Rheumatoid Arthritis: Pulmonary and Cardiovascular Manifestations

The most common extra-articular manifestations of rheumatoid arthritis involve the lungs and the heart. This article discusses the most important pulmonary and cardiac complications in individuals diagnosed with rheumatoid arthritis, beginning with two representative cases.

Patient Presentation

A 62-year-old male presented with a 10-month history of progressive shortness of breath and dyspnea on exertion. He also reported a chronic nonproductive cough, a recent 10-pound weight loss, and generalized fatigue and stiffness in his hands and feet lasting for a few hours, but denied any fever, rash, or chest pain. Other than mild hypertension, his general health had been good and there were no prior signs or symptoms to suggest a systemic rheumatic disease. He was a 1½-pack-per-day smoker for more than 30 years and the only medication he was taking was a diuretic for slightly elevated blood pressure.

Assessment

Pertinent findings on physical examination included crepitant rales in the bases of both lungs and a normal cardiac examination. The joint examination demonstrated tenderness with possible joint swelling involving several fingers and toes. A chest x-ray revealed ground glass opacites and small nodular densities in both lung bases. Abnormal laboratory tests included an anemia with a hematocrit of 32 and a significantly elevated ESR and CRP. Liver and kidney function tests were normal.

Case 1 involves a previously healthy middle-aged man presenting with new pulmonary symptoms for almost 1 year. The bibasilar rales on examination and chest x-ray suggest interstitial lung disease (ILD), which may be idiopathic or secondary to a comorbid illness. In view of the patient’s long-standing smoking history, weight loss, abnormal chest x-ray, as well as the nonspecific anemia and elevated acute phase reactants, an associated cancer must be considered.

However, the new onset of pain, stiffness, and possible swelling in the patient’s small joints of the hands and feet also increase suspicion of a systemic rheumatic disease.

This patient should be referred to a rheumatologist for further evaluation of the musculoskeletal symptoms and to a pulmonologist for complete evaluation of the pulmonary disease. The consulting rheumatologist noted symmetrical swelling of the proximal interphalangeal joints of both hands, and laboratory testing included a markedly elevated rheumatoid factor and anti-cyclic citrullinated peptide (anti- CCP antibody), highly suggestive of rheumatoid arthritis. The pulmonologist then ordered a chest CT scan, which demonstrated ILD with scattered subpleural consolidation and parenchymal fibrosis.

The most common pulmonary involvement in rheumatoid arthritis is ILD, occurring in 5% to 15% of people with rheumatoid arthritis.¹ Sub-clinical ILD has been found in up to 30% of people with rheumatoid arthritis, as demonstrated by routine high-resolution computed tomography (HRCT).² ILD can initially be clinically silent, and is known to shorten overall survival and quality of life.

Risks and Symptomology

The lung disease usually presents a few years after rheumatoid arthritis is diagnosed but can occur prior to obvious joint disease, as in the Case 1 scenario herein. Patients present with slowly progressive dyspnea on exertion and a nonproductive cough. Bibasilar crackles are present in more than 75% of patients and characteristic abnormalities are always found on chest and CT imaging. In general, smoking is a risk factor for rheumatoid arthritis, but it is a very strong risk factor for RA-associated ILD.¹˒² Rheumatoid-associated ILD laboratory testing usually demonstratesserologic evidence of very active rheumatoid arthritis, including high levels of anti-CCP antibody.

RA-Associated ILD Treatment

As in Case 1, the pulmonologist should attempt to stage the type and activity of the ILD, using high density CT, pulmonary function tests, and possibly a lung biopsy. It is especially important to determine whether the ILD demonstrates active inflammatory pathology or is more fibrotic in nature. The treatment of the interstitial lung disease should be coordinated by the rheumatologist jointly with the pulmonologist, guided by the activity of the rheumatoid arthritis. However, in the vast majority of patients, a trial with high doses of glucocorticoids is recommended initially, in the hope that much of the acute inflammation will subside.

There are insufficient data to determine which disease-modifying, anti-rheumatic drug (DMARD) is preferable to treat RA-associated ILD but most rheumatologists would not recommend the use of methotrexate because of its greater potential for pulmonary toxicity. There are some reports that certain biologic drugs, including the tumor necrosis factor (TNF) inhibitors, may be associated with lung toxicity in RA patients, but they are often used successfully to treat RA-associated ILD.² In patients with evidence of pulmonary fibrosis, antifibrotic agents may be tried.

In addition to interstitial lung disease, some people with rheumatoid arthritis may develop pleural inflammation, small pleural effusions, or pulmonary nodules. These nodules may consist of the same tissue as in the subcutaneous nodules found around the forearms and elbows in rheumatoid arthritis.

Each of these pulmonary manifestations of RA are usually noted on CT scan and typically not symptomatic. However, the pulmonary nodules require careful evaluation, often a biopsy, since patients with rheumatoid arthritis are more prone to develop opportunistic infections or malignancy.

Patient Presentation

A 53-year-old female with a 25-year history of deforming rheumatoid arthritis presented with a 6-week onset of chest pain and shortness of breath following modest exercise. She was first diagnosed with rheumatoid arthritis at age 28 and responded moderately well initially to NSAIDs, low dose glucocorticoids, and methotrexate but continued to have intermittent swelling in the knees, hands, and feet. At age 34 she was started on a TNF inhibitor, which resulted in significant improvement in the rheumatoid arthritis. Gradually the methotrexate, NSAIDs, and glucocorticoids were discontinued, and she was maintained on the TNF inhibitor for the next 19 years.

Assessment

At present, a joint examination demonstrated no evidence of increased activity of the rheumatoid arthritis, with some minimal deformities in a few fingers. Her lungs were clear, the cardiac examination was unremarkable, and blood pressure was normal. Laboratory studies were stable, including a normal ESR and CRP. (See also early RA diagnostic blood test.)

Recommendation

The second patient has a history of long-standing RA and now presents with new-onset chest pain and dyspnea. Her rheumatoid arthritis is under excellent control. Her new symptoms are most likely new cardiovascular disease (CVD) and she should be immediately fully evaluated by cardiology.

People with rheumatoid arthritis have a significantly increased risk of CVD, with large series demonstrating at least a 50% increased risk of cardiovascular events as well as death from cardiac disease.³ This markedly increased risk relates to the complex interaction of systemic inflammation with traditional cardiovascular risk factors. There is an increased risk of traditional CVD risk factors, such as dyslipidemia, hypertension, obesity, physical inactivity, and smoking in RA patients.

However, much of the increased CVD risk in RA is directly related to inflammation/immune activation. The immune/inflammatory system plays a crucial role in the pathogenesis of enhanced atherogenesis, primarily related to the impact of pro-inflammatory cytokines on cell function, oxidative stress, and endothelial dysfunction.

Symptoms of CVD in people with rheumatoid arthritis follow those of the general population with the caveat that individuals with RA are more likely to have clinically silent coronary artery disease and less likely to be diagnosed with angina pectoris. Some experts believe that may relate to concurrent use of NSAIDs and glucocorticoids, although this theory has not been clearly demonstrated. Not only is there an increased risk of coronary artery disease in RA, but also an increased risk of congestive heart failure and atrial fibrillation.³

RA-Associated CVD Treatment

It is important to aggressively decrease the risk of CVD in RA (see below). Traditional cardiac risk factors, including hypertension, diabetes, older age, and cigarette smoking are important to assess, and cigarette smoking is more prevalent in women with RA than in the general population. The prolonged use of glucocorticoids and NSAIDs are significant risk factors for hyperlipidemia and atherosclerotic coronary vascular disease and their use should be monitored and restricted.

The medical community now recognizes the importance of aggressively treating rheumatoid arthritis to decrease subsequent cardiac risk. Higher RA disease activity correlates with cardiovascular risk, and RA patients in complete remission have approximately the same cardiovascular risk as age-matched controls.³ Levels of inflammatory markers such as the ESR and CRP correlate with progression of coronary artery disease.³

Treat-to-Target

The goal of optimal RA treatment is “treat-to-target,” with the target being clinical and laboratory disease remission, whenever possible. DMARDs and biologic agents have been shown to decrease CVD, including each of the TNF inhibitors. The strongest evidence of CVD risk reduction has been demonstrated in long-term studies of methotrexate and the TNF inhibitors. There has been some concern that the targeted synthetic DMARDs, Janus kinase (JAK) inhibitors, have more CVD risk than TNF inhibitors. JAK inhibitors are currently being carefully evaluated to determine their risk-benefit profile in rheumatoid arthritis.⁵

• follow serial inflammatory markers, such as ESR and CRP
• aim for total disease remission, clinically and serologically
• consider methotrexate and TNF inhibitors as they have strong evidence of CVD risk reduction

Myocarditis and pericarditis are rare complications of RA and occur in patients with very active joint disease. These rare events usually respond to high doses of glucocorticoids and immunosuppressive drugs.

The most prominent non-articular, systemic manifestations of rheumatoid arthritis involve the lungs and heart. ILD is present in 5% to 15% of patients and may be a presenting feature of rheumatoid arthritis, as in Case 1. It is important to recognize that there is a significant increased risk of CVD in RA. Careful assessment of risk factors with appropriate mitigation are necessary to offset this risk. Current, aggressive treat-to target RA has been demonstrated to significantly lower the excess risk of CVD in rheumatoid arthritis.