonsmoking patients with RA and normal chest radiographs, five patients had basilar bronchiectasis and one had mild ILD by HRCT [56]. In a review of 84 patients with longstanding RA, 29 percent of asymptomatic and 69 percent of symptomatic patients had abnormalities on HRCT [57]. These findings included bronchiectasis or bronchiolectasis in the absence of fibrosis (19 percent); ground-glass attenuation (14 percent); nonseptal linear attenuation (18 percent); and honeycombing (10 percent). In general, the HRCT findings accurately predict the pathologic findings. (See "High resolution computed tomography of the lungs".)
HRCT can distinguish a predominantly ground-glass pattern from reticular changes and honeycombing, which is helpful in differentiating among the various types of ILD. As examples:
•Ground-glass opacification is consistent in NSIP, acute interstitial pneumonia, and desquamative interstitial pneumonia (DIP).
•Reticular changes, traction bronchiectasis, and honeycombing are more typical of UIP (image 1) [26,58-60]. Infrequently, however, the HRCT may suggest UIP, but NSIP will be identified by biopsy [7].
•Persistent areas of subpleural consolidation are more suggestive of organizing pneumonia [4].
Review of previously performed computed tomography (CT) images, including abdominal CTs with views that include the lung bases, may identify a pre-existing ILD. In addition, review of older images can help determine the rate of progression of ILD and whether the timing of changes in CT findings over time correlates with symptoms or medication usage.
The optimal method for using CT scans to identify the underlying histopathology and monitor for progression has not been determined. One method may be to combine scoring systems used in other forms of ILD. In combined case series, 157 patients with RA-ILD were characterized using a scoring system for systemic sclerosis ILD and the Fleischner Society guidelines for idiopathic pulmonary fibrosis (IPF) and automated computer-based CT analysis (CALIPER) and followed for approximately three years [61-63]. Among patients with RA-ILD, the combination of the two visual CT-based scoring systems predicted progressive fibrotic lung disease in 23 percent; the automated CT analysis further improved the predictive accuracy. Furthermore, the patients with RA-ILD and with definite or probable UIP radiographic patterns had a comparable survival to patients with IPF. Automated scoring systems are currently a research tool, but have promise for the future. (See "Prognosis and monitoring of idiopathic pulmonary fibrosis", section on 'Imaging'.)
●Nuclear imaging – Nuclear imaging with gallium and technetium-99m diethylene triamine penta-acetic acid (Tc-99m DTPA) may be abnormal in RA-ILD. However, the role of these studies in diagnosis or prognosis of RA-ILD has not been defined [23,64].
Bronchoalveolar lavage — The main role for BAL in patients with an acute onset of respiratory symptoms or fever and radiographic abnormalities is to exclude diffuse lung diseases other than RA-ILD, such as acute eosinophilic pneumonia, alveolar hemorrhage, malignancy, or opportunistic or atypical infection [52]. BAL is frequently abnormal in patients with RA-ILD, but the findings are nonspecific. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
Abnormalities in cellular constituents and mediators found on BAL are not useful for differentiating among the types of RA-ILD or predicting prognosis or response to therapy. As a result, BAL is not considered to be a routine part of the diagnostic approach to RA-ILD. The following BAL findings have been reported from research studies:
●In patients with clinical evidence of RA-ILD, total cells, neutrophils, and occasionally eosinophils are elevated [22].
●In the absence of symptoms, lymphocytosis is more common [65,66]. This finding may be associated with a better prognosis, as evidenced by the subclinical nature of the lung disease.
●Increases in the production of TNF-alpha by macrophages and the levels of superoxide anion, fibronectin, and collagenase activity in BAL have been noted in patients with RA-ILD [67,68].
Lung biopsy — As HRCT patterns have been found to correlate reasonably closely with ILD histopathologic patterns, lung biopsy is rarely required in most patients with RA-ILD [60]. However, when the results of the above evaluation do not allow the clinician to make a confident diagnosis of a given type of ILD (eg, UIP) and the patient’s lung disease is clinically significant and/or progressing, lung biopsy with careful examination of lung tissue may be appropriate. A transbronchial biopsy obtained via flexible bronchoscopy is usually inadequate for diagnosis, so lung biopsy is typically performed by either video-assisted thoracoscopy (VATS) or open thoracotomy. The decision about whether a lung biopsy should be performed should be made on a case-by-case basis, taking into account the patient's clinical condition and the impact of the results on the patient's management. As an example, lung biopsy may be warranted in younger patients in whom lung transplantation might be considered eventually. The role of transbronchial cryobiopsy remains unclear and is described separately. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Role of lung biopsy' and "Role of lung biopsy in the diagnosis of interstitial lung disease" and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Interstitial pneumonias'.)
Serum markers — No serum markers have demonstrated clinical utility for the diagnosis of RA-associated ILD, although some may be promising. Increased serum concentrations of KL-6, a glycoprotein found predominantly on type II pneumocytes and alveolar macrophages, have been reported in patients with interstitial pneumonia [69]. As an example, one study assessed the potential role of serum KL-6 for the diagnosis of ILD associated with systemic inflammatory disorders in 57 patients, 22 of whom had known ILD [70]. Patients with ILD had significantly higher KL-6 values than those without lung disease, with the sensitivity and specificity ILD estimated at 61 and 99 percent, respectively, in this selected population. Measurement of serum KL-6 remains a research tool at present, but may become clinically useful in the future if the high specificity of the test is confirmed.
Another report noted that serum anti-interleukin-1-alpha antibody titers were significantly higher in patients with RA and ILD, in comparison to patients with RA, but not ILD, and to controls. Higher titers were associated with higher serum lactate dehydrogenase (LDH) concentrations and larger alveolar to arterial oxygen gradients [71]. In addition, a matrix metalloproteinase-7 (MMP-7) and interferon-gamma-inducible protein-10 (IP-10/CXCL10) were found to be elevated in all patients with RA-ILD and a dose-response relationship was seen between the levels of these markers and radiographic severity [72].
In a case series (58 patients with RA-ILD; 27 with RA but no ILD), serum antibodies to citrullinated Hsp90 appeared specific (>95 percent), although not sensitive for RA-ILD [40]. Anti-citrullinated Hsp90 antibodies were not found in 41 patients with mixed connective tissue disease or 33 patients with IPF, further suggesting specificity. The role of these autoantibodies to citrullinated-Hsp90 in identifying patients with RA-associated ILD needs validation in other groups of patients with RA. In a separate study, a stronger association was observed between the number of ACPA and radiographic UIP than with NSIP [42]. In a meta-analysis, serum ACPA positivity was associated with an increased OR of ILD (OR 3.39, 95% CI 1.67-6.88) [54]. If confirmed, the serum ACPA would be a very useful test to help predict RA-ILD among patients with RA.
DIAGNOSIS — The diagnosis of RA-ILD is generally based on the combination of compatible clinical features, pulmonary function testing (eg, restrictive changes and a gas transfer abnormality), and high-resolution computed tomography (HRCT) findings (eg, reticular, ground-glass, or consolidative changes), and also exclusion of other processes, such as infection, drug-induced pulmonary toxicity, and malignancy. The use of a Multidisciplinary Team Meeting, including rheumatologists and immunologists, is encouraged [73,74]. (See 'Differential diagnosis' below.)
Determination of the underlying pattern of RA-ILD is based on a typical HRCT pattern or, less commonly, on lung biopsy findings. (See 'Imaging studies' above and 'Pathologic types of RA-ILD' above.)
DIFFERENTIAL DIAGNOSIS — In patients with rheumatoid arthritis (RA), the differential diagnosis of diffuse lung disease includes drug-induced lung toxicity, opportunistic infection, heart failure, recurrent aspiration, malignancy, and other inflammatory causes of ILD. In addition, patients presenting with new respiratory symptoms with evidence of ILD may have an exacerbation of previously unknown ILD. In the latter situation, obtaining old CT images, even if performed for an abdominal problem, may provide clues to pre-existing disease.
●Drug-induced lung toxicity – Drug-induced lung toxicity has been associated with most of the medications used to treat RA, including the nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, leflunomide, gold, penicillamine, and biologic agents (eg, tumor necrosis factor [TNF] inhibitors, rituximab, tocilizumab) [75]. Toxicity has rarely been reported with anakinra and not with abatacept. An essential step in the evaluation of possible drug-induced lung toxicity is to stop any implicated medication(s) and observe for improvement over the next few days to weeks. (See "Drug-induced lung disease in rheumatoid arthritis".)
Development of a sarcoid-like reaction in the lungs has been reported with infliximab, etanercept, and adalimumab and appears to be a class effect of anti-TNF-alpha agents [76-80]. Patients may present with dry cough, night sweats, and weight loss [81]. Onset of disease ranges from 1 to 50 months after initiation of the anti-TNF agent [81]. Sarcoid-like granulomas have also been reported in the skin, lymph nodes, and bone marrow in association with anti-TNF-alpha agents. In one series, the serum angiotensin converting enzyme level was elevated in 48 percent [82]. Cessation of the anti-TNF-alpha agent generally leads to resolution of the granulomas over several months [83]. Recurrences have been reported when the same anti-TNF-alpha agent is resumed, but appears less common when an alternate agent is used [81,83].
●Opportunistic infection – Opportunistic infections are well-known complications of immunosuppressive therapies used to treat RA. The diagnosis of opportunistic infection typically requires special stains and culture of induced sputum and/or bronchoalveolar lavage (BAL) specimens.
Pneumocystis (jirovecii) pneumonia (PCP) is associated with all of the immunosuppressive agents, particularly when the patient is receiving a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer in addition to a second immunosuppressive agent or taking an anti-TNF-alpha agent in combination with other intensive immunosuppression. PCP should be in the differential of new, recent onset dyspnea, fever, and diffuse of patchy radiographic disease. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV".)
Anti-TNF-alpha agents also increase the risk for new and reactivation of latent fungal infections, such as histoplasmosis, coccidioidomycosis, cryptococcosis, and other invasive fungal infections. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)
Mycobacterial disease (both tuberculous and nontuberculous) is well-described complication of anti-TNF-alpha agents. (See "Tumor necrosis factor-alpha inhibitors and mycobacterial infections".)
●Hypersensitivity pneumonitis – The clinical, imaging, and histopathologic characteristics of chronic hypersensitivity pneumonitis are similar to those of the usual interstitial pneumonia (UIP) pattern of RA-ILD. The radiographic findings typical of subacute hypersensitivity pneumonitis (eg, diffuse micronodules, ground-glass attenuation) are also seen in some patients with RA and organizing pneumonia. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)
●Other causes – Heart failure is generally excluded based on physical examination, natriuretic peptide measurement, and echocardiogram.
Recurrent aspiration typically affects the lower lobes; swallowing difficulties provide a clue to the diagnosis, although they are not always present.
The differential diagnosis of diffuse lung disease is discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
TREATMENT — The optimal treatment for RA-ILD has not been determined but generally parallels the treatments that have been used for the underlying type of interstitial pneumonia, whether that pattern is diagnosed by lung biopsy or presumed based on clinical presentation and high resolution computed tomography (HRCT) (table 3) [5,9]. Case series and clinical experience suggest a benefit to systemic glucocorticoids and immunosuppressive agents in selected patients [3]; antifibrotic agents, such as nintedanib and pirfenidone, may have a role in those with progressive fibrotic disease [84,85].
As with the idiopathic interstitial pneumonias (IIPs), the decision to treat the various histopathologic forms of RA-ILD needs to weigh prognosis, likelihood of response to therapy, and potential benefits of early therapy (ie, before fibrosis is established) against the potentially significant adverse effects of treatment (eg, uncontrolled diabetes, immunosuppression, osteoporosis). Abnormalities in any single pulmonary function test (PFT) are common in patients with RA. Thus, the diagnosis of clinically significant disease that warrants further monitoring or treatment is based upon the severity of impairment, rate of progression, and pattern of abnormalities identified by the investigations described above, rather than results of a single test.
As a way to guide treatment and monitoring strategies, a newer approach used in guidelines for IIPs has been to categorize the disease behavior as self-limited, reversible, stable, progressive, or irreversible, with or without the potential for long-term stabilization with therapy (table 4) [2,9,86]. This means that predictors of survival, such as a low diffusing capacity and extensive fibrosis on the HRCT, linked with observed rate of progression may better guide treatment in the face of infrequent pathologic confirmation, heterogeneous outcomes, and little data to guide treatment other than clinical behavior.
General measures — Patients who are current cigarette smokers should be encouraged to stop smoking. All patients should be encouraged to obtain age-appropriate pneumococcal, influenza, and SARS-CoV-2 vaccination. Pulmonary rehabilitation, modified as needed for arthritis, may improve exercise tolerance. (See "Overview of smoking cessation management in adults" and "Pneumococcal vaccination in adults" and "Seasonal influenza vaccination in adults" and "COVID-19: Vaccines" and "Pulmonary rehabilitation".)
Patients who can be monitored without specific treatment — Asymptomatic patients and those with mild RA-ILD are monitored with clinical assessment, PFTs, and a chest radiograph at six- to twelve-month intervals, or sooner if symptoms worsen. Similarly, patients with a usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) pattern and stable disease by symptoms, PFTs, and HRCT are monitored without specific therapy (other than treatment of their articular disease). However, close monitoring for progressive fibrotic disease is important. (See 'Progressive fibrosing interstitial lung disease' below.)
Typically, these latter patients are older, and their RA-ILD is unlikely to respond to glucocorticoids or immunosuppressive therapies. Therapy of their joint disease continues as indicated, although any drugs that may have contributed to lung toxicity are discontinued. (See "Drug-induced lung disease in rheumatoid arthritis".)
Approach to treatment with glucocorticoids and immunosuppressants — Features that suggest that treatment of RA-ILD with glucocorticoids and/or immunosuppressive drugs is likely to be beneficial include younger age; HRCT with predominant ground-glass opacities; and worsening of symptoms, PFTs, or HRCT over the preceding three to six months. The decision to commence therapy is also influenced by the presence of comorbid disease that might increase the risk of adverse effects (eg, diabetes mellitus, osteoporosis).
Some clinicians would also treat selected patients with RA-ILD and a radiographic UIP pattern who are young, have a shorter duration of ILD, and deteriorating lung function, but no significant comorbid problems [86]. This approach was addressed in a retrospective study of 144 patients with rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) of whom 41 percent received immunosuppressive treatment due to poor initial lung function or ILD progression [87]. After a median follow-up of 33 months, 50 percent of those treated had improved or remained stable, despite an expectation that these patients would be most likely to progress. Furthermore, there was no difference in outcome between the treated and untreated groups, despite worse initial lung function in the treatment group. This study, while not randomized, would suggest that the outlook with treatment is better in RA-UIP than IPF or that the clinical diagnosis of RA-UIP is not accurate and may include patients with RA-nonspecific interstitial pneumonia (NSIP), shown to have a better prognosis and response to treatment. Thus, treatment with a goal of slowing disease progression may reasonably be considered in such patients, while awaiting further data [86].
Patients with the organizing pneumonia, NSIP, and lymphoid interstitial pneumonia (LIP) histopathologic types of RA-ILD are believed to be likely to respond to glucocorticoid/immunosuppressive therapy based on experience with the idiopathic forms of these ILDs and on clinical reports [88]. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Overview of treatment' and "Lymphoid interstitial pneumonia in adults", section on 'Treatment' and "Cryptogenic organizing pneumonia", section on 'Treatment'.)
Initiation of glucocorticoid therapy — Glucocorticoid therapy produces variable subjective and objective improvement in the treatment of RA-ILD, although some of the reported variability in response may be due to a lack of precision in determining the histopathologic subtype [89]. As with the IIPs, the results may depend upon the relative proportions of inflammatory or fibrotic changes within the pulmonary parenchyma (image 1).
For symptomatic patients with RA-ILD and organizing pneumonia or a predominance of ground-glass opacities on HRCT, and no evidence of lung infection, we suggest initiating therapy with oral prednisone at a dose of 0.5 mg/kg per day, based on ideal body weight (calculator 1), as a single morning dose [52]. A maximum dose of 60 mg/day should not be exceeded, as there is no clear benefit but significant risk above this level. If a response is going to occur, it is usually seen within one to three months. The prednisone dose should be slowly reduced to a maintenance dose of 10 mg/day once a response occurs, using symptomatic response and PFTs to monitor disease activity. Where the pattern of lung involvement is UIP, fibrotic NSIP, or cystic LIP, glucocorticoids would rarely be used.
In severe, rapidly progressive disease, after excluding infection, glucocorticoids are administered intravenously, as described for fulminant disease. (See 'Fulminant disease' below.)
Failure to respond to systemic glucocorticoids — Patients who fail to respond to glucocorticoids alone may benefit from addition of a disease-modifying antirheumatic drug (DMARD) after exclusion of infection or drug toxicity as a cause for persistent or worsening ILD [90-95]. In general, data are insufficient to guide selection between DMARDs such as mycophenolate, methotrexate, abatacept, or rituximab, although British and Spanish guidelines favor abatacept and rituximab as they appear to have a lower likelihood of worsening pre-existing ILD or development of new-onset ILD compared with other biologic DMARDs (low-level evidence) [96,97]. Decisions are made on a case-by-case basis, taking into account previous medications used to control joint disease and the need to actively treat joint disease. Cyclophosphamide is generally reserved for more severe or refractory disease. (See 'Fulminant disease' below.)
●Mycophenolate – When used for rheumatic disease, mycophenolate mofetil is initiated at 500 mg given twice a day and is increased as tolerated to a target dose of 1.5 to 3 g/day. The administration of mycophenolate is described separately. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)
Evidence in favor of mycophenolate for RA-ILD comes from a series of 125 patients with connective tissue disease-associated interstitial lung disease (CTD-ILD), including 18 with rheumatoid arthritis [93]. Mycophenolate mofetil was associated with modest improvements in forced vital capacity (FVC) and diffusing capacity and reductions in the prednisone dose (mean decrease among RA patients 20 mg). However, mycophenolate is not effective in the treatment of articular manifestations of RA [95]. The discontinuation rate for adverse effects (gastrointestinal intolerance, hepatic transaminase elevation, cytopenia, and nonspecific symptoms) was under 10 percent [93]. One study using registry data does not suggest an increased risk for malignancy with mycophenolate treatment for connective tissue disease-associated ILD [98].
●Methotrexate – Methotrexate is an option in RA-ILD if it is otherwise appropriate and effective for the management of the patient’s joint disease. In the past, methotrexate was avoided in patients with RA-ILD because of concern that it could contribute to progressive pulmonary fibrosis. However, accumulating evidence suggests that methotrexate does not cause worsening of lung disease and in fact may be protective from developing ILD [99]. Furthermore, methotrexate-related acute (hypersensitivity) pneumonitis is exceedingly rare. (See "Drug-induced lung disease in rheumatoid arthritis", section on 'Methotrexate'.)
The dosing, administration, and monitoring of methotrexate in RA are described separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis".)
●Rituximab – Rituximab is a B lymphocyte-depleting biologic agent used in patients whose RA is inadequately controlled by other biologic DMARDs. After preparative immunizations (eg, pneumococcal, seasonal influenza, SARS-CoV-2), serologic testing (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV]), checking immunoglobulin levels (immunoglobulin G [IgG] and immunoglobulin M [IgM]) and screening for tuberculosis (TB), rituximab is administered as two intravenous infusions of 1000 mg, 14 days apart. Details of the treatment protocols are provided separately. In general, low-dose glucocorticoids (eg, 10 mg daily) or a DMARD is continued. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)
Evidence in favor of rituximab comes from a retrospective cohort study of 44 patients with moderate-to-severe RA-ILD, in which addition of rituximab was associated with stabilization or improvement in lung function in 30 patients (68 percent) [100]. However, 14 patients (32 percent) experienced progressive lung disease and, of these, seven died. In two smaller case series, rituximab was associated with stabilization of lung disease or modest improvement in a portion of the patients [101,102], although adverse effects included infusion reactions, heart failure, and possible pneumonia.
●Abatacept – Abatacept is a fusion protein (CTLA-Ig) that inhibits activation of T lymphocytes by blocking interaction between CD28-CD80. Screening for infection and preparation with vaccination, as for many of these agents, should occur before treatment is commenced. Abatacept is administered by intravenous infusion every four weeks or subcutaneous injection that can be self-administered weekly, as described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)
In general, patients remain on either low-dose glucocorticoids (10 mg) or a DMARD with abatacept added.
Retrospective data suggest a beneficial effect of abatacept in RA-ILD [95]. A multicenter, open-label study in 63 patients with RA-ILD revealed that abatacept was associated with stabilization in two-thirds and improvement in one-fourth of patients; 11 patients (17 percent) discontinued therapy due to adverse effects [103].
Abatacept was associated with stability or improvement in lung function and HRCT in the majority of 44 patients with RA-ILD followed for six months [104]. In a separate series, abatacept appeared protective against the emergence of ILD in a small number of patients with RA [105]. A clinical trial to assess the role of abatacept in RA-ILD is in progress (NCT03084419). (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)
●Agents that are less commonly used – Tumor necrosis factor-alpha (TNF-alpha) inhibitors are less often used in patients with RA-ILD because of multiple, although infrequent, case reports of lung toxicity with these agents [95-97]. Conflicting data have been presented for azathioprine in RA-ILD [95,106]. Hydroxychloroquine was used successfully in combination with mycophenolate in a small case series, but it is almost never used as a single agent for RA-ILD [91].
Inability to taper glucocorticoids or intolerance of adverse effects — For patients who are unable to taper the glucocorticoid dose or have intolerable adverse effects, addition of an immunosuppressive agent may enable successful tapering of the glucocorticoids. Although published experience in RA-ILD is limited, this approach is used for several of the idiopathic ILDs [93]. As an example, mycophenolate or azathioprine can be added at the doses described above, while continuing prednisone at as low a dose as possible (eg, 0.2 to 0.25 mg/kg per day, or ≤10 to 15 mg daily). (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Additional immunosuppressive drugs' and "Cryptogenic organizing pneumonia", section on 'Glucocorticoid-sparing agents for recurrent relapses or glucocorticoid intolerance'.)
Progressive fibrosing interstitial lung disease — For patients with RA, HRCT features of fibrosing ILD, and clinical evidence of declining lung function despite immunosuppressive therapies, we suggest treatment with the antifibrotic nintedanib to slow disease progression. Imaging features of fibrotic ILD include a reticular abnormality with traction bronchiectasis, with or without honeycombing. Nintedanib also slows decline in lung function in other predominantly fibrotic lung diseases, including IPF and systemic sclerosis-associated ILD (SSc-ILD) (See "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Nintedanib'.).
Nintedanib was evaluated in a trial (INBUILD) that included 663 patients with various progressive fibrosing ILDs that had worsened despite standard of care and who had at least 10 percent of the lung affected as seen on HRCT [84]. Thirteen percent of patients included had RA-ILD. Evidence of disease progression required for enrollment included any of the three following criteria: relative decline in the FVC of at least 10 percent of the predicted value; a relative decline in the FVC of 5 to 10 percent of predicted and worsening of respiratory symptoms or increased extent of fibrosis on HRCT; or both worsening of respiratory symptoms and an increased extent of fibrosis. After 52 weeks:
●In the overall population, nintedanib slowed the overall adjusted rate of decline in FVC with a between-group difference of 107.0 mL/year (95% CI 65.4-148.5), which is comparable to the benefit seen in IPF. The results of this trial lend support to the concept that fibrotic lung disease reflects a final common pathway that is initiated in a spectrum of ILDs and that this phase of disease may respond to antifibrotic agents that are not disease specific. Additional details about the trial are described separately. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention", section on 'Antifibrotic agents' and "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib' and "Treatment and prognosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Nintedanib'.)
●In a post-hoc subgroup analysis of 89 patients with RA-ILD, the rate of FVC decline was -79 mL/year with nintedanib compared with -197 ml/year with placebo (absolute difference 118 mL/year, 95% CI 5.2-231 mL) [107]. Among a larger subgroup of 170 patients with progressive fibrosing ILD associated with autoimmune diseases, there was a trend towards decreased ILD exacerbation or death that did not reach statistical significance (10 versus 18 events).
The dosing of nintedanib for patients with RA and progressive fibrotic lung disease follows that for IPF and is described separately, as are potential adverse effects. Cost, side effects, and availability may limit use. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Nintedanib'.)
Although patients with progressive lung fibrosis frequently require systemic glucocorticoids, oral immunosuppressants, or biological agents for extrapulmonary disease, there are limited data regarding the co-administration of these agents and antifibrotics. In our practice, we typically add nintedanib onto the patient's current disease-controlling therapies. The INBUILD trial excluded patients on azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, rituximab, cyclophosphamide, or oral glucocorticoids >20 mg/day. Ongoing trials are evaluating the safety and efficacy of combinations of agents.
Fulminant disease — For the minority of patients who develop rapidly progressive acute ILD or organizing pneumonia as a complication of RA, after excluding infection and drug-induced lung toxicity, we follow treatment regimens for the particular type of ILD (eg, acute interstitial pneumonitis, organizing pneumonia). As these patients typically have impending or actual respiratory failure, we suggest high-dose systemic glucocorticoids (eg, methylprednisolone 1 to 2 g per day given intravenously as a pulse or in divided doses for three to five days) [95,108]. An immunosuppressive agent may be added at the same time, such as cyclophosphamide [109] or azathioprine, although evidence in favor of this practice is limited. Concomitant empiric antibiotics are prudent pending results of microbiologic studies. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)", section on 'Treatment' and "Cryptogenic organizing pneumonia", section on 'Patients with rapidly progressive disease or respiratory failure'.)
Data are limited regarding the role of cyclophosphamide in fulminant RA-ILD [109]. A systematic review of cyclophosphamide in CTD-ILD found that cyclophosphamide has, at best, a modest benefit in preserving lung function [110]. Cyclophosphamide can be administered as intravenous infusions monthly or taken orally every day. Given the toxicity of cyclophosphamide, use of this drug is generally reserved for more severe or refractory disease, and the duration of treatment is limited to six months. The administration of cyclophosphamide is described separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".)
Prognosis in fulminant disease is poor, and depending on the patient's age, other comorbidities, and patient wishes, a symptom-based palliative approach may be appropriate. (See "Palliative care for adults with nonmalignant chronic lung disease".)
Monitoring — For patients who are being treated with systemic glucocorticoids or other immunosuppressive therapy, monitoring for an objective response to treatment is generally performed at one- to three-month intervals with clinical assessment, serial chest radiographs or HRCT, and PFTs (eg, spirometry, lung volumes, diffusing capacity [DLCO], six-minute walk test with monitoring of oxygen saturation).
Monitoring for adverse effects of therapy for RA-ILD is essential. As examples:
●Monitoring for hematologic and hepatic toxicity – Close hematologic monitoring is needed with all of the immunosuppressive agents (eg, monthly initially and then every three months). Toxicity of azathioprine is partly related to deficiency in the enzyme thiopurine methyltransferase (TPMT), and analysis of the TPMT gene prior to the administration of azathioprine may help predict those individuals at risk for severe toxicity. In addition to hematologic monitoring, liver function tests are obtained monthly at first and then every three months. The pharmacology and adverse effects of azathioprine are discussed separately. With cyclophosphamide, liver function monitoring follows a similar frequency, while renal function is assessed every two to four weeks. Additional details about the administration and monitoring of these agents are provided in the table and separately (table 5). (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing' and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Mycophenolate dose and administration'.)
●Drug-induced pulmonary toxicity – Almost all of the DMARDs and biologic therapies have been associated with lung toxicity (table 2), so clinicians should keep this possibility in mind should unexpected worsening of ILD occur during therapy. (See "Drug-induced lung disease in rheumatoid arthritis".)
An important clinical question is whether drugs known to cause lung toxicity should be avoided in patients with underlying lung abnormalities due to concern about potential exacerbation. A systematic review has shown the overall risk of a drug reaction is low (1 percent), although if a reaction occurs, it often has a high mortality [75]. Potentially life-benefiting antirheumatic medications should not necessarily be withheld for what appears to be an uncommon side effect, but such patients do require ongoing monitoring for worsening respiratory symptoms or function. (See "Drug-induced lung disease in rheumatoid arthritis", section on 'Evaluation and diagnosis'.)
●Infection – A variety of serious infections have been described with use of these immunosuppressive therapies. Prophylaxis against Pneumocystis (jirovecii) pneumonia (PCP) may be warranted for some of the above treatment regimens. While the low doses of prednisone and methotrexate typically used in RA do not warrant prophylaxis, the combination of a glucocorticoid dose equivalent to ≥20 mg of prednisone daily for one month or longer and a second immunosuppressive agent or the combination of an anti-TNF-alpha agent with other intensive immunosuppression may warrant prophylaxis. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications' and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections", section on 'Pneumocystis pneumonia'.)
Vaccination with the influenza vaccine should be provided annually to all patents with rheumatoid arthritis. Vaccination to prevent COVID-19 is recommended for all individuals 12 years and older. Administration of the polysaccharide pneumococcal vaccine is recommended in all adults with chronic lung disease. In addition, a second dose of the polysaccharide vaccine five years after the first is suggested in patients receiving immunosuppressive therapies. The pneumococcal conjugate vaccine is also suggested in such patients (table 6). (See "Seasonal influenza vaccination in adults" and "COVID-19: Vaccines" and "Pneumococcal vaccination in adults".)
●Prevention of osteoporosis – For patients on long-term oral glucocorticoids, osteoporosis is a concern, and oral calcium and vitamin D supplementation are recommended (eg, daily calcium 1200 mg and vitamin D 800 international units) for prophylaxis. Depending on the patient’s age and baseline bone density, pharmacologic therapy (eg, bisphosphonates) may also be indicated. The prevention and treatment of osteoporosis are discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
●Cyclophosphamide and hemorrhagic cystitis – A high fluid intake is encouraged to prevent hemorrhagic cystitis with cyclophosphamide. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.)
●Malignancy – Patients on long-term therapy with cytotoxic medications are at risk of developing malignancy, particularly skin, cervical, and, with cyclophosphamide, bladder cancer. Thus, patients should be educated about avoidance of the sun and use of sunblock, and women should receive regular mammograms and cervical Papanicolaou smears.
Lung transplantation — Lung transplantation may be an option in end-stage RA-ILD. Among ten patients with RA-ILD who underwent lung transplantation, survival at one year was comparable to lung transplantation recipients with IPF, 67 and 69 percent, respectively [111]. A modest improvement in quality of life with respect to respiratory symptoms was also noted. Side effects of the therapy for RA (eg, osteoporosis) may be a contraindication; other extrapulmonary disease manifestations may also complicate transplantation. (See "Lung transplantation: General guidelines for recipient selection".)
FUTURE DIRECTIONS — Newer therapies for RA (eg, anti-tumor necrosis factor-alpha [anti-TNF-alpha] regimens, tocilizumab) and the antifibrotic agent pirfenidone, which is used in idiopathic pulmonary fibrosis (IPF), may also have a role in RA-ILD [1,112-114]. Research examining their effects is awaited with interest.
●A small retrospective study of tocilizumab in 28 patients with RA-ILD followed for a mean duration of 30 months, showed stabilization, improvement, or decline in forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) in 56 percent, 20 percent, and 6 percent of participants, respectively [115].
●Any potential benefit of anti-TNF-alpha therapy should be viewed in the context of several cases of rapid, occasionally fatal progression of lung disease in patients with RA-ILD treated with anti-TNF therapy [116,117]. Abatacept and tocilizumab have had a beneficial effect in case reports, although tocilizumab has also been reported to have adverse lung effects as discussed above [118,119]. A retrospective case series of 131 patients with RA who were treated with abatacept for more than one year found that the use of methotrexate in these patients was a risk factor for deterioration of ILD [120]. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)
●Nintedanib has shown benefit in progressive fibrotic ILD as described above (see 'Progressive fibrosing interstitial lung disease' above). The antifibrotic agent pirfenidone slows disease progression in IPF and is being assessed in other progressive fibrotic lung diseases in an ongoing clinical trial (NCT#02808871) [85]. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Pirfenidone'.)
PROGNOSIS — In patients with RA, the presence of RA-ILD is associated with greater mortality compared with the absence of ILD (five-year mortality 36 percent and 18 percent, respectively) [121]. Among patients with RA-ILD, the following factors affect prognosis:
●Demographics – The prognosis of RA-ILD depends on sex and age. Females contribute to the greatest number of deaths given the increased prevalence of RA in females, but males with RA are at increased risk of developing RA-ILD [31,122]. Older age has been significantly associated with increased mortality in several cohorts of patients with RA-ILD [31,87,123].
●Disease subtype – Overall, a radiographic or histologic pattern consistent with usual interstitial pneumonia (UIP) portends a greater likelihood of ILD progression and mortality [124-126]. For example, the effect of presumed histopathologic subtype was assessed in a retrospective review of 144 patients with RA-ILD using high-resolution computed tomography (HRCT) and (in a smaller number of patients) pathology [124]. The poorest survival at five years was in those with diffuse alveolar damage (DAD; 20 percent) and UIP (37 percent), while a better prognosis was found for organizing pneumonia (60 percent), bronchiectasis (87 percent), bronchiolitis (89 percent), and NSIP (94 percent).
•However, for some patients with RA-ILD and a UIP pattern, the pulmonary abnormalities do not progress and may remain subclinical. In a retrospective review of 84 patients with rheumatoid arthritis-associated usual interstitial pneumonia (RA-UIP) who were monitored for 33 months, respiratory abnormalities remained stable in approximately 50 percent (for a median of 45 months), progressed in 30 percent, and deteriorated rapidly in 17 percent [87].
●Respiratory impairment – Baseline pulmonary function tests (PFTs) and their course over time are correlated with survival. For example, in a cohort of 158 patients with RA-ILD, a lower forced vital capacity (FVC) or a 10 percent decline in FVC was independently associated with an increased risk of death regardless of baseline CT pattern [127]. Decreased diffusing capacity (DLCO) and a 10 to 15 percent decline in DLCO showed similar associations with progression of disease and mortality [125,127].
●Acute exacerbations – Acute episodes of pulmonary decompensation are a common feature of several interstitial lung diseases and are associated with a poor prognosis, including in patients with RA-ILD [128,129]. In one study of 310 patients with RA-ILD followed for a median of 48 months, 20 percent of patients experienced an acute exacerbation within three years [129]. Even after accounting for age, sex, smoking status, lung function, exercise capacity, and CT scan pattern, acute exacerbations were associated with decreased survival. Thirty-day and 90-day mortality after an acute exacerbation were 13 and 30 percent, respectively.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis" and "Society guideline links: Interstitial lung disease".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and risk factors – The prevalence of interstitial lung disease (ILD) in rheumatoid arthritis (RA) is somewhere between 10 and 50 percent, depending on the study. Risk factors for rheumatoid arthritis-associated ILD (RA-ILD) include more severe RA, high C-reactive protein, male sex, older age, obesity, cigarette smoking, exposure to fine particulate matter, anticyclic citrullinated peptide (anti-CCP) antibodies, and the presence of MUC5B promoter variant. (See 'Epidemiology' above and 'Risk factors and genetic predisposition' above.)
●Histopathologic patterns in RA-ILD – The most common histopathologic patterns among patients with RA-ILD are those of usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), with UIP and NSIP occurring in similar proportions. Other pathologic patterns include organizing pneumonitis, lymphoid interstitial pneumonitis (LIP), and diffuse alveolar damage (DAD) (table 3). (See 'Pathologic types of RA-ILD' above.)
●Clinical features – Symptoms of RA-ILD typically include dyspnea and a nonproductive cough that are insidious in onset. Recognition of exertional dyspnea may be delayed due to the exercise limitation associated with joint disease. Fever and chest pain are less common. An acute presentation is atypical for RA-ILD. (See 'Clinical features' above and 'Evaluation' above.)
●Pulmonary function tests – Pulmonary function tests (PFTs), including spirometry, lung volumes, diffusing capacity of carbon monoxide (DLCO), and pulse oximetry, are obtained in all patients with suspected ILD to assess the pattern, severity, and progression of respiratory impairment. Typical findings in RA-ILD include a restrictive pattern on lung volumes and abnormal gas transfer on DLCO and pulse oximetry. (See 'Pulmonary function tests' above.)
●Imaging – High-resolution computed tomography (HRCT) is helpful to determine the radiographic pattern (eg, ground-glass or consolidative opacification, reticular changes, honeycombing) and extent of disease. (See 'Imaging studies' above.)
●Differential diagnosis – A key step in the diagnosis of RA-ILD is excluding other processes in the differential diagnosis, such as drug-induced lung disease, infection, heart failure, recurrent gastroesophageal aspiration, and malignancy. These may also be present in addition to ILD and be the cause for an apparent deterioration in the ILD. (See 'Evaluation' above and 'Differential diagnosis' above.)
●Diagnosis – The diagnosis of RA-ILD is generally based on the combination of clinical presentation, pulmonary function testing, HRCT, and, in selected cases, lung biopsy. Bronchoalveolar lavage (BAL) findings are nonspecific, so BAL is more useful for excluding other processes such as infection or malignancy than in the confirmation of RA-ILD. Lung biopsy is reserved for patients with clinical manifestations or HRCT findings that are atypical for RA-ILD (eg, rapid progression, fever, predominance of ground-glass opacities over reticular) where a BAL has ruled out infection. In patients who need a pathologic diagnosis, transbronchial biopsy usually provides insufficient tissue, so lung biopsy is typically performed by video-assisted thoracoscopy (VATS) or thoracotomy. (See 'Evaluation' above and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
●Approach to treatment – The main factors that influence the decision to treat RA-ILD are the patient's age, HRCT with predominant ground-glass opacities, severity and rapidity of progression of the disease, and the presence of coexisting disease, along with patient wishes. Treatment is more likely to be beneficial in patients of younger age (eg, <60, rather than >70) and in those with radiographic (or rarely biopsy) evidence of NSIP, organizing pneumonia, or LIP, rather than UIP, fibrotic NSIP, or cystic LIP. Deterioration of lung function over a period of one to three months strengthens the case for intervention. (See 'Treatment' above.)
●Initiation of glucocorticoids – For patients who have RA-ILD with features that favor a treatment response and no evidence of lung infection or drug-induced lung disease, we suggest initiating therapy with oral prednisone or the equivalent (Grade 2C). The usual dose of prednisone is 0.5 mg/kg per day (based on ideal body weight) as a single morning dose. A maximum oral dose of 60 mg/day should not be exceeded. (See 'Initiation of glucocorticoid therapy' above.)
For patients who present with fulminant ILD, after excluding infection and drug-induced lung toxicity, we suggest initial high-dose systemic glucocorticoids (eg, methylprednisolone 1 to 2 g per day given intravenously as a pulse or in divided doses for three to five days) (Grade 2C). (See 'Fulminant disease' above.)
●Second immunosuppressive agent – For patients who fail to respond to initial therapy with systemic glucocorticoids or who present with fulminant ILD, a second immunosuppressive agent is typically added. Similarly, a second immunosuppressive agent may be added to glucocorticoids in patients who are unable to taper glucocorticoids to a level that does not cause adverse effects. Possible choices include mycophenolate, azathioprine, or cyclophosphamide, depending on the severity of ILD, familiarity of the treating physician with the individual agents, and the specific adverse-effect profiles of the agents. (See 'Failure to respond to systemic glucocorticoids' above.)
●Progressive fibrosing interstitial lung disease – For patients with predominant fibrotic changes on HRCT and clinical progression of disease despite immunosuppressant treatment, we suggest the addition of the antifibrotic nintedanib to maintenance agents for extrapulmonary RA rather than either therapy alone (Grade 2C). Cost, side effects, and availability may limit the use of nintedanib. (See 'Progressive fibrosing interstitial lung disease' above.)
●Monitoring and prognosis – Monitoring response to treatment is generally accomplished with clinical assessment, serial HRCT, and testing of pulmonary function, including a six-minute walk test with measurement of pulse oxygen saturation, at one- to three-month intervals. An important component of monitoring is surveillance for the adverse effects of immunosuppressive therapies and, when possible, implementation of preventive measures. Overall, the prognosis of RA-ILD appears slightly better than that seen in idiopathic pulmonary fibrosis (IPF). However, older age, a UIP pattern on histology or chest imaging, decreased pulmonary function, and acute exacerbations of ILD are significant risk factors for disease progression and mortality. (See 'Monitoring' above and 'Prognosis' above.)
