Imaging Biomarkers in Crohn's Associated Spondyloarthritis

IMAGING AND CROHN'S ASSOCIATED SpA: Crohn's disease (CD) is the most common type of
inflammatory bowel disease (IBD). It affects an estimated 0.7 million patients in United
States and is responsible for 0.2 million hospitalizations each year.1 Although the
gastrointestinal tract is the primary site of inflammation, inflammatory arthritis (both
peripheral and axial) can affect between 12.8-23% of patients with Crohn's Disease2,3, and
axial SpA alone has been reported to effect 6.7% to 18% of Crohn's patients.4 However, in 2
recent studies5,6, radiological sacroiliitis was reported to be present in 27% and 52% in IBD
patients. MRI changes of inflammation precede radiological sacroiliitis by years but it is
not clear when this occurs. Presence of damage on x-ray in asymptomatic patients may suggest
that Crohn's associated axial SpA could be underdiagnosed. Since Crohn's associated SpA often
affects younger patients, undertreatment or missed diagnoses could have a significant impact
on health related quality of life (HR-QoL) and disability during prime wage earning and child
rearing years.7

"Non-radiographic axial spondyloarthritis" is a term used to describe patients with
symptomatic SpA who do not have findings on plain x-rays. These patients can have identical
symptoms to those with radiographic evidence of cartilage loss and erosions, and anti-TNF
(anti-Tumor Necrosis Factor) therapy has been shown to be effective in those with
non-radiographic SpA.8 These patients are a clinically relevant subgroup, as 20% of patients
with only MRI evidence of sacroiliitis will progress to non-reversible radiographic SpA over
two years.9 Therefore, MRI evidence of sacroiliitis, in conjunction with inflammatory back
pain is now sufficient to diagnosis SpA. In fact, MRI imaging is a standard component of
current SpA diagnostic criteria, (ASAS: Assessment of SpondyloArthritis International
Society),10 and MRI changes of sacroiliitis are routinely used to identify SpA patients for
clinical trials.11

However, despite these new definitions there is a deficiency of published research evaluating
the clinical significance of MRI findings in patients with Crohn's disease. Of all the
SpA-associated diseases, Crohn's-associated SpA has a particularly high burden of
extra-articular inflammation. Studies suggest only half to two thirds of patients with CT or
MRI evidence of inflammation have symptoms of inflammatory back pain.1,12 This suggests that
in Crohn's disease, MRI imaging biomarkers may be identifying early disease, analogous to the
way that ultrasound can identify subclinical rheumatoid arthritis.13 We therefore hypothesize
that in a mixed cohort of Crohn's patients with and without inflammatory back pain, MRI
imaging biomarkers will correlate with measures of health status which reflect systemic
inflammatory burden, (i.e. BASDAI, SF-12) independent of symptoms of inflammatory back pain.

MRI IMAGING BIOMARKERS: A POTENTIAL CARDIOVASCULAR RISK FACTOR? The observed discordance
between axial inflammation seen on MRI and inflammatory back pain raises a particularly
intriguing clinical question: could Crohn's patients with imaging evidence of axial
inflammation but without axial symptoms potentially benefit from therapy?

It is very well established that in rheumatoid arthritis and psoriatic arthritis, systemic
inflammation is associated with myocardial infarction, stroke and death, and that treating
inflammation improves cardiovascular outcomes.14,15.

Recent population based study from Europe and Canada showed increased risk of cardiovascular
mortality in patients with Ankylosing Spondylitis.16,17 Despite clear evidence that
cardiovascular risk is increased in SpA, how to quantify the increased risk is not
straightforward. There is no consistently reliable marker of systemic inflammation in these
patients; sedimentation rate (ESR) and C-reactive protein (CRP) may not always reflect
ongoing inflammation, especially in patients with non-radiographic axial SpA9. Therefore,
accurately measuring the inflammatory burden in Crohn's patients, regardless of
musculoskeletal symptoms, is an important area for future research. Initiation of earlier
targeted therapy to decrease inflammation may not only prevent incident Crohn's associated
SpA, progression of prevalent SpA, with concurrent improvements in HRQoL, but may also
improve cardiovascular morbidity and mortality.

In addition, although sacroiliitis is the primary axial feature in SpA, there is increasing
evidence that there can also be spinal involvement even in the absence of SI joint
inflammation. Recent studies suggest that spinal inflammation can occur in up to one-third of
nonradiographic SpA patients with <5 years of disease duration.18 This could be an important
early imaging inflammatory biomarker. To our knowledge there are no published studies
evaluating spinal and SI joint MRI imaging biomarkers in Crohn's associated SpA.

THE MICROBIOME: A CORRELATE OF INFLAMMATION IN CROHN'S DISEASE? The etiopathogenesis of
Crohn's Disease-associated SpA remains a puzzle. As with other autoimmune diseases, interplay
between genetic factors such as HLA B27 (Human Leukocyte Antigen- B27) and environmental
factors likely play a role. The joint symptoms of SpA are not consistently correlated with
bowel disease flares.19 Intestinal microbiota plays a critical role in evolution of our
entire immune system, since axenic laboratory animals (germfree animals raised in sterile
environment) were noted to have partial restoration of T cell population when these animals
are colonized with filamentous bacteria. A symbiotic relationship between the main bacterial
phyla is necessary for proper functioning of immune system, since notable alterations in the
intestinal microbiome (i.e. dysbiosis) have been suggested in various autoimmune diseases.
Reduction in taxa-diversity (such as, enterobacteriaceae, Bacteroidales and Clostridiales)
and expansion of certain phyla in the intestine have been recently reported in a large cohort
of new onset treatment-naïve Crohn's disease (CD) patients.20 In addition, Dr. Longman's lab
has shown that the expansion of immunologically relevant Enterobacteriaceae correlates with
Crohn's related SpA among a mixed group of patients with Crohn's and ulcerative colitis, (in
press). However, while these are exciting data, SpA cases were identified using a
non-validated clinical diagnosis, without systematic rheumatology evaluation and no imaging
studies. This will be first study evaluating the microbiome in a carefully phenotyped cohort
of Crohn's associated SpA, who will also have detailed MRI imaging.

Inclusion Criteria:

1. Patients with biopsy proven Crohn's Disease

2. 50% patients with inflammatory back pain and 50% without inflammatory back pain.

3. Age 18 years and above

4. English Speaking patients only

Exclusion Criteria:

1. History of psoriasis, other inflammatory arthritis

2. No exposure to biologic agent within the past six months (except Vedolizumab, which
exerts its effect locally)

2. Contraindication to MRI

3. History of malignancy <5 years in remission, (except for non-melanomatous skin cancer).

4. Non English speaking

5. Unable to comply with study protocol.

6. Critically or terminally ill patients

7. Pregnancy