Imaging Biomarkers in Crohn's Associated Spondyloarthritis

Completed

Conditions: Spondyloarthritis
Crohn's Disease

Registration Number: NCT02709694

Lead Sponsor: Hospital for Special Surgery, New York

Brief Summary: In patients with Crohn's Disease, symptoms of inflammatory back pain (IBP) precede changes on plain X-rays by years, and MRI changes of axial inflammation precede development of X-ray changes. Sacroiliitis on MRI without x-ray changes (i.e.Non radiographic SpA) is a valid diagnostic criterion for Spondyloarthritis (SpA) and leads to earlier diagnosis of SpA in patients with IBP. It is unclear when MRI changes occur, and if they precede clinical symptoms of IBP. There are reports of asymptomatic sacroiliitis noted on MRI in Crohn's patients. This is important, as MRI evidence of inflammation may be the first sign of incipient SpA. Inflammation in other regions of the axial skeleton in SpA patients has also been documented, but its significance is unknown. The prospect of undiagnosed and untreated inflammation is concerning, as it can lead to significant morbidity. Moreover, relationship between MRI evidence of axial inflammation-likely a proxy for systemic inflammation- and patient reported outcomes (e.g. ASDAS-CRP= Ankylosing Spondylitis Disease Activity Score- C reactive protein, BASDAI= Bath Ankylosing Spondylitis Disease Activity Index, SF-12 = Short Form- 12, HBI= Hervey Bradshaw Index and PROMIS-29= Patient Reported Outcome Measurement Information System-29), has not been reported. Recent unpublished data from Dr. Longman's lab (collaborator) suggest a distinct intestinal dysbiosis in Crohn's associated SpA. But relationship between this microbiome and MRI changes is yet to be determined.

Identifying inflammation earlier on MRI- in the absence of clinical symptoms will provide an opportunity to intervene early with available therapies, such as- biologics etc. Asymptomatic MRI changes could be a marker of underlying systemic inflammation- which is a risk factor for poor outcomes in Crohn's associated SpA. Studying association between whole spine MRI changes with patient reported outcomes) may facilitate informed clinical decision making to initiate targeted therapy to prevent progression of structural damage. Understanding microbial dysregulation in this population, and correlation with MRI changes, could lead to development of therapy targeted to restore intestinal symbiosis.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 33

Inclusion Criteria

Patients with biopsy proven Crohn's Disease
50% patients with inflammatory back pain and 50% without inflammatory back pain.
Age 18 years and above
English Speaking patients only

Exclusion Criteria

History of psoriasis, other inflammatory arthritis
No exposure to biologic agent within the past six months (except Vedolizumab, which exerts its effect locally)
Contraindication to MRI
History of malignancy <5 years in remission, (except for non-melanomatous skin cancer).
Non English speaking
Unable to comply with study protocol.
Critically or terminally ill patients
Pregnancy

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Number of Participants With MRI Positivity- Global Assessment Positive	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. MRI was considered "positive" for presence of sacroiliitis if it met global evaluation, based on the reader's overall evaluation of presence or absence of sacroiliitis by taking into account the contextual signature of both active and structural SIJ lesions. For analysis, MRI positivity for sacroiliitis was defined based on majority-of-readers agreement (≥2 out of 3).
Number of Participants With MRI Positivity- ASAS Positive	one study visit	Assessment of SpondyloArthritis international Society. Subjects are positive if they fulfill 4 out of following 5 back pain parameters: onset of symptoms \<40 years of age, insidious onset of pain, nocturnal pain, improvement with exercise and no improvement with rest.
Number of Participants With MRI Positivity- SPACE Positive	one study visit	SpondyloArthritis Caught Early. Positivity based on presence of erosions and fat metaplasia.
Number of Participants With MRI Positivity- Morpho Positive	one study visit	Positivity based on presence of bone marrow edema (BME) and/or erosion.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Axial Spondyloarthritis Based on European Spondyloarthropathy Study Group (ESSG) Guidelines	one study visit	Assessment of SpondyloArthritis international Society criteria was utilized to define inflammatory back pain.
Number of Participants With a History of Peripheral Arthritis	one study visit
Number of Participants With Current Peripheral Arthritis	one study visit
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)	one study visit	Minimum 0. Maximum 10. A score of 0 = none (no symptoms), and a score of 10 = very severe symptoms.
Bath Ankylosing Spondylitis Metrology Index (BASMI)	one study visit	The scale of the BASMI ranges from 0 to 10, where 0 is no mobility limitation and 10 is a very severe limitation.
Ankylosing Spondylitis Disease Activity Index C-reactive Protein (ASDAS-CRP)	one study visit	A higher score indicates worse symptoms. ASDAS-CRP = 0.12 x Back Pain + 0.06 x Duration of Morning Stiffness + 0.11 x Patient Global + 0.07 x Peripheral Pain/Swelling + 0.58 x Ln(CRP+1)
CRP (C-reactive Protein)	one study visit	Peripheral blood was collected for measurement of CRP.
Duration of Crohn's Disease for Participants	one study visit
Number of Participants Who Have Had Surgery Related to Crohn's Disease	one study visit
Number of Participants Using Vedolizumab for Crohn's Disease	one study visit
Crohn's Disease Activity (Harvey Bradshaw Index (HBI) Score)	one study visit	HBI consists of five parameters, which are all clinical. These parameters are: patient well-being (previous day). abdominal pain (previous day), number of liquid or soft stools (previous day), abdominal mass, and complications. Patient well-being is scored with: 0 = very well, 1 = slightly below par, 2 = poor, 3 = very poor, 4 = terrible. Abdominal pain is scored as: 0 = none, 1 = mild, 2 = moderate, 3 = severe. Abdominal mass is scored as: 0 = none, 1 = dubious, 2 = definite, 3 = definite and tender. Complications can be answered with "No" (0 points) or by choosing from a list, with each selection being 1 point. The list is: arthralgia, uveitis, erythema nodosum, aphthous ulcer, pyoderma gangrenosum, anal fissures, appearance of a new fistula, abscess. Calculation formula: sum of the scores of all 5 parameters. \< 5 remission 5 - 7 mild activity 8 - 16 moderate activity \> 16 severe activity
Interleukin 17A	one study visit	Concentration of IL-17A in peripheral blood of participants.
Number of Participants With a Past History of Biologic Use for Crohn's Disease	one study visit
Duration of Crohn's Disease	one study visit
Interleukin 13	one study visit	Concentration of IL-13 in peripheral blood of participants.
Interleukin 12-23	one study visit	Concentration of IL 12-23 in peripheral blood of participants.
Number of Participants With ≥2 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Number of Participants With Inflammatory Back Pain	one study visit
Number of Participants With Current Enthesitis	one study visit
Number of Participants With a History of Uveitis	one study visit
Number of Participants With a History of Dactylitis	one study visit
Number of Participants With HLA-B27 (Human Leukocyte Antigen B-27)	one study visit
Number of Participants With a Prior History of Biologic Use for Crohn's Disease	one study visit
Interleukin 2	one study visit	Concentration of IL-2 in peripheral blood of participants.
Interleukin 4	one study visit	Concentration of IL-4 in peripheral blood of participants.
Interleukin 9	one study visit	Concentration of IL-9 in peripheral blood of participants.
Interleukin 22	one study visit	Concentration of IL-22 in peripheral blood of participants.
TNF-α (Tumor Necrosis Factor)	one study visit	Concentration of TNF-α in peripheral blood of participants.
Number of Participants With ≥1 Quadrant Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Interleukin 5	one study visit	Concentration of IL-5 in peripheral blood of participants.
Interleukin 21	one study visit	Concentration of IL-21 in peripheral blood of participants.
Number of Participants With ≥6 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Interleukin 6	one study visit	Concentration of IL-6 in peripheral blood of participants.
Interleukin 10	one study visit	Concentration of IL-10 in peripheral blood of participants.
Interleukin 17F	one study visit	Concentration of IL-17F in peripheral blood of participants.
Interferon-γ	one study visit	Concentration of INFγ in peripheral blood of participants.
Mean Number of Sacroiliac Joint (SIJ) Quadrants Affected by BME or Structural Lesions for Each Participant	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant.
Median Number of Sacroiliac Joint (SIJ) Quadrants Affected by BME or Structural Lesions for Each Participant	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant.
Number of Participants With ≥3 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Number of Participants With ≥4 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Number of Participants With ≥5 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.
Number of Participants With ≥7 Quadrants Affected by BME or Structural Lesions	one study visit	MRIs were independently read and scored by 2 expert rheumatologists and 1 newly trained rheumatologist reader, blinded to any clinical information. MRIs were evaluated and scored for presence of bone marrow edema (BME) and structural lesions (erosion, fat metaplasia, backfill and ankylosis) using a validated scoring method originally derived from the Spondyloarthritis Research Consortium of Canada SIJ module. Readers determined whether BME and the structural lesions were present in each of the quadrants for each participant. There are 2 sacroiliac joints and 4 quadrants for each joint, for a total of 8 quadrants for each participant. A quadrant is deemed affected if concordantly reported by ≥ 2/3 readers.