IBD: A Link To Cancer And Infection
Individuals diagnosed with inflammatory bowel disease (IBD) face higher susceptibility to malignancy and infection when compared to the general population.
The primary objective of this study was to identify and describe risk factors associated with malignancy or serious infection in patients with IBD, with a specific focus on evaluating the impact of immunosuppressive treatments.
Background
Inflammatory bowel disease
Inflammatory bowel disease (IBD) is a persistent inflammatory condition of the gastrointestinal tract, encompassing two main types: Crohn’s disease (CD) and ulcerative colitis (UC). Globally, IBD is a common gastrointestinal disease that affects up to 6.8 million individuals, leading to significant physical and psychosocial symptoms for patients and exerting an impact on society due to reduced productivity and escalated healthcare expenses.
The medical approach used for IBD
Medical treatment for IBD involves the administration of immunosuppressive drugs to reduce inflammation in the intestines. The primary objective of this treatment is to initiate and sustain disease remission without the need for steroids. Due to the chronic and recurring nature of IBD, patients are often exposed to long-term use of immunosuppressants. Commonly utilized in the maintenance of disease remission are immunosuppressive agents such as thiopurines and a growing range of biological anti-inflammatory drugs. Additionally, there have been recent advancements in small-molecule drugs targeting novel pathways associated with IBD, including Janus-Kinase inhibitors, S1p modulators, and Laquinimod.
Study Design
Data were collected from electronic medical records, including patient demographics, disease details (IBD phenotype, date of diagnosis, and follow-up information), and treatment history with immunomodulators or biologic immunosuppressants. Outcome data for malignancy or serious infection were obtained through clinical notes and ICD10 diagnostic codes, with serious infection defined as an infection leading to hospitalization or requiring treatment with intravenous antibiotics. Infections were categorized based on the affected body system.
Statistical Analysis
Patients were categorized based on their immunosuppressant exposure history into groups: thiopurines, anti-TNF agents, other biologics, a combination of thiopurines and anti-TNF agents, and non-immunosuppressed patients. Non-immunosuppressed patients either did not receive medical therapy for their disease or were treated only with 5ASA preparations (e.g., mesalazine or sulfasalazine).
The impact of immunosuppressant exposure duration was assessed by calculating cumulative years of exposure to each class of immunosuppression. Data analysis was performed using the STATA-SE version 16.1 statistical package.
Descriptive statistics were computed for the study cohort, and differences between the groups were evaluated using non-parametric tests such as the Mann-Whitney U test for continuous outcome variables and Fisher’s exact test for categorical outcome variables.
To assess the association of risk factors with malignancy or serious infection, logistic regression modeling was employed to generate odds ratios (ORs). Furthermore, multivariate logistic regression was used to provide adjusted estimates for the analyzed risk factors.
Results
Out of the 860 patients who attended an IBD clinic appointment from 2015 to 2020, 549 patients (63.8%) were considered eligible for inclusion in the study. The reasons for exclusion included the inability to accurately determine their complete history of immunosuppressant exposure (n=156), losses to follow-up at the clinic due to non-attendance at review appointments or transfer of care to private practice or another clinic (resulting in the unavailability of patient data) (n=154), and one patient was excluded due to a history of cancer preceding their IBD diagnosis.
Researchers conducted a thorough analysis of data from an Australian IBD referral center cohort to investigate risk factors associated with adverse events, including malignancy and serious infection, in patients with IBD.
During the study, researchers found that over a median follow-up duration of 11 years, there was no increased risk of overall malignancy for patients exposed to either thiopurine or anti-TNF maintenance treatments when compared to patients who were not exposed to these treatments. These findings align with previous studies that utilized similar-sized referral-center cohorts.
Moreover, researchers observed that certain factors, such as increasing IBD duration, patient age, and the presence of ileocolonic CD, were associated with a higher risk of overall cancer in this cohort.
To enhance the precision of risk estimates, future analyses could involve pooling detailed data sets from multiple study sites. Additionally, there is a need for further research to examine the impact of immunosuppression on the risk of less severe infections, such as those treated outside of hospital settings, to gain a broader understanding of the risk profile of immunosuppressants in IBD.
The majority of these cancers were skin cancers (81.3%), consisting of 20 basal cell carcinomas and 19 squamous cell carcinomas. Additionally, there were three cases of haematologic malignancies (6.3%), including one Hodgkin lymphoma (HL), one non-Hodgkin lymphoma (NHL), and one low-grade lymphoproliferative disorder. Six solid organ malignancies (12.5%) were also observed, which in bbb included two colorectal cancers, and one each of thyroid, breast, renal, and endometrial cancer.
In terms of risk factors for malignancy, on univariate analysis, patient age, IBD disease duration, and having Crohn’s disease (especially ileocolonic CD) were associated with higher odds of developing cancer. After accounting for confounding variables, patient age, disease duration, and ileocolonic CD remained significant risk factors for overall malignancy.
To assess the impact of longer exposure to immunosuppressive treatments, logistic regression was performed for patients with cumulative exposure durations of thiopurine or anti-TNF agents greater than 2 years and more than 5 years. However, even with these longer exposure durations, no significant association was found between cumulative exposure to thiopurine or anti-TNF treatments and an increased risk of malignancy compared to patients not exposed to these treatments.
Summary
Physicians and patients are concerned about the occurrence of adverse events in individuals with IBD. It is believed that persistent intestinal inflammation and long-term use of immunosuppressant drugs contribute to the higher incidence of adverse events, including infections and malignancies, in the IBD patient population. To explore the predictors of these adverse events, a retrospective analysis was conducted on a group of IBD patients from an Australian tertiary referral center. The analysis revealed that certain characteristics such as patient age, duration of IBD, and the presence of ileocolonic (L3) Crohn’s disease (CD) were identified as risk factors for the development of malignancy. However, the exposure to immunosuppressive maintenance treatments, including immunomodulators and anti-TNF biologic agents, did not seem to increase the overall risk of cancer in this cohort. When analyzing patients with cumulative immunosuppressant exposure durations greater than 2 years and greater than 5 years, no significant correlation was found between exposure to thiopurine or anti-TNF immunosuppression and an increased incidence of cancer compared to those not exposed to these drugs. Serious infections requiring hospitalization or intravenous antimicrobial therapy were also studied. The analysis found that only the duration of exposure to anti-TNF agents was associated with infection risk. Interestingly, increasing anti-TNF exposure appeared to be protective against serious infection in this cohort. Thiopurines, however, were identified as potentially contributing to carcinogenesis through various mechanisms, such as enhancing the effects of UVA light in generating oxidative DNA damage and impairing tumor-cell immunosurveillance, as well as directly altering cellular DNA.
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