How to deal with autoimmune diseases, such as atopic dermatitis?

I met a girl who had severe atopic dermatitis. She said she had skin lesions and pigmentation on many parts of her body. Recently, she met a boy who she liked very much, but because of the scar problem, she was afraid to face it calmly. She even felt that she would carry this burden for the rest of her life and would never be happy.

In fact, I think we should not be so pessimistic, because new technologies are constantly emerging, which may help to solve the problem of atopic dermatitis. Today, let's talk about how to deal with autoimmune diseases.

01. Chimeric immune cells for the treatment of autoimmune diseases

Take 2024 as an example. If you have paid attention to technological progress, you will also find the accelerated application of new technologies.

What is the most noteworthy technology in 2024? People in different fields have different focuses. Interestingly, the top journals Nature and Science have the same view on the same scientific issue in their annual top ten scientific technologies, namely the use of chimeric immune cells to treat autoimmune diseases [1,2]. Autoimmune diseases are often accompanied by the coexistence of multiple diseases. The emergence of new biological therapies has brought new hope for the treatment of such complex diseases.

The top ten papers in Nature and Science are all about chimeric immune cell therapy

At present, many innovative pharmaceutical companies have emerged in China, developing various drugs targeting the pathogenic factors of autoimmune diseases, such as scipitobazumab targeting IL-4 (used to treat atopic dermatitis, chronic sinusitis with nasal polyps); rilonacept targeting IL-1 (used to treat juvenile cryopyrin-associated periodic syndrome); and celecoxib targeting IL-17 (used to treat psoriasis), etc.

This time, both Nature and Science Top Ten gave chimeric immunotherapy for the use of autoimmune diseases, which may be a new possibility for autoimmune diseases such as atopic dermatitis.

02. Autoimmune disease, the immune system's "self-attack"

In the TV series “Wulin Wai Zhuan”, the wonderful debate between Xiucai and Ji Wuming led Ji Wuming to the paradox of “I kill myself”. Since then, “I x myself” has become a classic stalk and widely spread in many barrages and chats. Autoimmune diseases are the “I x myself” in reality. The human immune system is a powerful guardian. It can not only resist harmful microorganisms such as foreign bacteria and viruses, but also clean up harmful lesions such as inflammation and mutant cells. However, in patients with autoimmune diseases, the immune system “does not distinguish between friend and foe” and points the attack to itself.

Among the many autoimmune-related diseases, type 2 inflammatory diseases are relatively common and complex, covering atopic dermatitis, allergic rhinitis, asthma, food allergies, etc. Let's take atopic dermatitis, which has a relatively mature development and a clearer logical chain, as an example to see how scientists and doctors solve the problem of autoimmunity.

03. What is atopic dermatitis?

Atopic dermatitis (AD) is a chronic skin inflammation. Unlike other dermatitis, it is an autoimmune disease. Because the body's immune cells produce persistent abnormal responses to damaged skin barriers, it causes difficult-to-cure dermatitis symptoms. Not only that, atopic dermatitis often causes rhinitis, asthma and other diseases, which can be described as "one lesion causing multiple diseases". Therefore, it is urgent to explore effective coping methods.

So how do you deal with the autoimmune disease atopic dermatitis? Let’s talk about it below.

04. Simple and crude method - suppressing immunity

First, a simple and crude start: suppressing immunity. Since a large number of people suffer from atopic dermatitis, relevant research has been carried out very early. Researchers found that atopic dermatitis is closely related to immunity, so the clinic chose a seemingly simple and direct method: suppressing immunity. After all, immunity plays a key role in the onset of atopic dermatitis, and suppressing immunity can indeed alleviate dermatitis symptoms. But soon, problems ensued.

Human immunity is an all-round guarantee of the body's health. When the overall immunity is suppressed, various problems emerge. After the use of immunosuppressants, the incidence of immunosuppressant-related clinical events such as acute kidney injury, liver poisoning, and fever increases [3]. At the same time, the incidence of cancer has also increased. This is not difficult to understand, because identifying and clearing tumor cells is one of the important functions of immunity. When immunity is suppressed, the ability to regulate tumors is weakened, and the risk of cancer naturally increases.

05. Relatively precise breakthrough: JAKi immunosuppressants

Faced with the problem of extensive immunosuppressants, researchers have discovered through continuous exploration that JAK plays an important role in the pathogenesis of atopic dermatitis. As a non-receptor tyrosine kinase, JAK can interact with a variety of cytokines (such as interleukins ILs) to form a complex immune signaling network, and JAK inhibitors can inhibit the activity of JAK, block the signal transduction of immune cells, and regulate immune responses, thereby exerting an immunosuppressive effect.

Soon, a series of JAK inhibitors were developed, such as the oral JAK inhibitors Upadacitinib, Abrocitinib, the topical JAK inhibitors Delgocitinib and Ruxolitinib, which greatly enriched the treatment options for atopic dermatitis.

However, as the duration of medication increases, new problems gradually emerge. On the one hand, JAK is involved in multiple cytokine signaling pathways, and inhibiting JAK will inevitably affect other normal physiological functions. On the other hand, when the concentration of JAK1 inhibitors in cells increases, JAK1 inhibitors will lose selectivity, resulting in a decrease in therapeutic effect. Therefore, we still need more precise treatment strategies.

06. More precise advancement: monoclonal antibody drugs

How to achieve more precise treatment? As the research on atopic dermatitis deepens, it is found that this is an extremely complex process, because atopic dermatitis involves multiple genes, and it is difficult to solve the problem by targeting a single gene, and broad-spectrum treatment will repeat the same mistakes. So, can we find a way to deal with multiple genes at the same time? This requires the help of protein structure. There are corresponding binding sites in different parts of the spatial conformation of the protein structure, and this feature can be used to allow proteins to perform multiple functions.

When dealing with type 2 inflammatory diseases such as atopic dermatitis, allergic rhinitis, asthma, and allergies, scientists have turned their attention to the IL family outside of JAK, and the key is to find protein antibodies that can bind to multiple ILs. In fact, this idea is extremely difficult. Taking the development of scipibaimab as an example, most antibodies screened from a library of tens of billions of antibodies cannot bind to multiple sites or have problems such as binding stability.

After multiple screenings, 500 highly binding antibodies with great potential were finally obtained. After further screening based on spatial conformation, finally, sepkizumab with good stability and immunogenicity was obtained. From the perspective of protein structure, sepkizumab has obvious advantages in binding to the spatial structure of proteins. It can bind to IL-4Rα, IL-13 Rα1 and IL-13 at the same time. These interleukin factors are the key factors in the occurrence of atopic dermatitis.

Clinical studies have shown that scipibaimab can better cope with atopic dermatitis, with an EASI-75 response rate of up to 92.5%. It can also effectively improve the itching symptoms of atopic dermatitis, and the effect is relatively rapid. According to doctors' feedback, some patients can feel the itching improve after taking the medicine for one day, and then the rash gradually subsides. The overall improvement speed is leading among similar drugs.

Clinical data also show that sepakilimumab has an improvement effect on the head and neck, trunk, and limbs. In particular, sepakilimumab can achieve good improvement in the head and neck, where biological agents have previously been ineffective in reducing skin lesions.

Because scipibaimab more precisely targets atopic dermatitis, it avoids many problems of traditional broad immunosuppressants to a certain extent. At the same time, it also shows application prospects in other immune-related diseases, such as the newly approved indication of chronic sinusitis with polyps.

07. CAR-T therapy is promising

Nowadays, with the development of immunology, a new generation of immunotherapy, CAR-T therapy, is emerging. CAR-T is the abbreviation of chimeric antigen receptor T cells, which means chimeric antigen receptor T cell therapy in Chinese. As the name suggests, it transforms immune T cells to give them stronger cell recognition capabilities. Immune cell failure is precisely the root cause of various immune diseases, and atopic dermatitis is no exception. During its onset, autoreactive T cells can participate in the immune response of the skin at all levels [5].

Traditionally, it is difficult for us to directly manipulate T cells, but the development of CAR-T technology in recent years has made it possible. Perhaps in the future, we will be able to see more applications of CAR-T technology in the treatment of atopic dermatitis.

Finally, I think that the fact that the top ten articles in Nature and Science in 2024 both gave priority to chimeric immunotherapy for the treatment of extremely difficult diseases such as autoimmune diseases means that this technology is making rapid breakthroughs, so the solution to atopic dermatitis is not far away, so don’t be pessimistic!

1 NATURE'S 10 Ten people who helped shape science in 2024.Nature | Vol 636 | 19/26 December 2024 | 543

2 SCIENCE 2024 Breakthrough of the year.Science Volume 386, Issue 6727: 2024 Dec 2024

3 Armstrong, April W., et al. "Real-world utilization patterns of systemic immunosuppressants among US adult patients with atopic dermatitis." PLoS One 14.1 (2019): e0210517.

4 Weidinger, Stephan. "Atopic dermatitis. Nature Reviews (2018) 4: 1."

5 Carlier, Tina De Bruyn, et al. "Autoreactive T cells and their role in atopic dermatitis." Journal of autoimmunity 120 (2021): 102634.