Cardiovascular Complications of Systemic Sclerosis: What to Look For

Bob Saget 'Wanted People To Understand How Bad' Scleroderma Can Be: 'This Was His Life's Work'

Bob Saget was a tireless champion for causes of all kinds, but none were as close to his heart as scleroderma research.

The beloved comedian — who died Sunday at age 65 — had spent the last 25 years "committed" to raising awareness of scleroderma, the rare autoimmune disorder that his older sister Gay died from in 1996.

"He was very close to his sister, and I think part of his long-term commitment was because he was really disappointed with the understanding of her condition," Luke Evnin, the chairman of the Scleroderma Research Foundation and co-board member with Saget, tells PEOPLE. "He was very disappointed with the sophistication of the tools that were available at the time to alleviate or change the course of her disease, and even just ease her suffering at the end. I think that he was committed to really see[ing] that it would not happen to any other patient."

Saget had first heard of the Scleroderma Research Foundation (SRF) in 1991, when, in a "weird coincidence," he generously agreed to host their annual Cold Comedy, Hot Cuisine fundraiser, despite not knowing about the disease at the time, Evnin says.

Bob Saget and Luke Evnin. Steve Jennings/Getty

"That was the kind of person that Bob was — he had no connection to scleroderma but was willing to help and headlined one of those early benefits," he explains. "Then, as fate may have it, his sister was diagnosed with scleroderma a year or so later, and unfortunately, succumbed to complications of the disease not long after that."

Saget joined SRF's board of directors in 2003, "but was making major contributions even well before that," says Evnin. Each year, Saget would call on his comedian friends to take the stage at their Cool Comedy, Hot Cuisine benefit and bring greater awareness to the cause.

"This disease is rare and, certainly back then, had relatively little common notoriety, which makes it super hard to fundraise and just attract attention. Bob really wanted to change that," Evnin says. "He wanted people to understand how bad this was and to have an appreciation for what these patients were going through."

Saget's contributions to the cause are "immeasurable," adds Evnin.

"I really feel like the progress that we've made is just so intertwined with his personal commitment," he notes. "I don't even know how to deconvolute the two anymore. He's just been an amazing partner and really a backbone of everything we've gotten accomplished over the [past] 20 years."

Since Saget's sister was diagnosed in 1994, "the standard of care has markedly changed," Evnin says. Because there's greater awareness of the disease, patients can get diagnosed sooner and start immunosuppressive therapy earlier.

"Early intervention has really made a big difference for a lot of patients," Evnin explains. "Unfortunately, we still don't have a drug that can reverse scleroderma, but we have drugs that slow the progression and can meaningfully extend life and minimize the symptoms. That's a really big difference to where we were 25 years ago."

Bob Saget. Amanda Edwards/Getty

Though they've made progress, Evnin says losing Saget before researchers could find a cure is incredibly tough to accept.

"I sort of always imagined that Bob and I would be working together on this for another — I don't even know, decade — while we were solving the rest of the problems and we'd be there when we had the cure in hand and looking back on all we'd been able to accomplish together," he says. "I don't think there'll be a board meeting that will go by when we won't be wondering when Bob's going to walk in the room."

Still, he says, Saget's "contributions will live on."

"This was his life's work," explains Evnin. "He put his heart and soul into the foundation over so long. It started with his sister, but I think it really grew even beyond that, after he touched all these patients. I honestly believe that Bob would want people to think about the Scleroderma Research Foundation when they think about him."

Those interested in donating to the Scleroderma Research Foundation in Saget's memory can do so here.

Researchers Discover Why Scleroderma Affects Women More Than Men

Two new studies led by researchers at Hospital for Special Surgery (HSS) have uncovered key biological mechanisms driving systemic sclerosis (SSc), or scleroderma – a rare and often devastating autoimmune disease that causes fibrosis (tissue hardening) and inflammation. The research, published in the March issue of the Journal of Experimental Medicine, helps explain why the disease disproportionately affects women and reveals potential treatment targets, some of which are already in development. 

Scleroderma affects approximately 300,000 people in the U.S., with about one-third developing systemic disease, which can affect major organs such as the lungs, kidneys or heart. Women are four times more likely than men to be diagnosed with the disease, but until now, the underlying reason for this gender disparity had remained elusive.

In one study, a team of researchers led by Franck Barrat, PhD, found that two genetic receptors called TLR7 and TLR8, which are present on the X chromosome, are important drivers for the activation of plasmacytoid dendritic cells (pDCs), fueling chronic fibrosis. PDCs are immune cells found in fibrotic skin but not in healthy skin and have previously been shown to contribute to scleroderma.

In healthy cells, one X chromosome is typically deactivated, however, the study revealed that in patients with scleroderma, this process is disrupted due to the ability of TLR7 and TLR8 to escape X chromosome deactivation in pDCs. 

"The magnitude of this escape was striking," says Dr. Barrat. 

In healthy individuals, 10 to 15 percent of cells can evade the deactivation process. But in scleroderma patients, the escape occurred in more than 35 percent of the pDCs. This was a significant and unexpected difference.

The expression of two copies of the TLR7 and TLR8 in such a large number of cells can very well explain the chronic activation of these immune cells and why this disease is so prevalent in female patients."

Dr. Franck Barrat, PhD

In a separate study, armed with insights about the role of pDCs in driving fibrosis, Dr. Barrat and colleagues set out to understand why the body's natural mechanisms fail to shut down inflammation in scleroderma patients. Normally, following a wound in the skin, immune cells infiltrate the skin and trigger an inflammatory response until the scarring process begins. A pause signal is then delivered to the immune cells to resolve the inflammation. But in scleroderma patients, this process stalls.

The culprit? A cytokine (a type of protein that helps control inflammation in the body) called CXCL4, which researchers found to be highly expressed in the skin of scleroderma patients. Instead of allowing inflammation to subside, CXCL4 prevents immune suppression, keeping pDCs in a state of chronic activation and promoting skin fibrosis.

"We show that CXCL4 prevents the normal termination of the immune response in the skin," explains Dr. Barrat. "Basically, the pDCs are attracted by the fibrosis, but instead of being suppressed as they should be, CXCL4 keeps them active, in turn contributing to the cycle of fibrosis in these patients."

While there is currently no cure for scleroderma, the research highlights the potential of several therapeutic strategies.

 "This body of research makes a very strong case for exploring drugs that target and interfere with pDCs. There are already drugs in development that we can try," says Dr. Barrat, noting that several therapies in clinical trials have shown promise in blocking pDCs and preventing skin lesions in patients with lupus. 

Both new studies were a collaborative work. Co-authors from the first study include Dr. Jean-Charles Guéry, PhD, of the University of Toulouse, as well as clinicians from the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS and investigators from the HSS Research Institute. Co-authors from the second study include investigators from the HSS Research Institute; the Scleroderma, Vasculitis & Miositis Center of Excellence at HSS; Institut Toulousain des Maladies Infectieuses et Inflammatoires, Université de Toulouse, INSERM, France; Institut Cochin, Université Paris Cité, INSERM, France; and ImmunoConcEpt, CNRS, UMR 5164, University of Bordeaux, France.

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