Symposium on Rare But Fatal Disease to Bring Worldwide Experts to Stanford
March 21, 2023 - By John Knox
Unbeknownst to prescribers of Aminorex in the 1960s, the popular diet drug would later be linked to a rare, but extremely fatal disease – pulmonary hypertension, or PH. The scenario repeated itself in the 1990s with the popularity and later withdrawal from the market of fenfluramine and phentermine, commonly known as Fen-Phen.
To avoid further repetition of this grave occurrence, a worldwide team of medical scientists will convene April 13-14 on the Stanford campus to apply lessons learned from the Aminorex epidemic during a two-day Drug-induced Pulmonary Hypertension Symposium.
“Physicians are dedicated to the concept of doing no harm, but we have found that therapies we believe are helpful can actually be harmful. We expect this symposium to raise awareness by highlighting the unintended consequences of drugs and their toxicities, specifically on the pulmonary vasculature,” says Roham Zamanian, MD, professor of pulmonary and critical care medicine.
The conference will also focus on the global burden of methamphetamine abuse and its toxicity. “Not to downplay the needed attention on the opioid epidemic, but we want to remind people that illicit use of methamphetamine also is an epidemic of huge proportions,” Zamanian adds.
“Many of my colleagues in Europe feel that this is not their problem, but they may not be aware, for example, that six percent of the UK population reports ever using illicit methamphetamines in their lifetime; that it’s not just a regional issue. It also has implications because recent studies show that Ritalin and Adderall also may also be associated with pulmonary hypertension, a sign that the cardiopulmonary toxicity associated with methamphetamine maybe seen in pharmaceutical grade drugs as well,” he says.
A wide range of interested parties
The conference will bring together the many stakeholders in the drug toxicity issue, including regulators, scientists, experts from the pharmaceutical industry, patient advocacy groups, and families of patients.
Keynote speaker Marissa Mayer, a well-known Silicon Valley business leader, will address the perspective from patients and caregivers. Her involvement in the symposium underscores the fact that this is a multi-stakeholder issue that needs to be addressed.
“We not only wanted to bring experts from around the world, but also bring the voice of families affected by drug-induced pulmonary hypertension,” says Zamanian.
“Even expert physicians need to understand how to make the link between drugs and PH. The regulatory agencies – the FDA, its equivalent in Europe, and others – need to guide us on how to be vigilant around toxicities in common drugs by teaching us how to pick up the next signal and how to know what impact a new drug will have,” he adds.
Qun-Ying Yue, MD, PhD, a clinical pharmacologist at the Uppsala Monitoring Centre in Sweden will discuss the concept of pharmacovigilance for this and other rare diseases. The Uppsala Monitoring Centre is an epidemiology group with links to the World Health Organization that is looking carefully at drug toxicity issues around the world. Yue was previously with the European Medicines Agency (EMA), the umbrella organization of all the medicines agencies in Europe, where she was involved in the evaluation and the linking of certain rheumatic drugs known as TNF alpha drugs with PH.
Seventeen of the 29 speakers are from outside the United States, including Marc Humbert, MD, PhD, professor of Respiratory Medicine at the Université Paris-Saclay in Le Kremlin-Bicêtre, France. A pulmonologist who is now dean of the School of Medicine at the Université Paris-Saclay, he is widely regarded as an authority in the field who has mentored several of the symposium’s other speakers and is a big proponent of turning the concept of drugs and associated PH into a field of its own.
“Physicians are dedicated to the concept of not wanting to do harm, and we have found that therapies we believe are helpful can actually be harmful. We expect this symposium to raise awareness by highlighting the unintended consequences of drugs and their toxicities specifically on the pulmonary vasculature.
The French connection
Humbert will be joined on the panel by six other French colleagues, and the scientific attaché from the office of the Consulate General of France in San Francisco will also attend the symposium.
Much of the symposium’s latest science comes from Stanford and France, with the France-Stanford Center For Interdisciplinary Studies supporting collaborations and the exchange of ideas between academics in France and at Stanford.
While many of the sessions are aimed at cardiologists, pulmonologists, other subspecialists, and the regulators directly involved with this rare disease, there will be great benefit for internal medicine physicians, oncologists, and rheumatologists to attend and learn about dangers connected with therapeutics that are prescribed by almost every physician in the world in hopes of changing practice patterns.
“The topic itself is a cardiology and pulmonary focused concept, but we will be looking at the next level of initiatives that we need to put forward to help save patients from pulmonary hypertension, and we need to be talking also to the people who are prescribing these drugs. We need to educate physicians from other disciplines (oncology, rheumatology, and even primary care medicine) to consider risk of a rare disease as a potential side-effect of a therapy for a relatively common disorder. For example, the parents of a child who is going to take Ritalin need to know that while taking that drug the risk of pulmonary hypertension may increase from one in a million to one in 30,000. You can imagine, it’s a tough ask, since we are dealing with a rare disease. The rare disease community should be empowered by advances in technology to address this problem,” says Zamanian.
“My hope is that we can bring together a group of regulators and epidemiologists to set up tools for physicians to use in reporting drugs that may cause pulmonary hypertension and making the diagnosis sooner,” he adds.
Every five years
The first symposium on the topic took place in Vienna in 2016 to mark the 50th anniversary of the Aminerex epidemic, a devastating event for the patients who were lost. The plan was to meet every five years after that to maintain the progress gained from recognizing how drugs can cause PH and to apply the lessons learned from the Aminerex and Fen-Phen tragedies. While the COVID-19 pandemic prevented a 2021 meeting, this year’s symposium will resume the sharing of expertise and broaden the discussion to include more stakeholders, including epidemiologists, drug regulators, and safety experts.
A leadership role for Stanford
The Department of Medicine is a natural host for the conference, if only by virtue of its Vera Moulton Wall Center for Pulmonary Vascular Disease, which is placed within the Stanford Cardiovascular Institute. A gift from anonymous donors in 2000 established the Wall Center as an outgrowth of a combined adult and pediatric program for the evaluation and treatment of patients with pulmonary vascular disease. The center was built on the pioneering pulmonary vascular disease program at Stanford that grew out of the adult lung and heart-lung transplant program.
According to its mission statement, the Wall Center “seeks to enhance the lives of patients with pulmonary vascular disease by providing the highest level of clinical care, providing advanced training opportunities for physicians and other health care providers, and participating in clinical and bench-top research in pulmonary vascular disease.”
The center has the longest running curriculum-based training program for pulmonary hypertension in the nation. It has trained some 28 fellows, who have gone on to either found or run pulmonary hypertension programs around the world.
“The Wall Center has hosted previous symposia, and this one is especially important for the center and the Department of Medicine because it underscores our role as leaders of the conversation about drugs and toxicity,” says Zamanian.
“This is a rare disease, so we need to have hundreds of thousands of patients being exposed just to get a couple of signals of the disease. What can really help in that regard is the development of a consortium and network of academic centers.
On the horizon
Zamanian points to the great value of international academic centers and global organizations working together to help us understand and approach drug-induced pulmonary hypertension.
“This is a rare disease, so we need to have hundreds of thousands of patients being exposed just to get a couple of signals of the disease. What can really help in that regard is the development of a consortium and network of academic centers. We’d want to set up a structure and process that could facilitate the reporting of occurrences of this rare disease associated with a certain kind of drug and then make sense of that by identifying and curating all the associated data. And anyone in the world can be involved in that effort just by first recognizing that this is an issue and then indicating that they’d want to be part of the endeavor,” he says.
Primary Pulmonary Hypertension and Aminorex: A Cautionary Tale
Cases of primary pulmonary hypertension—a disease where high blood pressure in the lungs leads to heart failure and death— are very rare, affecting one in a million people on average. However, globally the disease occurs four times more frequently in women than in men.
In the early 1960s, three academic referral centers in Switzerland, Austria, and Germany were monitoring the number of cases they saw on an annual basis and reported about five or six cases a year in each center. But within a few years those three centers began to see a nearly 20-fold increase in the rates of primary pulmonary hypertension for no apparent reason. Detailed sleuthing revealed a connection to an amphetamine-based diet pill called Aminorex that was being prescribed in the U.S. and Europe at the time. That connection led to the realization that Aminorex was toxic and resulted in the withdrawal of Aminorex from the market.
Curiously, a similar event occurred about 30 years later with Fen-Phen (the combination of fenfluramine and phentermine), which was widely prescribed in the United States for weight loss. Among many studies, a famous one published in 1996 in the New England Journal of Medicine demonstrated that more than three months’ use of Fen-Phen was associated with a 20-fold increase in the rates of pulmonary hypertension.
“While the concept of drugs causing pulmonary hypertension arose with Aminorex and Fen-Phen, the modern era has led to the realization that there are other stimulants that can lead to this fatal disease,” Zamanian says.
The rise of methamphetamine abuse in the western region of the U.S. causes concern for Zamanian, as does the recognition that drugs like leflunomide and other treatments for arthritis, cancer, and other ailments may have links to the development of pulmonary hypertension.