How to choose different biologics therapies for IBD?

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Listening to your words is better than ten years of medicine
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Exquisite explanation, divine enlightenment, famous doctor Kung Fu tea, handed over to millions of doctors! The 9th Asian Crohn’s Disease and Colitis Organization Annual Conference (AOCC 2021) will be held in Guangzhou, Yangcheng on October 14-16, 2021.
The theme is "Breaking the Boundaries for Asian Inflammatory Bowel Disease"
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 The "medical community" specially invited Professor Ran Zhihua from Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Professor Gao Xiang from the Sixth Hospital Affiliated to Sun Yat-Sen University at the conference site to be a guest of "Famous Doctor Kung Fu Tea" in the AOCC 2021 Interview Room on Inflammatory Bowel Disease (IBD) Communicate and share multiple hot topics in the diagnosis and treatment
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 Professor Ran Zhihua: Emerging methods of IBD treatment can be expected in the future Interview Video Host: Hello Professor Ran, you have shared a number of topics related to IBD treatment at this AOCC conference.
Can you introduce to the grassroots workers, the current IBD treatment What are the main methods? Professor Ran Zhihua: At present, IBD treatment can be divided into two categories: traditional treatment and biological treatment.
Traditional treatment mainly includes 5-aminosalicylic acid, glucocorticoids, immunosuppressants and other drugs.
In 1998, tumor necrosis factor (TNF)- The alpha inhibitor infliximab was approved by the U.
S.
Food and Drug Administration (FDA), which allowed IBD treatment to enter the era of biological agents, greatly improving the therapeutic effect.
In recent years, new biological agents have appeared, such as integrins.
Receptor antagonists, interleukin (IL) inhibitors, etc.
, as well as the new small molecule drug tofacitib, have been approved for the treatment of ulcerative colitis (UC)
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 Moderator: In your opinion, what are the unmet needs of the existing IBD treatment? What is the direction of treatment? Professor Ran Zhihua: Biological agents have significantly improved the effect of IBD treatment, but there are also limitations.
It is well known that the onset of IBD is multi-factorial.
Even with TNF-α antagonist treatment, the mucosal healing rate after 1 year of treatment is only over 30%.
In addition, about 50% of patients will have primary non-response or secondary non-response.
Obviously, there is a huge unmet need for treatment.
This has led to the emergence of more monoclonal antibodies or small molecule drugs targeting different pathogenic mechanisms, but the efficacy is still insufficient Ideally, this requires further exploration and clarification of the pathogenesis of IBD, and continuous research and development of new drugs
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 Moderator: In recent years, the research and development of new drugs for IBD has also been very rapid.
Can you talk about the new treatments that you personally look forward to most? How is their research progress? Professor Ran Zhihua: The disease of IBD is highly heterogeneous, so the research and development of drugs is not limited to TNF-α inhibitors.
The emerging treatments can be divided into the following categories.
The first is drugs targeting the lymphocyte migration pathway, such as those that have been approved for marketing.
Integrin receptor antagonists, as well as small molecule drugs such as Ozanimod and Etrasimod that inhibit the sphingosine phosphate receptor (S1PR) in the lymph nodes, are undergoing clinical phase III studies
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For other inflammatory pathways, such as phosphodiesterase 4 (PDE4) inhibitors are also in the research and development stage.
In addition, some monoclonal antibody biologics can selectively block the IL-23p19 subunit in the IL-12/23 pathway, such as Risankizumab , Guselkumab and so on
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 However, traditional biological preparations are basically macromolecular monoclonal antibodies, and immunogenicity-related problems may cause failure to respond, and most of them are intravenous infusions.
Therefore, they have a wide range of tissue distribution, rapid metabolism and onset of action, and oral administration without immunogenic characteristics.
Small molecule drugs are expected to improve the therapeutic effect and compliance, and oral oligonucleotide drugs are also being studied
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Based on changes in the intestinal flora, the fecal bacteria transplantation (FMT) therapy to correct the abnormal intestinal microbes of IBD patients has also been applied to the treatment of UC, but the source and preparation of fecal bacteria need to be resolved
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In addition, mesenchymal stem cells have been approved in Europe and the United States for the treatment of anal fistulas in patients with Crohn's disease (CD), but the efficacy of treating intestinal diseases remains to be seen
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 Moderator: What are your expectations for the future development of IBD diagnosis and treatment? Professor Ran Zhihua: In recent years, the incidence of IBD has increased significantly in China.
On the one hand, there are indeed more patients.
On the other hand, doctors and patients have increased awareness and awareness of the disease, and more patients can be diagnosed.
Therefore, I think There are two major directions for the development of IBD diagnosis and treatment-popularization and improvement
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 Popularization means that grassroots doctors should focus on the intestinal symptoms related to IBD in young patients.
Patients with abdominal pain, diarrhea, perianal lesions and other manifestations should be referred to a specialized IBD center as soon as possible, and specialists will make early diagnosis and early treatment.
In order to change the disease process of IBD, it is necessary to fully publicize and teach grassroots doctors, and popularize the knowledge of IBD diagnosis and treatment through tour lectures, opening study classes, regional exchanges and case sharing
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 Improvement refers to the use of scientific research to guide and improve the level of clinical diagnosis and treatment to minimize the diagnosis and treatment gap between China and Europe and the United States.
In recent years, we have achieved considerable development.
For example, many domestic centers can directly participate in the international market of new IBD drugs.
Sexual, multi-center research is of great significance.
China's drug regulatory authorities can directly approve the listing of new therapeutic drugs based on domestic patient data, which will benefit domestic patients more quickly
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 In addition, in recent years, domestic related societies have carried out a lot of work.
After the review process, a number of regional IBD diagnosis and treatment centers have been successfully covered in major provinces and cities, thereby making it more convenient for IBD patients to see and improve the effectiveness of diagnosis and treatment
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 Professor Gao Xiang: Reasonably choose the most suitable biologics for patients with IBD Interview Video Host: Hello Professor Gao, the topics you shared at this AOCC conference are mainly related to IBD biologics.
Could you please introduce us first, it is widely used What are the biological agents? Professor Gao Xiang: First of all, TNF-α inhibitor biologics are widely used clinically.
Among them, infliximab was approved by the US FDA in 1998 and landed in China in 2006.
Chinese clinicians have had 15 years of experience.
Medication experience
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In recent years, other biologics, such as uzinuzumab and other drugs, have been approved for marketing
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 Moderator: In your opinion, what are the advantages of biologics compared with traditional medicines? Professor Gao Xiang: First, let’s talk about the status of traditional medicines.
From the 1950s to the beginning of this century, traditional medicines were used for IBD treatment, including 5-aminosalicylic acid, glucocorticoids, mercaptopurine and cycloheximide.
Immunosuppressive drugs such as spores and tacrolimus
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Traditional therapeutic drugs have a good effect on IBD patients.
For example, glucocorticoids can induce about 86% of UC patients, and 60% of CD patients have clinical remission.
However, various side effects restrict long-term medication.
Only immunosuppressive drugs can be used.
Long-term maintenance treatment, but side effects such as bone marrow suppression cannot be ignored.
Our center has previously discovered the specific mechanism of azathioprine-induced bone marrow suppression and NUDT15 gene polymorphism
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 Moreover, the long-term efficacy of traditional therapeutic drugs is not ideal.
60%-80% of patients will relapse within 1-2 years of treatment, and most patients cannot achieve mucosal remission, the natural course of the disease cannot be changed, and the quality of life of patients cannot be improved.
, All these make biological preparations have high hopes
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Different biological agents have fast or slow onset, but generally they can effectively induce clinical remission, promote mucosal healing, reduce the proportion of surgery, and improve the quality of life.
The side effects are generally lower than those of hormone + azathioprine
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In terms of safety and durability, biological agents have better performance
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 Moderator: What factors and indicators need to be considered when selecting biologics for patients in clinical practice? Professor Gao Xiang: Most clinical studies of biological agents are not head-to-head designs and cannot provide evidence-based medical evidence for preferred biological agents.
Therefore, the first-line drug selection basis in clinical practice is mainly based on real-world research data and physicians’ personal experience and considerations, and The patient’s disease severity, scope of involvement, and high-risk factors affecting the prognosis, such as smoking in CD patients, young age of onset, combined anal fistula, age of onset of UC patients <40 years old, more rapid onset and severer are all high-risk factors and need to be selected Biological preparations with quick onset and strong curative effect can quickly induce the patient's condition to be relieved and even the mucosal healed
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 Another important selection factor is the availability of drugs.
Whether the drug is approved and included in medical insurance, and the proportion of patient out-of-pocket expenses will affect the choice of biologics
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Clinicians cannot make unilateral decisions when making treatment decisions.
They need to fully communicate with patients and their families to choose the most appropriate treatment drugs at this stage
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 The third factor is the safety of drug use.
"Do No Harm" is the basic principle.
The patient's basic physical condition and past medical history should be considered.
The use of biological agents should not cause greater negative effects.
This also requires patients to fully Informed consent
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 Moderator: In recent years, the biologics for the diagnosis and treatment of IBD have made rapid progress.
What new drug researches do you personally look forward to most, can you share? Professor Gao Xiang: In recent years, our center has also participated in a number of global and multi-center studies of IBD therapeutic drugs, from phase I, phase II to phase III studies, including both macromolecular monoclonal antibodies and small molecule drugs.
Before the drug is marketed I already have a certain amount of experience
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I personally look forward to monoclonal antibodies that target the IL-23 p19 subunit in the IL-12/23 pathway, such as Guselkumab, Mirikizumab, and Risankizumab.
In clinical studies, some patients in the treatment group respond better
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In terms of small molecule drugs, there are also drugs that have been approved by the US FDA for marketing
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In terms of integrin receptor antagonists, Etrolizumab's Phase III clinical study has been declared a failure, and it has not brought significant benefits
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As for the monoclonal antibody targeting IL-23 p19 subunit, it is currently believed to be expected to surpass previous biological agents and change the treatment decision of IBD
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