Biologic medicines | Crohn’s & Colitis UK

Deciding to take a biologic medicine can feel like a big step. But if you’re not well and other treatments aren’t working, they can make a huge difference to your quality of life. Whether you’ve been prescribed a biologic for Crohn’s or Colitis or you’re considering it as an option, this information sheet is for you.

It looks at:

Biologic medicines are treatments for people with moderate to severe Crohn’s Disease or Ulcerative Colitis. They may be an option when other drugs such as immunosuppressants (azathioprine, mercaptopurine, methotrexate) or steroids haven’t been effective, or side effects have been hard to manage.

Biologic medicines are produced by biological rather than chemical processes. Living organisms, such as living cells, produce the active substance which is made of proteins.

There are five different biologic medicines available to treat moderate to severe Crohn’s Disease or Ulcerative Colitis. These are infliximab, adalimumab, golimumab, vedolizumab and ustekinumab.

Not all drugs are available to treat both conditions – find out more in our individual drug treatment information. 

Crohn’s Disease

Infliximab is available to treat active fistulising Crohn’s Disease that hasn’t responded to treatment. Adalimumab has also been used successfully to treat fistulas in people with Crohn’s who also have active inflammation. Find out more in Living with a Fistula.

Vedolizumab is a treatment option only when infliximab or adalimumab (anti-TNF drugs) haven’t been effective or there is a reason why you shouldn’t take these.

Ustekinumab may be used where immunosuppressants or steroids haven’t worked, or an anti-TNF drug hasn’t been effective or has stopped working.

Ulcerative Colitis

Vedolizumab may be an option if other treatments such as steroids or immunosuppressants haven’t helped your condition. This and ustekinumab may also be an option if infliximab, adalimumab or golimumab (anti-TNF drugs) haven’t worked for you, have stopped working or side effects have been difficult to manage.

Gut inflammation in Crohn’s and Colitis is caused by over-activity of the immune system. Biologic medicines act to block some parts of this, reduce the inflammation and so improve symptoms.

They work in different ways:

Blocking the activity of cytokines (TNF-alpha or interleukins). Cytokines are specific proteins usually produced as a response to infection or injury. In Crohn’s and Colitis overproduction of these proteins is thought to be partly responsible for the inflammation in the gut.

• Infliximab, adalimumab, golimumab – Anti-TNF. These drugs work by targeting a protein in the body called tumour necrosis factor-alpha (TNF-alpha). They bind to the TNF-alpha, this reduces the inflammation and helps to relieve symptoms. They are known as anti-TNF drugs.
• Ustekinumab – Anti-interleukin. Ustekinumab targets the proteins interleukin-12 (IL-12) and interleukin-23 (IL-23) which contribute to ongoing inflammation in the gut. Ustekinumab binds to both these proteins and prevents them from working, helping to reduce inflammation and improve symptoms.

Blocking white cells moving into the gut – Gut-selective integrin blocker. White blood cells are made by the immune system to fight infection, but in Crohn’s and Colitis, overproduction of these cells leads to gut inflammation.

• Vedolizumab – Anti-integrin. This works by stopping the white blood cells from entering the lining of the gut and causing inflammation. The drug only targets the immune system of the gut and because the action is local, it may cause fewer immunosuppressive side effects.

This can mean that if one type of treatment hasn’t worked for you, trying a drug that works in a different way could be an option. The decision about which treatment to try next depends on several factors which you could discuss with your IBD team. 

Biologic drugs have all been shown to be effective in improving gut symptoms, bringing about and maintaining remission (preventing flares) in people with moderate to severe Crohn’s or Colitis. They can also reduce the need for hospitalisation or surgery. But they don’t work for everyone, and for some people they stop working after some time.

Because they suppress parts of the immune system, all biologics carry an increased risk of infections, which in rare cases can be serious. Find out more in our individual drug treatment information.

Symptoms outside the gut
Some biologic medicines (infliximab, adalimumab) have been shown to be effective in improving symptoms outside the gut related to Crohn’s or Colitis. These are also known as extra intestinal manifestations (EIMs) and can include problems with:

• Joints – pain (arthralgia), pain and swelling (arthritis). Find out more in Joints.
• Skin – erythema nodosum, this is swollen fat under the skin causing red bumps and patches.
• Eyes – uveitis, this is inflammation of the eyes that causes redness and soreness.

My experience of having been on Humira, Remicade and Remsima are only positive, all can be life changing, and when they work it is like you no longer have IBD. Ensure you keep in contact with your IBD team and let them know how you are doing – remember they have lots of experience of IBD and are the best people to talk to.

Barry, age 41
Diagnosed with Crohn’s Colitis in 2006

All these drugs are taken either by injection under the skin or through a drip in the arm (IV infusion). You can’t take biologics by mouth because the digestive system would break down and destroy the drug.

The decision about your treatment should be made a after full discussion between you and your IBD team. You should consider the potential benefits, possible risks, and the goals of your treatment together.

This will include how active the condition is, how the medicine doses are taken and the impact on other symptoms you may have such as joint or skin problems. You might like to think about whether a hospital infusion or an injection at home would work best for you; will you be able to arrange time off for infusions with your employer? Do you have a reliable fridge at home?

The first biologic medicines that are often tried are infliximab or adalimumab. This is because they have been used for a long time and are shown to be effective. But, if they don’t work well for you, there may be other biologics you can try. 

Treatment doesn’t work or stops working

Treatment isn’t effective from the start. Biologic medicines don’t work for everyone. Some people find that treatment doesn’t make them feel better. Your IBD team will monitor how treatment is working for you in the first three months.

If your symptoms haven’t improved treatment will be stopped, and another approach tried. Some people may not respond to the way one biologic works, so switching to a biologic that acts in a different way can be helpful.

Treatment loses effect over time. Some people find treatment is effective to begin with, but this becomes less over time. This often happens because the immune system recognises the drug as a foreign substance and thinks it is harmful. It then produces proteins called antibodies against the biologic drug and these stop it from working as well.

If this happens there may be a few options:

• Increase the dose.

• Add an immunosuppressant so that you would be taking a combination of medicines. There is evidence that this can reduce the levels of antibodies.

• Change to a biologic that works in a different way.

• Change to a different biologic that works in the same way.
   

Side effects are severe or difficult to mange
Treatment may be stopped if you experience side effects that are difficult to manage.

Stable remission
If you are in stable remission after one year of treatment, your IBD team may decide that you can stop taking your biologic. Stable remission means that your symptoms have gone away, and you haven’t had any flares in that time. You’ll continue to be monitored and if a relapse happens you should be able to start treatment again.

If you’ve been taking the biologic together with an immunosuppressant such as azathioprine, your IBD team may suggest you continue treatment with the immunosuppressant alone. 

It isn’t possible to produce an exact copy of a biological drug because they are complex medicines made from living cells.

As you can see, aspirin is a small molecule so it’s easy to replicate compared to a complex biologic medicine. 

A biosimilar is a biological medicine which is highly similar to the original drug. The first brand produced is known as the “originator”, other brands of the same medicine are known as “biosimilars”.

Infliximab and adalimumab have biosimilars. Both these medicines should always be prescribed by the brand name so there is no uncertainty about which one is being used.

Infliximab: the originator product is Remicade. Biosimilar versions are Inflectra, Remsima and Flixiabi which became available from February 2015. Zessly is a biosimilar which became available in 2018.

Adalimumab: the originator product is Humira. Biosimilar versions are Amgevita, Hulio, Imraldi and Hyrimoz. These became available in 2018.

What are the advantages of biosimilar medicines?
Biosimilars are much cheaper for the NHS to use than the originator medicine. The money saved can be reinvested in new drugs and treatments.

What differences might there be?
Biosimilars are thoroughly tested. They meet strict standards to show they are as safe, effective and have no clinically meaningful differences from the originator. Where NICE has recommended the use of a biological medicine, they state that the same guidance applies to the biosimilar.

However, there are likely to be some small differences including:

• Injection device: Injection devices for all the different products vary. If you have changed brand, this is likely to be different from the one you have been used to using. You will receive full training until you are confident to use the new one.
• Homecare delivery service: If you change to a different product, you are likely to have this delivered by a different homecare delivery service.
• Side effects: Because the formulations are not the same, some people who switch products may experience new injection site reactions. Your IBD team can help you with tips to reduce these.

Some people may be sensitive to latex, which is used as a needle cover in some of some types of biosimilars, or citrate which is sometimes included as one of the ingredients.

Some types of adalimumab are available without citrate or latex, and you can ask to try one of these. 

How will my hospital tell me if it wants to use a new biosimilar medicine?
Your IBD team will contact you by letter.

Do I have to change to the biosimilar or can I stay on the originator product?
Talk to your IBD team about any concerns you have. Each hospital should have alternative versions of adalimumab or infliximab but you can say if you are happy with your medication and don’t want to change brand. 

What are my rights when it comes to changing to a new medicine?
Switching to any new medicine should involve a discussion between you and your IBD team. This should consider your needs, preferences and values as well as all the available clinical evidence.

Can I change back if I don’t feel as well on the biosimilar?
Your IBD team will discuss any problems you’re experiencing with you and together you can agree the best way forward. A new side effect may be a good reason to change back. But if you feel your condition is not as well controlled on the biosimilar, it could be that you are losing response to the medication and a completely different biologic could be tried.

I was moved from Remicade to a biosimilar in February 2015, when the patent expired. I have found the biosimilar to be no more different in effect from infliximab: I have had no side effects and it is just as an effective a treatment for me.

Claire, age 64
Diagnosed with Colitis in 2009

It can feel daunting starting a new medicine. You’ve probably never had to inject yourself before or you might be worried about taking time off to go for an infusion. But it’s all done with the aim of getting you better, and you’ll probably find you get used to it faster than you thought.

Our Helpline takes many calls on these issues so you’re not alone. We can’t advise but it may help to talk through your worries. We can also provide you with more information about the individual biologics.

We offer more than 50 publications on many aspects of Crohn’s Disease, Ulcerative Colitis and other forms of Inflammatory Bowel Disease. You may be interested in our comprehensive booklets on each disease, as well as the following publications:

Health professionals can order some publications in bulk by using our online ordering system. If you would like a printed copy of a booklet or information sheet, please contact our helpline.

Our helpline is a confidential service providing information and support to anyone affected by Crohn’s or Colitis. Our team can:
• help you understand more about Crohn’s or Colitis, diagnosis and treatment options
• provide information to help you to live well with your condition
• help you understand and access disability benefits
• be there to listen if you need someone to talk to
• put you in touch with a trained support volunteer who has a personal experience of Crohn’s or Colitis

Call us on 0300 222 5700 
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This closed-group community on Facebook is for everyone affected by Crohn’s or Colitis. You can share your experiences and receive support from others.

Crohn’s & Colitis UK Patient Panels
IBD Patient Panels, which are supported by Crohn’s & Colitis UK, are groups of people with Crohn’s or Colitis who use their perspective as a patient to work with their IBD healthcare team to help improve their hospital services. For more information on patient panels, please read our information leaflet or contact our Patient Engagement Team.

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Ulcerative colitis – Diagnosis and treatment

Diagnosis

Endoscopic procedures with tissue biopsy are the only way to definitively diagnose ulcerative colitis. Other types of tests can help rule out complications or other forms of inflammatory bowel disease, such as Crohn’s disease.

To help confirm a diagnosis of ulcerative colitis, you may have one or more of the following tests and procedures:

Lab tests

• Blood tests. Your doctor may suggest blood tests to check for anemia — a condition in which there aren’t enough red blood cells to carry adequate oxygen to your tissues — or to check for signs of infection.
• Stool studies. White blood cells or certain proteins in your stool can indicate ulcerative colitis. A stool sample can also help rule out other disorders, such as infections caused by bacteria, viruses and parasites.

Endoscopic procedures

• Colonoscopy. This exam allows your doctor to view your entire colon using a thin, flexible, lighted tube with a camera on the end. During the procedure, your doctor can also take small samples of tissue (biopsy) for laboratory analysis. A tissue sample is necessary to make the diagnosis.
• Flexible sigmoidoscopy. Your doctor uses a slender, flexible, lighted tube to examine the rectum and sigmoid colon — the lower end of your colon. If your colon is severely inflamed, your doctor may perform this test instead of a full colonoscopy.

Imaging procedures

• X-ray. If you have severe symptoms, your doctor may use a standard X-ray of your abdominal area to rule out serious complications, such as a perforated colon.
• CT scan. A CT scan of your abdomen or pelvis may be performed if your doctor suspects a complication from ulcerative colitis. A CT scan may also reveal how much of the colon is inflamed.
• Computerized tomography (CT) enterography and magnetic resonance (MR) enterography. Your doctor may recommend one of these noninvasive tests if he or she wants to exclude any inflammation in the small intestine. These tests are more sensitive for finding inflammation in the bowel than are conventional imaging tests. MR enterography is a radiation-free alternative.

More Information

Show more related information

Treatment

Ulcerative colitis treatment usually involves either drug therapy or surgery.

Several categories of drugs may be effective in treating ulcerative colitis. The type you take will depend on the severity of your condition. The drugs that work well for some people may not work for others, so it may take time to find a medication that helps you.

In addition, because some drugs have serious side effects, you’ll need to weigh the benefits and risks of any treatment.

Anti-inflammatory drugs

Anti-inflammatory drugs are often the first step in the treatment of ulcerative colitis and are appropriate for the majority of people with this condition. These drugs include:

• 5-aminosalicylates. Examples of this type of medication include sulfasalazine (Azulfidine), mesalamine (Asacol HD, Delzicol, others), balsalazide (Colazal) and olsalazine (Dipentum). Which one you take, and whether it is taken by mouth or as an enema or suppository, depends on the area of your colon that’s affected.
• Corticosteroids. These drugs, which include prednisone and budesonide, are generally reserved for moderate to severe ulcerative colitis that doesn’t respond to other treatments. Due to the side effects, they are not usually given long term.

Immune system suppressors

These drugs also reduce inflammation, but they do so by suppressing the immune system response that starts the process of inflammation. For some people, a combination of these drugs works better than one drug alone.

Immunosuppressant drugs include:

• Azathioprine (Azasan, Imuran) and mercaptopurine (Purinethol, Purixan). These are the most widely used immunosuppressants for the treatment of inflammatory bowel disease. Taking them requires that you follow up closely with your doctor and have your blood checked regularly to look for side effects, including effects on the liver and pancreas.
• Cyclosporine (Gengraf, Neoral, Sandimmune). This drug is normally reserved for people who haven’t responded well to other medications. Cyclosporine has the potential for serious side effects and is not for long-term use.

• Tofacitinib (Xeljanz). This is called a “small molecule” and works by stopping the process of inflammation. Tofacitinib is effective when other therapies don’t work. Main side effects include the increased risk of shingles infection and blood clots.

  The U.S. Food and Drug Administration (FDA) recently issued a warning about tofacitinib, stating that preliminary studies show an increased risk of serious heart-related problems and cancer from taking this drug. If you’re taking tofacitinib for ulcerative colitis, don’t stop taking the medication without first talking with your doctor.

Biologics

This class of therapies targets proteins made by the immune system. Types of biologics used to treat ulcerative colitis include:

• Infliximab (Remicade), adalimumab (Humira) and golimumab (Simponi). These drugs, called tumor necrosis factor (TNF) inhibitors, or biologics, work by neutralizing a protein produced by your immune system. They are for people with severe ulcerative colitis who don’t respond to or can’t tolerate other treatments.
• Vedolizumab (Entyvio). This medication is approved for treatment of ulcerative colitis for people who don’t respond to or can’t tolerate other treatments. It works by blocking inflammatory cells from getting to the site of inflammation.
• Ustekinumab (Stelara). This medication is approved for treatment of ulcerative colitis for people who don’t respond to or can’t tolerate other treatments. It works by blocking a different protein that causes inflammation.

Other medications

You may need additional medications to manage specific symptoms of ulcerative colitis. Always talk with your doctor before using over-the-counter medications. He or she may recommend one or more of the following.

• Anti-diarrheal medications. For severe diarrhea, loperamide (Imodium A-D) may be effective. Use anti-diarrheal medications with great caution and after talking with your doctor, because they may increase the risk of an enlarged colon (toxic megacolon).
• Pain relievers. For mild pain, your doctor may recommend acetaminophen (Tylenol, others) — but not ibuprofen (Advil, Motrin IB, others), naproxen sodium (Aleve) and diclofenac sodium, which can worsen symptoms and increase the severity of disease.
• Antispasmodics. Sometimes doctors will prescribe antispasmodic therapies to help with cramps.
• Iron supplements. If you have chronic intestinal bleeding, you may develop iron deficiency anemia and be given iron supplements.

Surgery

Surgery can eliminate ulcerative colitis and involves removing your entire colon and rectum (proctocolectomy).

In most cases, this involves a procedure called ileoanal anastomosis (J-pouch) surgery. This procedure eliminates the need to wear a bag to collect stool. Your surgeon constructs a pouch from the end of your small intestine. The pouch is then attached directly to your anus, allowing you to expel waste relatively normally.

In some cases a pouch is not possible. Instead, surgeons create a permanent opening in your abdomen (ileal stoma) through which stool is passed for collection in an attached bag.

Cancer surveillance

You will need more-frequent screening for colon cancer because of your increased risk. The recommended schedule will depend on the location of your disease and how long you have had it. People with proctitis are not at increased risk of colon cancer.

If your disease involves more than your rectum, you will require a surveillance colonoscopy every one to two years, beginning as soon as eight years after diagnosis if the majority of your colon is involved, or 15 years if only the left side of your colon is involved.

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Lifestyle and home remedies

Sometimes you may feel helpless when facing ulcerative colitis. But changes in your diet and lifestyle may help control your symptoms and lengthen the time between flare-ups.

There’s no firm evidence that what you eat actually causes inflammatory bowel disease. But certain foods and beverages can aggravate your signs and symptoms, especially during a flare-up.

It can be helpful to keep a food diary to keep track of what you’re eating, as well as how you feel. If you discover that some foods are causing your symptoms to flare, you can try eliminating them.

Here are some general dietary suggestions that may help you manage your condition:

• Limit dairy products. Many people with inflammatory bowel disease find that problems such as diarrhea, abdominal pain and gas improve by limiting or eliminating dairy products. You may be lactose intolerant — that is, your body can’t digest the milk sugar (lactose) in dairy foods. Using an enzyme product such as Lactaid may help as well.
• Eat small meals. You may find that you feel better eating five or six small meals a day rather than two or three larger ones.
• Drink plenty of liquids. Try to drink plenty of liquids daily. Water is best. Alcohol and beverages that contain caffeine stimulate your intestines and can make diarrhea worse, while carbonated drinks frequently produce gas.
• Talk to a dietitian. If you begin to lose weight or your diet has become very limited, talk to a registered dietitian.

Stress

Although stress doesn’t cause inflammatory bowel disease, it can make your signs and symptoms worse and may trigger flare-ups.

To help control stress, try:

• Exercise. Even mild exercise can help reduce stress, relieve depression and normalize bowel function. Talk to your doctor about an exercise plan that’s right for you.
• Biofeedback. This stress-reduction technique helps you reduce muscle tension and slow your heart rate with the help of a feedback machine. The goal is to help you enter a relaxed state so that you can cope more easily with stress.
• Regular relaxation and breathing exercises. An effective way to cope with stress is to perform relaxation and breathing exercises. You can take classes in yoga and meditation or practice at home using books, CDs or DVDs.

Alternative medicine

Many people with digestive disorders have used some form of complementary and alternative medicine (CAM). However, there are few well-designed studies showing the safety and effectiveness of complementary and alternative medicine.

Although research is limited, there is some evidence that adding probiotics along with other medications may be helpful, but this has not been proved.

Preparing for your appointment

Symptoms of ulcerative colitis may first prompt you to visit your primary care doctor. Your doctor may recommend you see a specialist who treats digestive diseases (gastroenterologist).

Because appointments can be brief, and there’s often a lot of information to discuss, it’s a good idea to be well prepared. Here’s some information to help you get ready, and what to expect from your doctor.

What you can do

• Be aware of any pre-appointment restrictions. At the time you make the appointment, be sure to ask if there’s anything you need to do in advance, such as restrict your diet.
• Write down any symptoms you’re experiencing, including any that may seem unrelated to the reason for which you scheduled the appointment.
• Write down key personal information, including any major stresses or recent life changes.
• Make a list of all medications, vitamins or supplements that you’re taking. Be sure to let your doctor know if you’re taking any herbal preparations, as well.
• Ask a family member or friend to come with you. Sometimes it can be difficult to remember all the information provided to you during an appointment. Someone who accompanies you may remember something that you missed or forgot.
• Write down questions to ask your doctor.

Your time with your doctor is limited, so preparing a list of questions ahead of time can help you make the most of your time. List your questions from most important to least important in case time runs out. For ulcerative colitis, some basic questions to ask your doctor include:

• What’s the most likely cause of my symptoms?
• Are there other possible causes for my symptoms?
• What kinds of tests do I need? Do these tests require any special preparation?
• Is this condition temporary or long lasting?
• What treatments are available, and which do you recommend?
• What types of side effects can I expect from treatment?
• Are there any prescription or over-the-counter medications I need to avoid?
• What sort of follow-up care do I need? How often do I need a colonoscopy?
• Are there any alternatives to the primary approach that you’re suggesting?
• I have other health conditions. How can I best manage them together?
• Are there certain foods I can’t eat anymore?
• Will I be able to keep working?
• Can I have children?
• Is there a generic alternative to the medicine you’re prescribing?
• Are there any brochures or other printed material that I can take with me? What websites do you recommend?

What to expect from your doctor

Your doctor is likely to ask you a number of questions. Being ready to answer them may reserve time to go over points you want to spend more time on. Your doctor may ask:

• When did you first begin experiencing symptoms?
• Have your symptoms been continuous or occasional?
• How severe are your symptoms?
• Do you have abdominal pain?
• Have you had diarrhea? How often?
• Have you recently lost any weight unintentionally?
• Does anything seem to improve your symptoms?
• What, if anything, appears to worsen your symptoms?
• Have you ever experienced liver problems, hepatitis or jaundice?
• Have you had any problems with your joints, eyes, skin rashes or sores, or had sores in your mouth?
• Do you awaken from sleep during the night because of diarrhea?
• Have you recently traveled? If so, where?
• Is anyone else in your home sick with diarrhea?
• Have you taken antibiotics recently?
• Do you regularly take nonsteroidal anti-inflammatory drugs, such as ibuprofen (Advil, Motrin IB, others) or naproxen sodium (Aleve)?

Feb. 23, 2021

Can Takeda’s Entyvio Be a first-line biologic For UC treatment?

At the 13^th Congress of the European Crohn’s and Colitis Organization (ECCO) – Inflammatory Bowel Diseases (IBD) in Vienna, Austria, which took place from February 14–17, Takeda announced real-world data that evaluated the effectiveness of Entyvio (vedolizumab) versus tumor necrosis factor (TNF) alpha inhibitors for patients suffering from moderate to severe ulcerative colitis (UC). The study was conducted by the Vedolizumab Health OuTComes in InflammatORY Bowel Diseases (VICTORY) consortium. The compiled analyses showed that patients treated with Entyvio had statistically significant, higher rates of mucosal healing and clinical remission compared with those treated with TNF alpha inhibitors. With the arrival of this new data, the question becomes whether or not physicians should consider using Entyvio as a first-line biologic for UC.

UC is a chronic inflammatory disease of the colon or large intestine that usually initially manifests in the terminal part of the colon (rectum) and extends either to the left part of the colon or to the entire colon as the disease progresses. According to GlobalData, there were over 1,754,677 diagnosed prevalent cases of moderate to severe UC globally in 2017, across all ages. When patients fail to respond to conventional therapies, physicians prescribe biologics such as TNF alpha inhibitors—including Johnson & Johnson’s (J&J’s) Remicade (infliximab), AbbVie’s Humira (adalimumab), and J&J’s Simponi (golimumab). Takeda’s anti-integrin therapy, Entyvio, is usually prescribed as a second-line biologic for patients who are unresponsive to TNF alpha inhibitor therapy; one reason for this may be the price, as US key opinion leaders (KOLs) interviewed by GlobalData have suggested that many hospitals do not prescribe the drug because its cost is too high.

Data from 334 patients out of the 646 UC patients in the VICTORY consortium study was analysed. Patients treated with Entyvio had higher mucosal healing and clinical remission rates compared to those treated with TNF alpha inhibitors (Entyvio: 50% versus 42%; hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.10–2.73) (TNF alpha inhibitors: 54% versus 37%; HR 1.54, 95% CI 1.08–2.18). This data reveal that Entyvio is more efficacious than anti-TNF alpha agents for this set of patients with moderate to severe UC. KOLs interviewed by GlobalData indicated that an increasing number of gastroenterologists are starting to prescribe Entyvio as a first-line biologic. As such, the data above could potentially influence these physicians to prescribe Entyvio to patients. Furthermore, one European KOL suggested that Entyvio is a better choice because of its superior safety profile compared with TNF inhibitor agents, which also makes patients more willing to use the drug.

Currently, Takeda is sponsoring an ongoing Phase III, double-blind, multicentre trial to evaluate the efficacy and safety of Entyvio compared to Humira. Positive results from this trial would reinforce the analyses that were compiled by VICTORY. Additionally, Entyvio could obtain a larger share of the UC market and become a first-line biologic if it boasted a superior efficacy profile over Humira. Therefore, it is very important for Takeda to be successful in this trial before competitor molecules such as Roche’s etrolizumab reach the market and erode Entyvio’s sales.

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20 Years of Colectomy and Biologics for Ulcerative Colitis – Consult QD

Colectomy rates in patients with ulcerative colitis (UC) are declining as biologic therapy utilization increases, according to the largest population-based study of UC patients to date. Cleveland Clinic researchers presented the analysis of 20 years of data at the 2020 Annual Meeting of the American College of Gastroenterology.

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“The trends revealed in this study are consistent with smaller cohort studies around colectomy rates and the advent of biologic therapies,” says George Khoudari, MD, an internist and research fellow at Cleveland Clinic’s Digestive Disease & Surgical Institute, and lead author of the abstract. “Biologics have been a game changer for the treatment of UC, and while not effective for everyone, have improved the quality of life for our patients, reducing hospitalizations and surgeries.”

Rates of utilization

Researchers mined a commercial database of 20 years of electronic medical record data from 61,592,650 patients from 26 U.S. healthcare systems. From 2000 to 2019, 146,430 patients ages 18 and older were identified as having UC according to the Systematized Nomenclature of Medicine Clinical Terms. During the entire period, 10.2% of patients had a colectomy, and 6.8% were treated with biologics, including tumor necrosis factor, integrin and interleukin inhibitors. Researchers compared the rates of colectomy and biologics use over 20 years using linear regression.

“We expected that after we controlled for other therapies, we’d see a decline in the use of colectomy over the years, but the rates of decline were more pronounced than we predicted,” says Miguel Regueiro, MD, senior author of the study and Chair of Cleveland Clinic’s Department of Gastroenterology, Hepatology and Nutrition.

The trend of colectomy and biologic use prevalence over two decades

The prevalence of colectomy declined from 10.8% to 2.1% from 2000 to 2019, respectively. At the same time, there was an associated linear increase in the prevalence of biologic usage from 0.5% to 12.8% (P < 0.001). Researchers adjusted the data to include other therapies such as mesalamine, thiopurines and corticosteroids and found that biologics were inversely related to colectomy (P < 0.001).

“The treatment for ulcerative colitis has changed significantly over the past 20 years with biologics being initiated earlier in the inflammatory bowel disease [IBD] course,” says Dr. Khoudari. “In this patient population, we noticed a falling trend of colectomy prevalence that coincides with a rising trend in biologics use. This is a very important observation and may change the natural course of IBD.”

Biologics and beyond in IBD

This research is part of a new era of IBD care at Cleveland Clinic combining novel medical and surgical therapies with pioneering research. The outcome is IBD care that is setting a high standard, exceeding that of traditional IBD centers of excellence.

Perhaps the most fundamental shift has been the introduction of Cleveland Clinic’s IBD medical home, which pairs patients with a team of colorectal surgeons, pain specialists, pharmacists, dietitians, social workers, psychologists and others, all led by a gastroenterologist.

“While it’s still early, we’re seeing that our patients with ulcerative colitis and other inflammatory bowel diseases experience improved quality of life, decreased emergency department visits and hospitalizations, and reduced total cost of care thanks to the medical home model,” says Dr. Regueiro, who leads the program. “We plan to set the trends for treating these diseases for many years to come.”

Ulcerative Colitis: Today, Tomorrow, and the Future

Chairperson: Jean-Frederic Colombel¹

Speakers: Jean-Frederic Colombel,¹ Silvio Danese,² Laurent Peyrin-Biroulet³
1. Icahn School of Medicine at Mount Sinai, New York City, New York, USA
2. Inflammatory Bowel Diseases Center, Humanitas University, Milan, Italy
3. Nancy University Hospital, Nancy, France

Disclosure: Prof Colombel is a shareholder of Intestinal Biotech Development and GENFIT; has received grant/research support from AbbVie, Janssen, and Takeda; has acted as a consultant or advisory board member for or received honoraria from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enterome, Ferring Pharmaceuticals, Geneva Biotech, Genentech, Gilead, Ipsen, Imedex, Immunic, Janssen, Landos Biopharma, LimmaTech Biologics AG, MedImmune, Merck & Co., Novartis, OMass Therapeutics, Otsuka, Pfizer, Shire, Takeda, TiGenix, and Viela Bio; and has participated in speakers bureau for AbbVie, Amgen, Allergan, Bristol Myers Squibb, Ferring Pharmaceuticals, Shire, and Takeda. Prof Danese has acted as a consultant or advisory board member for or received honoraria from AbbVie, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor Pharma. Prof Peyrin-Biroulet has acted as a consultant or advisory board member for or received honoraria from AbbVie, Allergan, Alma S.R.L., Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Boehringer Ingelheim, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enterome, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, InDex Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Nestlé, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Roche, Samsung Bioepis, Sandoz, sterna biologicals, Sublimity Therapeutics, Pfizer, Pharmacosmos, Takeda, Theravance, Tillotts, and Vifor Pharma.

Acknowledgements: Medical writing assistance was provided by Stefan Amisten, Amisten Consulting Limited, Epsom, UK.

Support: The symposium and publication of this article were funded by Galapagos NV, Mechelen, Belgium and Gilead Sciences, Inc, Foster City, California, USA.

Citation: EMJ Gastroenterol. 2020;9[1]:30-40.

Meeting Summary

This was a Gilead- and Galapagos-sponsored symposium devoted to today, tomorrow, and the future of ulcerative colitis (UC), as part of the United European Gastroenterology (UEG) Week Virtual 2020.

Prof Colombel welcomed the audience and provided the first talk, summarising the current treatment landscape and unmet needs in UC, and highlighting the limitations of pharmaceutical and surgical therapies for UC, as well as the divergent views of the condition by patients with UC and their physicians.

Prof Danese discussed the late-stage clinical development of sphingosine-1-phosphate (S1P) receptor modulators, IL-23 inhibitors, leukocyte adhesion inhibitors, and JAK/tyrosine kinase 2 (TYK2) inhibitors for the treatment of UC, and considered how these new drugs could change clinical practice.

Finally, Prof Peyrin-Biroulet shared his vision of what the future might hold for the treatment of patients with UC. He summarised the late-stage clinical development pipeline for potential UC therapeutics and shared his view on how the increasing deployment of biosimilars, as well as novel treatment concepts such as dual-targeted biologics and biologic/small-molecule combination therapies, may change the way that UC is treated in the future. He also highlighted the importance of personalised treatment targets and how patient education and patient-specific treatment guidelines could empower patients with UC, to help close the existing gap between routine real-world clinical practice and best practice for the management of UC.

Ulcerative Colitis: Today

Professor Jean-Frederic Colombel

Crohn’s disease (CD) and UC are chronic inflammatory bowel diseases (IBD) that lead to digestive disorders and inflammation in the digestive system.¹ Very often, UC is seen as a minor disease; however, UC is a progressive gastrointestinal inflammatory disease of the colon. The extent of colorectal inflammation fluctuates over time and may result in long-term complications, which can be aggravated by structural changes such as strictures, pseudopolyposis, bridging fibrosis, and neoplastic transformation. Functional abnormalities are important because they can cause distressing symptoms, such as urgency and incontinence, and they are linked to decreased contractility and impaired colonic motility. In addition, anorectal dysfunction may lead to ‘lead pipe’ colon, rectal narrowing, widening of the presacral space, and impaired continence.^2,3

Systemic, gastrointestinal, and psychological symptoms cause severe disease burden for patients with IBD as they occur with high frequency and severity, and cause significant distress. The top six symptoms include lack of energy, bowel urgency, diarrhoea, flatulence, feeling bloated, and worrying.⁴ In particular, the lack of energy, experienced as fatigue, and the impact of the psychological burden, such as worrying, were highlighted by Prof Colombel as very important causes of distress in patients with IBD. The prospective, multicountry, observational ICONIC study assessed the cumulative burden in adult patients with UC under routine care, and reported a disconnect between physicians’ and patients’ perceptions, as approximately 40% of patients classified their disease activity differently from their physicians.⁵ Patients also reported being highly concerned about the disease treatment and potential complications, particularly the potential to require an ostomy bag or to need surgery, unwanted effects of their medication, uncertainty about the course of their disease, and decreased energy levels.⁶

Although a wide range of therapies are currently approved for the treatment of UC, including anti-IL, anti-integrins, and, more recently, small molecules targeting intracellular processes, (Figure 1),^7-10 unmet needs in the treatment of UC remain, both in clinical trials and in clinical practice, with many patients still not able to achieve adequate disease control.¹¹ For anti-TNF drugs, nonresponse rates of 20–40% have been reported in clinical trials and 10–20% in real-world studies.¹² Similarly, real-world nonresponse rates of 49–57% have been reported for the α4β7 integrin inhibitor vedolizumab, 38–49% for the IL-12/IL-23 inhibitor ustekinumab in the UNIFI study, and 40–45% for the JAK inhibitor tofacitinib in the OCTAVE study.^13,14

Figure 1: Schematic overview of therapies currently approved for ulcerative colitis.^7-10
*Cells and cytokines listed are examples and do not provide an exhaustive list.
†Th27 cells are not the only cells targeted by JAK inhibitors and are used an example to illustrate their action on an intracellular pathway.
MAdCAM-1: mucosal addressin cell adhesion molecule-1; P: phosphate; T_Reg: regulatory T cell.

Another concern is the plateauing in the rates of steroid-free remission. The proportion of treated patients not achieving steroid-free remission has been reported to be 60–84% with adalimumab or infliximab,^15-17 62–87% with vedolizumab in the GEMINI 1 and VARSITY studies,^18,19 58–62% for ustekinumab in the UNIFI study,²⁰ and 72% for tofacitinib in the OCTAVE study.¹⁴ Although the definitions of steroid-free remission vary between studies, the concept remains useful as a high-hurdle endpoint.

An excessive use of steroids has also been noted in patients diagnosed with IBD and seems to be associated with treatment initiation outside of specialist care, or by a gastroenterologist in training.²¹ Steroid dependency, defined in the European Crohn’s and Colitis Organisation (ECCO) guidelines as either the prescription of ≥1 steroid over 12 months, the inability to wean from steroids within 3 months, or a disease flare within 3 months of steroid cessation, also remains problematic, particularly in patients with UC.²² An additional burden of steroid therapy is that it may lead to fatigue, which has been reported by nearly 50% of patients with IBD.²³

Furthermore, in the real world, not all responders persist on treatment. A real-world study of patients with UC being treated with vedolizumab or infliximab reported that <80% of induction responders persisted for 24 months on treatment.²⁴ Similarly, the Dutch Initiative on Crohn and Colitis (ICC) registry study reported that only 60% of patients who initiated treatment with tofacitinib remained on treatment after 24 weeks.²⁵ Taken together, these illustrate that there is a clear unmet need for new, long-term, effective treatment options for patients with UC.

Colectomy is a major surgical procedure that may significantly affect both mortality rates and the quality of life of patients with UC.²⁶ Although UC colectomy rates have been decreasing since the introduction of biologics,^27,28 they still remain high in the long term.²⁹ Furthermore, a majority of patients may not be able to benefit on this decrease in colectomy rates, due to the still limited use of biologics in UC, coupled with an excessive use of steroids.^22,30

The research of today shows that UC has a high economic and treatment burden, and patients and physicians do not always share the same view on the disease. There are clear treatment unmet needs, as many patients do not achieve long-term, steroid-free remission without colectomy. Despite updated clinical evidence, new guidelines, and aggressive treatment targets, the early use of effective therapies remains surprisingly uncommon. However, Prof Colombel concluded that the gastroenterological community has nevertheless come a long way: there is now a recognised predictive biomarker (faecal calprotectin) for treatment monitoring, more stringent clinical trial endpoints in the form of long-term remission and histological endpoints, and the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) guidelines help to codifying ambitious treatment targets.^31-34

Ulcerative Colitis: Tomorrow

Professor Silvio Danese

Emerging therapies for UC currently undergoing Phase III development fall under four main mechanisms of action: leukocyte retention in lymphoid organs by S1P receptor modulators (etrasimod and ozanimod), IL-23 inhibitors (mirikizumab, guselkumab, brazikumab, and risankizumab), JAK/TYK2 inhibitors (filgotinib and upadacitinib), and leukocyte adhesion inhibitors (integrin blockers and etrolizumab).³⁵

S1P modulators are structural analogues of the lipid signalling molecule S1P, with antagonist actions leading to selective immunosuppressive action through the sequestration of lymphocytes in secondary lymphoid tissues and a rapid reduction of peripheral blood lymphocytes.³⁶ In the True North study,³⁷ the S1P modulator ozanimod demonstrated highly statistically significant (p<0.0001) results for the induction of clinical remission at Week 10 and in maintenance at Week 52. Key secondary endpoints of clinical response and endoscopic improvement at Week 10 and at Week 52 were also met, and the safety profile of ozanimod was consistent with that observed in previously reported trials. The leukocyte adhesion inhibitor etrolizumab selectively targets the β7 subunit of both α4β7 and αEβ7 integrins and blocks interactions with their respective ligands, mucosal vascular addressin cell adhesion molecule 1 and E-cadherin, to reduce gut-specific lymphocyte trafficking to the inflamed colon.³⁸ In the HICKORY study, etrolizumab met its primary endpoint of inducing remission versus placebo for patients with UC but failed to meet its primary endpoint versus placebo as maintenance therapy.³⁸ Additionally, in people who had received prior anti-TNF treatment, etrolizumab met the primary endpoint at induction but not at maintenance.³⁹

JAK inhibitors are orally administered small molecules that, by temporarily blocking signalling through the JAK/signal transducer and activator of transcription pathway, inhibit key mechanisms of the innate and adaptive immune response.⁴⁰ They differ in their selectivity for different JAK: tofacitinib is more selective for JAK1/2/3 than for TYK2, upadacitinib is more selective for JAK1/3 than for JAK2, and filgotinib is more selective for JAK1 than for JAK2.^41-43 The blocking of specific JAK kinases by selective JAK inhibitors may be of clinical relevance, as it may translate into therapies with improved safety and efficacy.¹⁰

Tofacitinib is the only JAK inhibitor approved for the treatment of moderate-to-severe UC but has shown no efficacy in CD, which has been speculated to be at least partly because of the design of the Phase II and III studies of tofacitinib in CD.^42,44,45 Infections and infestations, including a herpes zoster virus safety signal, have been reported for tofacitinib in the OCTAVE Induction 1 and Induction 2 studies,^14,46 and a similar safety profile was recently reported in the real-world TROPIC consortium study of 260 patients with UC.⁴⁷

Preferential JAK1/3 inhibitors, such as upadacitinib, are currently in clinical development for UC.³⁵ Upadacitinib was evaluated in the Phase II part of the U-ACHIEVE study and found during the induction phase to have a safety profile similar to that of placebo; the study is currently recruiting for Phase III.⁴⁸

Filgotinib, a preferential JAK1 inhibitor, has been evaluated for UC in the combined Phase IIb/III study SELECTION.⁴⁹ The primary objective of the Phase III part of SELECTION was to evaluate the safety and efficacy of filgotinib in the induction and maintenance treatment of moderately to severely active UC in participants who were either biologic-naïve (n=659) or biologic-experienced (n=689).^49,50 The primary endpoints were remission based on components of the Mayo Clinic Score at Weeks 10 and 58, and the use of steroids was tapered during the maintenance phase of the study.^49,50 Filgotinib 200 mg demonstrated superior clinical remission in both the biologic-naïve and the biologic-experienced treatment arms, with more patients achieving clinical remission with filgotinib than with placebo during the induction and maintenance phases (11% and 26%, respectively; Figure 2).^49,50

Figure 2: SELECTION primary endpoint results at induction and maintenance.
Figure portrays the proportion of biologic-naïve or biologic-experienced patients with ulcerative colitis achieving clinical remission during the induction phase (Week 10) and for the rerandomised responder cohort during the maintenance phase (Week 58) in SELECTION.
Reproduced with permission from Peyrin-Biroulet⁴⁹ and Feagan.⁵⁰

Although adverse events such as infections and infestations were more prevalent in patients treated with filgotinib compared with patients that received placebo during the induction period, rates of herpes zoster were in line with placebo during the maintenance phase (Week 58)⁵⁰ and were also consistent with the rates observed for patients with rheumatoid arthritis, including those treated with adalimumab or methotrexate.⁵¹ Venous thromboembolism rates in SELECTION were also consistent with the low rates observed in rheumatoid arthritis.^49,51 Additionally, in the Phase II DARWIN 2 study, filgotinib 200 mg increased the mean levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol. The LDL:HDL ratio, however, fell slightly over the study period, which indicated that the JAK1 selectivity of filgotinib might lead to proportionally greater increases in HDL cholesterol compared with the increases seen for LDL cholesterol.⁵²

In animal studies, histologic changes have been observed in the testis and in the epididymides at filgotinib doses several-fold higher than the dose recommended for human use. No testicular toxicity has been observed with doses equivalent to the 200 mg dose.⁵³ However, as a precaution and follow-up to this potential safety signal, the randomised, placebo-controlled Phase II studies MANTA (in males with UC or CD) and MANTA-RAy (in males with rheumatic diseases) have been initiated to evaluate the testicular safety of filgotinib in humans.^54,55

For adults with moderately to severely active UC, investigational new treatments could, once approved, fit into existing treatment algorithms during both the induction and maintenance phases, with the goal of maintaining steroid-free, clinically and endoscopically defined remission in patients diagnosed with UC (Figure 3).²² Several of the new investigational therapies, such as ozanimod and filgotinib, appear to have benign safety profiles and may, from a safety point of view, be suitable as both first- and second-line therapies (i.e., both before and after biologics). Regarding efficacy, these new molecules could be considered as both first- and second-line therapies, including for long-term maintenance therapy.²²

Figure 3: Potential roles of new therapies for the treatment of adults with moderately to severely active ulcerative colitis.
*Refractory to oral steroids or immunomodulator therapy.
IFX: infliximab; IV: intravenous; MTX: methotrexate; UC: ulcerative colitis; VEDO: vedolizumab.

However, patient preferences for oral, intravenous, or subcutaneous modes of administration need to be considered, as modes of administration are becoming more important considerations for novel therapies, particularly as the efficacy and safety profiles of available drugs are plateauing.⁵⁶ Drug preferences are also influenced by cost, reflected in the higher uptake of biosimilars in Europe compared with the USA, which are more affordable compared with their reference biologics.⁵⁷ In summary, multiple new therapeutic modalities are in clinical development for UC, and several of these new molecules have shown favourable benefit–risk profiles in late-stage clinical trials.

Ulcerative Colitis: the Future

Professor Laurent Peyrin-Biroulet

Biologics used to treat immunologic conditions such as UC are large molecular weight (>1 kilodaltons [kDa]) protein therapeutics requiring parenteral administration, which preferentially interact with extracellular drug targets. Small molecule therapeutics, on the other hand, are small molecules (<1 kDa) of synthetic origin designed to modulate either intra- or extracellular targets, and are most commonly administered either orally or topically.^58,59 Although low trough concentrations of both biologics and small molecule drugs may result in breakthrough symptoms, only biologics are known to be potentially immunogenic, which may lead to the neutralisation of the therapeutic effect of the biologic.⁶⁰

Biosimilars are defined as biologics with no clinically meaningful differences in efficacy or safety from their licensed originators. The lower cost of biosimilars stimulates market competition and facilitates patient access to biologics because of their lower costs.⁶¹ Biosimilars have significantly reduced the treatment cost for biologics both in the European Union (EU) and in the USA, exemplified by the approval of several biosimilar anti-TNF therapeutics for the treatment of immune disorders such as IBD.^62-65

Several head-to-head trials are expected to provide some answers regarding the drugs that will constitute the future of IBD therapy. The outcomes of a study,⁶⁶ which compared the adalimumab biosimilar candidate BI 695501 with EU-approved Humira® (Boehringer Ingelheim, Ingelheim am Rhein, Germany), have recently been reported,⁶⁷ and results are expected in 2020 from the GARDENIA (etrolizumab versus infliximab) and HIBISCUS (etrolizumab versus adalimumab) Phase III studies.⁶⁸ In 2021, readouts are expected from the Phase II EXPEDITION trial, which evaluates brazikumab versus vedolizumab in UC,⁶⁹ and from the Phase III SEAVUE trial comparing adalimumab with ustekinumab in UC.⁷⁰ Results are also expected in 2022–2023 from the Phase II/III study INTREPID,⁷¹ which compares brazikumab with adalimumab, and from the Phase III study VIVID-1,⁷² which evaluates mirikizumab versus ustekinumab. Outcomes of the Phase II/III study GALAXI,⁷³ which investigates guselkumab versus ustekinumab in patients with moderately to severely active CD, are expected in 2024. In addition, studies evaluating combinations of two different biologics for achievement of remission are being conducted; one example is the Phase II VEGA study, evaluating combination treatments of guselkumab and golimumab in patients with UC.⁷⁴

“Small molecules have a number of advantages in the treatment of UC” – Prof Silvio Danese, 2020

Although biologics have revolutionised the management of autoimmune diseases,⁷⁵ small molecules have a number of advantages for the treatment of UC. This is mainly because of their oral mode of administration, effectiveness in patients previously treated with TNF inhibitors, short serum half-life, potential high cost–effectiveness ratio, lack of immunogenicity, previous treatment experiences from other patient types and in other diseases, potential as first-line therapy after aminosalicylates and steroids, rapid absorption time, and potential for use in mild, moderate, and severe UC.⁷⁶ Prof Peyrin-Biroulet indicated that the lack of immunogenicity associated with small molecule drugs also opens up the possibility of treatment holidays for patients with IBD on small molecule therapies; however, additional research is needed to define which patients and disease stages are most suited for stop/start treatment regimens in IBD.

The immunosuppressive mechanisms of action of drugs used to treat IBD result in reductions in disease activity; however, they are also associated with an increased risk of infections and a potential increase in the risk of developing cancers.^77,78 The I-CARE study, a European-wide, prospective, longitudinal, observational, multicentre cohort study, has been designed to evaluate the risk of developing cancer or serious infection in patients that are using immunosuppressive and biologic therapies.⁷⁹ I-CARE has thus far enrolled >10,000 patients with IBD, and the first results are expected to be presented at ECCO 2021.⁸⁰

Dual-targeted, or bispecific, antibodies have been proposed as a novel therapeutic approach for the treatment of immune disorders such as IBD. This unique class of biologics combines two distinct binding specificities within a single therapeutic entity, which allows for the simultaneous targeting of two different disease-causing cytokines or pathways by the same therapeutic. Several bispecific biologics are currently in preclinical or clinical development for the treatment of a variety of autoimmune and inflammatory diseases.⁸¹

Another approach is combination therapy, in which separate biologics and small molecule drugs are administered concomitantly.^82-84 The selection of drugs that might be suitable for combination therapies needs to be based not only on safety profiles, but also on mechanisms of action. However, challenges remain in predicting how effects of crosstalk and synergy from the combination of two different drugs will influence the overall safety and efficacy of a combination therapy. Filgotinib, for example, appears to have a favourable safety profile so could be considered for combination therapy trials with other drugs with favourable safety profiles, such as vedolizumab, ozanimod, or etrolizumab.

Additionally, experimental treatment concepts to modulate immune dysregulation conditions such as IBD are currently being explored, including targeting the human genome, where approximately 99% of the DNA sequence has unknown function, and the gut microbiome.^85,86

The future of UC management is envisioned as a stepwise approach, starting with symptom remission (patient-reported outcomes Stages 1–2), followed by endoscopic, histologic, and ultimately molecular healing.⁸⁷

“The good physician treats the disease; the great physician treats the patient who has the disease” – Sir William Osler, 1903

To achieve this, STRIDE guidelines have been published that include evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD. The treatment of patients with UC should target the resolution of rectal bleeding and the normalisation of bowel habits, and outcomes should be assessed every 3 months until symptom resolution and every 6–12 months thereafter. Similarly, the treatment of intestinal inflammation should aim for a Mayo endoscopic subscore of 0 as the optimal target, with a Mayo endoscopic subscore of 1 as a minimum target within 3–6 months after the start of therapy. Histopathology may be used as a sensitive measure of inflammation but not as a target, and available biomarkers, such as C-reactive protein and faecal calprotectin, should be used as adjunctive measures of inflammation for monitoring in patients with UC.³⁴

These ambitious treatment targets may be supported by the implementation of home-based biomarker monitoring, virtual clinics, and telemedicine, which may lead to increased adherence rates and improved treatment outcomes.⁸⁸ Interest in, and development of, telemedicine and remote monitoring has been greatly accelerated by the ongoing coronavirus disease (COVID-19) pandemic.⁸⁹

Prof Peyrin-Biroulet outlined his 5-year perspective on the treatment of UC: this included reduced reliance on endoscopy in UC, except for colorectal cancer screening; patients being able to receive treatment from home; targets based on symptoms, endoscopy, and/or histology; and treatments tailored to individual patients and not to molecular pathways, with the ultimate goal of achieving a normal life with UC. Unfortunately, there is still a significant gap between current healthcare practice and optimal treatment strategies in UC⁹⁰ and more education needs to be aimed at patients rather than at healthcare providers, for example through the development of patient guidelines to educate patients on which treatment options are available.⁹¹ The focus also needs to shift from inflammation toward disease modification and quality of life improvements, with the ultimate aim of improving overall patient outcomes.

Conclusion

Although therapies such as biologics and novel small molecule drugs targeting different immune pathways have revolutionised the treatment of autoimmune disorders including IBD in recent decades, unmet needs remain. A new generation of drugs for IBD are in clinical development, including S1P modulators, IL-23 inhibitors, leukocyte adhesion inhibitors, and preferential JAK1 inhibitors. Novel treatment concepts such as bispecific biologics and biologic/small molecule drug combination therapies are also being developed. In parallel, the clinical management of IBD is being improved through the implementation of personalised treat-to-target strategies, biomarker-based disease activity monitoring, and empowerment of patients through improved patient education.

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Faculty of Biology, Lomonosov Moscow State University

Janssen announces registration of new indications for Stelara® in Russia

Media contact:
Yulia Veseneva
[email protected]
+7 495 755 8357 (ext.2044)

The Ministry of Health of the Russian Federation approved new indications for the use of the drug Stelara ^® (ustekinumab) for the treatment of moderate to severe active ulcerative colitis

MOSCOW, June 2, 2020 – Janssen, Pharmaceuticals Division of Johnson & Johnson LLC, announces that the Ministry of Health of the Russian Federation has approved the expansion of indications for the use of ustekinumab in the treatment of moderate to severe active ulcerative colitis in adult patients with inadequate response, loss of response or intolerance to standard or biological therapy, or with medical contraindications to such treatment ¹ .Ustekinumab is the first genetically engineered biological drug available that targets interleukins IL12 and IL23, which play a key role in the inflammatory and immune responses of the body seen in immune-mediated diseases such as ulcerative colitis and Crohn’s disease ² .

“We are taking an important step in the fight against ulcerative colitis,” notes Katerina Pogodina, General Director of Johnson & Johnson LLC, Managing Director of Janssen in Russia and the CIS. – We are pleased that our innovative therapy can support patients in the fight against inflammatory bowel diseases – Crohn’s disease, for the treatment of which ustekinumab was registered in Russia in 2019, and now with ulcerative colitis.Unfortunately, the severity of this disease is often underestimated. Ulcerative colitis most often occurs in young people who are still receiving education or taking their first steps in their careers, and the disease can become a serious obstacle to self-realization. ”

Ulcerative colitis is a serious chronic immune-mediated inflammatory disease of the colon ³ . Symptoms can vary, but usually include tenesmus, diarrhea, blood in stools, weight loss (weight loss).These symptoms can be prolonged and debilitating, causing the patient to feel embarrassed and uncomfortable ^{4 , 5} . The disease is chronic, progressive, with the development of complications such as intestinal bleeding, toxic dilation and perforation of the colon, as well as colorectal cancer ⁶ . For two out of three patients with ulcerative colitis, the available treatments are not entirely effective. ^{7 , 8 , 9 , 10}

“Several genetically engineered biologicals and small molecules are currently registered for the treatment of inflammatory bowel diseases.Despite a fairly large arsenal of therapeutic agents, none of the drugs can achieve the desired results in changing the nature of the course of the disease. Each new treatment option gives patients an additional chance to achieve deep long-term remission and improve their quality of life. Registration of the drug ustekinumab for a new indication, for the treatment of ulcerative colitis, gives Russian patients these new hopes and opportunities “, – comments MD, Professor Elena Aleksandrovna Belousova, President of the All-Russian Society for the Study of Inflammatory Bowel Diseases

In patients with ulcerative colitis, as a result of therapy with Stelara ^® , the achievement and maintenance of steroidal remission, the achievement of histological endoscopic remission (healing of the intestinal mucosa), a significant decrease in the levels of inflammation markers, including C-reactive protein and fecal calprotectin, were noted. improving the quality of life of patients ¹¹ .In patients who received the drug for 44 weeks, compared with the placebo group, a decrease in serum concentrations of TNF-a and IL-17A, which are pro-inflammatory cytokines regulated by IL-12 and IL-23 ¹ , was achieved and maintained.

The most frequent (> 5%) side effects observed in controlled periods of clinical trials of Stelara ^® were nasopharyngitis and headache. Most cases were considered mild and did not require discontinuation of therapy ¹ .

###

About ulcerative colitis

Ulcerative colitis is a chronic disease of the colon, characterized by immune inflammation of its mucous membrane. The disease develops as a result of a combination of several factors, including primarily a genetic predisposition, defects in innate and acquired immunity, a violation of the intestinal microflora and various environmental factors. Symptoms vary, but may include chronic diarrhea, bloody stools, tenesmus, abdominal pain, loss of appetite, weight loss and fatigue ⁵ .

About Stelar ^®

Stelara ^® is approved by the Ministry of Health of the Russian Federation for the treatment of adult patients and children from 12 to 18 years old with moderate or severe plaque psoriasis in the absence of treatment effect or in the presence of contraindications, or in case of intolerance to other methods of systemic therapy or phototherapy. The indication for the use of Stelara ^® is the treatment of patients over 18 years of age with active psoriatic arthritis (PsA) as monotherapy or in combination with methotrexate.The drug is also indicated for the treatment of adult patients with moderate to severe active Crohn’s disease, in whom disease progression continued during therapy with immunomodulators or corticosteroids, or was found to be intolerant to these drugs, or depended on corticosteroids, or disease progression continued during therapy with one or several TNF inhibitors, or intolerance to one or more TNF inhibitors has been identified. Stelara ^® is intended to induce and maintain clinical response and clinical remission, achieve steroidal remission, induce endoscopic remission, and improve health-related quality of life.

O Janssen , pharmaceutical companies Johnson & Johnson

At Janssen, we are creating a future where disease is a thing of the past. We are Johnson & Johnson pharmaceutical companies, and we spare no effort to make this future a reality for patients around the world. We conquer disease with cutting-edge science. We invent how to help those who need help. We heal hopelessness with human warmth.

We work in those areas of medicine where we can bring the most benefit: cardiovascular diseases, immune-mediated diseases and metabolic disorders, infectious diseases and vaccines, diseases of the central nervous system, oncology, pulmonary arterial hypertension.

Find out more at janssen.com. Subscribe: twitter.com/JanssenGlobal. Johnson & Johnson LLC in Janssen Pharmaceutical Companies, Johnson & Johnson.

References:

[1] Instructions for medical use of the medicinal product Stelara.Ministry of Health of the Russian Federation LSR-006465 / 09-23.04.2020, LP-005728-24.05.2020. URL .: https://grls.rosminzdrav.ru/ Date of treatment 05/26/2020
[2] Toussirot E. The IL23 / Th27 pathway as a therapeutic target in chronic inflammatory diseases. Inflamm Allergy Drug Targets 2012; 11: 159-68.
[3] Ng SC, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet 2017; 390: 2769–78.
[4] Crohn’s & Colitis Foundation. ‘Living with Ulcerative Colitis’ leaflet. Available at: https: //www.crohnscolitisfoundation.org/sites/default/files/legacy/asset … (Accessed August 2019).
[5] Crohn’s & Colitis UK. What is Ulcerative Colitis? Available at: https://www.crohnsandcolitis.org.uk/about-inflammatory-bowel-disease/ulcerative-colitis (Accessed August 2019).
[6] Belousova E.A., Abdulganieva D.I., Alekseeva O.A., Achkasov S.I., Valuiskikh E.Yu., Vardanyan A.V., Veselov A.V., Veselov V.V., Golovenko O.V., Gubonina I.V., Zhigalova T.N., Kashnikov V.N., Knyazev O.V., Makarchuk P.A., Moskalev A.I. , Nanaeva B.A., Nizov A.A., Nikitina N.V., Nikolaeva N.N., Pavlenko V.V., Poluektova E.A., Svetlova I.O., Tarasova L.V., Tkachev A.V., Frolov S.A., Khlynova O.V., Chashkova E.Yu., Shapina M.V., Sheptulin A.A., Shifrin O.S., Shchukina O.B. DRAFT CLINICAL RECOMMENDATIONS FOR THE DIAGNOSTICS AND TREATMENT OF ULCERIC COLLITIS. Coloproctology. 2019; 18 (4): 7-36. https://doi.org/10.33878/2073-7556-2019-18-4-7-36
[7] Lopez-Sanroman A, et al .Perceived emotional and psychological impact of ulcerative colitis on outpatients in Spain: UC-LIFE survey. Dig Dis Sci 2017; 62: 207-216.
[8] Rubin D, et al . The impact of ulcerative colitis on patients ’lives compared to other chronic diseases: A patient survey. Dig Dis Sci 2010; 55: 1044-1052.
[9] Devlen J, et al . The burden of inflammatory bowel disease: A patient-reported qualitative analysis and development of a conceptual model. Inflamm Bowel Dis 2014; 20: 545-552.
[10] Lonnfors S, et al . IBD and health-related quality of life – Discovering the true impact. J Crohn’s Colitis 2014; 8: 1281-1286.
[11] Sands BE et al. N Engl J Med. 2020 Jan 2; 382 (1): 91. doi: 10.1056 / NEJMc1915042

Johnson & Johnson LLC
SR-158572

90,000 Scientists have proven the link between autism and pesticides used in agriculture and horticulture. Their list is known

Non-folding puzzle

In 1963, Gerald Gasson, father of a child with autism and a councilor for the National Autistic Society of Great Britain, drew a jigsaw puzzle for his organization.Most likely, he did not suspect then that the puzzle would become a symbol of autism, which would be actively used by charities, parental communities, journalists and politicians.

When the US Autism Community adopted the puzzle ribbon as its emblem in 1999, its leaders advised that it should symbolize the complexity of autism.

Puzzle means “puzzle” in English. It is also called a set of various pieces with uneven edges, which must be connected together in the correct order to get a picture.

Indeed, autism has long been a puzzle. Its causes were not clear, it was not clear how to treat it, and for a long time it was impossible to isolate those biological mechanisms, influencing which, doctors could reduce the manifestations of autistic symptoms.

The puzzle did not take shape for a long time, and the prevalence of autism grew with each new generation of children.

Is it an epidemic or not?

Today, science knows quite a lot about autism, although it can not answer all the questions.One of the most controversial questions remains whether there is a real epidemic of autism in the world.

The fact is that at the time of G. Asperger and L. Kanner (the scientists who first described this developmental disorder in the 40s of the twentieth century), the prevalence of autism in the population was calculated in fractions of a percent, and today it is, according to various estimates, from 1 to 2.5%.

Some scientists are convinced that there is no real growth, there is only a visible increase in the proportion of autists in the population due to changes in diagnostic criteria.Previously, they say, a child who does not correspond to age markers of intelligence development was diagnosed with mental retardation, but now it has become customary to find out the nature of such a lag, to look for symptoms characteristic of a particular developmental disorder.

Given the fact that the diagnosis of autism spectrum disorder in advanced countries opens up access to a number of therapies at public expense, doctors tend to put the little patient on him to help the child and his family.

Not everyone, however, shares this point of view; a number of scientists dispute it with numbers in hand.

From 1987 to 1998, California, renowned for its exemplary statistics, recorded a 237 percent increase in autism cases. This led the state administration to commission a study from experts at the University of California at Davis to carefully analyze and explain these mind-boggling numbers.

After analyzing the data, scientists came to the conclusion that changes in diagnostic criteria only partially explain the phenomenon.According to Dr. Irva Herz-Picciotto, the increase in autism cases is highly likely associated with the influence of certain environmental factors that became widespread in the 80s of the last century, and they need to be established and studied. This is confirmed by the fact that, despite changes in diagnostic criteria, there is no increase in the incidence of autism in adults.

At the same time, everything is called environmental factors, except for genetics, which, as is now known, in most cases only predisposes to the disease and does not come into play without an additional trigger, be it an infection transmitted by the mother, a drug that she took during pregnancy, or the influence of the environment in the sense in which we are used to using this expression.

The Danish colleagues, who are also distinguished by exemplary medical records and high reliability of medical statistics, agreed with the American scientists.

In 1994, the diagnostic criteria for autism in Denmark changed, followed by a change in the criteria for including outpatients in autism registries in 1995.

In 2015, researchers at the University of Arhus published a study to assess the extent to which these changes have contributed to the rise in the incidence of autism in Denmark.

The object of the study was children born in the country in the period from January 1, 1980 to December 31, 1991. The children were followed up until the diagnosis of ASD or until the end of the study.

Scientists have concluded that changes in diagnostic criteria may explain the 60% increase in the incidence of autism from 1980 to 1991 in Denmark. How did another 40% appear?

Genetic changes cannot occur so quickly, which means that you need to look for environmental factors.

New pieces

Landfill for solid household waste “Novoselki”, St. Petersburg. 04/27/2017. Photo: Anton Vaganov / TASS

In the process of searching, scientists have come to an important conclusion: autism is a multicomponent disease. There is no single gene whose mutation would lead to this developmental disorder, just as there is no single external factor that would certainly lead to autism.

Almost always (with the exception of a few genetically determined syndromes), autism spectrum disorder is the result of the interaction of two or more factors.Genetic disorders predispose to ASD, but this predisposition will not go off in a huge proportion of cases without a trigger.

The analogy can be drawn not with a shot, but with a puzzle: until several pieces fit together, the autistic picture will not work, and the autism emblem has acquired a new symbolic meaning. Research into the causes of autism has gone in two main directions: some scientists continue to study genes, others – external factors.

One of these factors that came under suspicion was environmental pollution.This looks quite logical, because if we assume that in the second half of the last century something changed very much in the life of civilization and influenced the increase in the prevalence of autism and some other mental disorders, then it is impossible to ignore anthropogenic changes in ecology.

To date, a large body of scientific data has been accumulated, which speaks in favor of the ecological hypothesis. In most cases, such studies are statistical in nature.

American scientists have found that air and soil pollution significantly increases the risk of mental illness in people living in areas with high concentrations of pollutants.Chinese scientists have come to similar conclusions already specifically in relation to autism.

University of Pennsylvania scientists have gone further. They investigated combinations of autism-predisposing gene variants and air pollution and found an interesting fact: the ozone in the air itself slightly increased the risk of autism, but in combination with certain gene mutations, it reached the maximum level of risk compared to combinations of other genetic factors. and pollutants.

The researchers suggested that such a strong effect of the combined action of these two factors is due to the fact that ozone is an oxidizing agent that produces reactive oxygen species, which, in turn, lead to oxidative stress in cells, which negatively affects their functioning.

Analysis of statistical data allows us to track some correlations of the risk of autism in a child with the living of a pregnant woman in an environment with a high level of pollution and to suggest what biological mechanisms work in this case.

The difficulty is that until recently it was impossible to test the theory with practice – not to conduct experiments on people. I had to be content with laboratory animals, which confirmed the hypothesis, but it was still impossible to consider it proven.

And now new technologies appeared.

Puzzle formed

Mini-brain. Photo: Muotri Lab / UC San Diego / neuronovosti.ru

Quite recently, in July 2021, an extremely interesting, important and very elegant study by scientists from the Bloomberg School of Public Health at Johns Hopkins University (USA) was published under the guidance of Lena Smirnova, Ph.D.

Experimenters applied two innovative technologies at once.

First, they grew organelles — miniature copies of the brain — from human pluripotent stem cells. Second, they used CRISPR / Cas technology to edit genes in these organelles. They changed the gene CHD 8 in such a way that it reduced the production of the corresponding protein.

Onomatological explanation

In the scientific literature, the names of genes are usually italicized, and the proteins that are the products of these genes have the same names, but are not italicized.

From previous studies, it was known that CHD8 protein regulates the activity of other genes that play an important role in brain development, and therefore mutations in the gene encoding it are very dangerous.

The researchers found that brain organelles with only one copy of the gene CHD 8 contained only two-thirds of the normal level of CHD8 protein in their cells, but they didn’t stop there.

Scientists decided to investigate the combination of a genetic factor with an environmental factor.They exposed the brain cells to chlorpyrifos.

Chlorpyrifos is

Organophosphate pesticide, used in agriculture and horticulture, as well as in the practice of medical, sanitary and household disinsection to combat insects (including in mixtures with other active ingredients). Entering the insect’s body through the respiratory tract, it phosphorylates acetylcholinesterase and paralyzes its nervous system. Has a long lasting effect.The drugs using chlorpyrifos belong to the 2nd and 3rd levels of danger to humans.

The effect was striking: exposure to chlorpyrifos further reduced CHD8 levels, converting moderate to severe deficiency.

But even this did not become the end of the study.

To make sure that this deficiency does lead to autism, scientists have compiled a list of substances in the blood, urine and brain tissue, the levels of which, previous studies have shown, do not correspond to the norm in real patients with ASD.

It turned out that the levels of some of these obvious biomarkers of autism were also significantly reduced in experimental organelles due to a lack of CHD8 protein or chlorpyrifos alone, and even more so when the body was influenced by both factors.

“Thus, we have shown that the changes in these organelles correspond to the changes observed in patients with autism,” says Lena Smirnova, Ph.D.

Now what?

“Now we can study how other genes and potentially toxic substances interact with each other,” says Smirnova, and it is possible that over time we will have a list of autism triggers that expectant mothers will need to avoid.

In the meantime, we know for sure: in no case should pregnant women use these insecticides in the garden or at home, especially if the family already has a child with autism, that is, the risk of autism in the fetus is already increased.

Insecticides with active ingredient chlorpyrifos – LIST

Averfos CE
Agran CE
Maxifos VP
Sichlor CE
Chlorpyrimark CE
Sinuzan CE
PhosLAD-50 CE
Produced in the form of emulsion concentrates (CE), wettable powders (SP), water dispersible granules (VDG) ) and food poisoned baits.

Sustaflex instructions for use: indications, contraindications, side effects – description Sustaflex Capsules (57152)

The dietary supplement Sustaflex ^® contains undenatured type II collagen (UC-II ^® ). It is an additional source of collagen, vitamin C, vitamin D ₃ , manganese and copper. In the daily human diet, these components are vital for the restoration of the cartilaginous surface of the joints.In a multicenter clinical study lasting 180 days with the participation of 191 patients, it was reliably proven: reduction of pain, reduction of stiffness, improvement of physical function of the knee joint in the group of patients taking UC-II ^® , compared with patients taking placebo or a combination of glucosamine + chondroitin sulfate. Thus, it was reliably established that UC-II ^® contributed to a decrease in the severity of symptoms of knee osteoarthritis and was well tolerated.

Type II collagen is a protein and component of articular cartilage. Type II collagen can be obtained from a variety of foods. If type II collagen is extracted from chicken breast cartilage using conventional technology, then the original natural structure of collagen will change, it will become denatured and lose its natural properties and quality. Therefore, denatured collagen is useless for the joint. A special patented collagen extraction technology allows you to preserve its natural properties.The unaltered structure of type II collagen is a very important condition for protecting the healthy state of the joint. Only undenatured type II collagen works in the body because it retains physiological activity.

Undenatured Type II Collagen (UC-II ^® ) is a proprietary glycosylated form of collagen derived from chicken breast cartilage. In studies, it showed active properties at a dose of 40 mg / day. The role of undenatured type II collagen is that it inhibits the action of killer T cells, which, due to a violation of the immune system, attack the collagen cells of the body’s own body, contributing to inflammation.