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Autoimmune Disease and Skin Problems: Yale Researchers Uncover Clues to Improve Patient Care

Yale Medicine Magazine, 2022 Issue 168 More than skin deep
by Jeanna Lucci-Canapari

Scleroderma and other autoimmune disorders that cause skin problems may provide have commonalities that provide clues for better patient care.

https://www.yalemedicine.org/c...Autoimmune diseases, such as scleroderma, that attack the skin can be deadly and disfiguring. The superficial marks borne by people with these conditions can indicate disease inside the body. In some cases, skin changes can even predict the disease’s occurrence. Yale researchers are working to understand the relationships between autoimmune disease and skin problems and how mapping them can help clinicians improve patient care.

Scleroderma and its Effects on Skin

Scleroderma (also called systemic sclerosis), which causes the skin to thicken to a debilitating degree, has the highest mortality of any autoimmune disease: People with diffuse scleroderma (a subtype) have an average survival rate of only 10 years. It is four times more common in women than in men. Scleroderma usually develops between the ages of 25 and 55, although it can occur in adults at any age.

“It is hugely distressing to patients,” said Ian Odell, MD, PhD, assistant professor of dermatology. “Thickening of the skin can become so bad that patients can’t open their hands to do daily tasks.” Some subtypes of scleroderma are limited to the skin, but diffuse scleroderma causes internal organ damage as well, including pulmonary hypertension and pulmonary fibrosis, which are the leading causes of scleroderma-related death.

Currently, says Odell, there is no effective therapy for this deadly disorder, and clinicians can only hope to slow its progression. Yet the patient’s skin can provide clues to potential serious damage inside the body, hastening more aggressive treatment of the disease.

The modified Rodnan Skin Score (mRSS) measures skin thickness in patients with scleroderma. A patient’s severe or worsening mRSS prompts dermatologists to work closely with rheumatologists to check the patient’s lungs, kidneys, and heart for problems.

“The severity of the mRSS parallels the severity of internal organ damage,” said Odell, who is working with Richard Flavell, PhD, the Sterling Professor of Immunobiology, on the development of a novel antibody to reverse the disease. Their work is being funded by an award from Yale’s Colton Center for Autoimmunity. Flavell and Odell are preparing the humanized antibody for future clinical trials.

“There are mechanisms that initiate and drive autoimmunity that are similar across systems,” said Mary Tomayko, MD, PhD, associate professor of dermatology and of pathology. “The collaborations across medicine and across departments can be very fruitful.”

The Yale Medicine Scleroderma Program has been designated as a Scleroderma Center of Excellence by the Scleroderma Foundation. “This means that we have successfully developed a program that is specifically geared to the special needs of scleroderma patients,” says Monique Hinchcliff, MD, MS, associate professor in the Section of Rheumatology, Allergy & Immunology at YSM and the director of the Yale Medicine Scleroderma Program. “We have specialists not only from rheumatology, but also from allergy & immunology, cardiology, dermatology, gastroenterology, nephrology, and pulmonary critical care that are experienced and dedicated to providing top-notch care to scleroderma patients.”

Cancer and Dermatologic Disease

One of the key intersections between autoimmune disorders lies between advanced cancer and a dermatologic disease called bullous pemphigoid, a rare but devastating condition in which the body’s immune system attacks the tissue under the top layer of skin, essentially causing the skin to fall apart at its cellular seams and blistering the outer layer of the skin.

Tomayko and her colleagues, William Damsky, MD, PhD, assistant professor in dermatology and dermatopathology, and Jonathan Leventhal, MD, assistant professor of dermatology, observed that in patients who receive immune checkpoint inhibitor therapy for cancer, the incidence of this rare disease increases by as much as a thousandfold over its incidence in the general population.

“Yale is a leading cancer center that has played a big role in the use of immune checkpoint inhibitors to treat advanced cancer,” Tomayko said. This novel cancer treatment works by striking back against a cancerous tumor’s ability to turn off the person’s antitumor response, thus allowing the body to mount a defense and have a chance to shrink the tumor.

While checkpoint inhibitors have revolutionized the treatments of advanced malignancies, they often cause immune-related adverse events. Because the checkpoint inhibitors block the same mechanisms that turn off the immune system when a typical immune response is complete, they also shut down the mechanisms preventing autoimmunity, leaving the body vulnerable to autoimmune diseases, most commonly those that affect the skin.

A New Way of Looking at Bullous Pemphigoid

Tomayko and her colleagues see potential in this unintentional side effect. “I think the mechanisms that are triggering bullous pemphigoid are similar to the mechanism that causes some people to develop other autoimmune diseases, such as type 1 diabetes, myasthenia gravis, or autoimmune thyroid disease,” she said. “It’s an exciting observation: What triggers autoimmunity?”

Tomayko suspects that cancer patients who can mount immune responses against both bullous pemphigoid and their tumors also create a stronger immune response throughout the body. Looking at skin cancer as an example, she and her colleagues began to find hints that this suspicion may be true. After examining data on melanoma patients collected by their Yale colleague, Ruth Halaban, PhD, a senior research scientist in dermatology, they discovered that melanomas express the same autoantigens as those of bullous pemphigoid.

Tomayko also points to the work of Caroline Nelson, MD, assistant professor of dermatology, who was able to show that individuals who had received checkpoint inhibitor therapy and then contracted bullous pemphigoid had better tumor responses than those who had not received the therapy. This “positive biomarker,” she says, is a second hint.

Finally, Tomayko observed that antibodies for bullous pemphigoid helped predict better tumor response. In this case, part of what initiated an autoimmune response was actually a result of inflammation in the tumor.

Tomayko and her colleagues are hopeful that tests detecting antibodies in the blood that signal bullous pemphigoid might be able to identify patients likely to develop this autoimmunity.

“Then you could consider starting to treat them before they have disease,” Tomayko said. “When you treat autoimmunity early, it’s more likely you can treat with lower doses of medications, with less strong medications. You can control it before a person ends up with life-altering disease.”

Originally published Jan. 24, 2022; updated May 16, 2022.