By: Christopher V. Tehlirian, MD
Dr. Tehlirian has no significant financial interest or relationships to disclose.
Release Date: February 5, 2009
Expiration Date: February 5, 2011
For CME credit,TAKE POST-TEST & EVALUATION
- The natural history and patterns of rheumatoid lung disease;
- Risk factors of each of the different types of rheumatoid lung disease;
- Methotrexate lung injury; and
- The clinical implications of the review of the literature.
A 79-year-old white woman with seropositive erosive nodular rheumatoid arthritis (RA) that was diagnosed in the 1960s presented. She’s been treated with NSAIDs, IM gold, and prednisone as well as methotrexate, which she was on for about 3 months but stopped because of nausea. She’s been on Arava since 2003. She’d had multiple surgical interventions, likely secondary to her active rheumatoid disease; she has allergies, and her most relevant current medications are methotrexate and etanercept, starting in December, 2005. Her family history includes cancers and myocardial infarctions, and there’s no tobacco or alcohol in the social history.
She fell almost a year ago and has a non-displaced fracture of her hip and constantly complains of hip pain, but she came to the emergency room in January 2006 complaining of hip pain. Incidentally, she is found to be saturating 84% on room air. They did an AVG on room air, and her PaO2 was 40, and her chest X-ray was abnormal.
Her medical, surgery and allergy histories show that she did smoke about a pack a day for 10 years, but quit in the 1950s. She came to the Bayview ER, complaining of dyspnea on exertion (DOE), a worsening cough from her baseline and saturating about 78 to 80% on room air. A week before the onset of these symptoms, she had a low-grade fever. Her chest X-rays are abnormal, with infiltrates in the periphery.
The patient in the third case is a 57-year-old woman with Sjogren’s syndrome that was diagnosed in 1985; she was then diagnosed with RA in 1989. Her previous treatments were with hydroxychloroquine, D-penacillamine, and IM gold; she has been on methotrexate and etanercept since 1999. Her medical history includes an Achilles tendon rupture. She had a rheumatoid nodule on her Achilles, which ended up contributing to the rupture. She has no history of tobacco or alcohol.
In May 2006 she was seen in the pulmonary clinic after 3 years of a non-productive cough. For 5 months prior to this visit, she had been having worsening DOE. She could only go up two flights of stairs, and got winded easily. A chest X-ray before this visit showed that she had increased lung volumes; a high-resolution CT, which was done at an outside facility and reviewed by the pulmonary staff, showed that the parenchyma was normal, but there was some thickening of the bronchial wall. Her pulmonary function tests, done soon after this visit, showed that she had an obstructive pattern.
Discussion –RA and the Rheumatoid Lung
RA is a systemic inflammatory disease that has a female predominance. It affects about 1% worldwide, and it’s thought that about 40% of all rheumatoid patients have some sort of extra-articular manifestation.
Compared with an age-matched general population, RA patients have a worse survival rate. Autopsies on 1,246 RA patients in 1993 revealed that 18% were thought to have died from lung disease, 27% were likely due to infections, and cardiovascular disease is somewhere around 27 % as well. But for RA patients with extra-articular manifestations, expectations of survival drop quite a bit in the years after diagnosis.
A big hazard, then, for RA patients is extra-articular involvement. Manifestations, from the most common to the least common, are:
- Sicca symptoms
- Rheumatoid nodules
- Pulmonary involvement
- Cardio involvement (pericarditis and myocarditis, which is extremely rare)
- Hematologic manifestations (from anemia chronic disease to Felty’s syndrome)
- Cervical myelopathy
- Opthalmologic involvement
- Vasculitis (a late-stage manifestation that can be systemic)
- Amyloid (from a chronic inflammatory state).
History of Rheumatoid Lung
It was first described in 1948 (Ellman et al. Rheumatoid disease with joint and pulmonary manifestations. BMJ 1948;2:816–820). They published several cases of patients with RA who had severe erosive joint disease who also developed an interstitial lung and suggested there may be an association between the inflammatory joint disease and interstitial lung disease. Then, in 1953, Anthony Caplan (Caplan, A. Certain unusual radiologic appearances in the chest of coal miners suffering from rheumatoid arthritis. Thorax 1953;8:29–37) described rheumatoid nodules within the lung parenchyma, associated with pneumoconiosis in coal miners, who were exposed to coal dust. But in 1954, rheumatoid lung nodules were found in patients with RA who were not exposed to coal dust and without pneumoconiosis. In 1955 there was a short case series (Sinclair et al. Clinical and pathologic study of sixteen cases of rheumatoid arthritis with extensive visceral involvement. Q J Med 1955;25:313–332) of about 10 patients with RA whose autopsies showed that the pleural disease was much higher in rheumatoid patients than in the general population, and much higher than what they had previously seen clinically. In 1961, Cudkowicz described the first pulmonary function tests and lung biopsies were done in RA patients. (Cudkowicz et al. Rheumatoid lung disease. Br J Dis Chest 1961;55:35-39).
What is Lung Disease?
At that point, then, the question became, what exactly is rheumatoid lung disease? It can be any one of the following, listed again from most common to the least common:
- Pleural involvement (pleurisy, effusions)
- Pulmonary parenchymal nodules
- Rheumatoid-associated interstitial lung disease
- Bronchiolitis obliterans organizing pneumonia
- Obliterative bronchiolitis (obstructive lung disease/bronchiectasis)
- Rheumatoid-associated pulmonary hypertension
- Pulmonary vasculitis/arteritis
- Shrinking lung syndrome
- Miscellaneous: MTX, cricoarytenoid arthritis, infection, cancer
It’s interesting to note that these studies in the late 1940s and 1950s were really describing interstitial lung disease with RA, and then Caplan obviously described pneumoconiosis associated with pulmonary nodulosis. But there’s a whole host of other types of lung involvement that can be seen with RA.
Pleural involvement is thought to be the most common manifestation, based somewhat on clinical studies and symptoms. Using large cohorts of rheumatoid patients as the standard, about 15 to 20% of them describe pleurisy. However, almost 75% of them have some form of pleural involvement; symptomatic-wise, it’s only 15 to 20%. Men are thought to be most at risk for getting pleural involvement, usually in their 40s and 50s, and nodules are associated with this.
On autopsy at least 40% of RA patients have some form of pleural involvement. Pleural thickening––just like pleural involvement––and pleural effusions are more common in men than in women, and in rheumatoid arthritis, again, in their fourth and fifth decade of life. However, based on the studies and the big discrepancy between autopsy and symptoms, most pleurisy is thought to be asymptomatic and may be incidentally found on physical exam or radiologic findings. Pleural effusions, typically small, are present in about 3 to 5% of rheumatoid patients. 25% of the cases are bilateral, and 25% may precede the joint disease.
The pleural effusion is usually filled with cholesterol crystals. Some are between 100 and 8,000 cells, predominant lymphocytes. There’s a high LDH, so it’s exudative, and the glucose is notoriously low, so infection needs to be ruled out.
This chest X-ray shows costophrenic blunting with a small pleural effusion.
Rheumatoid lung nodules are the only lung finding specific to RA. All other manifestations are found in other diseases and can be idiopathic. Rheumatoid lung nodules are more common in men than in women, and more common with patients who have nodules elsewhere and have positive rheumatoid factor. They are frequently in the periphery in the right, middle lung, and 50% of them can cavitate. Usually, they are asymptomatic. Of concern, if they centrally cavitate, they may cause a pneumothorax; they may cause hemoptisis or bronchial-pleural fistula.
Caplan’s syndrome is pulmonary nodulosis in RA and pneumoconiosis related to the exposure of coal dust, silica, or asbestos. Anthony Caplan described coal miners who had pulmonary lung nodules as well as pneumoconiosis, which was also described later not only in coal miners but in workers in other occupations that involved silica and asbestos exposure. It’s characterized by lung nodules that are greater than 1 centimeter and a periphery that can become much more calcified. The prevalence was thought to be 2 to 6% of patients with RA, but with coal mining declining as an occupation, the prevalence too has been declining. Treatment is to stay away from the coal mine.
Interstitial Lung Disease
Interstitial lung disease had a prevalence initially reported to be around 1.6% to 5%––but others think it might be up to 40%. Herein lies a big problem: defining the natural history and the prevalence of rheumatoid lung disease.
A lot of studies involve not only interstitial lung disease in RA, but also other forms of lung disease, including bronchiolitis obliterans, obliterative bronchiolitis and other interstitial diseases. This makes the prevalence difficult to define because the researchers were looking at a heterogeneous group of patients. The second reason why this is such a broad number is that researchers were using different tools to define the lung disease. Initially, when they came up with this number in the 1950s, they were using chest X-ray, which later was found to be relatively insensitive in picking up interstitial lung disease early on. Even higher numbers (40-60%) have been found on autopsy studies of rheumatoid patients. So here again there’s a big discrepancy between what is found clinically and what is found on autopsy.
Walker and his colleagues (reference) defined interstitial lung disease by the radiograph. In 1955, they found that 1.6% of a large cohort of rheumatoid patients had evident radiographic interstitial lung disease. Frank et al (reference) showed that pulmonary function testing was very useful as the Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) in about 40% of RA patients was diminished, but radiographs on that 40% showed that only 18% of them had radiographic abnormalities.
Thus, the clinical manifestations of interstitial lung disease in RA are relatively similar to idiopathic pulmonary fibrosis. Interstitial lung disease in RA can be a heterogeneous group of diseases. Most commonly, it’s a usual interstitial pneumonitis with bi-basilar infiltrates, but it also can be a non-specific interstitial pneumonitis, a lymphocytic interstitial pneumonitis, or a desquamative interstitial pneumonitis. In fact, it’s been described that in a single patient with multiple biopsies, you can find evidence on the biopsies of all three types of processes based on histopathology.
The most common symptoms are the same as interstitial pulmonary fibrosis. Seventy to ninety percent of the cases already have developed RA by a mean of 37 months. Men were seropositive nodular and had long-standing disease. It was initially thought that there was a 3-to-1 male-to-female ratio of prevalence. However, newer studies have shown that that may not be the case; rather it may actually be about 1 to 1. This again relates to the tools that are used to define this.
The age of onset is broad, 33 to 75 years old. In addition, long-standing rheumatoid disease does not need to be present. There’s an association with HLA-DRB1, as well as alpha1-anitrypsin phenotype. Greater than 50% have rheumatoid lung nodules, more than 65% have a high titer rheumatoid factor, and 75% have a high sedimentation rate.
Smoking is certainly a risk factor, both for causing more severe cases of RA and as an independent risk factor for interstitial lung disease in RA. The bronchoalveolar lavage can show a mixed picture of lymphocytes and neutrophils. A few studies have indicated that when there’s a lymphocytic predominance, mostly CD-4-predominant cells are present; when it’s neutrophilic, CD-8-positive cells are predominant. However, it’s not understood how this information impacts prognosis and treatment.
Pulmonary function tests, obviously, are helpful in showing an early restrictive pattern and a drop in the DLCL. Increased use of high-resolution CT scans since the 1980s has changed how we’re looking at interstitial lung disease in RA. The correlation between lung biopsy and high-resolution CT is about 90%. High-resolution CT, on the other hand, picks up rheumatoid lung disease in about 18% of all rheumatoid patients, whereas chest x-ray only 6%.
One study, published in 2001, did high resolution CT scans on 150 RA patients. In general, they did a cross-sectional view of these patients to evaluate them. The only statistically significant finding was bibasal crackles, whereas being male, having sub-cutaneous nodules, the amount of dyspnea cough, whether they smoked or not, and even the restrictive finding on pulmonary testing, as well as the rheumatoid factor, were not statistically significant. Based on this study using high resolution CT scans as a screening tool to find a positive predictive value, the most significant finding, again, was bibasal crackles, which is going to be obvious on exam and is going to be most helpful. The second-most helpful positive predictive finding was the restrictive pulmonary function test finding. This is what we’d expect to find just on chest X-ray with parenchyma involvement and verticular nodule finding and chest CT with the same.
As for therapy, with interstitial lung disease and RA, corticosteroids seem to be the mainstay, although this, too, is a big point of discussion: whether interstitial lung disease needs to be treated differently in RA versus the idiopathic forms, or whether RA needs to be treated in and of itself so as to improve the prognosis of the interstitial lung disease. Findings on mortality and prognosis are variable making treatment decisions difficult.
There have been studies showing that certain patients can develop a rapidly progressive interstitial lung disease and can essentially die in a 4-month period, which is worse than idiopathic pulmonary fibrosis. Then there also have been studies showing that mortality can be about the same as with idiopathic pulmonary fibrosis. There even have been studies showing that the prognosis is a little bit better.
Overall, the mean survival is about 3.2 years with RA and interstitial lung disease, just as it is with idiopathic interstitial lung disease. Looking back from the epidemiologic studies, the degree of pulmonary function test impairment, the rheumatoid factor, positivity, and the height of the sedimentation rate do not seem to correlate with a worsening survival rate. Survival was thought to improve with early institution of corticosteroids and by finding the disease early on by imaging.
Bronchiolitis obliterans-organizing pneumonia, or BOOP––a specific type of interstitial pneumonitis separate from interstitial lung disease. Its etiology is unknown. It has a male-to-female ratio in RA and otherwise of about 1 to 1, but it’s questionable whether there’s a female predominance. Mean age is 56 years old, and at least 30% of patients presenting with BOOP have a febrile flu-like illness. Usual symptoms are a non-productive cough and shortness of breath. Patients very commonly have an elevated sedimentation rate. Pulmonary function tests show a restrictive pattern with a reduced DLCO and BAO and usually show a lymphocytic infiltrate. It can also show a mixed bag of neutrophils and lymphocytes, which, again, is not helpful in diagnosing or prognosticating or in changing therapy down the road.
Histology is diagnostic with proliferative bronchiolitis a nonspecific reaction with an inflammatory intraluminal infiltrate with mucus in the distal alveoli. It does not involve the terminal bronchial that much, but rather the alveolus in and of itself, thereby producing a drop in the DLCO due to loss of gas transfer and a fixed lung, which can’t expand, creating a restrictive pattern. BOOP is treated very well with corticosteroids, and the prognosis is relatively good with high doses of steroids––about 60 mg of prednisone starting out and doing a slow taper over the subsequent 1½ to 2 years. Prognosis seems to be the same in idiopathic forms and in RA.
Obliterative Bronchiolitis (OB)
OB is within the alveolus in and of itself and peribronchiolar that you get this sort of infiltrate that’s visible. That’s important to remember because obliterative bronchiolitis is similar but different from bronchiolitis obliterans. It occurs equally in men and women, and it’s a part of RA; it, too, has been described as induced by D-penicillamine and intramuscular gold. But, obliterative bronchiolitis is common with connective tissue diseases. It’s also common with lung transplants and bone marrow transplants in certain types of infections, such as CMV pneumonitis. It presents with a non-productive cough and shortness of breath, as in BOOP, but there’s no febrile prodrome. Chest X-ray commonly shows hyperinflation due to an obstructive defect on the pulmonary function test. The DLCO can be low to normal. Almost the same histopathologic process is going on, but in a different anatomic region of the lungs. So, instead of muco-polysacride being laid down within the alveolus, it is being deposited circumferentially around the terminal bronchial, a constrictive bronchiolitis results, and, thus, an obstructive pattern. The DLCO stays the same, although it’s the same type of material being laid down. Constrictive bronchiolitis is another name for obliterative bronchiolitis, whereas BOOP is known as proliferative bronchiolitis.
High-resolution CT scan is not as helpful in obliterative bronchiolitis. There can be a tree-in-bud-like finding or just bronchial wall thickening or even bronchiectasis, but it’s not a specific finding. The prognosis of obstructive bronchiolitis is poor compared with BOOP. Treatment with corticosteroids, as well as azathioprine or cyclophosphamide, may improve the outcome; however, data from two studies (reference) indicated that macrolide antibiotics in conjunction with corticosteroids may be just as helpful as using corticosteroids with cyclophosphamide. It’s not understood why.
Methotrexate-Associated Lung disease
Methotrexate-associated lung disease–an idiosyncratic reaction to the use of methotrexate–is hypersensitivity pneumonitis that is thought to occur an average of 36 weeks after initiating methotrexate; However, this idiosyncratic reaction can occur at anytime. There’s no pleural involvement in methotrexate toxicity; it’s all parenchymal. Chest X-ray usually demonstrates an interstitial pattern, which creates a problem in trying to differentiate an infection, which is the most common finding in lung and RA patients, from rheumatoid-associated interstitial lung disease. The histopathology may help, but it is typically going to be non-diagnostic. The lung histology is not specific for methotrexate-associated lung injury; it’s just acute hypersensitivity pneumonitis with type II pneumocyte hyperplasia with fibroblastic proliferations and eosinophilia, both in the biopsy and peripherally, as it’s a type of allergic reaction.
There have been questions posed as to whether methotrexate can predispose to lung disease or whether patients with pre-existing lung disease who are put on methotrexate will develop lung disease thereafter. There’s no evidence for either of those. The fatality rate of patients with proven methotrexate-associated lung disease is around 17%, and re-challenging those patients is not usually recommended. It’s thought that re-challenging patients with methotrexate may somehow cause a stronger secondary response.
If there’s a suspicion of methotrexate-induced lung injury, holding the methotrexate and starting both empiric antibiotics and/or corticosteroids if an infection is ruled out is the mainstay. That usually involves getting blood cultures, sputum cultures, and even bronchi-alveolar lavage and biopsy to try to figure this out.
In making a diagnosis of methotrexate lung injury, you have major and minor criteria. The three major criteria are:
- Hypersensitivity pneumonitis by histopathologic examination
- Radiologic evidence of pulmonary interstitial or alveolar infiltrates
- Blood and sputum cultures negative for organisms
The minor criteria include:
- Shortness of breath
- A nonproductive cough
- O2 saturation ≤90% on room air at initial evaluation
- DLCO ≤70% of that predicted for age
- WBC ≤15,000 per mm3
Diagnosis is made by either major criteria 1 by itself, or criteria 2 and 3 together with three of the minor criteria.
Other Lung Manifestations
There are other manifestations of lung disease and rheumatoid arthritis:
- Pulmonary vasculitis is extremely rare by itself, and is usually part of a systemic vasculitis.
- Pulmonary hypertension is relatively uncommon, and is usually secondary to the parenchymal disease rather than pulmonary arterial hypertension.
- Bronchiectasis seems to be a non-specific finding that’s also more common in RA. As Imentioned earlier, it can be a precursor to an obliterative bronchiolitis or just what is seen radiographically in someone who has an obliterative bronchiolitis with RA. There’s an association, actually, with bronchiectasis and patients with RA who have a heterozygous gene mutation for cystic fibrosis, so there seems to be some interplay between the two.
- Apical emphysematous bullae can be seen, with emphysema and in people who smoke, but can be similar to what’s seen in ankylosing spondylitis, making it difficult to differentiate.
- Cricoarytenoid arthritis usually involves hoarseness, trouble swallowing, and obvious speaking or breathing problems.
- Shrinking lung is extremely rare.
There are a large variety of lung manifestations of RA. The natural history is not understood because, first of all, most studies have lumped together the different types of rheumatoid lung disease. There also have been only a few epidemiologic studies, mostly cross-sectional rather than longitudinal studies. So, what happens with these patients over time?
Additionally, the tools for evaluating this disease have changed. Initially, chest X-rays were used, then pulmonary function tests were added, which increased the sensitivity, and since the 1980s, high-resolution CT scan has been used. These changes have allowed detection of quite a few more patients with early onset fibrosing alveolitis, including patients who’ve had rheumatoid arthritis for less than two years.
Looking at risk factors, it’s difficult to know just what the risk factors for interstitial lung disease currently are because of the number of contradictory studies. The beliefs that lung disease was more common in men and that being rheumatoid factor-positive or having a high sedimentation rate were indicative of active disease have been contradicted in many studies. Then, too, differentiating rheumatoid lung disease and methotrexate-lung disease is usually very difficult. If there’s a suspicion, stopping the methotrexate and evaluating for infection or other processes is usually helpful. It’s also difficult to screen rheumatoid lung disease as it’s often asymptomatic and has somewhat of an insidious onset. Another factor that makes identification more difficult is the patient’s activity level. In patients with a low activity level, their lung disease has to become relatively severe before they notice that they have a problem.
The conclusions are four-fold:
- Examine each rheumatoid arthritis patient thoroughly. Listen to the lungs each time a rheumatoid patient is seen.
- Pulmonary nodules and pleural involvement seem to be more common in men (though it’s unclear whether they have to have long-standing disease or whether it has to be erosive), although this is not true for rheumatoid lung disease or BOOP or obliterative bronchiolitis.
- If interstitial lung disease or another parenchymal process is suspected, get a pulmonary function test and, especially, high-resolution CT. CT is the most sensitive test when looking at early disease and early onset of fibrosing alveolitis.
- Finally, further study is needed, looking at longitudinal cohorts of patients and trying to characterize the onset of each of the different manifestations and determine their risk factors, their prognosis, and how to treat them.
In terms of treatment, it always seems to be said, just treat their rheumatoid arthritis and their lung disease will go away. But that doesn’t seem to be the case.
This is the 79-year-old woman who was seropositive, presented in the ER because of hip pain, was saturating 84% on room air, PaO2 was 40 with the CT scan. She had a trans-bronchial biopsy, which showed normal fragments of alveoli lung, thickened septa, and increased reactive alveolar macrophages. There was no pulmonary edema. The stains were negative; culture and BAL were all normal-negative. Her pulmonary function test showed a restrictive pattern; a couple months later, with treatment, it had improved somewhat.
The treatment was to stop her methotrexate and Enbrel, which had been started about 1½ months prior. She was put on prednisone 60mg, which was weaned down to about 15 mg in about 1½ months, and she received a full dose of Levaquin for empiric treatment. She was previously on Arava for her joint disease, which was not controlling it well; that’s why the methotrexate and Enbrel were started. There was a paucity of symptoms as far as her breathing, but there were certainly findings on pulmonary function test and chest X-ray and high-resolution CT that something was going on. The stains were unfortunately negative, as well as the biopsy. She improved with just stopping of the methotrexate. After 2½ months, her chest CT was completely normal.
What can we infer from this? Returning to the list of diagnostic criteria, she certainly did not meet major criteria 1 because her biopsy was normal, essentially. She met major criteria 2 & 3 with the radiologic finding. Her blood cultures were negative. She did not complain of any shortness of breath. She did have a non-productive cough, but it was much of a problem for her. She was certainly saturating less than 90% on room air. Her DLCO was right at 71% predicted, and her white count was 8,000. She would theoretically meet the criteria for methotrexate lung injury. The other possibilities were that she may have had some sort of viral infection that resolved itself, or another process that was short-lived and resolved itself.
The woman with the infiltrate. She had chronic dyspnea on exertion, but it got worse. She had a febrile prodrome, dry cough, squeaks on exam, and the infiltrate on chest CT and X-ray. Sedimentation rate was 114 on admission in January. BL was negative. Unfortunately, her biopsy was non-diagnostic, and there was no alveolated lung seen, so they didn’t get a good trans-bronchial biopsy. Her pulmonary function test showed a restrictive pattern with a stream drop in the DLCO. Her methotrexate and Enbrel were also held, but she was given 60 mg of prednisone with a very slow taper. There was a high suspicion of bronchiolitis obliterans with that infiltrate, because of her febrile prodrome, being female, the high sedimentation rate, and having a restrictive pattern with a very low DLCO.
So, in this case, given the infiltrate, and signs of bronchiolitis, she was essentially given the diagnosis of bronchiolitis obliterans. Her CT, after the prednisone at high and slow taper, showed that the infiltrate is improving, and she’s doing better symptom-wise as well.
The woman who had a chronic cough and a high-resolution CT that showed some bronchial thickening. She was obstructive. DLCO was also diminished. She underwent a trans-bronchial biopsy and bronchial alveolar lavage, which showed alveolar macrophages and a large number of neutrophils, respectively. Based on the fact that she had RA and there was a large predominance in neutrophils in the obstructive pattern, she was given the diagnosis of obstructive bronchiolitis or an obliterative bronchiolitis. She was treated with prednisone as well as azithromycin. Her DLCO came back up to normal, but her pulmonary function tests have been actually worsening because, again, in obliterative bronchiolitis, the prognosis is relatively poor. It’s not very steroid-responsive. Macrolides are thought to help, and Cytoxan and azathioprine are second-course treatments, however, the prognosis is poor at this time due to lack of a proven treatment approach.
For CME credit,TAKE POST-TEST & EVALUATION