Antibodies, hormones and stem cells. How arthritis is treated in Russia today Academician of the Russian Academy of Sciences Evgeniy Nasonov spoke about modern methods of arthritis treatment 10/12/2023, 12:15

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Evgeny Nasonov

From personal archive

– There are many types of inflammatory arthritis: rheumatoid, psoriatic and crystal (gout). How do they differ from each other?

“These are all arthritis, and it turns out that the diseases are similar to each other, but they are completely different, with different mechanisms, clinical manifestations, prognosis and treatment. An experienced doctor can easily distinguish them.

In short: Rheumatoid and psoriatic arthritis are chronic diseases in which the patient experiences pain and deformity in the joints for many years and internal organs are affected. Moreover, more than one joint can be affected at the same time.

In gout, we usually talk about monoarthritis – one joint is affected. However, patients feel very severe pain, this is an acute attack. If left untreated, many patients develop chronic arthritis.

— Scientists have not yet determined the exact causes of these diseases. What role do you think it plays in the development of arthritis?

— Arthritis is a group of diseases called autoimmune diseases. It is unknown why they form.

We hypothesize that infections may play a role in the development of diseases that can trigger the development of arthritis, including COVID-19. But in general, there are many factors: These include excessive stress on the joints, injuries, smoking, obesity and vitamin D deficiency.

— Do genes also play a role?

— Of course, genetic factors contribute to approximately 50% of the development of rheumatoid arthritis. We are conducting research on this problem at our research institute: we are looking for genes responsible for the development of arthritis. It is clear that there are many of them.

— One of your scientific studies was devoted to the role of the FOXP3+ protein. Why are you working on it?

— There is such a concept: immunological tolerance. This is a process that prevents the immune system from attacking its own tissues.

FOXP3+ is a protein involved in the immune responses of T-regulatory cells that control uncontrolled inflammation. When the function of this protein is weakened, preconditions are created for immune system cells to destroy their own tissues. In other words, an autoimmune disease occurs.

— Is it possible to prevent the weakening of protein function in the early stages?

“The whole world is currently trying to find the answer to this question. Of course, there is progress, but I cannot say that any drug has emerged that can affect the immune system in this way.

However, such research is still at a very early stage. If a cure is found, it will solve the problems of many inflammatory chronic diseases.

— What is the most effective treatment method for arthritis today?

— Nowadays, the choice of treatment methods is quite large. The most advanced of these is the use of monoclonal antibodies, which are genetically modified biological drugs.

– How do they work?

— These are antibodies that are similar in properties to human immunoglobulins. Because of this similarity, they are relatively safe. So when we give them to the body, they do not cause negative reactions. This is their important property.

Second, they are specific to a particular protein. Until recently, all the drugs we used affected many different molecules involved in inflammation, but here we can target a specific protein.

— In other words, is this a topical treatment for arthritis?

— Yes, monoclonal antibodies act on a specific target. We use antibodies that essentially block the activity of pro-inflammatory mediators called pro-inflammatory cytokines. They cannot cure, but they can significantly increase the effectiveness of treatment and, of course, improve the prognosis of patients.

This is a personalized therapy. The problem here is that we do not always know which target is most important for a particular disease. However, this is still the most promising and innovative direction in the world.

— So how do you choose the target on which monoclonal antibodies will act?

— There are numerous experimental studies and so-called randomized placebo-controlled studies. When choosing goals, we focus on them. But still the diseases are very diverse, they can manifest themselves differently in different patients, so sometimes you have to act empirically.

— Do monoclonal antibodies block pro-inflammatory mediators, meaning they suppress the immune system? Wouldn’t the person then become vulnerable to other diseases, for example viruses?

— Yes, they suppress the immune system, but not as much as standard drugs. Of course, when treated with monoclonal antibodies, susceptibility to infections increases in these patients, but this is not as critical when using standard immunosuppressants (immunosuppressants), which block various parts of the immune system, including antiviral and antibacterial.

— Your research institute is working on biosimilars. Are these also monoclonal antibodies?

— There is such a term “generic”. When the original drug loses patent protection, manufacturers begin creating generic “copies” of the original drugs. Their main advantage is their low cost, because they do not have to spend a lot of money to evaluate their effectiveness and toxicity. In other words, the application and registration process is shorter and cheaper.

If we talk about genetically modified biologic drugs, we use the term “biosimilars”. Now we are conducting a lot of research on these drugs because Russian companies such as R-Pharm, Biocad have emerged that produce biosimilars. We evaluate its effectiveness and safety.

— Immunosuppressants are also used to treat arthritis. In what cases do doctors turn a blind eye to a decrease in immunity?

— Sometimes there is no better option. We must balance the effectiveness of the therapy with adverse reactions.

The fact is that chronic inflammation itself poses a risk for the development of infection. So when we suppress this, we reduce these risks. But there is a very fine line between effectiveness and safety. Therefore, it is important that the doctor is experienced in order not to miss the moment when it is necessary to change treatment.

— Glucocorticoids are used in the treatment of rheumatoid lesions, but they also have many side effects.

— Glucocorticoids are synthetic steroid hormones usually produced by the adrenal glands. They help regulate the body’s response to stress, control inflammation, and modulate the immune system.

The creation of glucocorticoids is a tremendous achievement in medicine. This has revolutionized our understanding of the possibility of treating inflammatory diseases. Monoclonal antibodies cannot replace them. But yes, there is actually a problem that glucocorticoids cause undesirable reactions when taken uncontrolled in high doses. These are osteoporosis, adrenal gland disorders, glaucoma and others.

— Hormones play an important role in the development of autoimmune diseases, including arthritis. One of your studies was devoted to the syndrome of hypogonadism, that is, a decrease in sex hormones, in men with inflammatory joint diseases. Can you tell us about this research?

– A similar disorder occurs in women – hypoestragenemia. There is a definite link between hypogonadism or hypoestragenemia and the development of chronic pain. It is known that women are more likely to suffer from autoimmune diseases, but less likely to suffer from infectious diseases. This is due to hormones.

Estrogen and androgen receptors are expressed in cells of the immune system. We are investigating whether estrogen and androgen drugs can be used in the treatment of inflammatory diseases. But since this is still in its early stages, I’ll avoid details.

– Non-steroidal anti-inflammatory drugs are also used. What are they used for?

— These are symptomatic drugs used mainly as analgesics. However, since their effects are quite short and not very strong, they are only used as symptomatic painkillers.

— Some studies suggest that cannabinoids are effective in treating arthritis. Can marijuana really help these conditions?

— Pain, including joint pain, is quite common, especially in older people. And they prevent people from living normally. Then in some cases they use all kinds of pain relief methods just to get rid of them. Even though people know all the harms of drugs, they use soft drugs in desperation.

However, this issue is more relevant in other countries where cannabinoids are legal and used for medical purposes. There is nothing like this in Russia.

— Some clinics offer services such as taping, reflexology and acupuncture to arthritis patients. The effectiveness of these methods has not been confirmed by evidence-based medicine. Do they help?

– Any way to relieve pain is good. Yes, the effectiveness of these methods has not been proven, but if it helps a person, why not use it?

There must be some kind of reasonable balance between pharmacological treatment and similar procedures. They still rely on the placebo effect, which is quite effective for rheumatic pain. Any pacifier causes pain relief in about 30% of people. For some patients, even a simple conversation with a good doctor can help.

— Your research institute also develops cellular technologies. What is this method used in the treatment of arthritis?

— This is the so-called regenerative medicine. This is mesenchymal stem cell therapy. Another method involves isolating the patient’s own cells and activating the FOXP3+ protein we discussed above and then introducing it into the patient’s body. This way we can restore immune tolerance and suppress inflammation.

However, I would like to emphasize that this is still an early stage of testing, so it is too early to recommend this method for clinical application.

— What research are you currently doing?

“Making therapy more personal is very important to us. We have a lot of medicines, but unfortunately we prescribe them empirically. We roughly imagine the general patterns of the development of inflammation, but it can occur differently in each patient and we do not always know exactly how to make the right choice of medication for the patient.

— How do you imagine the technology of personalization of treatment?

— This is a combination of clinical experience and molecular biological research.

— So, is the patient being tested for DNA?

— Yes, this is a study on the polymorphism of genes of various pro-inflammatory mediators. We hope to be able to predict the effect of a particular drug based on the data. These studies are carried out all over the world. However, so far there has been no progress that would allow these methods to be introduced into clinical practice.