Sacroiliitis in inflammatory bowel disease

REVIEW
URRENT
C
OPINION
Sacroiliitis in inflammatory bowel disease
Fardina Malik a and Michael H. Weisman b
Purpose of review
This review summarizes the recent evidence regarding the epidemiology of inflammatory bowel disease
(IBD) associated sacroiliitis, including the prevalence, pathogenesis, role of imaging, and therapeutic
challenges.
Recent findings
Sacroiliitis is an underappreciated musculoskeletal manifestation of IBD, a chronic inflammatory condition
of the gut affecting the younger population. Untreated sacroiliitis can lead to joint destruction and chronic
pain, further adding to morbidity in IBD patients. Recent publications suggest sacroiliitis can be detected on
abdominal imaging obtained in IBD patients to study bowel disease, but only a small fraction of these
patients were seen by rheumatologists. Early detection of IBD-associated sacroiliitis could be achieved by
utilization of clinical screening tools in IBD clinics, careful examination of existing computed tomography
and MRI studies, and timely referral to rheumatologist for further evaluation and treatment. Current
treatment approaches for IBD and sacroiliitis include several targeted biologic therapies, but IBD-associated
sacroiliitis has limited options, as these therapies may not overlap in both conditions.
Summary
With the advances in imaging, sacroiliitis is an increasingly recognized comorbidity in IBD patients. Future
studies focusing on this unique patient population will expand our understanding of complex
pathophysiology of IBD-associated sacroiliitis and lead to identification of novel targeted therapies for this
condition.
Keywords
inflammatory bowel disease, MRI, sacroiliitis, spondyloarthritis
INTRODUCTION
Inflammatory bowel disease (IBD) is a chronic
relapsing inflammatory disease of the gut with
Crohn’s disease and ulcerative colitis being the
major subtypes. Sacroiliitis, a hallmark of axial spondyloarthritis (axSpA), could impact up to 40%
patients with IBD. A seminal publication by Moll
and Wright in 1974 described IBD-associated arthritis (including ankylosing spondylitis, AS) as one of
the subtypes of seronegative SpA, based on their
shared clinical and immunological presentations
[1]. AxSpA has been subdivided into nonradiographic (nr-axSpA) and radiographic (AS) diseases
based on regulatory considerations, but most rheumatologists consider them as a single disease. Even
though the most common extra-intestinal manifestation (EIM) of IBD patients is musculoskeletal,
sacroiliitis is often underdiagnosed in this population. Similar to prototypical axSpA, the diagnosis of
sacroiliitis is often delayed and untreated sacroiliitis
can negatively impact quality of life of patients with
IBD [2–4,5 ]. IBD-associated sacroiliitis presents
clinically in a spectrum, ranging from nonradiographic axSpA to radiographic stages [6] and a small
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fraction of patients presenting without any back
pain, making it harder to diagnose. Furthermore,
the correlation between IBD activity and sacroiliitis
is poor, making the therapeutic decision challenging for physicians. Advances in targeted therapies
over the recent decades revolutionized disease outcomes in both IBD and sacroiliitis; however,
approved therapies for both diseases do not always
overlap. In this contemporary review, we summarize
prevalence, pathophysiology, clinical presentation,
diagnostic modalities, and treatment options of
IBD-associated sacroiliitis.
a
Division of Rheumatology, New York University Grossman School of
Medicine, New York, New York and bDivision of Rheumatology, Stanford
University School of Medicine, Stanford, California, USA
Correspondence to Fardina Malik, MBBS, MS, Assistant Professor of
Medicine, Division of Rheumatology, Department of Medicine, New York
University Grossman School of Medicine, New York, NY 10016, USA.
Tel: +1 646 501 7400; fax: +1 646 754 9607;
e-mail: [email protected]
Curr Opin Rheumatol 2024, 36:274–281
DOI:10.1097/BOR.0000000000001017
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Sacroiliitis in inflammatory bowel disease Malik and Weisman
KEY POINTS
Sacroiliitis is an under recognized comorbidity in
patients with inflammatory bowel disease (IBD).
Proper screening of patients in IBD clinics and utilizing
existing abdominal imaging to detect sacroiliitis could
ensure early diagnosis and timely referral.
Implementation of artificial intelligence based imaging
tools, diagnostic or prognostic biomarkers, and
development of novel therapeutic targets might improve
patient outcomes in this disease.
Prevalence of inflammatory bowel disease
associated sacroiliitis
IBD affects 0.7% of United States population
(approximately 2.4 million) with incidence peaking
in early adulthood [7]. Reported prevalence of sacroiliitis in IBD, however, varies widely. A systematic
review and meta-analysis in 2017 reported pooled
prevalence of AS and sacroiliitis as 3 and 10%,
respectively, with higher prevalence in European
countries, compared to North or South America.
IBD patients at tertiary care centers were also more
likely to have diagnosis of sacroiliitis than other
centers [8]. A more recent systematic review of
axSpA imaging study in IBD patients reported prevalence between 2.2 and 68%. This unusually wide
margin likely stems from heterogeneity of study
population across studies, differences in methodology and definitions of sacroiliitis, that is, modified
New York (mNY) criteria or MRI-based definitions
[9]. Prospectively enrolled IBD patients without any
back pain were noted to have occult sacroiliitis in
24–27.1% on radiographs [10,11]; however, it is
unclear whether these radiographs met mNY criteria. On follow-up studies, these IBD cohorts showed
an association of occult sacroiliitis with peripheral
arthritis and erythema nodosum and 18% developed back pain, and hence ax-SpA diagnosis in
3 years [10,11]. McEniff et al. [12] showed prevalence
of sacroiliitis meeting mNY criteria was slightly
higher (32%) when computed tomography (CT)
was utilized.
Assessment of SpondyloArthritis International
Society (ASAS) classification criteria was utilized in
some studies to determine prevalence of sacroiliitis
in IBD patients with back pain. It should be noted
that specificity of clinical arm of ASAS criteria
[13,14] in IBD patients can be low, as it does not
require imaging confirmation of sacroiliitis. For
example, an HLA-B27 positive IBD patient with
chronic back pain that started before 45 years of
age with only one other SpA feature (e.g. enthesitis,
inflammatory back pain, uveitis, etc.) will automatically meet clinical arm criteria of axSpA without confirmation on imaging. A population-based
retrospective cohort study using Rochester Epidemiology project reported incidence of axSpA
(meeting clinical arm of ASAS criteria) as 13.9
and 18.6% at 20 and 30 years after Crohn’s disease
diagnosis and only 0.5% with AS (mNY) [15]. But
incidence of axSpA and AS was reported as 7.7%
and 4.5%, respectively, among a prospective IBD
cohort from Norway at 20 years of follow up [16].
Incidence of Ax-SpA may be quite different in the
latter study owing to utilization of imaging arm of
ASAS criteria.
Cross-sectional studies of abdominopelvic CT
or CT enterography (CTE) obtained from IBD
patients as standard of care were retrospectively
reviewed by radiologists to determine presence of
sacroiliitis using standardized scoring system [17–
22]. Sacroiliitis was noted in 15–20% of IBD
patients and there was no difference between ulcerative colitis and Crohn’s disease patients. Chan
et al. [18] showed prevalence of sacroiliitis was
three-fold higher in IBD patients compared to
patients without IBD. A temporal relationship
with back pain was not established as these were
retrospective studies. Only 10% of these patients
were ever assessed by rheumatologists, suggesting
an underdiagnosis. Kelly et al. [17] reported association of sacroiliitis with male sex, history of
peripheral arthritis and Crohn’s disease inflammatory phenotype [17]. Standardized MRI of sacroiliac
joint (SIJ) showed sacroiliitis in 12–39% of patients
with IBD [23–26] and this wide range was again
due to differences in MRI interpretations in
these studies (e.g. ASAS definition of MRI positivity
vs. inclusion/exclusion of structural lesions). Magnetic resonance enterography (MRE) is a contrastenhanced imaging modality invariably used to
assess luminal disease activity in Crohn’s disease
patients, but it allows visualization of SIJ. MRE
images include T1-weighted and short tau inversion
recovery (STIR) sequences that are required to detect
SIJ structural lesions and bone marrow edema
(BME), respectively. Retrospective studies where
musculoskeletal radiologists reviewed previously
obtained MRE images for clinical care, reported
sacroiliitis was present in 15–16.7% of patients, with
up to two-thirds showing evidence of BME meeting
ASAS criteria of MRI positivity [27–29]. We showed
that structural lesions noted on MRE correlated with
rheumatologist diagnosis of ax-SpA in a follow-up
study [30]. Older age and female sex were associated
with MRE-based sacroiliitis, but there was no correlation between Crohn’s disease activity and ASASpositive cases.
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Spondyloarthritis including psoriatic arthritis
Pathogenesis of inflammatory bowel
disease associated arthritis
The term “gut-joint axis” was originally coined to
denote the intricate relationship between gastrointestinal inflammation and SpA. The association
between AS and IBD was first elucidated in seminal
publications in 1950 s [31,32]. Approximately 10–
15% AS patients develop IBD and up to 50% of SpA
patients have subclinical gastrointestinal inflammation with more than 50% having ileal inflammation
[33]. Furthermore, patients with axSpA tend to show
chronic inflammatory changes on gut histology, as
opposed to acute inflammatory changes in peripheral SpA [34,35]. These findings might suggest that
subclinical gut inflammation in axSpA patients is
similar to Crohn’s disease. Conversely, only 4% of
patients with IBD develop AS with higher incidence
associated with longer duration of IBD and up to
40% Crohn’s disease patients were found to have
sacroiliitis on MRI-based studies [24,25].
Despite HLA-B27 being the single most important genetic risk factor in AS with an estimated
heritability of more than 90% [36–38], it does not
play a role in IBD. Similarly, mutation of NOD2 is an
established risk factor for IBD [39,40] without any
association with AS. However, one study showed
that subgroup of SpA patients with histological
gut inflammation are more likely to carry NOD2
variant compared to those without [41]. IL-23R
mutation, endoplasmic reticulum aminopeptidase
(ERAP) 1 and 2 are all genetic loci associated with
both AS and IBD, suggesting a genetic link between
the two diseases [42–46]. In 2016, a large multicenter genome-wide association study (GWAS) of
52 262 cases of European patients showed over 150
genetic loci linked to AS, Crohn’s disease and ulcerative colitis with a significant overlap of several
risk alleles between these three diseases and it was
suggested that coexistence of Crohn’s disease or
ulcerative colitis with AS is a result of biological
pleiotropy, a phenomenon, which indicates two
or more distinct phenotypic traits that result from
a single genetic loci or mutation [47]. Other studies
also showed Crohn’s disease and ulcerative colitis
share several risk alleles and they are functionally
related to intestinal barrier function [48].
Intestinal type 3 immune cells and cytokines are
integral to maintaining the gut barrier homeostasis
and intestinal permeability, dysregulation of which,
is central to pathogenesis of both IBD and SpA
[49,50]. Healthy human entheseal tissue from spine
contain gdT and innate lymphoid cells [51,52]. Both
IL-23 and IL-17 concentration increase in intestinal
lining of Crohn’s disease patients and IL-17 concentration is elevated in serum of AS patients [53,54]. In
the setting of IL-23 overexpression in IBD, IL-23
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responsive gdT cells, innate lymphoid cells, Th17
cells elaborate IL-17 and 22, hypothetically resulting
in axial inflammation [55]. Another dominant cytokine that plays a critical role in IBD and sacroiliitis
pathogenesis is tumor necrosis factor a (TNFa)
establishing the strong link between the two diseases [56–59].
Risk factors and clinical presentation of
inflammatory bowel disease associated
sacroiliitis
Sacroiliitis in IBD presents in a similar manner as
other subtypes of axSpA, including chronic back
pain with or without other EIMs of IBD, that is
peripheral arthritis, enthesitis, dactylitis, uveitis,
erythema nodosum, pyoderma gangrenosum. Psoriasis can frequently accompany IBD given shared
immunological and genetic features [60,61]. Fortysix percent of IBD patients can present with back
pain and only 10–30% of them have inflammatory
back pain (IBP) meeting ASAS or Calin criteria
[5 ,16]. Although IBP (age 40 years, insidious
onset, nocturnal awakening, improvement with
exercise and no improvement with rest) is an established SpA feature in ASAS criteria, longitudinal IBD
cohort study showed only two-thirds of IBD patients
with IBP were diagnosed with axSpA and one third
carried a diagnosis of AS (7.7 and 4.5% of all IBD
patients, respectively). AxSpA incidence in IBD
peaks between 20 and 30 years of age [8]. As discussed earlier, male sex associated with sacroiliitis
diagnosed on X-ray or CT, while female sex associated more with sacroiliitis on MRE.
Both IBD and axSpA can have insidious onset
and chronology of first appearance of either disease
can be difficult to ascertain. A large Swiss IBD cohort
of 1249 patients [62] revealed axSpA/AS was diagnosed in 40% of cases before IBD diagnosis and
majority presented 2 months prior to IBD diagnosis
(range 0–16 years). However, majority of EIMs in
this cohort, including axSpA were diagnosed more
often after IBD diagnosis. AxSpA is more commonly
associated with Crohn’s disease than ulcerative colitis [8,63–65] in studies where IBD patients were
phenotyped clinically for SpA but image-based studies (CT, CTE) did not show such difference.
It is traditionally accepted that IBD activity and
axSpA disease activity does not correlate. However,
this could be due to the fact that earlier studies
defined sacroiliitis based on radiographs as a binary
outcome and correlation with IBD disease activity
could not be established. Most of these studies were
also retrospective and did not have data on validated
measures of IBD and axSpA activity. Ossum et al. [16]
suggested correlation of axSpA with more active IBD
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Sacroiliitis in inflammatory bowel disease Malik and Weisman
(both acute and chronic). A very small (n ¼ 8) study
reported positive correlation between high Crohn’s
disease activity index (CDAI) and BASDAI and BASFI
[66]. Our study that utilized MRE ASAS positivity,
CDAI, MRE-based Crohn’s disease activity, endoscopic Crohn’s disease activity and did not find
any association between active sacroiliitis and
Crohn’s disease activity [29]. Relationship with
IBD phenotype (location and nature of IBD), such
as upper GI involvement, perianal disease [22] have
been reported, but these were not consistently
reproduced.
HLA-B27 is a known genetic marker for axSpA,
but it is present only in 10–30% of all IBD patients
[16,67]. Up to 90% of patients with AS in IBD were
found to have B27 positivity is earlier studies [68],
but more recent studies show B27 positivity only in
57–62% IBD-associated axSpA [16,25,67,69], suggesting half of IBD associated sacroiliitis patients
will be B27 negative.
Role of imaging in early detection of
inflammatory bowel disease associated
sacroiliitis
Asymptomatic sacroiliitis on imaging studies suggests that sacroiliitis in IBD patients can remain
underdiagnosed. This delay is analogous to delay
in AS diagnosis in general and might be related to
other reasons, such as- discrepancy between IBD and
axSpA disease activity, asymptomatic phase and low
number of rheumatology referral in community
settings [8]. HLA-B27 positivity confers increased
risk of AS/axSpA, especially with history of uveitis
[70] but B27 is negative in half of IBD patients with
axSpA and uveitis is an infrequent EIM, affecting
only less than 15% of IBD patients [62,64]. There is
paucity of established classification criteria, serum
biomarkers or IBD related risk factors carrying strong
association with IBD-associated sacroiliitis that
would trigger referral to rheumatologists. So, imaging plays a crucial role, not only in diagnosis of
axSpA in IBD patients presenting with back pain
but also as a potential screening tool. Standard CT,
CTE and MRE of abdomen-pelvis are routinely
obtained in IBD patients in clinical setting to assess
IBD disease activity and complications (e.g. perforations or obstruction, etc.).
As noted above, retrospective studies showed
20% patients of IBD patients had sacroiliitis on these
imaging modalities after these images were read by
musculoskeletal radiologists using validated scoring
system. Up to 90% of these IBD patients were never
seen by rheumatologists [17,18,29]. Presence of erosions, subchondral sclerosis, ankyloses are imaging
features commonly attributed to sacroiliitis on CT
(Fig. 1). But CT evidence of sacroiliitis reflects structural damage that results from a preceding phase of
inflammation and does not provide information on
extent of sacroiliitis activity and overlooks the early
phase of inflammation. STIR sequences of MRI allow
detection of sacroiliitis in its early stages in the form
of BME, and can assess degree of inflammation while
simultaneously showing structural lesions (erosions, ankylosis, fat metaplasia and backfill) on
T1-weighted images. MRE is a noninvasive study
utilized by gastroenterologists to monitor Crohn’s
disease activity, mucosal healing and has correlation
with endoscopic Crohn’s disease activity [71]. It is
preferred over CT due to lack of ionizing radiation.
MRE allows visualization of sacroiliac joints and
STIR images can detect BME, while T1-weighted
images can show erosion, fat metaplasia and ankylosis [29] (Fig. 2a, b). MRE or CTE-based sacroiliitis
FIGURE 1. (a) Computed tomography enterography (CTE) obtained in a 66-year-old woman with Crohn’s disease with
symptoms of intermittent back pain (2--3 flares/year, lasting for a week each episode) for the past 25 years was noted to have
bilateral SIJ sclerosis (arrows) and erosions (arrowheads) with irregular joint space. (b) A 27-year-old male patient with
Crohn’s disease who presented to emergency room with abdominal pain due to Crohn’s flare. CT showing dense subchondral
sclerosis (arrows) and ankylosis (asterisk).
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Spondyloarthritis including psoriatic arthritis
FIGURE 2. (a) Magnetic resonance enterography (MRE) obtained on 26-yearold male patient with Crohn’s disease to monitor
CD activity. MRE STIR image show acute bone marrow edema (arrows) along bilateral SIJs. (b) A 46-year-old female patient
with CD and T1W images on MRE showing irregular joint space, fat metaplasia (asterisk) and sclerosis (arrowhead).
has not been validated as of yet and prospective
studies should be undertaken to establish their role
as a screening tool to detect sacroiliitis in IBD
patients, which can prompt early referral to rheumatologists for further management.
Contemporary treatment options for
inflammatory bowel disease associated
sacroiliitis
Management of active axSpA/sacroiliitis in IBD is
extrapolated from established guideline for management of axSpA/AS and IBD (Table 1) [72–76]. Choice
of pharmacological agent should be based on shared
decision between patients and providers and need to
be individualized based on patient’s clinical presentation, that is presence of other EIMs (especially
uveitis, peripheral arthritis), disease status (active
vs. quiescent axSpA or IBD), etc. NSAIDs are the
preferred first-line agents for treatment of axSpA/
AS, but its use is limited in IBD amidst conflicting
data regarding safety in IBD and concern for flares
[77–79]. Although some studies suggest relative
safety of selective cyclooxygenase-2 (COX-2) inhibitors in IBD [80,81], Italian expert panel suggested
limiting COX-2 use to less than 2 weeks in quiescent
IBD and avoiding altogether when IBD is active [82].
TNF-a inhibitors (TNFi) are the most preferred
agents in patients with active axSpA/AS with
Crohn’s disease or ulcerative colitis given their well
Table 1. Treatment recommendations for axial spondyloarthritis, Crohn’s disease and ulcerative colitis
Medication class
Medications
NSAIDs
csDMARDs
Parenteral MTX
axSpA
CD
UC
Notes
þ
May cause IBD flare
þ
þ
Monotherapy in CD, combination with biologic in both CD and UC
Mild CD colitis or UC, IBD patients with pSpA. axSpA patients with pSpA
þ
þ
Adalimumab
þ
þ
þ
Infliximab
þ
þ
þ
Certolizumab
þ
þ
Etanercept
þ
Golimumab
þ
þ
Tofacitinib
þ
þ
Upadacitinib
þ
þ
þ
Sulfasalazine
TNF-a inhibitors
JAK inhibitors
Secukinumab
þ
Ixekizumab
þ
a4b7 integrin inhibitor
Vedolizumab
þ
þ
IL-12 and 23 inhibitor
Ustekinumab
þ
þ
Risankizumab
þ
IL-17A inhibitor
Not recommended in CD with perianal fistula
Awaits approval for UC
csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; IL, Interleukin; JAK, Janus Kinase inhibitor; MTX, methotrexate; TNF, tumor necrosis
factor.
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Sacroiliitis in inflammatory bowel disease Malik and Weisman
established efficacy in these diseases, particularly
infliximab and adalimumab. Etanercept, a TNF-a
receptor fusion protein, showed no efficacy in IBD
in clinical trial and can precipitate flares [83,84].
Certolizumab is approved for Crohn’s disease, but it
is least preferred by experts compared to other biologic DMARDs for moderate to severe Crohn’s disease and perianal disease [74]. Golimumab is
approved only for ulcerative colitis, not Crohn’s
disease. Recent approval of Janus kinase (JAK) inhibitors (JAKi) for treatment of axSpA/AS as well as
for IBD expanded the therapeutic armamentarium
of axSpA-IBD management with few exceptions
(Table 1). Upadacitinib, a selective JAK1 inhibitor
is approved for axSpA, ulcerative colitis and Crohn’s
disease but JAK1, 3 inhibitor (tofacitinib) is not
approved for Crohn’s disease.
Despite the critical role of IL-23/Th17 pathway
in IBD and axSpA pathogenesis, mAb therapies
designed to target this pathway showed unexpected
and paradoxical results in clinical trials. IL-17 inhibitors (IL-17i) performed worse than placebo in IBD
phase II clinical trial [85] but showed remarkable
efficacy in axSpA in clinical trials, which included
only small amount of quiescent IBD patients with
axSpA [86,87]. Several case reports allude to new
onset IBD in SpA patients treated with secukinumab
[88]. But pooled data from 21 clinical trials suggests
incidence is rather low [89] and large populationbased study showed risk of incident IBD is similar to
etanarcept [90]. On the other hand, IL-12/23i ustekinumab, an inhibitor of p40 subunit of IL-12/23
showed great efficacy in both Crohn’s disease and
ulcerative colitis [91,92] but failed to show efficacy
in axSpA [93]. Similarly, risankizumab blocks p19
subunit of IL-23 and efficacious in both Crohn’s
disease and ulcerative colitis (awaits approval for
ulcerative colitis) but, not in axSpA [94]. McGonagle
attributed this discrepant response partially to IL-17
producing gdT cells in human spinal entheses are
independent of IL-23 production [95]. IBD treatment guidelines also recommend vedolizumab, an
a4b7 integrin inhibitor, for moderate to severe
Crohn’s disease and UC but efficacy in axSpA
remains unknown. A case series of 11 IBD patients
[96] described acute axSpA with acute BME on MRI
spine and SIJ in seven patients on vedolizumab (five
without any known prior SpA), but Orlando et al.
[97] reported no worsening of SpA in 53 IBD patients
followed for 6 weeks. These discrepant responses
to approved therapeutics in IBD and axSpA exemplify need for combination biologic therapy, especially in IBD subgroups with severe gastrointestinal
and SIJ disease activity and history of nonresponse
to more than one biologics. A phase 2 proof-ofconcept study utilizing guselkumab and golimumab
combination therapy versus monotherapy of either
biologic showed superiority of combination therapy
in achieving more stringent definition of clinical
remission in ulcerative colitis patients without significantly increasing risk of infection [98 ]. This
opens the door to use the same approach to address
active axSpA in IBD patients.
&&
CONCLUSION
Sacroiliitis is an under recognized comorbidity in
IBD patients, most of whom are at prime years of
their lives and less than 10% of these patients are
referred to rheumatology for evaluation. Routine
screening of IBD patients with validated questionnaires, timely detection of sacroiliitis on abdominopelvic CT, CTE and MRE obtained in IBD patients as
a standard of care can improve referral. Awareness of
this entity amongst IBD patients, IBD gastroenterologists and abdominal radiologists through educational activities could result in early detection of
sacroiliitis in clinical settings and improve outcome.
Image-based artificial intelligence decision support
tools using existing CT or MRI studies may further
facilitate early diagnosis and referral of these
patients in near future. Furthermore, advances in
next-generation sequencing, exosome profiling,
and proteomics may result in identification of
blood-based biomarkers for diagnosis and prognosis
of patients with IBD-associated sacroiliitis. Disconnect in targeted therapeutics in IBD and axSpA
expound on as yet unidentified shared immunological pathways between the two diseases. Future basic
and translational studies are needed to unveil shared
pathways, leading to discovery of novel therapeutic
targets that can improve outcomes of IBD patients
with axSpA.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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&&
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An exciting clinical trial data that will encourage more combination biologic, very
much applicable in this patient population
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