Patient Selection and Safety with TNF Inhibitors - Episode 4
Accurately Diagnosing an Autoimmune Disease
Criteria and the significance of biomarkers to help healthcare professionals avoid a misdiagnosis of an autoimmune disorder, such as an inflammatory bowel disease.
Marla Dubinsky, MD: With regard to diagnostic strategy, I’m going to start with the basics. For inflammatory bowel disease [IBD], the diagnosis is based on gold standard criteria. The gold standard would be endoscopy and colonoscopy with ileal visualization. If you don’t get into the ileum, you’re missing the potential for Crohn. So endoscopy means ileal colonoscopy, in my opinion. So you have your gold standard endoscopy. As I noted, ulcerative colitis [UC] looks different from Crohn, in most cases. We look at location. Is it patchy? Patchiness is more of a Crohn thing. Continuous is more of a UC thing. So there are aspects, even to the eye of the endoscopist, which we call macroscopic visualization, that differentiate UC from Crohn, but both are made by colonoscopy.
The other part of the standard would be to use radiologic procedures. If you couldn’t get into the ileum for some reason because it was narrowed, or if you couldn’t find it at the time of the endoscopy, then you’d do imaging to look at the small bowel. The gold standard now is cross-sectional imaging, which involves either a CT enterography or an MR enterography. In Europe and Canada and some parts of the United States, we’re actually using small-bowel ultrasound to look at the small bowel.
The limitation of the small-bowel ultrasound has been that it really looks at only part of the small bowel. Your bowel dives down, and you can’t find it, which is why the CT enterography or MR enterography have sort of become the gold standard for what we call cross-sectional. When we say cross-sectional, this means that we can see all 4 walls of the bowel, by definition for Crohn. In Crohn patients, we can see how long the segment is. With our scope, we can see only up to a certain number of centimeters. Our scope is only so long. But imaging can help to literally look from the stomach, down. So that enhances our diagnostic yield.
Histopathology means biopsies. There are some findings in biopsies that differentiate UC from Crohn. The most notorious is called granulomas—non-necrotizing granulomas. We often worship the granuloma because when we do see it, we’re like, “Yup, this is Crohn.” But unfortunately, only a small percentage of biopsies show granulomas. So when we find them, we’re excited. When we don’t find them, it doesn’t mean that the patient doesn’t have Crohn.
So those are the things we look for. We look for chronicity on the biopsies, not just acute, because acute could be infection-only. So we look for acute and chronic changes on the biopsies. And clinical symptoms, which we’ve described, are what sort of help differentiate these from Crohn and where the disease can be located.
In terms of biomarkers, that’s a very hot topic right now. Biomarkers are not, in any way, replacing our gold standard. Biomarkers are coming into play when we make the diagnosis. We have biomarkers that we benchmark against our foundation of diagnosis—endoscopy and radiology.
We consider fecal biomarkers. Fecal calprotectin is a very hot topic. Can we look at whether inflammatory mediators, in a sense, in the stool, represent the mucosal integrity? Maybe we can sometimes use that for a differential diagnosis between functional and inflammatory diseases, but you make that based on your scope. You’re not going to say, “You don’t have IBD,” based on stool. You need the endoscopic confirmation.
But when you do have IBD and you benchmark with a fecal marker, you can then use the fecal marker for disease monitoring. If there’s a change, you want to look at treatment response. You can look at the drop in the calprotectin. The nice thing about this is that it could be up to 4 to 6 months before clinical symptoms arrive. And we’ve shown that calprotectin correlates not just with the IV [intravenous] endoscopy but the pathology.
So even for patients who look good to the IV endoscopist but still have inflammation under the microscope, the calprotectin will be elevated as a reflection of that. This is really interesting because in UC, in particular, we’re heading toward histologic healing, where we’re actually getting normalization of the mucosa under the microscope. That’s how good our drugs could be, which is pretty spectacular. It’s been shown that even when the scope looks good but the pathology is abnormal, it could also predict flare. So we’re getting really deep. I guess the next level would be molecular remission, which we’re not going to talk about because we’re not there yet, in terms of biomarkers.
The other classic biomarker is CRP, or C-reactive protein, which we follow more so in Crohn than in UC. UC is only the mucosa. If they have really high CRP, that’s troubling. They either have an infection or their disease is starting to become transmural. That means the patient is sick. So CRP in a UC patient is a marker of severity.
In Crohn disease, a significant number of patients have CRP that’s elevated. Just like the fecal marker, we look for a drop in the CRP as a response to treatment. The only problem with CRP is that about a third of patients may not even mount CRP genetically, so it’s complicated. That’s why we don’t rely on biomarkers for diagnosis. Perhaps we shouldn’t be making treatment decisions based on biomarkers alone, because their predictive value is not 100%.
People are interested in the future of biomarkers in the blood itself, or biomarkers in the mucosa—meaning looking at gene expression to look to use those biomarkers to tell you which treatment a patient should get. We have a lot of toys in our toy box, but we’re not so sure how to use all of them. Sequence of therapy is important for patients.