Cross-specialty co-management ‘lead to better outcomes’ in ankylosing spondylitis, IBD
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Sometimes, the best way to care for a patient is to know one’s own limitations.
For rheumatologists and gastroenterologists who manage patients with ankylosing spondylitis-associated inflammatory bowel disease, or IBD-related AS, recognizing one’s own limitations, and reaching out for multidisciplinary assistance, can mean the difference between a happy patient and one who falls into a cycle of “slow burn.”
“Sometimes, you know what you know, and you know what you don’t know,” Brett Smith, DO, of Blount Memorial Physicians Group-Rheumatology, in Maryville, Tennessee, and East Tennessee Children’s Hospital, in Knoxville, told Healio Gastroenterology. “We can’t know everything, and that is where our colleagues come in to support the patient. I believe it important to check in with both specialists so the disease is not left in a state of slow burn, where low disease activity causes damage or scar tissue over time, which could have been prevented.”
Failure to coordinate between rheumatologists and gastroenterologists when caring for these patients can lead to delayed diagnoses, mismanaged treatment and potentially irreversible damage. Meanwhile, the benefits of working together include a well-managed disease in a particularly challenging patient population.
The issues start with diagnosis, according to Nicole Cotter, MD, a rheumatologist at the University of Colorado Health rheumatology clinic in Steamboat Springs.
“Delays in diagnosis of AS may occur because back pain is common in our population,” she told Healio Gastroenterology. “Spondyloarthritis is not the first thing most health care providers think of when a person presents with back pain.”
A similar phenomenon occurs in IBD.
“It is not uncommon to have a delay in IBD diagnosis due to nonspecific GI symptoms that are labeled as irritable bowel syndrome (IBS), rather than IBD,” Miguel Regueiro, MD, chair of the department of gastroenterology and hepatology, and chair of the Digestive Disease and Surgery Institute, at the Cleveland Clinic Lerner College of Medicine, said in an interview.
Even when diagnosis occurs in a timely fashion, both AS and IBD can be challenging to treat as individual diseases. However, when they occur together, the challenges are more than multiplied, according to Fragoulis and colleagues, who published one of the key papers on the link between the two conditions in the World Journal of Gastroenterology.
In their findings, they wrote that IBD is so prevalent in AS that it is, in fact, one of the accepted extra-articular manifestations of the disease.
“Bowel involvement seems to be the most common of these manifestations,” they wrote. “Clinically evident IBD is observed in 6% to 14% of AS patients, which is significantly more frequent compared to the general population.”
Further data from the study demonstrate that so-called “silent” microscopic gut inflammation may be present in as many as 60% of patients with AS.
“We do not know why these conditions are associated, but there are some theories,” Seyedehsan Navabi, MD, director of the Inflammatory Bowel Disease Program and director of gastrointestinal motility disorder management in the division of gastroenterology and hepatology at the Rutgers New Jersey Medical School, in Newark, told Healio Gastroenterology.
The most likely theories pertain to overall inflammatory processes due to an autoimmune condition in patients with genetic susceptibility, but the picture may be murkier than that and likely environmental factors as well as gut microbiota can play a role, Navabi said.
However, the obstacles presented by AS and IBD do not stop at diagnosis. For example, there are also treatments that may be used in one condition but not the other.
The good news is that with early recognition, timely diagnosis and an understanding of the therapeutic landscape, AS-associated IBD and IBD-associated AS can be managed. But management starts with communication.
Source: Seyedehsan Navabi, MD.
Lessons From Rheumatology: A ‘High Index of Suspicion’
It is important for gastroenterologists to understand that spondyloarthropathies are subdivided into axial and peripheral disease, according to Fragoulis and colleagues. They noted that it is also vital to recognize that under the broad umbrella that is spondyloarthritis, AS is the “prototype disease.”
The paper also includes some concrete advice for what to look for in the clinic.
“Both axial and peripheral SpA occur more frequently in Crohn’s disease than ulcerative colitis,” they wrote.
Armed with this knowledge, Cotter offered a simple starting point for gastroenterologists dealing with IBD in the clinic.
“The most important thing about diagnosing musculoskeletal manifestations of IBD is to have a high index of suspicion to begin with,” she said.
These manifestations can range from peripheral inflammatory arthritis to AS.
“Knowing to look is the first step,” she said. “Knowing what to look for and what questions to ask the patient can make all the difference in recognizing these problems.”
Fortunately, there are mechanisms in place to help ask the right questions and understand exactly what type of back pain the patient is experiencing.
“One of the most effective strategies to identify AS in the clinic is to provide a screening questionnaire on inflammatory back pain upon check-in for appointments,” Brett Smith said. “A positive screen could trigger the gastroenterologist to order sacroiliac and spinal X-rays or refer to rheumatology. Inflammatory back pain questionnaires can be very helpful because many patients have AS without overt radiographic changes on X-ray and may only have MRI changes.”
Trained rheumatologists know this, provided they are familiar with the Assessment of Spondyloarthritis International Society (ASAS) criteria published by Rudwaliet and colleagues in the Annals of Rheumatic Diseases. The criteria stipulate that features of AS-associated inflammatory back pain include onset prior to age 40 years, insidious onset, improvement with exercise, no improvement with rest and night-time pain.
“If your IBD patient gives a description of back pain with these features, it should raise suspicion for a bowel-related spondyloarthritis,” Cotter said.
For patients with these classic signals, an AS diagnosis in the IBD setting can be straightforward. The complicating factor is that AS is not the only type of arthritis seen in IBD.
“Arthritis in general — also known as enteropathic-related arthritis — has been estimated to occur in up to 50% of patients with IBD,” Cotter said.
With so many patients to manage, gastroenterologists are encouraged to maintain ongoing contact with a rheumatologist in managing IBD. However, the potential gastrointestinal complications in patients with AS necessitate constant communication going the other way, as well.
Lessons From Gastroenterology: ‘Question All AS Patients on Bowel Symptoms’
IBD is a chronic relapsing and remitting inflammatory status in the gut that gastroenterologists generally divide into two broad categories — Crohn’s disease and ulcerative colitis.
However, according to Navabi, it is critical for rheumatologists to understand that, for the most part, these conditions are not necessarily clearly characterized separately.
“It is more of a spectrum of disease,” he said. “Sometimes, it is difficult to determine the details or distinguish between the two conditions, and it may categorize as ‘indeterminate colitis.’”
According to Cotter, gut inflammation, even if it does not meet the diagnostic criteria for IBD, may be present in most patients with AS.
According to Regueiro, many patients with AS will have concomitant gastrointestinal symptoms, such as rectal bleeding, diarrhea or bowel function changes, as AS is often associated with ulcerative colitis, and ulcerative colitis is inflammation in the rectum and colon.
“So, a tip for the rheumatologist seeing a patient with AS is to simply ask the patient if they have any of these GI symptoms,” he said.
Additionally, when asking these questions, it is important to be specific, said Ashwin N. Ananthakrishnan, MD, MPH, MBBS, associate professor of medicine at Massachusetts General Hospital and Harvard Medical School.
“When diarrhea is particularly persistent or frequently occurs at night, a high suspicion of IBD is warranted,” he said.
This suspicion should lead to questions about symptoms for the patient, according to Sharon Dudley-Brown, PhD, FNP-BC, assistant professor of medicine in gastroenterology and hepatology at Johns Hopkins University, who cited findings to this end from Stebbings and colleagues that were published in Rheumatology (Oxford). The questions can come in the form of the Dudley Bowel Disease Questionnaire (DISQ), she said.
“Many patients with AS have mild GI symptoms,” Dudley-Brown said. “But of those who have symptoms, a workup by GI many times reveals mild to moderate Crohn’s disease. Thus, the rheumatologist needs to question all AS patients on bowel symptoms.”
Dudley-Brown added that in the presence of “significant symptoms” pointing to Crohn’s disease, a colonoscopy may be warranted.
Another intervention in the setting of suspected IBD, fecal calprotectin, is a good stool marker for bowel inflammation, according to Regueiro.
“If this is elevated, then a referral to a GI specialist is prudent,” he said.
Other useful laboratory results signifying IBD include anemia, low iron or low albumin levels, Ananthakrishnan added.
Disease activity is another important consideration for IBD in the AS setting. For example, further information from Fragoulis and colleagues demonstrate that IBD may be associated not only with AS, but with AS disease activity, as well.
Fortunately, experts in the two specialties are accustomed to communicating these particulars to one another. However, both AS and IBD have a long history of diagnostic delays, even as independently occurring conditions. When one condition is a function of the other, those delays can lead to significant morbidity.
Consequences of Delay: ‘Irreversible Bowel Damage’
The typical delay between symptom onset and a diagnosis of IBD is 1 to 2 years, according to Ananthakrishnan. He added that it is often possible that subclinical inflammation may have been present for considerably longer.
“The consequences of diagnostic delay are protracted morbidity from symptoms and increased risk of irreversible bowel damage from persistent inflammation,” Ananthakrishnan said.
Digging deeper, Dudley-Brown noted that diagnostic delays are frequently more common in Crohn’s compared with ulcerative colitis.
“Part of this is because many patients think that their symptoms of abdominal pain and diarrhea are normal or may be due to IBS, and do not consider IBD,” she said.
It is for this reason that early intervention is critical, Ananthakrishnan said.
“Studies have shown that treatment response is better early on in the course of IBD and diagnostic delay may potentially impact subsequent treatment effectiveness,” he said.
In addition, any delay in diagnosis of Crohn’s disease delays treatment, which can further lead to progression, complications and surgery, Dudley-Brown added.
“Whereas, if patients are diagnosed with Crohn’s early in the disease, therapies such as biologics can begin and hopefully delay progression and complications,” she said.
Those complications in Crohn’s can range from fistula to malnutrition and vitamin deficiencies, according to Regueiro.
“For ulcerative colitis, anemia, more refractory disease, and over the long-term higher rates of dysplasia and colon cancer can also occur,” he said.
Meanwhile, in a paper published in Current Allergy & Asthma Reports, Judith A. Smith, MD, PhD, examined the “long delays” in AS diagnosis, describing the disease as an “insidiously progressive and debilitating form of arthritis.”
It is easy to understand why AS is so insidious, according to Brett Smith.
“AS is well known for being underdiagnosed largely due to the widespread prevalence of acute or chronic back pain in many age groups being treated as mechanical back pain,” Brett Smith told Healio Gastroenterology.
Questionnaires targeting this inflammatory back pain are underused in the clinic, he added.
“These questionnaires can be very helpful for catching early and late AS,” he said. “A significant diagnostic delay is seen in early AS as it can take 8 to 10 years to detect X-ray changes to make a diagnosis.”
MRI of the sacroiliac joints are also valuable in early AS, as they can show erosions, marrow edema, joint space widening or synovitis, according to Brett Smith.
“The early phase of AS where the X-ray is negative but inflammatory back pain is present could raise the possibility of non-radiographic axial spondyloarthritis,” he said.
This is not the only imaging-based approach in AS.
“Another successful strategy has been to have radiology review prior or new CT abdomen/pelvis imaging for the presence of sacroiliac changes to support an AS diagnosis,” Brett Smith added.
All of that said, diagnosis — with all of its potential pitfalls — is just the beginning. Treating patients on the AS-IBD continuum is similarly no easy task.
Dodging Treatment Landmines
Experts from both the rheumatology and gastroenterology fields encourage providers to do their research to understand exactly which therapies they should be using in which patients.
Brett Smith suggested starting with the basics.
“When treating AS, it is pertinent to obtain a full history and exam,” he said. “Specific items to evaluate for include psoriasis, history of uveitis, enthesitis and gastrointestinal symptoms, such as chronic diarrhea, bloody stool, chronic abdominal pain and weight loss.”
Once the patient has been fully evaluated, it is important to heed all evidence-based warnings, even for medications that are generally thought to be low-risk.
“NSAIDs may be used to manage inflammation or pain in AS, but they can cause worsening of IBD,” Regueiro said.
In the IBD setting, glucocorticoid injections may be a better choice for managing AS-associated joint pain, he added.
Meanwhile, interleukin-17 inhibitors are well recognized therapies for AS, but are known to exacerbate IBD, particularly Crohn’s, according to Brett Smith. Secukinumab (Cosentyx, Novartis) and ixekizumab (Taltz, Eli Lilly) fall into this category. However, while it is true these drugs may worsen existing IBD, IL-17 inhibition is “unlikely” to cause new IBD, so it may be safe in AS patients who have not shown signs of the disease as yet, Brett Smith said.
“Regarding medications for IBD and AS, only TNF inhibitors such as infliximab (Remicade, Janssen) and adalimumab (Humira, AbbVie) have an indication for both conditions,” Regueiro said.
However, other TNF inhibitors, including etanercept (Enbrel, Amgen), have shown some efficacy in AS but less in IBD.
According to Brett Smith, there are some circumstances where an IBD therapy, such as an IL-12/23 inhibitor, may improve the IBD, but will be ineffective in AS.
“Other agents for IBD may — and I emphasize the word ‘may’ — be effective for AS, including ustekinumab (Stelara, Janssen) and tofacitinib (Xeljanz, Pfizer),” Regueiro said. “Certain agents may be used for IBD but may do nothing for AS, such as vedolizumab (Entyvio, Takeda).”
In short, treating these patients is filled with landmines. However, a growing body of evidence describing the connection between the two conditions may make it easier to find and hit therapeutic targets.
To HLA-B27 and Beyond
Although Fragoulis and colleagues suggested that the shared pathogenetic mechanisms between IBD and AS remain “ill-defined,” they did offer some possible explanations.
“The role of dysregulated microbiome along with migration of T lymphocytes and other cells from gut to the joint (‘gut-joint’ axis) has been recognized, in the context of a genetic background including associations with alleles inside or outside the human leukocyte antigen system,” they wrote.
Navabi boiled down the basics of how these inflammatory processes work.
“With the inflammation in the gut, you get ulcerative colitis or Crohn’s,” he said. “And if it is in the synovium, you get spondylitis. The inflammatory cytokines usually migrate to blood and eventually to synovium from the leaky gut that is inflamed in such patients with Crohn’s and ulcerative colitis, as the protective barrier is damaged due to chronic inflammation.”
However, genetic factors are also coming into focus. One culprit is HLA-B27, a signature that requires further analysis particularly in patients with both conditions.
“Upwards of 90% of patients with AS have an HLA-B27, but only 50% to 70% have HLA-B27 in IBD,” Brett Smith said.
For reference, the presence of HLA-B27 is apparent in less than 10% in the general population, according to Brett Smith.
Despite this advancing knowledge, clinicians are still left to sort out the data on their own when it comes to treatment decisions.
Fortunately, specialists in both rheumatology and gastroenterology are generally on the same page when it comes to treating this patient population.
“Co-managing is likely to lead to better outcomes as we all see things a little differently, which leads to discussions, ideas and treatment options,” Brett Smith said. “Although there is notable association between IBD and AS, gastroenterologists are better equipped to monitor IBD symptoms and rheumatologists are better equipped to follow musculoskeletal outcomes.”
Although experts in major centers often have rheumatologists, gastroenterologists, radiologists, dermatologists and other specialists at their disposal, Navabi acknowledged that clinicians in suburban, rural or underserved areas may not have that luxury. As such, he encouraged rheumatologists and gastroenterologists from all corners to make use of close collaboration and communication to meet patient needs.
“Medical management of these patients can be challenging, a little more difficult than some other patient groups,” he said. “But in communities of caregivers near you, there are always some physicians who have expertise in the management of such patients who are willing to help. Just pick up the phone. It is doable. We can manage these patients.”
- References:
- Fragoulis GE, et al. World J Gastroenterol. 2019;doi:10.3748/wjg.v25.i18.2162.
- Rudwaleit M, et al. Ann Rheum Dis. 2009; 777-783.
- Smith JA. Curr Allergy Asthma Rep. 2015;doi: 10.1007/s11882-014-0489-6.
- Stebbings S, et al. Rheumatology (Oxford). 2012;doi:10.1093/rheumatology/ker359.
- For more information:
- Ashwin N. Ananthakrishnan, MD, MPH, MBBS, can be reached at 165 Cambridge Street, 9th Floor, Boston, MA 02114; email: aananthakrishnan@mgh.harvard.edu.
- Nicole Cotter, MD, can be reached at 940 Central Park Drive, Suite 190, Steamboat Springs, CO 80487; email: nicole.cotter@uchealth.org.
- Sharon Dudley-Brown, PhD, FNP-BC, can be reached at 525 N. Wolfe Street, Baltimore, MD 21205; email: djacob41@jhmi.edu.
- Seyedehsan Navabi, MD, can be reached at 185 South Orange Avenue, Suite H-528, Newark, NJ, 07103; email: ehsan.navabi@rutgers.edu.
- Miguel Regueiro, MD, can be reached at 9500 Euclid Ave. Cleveland, Ohio, 44195; email: regueim@ccf.org.
- Brett Smith, DO, can be reached at 653 Morganton Square Drive, Maryville, TN 37801; email: blsmith@protonmail.com.
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