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Musculoskeletal Manifestations of Inflammatory Bowel Disease
Definition and Classification
Inflammatory bowel disease (IBD) denotes a group of related and heterogeneous disorders characterized by chronic intestinal inflammation and generally classified into Crohn disease (CD) and ulcerative colitis (UC). When there are features of both UC and CD, as can occur in the setting of predominantly colonic IBD, the term IBD-unclassified (IBD-U) is applied. Some children initially considered to have IBD-U will over time develop clear features of CD, but the majority behave as UC with respect to both medical and surgical treatment response. IBD represents a growing global burden. The prevalence overall in children and adults is highest in the Western world, in countries such as Canada, where it is predicted to approach 1% by the year 2030.
Arthropathies are the most common extraintestinal manifestations (EIMs) of IBD. In adults, IBD-associated arthritis is classified as one of the seronegative (i.e., rheumatoid factor-negative) spondyloarthritides, along with ankylosing spondylitis (AS), reactive arthritis, and psoriatic arthritis. Numerous adult spondyloarthritis (SpA) classification systems exist, including the widely used Assessment in Spondyloarthritis International Society (ASAS) criteria (see Chapter 20 ). , In the ASAS and most other adult classification schemes, IBD is explicitly acknowledged as an SpA diagnostic criterion. Historically, the classification of SpA has been handled differently in children and adolescents, and no analogous pediatric SpA classification systems are currently in common usage. Instead, most pediatric arthritis is classified as a type of juvenile idiopathic arthritis (JIA) according to the International League Against Rheumatism (ILAR) criteria. , In this system, most juvenile SpA (JSpA) falls into the category of enthesitis-related arthritis (ERA), but this category does not specifically address children with coexisting IBD. IBD is not explicitly listed as an exclusion criterion, but IBD-associated arthritis is generally considered outside the JIA rubric. Although children with arthritis and IBD do not formally fall under the umbrella of JIA, they do share features with the ERA group and may be best considered a type of JSpA, typically characterized by enthesitis, lower extremity oligoarthritis, possible axial involvement, and the presence of human leukocyte antigen (HLA)-B27.
Musculoskeletal (MSK) manifestations of IBD extend beyond SpA to include noninflammatory entities like arthralgia and osteoporosis, and rare associations with conditions like chronic recurrent multifocal osteomyelitis (CRMO) (see Chapter 40 ), vasculitis, and familial Mediterranean fever (FMF). In this chapter, we review the epidemiology, pathogenesis, clinical manifestations, and treatment of these MSK manifestations. Cutaneous and ocular manifestations of IBD are considered outside the scope of this chapter.
Epidemiology
The precise rates of arthropathies in pediatric IBD are difficult to ascertain because of heterogeneity across studies in patient characteristics and definitions. These limitations acknowledged, Table 51.1 summarizes rates of various MSK manifestations in recent pediatric IBD cohorts. Peripheral arthritis is substantially more common than axial involvement, with rates in these studies ranging from 1.8% to 12.3% for peripheral arthritis and 0% to 3.7% for axial involvement. Arthralgia is the most frequent articular manifestation in pediatric IBD, occurring in close to 20% in some series. Pediatric epidemiological data on other MSK manifestations are scarce, but enthesitis was found in 21% of a 43-patient pediatric IBD cohort specifically examined for this finding, and osteopenia was documented in 13% of a large 1600-patient pediatric IBD cohort. There are conflicting data regarding whether IBD-associated arthropathies are more common in pediatric or adult populations. In a recent meta-analysis of 71 studies including 27,524 adults with IBD, the pooled prevalence of peripheral arthritis, sacroiliitis, and AS were 13% (95% confidence interval [CI], 12 to 15), 10% (95% CI, 8 to 12) and 3% (95% CI, 2 to 4), respectively. Enthesitis and dactylitis were reported in 1% to 54% and 0% to 6%, respectively. There is evidence to suggest that peripheral IBD-associated arthropathies are more common in women, and in CD versus UC. In adults, axial involvement is said to be equal between the sexes and IBD types. In UC, arthropathies seem to be more common in patients with pancolitis and, in CD, in patients with colonic versus isolated small bowel involvement, an observation in keeping with the original term colitic arthritis . , , Importantly, arthropathies may be underrecognized in IBD. In a Canadian study of consecutive adult IBD patients seen for outpatient follow-up, 129 of 350 (37%) reported at least one SpA feature, but only half had visited a rheumatologist. Similarly, in a study of 316 adults with IBD undergoing computed tomography for any indication, 49 (16%) were found to have radiographic evidence of sacroiliitis, but only five had been to a spondylitis clinic. The precise prevalence of IBD in children with ERA is unclear given a paucity of data. In adults, 5% to 15% of SpA cases are thought to coexist with IBD. In a large meta-analysis of 69 studies including 30,410 adult AS patients, the pooled prevalence of IBD was 6.8% (95% CI, 6.1 to 7.7).
TABLE 51.1
Studies Reporting Musculoskeletal Manifestation Rates in Pediatric IBD Cohorts
| Study | IBD Type | Number of Patients | MSK Manifestation | Number Affected (%) |
|---|---|---|---|---|
| Levy ( 2019 ) | IBD | 715 | Arthritis and/or arthralgia | 137 (19%) |
| Nir ( 2017 ) | CD UC |
301 129 |
Arthralgia Peripheral arthritis Axial arthritis Arthralgia Peripheral arthritis Axial arthritis |
44 (14.6%) 30 (10.0%) 11 (3.7%) 16 (12.4%) 2 (1.6%) 2 (1.6%) |
| Greuter ( 2017 ) | IBD | 329 | Peripheral arthritis Axial arthropathy |
26 (7.9%) 5 (1.5%) |
| Horton ( 2012 ) | IBD | 42 | Enthesitis | 9 (21%) |
| Dotson ( 2010 ) | CD UC |
728 281 |
Arthritis Arthralgia AS Arthritis Arthralgia AS |
32 (4.4%) 124 (17%) 4 (0.5%) 5 (1.8%) 42 (14.9%) 0 |
| Guariso ( 2010 ) | IBD | 133 | Joint problems | 6 (4.5%) |
| Jose ( 2009 ) | IBD | 1649 | Peripheral arthritis Axial arthritis Peripheral and axial arthritis Osteopenia/osteoporosis |
45 (11.6%) 12 (3.1%) 14 (3.6%) 7 (1.8%) 51 (13.2%) |
AS, Ankylosing spondylitis; CD, Crohn disease; IBD, inflammatory bowel disease; MSK, musculoskeletal; UC, ulcerative colitis.
Etiology and Pathogenesis
Genetic Background
IBD is thought to result from a complex interplay of host immune mechanisms and environmental factors (including the gut microbiome) in genetically predisposed individuals. The precise mechanistic underpinnings, however, remain obscure. The role of the gut in joint pathology (the “gut-joint” axis) is also incompletely understood. Whether the relatively frequent occurrence of arthritis in IBD populations simply reflects the coexistence of comorbid conditions with shared susceptibility factors, or instead suggests that gut abnormalities are causally involved in the pathogenesis of the joint disease, is unclear. Genes within the major histocompatibility complex (MHC) region, particularly HLA-B27 (as detailed in Chapter 20 ), account for the majority of the currently known susceptibility of individuals to AS, the prototypical SpA. However, additional genes outside the MHC region involved in intracellular antigen processing and cytokine production (especially genes in the interleukin [IL]-17/IL-23 pathway) also contribute to SpA heritability. As for IBD, well over 200 susceptibility loci or genes have been identified thus far, including many shared between CD and UC. IBD susceptibility genes include those involved in either innate or adaptive immunity, including autophagy, T helper (Th)17, and nuclear factor-κβ (NF-κβ) pathway genes. , At least eight risk genes have been shown to overlap between IBD and AS; they include IL23R , IL12B , STAT3 and PTGER4 (linked to the Th17 pathway), CARD19 (linked to the NF-κβ pathway), and ILR2 and ORMDDL3 (linked to immune responses). , , Such findings support a common genetic background (and related immunological processes) beyond the MHC complex. Although a single study reported NOD2/CARD15 polymorphisms, known to be strongly associated with ileal CD, to be much more frequent in CD patients with sacroiliitis compared with those without sacroiliitis, these findings have not proven reproducible.
Gut Inflammation and the Microbiome
The gut-joint association seems to extend beyond the mere comorbidity of arthritis and IBD. The literature suggests that a substantial fraction of individuals with SpA may have subclinical gut inflammation. In various series, this fraction ranged from 40% to 70%, but it should be noted that, in many cases, “inflammation” included nonspecific microscopic changes only, the significance of which is unknown. Calprotectin, a cytosolic protein in neutrophils and therefore a marker of intestinal inflammation when measured in the stool, has also been used to investigate this issue. In a small pediatric study (n = 26), Stoll et al. observed higher fecal calprotectin (FCP) concentrations in children with ERA (171 μg/g), compared with other types of JIA (51 μg/g), connective tissue disease (CTD) controls (26 μg/g), and noninflammatory controls (80 μg/g). Sixty-seven percent of ERA patients had FCP greater than 120 μg/g, compared with 18%, 11%, and 17% of the respective control groups. Adult SpA populations have similarly been shown to have higher FCP values than controls. , , It is critical to note, however, that the confounding effect of nonsteroidal antiinflammatory drugs (NSAIDs), which are widely used in this population and well-recognized to cause gut inflammation and falsely elevated FCP, was not systematically considered in these studies, such that the reported prevalence of subclinical inflammation may be overestimated. Whether subclinical gut inflammation in these patients represents the earliest stage of IBD is unclear, but in at least two series, only 7% developed overt IBD over time, , perhaps suggesting that the gut pathology in such individuals is a separate entity from conventional IBD.
How gut pathology might relate to arthritis pathogenesis remains speculative. Some of the processes that have been implicated, such as dysbiosis, bacterial translocation with consequent triggering of dysregulated immune responses, and aberrant lymphocyte homing, are outlined in Box 51.1 . Early animal experiments, such as those demonstrating that HLA-B27/human β2-microglobulin transgenic rats (an animal model for human SpA) fail to develop gut and joint inflammation under germ-free conditions, provide compelling evidence for the role of the intestinal flora in SpA pathogenesis. Several studies have described differences in the gut microbiota of children with ERA compared with controls, such as decreased Faecalibacterium prausnitzii, , as has also been reported in CD, but such studies have mostly been associative. Interestingly, the addition of Akkermansia muciniphila cultures to fecal microbial transplant (FMT) preparations transferred from children with SpA to germ-free KRN/B6xNOD mice resulted in greater ankle swelling, offering some support for a potential causal link. This organism is generally considered a commensal organism but can degrade intestinal mucin.
BOX 51.1
Potential Pathogenic Mechanisms Linking Gut Inflammation and Arthritis
Dysbiosis (altered gut microbiome)
Increased intestinal permeability
Translocation of and increased exposure to (systemically or locally in joints) bacteria/bacterial metabolites
Molecular mimicry
Triggering of immune responses by bacteria/bacterial products via Toll-like receptors and/or macrophages (including CD163-positive macrophages) ,
Aberrant homing of lymphocytes via adhesion molecules (such as vascular adhesion molecule-1)
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