Rheumatoid Arthritis-Associated Lung Diseases
Phasawee Thandechhirun M.D.
Division of Respiratory Disease and Tuberculosis
Department of Medicine
Faculty of Medicine Siriraj Hospital
Rheumatoid arthritis (RA) is the second most prevalent autoimmune condition, affecting 1% of the world population. It is a chronic, inflammatory, autoimmune disease that primarily involves the peripheral synovial joints with high morbidity and enhanced mortality, and is associated with autoantibodies targeting various molecules including modified self-epitopes. The basic pathogenesis of RA is connected with pathogenic humoral and cellular immunity to citrullinated proteins.
Therefore, a significant proportion of RA patients exhibits RA- related autoantibodies, which include rheumatoid factor and antibodies to citrullinated protein antigens (ACPAs)1. The subclinical phase of RA where ACPAs are detected before the onset of clinically apparent disease may persist from 3 to 5 years2-5. ACPA reactivity is directed against various citrullinated intracellular and extracellular antigens, including vimentin, histones, fibrinogen, and enolase. Reactivity to citrullinated antigens correlates with the presence of the HLA-DRB1*04:01 shared epitope, which includes HLA-DRB1*04:01, HLA-DRB1*04:04, and HLADRB1*01:01, haplotypes associated with risk of developing RA6-7. Citrullination of specific anchor residues enhances the ability of peptides to bind and be presented by the major histocompatibility complex class II (MHC II)–shared epitope alleles, allowing the activation and expansion of citrulline-specific CD4+ T cells, and the subsequent promotion of ACPA generation8-12.
Genetic factors clearly play a critical role in RA risk, severity, and progression. The most important genetic risk allele for RA resides in the class II major histocompatibility (MHC) locus, accounting for about 40% of the genetic influence13. The odds ratio of developing RA in individuals with MHC class II HLA-DR4 alleles is about 5:1. A so-called shared ‘‘susceptibility epitope’’ (SE) was identified in amino acids 70 through 74 in the third hypervariable region of the DRβchain. The sequence associated with disease is generally glutamine-leucine-arginine-alanine-alanine (QKRAA), which is present in some DR4 and DR14, in addition to DR1β chains13. The SE is also associated with increased disease severity, such as extra-articular manifestations and progression of erosions14. The SE region predominantly faces away from the antigen binding groove that binds processed peptides for presentation to T cells, which has raised some questions about their precise contributory role15. RA-specific peptides that bind to QKRAA-containing molecules have been difficult to identify16. This observation led to the notion that SE might also partially contribute by shaping the T cell repertoire in the thymus, altering intracellular HLA-DR trafficking and antigen loading, or serving as an autoantigen. RA-associated alleles present citrullinated peptides efficiently to T cells, which, in turn, produce higher amounts of cytokines IL-17 and IFN-g than to native peptide. Adaptive immune responses to citrullinated peptides are also characterized by the presence of ‘‘anti-citrullinated peptide antibodies’’ (ACPAs), observed in 80%–90% of RA patients. Together these data support the hypothesis that HLA-DR risk for RA is based at least in part on the increased efficiency of antigen presentation for altered peptides rather than native proteins. Citrullination of peptides in the presence of environmental stress is ubiquitous in mammalian cells and is not a unique feature of RA. Instead, production of antibodies recognizing citrullinated peptides differentiates individuals at risk. The emergence of numerous other post-translationally modified protein targets, e.g., via carbamylation or acetylation, recognized by autoantibodies in RA is consistent with the notion of altered presentation of post-translationally modified peptides; other families of altered peptides could be implicated in discrete subsets of patients13.
There are two potential models for sequence of events leading to the development of clinically detectable RA. In the first model, a pre-RA phase comprises early generation of autoantibodies (ACPAs) that can bind post-translationally modified self-proteins, particularly via citrullination. This is followed by amplification of the range of specificities of ACPA and by the elaboration of cytokines and chemokines, complement, and metabolic disturbance in the months prior to clinical development of disease. A transition event that requires a ‘‘second hit’’ (as yet poorly understood) permits the development of synovitis. The latter is characterized by frank inflammation, stromal compartment changes, and tissue modification leading to articular damage13. In the second model, which is not mutually exclusive, there is an early interaction between innate immune activation and stromal factors that lead to stromal cell alteration, including epigenetic modifications that initiate a cycle of inflammatory stromal-mediated damage. Autoimmunity can arise as a result of these interactions that in turn can contribute directly or in an amplification loop to disease perpetuation13.
Rheumatoid arthritis produces destructive joint inflammation that is a key feature. The normal knee is a synovial joint that encloses a space containing a clear, viscous, largely acellular fluid filtrate of plasma and is bordered by synovium, a tissue consisting of lining cells, stromal matrix molecules, and blood vessels. Traditionally, platelets and rheumatoid arthritis do not go together. Recent study has reported that they do. Microparticles, vesicles shed by activated platelets17 and their presence in knee joint fluid in rheumatoid arthritis, may be incendiary devices in the conflagration of a hot, swollen, and painful rheumatoid joint18. A mouse model demonstrated that activation of glycoprotein VI, a platelet-specific receptor for collagen, induces microparticle shedding19. In addition, fibroblast-like cells that line the synovial cavity of the joint can also trigger microparticle release19. Because these fibroblast-like synoviocytes and collagen are present in the inflamed synovium, platelet interactions in this milieu could lead to local release of microparticles and their translocation into the joint space. Confirmation in human showed that microparticles from the joint fluid of patients with rheumatoid arthritis can reciprocally activate fibroblast-like synoviocytes, and this interaction induces synoviocytes to secrete inflammatory chemokines and cytokines19. Interleukin-1—a pleiotropic cytokine that is rapidly synthesized by activated human platelets20 and is packaged into microparticles19 –accounted for much of this stimulatory activity. Thus, a vicious cycle ensues: Fibroblast-like synoviocytes induce formation of platelet-derived microparticles. The microparticles then deliver interleukin-1, which triggers synoviocytes to synthesize other cytokines and chemokines, some of which attract polymorphonuclear leukocytes and thereby fan the fire of inflammation.
In addition to involvement of synovial joints, pulmonary complications are an important extra-articular feature of RA and a major cause of morbidity and mortality21- 22. The underlying pathogenesis probably involves multiple cellular compartments, including epithelium, lung fibroblasts, and the innate and adaptive immune system. Heterogeneity in the extent and progression of lung fibrosis probably reflects differences in underlying pathogenic mechanisms. Growing understanding of the key pathogenic drivers of lung fibrosis might lead to the development of more effective targeted therapies.
Lung involvement in RA
The commencement of pulmonary symptoms usually occurs within 5 years after initial RA diagnosis. The multiplicity of pulmonary disease processes exists across lung structures as shown in table 1, including airway disease, interstitial lung disease, pulmonary vasculopathy and extrapulmonary restriction. The most common form of RA-associated lung disease is interstitial lung disease23. The diagnostic evaluation of pulmonary abnormalities is complexed by underlying risk for infection, the use of therapeutic drugs with known pulmonary toxicity, and the frequency of lung disease related to rheumatoid arthritis itself. Therefore, the assessment and management of RA-associated lung diseases necessarily requires a multidisciplinary approach.
Interstitial lung disease (ILD)
Interstitial lung disease (ILD) can occur in any of the connective tissue diseases (CTD) with varying frequency and severity and has now been appreciated to be a major cause of morbidity and mortality of patients with connective tissue diseases (CTDs). With improved overall survival in these disorders, clinicians are required to evaluate and manage a rapidly increasing number of patients with clinically important ILD.
The prevalence of ILD is varying dependent on the diagnostic tools and population studied. Original studies using simple chest radiography estimated the prevalence of ILD at 5 %24. However when assessed by High Resolution Computed Tomography (HRCT), lung abnormalities have been found in 50–70 % of unselected RA patients25. ILD is the most common manifestation among other forms of RA lung involvement and may be an early feature of RA. The diagnosis of ILD in RA portends a poor prognosis.
Epidemiology and risk factors
The epidemiology of parenchymal lung disease occurring in the context of autoimmune rheumatic disease is difficult to determine for several reasons. First, the classification criteria for individual diseases are not always well defined and many current criteria have limitations in specificity or sensitivity26. In addition, overlap syndromes and undifferentiated CTD is frequent and pose both a clinical and epidemiological challenge27. Although the overlap between the pathology and clinical features of parenchymal lung disease across the spectrum of CTDs is clear, differences in the pattern and frequency of lung involvement, and also in the rate of progression and long-term outcome can be observed28-29. The disease that is most often associated with lung fibrosis is systemic sclerosis (SSc) and studies have defined the timing and frequency in the major SSc subsets. Thus, patients with diffuse SSc are roughly twice likely to be affected by moderate-to-severe lung fibroses than patients with limited SSc27, 30. However, as limited SSc is at least twice as common as diffuse disease the number of cases with lung fibrosis in the two subsets is similar in most reported cohorts. A nonspecific interstitial pneumonia (NSIP) pattern is most often seen in SSc, but a usual interstitial pneumonia (UIP) pattern is more frequent in RA than in the other CTDs31. Indeed, the occurrence of clinically significant lung fibrosis in the context of poorly defined or undifferentiated conditions has led to the concept of lung-dominant CTD32.
RA can have a UIP or NSIP pattern of lung disease, with UIP more common31. Although rheumatoid arthritis is found mostly in females. However, both rheumatoid arthritis associated-ILD (RA-ILD) and rheumatoid nodule are more common in males, with a male to female ratio as high as 2:133-34 Saag KG et al. found that history of smoking is a major risk factor, odd ratio 3.5 for smoke >25 pack-years35. High level of rheumatoid factor is risk factor for extra-articular manifestations of RA, including ILD36.
Pathogenesis13, 37 – 38
Cellular pathogenesis of fibrosis in CTD involves multiple cell types and the interplay between the various cellular components probably determines the pattern and severity of fibrosis. Key cellular interactions might determine the development and pattern of lung fibrosis through fibrotic lung injury. Cells in the epithelial, endothelial and interstitial compartments, together with components of the innate and adaptive immune system, interact with the ECM and with each other to produce architectural disruption and collagen-rich ECM. Inflammation and fibrosis can co-exist, especially at early stages, the former of which will be delineated in details later. A plausible model of pathogenesis for parenchymal lung involvement in connective tissue disease includes initial alveolar epithelial injury triggered by environmental pathogens or inflammation. These processes result in damage to lung tissue and initiation of repair pathways, including recruitment of fibroblasts and myofibroblasts. Close anatomical and functional interactions between alveolar epithelial and endothelial compartments results in recruitment of circulating cellular components and mediators including platelets and progenitor cells. Myofibroblasts are critical profibrotic cells that persist in affected lung tissue. The extent of this persistence determines the pattern and type of fibrotic reaction. Interplay with ECM components via matricellular proteins including integrins and microfibrils together with soluble factors such as CTGF drive the process, and the degree of irreversible destruction and architectural disruption probably determine the progression or reversibility of the lung condition.
Inflammation is likely to be one of the earliest events in CTD-ILD pathogenesis, leading to the influx of inflammatory cells into the interstitial and alveolar airspaces. Resultant epithelial damage occurs to some extent and studies focusing on this aspect suggest that the degree of alveolar epithelial damage at this stage is a major determinant of the likelihood of progression of the disease39-40. A variety of methods have been used to assess the extent of alveolar epithelial damage including diethylenetriamine penta-acetate (DTPA) clearance and serum levels of surfactant D or KL-6 glycoprotein41-42. Inflammation disintegrates lung tissue with loss of normal architecture. The extent to which this process occurs and the degree of disruption to the normal lung extracellular matrix, especially the basal matrix layers that delineate the alveolar structure, probably determines the extent to which recovery and resolution of the process occurs and, ultimately, the potential for recovery of lung structure and function14.
Once inflammation and epithelial damage have been established, resident interstitial pulmonary fibroblasts that are normally present in the connective tissue spaces of the lung and are located in the alveolar wall become activated43. These resident pulmonary fibroblasts seem to be activated through a variety of pathways and mediators, including transforming growth factor (TGF)-β-dependent pathways critical to their normal function 44. These cells then regulate and control other cellular processes that lead to the development of a profibrotic microenvironment in the damaged lung tissue; one consequence of the activation of resident fibroblasts is the activation and recruitment of active TGF-β from the lung tissue45. The activation of latent matrix-bound TGF-β is probably a conserved and important injury response process requiring initiation to minimize and localize pathology and might be especially important for some forms of infectious pathogen. That infection, environmental or chemical stimuli for lung epithelial damage and inflammation has an important role in initiation, amplification or persistence of these processes and might determine the progression of lung fibrosis in CTD is plausible43-44.
The developmental process of lung fibrosis requires activated fibroblasts and myofibroblasts to produce increased amounts of extracellular matrix proteins and populate fibrogenic cellular scarring within the lung43. This population of activated fibroblasts and myofibroblasts has three potential sources and all might be highly relevant in the development of interstitial fibrosis. There is generation of profibrotic myofibroblasts after lung injury. Experimental evidences indicates that the profibrotic myofibroblast population is a key inducer of the fibrotic response to injury that develops and persists at sites of fibrosis. In the lung, these cells probably arise from resident fibroblasts, transdifferentiation of epithelial cells and from circulating progenitor cells including fibrocytes. Resident fibroblasts seem to influence this process, probably controlling recruitment, differentiation and persistence in a TGF-β dependent manner via regulation of the local microenvironment in the injured lung tissue. Experimental work in transgenic mice suggests that the resident interstitial pulmonary fibroblasts are critical to the retention and/or differentiation of these circulating cells as they are recruited to sites of injury in mutant mice in which TGF-β signalling in resident fibroblasts is genetically attenuated, but they do not develop into a population of fibrogenic myofibroblasts46-48. Pulmonary epithelial cells might contribute to the profibrotic mesenchymal cell population in lung fibrosis. Multiple reports demonstrate epithelial–mesenchymal transdifferentiation, although the precise importance and role of the process remains unclear49.
The overall model of the development of lung fibrosis supports the concept that minor injury and possibly chronic disease processes lead to the development of a lung microenvironment that favours fibrosis. The lung is primed to develop fibrosis in response to injury and in certain contexts, which is likely to be more severe and persistent than in individuals who do not have CTD. SSc and other autoimmune rheumatic diseases therefore provide a scenario in which lung fibrosis or parenchymal lung disease occurs and it is likely that intrinsic differences in the pathogenic mechanisms of associated dis ease are reflected in the different patterns of lung fibrosis and inflammation. In addition, subtypes of individual disease are relevant and might have other surrogate markers such as the hallmark autoantibodies of SSc. For example, patients with anti- topoisomerase antibodies are more likely to develop clinically significant lung fibrosis and those with anti-RNA polymerase III antibodies less likely. Other minor antibodies are also associated with increased risk of lung fibrosis in SSc, including anti-U11/U12 ribonucleoprotein (RNP) antibodies or anti-Th/To RNP antibodies. Similarly, there is upregulation of the citrullination pathway in RA-ILD50.
Despite considerable studies, mostly in systemic sclerosis, there are quite a few researches particularly focusing on RA-ILD-associated pathogenesis of lung fibrosis that possibly can be assumed comparable to other CTDs. The pathogenesis of RA-ILD is unknown but may be related to genetic susceptibility, immune dysregulation, and impair wound healing. Autoimmunization provides source of antigenic stimulation in RA, and reaction of the Rheumatoid factor with immune complexes produces insoluble complexes, which might occur in the capillaries. First large capillary bed is in lungs. IgM and rheumatoid factor deposit in rheumatoid lung tissue51. Alveolar macrophage dysfunction result in recruitment of inflammation and immune effector cell such as neutrophil and lymphocyte to lungs. T lymphocyte abnormality in RA may be predict that patients will have clinical progression and evolution to ILD. HLA-DRB1 alleles were found that have high binding affinity to citrullinated proteins52, 34. Smoking may contribute to RA-ILD development by promoting citrullination of lung proteins, thus leading to the development of anti-CCP antibody53. Aubart and colleagues found that high anti-CCP antibody levels were associated with RA-related lung disease34. Several lines of data support the concept in which the lung represents the site for immune tolerance breakdown. There are many studies demonstrating the presence of RF and anti-CCP antibodies in the airways of patients with pre-clinical RA, which are not associated with corresponding changes in serum54. This disconcordant phenomenon is even markedly enhanced in RA-ILD bronchoalveolar lavage fluid (BALF) relative to matched serum5. The association of RA-ILD with citrullinated autoantigen targets in the lung is supported by studies demonstrating the relationship between RA-ILD and anti-PAD3/PAD4 antibodies capable of activating protein deimination55, suggesting that alternative post-translational modifications of lung-derived proteins may generate “cryptic” epitopes capable of driving autoimmune/ inflammatory responses which culminate in interstitial lung abnormalities56. Collectively, these data support the conceptual pathogenesis in which environmental insults (such as smoking) lead to oxidative stress which, in conjunction with posttranslational modifications and associated autoimmune responses, triggers inflammatory processes characterized by cellular infiltration and release of selected cytokines, chemokines, and growth factors. In cooperation with growth factors such as PDGF, many of these cytokines (IL-4, IL-13, and TGF-β) promote fibroblast differentiation and proliferation, providing a potential link between inflammation and fibrosis. Simultaneously, matrix metalloproteinases (MMPs) elaborated from damaged epithelia promote cellular recruitment (through breakdown of tissue barriers) as well as activation of cytokines and pro-fibrotic mediators (through cleavage of molecular precursors), thereby contributing to the cross-talk between inflammatory cascades and tissue remodeling pathways56.
RA-ILD is most commonly classified as UIP, overlapping mechanistically and phenotypically with IPF. However, subclinical disease can radiographically resemble NSIP, raising the question of whether RA-ILD encompasses a spectrum of temporally linked histopathologic subtypes or is comprised of pathogenically distinct subsets56. These paradigms suggest at least two possible pathways that could explain the coexistence of RA and ILD: (1) RA-ILD with a NSIP pattern may occur as a result of an immune response against post-translationally modified proteins (e.g., citrullinated proteins) taking place in another site (such as the joints) that subsequently cross-react with similar antigen targets in the lungs; (2) RA-ILD may represent a disease process in which interstitial lung abnormalities (including UIP) trigger an immune response against posttranslationally modified proteins (generated in response to smoking or other oxidative stressors) that promotes articular disease indicative of RA57. This leads to a considerable number of studies as to whether biomarkers in serum and bronchoalveolar fluid could differentiate between IPF and RA-ILD.
RA-ILD can present unique challenges to diagnosis and management, often leading to delays that may augment morbidity and mortality as some patients may remain asymptomatic even the presence of significantly abnormal radiologic findings suggestive of RA-associated ILD (RA-ILD). In addition, despite recent advances in our diagnostic armamentarium with high-resolution CT scans and digital quantification schemes, for example, there is still a significant lack ofcomprehension regarding the natural history of RA-ILD— limiting our ability to predict which patients will have a progressive disease pattern warranting more aggressive treatment. In view of the potential mechanistic and epidemiological overlap between RA-ILD and idiopathic pulmonary fibrosis (IPF), understanding factors that determine risk of disease progression is clearly important.
Dyspnea on exertion and nonproductive cough are the most common pulmonary symptoms. Pleuritic and nonpleuritic chest pain, fever and hemoptysis are rare24.
Physical signs might be absent despite abnormal radiographic finding. Tachypnea and basilar crackle are common. If the disease is severe, cyanosis, peripheral edema and sign of pulmonary hypertension may be detected4
Pulmonary symptoms usually occur 5 years after arthritic symptoms. Although pulmonary symptoms often follow the arthritis, simultaneous onset or exacerbation may occur. The severity of pulmonary disease does not correlate with the severity of underlying arthritis. The presence of ILD has been largely ignored in the management of RA, mainly because more typical symptoms of cough and dyspnea are subclinical in most patients. Given that early recognition and treatment of RA-ILD is of paramount importance to potentially slow/alter disease course, the discovery and validation of biomarkers that can enhance our ability to diagnose early stage RA-ILD and/or predict response to treatment in clinical trials has garnered significant attention. Although the pathogenesis of RA-ILD remains poorly defined, early identification and institution of anti-fibrotic therapy in other models of fibrosing disorders has actually led to amelioration of disease progression, exemplifying the importance ofthis strategic approach in conditions such as RA-ILD, in which early disease may be a precursor to pulmonary fibrosis.
The chest radiograph findings include bibasilar ground glass opacities, reticular and nodular opacities. In advanced disease, finding of pulmonary hypertension may be found. With new exacerbation, new opacities can become superimposed on fibrotic areas.
Computed tomography (CT) can detect abnormalities earlier than chest radiography. HRCT pattern is thought to mirror the histopathologic pattern. The most common is usual interstitial pneumonia pattern, HRCT scans show subpleural, basal predominant, reticular abnormalities with honeycombing, and traction bronchiectasis but a relative absence of ground-glass opacities (fig. 1)33.Nonspecific interstitial pneumonia is the second most common pattern that is characterized by basilar predominant ground-glass opacities and absence of honeycombing (fig. 2)33.
Pulmonary function test
Abnormalities associated with RA-ILD are identical to other fibrosing lung disease. There are reductions in lung volumes and diffusing capacity for carbon monoxide, oxygen desaturation during exercise, and in late disease, resting hypoxemia. Abnormal pulmonary function may be found in patients with normal chest radiography58.
Bronchoalveolar lavage (BAL)
Patients with RA-ILD tend to have alveolitis characteristics by increase in macrophages and neutrophils whereas those without lung disease have BAL lymphocytosis59. Abnormal BAL findings can also be seen in patients with RA and subclinical ILD60 and elevated lymphocyte counts in these patients may help to distinguish them from those with normal physiology and chest radiographs61. However, bronchoalveolar lavage (BAL) findings are not specific for the diagnosis of RA-ILD, but do play an important role in the exclusion of infection (e.g. Pneumocystis Jeroveci pneumonia), drug reactions, co-existing disease or malignancy62. Quantification of alveolar proteins has provided further insight regarding potential pathogenic mechanisms distinguishing RA patients with various stages of ILD. Bronchoalveolar lavage fluid (BALF) levels of platelet-derived growth factor isoforms AB and BB were higher in RA patients with subclinical ILD relative to RA patients without radiographic evidence of ILD63. More importantly, elevated BALF levels of IFN-γ and TGFβ-1 were associated with increased risk of radiographic progression in patients with subclinical RA-ILD63.
Usual interstitial pneumonia
UIP is more common in RA-ILD, which is different from other types of connective tissue disease that nonspecific interstitial pneumonia are most common64. Lee et al found UIP pattern in RA-ILD patients (56%). This was followed by NSIP (33 %) and organizing pneumonia (11 %). In UIP, a characteristic heterogenous pattern of fibroblast foci amid regions of normal tissue is seen (Fig. 3)65. More extensive disease, and rapid decline of pulmonary function during follow-up were found to associate with poor prognosis.
Nonspecific interstitial pneumonia
Fibrotic NSIP may occur often than cellular NSIP. The lesions are often characterized by, relatively uniform appearance at low magnification due to a cellular interstitial infiltrate of mononuclear inflammatory cells associated with varying degrees of interstitial fibrosis(fig.4)65.
Lymphocytic interstitial pneumonia
LIP is a spectrum of pulmonary lymphoid proliferation ranging from follicular bronchitis/bronchiolitis to low grade malignant lymphoma. It is characterized by infiltration of the interstitium and alveolar spaces of the lung by lymphocytes, plasma cells. Although LIP is commonly seen in Sjögren’s syndrome, it has also been reported in RA and is associated with autoantibody production (especially with dysproteinemias)
Characteristic of OP include excessive proliferation of granulation tissue, which consists loose collagen-embedded fibroblasts and myofibroblasts, within small airway, and alveolar duct, along with chronic inflammation in surround alveoli. OP has better prognosis than other RA-ILD.
Prognosis and management
The treatment for RA-ILD is quite empirical, because there have been no randomized placebo-controlled trials. Patients with non-UIP histopathologic patterns are more likely to respond to steroid and/or immunosuppressive agents.
Asymptomatic patients can be monitored though clinical assessment, pulmonary function test, and chest radiography at 6-12 months interval or whenever the symptoms get worse.
Treatments should be considered in the following patients: younger age, histopathologic patterns other than UIP, and worsening of symptoms, pulmonary function test or HRCT over the preceding 3-6 months.
For symptomatic patients who have an evidence of progressive respiratory impairment or have non-UIP histopathologic types (based on HRCT or biopsy), initial treatment should be prednisolone 0.5 mg/kg/day after excluding infection. The maximum dose is 60 mg/day as higher dose carries significant risk of infection without providing additional benefit. If response occurs (usually within 1-3 months), prednisolone should be slowly tapered to the maintenance dose of 10 mg/day.
For patients who fail to response to initial treatment with glucocorticoid, immunosuppressive agents such as azathioprine (3 mg/kg orally up to 200 mg/day), mycophenolate mofetil (250 mg given twice a day initially with a target dose of 1.5 to 2 g/day), or cyclophosphamide (100 to 120 mg orally/day as a single daily dose) could be added33.
For patients who develop rapidly progressive acute interstitial lung disease (Hamman-Rich syndrome) or organizing pneumonia after excluding infection, high-dose intravenous glucocorticoids (methylprednisolone 1-2 g/day) should be given. If those patients develop impending or ongoing respiratory failure, immunosuppressive agent may be added at the same time.
Airway Disease in Rheumatoid Arthritis
Along with interstitial lung disease, airway disease is now regarded as one of the major lung complications in RA. Both upper and lower airway diseases can be involved.
Upper airway involvement
The prevalence of laryngeal involvement in RA ranges from 13-75 % in different series66. Cricoarytenoid arthritis is the most common cause of upperairway obstruction. Other causes are less common such as rheumatoid nodules on the vocal cord or vasculitis involving the recurrent laryngeal or vagus nerves, causing vocal cord paralysis. Upper airway disease is frequently found in females with longstanding and severe RA67. Early manifestation includes hoarseness of voice, dysphagia, odynophagia, tenderness of the throat, pain on coughing or speaking, and exertional dyspnea. Acute stridor or obstructive respiratory failure might occur from sudden subluxation or superimposed airway edema from infection or recent endotracheal intubation. However, symptoms usually are absent until significant obstruction occurs.
HRCT is more sensitive than direct laryngoscopy and can detect abnormalities before symptoms develop. These HRC findings include prominent hyperdense intra-articular sclerotic foci in the arytenoid and cricoid cartilages, increased spacing between the arytenoid and cricoid cartilages due to joint effusion, and subluxation of the joint68.
Mild symptoms may be treated with non-steroidal anti-inflammatory drugs (NSAIDs) and other medications to control RA joint inflammation. For more severe obstruction, surgical intervention with mobilization of the cricoarytenoid joints and lateral fixation of one of the cords may be required in addition to immediate airway management33.
Lower airway involvement
The prevalence of small airway obstruction and bronchial hyperresponsiveness remains uncertain as studies have been confounded by smoking or RA-ILD. Mori et at. found that prevalence of obstructive small airway disease was 30.3 % in RA patients without RA-ILD or bronchiolitis on HRCT. However,17.4 % of participants in this study were former or current smokers. Factors that were significantly associated with abnormal FEF25–75include respiratory symptoms, smoking history, and disease duration more than 10 years69. The prevalence of small airways abnormalities detected from HRCT is greater than physiologic airway obstruction detected from PFT70.
Bronchiectasis is the feature of permanent irreversible dilatation of cartilage-containing airways. Symptoms typically include recurrent cough, sputum production, and respiratory infections. The prevalence in case series has varied from 0 % to 10%. HRCT can detect bronchiectasis up to 30 % in RA without ILD (Fig. 5)71–72. The most common radiographic abnormalities are bibasilar diffusely interstitial marking and focal opacities. However, cysts and air-fluid level can be found. Obstructive and restrictive patterns can be found in PFT.
Shared genetic risk factors in terms of share epitope (SE) might contribute to the association between bronchiectasis and RA. In RA patients with bronchiectasis, more protease inhibitor phenotype MM and HLADR4- antigen positive were observed52. Remy et at. found that CFTR abnormalities may predispose to the development of bronchiectasis in RA72. RA patients with bronchiectasis, recurrent pulmonary infections, and respiratory failure could have a mortality rate 7.3 times of general population, 5 times of RA patients alone, 2.4 time of bronchiectasis patients alone73. Treatment is similar to other forms of bronchiectasis.
Obliterative bronchiolitis (OB) is rare but fatal, characterized by progressive concentric narrowing of membranous bronchioles that associated with previous penicillamine treatment. OB is more common in women and in patients with positive rheumatoid factor tests.
The clinical manifestations include abrupt onset of dyspnea and dry cough. Its rapid onset allows us to distinguish this condition from other pulmonary diseases in RA.
Physical examination may find inspiratory rales and mid-inspiratory squeak.Chest radiography can be normal but may show sign of air trapping. HRCT often shows bronchial wall thickening, centrilobular emphysema, areas of low attenuation with a mosaic pattern, and bronchiectasis (Fig. 6)74. PFT may reveal airflow obstruction, normal or reduced diffusing capacity (DLCO), and mild to moderate arterial hypoxemia as well as respiratory alkalosis in arterial blood gases. BAL mayshow an increase in the percentage of neutrophils (range 60 to 78 %)74.
Constrictive bronchiolitis is the most common histopathologic finding that shows lymphoplasmocytic infiltration of airway wall that are confined to small bronchi and bronchioles. Bronchiolar lumens are obliterated and bronchial walls are destroyed by granulation tissue. Parenchymal involvement may be affected only to the surrounding bronchiolitis (Fig. 7)74.
The initial treatment of RA-associated OB is to discontinue the offending agent such as penicillamine, gold, or sulfasalazine. The use of antibiotics and bronchodilator is usually ineffective. The prognosis is generally poor due to the lack of satisfactory response to immunosuppressive agents. High-dose corticosteroids are often used. Azathioprine, cyclophosphamide75, etanercept (a TNF-inhibitor)76, erythromycin77, could be used. However, data from large series or randomized trials are lacking. In severe cases, lung transplant may be necessary.
Follicular bronchiolitis is defined as lymphoid hyperplasia of bronchus-associated lymphoid tissue (Fig. 8)71. The obstruction is caused by external compression of bronchioles which is different from direct luminal occlusion seen in OB. In study of Tansey and colleague, follicular bronchiolitis (23 %) was most commonly seen in RA patients.
Clinical presentations include dyspnea (100%), both fever and cough infrequently occur. High level (1:640 to 1:2560) of rheumatoid factor is usually seen.
Chest radiography shows bilateral reticular or nodular opacities. The most common findings in HRCT are bilateral, diffuse centrilobular nodule (less than 3 mm.), and ground grass opacity. Mosaic pattern and honeycombing are usually not seen. PFT shows both obstructive and restrictive pattern, but restrictive is more common.
The optimal treatment of follicular bronchiolitis in RA is not known. Patients with mild symptoms may be observed without treatment. For symptomatic patients, corticosteroid and macrolide may be used33.
Rheumatoid nodule is the only pulmonary manifestation specifically for RA.Prevalence of pulmonary rheumatoid nodules in RA patients depends on methods used for detection such as chest radiography can detect lung nodules approximately 0.2 % of RA patients. HRCT increases the yield of detection to 22 % 78. Rheumatoid nodules often occur in patients with longstanding disease and with concomitant subcutaneous rheumatoid nodules. The HLA-DR4 haplotype (including the heterogeneous group of DRB1 alleles) is predictive of the risk of developing subcutaneous nodules in RA.
Patients are usually asymptomatic, but hemoptysis (from cavitation lesion),pleural effusion, pyopneumothorax and pneumothorax (from erosion pleural space) can occur. (Fig. 9)71.
The nodules in the lung could be recurrent or appearing first in one lung then the other lung later. These nodules may be solitary or multiple, and may enlarge, remain static or shrink to scar. They are round and varying in size from 0.5-7cm. They are located in subpleural areas or interlobular septa in the middle and upper lung zones78. The central necrosis may occur in some of pulmonary nodules. Histopathology of the nodules are central area of necrosis surrounded by palisading macrophages and then inflammatory cells including lymphocytes and plasma cells.The radiographic finding may mimic malignancy.
Etiology of rheumatoid nodule is unknown. It is hypothesized that repeated trauma including local vascular damage resulting in neoangiogenesis and granulation formation. Endothelial injury causes accumulation of IgM immune complex on small vessel walls. The deposit of RF induces activation of monocytes and macrophages. These cells secrete interleukin-1, prostaglandin E2 and angiogenic factors. Chemotactic factors and fibronectin are responsible for necrotic matrix and formation of palisading granuloma. This can suggest that rheumatoid nodule may result from vasculitis process79.
Differentiation of rheumatoid nodules from a lung cancer is essential, especially in patients with a history of smoking. Prognosis of rheumatoid nodules is good, with spontaneous resolution. Complications are rare.
Pleural disease is one of the most common pulmonary complication of RA. In autopsy studies, 38-73% of RA patients had pleural involvement; however, symptomatic pleurisy was less frequent80–81. Biopsy reveals nonspecific chronic inflammation and fibrosis. Incidence of clinical pleural effusion in RA is 2-5 %. Male and subcutaneous nodule are thought to be at high risk of pleural involvement, usually at the age of 45 years31. Pleural disease is common in longstanding RA but can precede joint disease. A high prevalence of HLA-B8 and Dw3 is associated with rheumatoid pleural effusion82.
Mechanisms of pleural effusion include impaired fluid resorption in pleura, necrosis of subpleural rheumatoid nodules, and local production of cytokines and immune complexes leading to endothelial injury and capillary permeability33
The patients may be asymptomatic with effusion discovered in routine chest radiograph. When symptoms occur, chest pain and fever are common. These symptoms may mimic bacterial pneumonia. Usually, pleural effusion is small-moderate volume and unilateral.
Pleural effusion can be diagnosed on chest radiography, with blunting of the costophrenic angles in the upright position. Further evaluation of possible comorbid ILD, subpleural cavitating rheumatoid nodules, pleural thickening, or unexpandable lung might require HRCT to aid in diagnosis.
Thoracentesis should be performed for any effusion with >1 cm of layering on decubitus films. Rheumatoid effusion is a sterile exudative fluid with low pH (<7.3), low glucose (<60 mg/dl) and high lactate dehydrogenase (may be >700 IU/L).
This low glucose level is secondary to impaired membrane transport of glucose (due to pleural thickening) and increased utilization by inflammatory cell83.
Low level of pH reflects ongoing inflammation in pleural cavity with a high rate of glucose metabolism and lactate and carbon dioxide accumulation82. Infection should be ruled out as low pH, low glucose, and high LDH level seen in rheumatoid effusion is also typical for bacterial empyema.
Sterile emphysematous effusion is pus-like appearance with a very high WBC content (>50,000/mm3), low pH (<7.2) and glucose content (<40 mg/dl), and massive cellular debris without organisms found. This may be caused by rupture necrotic subpleural rheumatoid nodule into pleural space and subsequentformation of bronchopleural fistula (Fig.10)78. Long standing of chronic pleural inflammation may result in formation of fibrous peel causing trapped lung. Chronic pleural inflammation may cause pseudochylous pleural, milky appearance due to elevated cholesterol level (>200 mg/dl). Among the causes for pseudochylous pleural exudates, long standing TB and rheumatoid pleural effusion were the most common.
The rheumatoid factor is increased in pleural effusion and is usually greater than 1:320 and greater than found in serum. A finding of RF in the pleural effusion is strongly suggestive of a rheumatoid origin for the pleural exudate. RA cell or ragocytes (WBC with phagocytic intracellular inclusions and ability to liberate RF) are seen but are not diagnostic because they can be found in tuberculous pleurisy and malignant pleural effusions84. There are giant multinucleated macrophages, elongated macrophages, and background of granular debris in cytology examination33.
Rheumatoid pleuritis and rheumatoid effusion usually resolve spontaneously(with in average of 14 month) or with treatment of RA joint disease. However, symptomatic patients may require thoracentesis. When diseases do not resolve spontaneously, corticosteroid and immunosuppressive drug may be beneficial.Complete resolution of pleural effusion with high doses of oral corticosteroid was reported82.
Pulmonary arterial hypertension (PAH) is extremely rare in RA. This may be associated with vasculitis, symptoms and sign of systemic vasculitis should occur simultaneously. Secondary pulmonary hypertension has also been reported in patients with RA. Dawson et at. found that 6 % of RA patients had pulmonary hypertension due to lung disease85.
Risk of developing lung cancer may be slightly greater in patients with RA than in the general population. In one cohort study of 8768 patients with diagnosis RA, patients with RA were 43% (odds ratio 1.43) more likely to develop lung cancer than patients without RA86.
Pulmonary involvement is common among patients with rheumatoid arthritis. Almost all components of the lung structure are targets of injury, especially ILD. The presence of ILD is important because it leads to significant morbidity and mortality. The mechanism of lung injury is caused by genetic, environmental exposure and drug use. Some patients may develop pulmonary disease before arthritis symptoms, however some patients with pulmonary involvement may be asymptomatic. Advanced screening tools allow us to detect and treat at an early stage.
1. Holers VM. Autoimmunity to citrullinated proteins and the initiation of rheumatoid arthritis. Curr Opin Immunol 2013; 25:728-35.
2. Brink M, Hansson M, Mathsson L, et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum 2013; 65:899-910.
3. Arend WP, Firestein GS. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol 2012; 8:573-86.
4. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50:380-6.
5. Reynisdottir G, Karimi R, Joshua V, et al. Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol 2014; 66:31-9.
6. Blass S, Engel JM, Burmester GR. The immunologic homunculus in rheumatoid arthritis. Arthritis Rheum 1999; 42:2499-506.
7. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30:1205-13.
8. De Rycke L, Peene I, Hoffman IE, et al. Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: diagnostic value, associations with radiological progression rate, and extra-articular manifestations. Ann Rheum Dis 2004; 63:1587-93.
9. Vincent C, de Keyser F, Masson-Bessiere C, Sebbag M, Veys EM, Serre G. Anti-perinuclear factor compared with the so called “antikeratin” antibodies and antibodies to human epidermis filaggrin, in the diagnosis of arthritides. Ann Rheum Dis 1999; 58:42-8.
10. Kidd BA, Ho PP, Sharpe O, et al. Epitope spreading to citrullinated antigens in mouse models of autoimmune arthritis and demyelination. Arthritis Res Ther 2008; 10:R119.
11. Scally SW, Petersen J, Law SC, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med 2013; 210:2569-82.
12. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol 2003; 171:538-41.
13. Firestein GS, McInnes IB. Immunopathogenesis of Rheumatoid Arthritis. Immunity 2017; 46:183-96.
14. de Carvalho EF, Parra ER, de Souza R, A’B Saber AM, Machado Jde C, Capelozzi VL. Arterial and interstitial remodelling processes in non-specific interstitial pneumonia: systemic sclerosis versus idiopathic. Histopathology 2008; 53:195-204.
15. Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis?: II. T cell-independent mechanisms from beginning to end. Arthritis Rheum 2002; 46:298-308.
16. Kirschmann DA, Duffin KL, Smith CE, et al. Naturally processed peptides from rheumatoid arthritis associated and non-associated HLA-DR alleles. J Immunol 1995; 155:5655-62.
17. Perez-Pujol S, Marker PH, Key NS. Platelet microparticles are heterogeneous and highly dependent on the activation mechanism: studies using a new digital flow cytometer. Cytometry A 2007; 71:38-45.
18. Zimmerman GA, Weyrich AS. Immunology. Arsonists in rheumatoid arthritis. Science 2010; 327:528-9.
19. Boilard E, Nigrovic PA, Larabee K, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327:580-3.
20. Denis MM, Tolley ND, Bunting M, et al. Escaping the nuclear confines: signal-dependent pre-mRNA splicing in anucleate platelets. Cell 2005; 122:379-91.
21. Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev 2015; 24:1-16.
22. Olson AL, Swigris JJ, Sprunger DB, et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med 2011; 183:372-8.
23. Yohe ME, Gryder BE, Shern JF, et al. MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. Sci Transl Med 2018; 10. ( 488).
24. O’Dwyer DN, Armstrong ME, Cooke G, Dodd JD, Veale DJ, Donnelly SC. Rheumatoid Arthritis (RA) associated interstitial lung disease (ILD). Eur J Intern Med 2013; 24:597-603.
25. Cortet B, Flipo RM, Remy-Jardin M, et al. Use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis 1995; 54;815-9.
26. Fischer A, du Bois R. Interstitial lung disease in connective tissue disorders. Lancet 2012; 380:689-98.
27. Cottin V. Significance of connective tissue diseases features in pulmonary fibrosis. Eur Respir Rev 2013; 22 :273-80.
28. Tsuchiya Y, Takayanagi N, Sugiura H, et al. Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome. Eur Respir J 2011; 37:1411-7.
29. Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and survival. Lupus 2012; 21:1412-22.
30. Nihtyanova SI, Schreiber BE, Ong VH, et al. Prediction of pulmonary complications and long-term survival in systemic sclerosis. Arthritis Rheumatol 2014; 66:1625-35.
31. Kim EJ, Elicker BM, Maldonado F, et al. Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease. Eur Respir J 2010; 35:1322-8.
32. Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest 2010; 138:251-6.
33. Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev 2015; 24:1-16.
34. Aubart F, Crestani B, Nicaise-Roland P, et al. High levels of anti-cyclic citrullinated peptide autoantibodies are associated with co-occurrence of pulmonary diseases with rheumatoid arthritis. J Rheumatol 2011; 38:979-82.
35. Saag KG, Kolluri S, Koehnke RK, et al. Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities. Arthritis Rheum 1996; 39:1711-9.
36. Turesson C, Jacobsson LT, Sturfelt G, Matteson EL, Mathsson L, Ronnelid J. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:59-64.
37. Wells AU, Denton CP. Interstitial lung disease in connective tissue disease–mechanisms and management. Nat Rev Rheumatol 2014; 10:728-39.
38. Catrina AI, Ytterberg AJ, Reynisdottir G, Malmstrom V, Klareskog L. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol 201410:645-53.
39. Hsu E, Shi H, Jordan RM, Lyons-Weiler J, Pilewski JM, Feghali-Bostwick CA. Lung tissues in patients with systemic sclerosis have gene expression patterns unique to pulmonary fibrosis and pulmonary hypertension. Arthritis Rheum 2011; 63:783-94.
40. Peljto AL, Steele MP, Fingerlin TE, et al. The pulmonary fibrosis-associated MUC5B promoter polymorphism does not influence the development of interstitial pneumonia in systemic sclerosis. Chest 2012; 142:1584-8.
41. Stock CJ, Sato H, Fonseca C, et al. Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis. Thorax 2013; 68:436-41.
42. Hant FN, Ludwicka-Bradley A, Wang HJ, et al. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol 2009; 36:773-80.
43. Hoyles RK, Khan K, Shiwen X, et al. Fibroblast-specific perturbation of transforming growth factor beta signaling provides insight into potential pathogenic mechanisms of scleroderma-associated lung fibrosis: exaggerated response to alveolar epithelial injury in a novel mouse model. Arthritis Rheum 2008; 58:1175-88.
44. Christmann RB, Wells AU, Capelozzi VL, Silver RM. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis: clinical, radiologic, histopathologic, and treatment evidence. Semin Arthritis Rheum 2010; 40:241-9.
45. Walker N, Badri L, Wettlaufer S, et al. Resident tissue-specific mesenchymal progenitor cells contribute to fibrogenesis in human lung allografts. Am J Pathol 2011; 178:2461-9.
46. Borie R, Quesnel C, Phin S, et al. Detection of alveolar fibrocytes in idiopathic pulmonary fibrosis and systemic sclerosis. PLoS One 2013; 8:e53736.
47. Sonnylal S, Denton CP, Zheng B, et al. Postnatal induction of transforming growth factor beta signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma. Arthritis Rheum 2007; 56:334-44.
48. Hoyles RK, Derrett-Smith EC, Khan K, et al. An essential role for resident fibroblasts in experimental lung fibrosis is defined by lineage-specific deletion of high-affinity type II transforming growth factor beta receptor. Am J Respir Crit Care Med 2011; 183:249-61.
49. Goh NS, Desai SR, Anagnostopoulos C, et al. Increased epithelial permeability in pulmonary fibrosis in relation to disease progression. Eur Respir J 2011; 38:184-90.
50. Samara KD, Trachalaki A, Tsitoura E, et al. Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis. Respir Res 2017; 18:218.
51. Tomasi TB, Fudenberg HH, Finby N. Possible relationship of rheumatoid factor and pulmonary disease. Am J Med 1962; 33:243-8.
52. Wordsworth BP, Lanchbury JS, Sakkas LI, Welsh KI, Panayi GS, Bell JI. HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci U S A 1989; 86:10049-53.
53. Makrygiannakis D, Hermansson M, Ulfgren AK, et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann Rheum Dis 2008; 67:1488-92.
54. Willis VC, Demoruelle MK, Derber LA, et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum 2013; 65:2545-54.
55. Giles JT, Darrah E, Danoff S, et al. Association of cross-reactive antibodies targeting peptidyl-arginine deiminase 3 and 4 with rheumatoid arthritis-associated interstitial lung disease. PLoS One 2014; 9:e98794.
56. Brito Y, Glassberg MK, Ascherman DP. Rheumatoid Arthritis-Associated Interstitial Lung Disease: Current Concepts. Curr Rheumatol Rep 2017; 19(12):79.
57. Paulin F, Doyle TJ, Fletcher EA, Ascherman DP, Rosas IO. Rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary fibrosis: shared mechanistic and phenotypic traits suggest overlapping disease mechanisms. Rev Invest Clin 2015; 67:280-6.
58. Avnon LS, Manzur F, Bolotin A, Heimer D, Flusser D, Buskila D, et al. Pulmonary functions testing in patients with rheumatoid arthritis. Isr Med Assoc J 2009; 11(2):83-7.
59. Garcia JG, Parhami N, Killam D, Garcia PL, Keogh BA. Bronchoalveolar lavage fluid evaluation in rheumatoid arthritis. Am Rev Respir Dis 1986; 133:450-4.
60. Gilligan DM, O’Connor CM, Ward K, Moloney D, Bresnihan B, FitzGerald MX. Bronchoalveolar lavage in patients with mild and severe rheumatoid lung disease. Thorax 1990; 45:591-6.
61. Tishler M, Grief J, Fireman E, Yaron M, Topilsky M. Bronchoalveolar lavage–a sensitive tool for early diagnosis of pulmonary involvement in rheumatoid arthritis. J Rheumatol 1986; 13:547-50.
62. Kim DS. Interstitial lung disease in rheumatoid arthritis: recent advances. Curr Opin Pulm Med 2006; 12:346-53.
63. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, et al. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med 2008; 168:159-66.
64. Lee HK, Kim DS, Yoo B, Seo JB, Rho JY, Colby TV, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease. Chest 2005; 127:2019-27.
65. Kim EJ, Collard HR, King TE, Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest 2009; 136:1397-405.
66. Lawry GV, Finerman ML, Hanafee WN, Mancuso AA, Fan PT, Bluestone R. Laryngeal involvement in rheumatoid arthritis. Clinical, laryngoscopic, and computerized tomographic study. Arthritis Rheum 1984; 27:873-82.
67. Geterud A, Ejnell H, Mansson I, Sandberg N, Bake B, Bjelle A. Severe airway obstruction caused by laryngeal rheumatoid arthritis. J Rheumatol 1986; 13:948-51.
68. Greco A, Fusconi M, et al. Cricoarytenoid joint involvement in rheumatoid arthritis: radiologic evaluation. Am J of Otolaryngol 2012; 33:753-5.
69. Mori S, Koga Y, Sugimoto M. Small airway obstruction in patients with rheumatoid arthritis. Mod Rheumatol 2011; 21:164-73.
70. Wilsher M, Voight L, Milne D, et al. Prevalence of airway and parenchymal abnormalities in newly diagnosed rheumatoid arthritis. Respir Med 2012; 106:1441-6.
71. Chansakul T, Dellaripa PF, Doyle TJ, Madan R. Intra-thoracic rheumatoid arthritis: Imaging spectrum of typical findings and treatment related complications. Eur J Radiol 2015; 84:1981-91.
72. Remy-Jardin M, Remy J, Cortet B, Mauri F, Delcambre B. Lung changes in rheumatoid arthritis: CT findings. Radiology 1994; 193:375-82.
73. Puéchal X, Génin E, Bienvenu T, Le Jeunne C, Dusser DJ. Poor survival in rheumatoid arthritis associated with bronchiectasis: A family-based cohort study. PloS One 2014; 9:e110066.
74. Lynch JP, 3rd, Weigt SS, DerHovanessian A, Fishbein MC, Gutierrez A, Belperio JA. Obliterative (constrictive) bronchiolitis. Semin Respir Crit Care Med 2012; 33:509-32.
75. van de Laar MA, Westermann CJ, Wagenaar SS, Dinant HJ. Beneficial effect of intravenous cyclophosphamide and oral prednisone on D-penicillamine-associated bronchiolitis obliterans. Arthritis Rheum 1985; 28:93-7.
76. Cortot AB, Cottin V, Miossec P, Fauchon E, Thivolet-Béjui F, Cordier J-F. Improvement of refractory rheumatoid arthritis-associated constrictive bronchiolitis with etanercept. Respir Med 2005; 99:511-4.
77. Hayakawa H, Sato A, Imokawa S, Toyoshima M, Chida K, Iwata M. Bronchiolar disease in rheumatoid arthritis. Am J Respir Crit Care Med 1996; 154:1531-6.
78. Ozkaya S, Bilgin S, Hamsici S, Findik S. The pulmonary radiologic findings of rheumatoid arthritis. Respiratory Medicine CME 2011; 4:187-92.
79. Garcia-Patos V. Rheumatoid nodule. Semin Cutan Med Surg 2007; 26:100-7.
80. Fingerman DL, Andrus FC. Visceral lesions associated with rheumatoid arthritis. Ann Rheum dis 1943 ;3:168.
81. Horler A, Thompson M. The pleural and pulmonary complications of rheumatoid arthritis. Ann Intern Med 1959; 51:1179-203.
82. Balbir-Gurman A, Yigla M, Nahir AM, Braun-Moscovici Y. Rheumatoid pleural effusion. Semin Arthritis Rheum 2006; 35:368-78.
83. Dodson WH, Hollingsworth JW. Pleural Effusion in Rheumatoid Arthritis. N Engl J Med 1966; 275:1337-42.
84. Faurschou P, Faarup P. Pleural granulocytes with cytoplasmic inclusions from patients with malignant lung tumours and mesothelioma. Eur J Respir Dis 1980; 61:151-5.
85. Dawson JK, Goodson NG, Graham DR, Lynch MP. Raised pulmonary artery pressures measured with Doppler echocardiography in rheumatoid arthritis patients. Rheumatology (Oxford) 2000; 39:1320-5.
86. Khurana R, Wolf R, Berney S, Caldito G, Hayat S, Berney SM. Risk of development of lung cancer is increased in patients with rheumatoid arthritis: a large case control study in US veterans. J Rheumatol 2008; 35:1704-8.