How do biologics work for ulcerative colitis. What are the key factors to consider when starting biologic therapy. Why might biologics be recommended for moderate to severe UC. When should patients expect to see results from biologic treatments. Which types of biologics are available for ulcerative colitis management.

Understanding Biologics as a Treatment Option for Ulcerative Colitis

Biologics have emerged as a powerful treatment option for individuals with moderate to severe ulcerative colitis (UC) who have not responded well to traditional medications. These innovative drugs target specific inflammatory processes in the body, offering hope for those struggling to manage their symptoms effectively.

Ulcerative colitis, a form of inflammatory bowel disease (IBD), can significantly impact a person’s quality of life. When conventional treatments fail to provide relief, biologics may be recommended by healthcare providers. But what exactly are these medications, and how do they work?

What are Biologic Drugs?

Biologic drugs are complex proteins derived from living organisms. Unlike traditional pharmaceuticals, which are chemically synthesized, biologics are engineered to target specific components of the immune system involved in the inflammatory process of UC.

The Role of Biologics in the Treatment Hierarchy for UC

Where do biologics fit in the treatment plan for ulcerative colitis? Typically, they are not considered first-line treatments. Doctors usually prescribe them when patients have not responded adequately to traditional medications or cannot tolerate their side effects.

Traditional UC treatments often include:

• Aminosalicylates (5-ASAs)
• Immunomodulators
• Corticosteroids

If these fail to control symptoms or maintain remission, biologics may be introduced. However, in cases of severe UC, doctors might recommend starting biologic therapy earlier in the treatment course.

Mechanism of Action: How Biologics Target Inflammation

One of the key advantages of biologics is their targeted approach to reducing inflammation. Unlike broad-spectrum immunosuppressants, biologics are designed to interfere with specific steps in the inflammatory cascade.

Types of Biologics Used in UC Treatment

Several types of biologics are approved for treating ulcerative colitis, each with a unique mechanism of action:

1. Anti-TNF drugs (TNF inhibitors): These block tumor necrosis factor alpha (TNF-alpha), a protein that promotes inflammation. Examples include:
   • Humira (adalimumab)
   • Simponi (golimumab)
   • Remicade (infliximab)
2. Integrin receptor antagonists: These medications, such as Entyvio (vedolizumab), work by preventing inflammatory cells from migrating into the intestinal tissue.
3. Interleukin inhibitors: Drugs like Stelara (ustekinumab) target specific interleukins involved in the immune response associated with IBD.

Administration Methods and Treatment Schedules for Biologic Drugs

How are biologics administered to patients with ulcerative colitis? The method and frequency of administration can vary depending on the specific medication:

Injectable Biologics

Some biologics are available as subcutaneous injections that can be self-administered or given by a caregiver at home. The frequency of these injections can range from several times a month to once every three months. Often, a more intensive “loading dose” schedule is used at the beginning of treatment to quickly achieve therapeutic levels in the body.

Intravenous Infusions

Other biologic medications require intravenous (IV) infusion, typically administered in a healthcare setting. After initial loading doses, these infusions are usually given every eight weeks. The duration of an infusion can vary from about 30 minutes to several hours, depending on the specific drug.

Are you wondering about the convenience of these administration methods? While injections offer the flexibility of home administration, infusions require regular visits to a healthcare facility but may be preferred by those who are uncomfortable with self-injection.

Combination Therapy: Biologics with Other UC Medications

Can biologics be used in combination with other ulcerative colitis treatments? In many cases, yes. Combining a biologic with a traditional UC medication may enhance effectiveness. However, it’s crucial to note that using two biologics simultaneously is not recommended due to an increased risk of complications.

Current guidelines from the American College of Gastroenterology (ACG) suggest discontinuing 5-ASA medications if they were previously ineffective when transitioning to an anti-TNF biologic like adalimumab or infliximab. This approach aims to optimize treatment efficacy while minimizing unnecessary medication use.

Timelines for Effectiveness and Adjusting Biologic Therapy

When starting biologic therapy, patients often ask, “How long before I see results?” It’s important to understand that the response to biologics can vary from person to person.

Onset of Action

For anti-TNF drugs, it may take up to eight weeks before noticeable improvement in UC symptoms occurs. While some individuals experience rapid relief, others may require more time to see the full benefits of treatment.

Adjusting Treatment

If the initial biologic doesn’t provide adequate symptom control, healthcare providers may consider several options:

• Increasing the dose of the current medication
• Decreasing the interval between doses
• Switching to a different biologic drug

The ACG guidelines suggest that if anti-TNF therapy is ineffective, transitioning to a medication like Entyvio may be beneficial. However, the decision to modify treatment should be made collaboratively between the patient and their healthcare team, considering individual factors and response to therapy.

Long-Term Benefits and Considerations of Biologic Therapy

What long-term outcomes can patients expect from biologic therapy for ulcerative colitis? Many individuals experience extended periods of remission and improved quality of life when using biologics as maintenance therapy.

Positive Impacts on Disease Course

Biologic treatments have shown remarkable efficacy in reducing chronic inflammation associated with UC. This has led to several positive outcomes:

• Fewer hospital admissions
• Reduced need for surgical interventions
• Decreased disability related to ulcerative colitis

Maintenance Therapy

It’s crucial to understand that biologics are designed as long-term maintenance drugs. Once a patient begins biologic therapy and achieves remission, continuing the treatment is essential to prevent disease flares. Discontinuing biologic therapy without consulting a healthcare provider can lead to a resurgence of symptoms and complications.

Potential for Decreased Efficacy Over Time

While biologics can be highly effective, some patients may experience a diminishing response to treatment over time. This phenomenon, known as loss of response, can occur for various reasons:

• Development of antibodies against the biologic drug
• Changes in the individual’s immune system
• Alterations in the inflammatory pathways involved in UC

If a loss of response occurs, healthcare providers may recommend adjusting the dosage, switching to a different biologic, or exploring alternative treatment strategies.

Safety Considerations and Monitoring During Biologic Therapy

While biologics offer significant benefits for many UC patients, it’s essential to be aware of potential risks and the importance of ongoing monitoring during treatment.

Potential Side Effects

Common side effects of biologic therapy may include:

• Injection site reactions
• Infusion-related reactions
• Increased risk of infections
• Headaches
• Fatigue

More serious but rare side effects can include allergic reactions, reactivation of latent tuberculosis, and an increased risk of certain types of cancer. However, the overall risk-benefit profile of biologics is generally favorable for patients with moderate to severe UC who have not responded to other treatments.

Ongoing Monitoring

Patients undergoing biologic therapy require regular monitoring to ensure treatment effectiveness and catch any potential complications early. This may include:

• Regular blood tests to check for markers of inflammation and monitor liver and kidney function
• Periodic screening for infections
• Assessment of overall disease activity and quality of life

Healthcare providers will work closely with patients to establish an appropriate monitoring schedule and address any concerns that arise during treatment.

Emerging Biologics and Future Directions in UC Treatment

The field of biologic therapy for ulcerative colitis continues to evolve, with ongoing research into new targets and treatment strategies. What advancements can patients look forward to in the coming years?

Novel Biologic Targets

Researchers are exploring new molecular targets for biologic drugs, aiming to provide more options for patients who don’t respond to current therapies. Some areas of investigation include:

• Additional interleukin inhibitors
• Drugs targeting novel inflammatory pathways
• Combination therapies with existing and new biologics

Personalized Medicine Approaches

As our understanding of the genetic and molecular basis of UC improves, there is growing interest in developing personalized treatment strategies. This could involve:

• Genetic testing to predict response to specific biologics
• Biomarker-guided therapy selection
• Tailored dosing regimens based on individual patient characteristics

These advancements hold the promise of more effective and targeted treatments for individuals with ulcerative colitis, potentially leading to improved outcomes and quality of life for patients living with this chronic condition.

In conclusion, biologic therapy represents a significant advancement in the treatment of moderate to severe ulcerative colitis. While these medications offer hope for many patients who have not found relief with traditional treatments, they require careful consideration and ongoing management. As research continues to uncover new insights into the mechanisms of UC and potential therapeutic targets, the landscape of biologic therapy is likely to expand, providing even more options for personalized and effective treatment strategies in the future.

10 Things to Know About Biologics for Ulcerative Colitis

If you have moderate to severe ulcerative colitis (UC) and aren’t responding to or can’t tolerate the side effects of traditional medications, such as aminosalicylates (5-ASAs) or immunomodulators, your doctor may start you on a biologic.

Biologic drugs, such as Humira (adalimumab), Simponi (golimumab), Remicade (infliximab), Entyvio (vedolizumab), and Stelara (ustekinumab), can alleviate inflammation and keep your disease in remission if other UC medications aren’t effective.

But these drugs are also complex and may not work for everyone, so it’s important to learn more about them if you’re new to biologic therapy.

Here are 10 key facts about biologic drugs for UC.

1. Biologics Aren’t Considered a First-Line Treatment

Although many doctors believe it’s better to start a biologic drug sooner rather than later, it’s not likely to be your first ulcerative colitis treatment. “The current indications for biologics in ulcerative colitis are for people who haven’t responded to traditional medications or are dependent on corticosteroids to relieve their symptoms,” says Thomas Ullman, MD, the chief of the division of gastroenterology at the Albert Einstein College of Medicine in New York City.

It’s possible, though, that your doctor will recommend a biologic early in the course of your treatment if your ulcerative colitis reaches a certain threshold of severity. This decision will likely depend on your doctor’s personal judgment and experience.

2. Biologics Are Targeted Medications

While many UC medications have wide-ranging effects on your immune system, biologics are designed to block specific steps in the inflammatory process.

One group of biologic drugs for UC, known as anti-TNF drugs or TNF inhibitors, block a protein called tumor necrosis factor alpha (TNF alpha) that promotes inflammation in your intestines and certain other organs. Anti-TNF drugs include Humira, Simponi, and Remicade. Another type of biologic, Entyvio, is an integrin receptor antagonist, which works by blocking a protein on the surface of cells that can move out of blood vessels and into certain tissues. The newest biologic approved to treat UC, Stelara, blocks interleukin-12 and interleukin-23, proteins known to be involved in immune responses in inflammatory bowel disease (IBD) like UC.

3. Biologics Are Given by Injection

Some biologic medications are available as a shot that’s given from several times a month to once every three months, with more frequent “starter” doses in the beginning. You or a loved one can learn to administer these injections at home. Other biologics require an intravenous (IV) infusion, which typically happens every eight weeks after several initial infusions. Depending on the drug, an infusion can last about 30 minutes or two to four hours.

4. Biologics May Be Used Along With Other UC Medication

“A biologic medication combined with a traditional ulcerative colitis drug may work better than either drug alone,” Dr. Ullman says, but two biologics shouldn’t be taken together because of an increased risk of complications.

Current guidelines from the American College of Gastroenterology (ACG) also state that if you previously took a 5-ASA that wasn’t successful, you shouldn’t keep taking it if you move on to an anti-TNF drug, such as adalimumab or infliximab.

5. It May Take Time for Biologic Drugs to Take Effect

When you start taking an anti-TNF drug, it may take up to eight weeks before you notice any improvement in your UC symptoms, according to the Crohn’s & Colitis Foundation. While some people notice an immediate improvement, the possibility of a delayed effect means you’ll need to continue your treatment for several weeks before you determine it isn’t effective.

6. You May Need to Try Different Biologics

If one biologic doesn’t work for you, your doctor may suggest raising the dose or decreasing the interval between doses, or switching to another drug. The ACG guidelines also suggest that if anti-TNF therapy isn’t effective, you may want to try Entyvio. But because there are so many individual variations in Crohn’s and colitis patients, the ultimate decision is between you and your doctor.

7. Biologic Therapy Can Lead to Long Periods of Remission

Biologics are broadly effective at reducing chronic inflammation in UC. “We’re seeing fewer hospital admissions, fewer surgeries, and less disability from ulcerative colitis with the use of these drugs,” says Ullman.

They are also long-term maintenance drugs, so once you start on biologic therapy, you’ll need to keep taking it to prevent your UC from flaring. Don’t stop treatment without consulting with your doctor.

8. Biologics May Become Less Effective Over Time

While it isn’t exactly clear why, some people have an initial response to a biologic but lose this response over months or years of treatment. When this happens with an anti-TNF drug, your doctor may recommend trying a different anti-TNF drug or a different type of biologic like Entyvio or Stelara.

9. Biologics Have Some Side Effects and Long-Term Risks

The most common side effects of biologic drugs include injection site reactions, such as redness, itching, rash, swelling, or painful lumps under your skin. You might also experience headaches, fever, chills, nausea, aches and pains, a cough, or a sore throat. Reactions may differ depending on which medication you take.

Biologics change the way your immune system works, so the biggest risk is a higher susceptibility to infection, Ullman says. A previous tuberculosis or hepatitis B infection may be reactivated when you start on biologic therapy, so it’s important to screen for these conditions before getting started. You may also be at higher risk for more common infections, so it’s important to get vaccinated for the flu and pneumonia according to your doctor’s recommendation. Be sure to tell your doctor about any signs of infection right away, such as fever, fatigue, cough, or flu-like symptoms.

Some biologic drugs are associated with a slightly higher risk you’ll develop a blood cancer called lymphoma. In rare cases, biologics may also cause liver problems, joint pain, or nervous system problems. Talk to your doctor about all these risks before starting on a biologic.

10. Biologics Are Expensive

The “sticker price” of biologic drugs is high. But if you have health insurance, you’re not likely to pay the full price of any infusion drug or its administration.

Before starting on biologic therapy, make sure you can afford it through either your insurance coverage or your own finances. “In most cases, insurance companies do cover biologics, and most drug companies offer financial assistance programs to help cover the cost,” Ullman says.

Another, less expensive option than biologics are biosimilars, drugs that are nearly identical copies of biologics and contain the same active ingredients. Since scientists can’t make an exact copy of a biologic (a living cell), biosimilars are highly similar to biologics, rendering them bioequivalent.

Remicade (infliximab) has an FDA-approved biosimilar medication called infliximab-dyyb (Inflectra). Humira (adalimumab) has an FDA-approved biosimilar medication called Amjevita (adalimumab-atto).

Additional reporting by Ashley Welch.

5 Ulcerative Colitis Complications

Extraintestinal complications — those that exist outside the intestines — can overshadow symptoms in your bowels, making UC tricky to diagnose. They are…

By Heidi Tyline KingJune 6, 2023

6 Need-to-Know Nutrients for Ulcerative Colitis

People with ulcerative colitis (UC) may have a hard time getting the nutrients they need. Find out what nutrient deficiencies can come with UC and how…

By Jennifer WarnerJune 5, 2023

8 Ways to Prevent Osteoporosis if You Have Ulcerative Colitis

If you take steroids for ulcerative colitis, you might have an increased risk of osteoporosis or low bone density. Here’s how to keep your bones strong…

By Brian P. DunleavyJune 2, 2023

Best Meal Delivery Kits for People With Ulcerative Colitis

These online food services, which include lots of fruits and vegetables and plant-based proteins, are great options for people with ulcerative colitis…

By Blake MillerMay 26, 2023

How Well Is Your UC Treatment Working?

Ulcerative colitis medications can help reduce inflammation and ease your symptoms. Take this quiz to determine if your treatment is working or it’s time…

By Jen LaskeyMay 4, 2023

The Pros and Cons of Biologics for Ulcerative Colitis

The introduction of biologics has changed treatment for many people with ulcerative colitis. Here’s what you need to know about the risks and benefits.

By Ajai RajMedically Reviewed by Kareem Sassi, MD

Reviewed: August 3, 2021

Medically Reviewed

Biologics are a class of genetically engineered drugs that are made from living organisms.Andrew Brookes/Getty Images

Over the past 15 years, treatment options for ulcerative colitis (UC) have expanded quite a bit. Among the newer options is a class of drugs called biologics.

Biologics are derived from natural sources, such as human or animal genes or microorganisms, and are designed to act on the immune system, specifically the parts that play key roles in fueling inflammation.

“As inflammation is thought to be a cornerstone of the process involved in the manifestation of inflammatory bowel diseases, like Crohn’s disease and ulcerative colitis, they have proved to be very effective as treatment for certain patients,” says Donald Tsynman, MD, a gastroenterologist at NewYork-Presbyterian Hospital in New York City.

The fact that biologics target the activity of the patient’s own immune system is what sets them apart from some other medications for ulcerative colitis, Dr. Tsynman says.

How Biologics Work

“The biologics that have been approved for Crohn’s and ulcerative colitis involve antibodies that are developed in the lab to target proteins related to inflammation,” says Joel Pekow, MD, a gastroenterologist and an associate professor of medicine at the University of Chicago.

The biologics that are now approved by the U.S. Food and Drug Administration (FDA) for treating ulcerative colitis include:

• Humira (adalimumab)
• Simponi (golimumab)
• Remicade (infliximab)
• Entyvio (vedolizumab)
• Stelara (ustekinumab)

Many biologics, including Humira, Simponi, and Remicade, work by targeting a protein called tumor necrosis factor alpha (TNF-alpha), which contributes to inflammation.

Another way that biologics target inflammation is by addressing the problem of too many white blood cells in the GI tract. Entyvio works this way — it blocks these inflammatory cells from getting to the site of inflammation.

A review published in October 2019 in the United European Gastroenterology Journal examined the safety and efficacy of Humira, Simponi, Remicade and Entyvio, and found that all four biologics were effective at treating moderate to severe ulcerative colitis, and all were comparatively safe.

Stelara is the new biologic on the block. While the drug has been on the market since 2009 for the treatment of Crohn’s disease, psoriatic arthritis, and psoriasis, it was only approved in 2019 for the treatment of ulcerative colitis.

The new approved use for Stelara was based on results of a clinical trial published in September 2019 in the New England Journal of Medicine that found Stelara could safely and effectively induce and maintain remission in adults with moderately to severely active ulcerative colitis.

Stelara works by blocking interleukin-12 and interleukin-23, immune proteins known to be involved in immune responses in inflammatory bowel disease and other immune-mediated conditions.

RELATED: 10 Things to Know About Biologics for Ulcerative Colitis

The Advantages of Biologics for Ulcerative Colitis

Biologics can improve gut symptoms, bringing about and maintaining remission (preventing flares) in people with moderate to severe ulcerative colitis. They can also reduce the need for hospitalization and surgery, says the British organization Crohn’s & Colitis UK.

One key advantage of biologic therapies over other types of treatment for ulcerative colitis is that their mechanisms of action are more precisely targeted to the factors responsible for the condition, notes the Crohns & Colitis Foundation.

Unlike corticosteroids, for example, which affect the whole body and may produce major side effects, biologic agents act more selectively. These therapies are targeted to particular proteins that have already been proven to be involved in ulcerative colitis.

“Patients are often nervous about biologics,” says Laura Raffals, MD, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota. “But they’re not as scared about taking a corticosteroid, and that’s an important conversation to have because the data shows that patients on biologics are much safer and stay in remission longer. The serious side effects we see are from steroids or narcotics, not biologics.”

The Potential Downsides of Biologics

While biologics may be a promising option for treating your ulcerative colitis, not every drug is suited to every patient.

“We will work with patients for a while to tailor a treatment plan that is right for them,” says Dr. Raffals. “That may mean trying different biologics and small-molecule drugs, and, of course, taking into account what the patient’s insurance will cover.”

A person’s lifestyle, demographic factors, and the severity of the disease are all considerations in the choice of whether or not to use biologics, and which of them is the best option.

Some potential downsides of taking biologics include:

• Lack of long-term data While studies and clinical information indicate that biologics are generally safe, they are relatively new drugs, so — with the exception of Remicade (infliximab) — long-term safety information is not available.
• Cost Because most of these drugs are available only as name brands, they can be very expensive. The introduction of biosimilars — medicines that are very similar to an original biologic therapy that has come off patent — has increased competition in the biologics market and is helping to bring down the cost of this type of therapy.
• Method of treatment Taking biologics isn’t as simple as swallowing a pill. Some biologics, such as Humira, can be self-administered via an at-home injection, while others, like Entyvio, require intravenous infusion. Your level of comfort or schedule may influence your choice between biologics, or whether to take them at all.
• Side effects As with all medications, biologics come with potential side effects. These include: soreness at the injection site, aches and pains, fever, and increased susceptibility to infection.

If you’re considering biologics for treatment, speak to your doctor to find out what’s best for you. As Tsynman says, “At the heart of the decision is the relationship between the patient and the physician and specifically exploring what works best for each individual.”

Additional reporting by Jordan M. Davidson.

By subscribing you agree to the Terms of Use and Privacy Policy.

5 Ulcerative Colitis Complications

Extraintestinal complications — those that exist outside the intestines — can overshadow symptoms in your bowels, making UC tricky to diagnose. They are…

By Heidi Tyline KingJune 6, 2023

6 Need-to-Know Nutrients for Ulcerative Colitis

People with ulcerative colitis (UC) may have a hard time getting the nutrients they need. Find out what nutrient deficiencies can come with UC and how…

By Jennifer WarnerJune 5, 2023

8 Ways to Prevent Osteoporosis if You Have Ulcerative Colitis

If you take steroids for ulcerative colitis, you might have an increased risk of osteoporosis or low bone density. Here’s how to keep your bones strong…

By Brian P. DunleavyJune 2, 2023

10 Things to Know About Biologics for Ulcerative Colitis

Biologic medication for ulcerative colitis may work when other treatments fail. Learn 10 important facts about biologic therapy before you start.

By Chris Iliades, MDJune 1, 2023

Best Meal Delivery Kits for People With Ulcerative Colitis

These online food services, which include lots of fruits and vegetables and plant-based proteins, are great options for people with ulcerative colitis…

By Blake MillerMay 26, 2023

Experience with vedolizumab in ulcerative colitis (case report)

Experience with vedolizumab in ulcerative colitis (case report)

Website of the publishing house “Media Sfera”
contains materials intended exclusively for healthcare professionals. By closing this message, you confirm that you are a registered medical professional or student of a medical educational institution.

Tarasova L.V.

BU VO of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut State University”;
Chuvash State University I.N. Ulyanov» of the Ministry of Education and Science of Russia;
BU of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut Regional Clinical Hospital”

Busalaeva E.I.

State Autonomous Institution of the Chechen Republic DPO “Institute for the Improvement of Doctors” of the Ministry of Health of the Chuvash Republic;
Chuvash State University I.N. Ulyanov» Ministry of Education and Science of Russia

Tsyganova Yu.V.

Chuvash State University. I.N. Ulyanov» Ministry of Education and Science of Russia

Zhudylina N.V.

BU of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut Regional Clinical Hospital”

Matysyakevich I. D.

BU of the Khanty-Mansi Autonomous Okrug – Yugra “Surgut Regional Clinical Hospital”

Experience with the use of vedolizumab in ulcerative colitis (clinical case)

Authors:

Tarasova L.V., Busalaeva E.I., Tsy ganova Yu.V ., Zhudylina N.V., Matysyakevich I.D.

More about the authors

Magazine:

Evidence-based gastroenterology.

2020;9(3): 77‑82

DOI:

10.17116/dokgastro20207

How to quote:

Tarasova L.V., Busalaeva E.I., Tsyganova Yu.V., Zhudylina N.V., Matysyakevich I.D. Experience with vedolizumab in ulcerative colitis (clinical case). Evidence-based gastroenterology.
2020;9(3):77-82.
Tarasova LV, Busalaeva EI, Tsyganova YuV, Zhudtlina NV, Matysyakevich ID. Vedolizumab in ulcerative colitis: clinical case. Russian Journal of Evidence-Based Gastroenterology. 2020;9(3):77‑82. (In Russ.)
https://doi.org/10.17116/dokgastro20207

Read metadata

The description of a clinical case of severe ulcerative colitis in a patient with steroid dependence, complications of ongoing immunosuppressive therapy and ineffectiveness of basic treatment is presented. The described clinical case demonstrates the possibility of achieving clinical remission in patients with ulcerative colitis with a complex medical history.

Keywords:

vedolizumab

antivio

ulcerative colitis

treatment

Authors:

Tarasova L.V.

BU VO of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut State University”;
Chuvash State University I.N. Ulyanov» of the Ministry of Education and Science of Russia;
BU of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut Regional Clinical Hospital”

• SPIN RSCI: 4125-7935
• Scopus AuthorID:
  35777248600
• ORCID:
  0000-0003-1496-0689

Busalaeva E.I.

State Autonomous Institution of the Chechen Republic DPO “Institute for the Improvement of Doctors” of the Ministry of Health of the Chuvash Republic;
Chuvash State University I.N. Ulyanova» Ministry of Education and Science of Russia

Tsyganova Yu. V.

Chuvash State University. I.N. Ulyanov» Ministry of Education and Science of Russia

Zhudylina N.V.

BU of the Khanty-Mansiysk Autonomous Okrug – Yugra “Surgut Regional Clinical Hospital”

Matysyakevich I.D.

BU of the Khanty-Mansiysk Autonomous Okrug – Ugra “Surgut Regional Clinical Hospital”

References:

1. Feagan BG, Bhayat F, Khalid M, Blake A, Travis SPL. Respiratory Tract Infections in Patients with Inflammatory Bowel Disease: Safety Analyzes From Vedolizumab Clinical Trials. Journal of Crohn’s and Colitis. 2018;12(8):905-919. https://doi.org/10.1093/ecco-jcc/jjy047
2. Colombel JF, Sands BE, Rutgeerts P, Sandborn W, Danese S, D’Haens G, Panaccione R, Loftus EV Jr, Sankoh S, Fox I, Parikh A, Milch C, Abhyankar B, Feagan BG. The safety of vedolizumab for ulcerative colitis and Crohn’s disease. gut. 2017;66(5):839-851. https://doi.org/10.1136/gutjnl-2015-311079
3. Rosario M, Dirks NL, Milch C, Parikh A, Bargfrede M, Wyant T, Fedyk E, Fox I. A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab. Clinical Pharmacokinetics. 2017;56(11):1287-1301. https://doi.org/10.1007/s40262-017-0546-0
4. Ivashkin V.T., Shelygin Yu.A., Khalif I.L., Belousova E.A., Shifrin O.S., Abdulganieva D.I., Abdulkhakov R.A., Alekseeva O.P., Alekseenko S.A., Achkasov S.I., Baranovsky A.Yu., Bolikhov K.V., Valuyskikh E.Yu., Vardanyan A.V., Veselov A.V., Veselov V.V., Golovenko A O., Golovenko O.V., Grigoriev E.G., Gubonina I.V., Zhigalova T.N., Kashnikov V.N., Kizova E.A., Knyazev O.V., Kostenko N.V. ., Kulyapin A.V., Morozova N.A., Muravyov A.V., Nizov A.A., Nikitina N.V., Nikolaeva N.N., Nikulina N.V., Odintsova A.Kh., Osipenko M.F., Pavlenko V.V., Parfenov A.I., Poluektova E.A., Potapov A.S., Rumyantsev V.G., Svetlova I.O., Sitkin S.I., Timerbulatov V. .M., Tkachev A.V., Tkachenko E.I., Frolov S.A., Khubezov D.A., Chashkova E.Yu., Shapina M.V., Schukina O.B., Yakovlev A.A. . Clinical recommendations of the Russian Gastroenterological Association and the Russian Association of Coloproctologists for the diagnosis and treatment of ulcerative colitis. Coloproctology. 2017;1(59):6-30.
5. Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, Cottone M, de Ridder L, Doherty G, Ehehalt R, Esteve M, Katsanos K, Lees CW, Macmahon E, Moreels T, Reinisch W, Tilg H, Tremblay L, Veereman-Wauters G, Viget N, Yazdanpanah Y, Eliakim R, Colombel JF. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. Journal of Crohn’s and Colitis. 2014;8:443-468. https://doi.org/10.1016/j.crohns.2013.12.013
6. Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment options for inflammatory bowel diseases. Journal of Gastroenterology. 2018;5:585-590. https://doi.org/10.1007/s00535-018-1449-z
7. Borisov S.E., Lukina G.V. Recommendations for screening and monitoring of tuberculosis infection in patients receiving genetically engineered biological preparations. The link is active as of 04/20/20. https://www.rheumatolog.ru
8. Stepashina T. E., Tarasova L.V., Busalaeva E.I. The effectiveness of golimumab in severe ulcerative colitis with extraintestinal manifestations. Experimental and clinical gastroenterology. 2015;12(124):116-119.
9. Instructions for use of the medicinal product for medical use Remicade. Registration number П N012948/01. The link is active on 01/23/2020. https://grls.rosminzdrav.ru
10. Instructions for use of the medicinal product for medical use Humira. Registration number LS-002422-200814. The link is active as of 01/23/20. https://grls.rosminzdrav.ru
11. Instructions for use of the medicinal product for medical use Entivio. RU No. LP-003697. The link is active on 01/23/20. https://grls.rosminzdrav.ru
12. Instructions for use of the medicinal product for medical use Simponi. Registration number LP-003825. The link is active on 01/23/020. https://grls.rosminzdrav.ru
13. Osterman MT, Rosario M, Lasch K, Barocas M, Wilbur JD, Dirks NL, Gastonguay MR. Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimization. Alimentary Pharmacology and Therapeutics. 2019; 49(4):408-418. https://doi.org/10.1111/apt.15113
14. Vickers AD, Ainsworth C, Mody R, Bergman A, Ling CS, Medjedovic J, Smyth M. Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis. PLOS One. 2016;11(10): e0165435. https://doi.org/10.1371/journal.pone.0165435
15. Ng SC, Hilmi IN, Blake A, Bhayat F, Adsul S, Khan QR, Wu DC. Low Frequency of Opportunistic Infections in Patients Receiving Vedolizumab in Clinical Trials and Post-Marketing Setting. Inflammatory Bowel Diseases. 2018;24(11):2431-2441. https://doi.org/10.1093/ibd/izy153
16. Scribano ML. Vedolizumab for inflammatory bowel disease: From randomized controlled trials to real-life evidence. World Journal of Gastroenterology. 2018;24(23):2457-2467. https://doi.org/10.3748/wjg.v24.i23.2457
17. Loftus EV Jr, Colombel JF, Feagan BG, Vermeire S, Sandborn WJ, Sands BE, Danese S, D’Haens GR, Kaser A, Panaccione R, Rubin DT, Shafran I, McAuliffe M, Kaviya A, Sankoh S, Mody R, Abhyankar B, Smyth M. Jr. Long-term efficacy of vedolizumab for ulcerative colitis. Journal of Crohn’s and Colitis. 2017;11(4):400-411. https://doi.org/10.1093/ecco-jcc/jjw177
18. Toruner M, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, Colombel JF, Egan LJ. Risk factors for opportunistic infections in patients with inflammatory bowel disease. gastroenterology. 2008;134:929-936. https://doi.org/10.1053/j.gastro.2008.01.012

Close metadata

Genetically engineered biological therapy (GEBT) for inflammatory bowel disease (IBD) has firmly entered the treatment regimen for patients with ulcerative colitis (UC) and Crohn’s disease. In recent years, it has come to be realized that drug therapy regimens must be evaluated not only from the standpoint of “expensive” or “cheap”, but primarily from the standpoint of the ratio of costs, clinical efficacy and safety. There is a shift in the paradigm of modern health care towards a value-oriented model, when in the treatment of a particular patient with IBD, the focus shifts from the cost to the result of treatment.

An integral part of the work of a medical organization, which includes the IBD Center, is the choice of GIBT taking into account costs and efficiency, the timely formation of annual applications according to the true needs of patients with IBD registered in the dispensary, targeted justification for the appointment of GIBT, taking into account the individual “profile” patient. Understanding the safety aspects of new drugs (GEBDs) in IBD therapy is important to achieve and maintain clinical results, minimize risks, and eliminate side effects or complications if they occur.

Patients with IBD are known to have an increased risk of infectious complications, including influenza, pneumonia, herpes zoster, Clostridium difficile , tuberculosis, and others, compared with the population without IBD. According to multicenter studies, vedolizumab (antivio) is a drug with a minimal risk of infection activation [1–3].

This article describes our own clinical observation of the management of a patient with a long course of total UC with a history of pulmonary tuberculosis.

Clinical case

Patient L ., born in 1981. The disease debuted at the age of 14 with diarrhea mixed with blood 5-6 times a day. With suspicion of UC, she was observed by a pediatric gastroenterologist. At the age of 16, the diagnosis was verified in the conditions of the gastroenterological department of the Republican Clinical Hospital, Cheboksary. The protocol of colonoscopy (CS) of 1998 concluded: “The mucous membrane of the rectum is edematous, brightly hyperemic, with a white coating. The mucous membrane of the sigmoid colon is brightly hyperemic, granular. At a distance of 25-30 cm from the anus, a group of erosions 0.1 × 0.2 × 0.4 cm in size, some with a coating of fibrin. Proximal to the splenic angle of the large intestine, the mucous membrane is edematous, hyperemic, eroded, moderate contact bleeding is noted. In the analysis of blood taken a day before the CS, mild normochromic anemia (hemoglobin – 115 g/l), neutrophilic leukocytosis (12. 6 10 ⁹ /l), accelerated to 30 mm / h ESR and a twofold increase in the level of C-reactive protein.

Based on the given clinical and laboratory data and medical history (the patient had more than six months of remission), the following clinical diagnosis was formulated: “Ulcerative colitis, chronic relapsing course, total (according to the Montreal classification), moderate attack (according to Truelove criteria). -Witts), moderate endoscopic activity (according to Schroeder).”

Taking into account the total localization of UC of III degree of activity and moderate severity, sulfasalazine therapy was started at a dose of 3.0 g/day in combination with glucocorticoids (GCS) 60 mg/day. Clinical improvement was achieved, GCS was gradually completely canceled. Until 2004, she regularly took sulfasalazine 2.0 g/day or salofalk 3.0 g/day and topical salofalk suppositories 2 times a day. Periodically, GCS was added to the treatment at a starting dose of 60 mg/day with complete withdrawal when clinical remission was achieved.

The endoscopic picture in 2004 is described as follows: “The mucosa of the rectum, sigmoid and colon is moderately edematous, granular, with foci of hyperemia. Bauhin’s damper is pink, elastic. The mouth of the appendix without signs of inflammation. The mucous membrane of the caecum is edematous, with enhanced vascular pattern.

In 2004 the patient became pregnant. In the period of 11 weeks, an exacerbation of the disease developed: diarrhea appeared with blood up to 10 times a day. Appointed oral prednisolone at a dose of 40 mg, intravenous infusion of fresh frozen plasma. The condition was relatively stabilized, but at 28 weeks, an attack of urolithiasis occurred, for which ureteral catheterization was performed. Subsequently, the threat of abortion persisted, and premature birth occurred at 34 weeks’ gestation.

In accordance with the recommendations of the Russian Gastroenterological Association and the Russian Association of Coloproctologists for the diagnosis and treatment of adult patients with UC, pregnancy should be planned during remission. However, most drugs for the treatment of UC are associated with a low risk of adverse effects on the fetus (with the exception of methotrexate). Side effects of the use of corticosteroids can be reduced by the concomitant intake of calcium, proton pump inhibitors, and monitoring of blood glucose levels [4].

Until 2008, the patient felt well and remained in clinical remission. In 2009, another exacerbation developed: diarrhea up to 12 times a day with an admixture of blood, pus, mucus, abdominal pain syndrome. The dose of prednisolone was increased to 60 mg/day, metronidazole 1.0 g/day was added. When trying to reduce the dose of GCS to a daily dose (10 mg), all the symptoms of the disease returned within a few days. Thus, the patient developed hormone dependence. To overcome it, azathioprine at a dose of 150 mg/day was added to the treatment.

The literature provides information on the increased risk of developing opportunistic infections against the background of the use of corticosteroids by 2. 2 times, immunosuppressive therapy – by 3.4 times, and with their combined use – by 17.5 times [5, 6].

During therapy in 2009, the patient developed infiltrative tuberculosis of the apex of the left lung, which required discontinuation of cytostatics and anti-tuberculosis treatment according to a multicomponent regimen with rifampicin for 1 year. At the same time, it was not possible to completely cancel GCS, and the patient continued to receive prednisolone 10 mg/day until 2014. N.I. Pirogov (Moscow). The previously established diagnosis was confirmed, and it was recommended to resume therapy with azathioprine 100 mg/day in combination with methylprednisolone 16 mg/day. It was possible to achieve some clinical improvement in the course of the disease, however, complications of the therapy began to arise (furuncle of the skin of the face, furuncle of the labia majora). Since October 2014, aching pains along the colon resumed, most pronounced in the left iliac region, decreasing after passing gases and defecation, rumbling and transfusion in the abdomen, increased gas formation. Loose stools were noted up to 7 times a day with an admixture of pus, blood, mucus, with the remnants of undigested food, false urges and tenesmus disturbed. In addition, the patient noted severe general weakness (lost 5 kg in 2 months), arthralgia in the large joints of the lower extremities. The patient stopped taking azathioprine on her own, which led to a pronounced exacerbation of the disease. Over the next year, she was repeatedly hospitalized. At that time, according to laboratory data, hypochromic anemia (hemoglobin – 105 g / l), neutrophilic leukocytosis (14.6 10 ⁹ /l), ESR – 36 mm / h and a twofold increase in the level of C-reactive protein. Endoscopic examination revealed destructive changes in the mucous membrane, purulent plaque, many erosions and ulcers up to 4-5 mm in size, moderate contact and spontaneous bleeding. Intravenous administration of prednisolone 125 mg was carried out for 7 days, followed by a transition to oral administration at a dose of 75 mg with a gradual decrease to a daily dose of 40 mg and the addition of sulfasalazine 2. 0 g/day. Carried out infusion of metronidazole 500 mg/day, correction of electrolyte disturbances. The treatment was continued on an outpatient basis with aminosalicylic acid preparations at a dose of 3.0 g/day in combination with budesonide at a dose of 9mg/day When a relatively stable state is reached, rifaximin 800 mg/day for 7 days in combination with bifiform is recommended.

In May 2017, the condition worsened again: loose stools 14 times a day in a small amount with mucus and blood, more often at night, abdominal distention, tenesmus, periodic aching or spastic pains of low intensity in the left side of the abdomen, sometimes aggravated after defecation, arthralgia, weakness, lack of appetite, thirst, insomnia. Subfebrile body temperature persisted, anemia increased (hemoglobin – 95 g/l), neutrophilic leukocytosis (15.6 10 ⁹ /l), ESR – 53 mm/h, the level of C-reactive protein is increased three times. In addition, there was an increase in pancreatic amylase up to 51 U/l (reference values ​​- up to 50 U/l) and type 1 elastase up to 26 µg/l (reference values ​​- up to 3. 5 µg/l). The level of fecal calprotectin exceeded the norm by almost 20 times and reached 980 mcg/g.

During colonoscopy, the mucous membrane in all parts of the large intestine is sharply edematous with an abundance of acute ulcers of various sizes (some of the ulcers with traces of ongoing bleeding) and acute erosions, numerous submucosal hemorrhages. Severe contact bleeding, multiple polypoid formations in the sigmoid, rectum, transverse colon.

For differential diagnosis with Crohn’s disease, a test was performed for antineutrophil cytoplasmic antibodies (pANCA), IgG/IgA, antibodies to Saccharomyces cerevisiae (ASCA), IgG/IgA, antibodies to intestinal goblet cells, antibodies to the exocrine pancreas. These antibodies were not found in the patient’s blood.

Complex therapy (glucocorticosteroids, metronidazole, sulfasalazine) was prescribed, but it was not possible to achieve remission and overcome hormonal dependence. Since August 2017, the use of azathioprine was resumed, however, the clinical and endoscopic activity of the process remained. In accordance with clinical recommendations, in case of relapse that occurred during maintenance therapy with thiopurines, repeated administration of corticosteroids is indicated, however, in order to avoid the formation of steroid dependence, the appointment of biological drugs is recognized as more appropriate [4].

Taking into account the ineffectiveness of previous therapy with immunosuppressants, the high degree of inflammatory activity of the disease, the formation of hormone dependence, it was decided to begin the selection of a biological drug for the patient. Before starting anticytokine therapy, it is necessary to screen for the presence of tuberculosis infection, which includes: a thorough history taking, X-ray (not fluorography!) of the chest in two projections, a Mantoux test with intradermal administration of 2 tuberculin units, if necessary, a quantiferon test or diaskintest [7].

Biological drugs – tumor necrosis factor alpha (TNF-α) blockers – infliximab, adalimumab, golimumab have a fairly wide range of indications [8]. In addition to inflammatory bowel diseases, they are used for rheumatoid and psoriatic arthritis, ankylosing spondylitis, noninfectious uveitis, and psoriasis [9–12]. Preparations containing monoclonal antibodies to TNF-α lead to a certain decrease in the level of the body’s immune defense and increase its susceptibility to various infections, including tuberculosis, increase the risk of destruction of tuberculous granuloma and reactivation of latent tuberculosis [4]. The patient already had a history of infiltrative tuberculosis, so it was decided to refrain from using this group of drugs.

Vedolizumab (antivio) is the only biological drug registered in the Russian Federation for the treatment of IBD that selectively blocks inflammation in the intestine [11]. It is a humanized monoclonal IgG antibody that binds to α4β7 integrin on the surface of lymphocytes and selectively blocks its interaction with MADCAM-1 cell adhesion molecules of the intestinal mucosa. It is these molecules that play the leading role in the migration of T-helper lymphocytes, which cause a chronic inflammatory process characteristic of UC and Crohn’s disease [11].

Safety data over 4800 patient-years of exposure demonstrate no increased risk of infections, including severe infections, with vedolizumab. The frequency of adverse events when used in standard doses is comparable to placebo, which allows the use of the drug for a long time [13]. The probability of stable remission after a course of administration of vedolizumab, ceteris paribus, is 2–4 times higher than that with the use of drugs from the TNF-α group in moderate and severe UC in case of resistance to standard therapy [14]. The likelihood of discontinuation of vedolizumab due to the development of adverse reactions is 4.8-7 times lower than with adalimumab or golimumab therapy during 52 weeks of maintenance therapy in patients receiving treatment with monoclonal antibodies for the first time [14].

Clinical trials and post-marketing data have shown that the incidence of opportunistic infections and tuberculosis in patients receiving vedolizumab was low. No viral reactivation of hepatitis B or C has been reported [15]. The high selectivity of the immunosuppressive effect of vedolizumab makes it possible to prescribe it even to patients with an increased risk of developing opportunistic infections or to the elderly [16]. A similar trend is observed with regard to the incidence of neoplasms: it has been proven that vedolizumab has a favorable safety profile with low rates of malignant neoplasms over a long period of treatment [17].

This patient had the following indications for the use of this drug: moderate and/or severe active UC, inadequate response and/or treatment failure (or reduced efficacy), intolerance to one or more standard therapy drugs [11].

After screening for tuberculosis, yersiniosis, viral hepatitis, induction therapy with vedolizumab was started in November 2017 and continued azathioprine at a dose of 150 mg/day.

Vedolizumab (antivio) is administered intravenously at a dose of 300 mg over 30 minutes, then at the same dose 2 weeks and 6 weeks after the first injection, then every 8 weeks [11]. According to the literature, the therapeutic effect appears already after the first use of vedolizumab [18].

The patient tolerated the drug infusions satisfactorily. Signs of a significant improvement in well-being and regression of symptoms were noted after 3 weeks (after the second injection): tenesmus disappeared, body temperature returned to normal, the frequency of stools and the amount of pathological impurities in it decreased, and weakness became much less disturbing.

From the fourth week of therapy, the patient noted a significant improvement: stools – without pathological impurities, the frequency of not more than three times a day, sleep and appetite normalized, weakness decreased. Clinical improvement was confirmed by laboratory data: the hemoglobin level increased to 110 g/l, the severity of leukocytosis decreased to 90×10 ⁹ /l, normalized ESR (13 mm/h), levels of pancreatic amylase and C-reactive protein. Fecal calprotectin decreased from 890 to 90 mcg/g (reference values ​​- up to 50 mcg/g). Endoscopically: the rectum expands, there is cloudy mucus on the walls, the mucous membrane is edematous, with foci of atrophy and scars.

Patient has received 7 infusions of Entivio 300 mg every 8 weeks to date. Clinical response and remission were assessed according to generally accepted standards widely used in IBD clinical trials. Clinical response was defined as a decrease of ≥3 points in the Harvey-Bradshaw Index (HBI) and an absolute Simple Clinical Colitis Activity Index (SCCAI) score of ≤2 at follow-up from baseline. Clinical remission was defined as SCCAI ≤2. Adverse events associated with the preparation were not noted, the development of opportunistic infections, tuberculosis, and oncological processes were not registered. The patient’s condition is regarded as good. Complete clinical and endoscopic remission was achieved.

Conclusion

The described clinical case demonstrates the possibility of achieving clinical and endoscopic remission in patients with inflammatory bowel disease using the biological drug vedolizumab. The anti-integrin mechanism of action of the drug ensures the selectivity of its action in relation to the gastrointestinal tract and a favorable safety profile.

The authors declare no conflict of interest.

The authors declare no conflict of interest .



Possibilities of using biological therapy in inflammatory bowel diseases during pregnancy | #02/18

The number of studies related to the study of the safety of biological therapy in patients with inflammatory bowel diseases during pregnancy is growing, but the question still remains open due to the ethical complexity of their conduct. AT

#02/18

Keywords / keywords:

Pregnancy, Biological therapy, Crohn’s disease, Inflammatory bowel disease, Gastroenterology, Ulcerative colitis, Immunology, Pharmacology

O. &nbspV.&nbspGaus, V.&nbspA.&nbspAkhmedov, T.&nbspS.&nbspZhabrova

Possibilities of biological therapy application in intestinal inflammatory diseases against the background of pregnancy

Number of studies related to safety of biological therapy in women patients with intestinal inflammatory diseases during pregnancy is increasing, but the issue is still unsolved due to ethical difficulty of their conducting. The paper systematizes available modern data on the possibility of biological drug application in inflammatory intestinal diseases in the pregnant, the level of risk of their potential effect on the fetus was assessed.

The urgency of the problem of effective and safe drug treatment of inflammatory bowel diseases (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC), leaves no doubt. Pregnant women are a special category of patients, since the peak incidence of IBD occurs between 20 and 30 years of age and occurs during childbearing [1]. According to the European Crohn’s and Colitis Organization (ECCO), fertility, that is, the ability to conceive a child, in women with IBD is the same as in healthy women, with the exception of patients with severe activity of the inflammatory process , with a continuously relapsing course of the disease, who underwent surgical resection with the formation of an ileoanal reservoir anastomosis (IARA) [2]. However, in the literature there are quite heterogeneous data on the frequency of infertility in women with IBD – from 5–14%, which corresponds to the frequency of infertility in the general population, to 32–42% [1, 3]. In addition, the interpretation of the results of fertility studies in IBD is complicated by the fact that patients consciously decide not to plan a pregnancy, and it is this “voluntary childlessness” that makes data analysis difficult [4].

The main issue that worries women with IBD who are planning a pregnancy is whether the drugs they take will have an adverse effect on the fetus [4–6]. Insufficient awareness of patients can lead, on the one hand, to non-compliance with the dosing regimen or complete discontinuation of medications, on the other hand, to a decision to terminate a pregnancy if it occurs [1, 4, 6–8]. In this regard, the physician must have a clear understanding of the medications for the treatment of IBD, their benefits and possible risks for both the mother and the fetus. The tactics of managing a pregnant woman with IBD is chosen individually in each case.

The main goal of drug therapy for IBD is to achieve and maintain remission, not only clinical and laboratory, but also morphological (endoscopic and histological) [4, 9–13]. It has been established that discontinuation of IBD treatment and the development of an exacerbation against this background are more harmful to the fetus than continued therapy with any drugs [14, 15].

Progress in the study of the molecular mechanisms of inflammation in IBD has contributed to a significant breakthrough in the field of conservative treatment of CD and UC – the emergence of biological therapy [15, 16]. According to the clinical guidelines of the Russian Gastroenterological Association (RGA) and the Association of Coloproctologists of Russia (ARC), biological agents are used only for moderate and severe CD and UC, both as monotherapy and in combination with other anti-inflammatory drugs [17]. Biological preparations make it possible to quickly achieve stable clinical and laboratory, morphological remission of IBD, including during pregnancy [18–24].

This review article will analyze the available data on the advantages and disadvantages of biological therapy in the treatment of IBD during pregnancy (Table).

In the treatment of IBD, biological preparations are used that inhibit the key inflammatory molecule – antibodies to tumor necrosis factor alpha (infliximab, adalimumab, golimumab) and block the expression of so-called “adhesion molecules” – antiintegrins (natalizumab, vedolizumab) [1, 3, 11, 13] .

According to the PIANO registry, the use of biologics up to the third trimester of pregnancy in patients with IBD did not increase the risk of fetal anomalies, spontaneous abortions, intrauterine growth retardation, or underweight at birth [21]. It is known that the molecules of most drugs in this group are too large to cross the placenta, however, the placenta is able to actively accumulate and transfer a significant amount of all biological drugs (with the exception of certolizumab pegol) into the fetal circulation in the third trimester of pregnancy [22, 25].

Infliximab is a chimeric IgG1 monoclonal antibody consisting of human and mouse components, while adalimumab and golimumab are fully humanized human antibodies [4, 11]. Antibodies to tumor necrosis factor alpha (TNF-alpha) bind and neutralize this pro-inflammatory cytokine, fix complement and induce T-cell apoptosis, and also inhibit leukocyte migration [16]. These drugs do not cross the placental barrier in the first trimester of pregnancy, but are found in the fetus in the second and third trimesters, as well as in the blood of the newborn within 6 months after birth [4, 11]. Therefore, these drugs are generally not recommended after the 30th week of pregnancy if remission is achieved to avoid neonatal immunosuppression [1]. If remission is not achieved, drugs can be taken in the third trimester, but only if the threat to the life of the mother outweighs all the risks to the fetus [26]. The incidence of adverse pregnancy outcomes (spontaneous abortion, preterm birth, congenital anomalies, and intrauterine growth retardation) in patients with IBD treated with infliximab is similar to that in pregnant women with IBD not receiving anti-TNF-alpha therapy [27]. The PIANO registry does not indicate an increased risk of infection in newborns whose mothers were treated with infliximab, except when infliximab was used in combination with azathioprine [21]. However, there is a case report in the literature of a fatal infection following the administration of BCG vaccine to a child exposed to infliximab in utero [28]. Given this fact, it is not recommended to administer live attenuated vaccines to newborns within 6 months after birth, while the biological preparation can still circulate in the body [1].

Studies of adalimumab in animal models do not indicate an increased obstetric risk or teratogenic effect [19]. The drug is actively transferred through the placenta, however, there are no reports of congenital fetal anomalies in pregnant women treated with adalimumab [21].

There is insufficient information on the safety of golimumab use during pregnancy, and there is currently no data on its use in this category of women. In experimental studies of the reproductive function of animals against the background of the use of golimumab, no adverse events were noted [20].

Certolizumab pegol (CZP) is a pegylated Fab fragment of a humanized anti-TNF-alpha monoclonal antibody. This Fab fragment crosses the placenta by passive diffusion, so the concentration of the drug in the umbilical cord blood of the fetus is much lower, unlike infliximab, adalimumab or golimumab, and is not detected in the blood plasma of the newborn [22, 25]. An analysis of the course of 47 pregnancies during CZP therapy, according to the PIANO registry, showed no undesirable consequences for the fetus [21]. However, more data are needed to fully assess the safety and tolerability of the drug [20]. However, CZP is currently considered to be the most optimal biologic drug for pregnant women with IBD, especially in the third trimester [22].

Natalizumab is a humanized IgG4 antibody against the adhesion molecule α4-integrin [1]. There is insufficient information regarding the use of natalizumab in pregnant women. It was previously reported that in monkeys, when administered at a dose 2. 3 times higher than recommended for humans, it causes anemia, thrombocytopenia, atrophy of the liver, spleen, and thymus [29]. In a prospective follow-up of 13 pregnancies in women with multiple sclerosis who received natalizumab in the third trimester, mild to moderate hematological disorders were detected in 10 of 13 children [18]. The instructions for the drug indicate that natalizumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. However, it should be noted that so far in the territory of the Russian Federation the drug has only one indication for use – multiple sclerosis.

Vedolizumab is a new generation drug approved in 2014 for the treatment of IBD in the United States and EU countries, and in 2016 in Russia [30, 31]. It is a recombinant IgG1 antibody that binds to α4β7-integrin and selectively blocks the migration of leukocytes in the intestinal wall, thereby preventing the development of the inflammatory process [31]. This drug, similarly to anti-TNF, crosses the placenta, the concentration increases linearly with the course of pregnancy, reaching a maximum in the third trimester [4]. There is no teratogenic effect in animals exposed to high doses of vedolizumab, 20 times the recommended dose in humans [4]. To date, there are no data on the safety of vedolizumab in pregnant women, but a registry of pregnancy outcomes has been established [32].

Conclusion

Summarizing the above, it should be concluded that biological therapy can be used during pregnancy, given its high efficacy and relative safety. It should be remembered that the choice of the optimal drug for biological therapy and the timing of the therapy itself should be considered in relation to each individual patient, taking into account all possible risks for both the mother and the fetus.

Literature

1. Gaidos J. K. J., Kane S. V. Sexuality, Fertility, and Pregnancy in Crohn’s Disease // Gastroenterology Clinics of North America. 2017 Vol. 46(3). P. 531–546.
2. Van der Woude C. J. The Second European Evidenced-Based Consensus on Reproduction and Pregnancy in Inflammatory Bowel Disease // Journal of Crohn’s and Colitis. 2015. Vol. 9(2). P. 107–124.
3. Hosseini-Carroll P., Mutyala M., Seth A. et al. Pregnancy and inflammatory bowel diseases: Current perspectives, risks and patient management // World Journal Gastrointestinal Pharmacology and Therapeutics. 2015. Vol. 6 (4). P. 156–171.
4. Gaidos J. K. J., Kane S. V. Managing IBD Therapies in Pregnancy // Current Treatment Options in Gastroenterology. 2017 Vol. 15(1). P. 71–83.
5. Parfenov AI Inflammatory bowel disease and pregnancy // Experimental and Clinical Gastroenterology. 2012. No. 3. P. 80–86.
6. Ellul P., Zammita S. C., Katsanos K. H. et al. Perception of Reproductive Health in Women with Inflammatory Bowel Disease // Journal of Crohn’s and Colitis. 2016. Vol. 10 (8). P. 886–891.
7. Gallinger Z. R. et al. Perceptions and Attitudes Towards Medication Adherence during Pregnancy in Inflammatory Bowel Disease // Journal of Crohn’s and Colitis. 2016. Vol. 10(8). P. 892–897.
8. Maliszewska A. M. et al. Infammatory bowel disease and pregnancy // Ginecologia Polska. 2017 Vol. 88(7). P. 398–403.
9. Akhmedov V. A., Livzan M. A. Diseases of the gastrointestinal tract in pregnant women [Electronic resource]. M.: GEOTAR-Media, 2016.
10. Zimmerman Ya. S., Mikhaleva EN Possibilities of pharmacotherapy in the treatment of gastroenterological diseases during pregnancy // Clinical Medicine. 2015. No. 8. P. 8–18.
11. Kanis S. L., van der Woude C. J. Proper Use of Inflammatory Bowel Disease Drugs during Pregnancy // Digestive Diseases. 2016. Vol. 34(1). P. 61–66.
12. Nielsen O. H., Maxwell C., Hendel J. IBD medications during pregnancy and lactation // Nat. Rev. Gastroenterol. Hepatol. 2014. Vol. 11(2). P. 116–127.
13. Poturoglu S., Ormeci A. C., Duman A. E. Treatment of pregnant women with a diagnosis of inflammatory bowel disease // World Journal Gastrointestinal Pharmacology and Therapeutics. 2016. Vol. 7(4). P. 490–502.
14. Eremina E. Yu., Pungina M. Yu. Inflammatory bowel disease and pregnancy // Problems of Women’s Health. 2013. Vol. 8 (3). pp. 77–86.
15. Lazebnik LB et al. Biological therapy of inflammatory bowel diseases // Experimental and Clinical Gastroenterology. 2011. No. 2. P. 7–14.
16. Fiocchi K. Etiopathogenesis of inflammatory bowel diseases // Coloproctology. 2015. No. 1 (51). pp. 5–20.
17. Khalif IL Changes in clinical guidelines for the diagnosis and treatment of patients with IBD // Gastroenterology. 2017. No. 4. S. 20–26.
18. Friend S. , Richman S., Bloomgren G. et al. Evaluation of pregnancy outcomes from the Tysabri® (natalizumab) pregnancy exposure registry: a global, observational, follow-up study // BMC Neurology. 2016. Vol. 16(1). P. 150.
19. Khan N., Asim H., Lichtenstein G. R. Safety of anti-TNF therapy in inflammatory bowel disease during pregnancy // Expert opinion on Drug Safety. 2014. Vol. 13(12). P. 1699–1708.
20. Komoto S., Motoya S., Nishiwaki Y. et al. Pregnancy outcome in women with inflammatory bowel disease treated with anti-tumor necrosis factor and or thiopurine therapy: a multicenter study from Japan // Intestinal Research. 2016. Vol. 14(2). P. 139–145.
21. Mahadevan U., Martin C. F., Sandler R. S. et al. PIANO: a 1000 patient prospective registry of pregnancy outcomes in women with IBD exposed to immunomodulators and biologic therapy // Gastroenterology. 2012. Vol. 142(5). Suppl. 1.P.S-149.
22. Mariette X. et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study // Ann. Rheum. Dis. 2017 Vol. 10. P. 1–6.
23. Paramichael K., Mantzaris G. J., Peyrin-Biroulet L. A safety assessment of anti-tumor necrosis factor alpha therapy for treatment of Crohn’s disease // Expert opinion on Drug Safety. 2014. Vol. 15(4). P. 493–501.
24. Weber-Schoendorfer C. et al. Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study // British Journal of Clinical Pharmacology. 2015. Vol. 80(4). P. 727–739.
25. Mahadevan U., Wolf D. C., Dubinsky M. et al. Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease // Clin. Gastroenterol. Hepatol. 2013. Vol. 11(3). P. 286–292.
26. De Lima A. et al. Tailored anti-TNF therapy during pregnancy in patients with IBD: maternal and fetal safety // Gut. 2016. Vol. 65(8). P. 1261–1268.
27. Gisbert J. P., Chaparro M. Review Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease // The American Journal of Gastroenterolog. 2013. Vol. 108(9). P. 1426–1438.
28. Heller M. M., Wu J. J., Murase J. E. Fatal case of disseminated BCG infection after vaccination of an infant with in utero exposure to infliximab // J. Am. Acad. Dermatol. 2011 Vol. 65(4). P. 870.
29. Haqhikia A., Langer-Gould A., Rellensmann G. et al. Natalizumab use during the third trimester of pregnancy // JAMA Neurol. 2014. Vol. 71(7). P. 891–895.
30. Serpik VG Analysis of drug registration in Russia // Modern organization of drug supply. 2016. No. 3–4. pp. 10–19.
31. Khalif I. L., Shapina M. V. The use of vedolizumab in inflammatory bowel diseases // Russian Journal of Gastroenterology, Hepatology, Coloproctology.