Epidemiology, Pathogenesis, and Clinical Approach in Group 5 Pulmonary Hypertension

Understanding The Connection Between Lupus And The Lungs

Cheryl Russell of Highland Beach, FL, doesn't indulge in what she calls "symptom chasing." After more than three decades with lupus, she refuses to head to the doctor every time she has joint pain or some other problem.

"I learned early on that if I do that, I just end up going to specialist after specialist and having test after test, chasing symptoms that will disappear on their own," says Russell, who raised two now-grown children with her husband, Jake. "I let things have time to work themselves out before jumping on them." 

Trouble began in June 2011 when she noticed she could no longer take a deep breath. She couldn't yawn, and sneezing felt weird. She didn't say anything to her husband, her children, or her doctor. By July, her breathing was worse, and her feet started to swell. Still Russell stayed silent, unaware of the possible connection between lupus and lung disorders and intent on not spoiling a road trip to New England.

The couple had almost made it home from their three-week vacation when things came to a head. In the middle of the night in South Carolina, Russell woke up in their hotel room with intense chest pain and extreme difficulty breathing. She was intent on seeing her own doctors, so the couple hightailed it—so fast they got a speeding ticket—to the emergency room at Boca Raton Regional Hospital. The cause of Russell's breathing difficulties and her swollen feet was a potentially deadly blood clot in her lungs. She also had a rare lung condition called bronchiolitis obliterans with organizing pneumonia, or BOOP.

After eight days in the hospital, doctors sent Russell home with prescriptions for prednisone, a blood thinner, and an amped-up dose of the immunosuppressive drug CellCept®. Although Russell is now doing better, she still can't walk and talk at the same time.

The whole experience has been eye-opening. "Even for someone like myself who's been involved with lupus for so many years, I had never heard of anyone having any lupus-related lung problems," says Russell, who hopes a regimen of Benlysta® infusion therapy will let her get back to her favorite pastimes of cooking and gardening.

It surprises many people to learn that lung issues are common among people with lupus. According to the Johns Hopkins Lupus Center, about 50% of people with lupus will experience lung issues during the course of their disease.

In fact, lung complications rank just behind problems with joints, skin, and blood cell counts, says Ben deBoisblanc, M.D., a professor of medicine and physiology at the Louisiana State University Health Sciences Center in New Orleans.

Research has shown that at some point, most people living with lupus will show signs of lung involvement. "The more severe the lupus you have, the more likely you are to have lung problems," he says. 

Lung involvement in lupus

Although the underlying connective tissue disease is the root cause of lupus-related lung problems, the exact mechanism differs for each of the most common conditions.

The most frequent lung problem that affects people with lupus is pleuritis, also known as pleurisy. In this condition, the pleura—a membrane that covers the exterior of the lungs and the interior of the chest cavity—becomes inflamed. Although the pleura normally produces a small amount of fluid to lubricate the space between the chest wall and the lungs, that fluid can build up excessively. Pleural effusion, which occurs when the fluid between the lungs and the chest wall leaks out, can cause a lot of pain.

With lupus pneumonitis, the inflammation is within the lung tissue itself. The cause is usually an infection by bacteria, viruses, or fungi. It can also be caused by an autoimmune injury to the lung, deBoisblanc adds.

Blood clots in the lungs, known as pulmonary emboli, present another possible complication. "Lupus can cause blood clots to form and break loose and go to the lungs," deBoisblanc explains.

Some people with lupus have a condition called antiphospholipid antibody syndrome that puts them at even higher risk of pulmonary emboli. With this disorder, the body produces antibodies against normal blood proteins, which can cause clots to form in the arteries.

Less common—except among people who have both lupus and other types of connective tissue disorders such as scleroderma—is pulmonary hypertension, or high blood pressure in the blood vessels within the lungs.

The disorder is still a bit mysterious, says Steven M. Kawut, M.D., director of the pulmonary vascular disease program at the Perelman School of Medicine at the University of Pennsylvania. 

"We don't know the pathophysiology," he says. What doctors do know is that the high blood pressure in the lungs' blood vessels strains the right side of the heart and can cause shortness of breath, swelling of the lower extremities, and, eventually, heart failure.

Other lung complications include chronic diffuse interstitial lung disease, which can scar the lung and prevent oxygen from moving easily from the lungs into the blood; pulmonary hemorrhage, or bleeding into the lungs; and "shrinking lung" syndrome, which causes a sense of breathlessness and the feeling that the lungs are not able to expand.

Know the signs

The good news, according to lung specialists, is that diagnosing these potentially life-threatening conditions is usually straightforward, and treatment is successful for most conditions—especially if caught early. A pulmonologist can help with testing and diagnosis, but often a rheumatologist directs treatment.

When you have lupus, you should watch carefully for signs of pulmonary trouble. Keep an eye out for two common symptoms: shortness of breath and pain with breathing, deBoisblanc says. "Pulmonary issues often affect people with lupus who are younger, and who shouldn't be having significant breathing problems at all," he says.

Of course, each lung condition has its own symptoms and diagnostic methods. For example, a sharp pain in the chest that worsens during deep breathing, coughing, or even laughing suggests pleuritis, which a chest X-ray can confirm.

X-rays can also be useful in diagnosing pneumonitis, which may be suspected if you're coughing a lot, experiencing chest pain and shortness of breath, and running a fever. Your doctor may also order tests of your blood and sputum—the mucus from the lungs. A bronchoscopy looks inside your lungs to see if an infection is the pneumonitis' cause.  

The unexplained shortness of breath, fainting, and chest pain of pulmonary hypertension can be picked up via echocardiography and then right-heart catheterization. Your doctor will first rule out other possible causes, such as sleep disorders and other lung diseases, Kawut says. Chest pain and shortness of breath can also mean pulmonary emboli, as Russell discovered.   

For Paula Rostron of Killingly, CT, lung problems actually led to her lupus diagnosis. In 2004, Rostron noticed she was having palpitations and was out of breath, even when doing something as non strenuous as blow-drying her hair. Her doctor did an EKG and immediately sent Rostron to the hospital after seeing the results. There, she was diagnosed with pulmonary emboli. "Even a tiny blood clot can kill a person, and I had huge blood clots in my lungs," she remembers.

Rostron spent a week in intensive care, then went home with a prescription for blood thinners and was soon diagnosed with antiphospholipid antibody syndrome. She was diagnosed with lupus in 2010, after experiencing migraines, joint pain, and pleuritic symptoms.

Treating lupus and the lungs

Treatment should focus on both the underlying lupus and the specific lung problem, deBoisblanc says. For pleuritis, that means immunosuppressive drugs plus analgesics to soothe the pain. For pneumonitis, treatment typically begins with antibiotics to rule out infection, followed by corticosteroids and immunosuppressants such as Imuran®. Pulmonary emboli necessitate blood thinners, often indefinitely.

Treatment for pulmonary hypertension shows the progress being made in treating lupus-related lung problems.

"Twenty years ago, there were no therapies for pulmonary hypertension," says deBoisblanc, and life expectancy was very limited. "Now we have excellent therapies that allow patients to manage their pulmonary hypertension not too differently than you'd manage any chronic disease."

Renee Mestayer, one of Dr. DeBoisblanc's patients, witnessed the evolution of treatments firsthand. Diagnosed with lupus in 1983, Mestayer, of New Iberia, LA, developed pulmonary hypertension in 1999. Eventually, she could barely walk to the mailbox in front of her house and had to use an oxygen tank.

Mestayer has tried a number of new medications over the past decade in addition to her lupus medications. She now takes the pulmonary hypertension drug Tracleer®, as well as Revatio®, which relaxes the walls of arteries and lowers blood pressure, and Tyvaso®, which also helps keep arteries open.

"I'm very fortunate because of all the new medicines that have come out in the last 10 years," says Mestayer. Although she still tires easily, she can now walk long distances on her treadmill. She credits her medications and her faith for getting her through the experience.

"At the time I was diagnosed, my two boys were in sixth and seventh grade," says Mestayer. "I asked God to let me see them graduate high school—and now I'm a grandma!"

How Lupus Affects The Lungs And Pulmonary System

Inflammation caused by lupus may affect the lungs in many ways, and can involve the membrane lining of the lungs, the lungs themselves, the blood vessels within the lungs, and the diaphragm.

Pleuritis

The most common way that lupus can affect your lungs is through inflammation of the pleura, the lining that covers the outside of the lungs. The symptom of pleuritis that you may experience is severe, often sharp, stabbing pain in a specific area or areas of your chest. The pain, which is called pleurisy, is made worse when you take a deep breath, cough, sneeze, or laugh. You may also experience shortness of breath. Sometimes an abnormal amount of fluid will build up in the space between your lungs and your chest wall; when it leaks out it is called a pleural effusion. Pain from pleurisy, with or without effusions, is found in 40 to 60 percent of people with lupus.

Pneumonitis

The term for inflammation within the lung tissue is pneumonitis. The symptoms of pneumonitis that you may experience are fever, chest pain, shortness of breath, and cough. An infection caused by bacteria, virus, or fungi is the most common cause of pneumonitis.

Chronic diffuse interstitial lung disease

When inflammation in the lungs is chronic, it can cause scarring. This scar tissue can prevent oxygen from moving easily from your lungs into your blood and may cause diffuse (widespread) interstitial lung disease. The symptoms that you may experience include a chronic dry cough, chest pain, and difficulty breathing during physical activity.

Pulmonary emboli

Blood clots that block the arteries leading to the lungs are called pulmonary emboli. These blood clots will cause chest pain and shortness of breath, but can also lead to a decrease in oxygen flow in your lungs. You are at increased risk for pulmonary emboli if you have antiphospholipid antibodies, vascular damage, and/or an inactive lifestyle.

Striking Back At Lung Disease

A spin-out company in Austin, Texas could radically change the way we treat lung disease and conditions linked to fibrosis, such as idiopathic pulmonary fibrosis (IPF). Lung Therapeutics is developing a novel peptide drug that it expects will not only slow disease progression, but promote restoration of healthy lung function. Its novel mechanism enables the rebalancing of some fundamental biological signaling pathways. The drug may be the key to the treatment of a wider group of fibrosis-based conditions in multiple organs, such as cardiac fibrosis and scleroderma.

The company was co-founded in 2013 by Steven Idell and Andrew Mazar. Idell, a board-certified internist and pulmonologist, serves as the current CSO and is temple chair of pulmonary fibrosis at the University of Texas Health Science Center at Tyler. Mazar serves as the consulting head of product development and was recently director of the Center for Developmental Therapeutics at Northwestern University.

Since its first year, Lung Therapeutics has been led by CEO Brian Windsor, who has 18 years of experience in the formation and management of life-science-based technology ventures. He has rapidly developed the company's portfolio. Lung Therapeutics' first therapeutic candidate LTI-01 recently completed a phase 1b clinical trial in Australia and New Zealand for the treatment of loculated pleural effusions, a life-threatening condition associated with hospitalized pneumonia.

Understanding IPF

Given its unique pipeline and world-leading scientific team, Lung Therapeutics has raised outside funding of $17 million, in addition to leveraging $27 million in research and development grants. In 2017, Lung Therapeutics successfully completed a $14.3 million series B financing round to support not only the development of LTI-01, but also its transformative fibrosis treatment, LTI-03.

"LTI-03 has a very unique and as yet unexploited mechanism of action that makes it very attractive for addressing and resolving fibrosis and fibrosis-related conditions," said Windsor. The company is focusing on its use in the treatment of IPF, a chronic lung disease in adults aged 65 years and over, which is characterized by progressive tissue scarring and is usually fatal within 3–5 years of diagnosis. Deaths are estimated at between 28,000 and 65,000 in Europe and between 13,000 and 17,000 in the United States1. Current drugs are unable to do more than slow the scarring process, and thus there is a real unmet need to improve clinical outcomes.

IPF is not fully understood, but there seems to be both a loss of healthy lung cells and the proliferation of unwanted fibrotic cells, believed to be caused in part by the dysregulation of biological signaling pathways.

Lung Therapeutics has focused on the pathway that produces caveolin 1 (Cav1). "In a fibrotic state the Cav1 protein is missing from fibroblasts whereas it would normally be present," said Windsor, "and caveolin seems to have a role in keeping fibrosis in check, so when you lose it, you lose this ability." Cav1 may in fact be important in many diseases caused by fibrosis.

Fig. 1Restoring cell balance with LTI-03. Structural proteins are degraded and new proteins are formed.

Targeting IPF with LTI-03

Lung Therapeutics new molecular entity, LTI-03, is a seven-amino-acid peptide, representing a portion of the caveolin scaffolding domain, a critical portion of Cav1. "We are adding something back to restore a balance in the cells that has gone awry," explained Windsor. By replacing the missing protein, the cells are able to promote normal extracellular matrix turnover—the process by which structural proteins such as collagens, elastin, and proteoglycans are degraded and new proteins are formed (Fig. 1). "Again if you lose caveolin you have lost the lungs' ability to remodel fibrosis and restore lung or organ function, so adding back the critical portion of the caveolin protein potentially could have far-reaching effects," Windsor added.

What is so exciting about this breakthrough is its potential to restore healthy function in patients. In animal studies, LTI-03 has been shown to resolve bleomycin or transforming growth factor-β-induced lung injury when given 14 days after the induction of injury. LTI-03 has also shown promise in other models of fibrotic diseases. "We have proof of concept in ten different models of fibrosis including two models of cardiac fibrosis, kidney fibrosis and scleroderma," said Windsor, "and every model system just gives us more information on the benefit of addressing this pathway in fibrosis. Lung Therapeutics is taking the lead in doing just that." The company anticipates the launch of phase 1 trials of LTI-03 for IPF in early 2019.

Key opinion leader Ganesh Raghu summarized the potential of LTI-03. "The need to improve outcomes for patients with IPF that are meaningful to patients confronted with IPF beyond the current standard of care persists. While the etiology of IPF is unknown, preventing injury/damage to the epithelium barrier and consequent expansion of fibroblast and extracellular matrix is an appropriate step in the right direction. In this regard, the drugs delivered to reach the epithelium in distal pulmonary parenchyma by inhalation are ideal as the disease is confined to the lung besides minimizing (if any) systemic effects/ adverse reaction in the patient. LTI-03 has a great potential to accomplish this through unique signal transduction pathways. I look forward to continued research in developing the drug in an inhaled format for patients with IPF as it has the potential of improving outcomes for patients with IPF."

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