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Expert Critique
FROM THE ASCO Reading Room
The study by Rodriguez-Lago et al identifying asymptomatic IBD in about 0.35% of screening colonoscopies for colon cancer screening is important in noting how symptoms do not necessarily correlate with disease activity. The study demonstrated that disease activity preceded symptoms up to 42 months in advance. We similarly found a less than 0.2% occurrence of asymptomatic IBD in an internal review of screening colonoscopies, with the majority mild UC (unpublished data). Another major important point to highlight is the importance of advocating for age-related screening colonoscopies, as even the identification of early IBD with early therapy could potentially change the long-term complications of untreated disease.
One of the more interesting areas of focus is the potential role of using biomarkers to potentially predict the future occurrence of disease. The idea that serologies may be predictive of developing IBD got our attention when Israeli et al (2005) evaluated sera within the Israeli Defense Force (IDF) Medical Corps Serum Repository and isolated 32 subjects with CD before clinical diagnosis. A little over 30% of CD patients were anti-Saccharomyces cerevisiae antibody (ASCA) positive prior to clinical diagnosis, and the mean interval between ASCA detection and diagnosis was 38 months.
As mentioned within the article, Lochhead et al demonstrated the early rise of hsCRP and IL-6 within the Nurses’ Health Study. However, limitations need to be placed on the predictive role of hsCRP solely for IBD, due to its association with other inflammatory conditions and cardiovascular disease. The PREDICTS study offers more interesting insight into the potential of using biomarkers for early detection. The results showed that titers of 4 CD serological markers (ASCA IgA/IgG, anti-A4-Fla2, and anti-FlaX) prior to diagnosis were higher in soldiers who presented with complicated versus uncomplicated CD.
The role of biomarker testing to potentially predict early disease is unfortunately still not readily applicable nor available. As IBD is uncommon, the costs associated with routine screening would be cost-prohibitive, and the lack of effective "preventive" measures to potentially mitigate the outcomes have not been identified. We still have limited data on whether the use of early targeted therapy is truly changing disease outcomes, and it would be hard to convince a patient to start lifelong therapy on the "potential" of developing IBD.
More prospective data will be needed to assess whether inflammatory biomarkers are truly "predictive" but also need to parallel the development of potential "interventions" that could potentially manipulate outcomes. Research is ongoing, and the future looks bright as our technology and understanding of the disease process improves.
Since current treatments for inflammatory bowel disease (IBD) target established disease, gastroenterologists are eager to find ways to intervene at earlier, preclinical stages. Colorectal cancer screening and serum marker detection are poised to play a role in realizing that goal.
In recent decades, chance findings on cancer screening have identified increasing numbers of asymptomatic cases. Most recently, a 2017 of more than 31,000 screening colonoscopies performed in Spain after positive fecal immunochemical testing (FIT) during 2009-2014 reported new incidental IBD diagnoses in 0.35% of asymptomatic screened individuals.
The majority were of cases of ulcerative colitis, and more than a third of affected individuals developed symptoms during a mean follow-up of 25 months -- usually within the first year of diagnosis.
By IBD type, the results showed that colonoscopy led to 79 new diagnoses of ulcerative colitis, 24 of Crohn's disease, and seven of unclassified colitis within the male cohort (57% of the total), whose mean age was 57.
Among patients asymptomatic at IBD diagnosis, 36% developed symptoms during follow-up ranging from 10.5 to 42 months, presenting mostly with rectal bleeding and diarrhea. Treatment, usually mesalazine, was prescribed for 81 patients (88%) in the preclinical phase, and only one in five of these patients developed symptomatic disease. Two cases required surgery.
"According to disease subtype, we found that patients with a diagnosis of ulcerative colitis had a higher risk of developing symptoms as compared with Crohn's disease and IBD-unclassified patients," the study's lead researcher, Iago Rodriguez-Lago, MD, of Hospital de Galdakao in Vizcaya, Spain, told ľ¹ÏÖ±²¥. "We need further studies to evaluate the early phases of the disease and the potential influence of different treatments in modifying its natural history."
In another interesting finding, 23% of patients had had a negative FIT in the 24 months before IBD diagnosis. "This may reflect a time period in which the disease may not yet have started, but we cannot exclude that this may just be a consequence of intermittent disease activity," he said. "Moreover, as the symptoms usually appeared in the first year after diagnosis, our findings show a plausible time window in which the disease progresses from its subclinical phase to clinically apparent stages."
The identification of undiagnosed IBD through cancer screening goes back at least as far as 1989, when reported eight cases of undiagnosed IBD in a U.K. cohort of almost 18,000 screened individuals.
Although the preclinical phase has been extensively studied in other immune-mediated diseases such as rheumatoid arthritis and type 1 diabetes, research in IBD remains in its early stages. There is mounting evidence, however, that immune dysfunction and systemic inflammation precede clinical symptoms by several years and could justify early intervention to forestall irreversible tissue injury.
A correlation between such preclinical immune abnormalities and IBD risk was by Paul J. Lochhead, MD, of Massachusetts General Hospital in Boston, and associates. They found that the highest circulating plasma levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) was associated with an increased risk of Crohn's disease (CD) and ulcerative colitis (UC).
"Our study suggests that subclinical inflammation is a feature of this preclinical or pre-disease phase," Lochhead told ľ¹ÏÖ±²¥," adding that the findings are not yet relevant to clinical practice. "Further studies are required to better characterize preclinical IBD with the hope of identifying a window where intervention could avert disease progression or minimize long-term complications."
Elevated inflammatory markers may be a feature in individuals at increased risk of IBD, a state that may arise from genetic and environmental factors. "This is somewhat speculative, but the idea of a disease-predisposing state is supported by studies that have reported increased levels of sub-clinical inflammation and gut microbial dysbiosis in first-degree relatives of Crohn's disease patients," he said.
Studying blood specimens from a subset of participants in the Nurses' Health Study and the Nurses' Health Study II, Lochhead's group found that compared with the lowest quintile of IL-6 level, the highest quintile correlated to an odds ratio (OR) of 4.68 (95% confidence interval [CI] 1.91-11.46) for CD (P trend <0.001) and an OR of 3.43 (95% CI 1.44-8.15) for UC (P trend = 0.004).
In terms of hsCRP, the highest- versus the lowest-level quintile was associated with an OR of 2.82 (95% CI 1.15-6.87) for CD (P trend 0.019) and an OR of 1.79 (95% CI 0.80-3.99) for UC (P trend 0.015).
Lochhead said the team was surprised to find that markers appeared elevated many years before diagnosis: "In the case of IL-6 and ulcerative colitis, for example, the association was still statistically significant when the analysis was limited to blood specimens collected 7 years or more before diagnosis, and it was unusual that the association between inflammatory markers and IBD risk didn't appear to be modified by time."
In a similar vein, in 2016 in the PREDICTS (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects) study found that serological microbial markers such as anti-Saccharomyces cerevisiae antibody could predict CD many years before diagnosis.
"Interestingly, the PREDICTS study data also suggested that positivity for antimicrobial antibodies was associated with an increased risk of disease complications around the time of diagnosis," Lochhead said. "Whether the biologic events that lead to antimicrobial antibody formation are associated with subclinical inflammation and could be linked to elevated circulating inflammatory markers has not yet been examined."
Asked whether middle-aged individuals should be routinely screened for predictive IBD markers, he said: "Unlike conditions that we commonly screen for in this age group, IBD is relatively uncommon and, from a public health perspective, it is unlikely that population-based screening would be justifiable." Most IBD cases are diagnosed in adolescence and early adulthood, so screening at age 50 would be of questionable benefit. "Screening for the preclinical phase of IBD is likely to have the greatest utility among first-degree relatives of individuals with IBD."
Marker specificity presents another problem, since, for example, hsCRP is already associated with cancer, diabetes, and cardiovascular risk. "It seems unlikely that inflammatory markers alone would be able to reliably predict IBD. And even assuming the existence of an accurate screening test for future IBD, "it would be important to be able to offer an effective intervention that could modify that risk before offering screening."
In the meantime, research is working toward a future paradigm of therapeutic intervention at a stage when primary immune dysregulation, dysbiosis, or other key pathogenic processes could still be reversed. Investigators hope that drilling down on the pre-onset phases of IBD will uncover the genetic and environmental interconnections that trigger clinical disease and lead to predictive models and preventive strategies.