When Samuel Simmons wakes up in the morning, he is already dreading the big day of work ahead of him. It’s not just because of his job.

Every day Simmons spends as many as four hours scrubbing his skin to get rid of the dry, scaly layer accumulating on the surface. He has a rare genetic skin disease called ichthyosis that keeps old skin from shedding properly. To combat the growing layer of thick, dry skin, Simmons uses everything from lotion to washcloths — and a lot of manual labor. As much as he works to gently slough off the dead skin, however, the battle seems never-ending.

The negative impact that ichthyosis has had and continues to have on my life is indescribable.
– Samuel Simmons, patient with ichthyosis

“There's no way that I can manage or keep up with it,” he said. 

What Simmons wants more than anything is a cure; something that strikes right at the cause of ichthyosis. But research to develop ichthyosis treatment has been limited and slow. As is the case for many rare diseases, ichthyosis has not marshalled the level of pharmaceutical interest that more widespread — and lucrative — targets have done.

Instead, dermatologists, who see the impact on patients firsthand and the urgent need for treatments, are driving much of the ongoing research. These skin doctors have led efforts to repurpose drugs used for other skin conditions to treat ichthyosis, but what should have been a simpler way to find a drug has revealed a much more complicated molecular picture of ichthyosis.

An “indescribable” burden

Ichthyosis is not just one disease, but rather, a family of diseases caused by various genetic mutations impacting skin cell turnover. In people without ichthyosis, skin cells constantly renew: New cells grow, while old cells are shed. This keeps skin looking smooth and healthy. 

In people with ichthyosis, however, mutations either speed up the rate of skin cell growth or slow the rate of shedding. This causes old skin to accumulate on the surface and become dry and cracked. The disease’s name derives from the ancient Greek word “ikhthys,” or “fish,” alluding to the scaly appearance of affected individuals’ skin.

There are more than 30 different types of ichthyosis caused by different mutations. The most common type, ichthyosis vulgaris, is relatively mild and causes flaky skin. Harlequin ichthyosis is rarer and leads to thick plates of skin so extensive that they restrict movement. Simmons has a form called lamellar ichthyosis that creates a thin membrane covering an infant’s skin at birth. The membrane is shed in the first week or so, and the skin underneath forms dark, dry scales that persist through adulthood.

The dry skin characteristic of ichthyosis can cause serious problems. Skin is an important barrier organ, keeping unwanted pathogens out of the body. The cracks that develop in dry skin can disrupt this barrier and lead to redness, itchiness, and even a heightened risk of infections. People with ichthyosis also often cannot sweat, which makes body temperature regulation difficult. If skin around the eyes becomes thick enough, it can make it difficult for people to close their eyes without surgical intervention. Similar thickening in the ears can impair hearing, causing language delays for children.

“The negative impact that ichthyosis has had and continues to have on my life is indescribable,” Simmons said.

There are no approved treatments for ichthyosis, so when Joyce Teng, a dermatologist at Stanford University, sees patients, she tries to identify ways to at least alleviate the discomfort that comes with the disease. This includes moisturizing to reduce dryness and exfoliating to remove the scales.

One of the biggest breakthroughs occurred in the 1980s, when doctors realized that retinoids could decrease scaling. Retinoids are chemicals related to vitamin A that are often used to treat acne or skin blemishes. In some ichthyosis patients, retinoids seem to help skin cells grow and shed more normally. But in others, who have redder and more inflamed skin, retinoids don’t work as well, said Amy Paller, a dermatologist at Northwestern University.

“There’s definitely an unmet medical need,” Teng said.

Simmons takes acitretin, an oral retinoid, which has helped him manage his skin but is by no means a cure. He takes the drug off-label because it is not officially approved for ichthyosis. Acitretin is actually a drug for psoriasis, another skin condition that causes itchy, scaly skin. This ability for drugs to work across skin conditions intrigued Paller. After all, in the absence of effective drugs specifically for ichthyosis, she wondered if there may be solutions hiding elsewhere in a dermatologist’s medicine bag.

Scaly similarities

The catalog of skin disorders is seemingly endless, but many have surprising similarities. Take psoriasis and eczema, for example. In both, overactive immune cells lead to itchiness and scaly skin. In psoriasis, this creates discrete, thick areas where skin builds up, while eczema leads to more diffuse, itchy dry skin in skin folds.

Both of these conditions are reminiscent, in some ways, of ichthyosis. “They all share having defects in the outer skin barrier,” Paller said. “That means that they're more prone to stimulation of the immune system by external influences, such as bacteria or irritants.” 

Because dysfunctional immune cells cause eczema and psoriasis, this somewhat distinguishes them from skin-cell-driven ichthyosis. However, immune cells still play a role in ichthyosis; when pathogens infiltrate the degrading skin barrier, these cells promote redness and itching, and excessive immune responses in the skin that can exacerbate the thickening and scaling, further destabilizing the skin barrier in a vicious cycle.

Paller became especially interested in these similarities when the Food and Drug Administration began approving a wave of new drugs for psoriasis and eczema. This seemed like an opportunity for her dozens of ichthyosis patients lacking any effective treatments, especially the ones with rare and more severe ichthyosis subtypes such as lamellar and epidermolytic.

“These drugs were already approved, and it would be easy to repurpose them in the future if we found that they worked,” she said.

First, she needed to figure out if these conditions were actually similar at a molecular level. After all, ichthyosis is caused by individual mutations that disrupt genes’ function, while psoriasis and eczema do not have such a clear genetic driver. 

In 2017, Paller’s team published a study comparing gene expression in skin samples from people with different rare forms of ichthyosis, psoriasis, or a form of eczema called atopic dermatitis (1). Their results revealed that, although ichthyosis skin appeared thicker and more inflamed than the other diseases, they all shared similar immune signatures.

In particular, Paller noticed that both ichthyosis and psoriasis patients had elevated levels of IL-17, an immune molecule produced by a subset of T cells, but eczema patients did not. Higher IL-17 levels corresponded to worse scaling in ichthyosis. This was somewhat surprising to Paller, who had expected eczema to be more similar to ichthyosis based on their clinical features. “But it really made a lot of sense when we thought about it,” she said, citing certain subtypes of ichthyosis that have similar redness and inflammation as psoriasis.

Over the next seven years, Paller led many more studies to measure the types of immune cells, gene and protein levels, and even microbial species in ichthyosis skin (2-4). “What we discovered is that, across the board, it skewed towards the same immune picture as what we see in psoriasis,” she said. “That got us very excited.” She was especially surprised by how strong the immune signatures were in ichthyosis, something that also intrigued Teng, who was not involved in the studies.

“Increased inflammation further impairs the skin barrier, so addressing that immunological abnormality early on could have lasting benefits,” Teng said.

This discovery made the immunomodulatory drugs used for psoriasis seem even more promising for ichthyosis. In parallel with her research, Paller had launched a clinical trial in 2016 to test secukinumab, an IL-17-targeting psoriasis drug, in ichthyosis (5). She recruited 20 people with various forms of ichthyosis for the Phase 2 trial. Participants either received secukinumab or a placebo, and the researchers evaluated changes in their disease severity or infection risk after 32 weeks.

Paller was disappointed to see, however, that there was no overall improvement in disease severity or immune activity in patients who received secukinumab. She began another clinical trial in 2021 of a second IL-17-targeting psoriasis drug, ustekinumab, which just concluded this year. This trial also yielded underwhelming results, which the team has not yet published.

However, Paller noted that certain subsets of patients did appear to respond in both trials. These patients typically had ichthyosis subtypes characterized by faulty desmosomes — molecules that hold skin cells together — or ichthyosis subtypes that led to more inflamed and red skin. At the end of the secukinumab trial, five patients whose diseases had improved actually requested to remain on the drug. 

A diverse disease

In her own clinic, Paller has stopped giving IL-17 inhibiting drugs to some of her patients who have ichthyosis subtypes that seem similar to those of the patients who did not respond to those drugs in the trials. For some cases, though, she’s unsure. Even some patients with red and inflamed skin didn’t respond to the drugs in the trials.

“We now need to figure out who it works very well in, who it works somewhat in, and who shouldn't bother at all,” she said.

Teng agreed that there is an urgent need to understand the heterogeneity of ichthyosis. Part of the challenge is the vast diversity of the conditions under the broader ichthyosis umbrella. There are dozens of genes that can be mutated, making skin red, brown, thick, flaky, scaly, itchy, or any combination of these qualities. “If you study patients with heterogeneous diagnoses, they probably don't all have the same biomarkers,” she said. “In the future, it will be important to use a personalized approach to understand which drug may work better for whom.”

However, because ichthyosis is so rare, it can be hard to find enough participants for a clinical trial. Some clinical trials have been cancelled because they couldn’t enroll enough patients, “so now nobody will ever have the opportunity to see if that drug worked,” Paller said. It is even harder to find enough participants to represent the full diversity of the disease.

Engaging with the ichthyosis community is a critical part of conducting ichthyosis research, Paller said, in part because it helps scientists hear patients’ primary concerns. It also provides an avenue to recruit rare patients for trials — that’s how Simmons learned about and participated in clinical trials for lamellar ichthyosis. 

One institution is rarely enough, though. Northwestern University, where Paller works, has an especially high concentration of ichthyosis patients, but even that is not enough to run a robust clinical trial. Recruiting enough patients with these rare ichthyosis subtypes requires larger, often global consortia.

Part of the challenge may also stem from limitations in the current way that clinicians define ichthyosis subtypes. Each ichthyosis subtype is based on both physical symptoms and genetic mutations, but different genetic mutations can still lead to similar manifestations of the disease that may respond to similar treatments. Conversely, two people with the same mutation may actually have very different symptoms that warrant different treatments. Teng is part of a group of researchers working on reclassifying ichthyoses by using modern genomic technologies that reveal molecular differences.

“When we try to decide where these drugs fit and when we can use them, it's probably more important to look at the clinical response and biomarkers,” Teng said.

In the future, it will be important to use a personalized approach to understand which drug may work better for whom. 
– Joyce Teng, Stanford University

Teng also thinks dermatologists may need to prescribe multiple categories of drugs to tackle the disease from different angles. Secukinumab and ustekinumab target immune molecules, but she wonders if pairing that class of drugs with a retinoid, which targets skin turnover, may benefit certain patients. Currently, she is conducting clinical trials of just isotretinoin — a retinoid medication for acne, better known in its pill form as Accutane — to treat ichthyosis. The trial is testing a topical cream which Teng hopes can help manage specific areas of skin discomfort in a targeted way.

Simmons knows about all of this ongoing research. He keeps a close eye on ichthyosis-related clinical trials, published studies, and pharmaceutical companies with promising candidates. After all, the stakes are high for him: He has been living with the disease for more than 40 years now. “Over the several decades that I've been alive, there are lost opportunities that I'll never get back — a lost life that I'll never get back.”

So far, he has been largely disappointed, especially given the dearth of trials in his subtype of ichthyosis. He had been somewhat optimistic about LEO Pharma’s recent trial of isotretinoin for autosomal recessive congenital ichthyosis (ARCI) — which includes lamellar ichthyosis — but the recently released Phase 3 results found insufficient benefit to patients. Another gene therapy trial for ARCI at Krystal Biotech has been repeatedly delayed since 2021. He tried to get one of the IL-17-targeting drugs that Paller tested, but because lamellar patients didn’t respond well in the trial, he was denied.

Simmons is understandably frustrated, but he is glad to see that there are still some researchers committed to finding ichthyosis drugs. “I can appreciate that they are trying to repurpose and piggyback on what's already available,” he said. “I'm glad to hear there's been some positive results for other forms of ichthyosis, but if there's no help for lamellar, it’s personally disappointing for me.”

References

1. Paller, A.S. et al. An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis. J Allergy Clin Immunol   139, 152-165 (2017).
2. Czarnowicki, T. et al. The Major Orphan Forms of Ichthyosis Are Characterized by Systemic T-Cell Activation and Th-17/Tc-17/Th-22/Tc-22 Polarization in Blood. J Invest Dermatol   138, 2157-2167 (2018).
3. Malik K. et al. Ichthyosis molecular fingerprinting shows profound T_H17 skewing and a unique barrier genomic signature. J Allergy Clin Immunol   143, 604-618 (2018).
4. Tham K.-C. et al. Distinct skin microbiome community structures in congenital ichthyosis. Br J Dermatol   187, 557-570 (2022).
5. Lefferdink R. et al. Secukinumab responses vary across the spectrum of congenital ichthyosis in adults. Arch Dermatol Res   315, 305-315 (2022).