What are systemic steroids used for in ulcerative colitis treatment. How do corticosteroids reduce inflammation in IBD. What are the potential side effects of long-term steroid use. When should steroids be prescribed for ulcerative colitis flares.

Understanding Steroids as a Treatment for Inflammatory Bowel Disease

Steroids, also known as corticosteroids, have long been a cornerstone in the treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease. These powerful anti-inflammatory medications work by suppressing the immune system’s overactive response, which is responsible for the chronic inflammation in the digestive tract characteristic of IBD.

While steroids can be highly effective in reducing inflammation and inducing remission in IBD patients, they are not without their drawbacks. The potential for serious side effects, especially with long-term use, has led to a shift in treatment approaches, with doctors now reserving steroids for more severe flares or cases where other treatments have failed.

How do steroids work in treating ulcerative colitis?

Steroids work by mimicking the effects of hormones your body produces naturally in the adrenal glands. When administered in higher doses, they can:

• Reduce inflammation throughout the body
• Suppress the immune system’s overactive response
• Alleviate symptoms such as abdominal pain, diarrhea, and rectal bleeding
• Promote healing of the inflamed intestinal lining

It’s important to note that while steroids can effectively induce remission, they do not prevent future flares and are not considered a long-term solution for managing IBD.

Types of Steroids Used in Ulcerative Colitis Treatment

There are several types of steroids that doctors may prescribe for ulcerative colitis, each with its own characteristics and use cases. The most commonly used steroids for IBD include:

Prednisone and Prednisolone

Prednisone is one of the most widely prescribed systemic steroids for IBD. It is a potent anti-inflammatory medication that can be taken orally in tablet form or as a liquid solution. Prednisolone is the active form of prednisone and is sometimes prescribed instead, especially for patients with liver problems.

Budesonide (Entocort EC速 and Uceris速)

Budesonide is a newer steroid formulation that offers some advantages over traditional systemic steroids. It is designed to work primarily in the intestines, with less absorption into the bloodstream, potentially resulting in fewer systemic side effects.

• Entocort EC速 is formulated to target the end of the small intestine (ileum) and the beginning of the colon (cecum), making it particularly useful for Crohn’s disease.
• Uceris速 is designed to treat inflammation in the colon, making it more suitable for ulcerative colitis.

Administering Steroids: Dosage and Duration

The dosage and duration of steroid treatment for ulcerative colitis can vary depending on the severity of the flare and the individual patient’s response. Typically, doctors will prescribe a higher initial dose to quickly bring inflammation under control, followed by a gradual tapering of the dose over several weeks.

What is the typical dosing schedule for prednisone in ulcerative colitis?

A common prednisone regimen for a moderate to severe UC flare might look like this:

1. Initial dose: 40-60 mg per day for 1-2 weeks
2. Tapering: Reduce dose by 5-10 mg per week
3. Maintenance: Continue tapering until off the medication or reaching the lowest effective dose

It’s crucial to follow the prescribed tapering schedule and not stop taking steroids abruptly, as this can lead to serious side effects and a potential flare-up of symptoms.

Potential Side Effects of Steroid Use in IBD

While steroids can be highly effective in treating IBD flares, they come with a significant risk of side effects, especially when used long-term or at high doses. Understanding these potential side effects is crucial for patients and healthcare providers to make informed decisions about treatment.

What are the most common side effects of steroid use in ulcerative colitis?

Side effects can be categorized as minor or major, with some being more common than others:

Minor Side Effects:

• Acne
• Weight gain
• Facial roundness (moon face)
• Mood swings and irritability
• Increased appetite
• Insomnia
• Skin thinning and easy bruising

Major Side Effects:

• Osteoporosis (bone thinning)
• Increased risk of infections
• High blood pressure
• Diabetes or worsening of existing diabetes
• Cataracts or glaucoma
• Adrenal suppression
• Muscle weakness
• Growth suppression in children

The risk of side effects increases with higher doses and longer duration of use. This is why doctors aim to use the lowest effective dose for the shortest time possible when prescribing steroids for IBD.

Minimizing Risks: Best Practices for Steroid Use in UC

While the potential side effects of steroids can be concerning, there are several strategies that patients and healthcare providers can employ to minimize risks and maximize benefits:

How can patients reduce the risk of side effects when taking steroids for ulcerative colitis?

1. Take calcium and vitamin D supplements to protect bone health
2. Maintain a healthy diet low in sodium and high in potassium
3. Exercise regularly, including weight-bearing activities for bone strength
4. Monitor blood sugar levels, especially if at risk for diabetes
5. Have regular eye exams to check for cataracts or glaucoma
6. Report any new symptoms or side effects to your healthcare provider promptly
7. Never stop taking steroids abruptly; always follow the prescribed tapering schedule

Additionally, healthcare providers may prescribe medications to prevent or manage side effects, such as proton pump inhibitors to protect the stomach or bisphosphonates to prevent bone loss.

Alternatives to Systemic Steroids in UC Treatment

Given the potential for side effects with systemic steroids, researchers and clinicians have been exploring alternative treatments for ulcerative colitis. These newer options aim to provide effective inflammation control with fewer systemic side effects.

What are some alternatives to systemic steroids for treating ulcerative colitis?

• Biologics: Drugs like infliximab, adalimumab, and vedolizumab target specific inflammatory pathways
• Immunomodulators: Medications such as azathioprine and 6-mercaptopurine suppress the immune system
• JAK inhibitors: Newer drugs like tofacitinib work by blocking specific enzymes involved in inflammation
• 5-ASA drugs: Medications like mesalamine work locally in the colon to reduce inflammation
• Topical steroids: Rectal formulations of steroids can be used for distal UC with fewer systemic effects

These alternatives may be used alone or in combination, depending on the severity and extent of the disease. The choice of treatment is individualized based on factors such as disease severity, location of inflammation, and patient preferences.

The Future of Steroid Use in Ulcerative Colitis Treatment

As our understanding of IBD pathophysiology grows and new treatments emerge, the role of steroids in ulcerative colitis management continues to evolve. While they remain an important tool for managing severe flares, the trend is moving towards more targeted therapies with fewer side effects.

How is the use of steroids in ulcerative colitis treatment changing?

Several trends are shaping the future of steroid use in UC:

• Increasing use of steroid-sparing agents: Biologics and immunomodulators are being used earlier in the disease course to reduce reliance on steroids
• Development of novel corticosteroids: Research is ongoing to create new steroid formulations with improved safety profiles
• Personalized medicine approaches: Genetic and biomarker studies may help predict which patients are most likely to benefit from steroid therapy
• Combination therapies: Using steroids in conjunction with other medications may allow for lower doses and shorter treatment durations
• Enhanced monitoring: Improved tools for assessing disease activity may help optimize steroid use and tapering

Despite these advancements, steroids are likely to remain an important option for rapid symptom control in severe UC flares. The key lies in using them judiciously and in combination with steroid-sparing strategies to minimize long-term risks.

Patient Education and Shared Decision-Making in Steroid Therapy

Effective management of ulcerative colitis with steroids requires a partnership between patients and their healthcare providers. Informed patients are better equipped to adhere to treatment plans, recognize potential side effects, and participate in shared decision-making about their care.

What should patients know about steroid therapy for ulcerative colitis?

Key points for patient education include:

• The importance of taking steroids exactly as prescribed, including following the tapering schedule
• Potential side effects and when to seek medical attention
• The need for regular follow-up appointments and monitoring tests
• Lifestyle modifications that can help minimize side effects
• The temporary nature of steroid therapy and the goal of transitioning to steroid-free maintenance treatment
• The availability of alternative treatments and the pros and cons of different options

Healthcare providers should encourage open dialogue about treatment goals, concerns, and preferences. This collaborative approach can lead to better outcomes and improved quality of life for patients living with ulcerative colitis.

In conclusion, while steroids remain a powerful tool in the management of ulcerative colitis, their use requires careful consideration of benefits and risks. As treatment options continue to expand, the judicious use of steroids in combination with newer therapies offers hope for better disease control with fewer side effects. Patients and healthcare providers must work together to navigate the complex landscape of UC treatment, always striving for the best possible balance between efficacy and safety.

Steroids to Treat IBD

Prednisone and Prednisolone

What is Prednisone and What is it Used For?

• Prednisone is a steroid with anti-inflammatory effects. It is used to treat inflammation in ulcerative colitis and Crohn’s disease. However, steroids do not prevent symptoms from returning and have many side effects.
• Sometimes, it is necessary to use steroids to treat IBD, especially during “flares.”

What Do I Need to Know Before Taking Prednisone?

• Prednisone can be taken with or without food.
• The tablets may be crushed, and there is a liquid solution available.
• You should take extra calcium and vitamin D because prednisone affects bone strength.

What Do I Do If I Miss a Dose?

• If you are only taking prednisone once a day, take it as soon as you remember that day. If you don’t remember until the next day, just take one dose; do not double up on your dose.
• If you are taking Prednisone twice a day, take the missed dose as soon as you remember and resume your regular schedule.
• It is very important that you do not stop taking this drug suddenly. Doing this can have very bad side effects.

What Are the Food or Drink Interactions?

There are no known food or drink interactions. Prednisone may cause your body to retain more sodium/salt, so stay away from foods high in sodium/salt like potato chips, etc.

Are There Any Drug Interactions with Prednisone?

Prednisone may increase or decrease the effects of the following medicines:

• Birth control pills
• Aspirin
• Rifampin
• Amphotericin B
• Estrogen
• Barbiturates (Phenobarbital®, Donnatal®)
• Carbamazepine (Tegretol®)
• Cyclosporine
• Ketoconazole
• Coumadin
• Phenytoin (Dilantin®)

Is It Safe to Take Prednisone for Long Periods of Time?

It is best to be on the lowest dose of Prednisone that is effective for the shortest period of time because of the side effects. However, this is not always possible when treating IBD, so it is important for you to talk regularly with your doctor while on prednisone.

What Are the Side Effects of Prednisone?

Minor

• Acne
• Weight gain
• Facial roundness
• Rash
• Nervousness/mood swings

Major

• Abdominal pain
• Blurred vision
• Bloody or black stools
• Painful joints
• Osteoporosis
• Depression
• Infections
• Severe fatigue
• Stretch marks
• Headaches (pseudotumor cerebri)

Budesonide

Also called Entocort EC® and Uceris®

What is Budesonide and What Is It Used For?

• Budesonide is a steroid drug.
• Entocort works mainly at the end of the small intestine (ileum) and at the beginning of the colon (cecum) to reduce inflammation from Crohn’s disease.
• Uceris is a newer form of the same medicine that treats inflammation in the colon in Ulcerative Colitis.
• Budesonide is different than other steroids such as prednisone because very little medicine reaches the bloodstream. This causes fewer side effects than other steroids.

• Swallow the whole capsule; do not crush or chew.
• This medicine is usually taken in the morning.
• It should not be stopped suddenly and usually requires a “tapering period” (slowly lowering the dose).
• Notify your doctor if you are exposed to or develop chicken pox or measles.

What Are the Food or Drink Interactions?

Grapefruit juice may increase the effects of budesonide and should be avoided.

Are There Any Drug Interactions with Budesonide?

Budesonide may increase the effects of the following drugs:

• Erythromycin
• Ketoconazole and itraconazole
• HIV treatment

Is It Safe to Take Budesonide for Long Periods of Time?

It is FDA-approved for eight weeks. However, budesonide may be used longer in certain cases.

Minor

• Acne
• Nausea
• Headache
• Respiratory infections
• Skin striae or markings
• Swollen or moon face

Major

• Depression
• Knee or hip pain

Ulcerative Colitis Treatment: Systemic Steroids

Written by Rachel Reiff Ellis

• What Are the Types of Systemic Steroids?
• What Side Effects Might Happen?
• What Should You Expect When Taking Steroids?

The symptoms of ulcerative colitis happen because of inflammation in your digestive tract. Systemic steroids (corticosteroids) are powerful anti-inflammatory drugs doctors have turned to for decades as a first-line treatment for UC and Crohn’s disease, another inflammatory bowel disease. Because of serious side effects and newer medical treatments, doctors don’t use systemic steroids for UC as much as they used to.

Your body makes steroids, which are a type of chemical or hormone, naturally. Systemic steroids that treat UC are a lab-made version of the same hormone. The drug comes in a much higher dose than your body makes on its own. This leads to side effects. These drugs are different from anabolic steroids, which people sometimes use illegally to increase their muscle mass.

Steroids aren’t a cure for ulcerative colitis. But they are highly effective at reducing inflammation and getting you into remission, meaning you don’t have signs of the disease. They aren’t a long-term solution for UC symptoms, because of their serious side effects. Also, symptoms can come back while you’re on them.

Steroids are very good at healing an inflamed bowel. But they aren’t as good at preventing further flare-ups. Once your serious ulcerative colitis reaches remission on steroids, your doctor will switch you to different medications for longer-term use.

There are many types of steroids your doctor can prescribe for your UC, and different ways to take them. The most common is orally, or by mouth.

Options you take by mouth:

• Prednisone (Deltasone) is one of the most common corticosteroid choices. You take it as a pill.
• Budesonide (Enticer EC) is a modified steroid your body absorbs through the small intestine and colon. Your liver processes it much faster than prednisone. That means your risk of side effects is lower. This drug is a capsule.
• Budesonide-MMX (Uceris) is the same as budesonide, but it has a special coating on it. The coating keeps the medication inside the capsule until it gets to your colon. This helps more of the medication go straight to the colon. This option is best for treating inflammation in the colon only, which is what happens in ulcerative colitis.

Doctors usually recommend you take oral steroids in the morning so they’re less likely to affect your sleep. Oral options typically improve your symptoms within 1-4 weeks. They’re not recommended for use longer than 8 weeks.

Your doctor may give you steroids you can take rectally. These are not systemic steroids, but they go to work right in the areas where the inflammation is for mild to moderate UC:

• Suppositories of hydrocortisone help treat inflammation in your anus and rectum. You take them by inserting the small, round suppository into your anus, where it dissolves to deliver the drug.
• Enemas (cortisol, hydrocortisone, methylprednisolone) work best for inflammation higher up in your colon past your rectum where suppositories can’t reach. These choices also deliver medication straight to the affected area. That reduces your risk of side effects.
• Rectal foams (budesonide, hydrocortisone acetate, hydrocortisone/pramoxine) can deliver steroids to the rectum and colon. Foams stay in the area longer so the drug has a better chance to absorb.

Most people see their symptoms start to improve after 1 or 2 weeks.

For severe flares of UC, you may need hydrocortisone delivered into a vein through an IV in the hospital. This usually relieves symptoms within 4-10 days. Your doctor will then switch you to oral steroids.

Because systemic steroids slow down your immune system to reduce inflammation, your defenses against germs are much lower while you’re taking them. This means you’re at a higher risk for infection. People on steroids commonly deal with:

• Urinary tract infection
• Vaginal yeast infection
• Yeast infections of the mouth (thrush)

The side effects you get from a systemic steroid will depend on how strong a dose you’re on and how long you take it. But many different side effects are possible and common, including:

• Acne
• Cataracts (cloudy patches in the eye)
• Growth issues in kids
• High blood pressure (hypertension)
• High blood sugar
• Increased facial hair
• Bigger appetite
• Trouble sleeping
• Mood swings
• “Moon face” (a rounder, fuller face shape)
• Osteoporosis (weakening of bones)
• Psychosis
• Stretch marks
• Weight gain

Some side effects go away once you stop taking the steroid. That’s not the case for cataracts and osteoporosis, though. Your doctor may recommend you take extra calcium and vitamin D to help counteract the effects of osteoporosis (but it won’t prevent osteoporosis). Cataracts also require extra treatment, even after stopping the steroid.

Because of the serious side effects that come with steroids, doctors typically recommend you take them for only a short time, usually about 8 weeks.

About 1 in 5 people don’t respond to steroids. This is called being steroid refractory. If they don’t seem to be helping your symptoms after 3 months, your doctor may add an immunosuppressant such as azathioprine (Azasan, Imuran), mercaptopurine (Purinethol, Purixan), or methotrexate (Rheumatrex, Trexall) along with the steroid. If your UC is severe and these treatments don’t work, your doctor may move to biologic treatments like infliximab (Remicade) or adalimumab (Humira).

When you’re taking a steroid, your adrenal glands slow down or stop making cortisol, the natural steroid. Because of this, you shouldn’t stop taking steroids all at once. Your body needs time to crank its production of cortisol back up before that. Your doctor will guide you through a tapering-off process to completely wean you off your steroid over time.

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How to predict steroid response in acute severe ulcerative colitis

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March 04, 2022

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• Gastroenterologists

A new index has been developed to predict steroid response in patients with acute severe ulcerative colitis on admission.

Ulcerative colitis (UC) is a fairly common inflammatory bowel disease. Its true prevalence has not been established and varies according to various data from 50 to 230 cases per 100 thousand of the population. The disease is often severe and is characterized by a high mortality rate, accounting for 6 cases per 1 million population in the world, and 17 cases per 1 million population in Russia.¹

The first-line treatment for hospitalized patients with acute UC is intravenous steroids. However, about 30% of patients do not give the expected response to treatment and require second-line therapy or colectomy. bloody stools, increased erythrocyte sedimentation rate, increased C-reactive protein (CRP), hyperthermia, anemia, tachycardia.³ However, severe patients may not have systemic signs, and monitoring stool frequency takes time, the loss of which leads to a worse prognosis outcome. In this regard, there is a need for sensitive and accurate methods for identifying patients at high risk of not having an adequate response to steroids in order to make an early decision on surgical intervention or second-line therapy.

A 3-point test was developed and tested in the UK:

1. albumin ≤30 g/l;
2. CRP ≥50 mg/L;
3. increased endoscopic severity — Mayo endoscopic index 3 points.⁴

The test is called the “ACE index” after the first letters of the constituents – albumin, CRP, endoscopy. The diagnostic value of the index was evaluated in 235 cases of acute UC.

• 155 of 235 patients (66.0%) responded to steroid therapy.
• At admission, levels of CRP, albumin, and endoscopic severity varied significantly between responders and non-responders to first-line therapy.
• 78.1% (25 of 32) of patients with concomitant CRP ≥50 mg/l, albumin ≤30 g/l, and Mayo score 3 did not respond to intravenous steroids.
• The predictive value of the ACE index was rated as high – 78. 1%.⁵

The new test has a very great practical potential. Timely stratification of the risk of failure of first-line therapy allows making early informed decisions regarding the course of treatment.

The following materials were used in the article:

1. S.R. Abdulkhakov, R.A. Abdulkhakov. Nonspecific ulcerative colitis: current approaches to diagnosis and treatment. Bulletin of Modern Clinical Medicine, 2009, Volume 2, no. 1, pp. 32-41.
2. Narula N, Marshall J, Colombel J-F, et al. Systematic review and meta-analysis: infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids. Am J Gastroenterol. 2016;111:477-491.
3. Dinesen LC, Walsh AJ, Protic MN, et al. The pattern and outcome of acute severe colitis. J Crohn’s Colitis. 2010;4:431-437.
4. I. N. Ruchkina, O. V. Knyazev, I. E. Trubitsyna, N. A. Fadeeva, E. A. Dobrolyubova, S. V. Belousov, S. G. Khomeriki, and A. I. Parfenov . Effective domestic mesalazine in the treatment of ulcerative colitis. Attending physician No. 2/2018; pp: 32-37.
5. Rebecca K Grant et al. The ACE (Albumin, CRP and Endoscopy) Index in Acute Colitis: A Simple Clinical Index on Admission that Predicts Outcome in Patients With Acute Ulcerative Colitis. Inflammatory Bowel Diseases, Volume 27, Issue 4, April 2021, Pages 451–457, https://doi.org/ 10.1093/ ibd/ izaa088.

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Possibilities of systemic and topical steroids in the treatment of inflammatory bowel disease in children | #04/10

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is the most severe pathology of the gastrointestinal tract (GIT) and is characterized by a chronic, steadily progressive course with the risk of intestinal and extraintestinal complications. In about a third of patients, the disease first manifests itself before the age of 18 years. In recent years, in the developed countries of Europe and North America, there has been a steady increase in the incidence of IBD, the prevalence of which in children varies from 3. 4 to 7.1:100,000 [1]. In Russia, an increase in the incidence has been outlined only in recent years, but this growth turned out to be very significant. According to our data, the incidence among children in St. Petersburg is approximately 2:100,000 per year, and the prevalence is 6:100,000, that is, it corresponds to the European one. If the incidence of UC in children over the past 7 years has not changed and amounted to 0.4:100?000, the incidence of CD has been steadily growing almost exponentially: for example, in 2002 it was 0.125:100?000, and in 2008 – 1.7:100,000 of the children’s population of St. Petersburg, 4 times higher than the incidence of NUC.

The etiology of IBD remains unknown, but the breakdown of immunological tolerance to intestinal antigens is thought to be a key factor in pathogenesis. As a result, immunological control over the process of progressive inflammation in the intestine is lost. Due to the fact that inflammation is the dominant mechanism for the development of both UC and CD, exacerbation of both diseases is treated with anti-inflammatory drugs: 5-aminosalicylic acid (5-ASA) or glucocorticosteroids (GCS). According to our data, at least 70% of children with IBD require GCS therapy.

In the physiological state, endogenous glucocorticoids counteract the activation of the innate and adaptive immune response [1, 2]. Low doses of exogenous steroids may also follow this physiological pathway, but when given at high doses, corticosteroids involve other mechanisms of action. After passive diffusion into the cell, they bind to specific cytoplasmic glucocorticoid receptors, which are present in most body cells in the amount of 2000 to 30000 binding sites. This complex then enters the cell nucleus and comes into contact with glucocorticoid response elements (GRE) DNA in the region of specific genes. As a result, the genes encoding the transcription of inflammatory proteins, in particular, signaling molecules of the MAPK (mitogen-activated protein kinase) cascade, are suppressed. In parallel, the synthesis of IkBa, an inhibitor of the key transcription factor NFkB, is enhanced, which suppresses the formation of specific transfer RNAs (tRNAs) and shortens their half-life. Since tRNAs are responsible for the regulation of the synthesis and release of pro-inflammatory cytokines TNF-alpha, IFN-gamma, IL-23, IL-17 and others involved in the implementation of the inflammatory response in IBD, their level decreases when GCS is prescribed. It also reduces the formation of arachidonic acid and its subsequent metabolism with the formation of leukotrienes and prostaglandins [3].

The direct effect of corticosteroids on the transcription of genes, activators of inflammation, plays a major role in achieving the anti-inflammatory effect, but is not limited to them. Non-genetic mechanisms include inhibition of endothelial NO synthetase activation. NO is one of the important participants in the inflammatory cascade in IBD, affecting the leukocyte-endothelial interaction and contributing to vasodilation and microcirculatory disorders. GCS activate the processes of phosphorylation, facilitate the entry of calcium into cells [4].

Thus, corticosteroids, interacting with various molecules, have a multilateral effect, which through a number of mechanisms is realized in a powerful anti-inflammatory effect.

Systemic corticosteroids (prednisolone, hydrocortisone, methylprednisolone, etc.) have been used in the treatment of IBD for several decades. Patients with IBD usually respond well to systemic steroid therapy, and although placebo-controlled studies of the efficacy and safety of prednisolone in this pathology in children have not been conducted, comparison with enteral artificial nutrition as the only therapy showed that the effectiveness of systemic steroids in CD reaches 85% [5], with UC — 82% [6].

The patient’s response to GCS therapy, including hormone resistance, depends on the genetically determined density of glucocorticoid receptors, as well as on the affinity (affinity) for them of a particular GCS. If the first component is purely individual and is associated with mutations in the GCS receptor gene, then the second can be changed by the optimal choice of the drug. Comparative studies have shown that budesonide is among the drugs with the highest affinity. Topical activity, that is, activity in the field of release of the active substance, depends on affinity: the higher the affinity, the higher the local effect. Thus, budesonide can be attributed to the most effective topical steroids [7].

It is well known that long-term courses of systemic corticosteroids are associated with the development of a number of undesirable side effects: a moon-shaped face, striae, acne, hypertrichosis, increased blood pressure, hyperglycemia, osteoporosis, etc. Hormone dependence is also a serious problem: 31% of children with CD and 45% with UC were hormone-dependent a year after diagnosis, which required the appointment of cytostatic therapy [8, 9]. This is consistent with data obtained in adult patients [10]. In this regard, in the treatment of local inflammatory processes in recent years, preference has been given to hormonal drugs with the lowest systemic bioavailability and predominant local action, such as budesonide, beclomethasone, fluticasone, and hydrocortisone. This approach has become generally accepted in the treatment of diseases such as bronchial asthma and allergic rhinitis, but has not yet found wide application in gastroenterology. Only in recent years, budesonide Budenofalk® containing 3 mg of the active substance in each capsule has been used in the treatment of IBD. Budenofalk® capsules dissolve in the stomach, but each of them contains about 350 granules 1 mm in diameter, coated with an acid-resistant shell containing eudragit S. The coating is destroyed at a pH above 6.4, which corresponds to the level of the terminal ileum. Therefore, the maximum effect of the drug is achieved in the ileocecal region. Since budesonide is present in the drug in its active form, it begins to act immediately after release. Due to the chemical structure, namely C-16,17alpha-acetonide, budesonide has a high lipophilicity and quickly penetrates through cell membranes.

Classic GCS (hydrocortisone, prednisolone, methylprednisolone, dexamethasone, etc. ) have a high systemic bioavailability, while this indicator for budesonide is very low [11]. The low systemic bioavailability of budesonide is a consequence of gastrointestinal uptake regulated by P-glycoprotein, a product of the MDR1 (multidrug resistance) gene, and biotransformation in the liver by cytochrome p450 3A (CYP 3A). At the first entry of budesonide into the liver, its metabolites are formed: 6-beta-hydroxybudesonide and 16-alpha-hydroxyprednisolone, the glucocorticoid activity of which is only 1–10% of the activity of budesonide absorbed into the blood. Systemic bioavailability of budesonide in children (9± 5%) is close to that in adults (11 ± 7%) [12], respectively, systemic elimination, calculated from the half-life and clearance of the drug, does not differ in adults and children [13].

The conversion of the drug in the liver to 6-beta-hydroxybudesonide occurs 1.5 times faster in children than in adults, reflecting the higher activity of CYP 3A enzymes in the liver [13]. Due to these features of pharmacodynamics, budesonide (Budenofalk®) does not require calculation of the dose per kilogram of body weight or body surface area, the same dose is used in both adults and children, the starting dose of the drug is 9mg per day. Since the side effects of corticosteroids are due to their systemic action, the pharmacokinetics of budesonide, consisting in a combination of high affinity for local corticosteroid receptors and low systemic bioavailability, create unique properties for the drug. Budesonide has a pronounced local anti-inflammatory effect with a minimum number of adverse reactions, which is confirmed by clinical studies, but the experience of using this drug in pediatric practice is small.

The aim of our study was to evaluate the effectiveness of budesonide (Budenofalk®) in children with IBD in comparison with mesalazine and prednisolone therapy.

Material and methods: under our supervision were 37 patients (24 with UC and 13 with CD) aged 8 to 17 years (mean age 14. 3 years). The diagnosis of IBD was established for the first time in all patients. By the time the treatment began, all children were in the stage of exacerbation of the disease. UC in all patients had moderate activity and was of a total nature, CD was localized in the ileocecal region, in 6 patients with lesions of other parts of the colon. Extraintestinal manifestations in the form of primary sclerosing cholangitis were diagnosed in 2 patients with UC, arthritis in 1 patient with UC and 1 with CD. , 14 — prednisolone at a dose of 1 mg/kg/s for 2 weeks, followed by a gradual decrease to a maintenance dose of 5 mg/s, 11 children (4 with CD and 7 with UC) received Budenofalk® at a dose of 9mg / s for 2 months, followed by a decrease to 6 mg / s.

Patients were followed up for a year with evaluation at 1, 3, 6 and 12 months from the start of treatment. At the same time, a scoring of the severity of intestinal syndrome (CS), general clinical activity (OKA), endoscopic activity (E), laboratory activity (L), protein-caloric deficiency (PCN), dynamics of extraintestinal manifestations (EP) in their presence was carried out in dynamics, all data were summarized as a total score (S).

Results and discussion

During treatment with Salofalk, a decrease in the manifestations of CS and E was achieved after 3 months, while the difference compared to the baseline averaged 3.0 ± 0.4 points for both CS and E. Further treatment was accompanied by a slower rate of decrease activity, endoscopic remission was achieved in 60% of patients. The appointment of prednisolone was accompanied by a faster rate of decrease in activity, after 1 month the CS decreased by 7.1 ± 1.2 points, E – by 8.2 ± 0.8 points, L – by 5.1 ± 0.7 points, however after a dose reduction against the background of maintenance therapy, a gradual increase in the activity of CS and E by an average of 2.3 ± 0.3 points was observed already after 3 months. On the background of treatment with Budenofalk®, the decrease in activity occurred at a slower pace than on the background of prednisolone, after 3 months the CS decreased by 3.6 ± 0.7 points, E – by 6. 2 ± 0.8 points, L – by 5.4 ± 0.7 points.

In the following months, there was no deterioration in the condition, on the contrary, there was a further decrease in activity, after 6 months from the start of treatment, remission was achieved in 7 out of 11 patients (64%). Remission within 6 months of treatment was achieved in 50% of patients who received Salofalk, 57% – Prednisolone and 67% – Budenofalk® (Table 1), relapse of the disease during the year was observed in 8% of children while taking Salofalk, 64% – maintenance therapy with Prednisolone and 18% – Budenofalk®. Thus, the effectiveness of the topical steroid after 6 months was the highest in comparison with 5-SK and systemic corticosteroids, and its preventive effect in maintaining remission after 1 year was close to that of Salofalk. It should be noted, however, that too early a dose reduction of Budenofalk® from 9mg to 6 mg (after 1-2 months), given the gradual onset of the effect against the background of its administration, is associated with a risk of exacerbation, therefore it is advisable to prescribe the full dose for 6 months, until complete remission occurs, and only then gradually reduce it. In this case, not only the therapeutic, but also the anti-relapse effect of the drug is achieved. Strengthening of therapy in the form of switching to systemic corticosteroids or increasing their dose was required in 42% of patients who received Salofalk, 7% – Prednisolone and 18% – Budenofalk®, cytostatics were prescribed in 43% of patients on the background of Prednisolone and only 18% – on the background of Budenofalk® .

The most significant differences were obtained in the number and severity of adverse reactions to therapy. In children treated with Budenofalk®, only a slight moon-shaped face was observed in 27%, while against the background of Prednisolone, adverse reactions were observed in all patients (Table 2), adverse reactions were also noted in 11% of patients who received Salofalk. Thus, our study confirmed the rather high efficacy of Budenofalk® in relation to both patients with CD and UC with moderate activity. The drug showed efficacy comparable to systemic steroids against the background of significantly greater safety, which is especially important in childhood. Our data are consistent with the results of two randomized clinical trials comparing the efficacy and safety of systemic (Prednisolone) and topical (budesonide) corticosteroids, which were conducted in children. In the work of A.? Levin et al. [14] 33 patients (mean age 14.3 years) with active CD of mild or moderate activity were randomized into two groups, one of which received Budenofalk® at a dose of 9 for 12 weeks.mg / s, and the other – Prednisolone at a dose of 40 mg / s. The groups did not differ in age, localization, activity and duration of the disease. Remission as calculated by the Pediatric CD Activity Index (PCDAI < 10) at week 12 of treatment was achieved in 9 of 19 (47%) children treated with Budenofalk® and 7 of 14 (50%) treated with Prednisolone. However, side effects were observed in 71% of children treated with Prednisolone, and only 32% - Budenofalk®. The severity of cosmetic side effects was significantly lower with Budenofalk®.

J.?C.?Escher et al. [15] conducted a controlled, multicentre, randomized, double-blind study. Through the joint efforts of the ESPGHAN IBD Working Group, 36 centers from 8 European countries took part in it. The study included 48 patients with newly diagnosed active CD with ileocecal localization, the average age of which was 13 years. Patients were randomized into two groups, one of which received budesonide at a dose of 9 mg/s for 12 weeks, the second received prednisolone at a dose of 1 mg/kg/s for the first 4 weeks, followed by a decrease within 4 weeks to 2.5 mg /With. The first evaluation of the effectiveness was carried out after 8 weeks of treatment to achieve remission (Best index < 150). After 2 weeks of treatment, 50% of children in each group achieved remission. By the 8th week, remission in the group of children treated with prednisolone was observed in 71%, budesonide - in 55%, after 12 weeks, remission was maintained in 55% of patients treated with budesonide, and decreased to 60% in the group of children treated with prednisolone. Thus, as in the study by A.? Levin, there were no significant differences in the effectiveness of systemic and topical steroids in the treatment of active CD in children.

Side effects of budesonide, according to a multicenter study by J.?C.?Escher [15], were observed in children much less frequently than with the appointment of Prednisolone, as in our study, only a slight moon-shaped face, occasionally hirsutism and mood changes were noted. Suppression of the function of the adrenal cortex, according to the morning level of plasma cortisol, was practically not observed with the appointment of budesonide, in contrast to Prednisolone. A retrospective assessment of the growth of prepubertal children treated with budesonide showed that their growth rate corresponded to the lower age limit of the norm (2 cm/year) [16].

A meta-analysis of studies conducted in adults showed that budesonide is more effective than mesalazine, but is equal to or slightly inferior to the effectiveness of systemic corticosteroids in the treatment of CD with moderate ileocecal localization [17]. However, all studies conducted in adults have shown a significantly lower number of side effects of budesonide compared with systemic corticosteroids. Based on these data, the European Association for the Study of CD and UC (ECCO) recommends budesonide as the drug of choice for mild to moderate ileocecal CD [5].

Maintenance therapy with budesonide in remission has not been prospectively studied in children. Systemic corticosteroids at low doses have been ineffective in maintaining remission, and since their long-term use is associated in children with impaired growth and mineralization of bones, the recommended course of systemic corticosteroids in IBD exacerbations should not exceed 3 months. A meta-analysis of 4 randomized placebo-controlled trials in adults with CD showed that maintenance therapy with budesonide 6 mg/s is not effective in maintaining remission [18] and is not currently recommended in children. Our results allow us to recommend long-term courses of Budenofalk® (at least 6 months at a full dose with a subsequent reduction), in which not only the anti-inflammatory, but also the anti-relapse effect of the drug is realized. Taking into account the high safety profile noted both by us and foreign researchers, long-term administration of Budenofalk® (up to one year) can be used in children with IBD without the risk of developing unwanted side reactions.

Pins

1. The use of topical steroids (Budenofalk®) is effective in moderate activity of Crohn’s disease and ulcerative colitis in children.

2. Budenofalk® more effectively reduces intestinal, but not systemic manifestations of IBD.

3. Adverse reactions in the treatment of Budenofalk® are mild and are reduced to a slight moon-shaped change in the face.

4. Budenofalk® should be given at a starting dose of 9 mg/day for 6 months and reduced only after complete remission.

5. Budenofalk® at a maintenance dose may have an anti-relapse effect.

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E. A. Kornienko *, Doctor of Medical Sciences, Professor
E. A. Lomakina *
N. K. Zaletova *
S. A. Fadina **

* St. Petersburg State Pediatric Medical Academy of Roszdrav ,
** Children’s City Clinical Hospital N.