Treatment options for vulnerable patient populations

Vulnerable patient populations with inflammatory bowel disease (IBD) require individualized and advanced treatment options. For example, the proportion of childless individuals with IBD is increased, often due to inadequate information about pregnancy in IBD. And treatment in older patients also presents special challenges. Diagnosis takes longer and misdiagnosis is also more common.

One of the central concerns that young female and male patients with inflammatory bowel disease (IBD) in particular deal with is the question: Does the disease affect fertility? According to PD Sophie Restellini, MD, Director of the Crohn’s Disease and Colitis Center, Department of Gastroenterology at the Hôpital de La Tour in Geneva, these fears are not well-founded, because if you look at the infertility rate in the general population, it is about 12-18% [1]. Fertility rates are similar in women with Crohn’s disease (CD) and ulcerative colitis (UC) whose disease is in remission and who have never had surgery. Nevertheless, childlessness is common in IBD patients [2,3]. In particular, in Crohn’s disease patients, this is about 17% compared to 6% in the general population.

These numbers reflect the misinformation about pregnancy and IBD in this population, as well as the fear of passing the disease to their own children and the consequences that medication may have on the unborn child. The risks associated with treatment are one of the most common concerns of patients, Restellini points out.

IBD patients of childbearing age should always be asked if they plan to become pregnant in the near future. In this way, the gastroenterologist can take the time to discuss with the patient the safety of the treatments most often used during pregnancy and breastfeeding. He will also have the opportunity to reassess disease activity and achieve remission before conception occurs. Laboratory analysis, inflammatory markers, and endoscopy prior to conception if endoscopic remission has not been previously noted should be part of the workup. This is also a good time to make sure that basic care such as screening for anemia and vitamin deficiencies, updating immunizations, supplementing folic acid, and quitting smoking has been done.

The care of a pregnant IBD patient should be multidisciplinary, including gastroenterologists, IBD nurse, obstetrician, family physician, pediatrician, and surgeon, if appropriate. Communication among these providers is critical to avoid ambivalent or even conflicting advice, which is an additional source of anxiety for patients as well as potentially suboptimal treatment adherence.

Fertility in IBD

Therapies used to treat IBD do not usually affect fertility, with the exception of reversible oligospermia, which can occur with sulfasalazine [1]. Steroids, 5-aminosalycilates, immunomodulators, and biologic drugs do not affect fertility. However, women with active IBD may have decreased fertility, which may be related to decreased sexual activity in dyspareunia in women with severe perianal or pelvic disease, tubal obstruction due to pelvic adhesions, ovarian dysfunction due to inflammation, or malnutrition. In addition, there is evidence that patients who have undergone coloproctomy with ileoanal anastomosis (IPAA) are at increased risk of infertility. In this context, the decrease in fertility is mainly due to inflammation and scarring of the fallopian tubes. On the other hand, if a laparoscopic technique is chosen instead of a laparotomy, this risk is reduced [4].

Assisted reproductive technology

IBD patients who have tried unsuccessfully for six months to become pregnant should be referred for infertility testing, especially if they have had pelvic surgery. With assisted reproductive technology (ART), there is also a good chance for IBD patients to become pregnant. However, ART is not as effective in women with CD and UC as it is in infertile women in the general population and is less effective if the women with CD have already had surgery. Once pregnant, women with CD or UC have an equal chance of having a live birth compared to the general population undergoing ART. In addition, IBD medications have no effect on egg freezing or ART efficacy, as well as hormones used as part of ART have no negative effect on the course of IBD [5,6].

Effects of pregnancy on IBD

Typically, two-thirds of patients remain in remission if conception occurs during remission. Only one-third are at risk of disease flare-up, which is comparable to non-pregnant patients. However, if conception occurs during active disease, only one third of patients have a chance of spontaneous improvement, whereas in two thirds the disease persists or even worsens [4,7]. Especially in ulcerative colitis, there is an increased risk of relapses in both the first and second trimesters.

Effects of IBD on pregnancy

Ideally, the patient is already in remission three months prior to conception to give the pregnancy the best chance of success. Confirmation of remission should be by endoscopy or other objective markers. If this is the case and the disease is dormant, no increase in the rate of congenital anomalies or other adverse events is observed. Active disease, on the other hand, is associated with higher rates of adverse outcomes, including fetal loss and stillbirth, preterm birth, low birth weight, too small for gestational age, thromboembolic events, cesarean section, more frequent neonatal intensive care admissions, and low APGAR score. Adverse events also result from the level of activity and its timing during pregnancy. It is difficult to determine whether disease activity itself or other confounding factors such as treatment discontinuation influence the increased risks. Therefore, it is recommended to control the disease before conception and keep the mother in remission during pregnancy [6,8].

Women with IBD have twice as many cesarean deliveries as women in the general population. Most often, a cesarean section is suggested or requested by patients or caregivers because of unwarranted fears. Also, in most cases there is no contraindication to vaginal delivery, a healthy IBD patient should be able to have a successful vaginal delivery. Episiotomy should be avoided if possible, as it can cause perianal damage. The only contraindications to vaginal delivery are active perianal or rectal disease and/or an open rectovaginal fistula at the time of delivery. In these cases, a planned cesarean section must be performed.

Drug safety during pregnancy

Pregnant and breastfeeding women are generally excluded from clinical trials, and randomized controlled trials of drug safety data are lacking. However, the safety of drugs administered for IBD (with the exception of methotrexate and small molecules) during conception, pregnancy, and lactation has been supported by several cohort studies, databases, and recommendations from U.S. and European experts (PIANO study, DUMBO, Toronto consensus, ECCO Guidelines 2022). Recently, the U.S. Food and Drug Administration abandoned the product letter categories and replaced them with detailed subsections describing available information on potential risks and benefits to the mother, fetus, and breastfed infants [9,10]. Most of the drugs has been classified with a low risk during pregnancy.

The PIANO study, a prospective observational study conducted in North America from 2007 to 2019 and whose results were published last year, also found the risk of medication during pregnancy to be reassuringly low. Thus, use of biologics, thiopurines, or combination therapies (biologics and thiopurines) during pregnancy was not associated with increased maternal or fetal adverse outcomes at birth or in the first year of life. This study confirmed the feasibility of continuing these treatments in women with IBD throughout pregnancy to maintain control of the disease and reduce adverse events associated with a possible flare during pregnancy [11].

Corticosteroids may also be required during pregnancy to treat episodes of disease. Older studies suggested that exposure to steroids during the first trimester may be associated with an increased risk of developing cleft lip and palate. This observation was not reported in a large Danish cohort of patients exposed to any form of corticosteroids during the first trimester (OR 1.05; 95% CI 0.80-1.38) [12]. In the Pregnancy in IBD and Neonatal Outcomes (PIANO) registry, steroid use was associated with an increased risk of certain adverse maternal and fetal events, including preterm birth (OR 1.8; 95% CI 1.0-3.1), low birth weight (OR 2.8; 95% CI 1.3-6.1), and gestational diabetes (OR 2.8; 95% CI 1.3-6.0) [13]. It is difficult to separate the effect of disease activity from a side effect of the drug because the use of corticosteroids reflects that the disease is not in remission. Prolonged exposure should be avoided, and this drug should not be considered as maintenance therapy. Methylprednisolone and hydrocortisone should be the molecules of choice because their increased placental metabolism reduces the risk of fetal exposure compared with dexamethasone or betamethasone. However, in patients taking steroids, blood pressure and blood glucose should be monitored, and serial growth ultrasounds should be performed in the third trimester.

Data on safety in pregnancy with new biologics such as ustekinumab and vedolizumab are far less numerous than with anti-TNFa, but data available to date have not shown any particular alarming signals [14].

Effects of IBD on the infant

A systematic review of anti-TNF use during IBD pregnancies found no increased risk of infection in the infant’s first year of life exposed in utero. However, it is recommended that exposure to antibiotics be minimized, as some data suggest that this may increase the risk of developing celiac disease later in childhood. Infants exposed to biologics in utero may continue to have detectable drug levels six months to one year after birth. This explains why it is recommended that live vaccines be avoided in infants exposed to biologics in the third trimester of pregnancy until six months to one year after birth.

Impact of IBD on children and adolescents

25% of IBD patients are diagnosed before the age of 18. Pediatric IBD patients face unique challenges, such as growth failure and pubertal impairments. Psychological impairments are particularly important in this population.

Treating young adults with IBD is challenging in many ways. The patient must move from a pediatric care setting, where parental presence is central, to an adult care setting that requires autonomy and knowledge of the disease. A relationship of trust must be established so that adverse events, such as loss of sight, discontinuation of treatment, tobacco use, etc., can be avoided during the transition process.

IBD in older adults

Currently, there is no accepted universal definition of the term “Elderly” explains Prof. Dr. med. phil. Gerhard Rogler, Clinic Director for Gastroenterology and Hepatology at the University Hospital in Zurich. Although “elderly/elderly” is often defined in most developed countries as persons 65 years of age or older, there is still some discrepancy from a health care perspective, considering that other age characteristics, such as general health or the presence of comorbidities, may influence physical signs of aging. Evidence that IBD has relatively little impact on lifespan further contributes to the increase in the number of individuals aged >65 years living with IBD. Regardless of age at diagnosis, epidemiologic studies have estimated that approximately 25-35% of individuals with IBD are >60 years of age [15–17].

Overall, there are two distinct groups of older patients with IBD: those who have had IBD for several decades and those who received a diagnosis later in life (IBD in old age). It is estimated that up to 15% of patients were diagnosed after age 60, while up to 20% of these patients were diagnosed earlier and have progressed to older ages. Compared with younger adults, the initial diagnosis of IBD in older adults is generally more difficult and consequently of longer duration. Factors that may account for this difference include access to specialized health care and the prevalence of conditions similar to IBD, which allows for a broader differential diagnosis. Delay in diagnosis can have a negative impact on disease progression in terms of general complications and progression to stricture and/or penetrating disease, with a resulting increase in the need for surgery.

Clinical features

As a rule, the natural course of IBD in old age is less aggressive than in younger patients. Older patients with CD have greater colonic involvement with a lower incidence of strictures and fistulas compared with younger patients, whereas older patients with UC are more likely to experience left-sided or extensive colitis vs. proctitis. Furthermore, in UC patients, the localization of disease tends to remain stable, with only 16% of patients showing spread of disease during the course (Table 1) [18,19].

Although the clinical presentation of the disease often differs between older and younger adults, age-related differences in clinical presentation are more pronounced in CD patients than in UC patients. Compared with younger adults, CD in advanced age presents more often with rectal bleeding and less often with diarrhea, abdominal pain, and weight loss. Conversely, the severity of UC symptoms (especially rectal bleeding and diarrhea) is usually milder in older adults than in younger adults, and the presentation in older adults may be atypical (Table 2) [18–20].

Clearer differences between older and younger adults are also seen on endoscopic examination and (to a lesser extent) histopathology. In general, the presence of isolated colitis with less frequent penetrating or perianal disease is a more common finding in CD with onset at older ages, and small bowel and upper gastrointestinal tract involvement are less common.

Management challenges

Differential diagnosis is one of the most important challenges for disease management, especially in older adults. Several other diseases (such as ischemic colitis, motility disorders, drug side effects, etc.) have clinical features that may partially overlap with those of IBD. This may cause the aforementioned delay in establishing the correct diagnostic procedure or an incorrect diagnosis, which may ultimately lead to inappropriate therapy (Table 3) [21–23].

Comorbidities such as heart disease, diabetes, cancer, psychiatric disorders, and arthritis are often present in older adults with IBD. This contributes to a higher risk of complications and mortality after a severe episode of UC or CD in advanced age. In addition, polypharmacy has the potential to increase the risk of drug-drug interactions. Drugs used to treat IBD may contribute to either triggering or exacerbating concomitant diseases, as in the case of diabetes or psychiatric disease from steroid therapy, worsening of heart failure from anti-tumor necrosis factor (anti-TNF) antibodies, and cancer from immunomodulators (including lymphoma with thiopurines). This may lead to a poorer prognosis and increased risk of IBD-related complications.

Simultaneous administration of multiple medications in a significant proportion of older IBD patients further contributes to reduced adherence to therapy, worsening not only the course of IBD but also of other comorbidities. Use of simplified once-daily medication regimens and avoidance of unnecessary multiple concomitant medications may be associated with improved adherence and clinical outcomes.

Step-Up versus Top-Down Approach

Several approaches that have been established in younger patients can also be applied to the treatment of older IBD patients. In general, a step-up approach has been preferred for many years, adding conventional therapy when first-line treatment is ineffective. For example, oral/topical mesalazine and/or topical corticosteroids are generally used as initial therapy for mild to moderate CD, whereas systemic corticosteroids and biologics are more commonly used for moderate/severe forms. However, studies have shown that a top-down approach using an effective agent early in the disease, such as aggressive treatment with anti-TNF agents, may be associated with a reduction in hospitalizations and surgeries in CD patients, offsetting the lower cost of conventional therapies and with a lower risk of immunogenicity and associated infusion reactions. Therefore, the top-down approach may offer the potential advantage of achieving disease stabilization and minimizing complications leading to surgery while reducing the risk of adverse effects of corticosteroid therapy [24].

Although the medications available to treat IBD in older patients are the same as in younger patients and the effects of medical therapy are not related to age, the rate of response may be slower in advanced age.

Improving communication between the patient and the physician when making decisions about which approach is most appropriate may allow for rapid implementation of the most appropriate disease management on an individual basis. Further studies specifically limited to the elderly population would greatly help to increase knowledge about the characteristics of the disease in advanced age and thus better define the diagnostic process and therapeutic strategy, Rogler concludes.

Take-Home Messages

• The proportion of childless people is higher in IBD, often due to inadequate information about pregnancy in IBD.
• Ideally, stable remission is targeted for 3 months prior to conception.
• Limited data are now available for IBD patients during pregnancy and lactation.
• IBD is relatively common in older patients, with up to 35% of patients with IBD aged ≥60 years.
• Treatment in elderly patients presents unique challenges. Diagnosis takes longer and misdiagnosis is also more common.
• Due to phenotype-related differences and the presence of comorbidities, the treatment of IBD may be different in older patients than in younger patients.

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HAUSARZT PRAXIS 2023; 18(2): 6–11