Health Maintenance Consensus for Adults With Inflammatory Bowel Disease

Abstract

Background

With the management of inflammatory bowel disease (IBD) becoming increasingly complex, incorporating preventive care health maintenance measures can be challenging. The aim of developing these updated recommendations is to provide more specific details to facilitate their use into a busy clinical practice setting.

Method

Fifteen statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. We used a modified Delphi method and a literature review to establish a consensus among the panel of experts. The appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1–2 as inappropriate, and 4–5 as appropriate) by each panelist. Interventions were considered appropriate, and statements were accepted if ≥80% of the panelists agreed with a score ≥4.

Results

The panel approved 15 health maintenance recommendations for adults with IBD based on the current literature and expert opinion. These recommendations include explicit details regarding specific screening tools, timing of screening, and vaccinations for adults with IBD.

Conclusions

Patients with IBD are at an increased risk for infections, malignancies, and other comorbidities. Given the complexity of caring for patients with IBD, this focused list of recommendations can be easily incorporated in to clinical care to help eliminate the gap in preventative care for patients with IBD.

Introduction

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic autoimmune conditions involving the gastrointestinal tract that affect over 3 million adults in the United States.¹ Patients with IBD are at an increased risk of potentially preventable complications and developing other treatable comorbidities that are increasingly associated with IBD. These potential complications can be either due to the disease, in the setting of chronic systemic inflammation, or due to the medications used to treat IBD, which are often immunosuppressive. The potential complications include an increased risk for certain malignancies, new infections or reactivation of latent infections, and developing a decreased bone density.² Further, patients with IBD have been found to have a higher prevalence of anxiety and depression, leading to more health care utilization and disability.^{3, 4} Finally, tobacco use is known to negatively impact overall health; but in patients with Crohn’s disease, smoking has been shown to be associated with a higher risk of stricturing and perianal disease.⁵

Despite the increased risk of these potential complications, patients with IBD have been shown to be less likely to receive preventive care, as neither primary care providers (PCPs) nor gastroenterologists want to assume this responsibility. In a survey study of 108 gastroenterologists, only 52% obtained an immunization history for their IBD patients, 64% indicated that the PCP should be responsible for determining which vaccinations are needed, and 83% indicated that the PCP should administer the vaccines.⁶ In contrast, in a survey of family physicians, only 29% felt comfortable assuming responsibility for the preventative care for their IBD patients.⁷

Because of this inconsistency in providing preventive care for IBD patients, several GI societies have provided health maintenance guidelines for patients with IBD.^{8, 9} Despite these guidelines, compliance with health maintenance recommendations—particularly vaccinations—remains low.¹⁰ The objective of providing these updated health maintenance recommendations for adults with IBD was to achieve expert consensus on the appropriate evidence-based health maintenance practices that can be incorporated in to the routine clinical care of adults with IBD. We elected to focus our recommendations on the areas where patients with IBD are known to have an increased risk and not on the screening or vaccinations (such as vaccination for Hepatitis B and human papilloma virus) that are recommended for the general population. Hence, we would like to emphasize that other than the specific preventative care topics covered in this article and live vaccines in immunosuppressed patients, the screening and vaccination schedules recommended for the general US population also apply to IBD patients.

METHODS

Study Overview

We used a modified Delphi method, which is an iterative process that combines the best available evidence and the collective judgement of a group of experts to determine the appropriateness of processes of care in medicine as previously described.^{11, 12}

Literature Review

We performed a literature search using MEDLINE from inception to November 2019 using the MESH terms “ulcerative colitis,” “Crohn’s disease,” and “inflammatory bowel disease” and keywords from the subjects of interest: vaccination, immunization, specific infections and vaccines, cancer screening, cancer surveillance, colon cancer, cervical cancer, melanoma, nonmelanoma skin cancer, osteoporosis, smoking, anxiety, and depression. The search was limited to randomized controlled trials, cohort studies, and systematic reviews and meta-analyses. If these were unavailable on a topic of interest, case-control studies were included.

Based on the literature review, 15 health maintenance statements were formulated with recommendations regarding the target, timing, and frequency of the health maintenance interventions in patients with IBD. These statements were presented with the summary of the literature to the panel of experts before the first round of voting on the appropriateness of each intervention.

Appropriateness Panel

The panel consisted of 14 members of the Crohn’s and Colitis Foundation Professional Education Committee. The panelists included adult gastroenterologists, pediatric gastroenterologists, and colorectal surgeons with a special interest in IBD from both academic and private practice settings across the United States. The panel met in person on January 23, 2020, for the first round of voting. Appropriateness of each health maintenance statement was rated on a scale of 1 to 5 (1–2, inappropriate; 3, uncertain; and 4–5, appropriate) by each panelist. Interventions were considered appropriate and statements were accepted if 80% or more of the panelists agreed with a score ≥4. If less than 80% of the panelists agreed with a score ≥4, statements were discussed and revised based on the available evidence. These statements were then presented to the panel for a second round of voting that took place via a web-based survey in April 2020. In this round, the panelists rerated each statement and had the opportunity to modify their original rating, if desired. In both of the rounds, voting was confidential, and agreement among the panelists was not required. The final consensus document was subsequently formulated, which was reviewed and approved by the panelists via a video conference call on May 21, 2020.

RESULTS

The panel reached a consensus on all 15 statements (Table 1).

TABLE 1.

Health maintenance recommendations in individuals with IBD

	Statement	Percentage Vote Agreement
	Vaccination
1	All patients >6 months of age should receive annual inactivated influenza vaccine, irrespective of immunosuppression status	100% (14/14)
2	All patients >19 years of age receiving systemic immunosuppression* should receive PCV13, followed by PPSV23 at least 8 weeks later; patients <65 years need a booster of PPSV23 5 years later.	100% (14/14)
3	For varicella, seroprotection status should be checked with varicella zoster virus IgG antibodies in all patients without documented vaccination record or exposure. All patients who are not immune should receive 2-dose series, 4–8 weeks apart, ≥4 weeks before immunosuppression, if therapy can be postponed.	100& (14/14)
4	All patients receiving JAK inhibitor therapy should receive the recombinant adjuvanted zoster vaccine. Risk of zoster should be considered with combinations of other immunosuppressive* therapies.	100% (14/14)
5	IBD patients not immune to MMR should receive a 2-dose series, at least 4 weeks apart. If immune status is uncertain, IgG antibody titer should be checked. MMR should not be given to patients currently on systemic immunosuppressive* therapy.	100% (14/14)
Tuberculosis
6	All patients with IBD should undergo screening for latent TB at baseline. Clinical risk assessment for TB exposure should be performed annually in all patients with IBD.	86% (12/14)
Cancers
7a	All IBD patients with extensive colitis (>1/3 of the colon) for ≥8 years should undergo surveillance colonoscopy every 1 – 3 years, depending on cancer risk.	100% (14/14)
7b	IBD patients with a diagnosis of PSC should undergo colonoscopy starting at the time of PSC diagnosis, and annually thereafter.	100% (14/14)
7c	IBD patients with features that are high-risk for developing colon cancer (ie, prior history of adenomatous polyps, dysplasia, family history of colon cancer and extensive colitis) should have colonoscopies more frequently than every 3 years.	100% (14/14)
8	All women with IBD who are being treated with systemic immunosuppression* should undergo cervical cancer screening by cytology annually (if cytology alone) or every 3 years (if HPV negative).	100% (14/14)
9	All IBD patients being treated with systemic immunosuppression* should have annual total body skin exams to screen for skin cancer.	86% (12/14)
Osteoporosis
10a	All IBD patients should be screened for osteoporosis by central (hip & spine) DEXA if ANY risk factors for osteoporosis (ie, low BMI, >3 months cumulative steroid exposure, smoker, post-menopausal, hypogonadism) are present and it should be repeated in 5 years.	100% (14/14)
10b	Patients who have normal initial BMD assessment should undergo repeat testing in 5 years.	86% (12/14)
Depression and anxiety
11	All patients with IBD should be screened for depression (PHQ9) and anxiety (GAD7) at baseline, and annually. Patients who screen positive should be referred for counseling/therapy.	86% (12/14)
Smoking
12	All patients with IBD should be screened for smoking status at baseline, and current smokers should be referred for smoking cessation therapy.	100% (14/14)

*Systemic immunosuppression refers to current treatment with prednisone (>20 mg/day for more than 14 days), azathioprine (>2.5 mg/kg/day), mercaptopurine (>1.5 mg/kg/day), methotrexate (>0.4 mg/kg/week), cyclosporine, tacrolimus, infliximab, adalimumab, golimumab, certolizumab, ustekinumab or tofacitinib.

Vaccination

All patients >6 months of age should receive annual inactivated influenza vaccine, irrespective of immunosuppression status.

Patients with IBD are at an increased risk of influenza and its complications. A US administrative data-based study showed that the risk of influenza among IBD patients was 1.5-times that of non-IBD controls, and corticosteroid use was independently associated with a 1.2-fold increase in the risk.¹³ Moreover, IBD patients with influenza were at an increased risk of getting coinfection with pneumonia and requiring hospitalization. Unfortunately, despite the increased risk, the influenza vaccination rates among IBD patients remain low, suggesting opportunities for improvement.^{14, 15}

Multiple studies have shown that the influenza vaccination in children and adults with IBD is safe and generally yields good serological response.¹⁶ However, immunosuppressive therapy, particularly a combination of biologic and immunomodulator therapy, can blunt the influenza vaccine–induced immune response.^16–18 Nonetheless, it still leads to appropriate serological response in a significant proportion of these patients and is likely to be beneficial. Hence, the Advisory Committee on Immunization Practices (ACIP) guidelines recommend that all IBD patients older than 6 months of age should receive quadrivalent inactivated vaccine regardless of their immunosuppression status. Recent evidence suggests that high dose trivalent influenza vaccine might improve serological response compared with standard dose trivalent vaccine in IBD patients on antitumor necrosis factor (anti-TNF) therapy, but it requires further validation.¹⁹ Live attenuated influenza vaccine should be avoided in patients with IBD who are on immunosuppressive therapy due to the theoretical risk of inducing an infection.

All patients >19 years age receiving systemic immunosuppression should receive PCV13 followed by PPSV23 at least 8 weeks later, and those <65 years at the time of vaccination should receive a booster of PPSV23 5 years later.

The risk of pneumonia is increased 1.5- to 2-fold in patients with both UC and CD compared with non-IBD controls. This risk is particularly elevated in IBD patients older than 60 years of age and those on immunosuppressive therapy. Corticosteroid (odds ratio [OR], 3.62; 95% confidence interval [CI], 3.30–3.98) and anti-TNF drugs (OR, 1.28; 95% CI, 1.08–1.52) are associated with an increased risk of pneumonia, and thiopurines are associated with an increased risk of invasive pneumococcal disease (hazard ratio [HR] 2.38; 95% CI, 1.00–5.67) in IBD patients. The rates of vaccination against pneumococcal disease are dismal in IBD patients, even lower than influenza vaccination rates.¹⁵

Pneumococcus vaccination is licensed in the United States as the 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar13, Pfizer) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax, Merck and Co). Studies in IBD have shown that patients on immunosuppressive therapy, particularly the ones on a combination of anti-TNF and immunomodulator agents, have a blunted immune response to pneumococcal vaccination compared with patients not on immunosuppressive therapy.^{20, 21} A majority of IBD patients on immunosuppressive therapy are still able to mount an appropriate serological response after vaccination. To obtain broad protection against the most common and virulent strains, the Infectious Diseases Society of America (IDSA) recommends all adults 65 years of age and older and adults 19 to 65 years of age who are on immunosuppressive therapy receive both PPSV23 and PCV13 vaccines.²² The recommended schedule is a single dose of PCV13 followed by a single dose of PPSV23 at least 8 weeks later. Those who are younger than 65 years at the time of the initial vaccination should receive a booster dose of PPSV23 5 years later.²² Those who first receive PPSV23 should receive PCV13 at least 1 year after PPSV2322.

Note, systemic immunosuppression refers to current treatment with prednisone (>20 mg/day for more than 14 days), azathioprine (>2.5 mg/kg/day), mercaptopurine (>1.5 mg/kg/day), methotrexate (>0.4 mg/kg/week), cyclosporine, tacrolimus, infliximab, adalimumab, golimumab, certolizumab, ustekinumab or tofacitinib.

For varicella, seroprotection status should be checked with varicella zoster virus IgG antibodies in all patients without documented vaccination record or exposure. All patients who are not immune should receive 2-dose series, 4–8 weeks apart, ≥ 4 weeks before immunosuppression, if therapy can be postponed.

Varicella or chickenpox is a highly contagious infection caused by varicella-zoster virus (VZV) that can be spread by direct contact, inhalation of aerosols from vesicular fluid of skin lesions of acute varicella or zoster, and respiratory secretions of infected individuals. Patients with IBD seem to be at an increased risk of varicella-related complications. In a cross-sectional inpatient database pediatric study, diagnoses of CD (OR, 12.75; 95% CI, 8.30–19.59) and UC (OR, 4.25; 95% CI, 1.98–9.12) were independently associated with varicella-related hospitalizations.²³ Immunosuppressive conditions (malignancy, HIV, or a disorder of immunity) were associated with a 4.6-fold increase in the risk of hospitalization related to varicella.²³ Patient recall of exposure to varicella is often inaccurate, and studies have shown that a substantial proportion of patients have no measurable VZV IgG titer despite reported exposure and vice versa.^24–26 However, because the currently available commercial VZV serological assays are not accurate enough to evaluate for vaccine-induced immunity, a sincere attempt should be made to obtain documentation of prior exposure or vaccination whenever possible.²⁷ Varicella-zoster virus IgG should be checked in IBD patients without documented exposure or vaccination, and those found to be nonimmune should be vaccinated against varicella.

Varicella vaccine is a live attenuated vaccine. In children 13 years of age and older and adults who have no documented evidence of immunity in the form of IgG VZV antibodies in the serum or prior varicella infection are recommended to receive 2 doses of varicella vaccine 4 to 8 weeks apart.²⁸ The data on safety of varicella vaccination in immunocompromised IBD patients is limited to a case series of 6 children on thiopurine, anti-TNF or a combination of both who developed no adverse effects after receiving varicella vaccine.²⁹ Similarly, in a study of 25 children with rheumatic diseases who were receiving methotrexate and corticosteroids, no adverse effects of varicella vaccination were observed.³⁰ Nevertheless, the IDSA does not recommend varicella vaccination in patients on high-intensity immunosuppression (including treatment with anti-TNF medications or daily corticosteroid therapy with a dose of ≥20 mg of prednisone for ≥14 days) based on reports of death, VZV reactivations, and systemic reactions in children on chemotherapy.³¹ It recommends an interval of >4 weeks between varicella vaccination and initiation of immunosuppressive therapy based on the fact that replicating VZV clears completely after 3 weeks. Based on this, in patients who are not immune to varicella and are awaiting initiation of immunosuppressive therapy, therapy should be postponed until 4 weeks after completion of 2 doses of varicella vaccination if medically appropriate.

All patients receiving JAK inhibitor therapy should receive the recombinant adjuvanted zoster vaccine. Risk of zoster should be considered with combinations of other immunosuppressive therapies.

Herpes zoster (HZ), also known as shingles, is caused by reactivation of herpes-zoster (HZV) and presents as a painful, maculopapular rash commonly involving one or 2 dermatomes. It is a common condition, and roughly 1 in 3 people in the United States develops shingles in their lifetime. Multiple studies have shown that patients with IBD (both UC and CD) are at an increased risk of developing shingles than individuals without IBD.^32–34 Though the risk is highest in older IBD patients, it is increased even in younger patients.³² Immunosuppressive drugs used for treatment of IBD, including corticosteroids, thiopurines, and anti-TNF agents, are independently associated with a 1.5- to 2-fold increase in the risk of shingles. However, the risk seems to be highest in those who are on combination therapy (OR, 3.29; 95% CI, 2.33–4.65).^{32, 33} Tofacitinib, a novel small molecule Janus kinase (JAK) inhibitor that was recently FDA-approved for treatment of moderate to severe UC, is also associated with an increased HZ risk, particularly in patients with older age and those treated with 10 mg of tofacitinib twice daily.³⁵ The magnitude of risk of HZ with tofacitinib seems to be higher than with other medications used to treat IBD. In the tofacitinib maintenance randomized controlled trials and open label long-term extension studies in UC, the incidence rate of HZ was 4.07 (3.14–5.19) per 100 patient-years in patients who received tofacitinib compared with 0.97 per 100 patient-years in patients who received placebo.³⁵ In comparison, in a large nationwide cohort study of US veterans with IBD, the incidence rates of HZ infection on thiopurine monotherapy, anti-TNF therapy, and combination therapy were 1.1, 1.0, and 1.5 per 100 patient-years, respectively..³⁴ In a comparative risk study in patients with rheumatoid arthritis, the risk of HZ in patients treated with tofacitinib was higher than those treated with other biologic agents, including anti-TNF drugs.

Currently, there are 2 HZ vaccines approved in the United States—the live attenuated vaccine (Zostavax, Merck and Co, Inc.) licensed for use in 2006 and the more recent recombinant zoster vaccine (Shingrix, GlaxoSmithKline Biologicals) approved in 2017. Because of its greater efficacy, the ACIP now recommends the recombinant zoster vaccine over the live attenuated vaccine. Per ACIP recommendation, all adults 50 years of age and older should receive 2 doses of recombinant zoster vaccine 2 to 6 months apart irrespective of prior receipt of live attenuated zoster vaccine and without screening for a history of varicella. Though there is no current evidence of efficacy of recombinant zoster vaccine in patients with IBD, vaccination with live attenuated zoster vaccine was associated with reduced risk of HZ compared with no vaccination (adjusted HR, 0.54; 95% CI, 0.44–0.68) in a retrospective study of US veterans with IBD.³⁶ The recombinant zoster vaccine is safe to be given in patients on immunosuppressive therapy, though its effectiveness might be reduced in such patients.³⁷ Based on the available data, all patients with IBD 50 years of age and older and those receiving JAK inhibitor therapy should receive the recombinant adjuvanted zoster vaccine. In other high-risk groups like IBD patients on a combination of an anti-TNF agent and an immunomodulator, the vaccination against HZ should be considered on an individual basis. As the sale of live attenuated zoster vaccine in the United States stopped on July 1, 2020, we did not discuss its safety and cannot recommend it for IBD patients.

IBD patients not immune to MMR should receive a 2-dose series, at least 4 weeks apart. If immune status is uncertain, IgG antibody titer should be checked. MMR should not be given to patients currently on systemic immunosuppressive therapy.

The MMR vaccine is a live attenuated vaccine that protects against measles, mumps, and rubella, which are highly contagious viral infections. With the implementation of a universal immunization program in the United States, infections with these 3 viruses have reduced by more than 99% compared with the prevaccination era. Though there is no data on the risk of measles, mumps, and rubella infections in patients with IBD, immunosuppressed individuals are known to be at an increased risk of complications from measles.³⁸ Despite universal MMR vaccination programs, MMR vaccination rates are 89% to 93% in patients with IBD.^{39, 40} Studies also suggest that a substantial proportion of IBD patients, including those on immunosuppressive therapy, do not have protective antibody titers against measles, mumps, and rubella.^{40, 41}

The ACIP recommends that certain high-risk populations (HIV-infected patients without evidence of severe immunosuppression, household contacts of immunosuppressed individuals, health care workers, international travelers, and students at post-high school educational institutions) with no presumptive evidence of immunity (laboratory serological testing, documentation for vaccination, laboratory-confirmed disease, or being born before 1957) should receive MMR vaccinations with 2 doses each separated by at least 4 weeks.³¹ It should be noted that because the commercial serological assays for immunity against measles, mumps, and rubella have low sensitivity, an attempt should be made to obtain documentation of vaccination or a record of laboratory confirmed disease, whenever feasible.³¹ Because a significant proportion of IBD patients require immunosuppressive therapy, they should be considered a high-risk population and should be assessed for presumptive evidence of immunity and vaccinated with 2 doses of MMR in its absence. In patients whose immune status is uncertain, IgG antibody titer against measles, mumps, and rubella should be checked.

Because the MMR vaccine is a live attenuated vaccine, there is a theoretical concern of inducing an infection with vaccination in immunocompromised individuals. However, in a systematic review of randomized trials, observational studies, and case reports, 474 patients with immune-mediated inflammatory diseases, many of whom were on immunosuppressive therapy, received MMR vaccine, and only 1 patient developed a rash and fever presumed to be related to the disease.⁴² There is also a report of a patient on vedolizumab therapy for CD being successfully and safely vaccinated with MMR.⁴³ Nonetheless, due to lack of safety data in immunosuppressed patients, the CDC and IDSA recommends against MMR vaccination in subjects on either low level or high level immunosuppression.³¹ The MMR vaccine, like other live attenuated vaccines, can be safely administered ≥4 weeks before initiation of immunosuppressive therapy.³¹ A study in IBD patients on immunosuppressive therapy who previously received MMR vaccine showed that all patients had measurable antibody concentrations to the 3 viruses, which were comparable with health controls. This suggests that immunosuppressive therapy does not affect the maintenance of immunity after MMR vaccine in IBD patients.⁴⁴

Tuberculosis

All patients with IBD should undergo screening for latent TB at baseline. Clinical risk assessment for TB exposure should be performed annually in all patients with IBD.

A majority of individuals infected with Mycobacterium tuberculosis either clear the infection or develop latent infection, wherein the tuberculosis (TB)-causing bacteria lives dormant in the lungs of the infected individual. Around 5% to 10% of persons with latent TB (LTB) will go on to develop active TB at some time in their lives. Host defense against mycobacteria rely on the granulomatous response comprising macrophages, multinucleated giant cells, and necrotic debris surrounded by macrophages and lymphocytes that sequester the TB-causing bacilli. Tumor necrosis factor-alpha is critical for macrophage activation, cell recruitment at the site of infection, and continued function of the granuloma.⁴⁵ Hence, anti-TNF agents increase the risk of reactivation of latent TB. Before the widespread screening for latent TB prior to the initiation of anti-TNF therapy, the incidence of TB in patients treated with infliximab was around 1 per 100 patient-years.^{46, 47} With the implementation of screening for LTB before anti-TNF initiation, the risk is much lower, at 30 to 50 cases per 100,000 patient-years.^{47, 48} Similarly, the immune response mediated by T helper (Th)-1 cytokines interferon (IFN)-γ/interleukin (IL-) 12/IL-23 is important for host protection against intracellular pathogens such as Mycobacteria, and individuals with inborn defects in this pathway are particularly predisposed to mycobacterial infections.^{45, 49} Despite the theoretical risk with ustekinumab use, only 1 case of TB that was deemed unrelated to the study drug was reported in randomized controlled trials (RCTs) or long-term extension (LTE) studies in CD.⁵⁰ Only 2 cases of TB in patients with psoriasis treated with ustekinumab have been reported in literature.^{51, 52} Given the broad immune effects of JAK inhibition on cell-mediated immunity, tofacitinib is also associated with an increased TB risk. The incidence rate of TB in patients with rheumatoid arthritis on tofacitinib in phase 2 or 3 clinical trials and LTE studies was 170 to 210 per 100,000 patient-years.^{53, 54} Prolonged systemic corticosteroid therapy, suppressing tuberculin activity, can also be a risk factor for reactivation of latent TB.⁵⁵ Due to the increased risk of TB associated with immunosuppressive medications, including corticosteroids that are commonly used to treat IBD, and the potential for a change in therapy in the future, all IBD patients should be screened for latent TB at baseline.

Latent TB screening does not entirely prevent TB, and a small proportion of patients can develop TB while under anti-TNF treatment in populations with low TB risk.⁵⁶ This proportion can be as high as 20% in intermediate TB risk populations.⁵⁷ Thus, annual clinical risk assessment for TB exposure should be done in all IBD patients, and those with high risk should be retested for LTB. In IBD and other immune-mediated inflammatory diseases, interferon-gamma release assays (IGRA) perform better than tuberculin skin test an,d hence, are the preferred method of screening for LTB.^{58, 59} However, the IGRAs can be falsely negative or indeterminate in patients on immunosuppressive therapy.^{60, 61}

Cancers

Colorectal cancer surveillance in IBD

• a) All IBD patients with extensive colitis (>1/3 of the colon) for ≥8 years should undergo surveillance colonoscopy every 1 to 3 years, depending on cancer risk.

• b) Inflammatory bowel disease patients with a diagnosis of primary sclerosing cholangitis (PSC) should undergo colonoscopy, starting at the time of PSC diagnosis and annually thereafter.

• c) Inflammatory bowel disease patients with features that are high risk for developing colon cancer (ie, prior history of adenomatous polyps, dysplasia, family history of colon cancer, and extensive colitis) should have colonoscopies more frequently than every 3 years.

The risk of colorectal dysplasia and colorectal cancer (CRC) is increased in patients with IBD. In a meta-analysis, the annual incidence of CRC was estimated to be 0.16 (95% CI, 0.14–0.18) in UC, with a cumulative incidence of 0.9% at 10 years, 4% at 20 years, and 8.4% at 30 years from UC diagnosis.⁶² This risk of CRC is similarly increased in patients with CD who have extensive colonic involvement.⁶³ The risk factors independently associated with CRC in IBD include extensive colitis (at least 1/3 colon involvement), long-standing disease duration (>8 years), severity of inflammation, PSC, and family history of CRC.^63–66 Unlike IBD patients without PSC, in whom the risk of CRC increases 8 to 10 years after diagnosis, the risk of CRC in patients with IBD and PSC seems to increase within 2 years after the discovery of coexistence of the 2 diseases.⁶⁷ Patients with a prior diagnosis of colitis-associated, low-grade dysplasia (LGD) or high-grade dysplasia (HGD) are also at an increased risk of CRC, with a cumulative risk of 8.5% at 10 years with LGD and 24% with HGD.⁶⁸

There are no randomized controlled trials studying the effect of CRC surveillance in IBD. However, data from observational studies suggest that surveillance programs for CRC in patients with IBD can reduce the risk of CRC and CRC-related death. A Cochrane meta-analysis of 5 observational studies showed a significantly higher rate of cancer detection in the nonsurveillance group compared with the surveillance group (3.17% vs 1.83%; OR, 0.58; 95% CI, 0.42–0.80; P = 0.0009).⁶⁹ Death rate associated with CRC was also higher in the nonsurveillance group compared with the surveillance group (22% vs 8%; OR, 0.36; 95% CI, 0.19–0.69; P = 0.002) in 4 of these studies. Lastly, the pooled rate of early stage CRC (Dukes stage A and B) in the surveillance cohort was higher compared with the nonsurveillance cohort (16% vs 8%; OR, 0.46; 95% CI, 0.08–2.51; P = 0.37) in 2 studies. Hence, all IBD patients with extensive colitis should undergo regular surveillance colonoscopies at 1-year to 3-year intervals starting 8 years from the time of diagnosis. Because there is lack of specific data to guide colonoscopy intervals for CRC surveillance in IBD—except in patients with IBD and PSC—the surveillance intervals should be determined by the presence of risk factors for CRC. Those at high risk should undergo colonoscopies at intervals less than every 3 years. In patients with PSC and IBD, annual surveillance colonoscopies should be performed starting at the time of the diagnosis of their coexistence.

All women with IBD who are being treated with systemic immunosuppression should undergo cervical cancer screening by cytology annually (if cytology alone) or every 3 years (if HPV negative).

Almost all cases of cervical cancer are linked to persistent infection with oncogenic human papillomavirus (HPV).⁷⁰ Women with HIV infection and those on long-term immunosuppressive therapy after organ transplantation have an increased risk of HPV infection, decreased rate of clearance of HPV infection, and increased rates of cervical dysplasia and cancer.⁷¹ Several studies have shown that women with IBD have an increased risk of developing both low-grade and high-grade cervical dysplasia and have identified immunosuppressive therapy as an independent risk factor for the development of dysplasia.^72–74 In a meta-analysis of 77,000 women with IBD, the adjusted odds ratio of cervical high-grade dysplasia and cancer in those on immunosuppressive therapy compared with healthy controls was 1.34 (95% CI, 1.23–1.46).⁷⁵ Unfortunately, despite the increased risk, women with IBD, particularly those on immunosuppressive therapy, are screened less frequently than the recommended interval of 3 years for women without IBD.^{76, 77}

With the availability of cervical cancer screening programs and HPV vaccination, the incidence of cervical cancer and related death has significantly decreased in developed countries. In a study based on SEER data from 1976 to 2009, a significant decrease in the incidence of both early-stage and late-stage cervical cancer was observed. After adjusting for prescreening era rates of cervical cancer, it was estimated that Pap smears were associated with a reduction of between 105,000 to 492,000 cases of cervical cancer over the past 3 decades in the United States.⁷⁸ Based on the increased risk of cervical dysplasia and cancer among women with HIV, the American College of Obstetrics and Gynecology recommends screening with cervical cytology annually in women younger than 30 years of age and with annual cytology alone or with co-testing (cytology and HPV) every 3 years in women older than 30 years.⁷⁹ No studies or major society recommendations exist to guide cervical cancer screening in women who are immunocompromised because of non-HIV causes, including women with IBD on immunosuppressive therapy. However, it is reasonable to extrapolate the recommendations for women with HIV infection to this group.

All IBD patients being treated with systemic immunosuppression should have annual total body skin exams to screen for skin cancer.

Melanoma and nonmelanoma skin cancers (NMSCs) have been well recognized as malignant complications of immunosuppressive therapy in patients in IBD. Studies have shown an increased risk of melanoma (incidence rate ratio (IRR), 1.29; 95% CI, 1.09–1.53) and NMSC (IRR, 1.46; 95% CI, 1.40–1.53) in patients with IBD compared with non-IBD controls.⁸⁰ A nested case-control study showed an increase in the risk of melanoma associated with anti-TNF medication use (adjusted OR, 1.88; 95% CI, 1.08–3.29), whereas no significant association of melanoma was noted with thiopurine or 5-ASA.⁸¹ The study also found an increased risk of NMSC with any thiopurine use (adjusted OR, 1.85; 95% CI, 1.66–2.05) but not with anti-TNF use. A meta-analysis of population-based studies found that the risk of developing NMSC with thiopurine use in IBD patients was 1.83 (95% CI, 1.2–2.80).⁸² In the French CESAME cohort, the risk of NMSC in IBD patients on thiopurines was increased with an HR of 5.9 (95% CI, 2.1–16.4) and remained elevated at 3.9 (95% CI, 1.3–12.1) even after thiopurine drugs are discontinued.⁸³

There are no randomized controlled trials to assess the effectiveness of skin cancer screening in patients with IBD. However, early detection of skin cancer can result in diagnosis at an earlier stage when the disease is more easily treatable, especially melanoma.⁸⁴ Based on these data, all IBD patients on systemic immunosuppressive therapy should undergo a total body skin exam to screen for melanoma and NMSC annually. A cost-effectiveness study showed annual skin cancer screening in patients with CD to be cost-effective for NMSC.⁸⁵ In another study, though annual skin examination for melanoma was effective, it costs $143,959 per quality-adjusted life year gained.⁸⁶ Though no studies have confirmed this, it is plausible that if the skin cancer screening is directed only toward patients on immunosuppressive therapy who are at an increased risk, it might prove to be cost-effective.

Osteoporosis

Osteoporosis screening

a) All IBD patients should be screened for osteoporosis by central (hip and spine) DEXA if any risk factors for osteoporosis (ie, low BMI, >3 months cumulative steroid exposure, smoker, postmenopausal, hypogonadism) are present.

b) Patients who have normal initial BMD assessment should undergo repeat testing in 5 years.

Individuals with IBD are at an increased risk of developing osteopenia and osteoporosis due to several factors including type of IBD, age, current and recent corticosteroid use, malnutrition, vitamin D deficiency, calcium malabsorption, immobilization, and underlying inflammatory state.^{87, 88} The prevalence of osteoporosis in IBD in the published literature varies from 15% to 40% based on the study population, location, and design.^{87, 89–91} In a population-based study, the risk of hip fractures was increased in patients with CD (risk ratio (RR), 1.68; 95% CI, 1.01–2.78) compared with non-IBD controls.⁹² Another study showed that persons with IBD had a significantly increased risk of fractures of the spine, hip, wrist/forearm, and an overall 41% increase in the risk of any of these fractures.⁹³ Inflammatory bowel disease has also been associated with a statistically significant, albeit small, decrease in the bone mineral density as measured by T-score; the risk is increased in CD more than UC.⁹⁴ A meta-analysis showed a 38% absolute increase in fracture risk in individuals with IBD compared with controls. The risk was increased 2.26 times for vertebral but not other fractures.⁹⁵

No studies have been conducted thus far to evaluate the benefit of bone mineral density screening in individuals with IBD. Data for the benefit of bone mineral density (BMD) screening in women from the general population age 70 to 85 years comes from the SCOOP trial, which was an RCT comparing BMD screening to usual management. Screening did not reduce the incidence of all osteoporosis-related fractures or all clinical fractures at 5 years but was associated with a decrease in the incidence of hip fractures (HR, 0.72; 95% CI, 0.59–0.89) compared with usual management.⁹⁶ United States Preventive Services Task Force (USPSTF) recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older and in postmenopausal women younger than 65 years at an increased risk of osteoporosis as determined by a formal clinical risk prediction tool.⁹⁷ Given the increased risk of abnormal bone mineral density and osteoporosis-related fractures, individuals with IBD and at least 1 risk factor should undergo screening for osteoporosis. Guidance on the frequency of BMD testing for osteoporosis screening in older women (65 years and older) comes from a large prospective study that showed that after an initial normal screen, osteoporosis develops in less than 10% of women at 15 years.⁹⁸ However, in individuals with IBD who have at least 1 of the aforementioned risk factors, the risk of osteoporosis development is likely higher than women 65 years of age and older without IBD. Hence, it is reasonable to repeat BMD testing after 5 years in individuals with IBD and risk factor(s) for osteoporosis who have normal initial BMD testing.

Depression and Anxiety

All patients with IBD should be screened for depression (PHQ9) and anxiety (GAD7) at baseline and annually. Patients who screen positive should be referred for counseling/therapy.

Depression and anxiety are common in individuals with IBD. A systematic review noted the rates of depression and anxiety to be higher in patients with IBD at 21.2% and 19.1%, respectively, than in healthy controls. Interestingly, the rates of depression (34.7% vs 19.9%) and anxiety (66.4% vs 28.2%) were higher in active IBD than in inactive IBD. No difference was seen in the rate of depression in CD and UC.⁹⁹ Other risk factors for depression include female sex, lack of social support, and corticosteroid therapy.¹⁰⁰ Depression in IBD patients is associated with an increased risk of 90-day readmissions,¹⁰¹ surgeries, and unnecessary CT scans and colonoscopies.¹⁰² In one study, depression was associated with a $17,706 increase in mean annual IBD-related health care costs and an increased incidence of emergency visits (adjusted IRR, 1.5; 95% CI, 1.5–1.6). Of the screening tools for depression, patient health questionnaire-9 has the highest sensitivity in patients with IBD.¹⁰³ Given the high prevalence of anxiety and depression in individuals with IBD, all patients with IBD should be screened for both at baseline and then annually.

A systematic review and meta-analysis of psychotherapy in patients with IBD showed a short-term improvement in depression scores and quality of life compared with controls. Cognitive behavioral therapy was the only form of psychotherapy that had a significant beneficial effect (RR, 0.37; 95% CI, 0.02–0.72) on quality of life.^{104, 105} In another study, baseline antidepressant use had a trend toward lower rates of escalation of medical therapy (HR, 0.59; 95% CI, 0.35–1.00; P = 0.05).¹⁰⁶ A recent Cochrane meta-analysis concluded that the effect of antidepressants on anxiety and depression in IBD patients was uncertain.¹⁰⁷ Similarly, the effect of antidepressants on maintenance of clinical remission and endoscopic relapse was uncertain. Due to its possible benefit, all patients who screen positive for depression and/or anxiety should be referred for psychotherapy.

Smoking

All patients with IBD should be screened for smoking status at baseline, and current smokers should be referred for smoking cessation therapy.

Smoking has been shown to increase the risk of development of CD (OR, 2.0; 95% CI, 1.65–2.47) and negatively affect its disease course. Crohn’s disease patients who smoke are more likely to develop extraintestinal manifestations, complications, have a higher rate of hospitalization, exhibit poor response to treatments, and have a greater need for surgery.^108–111 Clinical and endoscopic CD recurrence rates after ileal resection are also significantly higher in smokers.¹¹² The proposed mechanisms for this effect on CD include mucosal damage, changes in gut permeability, and impaired mucosal immune response.¹¹³ On the contrary, cigarette smoking seems to have a protective effect on the development of UC114, and the risk of developing UC increases after smoking cessation.¹¹⁵ Though it was previously believed that UC patients who were smokers have a more benign disease course than nonsmokers, recent data suggest that smoking might not have any effect on the UC course. In a nationwide study from the United Kingdom, UC patients who were smokers had a similar risk of corticosteroid requiring disease flares, corticosteroid dependency, thiopurine use, hospitalization, and colectomy compared with those who did not smoke.¹¹⁶ In a British study, the prevalence of cigarette smoking (15%) and e-cigarette use (5%) in patients with IBD was similar to the general population.¹¹⁷

In a survey, a majority of US-based gastroenterologists agreed with the importance of smoking cessation in patients with CD. However, only 62% provided smoking cessation counseling more than 75% of the time mainly because they did not feel equipped to discuss smoking cessation strategies.¹¹⁸ Smoking cessation therapies can help patients to quit smoking. In one study, verbal and written information on smoking cessation tips and nicotine replacement therapy led to 53% and 37% of patients remaining tobacco-free at 6 months and 12 months, respectively.¹¹⁹ Most importantly, smoking cessation has well-known beneficial effects on CD. Crohn’s disease patients who quit smoking have a more benign course with less disease exacerbations and less need for steroids and immunosuppressive therapy.¹²⁰

Discussion

Caring for patients with IBD is becoming more complex as our treatment targets have changed and the treatment options expand, each with their own list of potential adverse effects that must not only be discussed with patients before treatment but must also be monitored throughout the course of treatment. As we work to target specific objective measures of symptomatic and endoscopic improvement while also managing pre- and postmedication lab monitoring, it may seem difficult to also assess and update the preventive care needed for our IBD patients. Given the increasing demands of care and the previously documented knowledge gaps among providers,¹⁰ there is a need to develop updated evidence-based preventive care recommendations that can be incorporated in to clinical practice.

The 15 statements presented here (Table 1) are based on a systematic review of evidence published in the medical literature and on expert consensus including IBD experts in gastroenterology and surgery, in academics and private practice, from across the U.S. We have included a summary of the current evidence available to support each statement. Only statements with a very high level of expert agreement (with a score ≥4) were included in the final health maintenance recommendations.

The statements generated in this process represent practice-focused guidance, to complement position articles from professional societies, such as the 2017 American College of Gastroenterology Clinical Guideline on preventive care in inflammatory bowel disease.⁸ To provide practical measures, the statements provided here include the specific order for administering certain vaccinations (eg, for the pneumococcal vaccines), the specific antibodies to obtain to assess seroprotection (eg, for varicella), and the appropriate timing of multidose vaccines (eg, for MMR). Our recommendations include zoster vaccination for patients being treated with JAK inhibitors, which is a new therapy since the ACG Clinical Guidelines were published.

The guidelines provided here expand or update those previously published by the gastroenterology professional societies; we have included statements on colon cancer screening and provided details on the specific risk factors that indicate a higher risk for a possible complication, such as colon cancer or osteoporosis. Second, we have simplified the recommendations for skin cancer screening to include all IBD patients on immunosuppressive medications and for smoking cessation to include all IBD patients who smoke. The included statements also updated the cervical cancer screening recommendations to include the new screening intervals based on ACOG recommendations.⁷⁹ And lastly, we have provided the specific screening tools that can be used in clinical practice to assess for anxiety and depression in our IBD patients.

The major limitation of these consensus statements is the lack of evidence to support the impact of vaccination and screening on IBD outcomes. There was a randomized control trial on the benefit of bone mineral density testing for women but not specifically women with IBD. For other recommendations, there are systematic reviews and meta-analyses. However, for some recommendations, the impact of screening or vaccination is extrapolated from data in other populations, such as in patients with HIV. However despite the lack of evidence to support a clear benefit, there is no data to support a detrimental effect of preventative care in the IBD population either.

Providing updated, evidence-based recommendations supported by expert consensus can help providers focus on the key measures to implement in the care of adults with IBD. Given the complexity of caring for patients with IBD, our goal is to provide a simplified, clarified, and focused list of recommendations that can be implemented in to the clinical care of patients with IBD. Our intent is to facilitate the use of these screening and vaccination recommendations to eliminate the gap in preventative care for patients with IBD.

Conflicts of Interest

GS has received research funding from Pfizer and consulting fees from Prometheus Laboratories and Gilead. BLC has received the following financial support: advisory board member and consultant for Abbvie, Celgene-Bristol Myers Squibb, Pfizer, Sublimity Therapeutics, TARGET, and RWE, in addition to CME Companies, including cornerstones for Vindico and speaking for Abbvie. FR disclosures include Agomab, Allergan, AbbVie, Boehringer-Ingelheim, Celgene/BMS, CDISC, Cowen, Genentech, Gilead, Gossamer, Guidepoint, Helmsley, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Morphic, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Surrozen, Takeda, Techlab, Theravance, Thetis, and UCB. CS serves on speaker’s bureau for Takeda, Janssen, Abbvie, and Shire. BA received research funding from Takeda and consultant fees from AbbVie Janssen, Pfizer, Samsung bioepis, Medtronics, Ferring, Bristol Myers Squibb, and Takeda. DH has received research funding from Pfizer and consultant fees from AbbVie BMS, Janssen, Pfizer, and Takeda. LM received medical education grants from AbbVie, Janssen, Pfizer, UCB, and Takeda and served on an advisory board for Gilead. SH disclosures include Shionogi and Takeda. AA has received consulting/speaking fees from Abbvie, Janssen, Pfizer, Celgene/Bristol Myers Squibb, Takeda, and Gilead, research funding from AbbVie, Janssen, Takeda, Eli Lilly, and Bristol Myers Squibb, and is a founder/board member for IBD Horizons (not for profit educational organization). ASC has received consultancy fees from AbbVie, Janssen, Takeda, Bacainn, Arena pharmaceuticals, Grifols, Prometheus, Samsung, Bristol Myers Squibb, and Pfizer and research support from Inform Diagnostics. JG has received research funding from AbbVie, Boehringer Ingelheim, Pfizer, Red Hill, BMS, Janssen, Genentech, Gilead, and Takeda; has received consulting fees from BMS, Celgene, and Gilead; and served as speaker for AbbVie and Takeda. AM has received consulting fees from Pfizer, Janssen, and LabTech and a research grant from Pfizer. All other authors have nothing to disclose.