Enteropathic Spondyloarthritis: A Review of Mechanisms and Effective Treatment Strategies

Enteropathic spondyloarthritis (ESpA) encompasses a group of rheumatic disorders that share overlapping pathophysiology with other immune system disorders, particular those of the gut. Therefore, a multidisciplinary approach is important to recognizing the varied manifestations of ESpA in patients with IBD in order to achieve a prompt and accurate diagnosis leading to comprehensive care.

Spondyloarthritis (SpA) comprises a class of inflammatory disorders of the large and small joints and the axial skeleton and local connective tissue, including ankylosing spondylosis (AS), reactive arthritis, psoriatic arthritis (PsA), non-radiographic axial (nr-ax) SpA, and nonspecific forms often referred to as “undifferentiated” SpA.1

Patients are often diagnosed with SpA on the basis of inflammatory low back pain in the lumbar, buttock, and hip area. The pain usually lasts more than 3 months, with morning stiffness of at least 30 minutes.2 SpA pain is responsive to non-steroidal anti-inflammatory drug (NSAID) therapy.

Autoimmune conditions such as inflammatory bowel disease (IBD), or anterior acute uveitis (AAU) are frequently associated with SpA, in addition to psoriasis, which can lead to an enteropathic SpA (ESpA) diagnosis. The pathophysiology of ESpA is not well understood, but the coexistence of SpA and IBD bowel symptoms in patients suggests a shared etiology.

Prevalence of Overlap With Gut Mechanisms

An overlapping etiology between SpA and the gut has been observed in a number of studies, which could result from a lymphocytic mechanism. An estimated 70% of SpA patients demonstrate involvement of the gastrointenstinal (GI) tract, and 7-12% are diagnosed with IBD.4-8 Likewise, joint pain and swelling are reported in 16-33% of patients with IBD.5-8

In vitro studies of the binding properties of activated human intestinal immunoblasts have demonstrated efficient attachment to mucosal cells within the intestine. They also demonstrated attachment to extra-intestinal high endothelial venules (HEVs) without binding to lymph node vascular walls, conceivably providing the opportunity for intestinal lymphocytes to travel to joints.9 Once there, antigen-activated T cells may induce a synovial inflammatory response in what has been called the “gut iteropathy concept.”10  

Overlapping clinical features between SpA and IBD have also pointed to mechanisms involving the human leukocyte antigen (HLA) B27 common to both conditions, which has been examined in a number of studies.4 Transgenic rats induced with HLA-B27/human B2 microglobulin rapidly progressed to inflammatory disease simultaneously in the intestines and joints with the introduction of normal intestinal bacteria, while rats that were kenervept germ-free did not develop symptoms of inflammation.11,12 This study provided the first convincing evidence a link between intestinal bacteria and joint inflammation.12

Although the prevalence of AS, the most frequent form of SpA, in IBD has only been reported in 1% to 10% of patients, this prevalence was determined using New York  criteria, which prevent definitive diagnosis at disease onset, and may result in underestimation of the coexistence of the two conditions.13-15

Contradictory to previous results, one clinical study of AS patients reported that greater than 90% tested positive for HLA-B2716, while studies of IBD patients with AS have found that 25% to 78% of them are HLA-B27 positive.15,17-19 The role of HLA-B27 in inflammation is not yet clear and several theories are under investigation, involving mechanisms of altered or defective cell death and misfolding of the HLA-B27 beta pocket, as well as the possible cross-reactions with bacterial antigens that are normally restricted to HLA-B27.20-22

Another study found an overlap  between SpA and Crohn’s disease (CD) in which scavenger receptor CD163+ macrophages are increased in gut mucosa, suggesting that antigen-presenting cells may contribute to both gut and joint inflammation, in addition to T-cell mechanisms.23

Prevalence and Diagnosis

The clinical manifestations of ESpA are extremely broad with multi-organ involvement, which contributes to variations in diagnostic approaches and a general underestimation of the prevalence of ESpA. A recent prospective study by Conigliaro et al., published in Autoimmune Review, evaluated 269 patients diagnosed with IBD accompanied by joint pain. The patients were assessed in a multidisciplinary gastrointestinal and rheumatologic clinic setting (GI-Rhe Clinic) and revealed significantly higher rates of joint pain than previously thought.3

Evaluations of clinical and biochemical assessments were consistent with ESpA in 50.5% of cases (136 patients), with peripheral involvement, axial involvement, and both peripheral and axial involvement in 53%, 20%, 26.4% of those cases, respectively.3 The prevalence of other autoimmune disorders including psoriasis, uveitis, primary sclerosing cholangitis, and erythema nodosum was also collectively higher in ESpA (9.2% vs 6.8%) in non-ESpA IBD patients.3

Within the total cohort of 1495 IBD patients, 18% had joint inflammation, and 9% were diagnosed with ESpA. The patient demographics were similar between those with ESpA and those without. Patients reassigned a diagnosis of ESpA indicated a greater number of extra-instestinal autoimmune manifestations, and were more likely to be given anti-tumor necrosis factor (TNF) treatment compared with patients diagnosed with IBD alone (35.6% vs 16.3%, P=0.003).3

Impact of Diagnostic Delay

The GI-Rhe Clinic study reported an average delay to diagnosis of ESpA of 5.2 years between 2002 and 2012. This represented a substantial reduction when compared with the two prior decades, most likely due to better assessment criteria and improvements in magnetic resonance imaging (MRI) and ultrasound images that identify inflammation at axial and peripheral joints.3

Diagnostic delay was attributed to multiple factors, including the generally mild nature of early joint symptoms, and common treatment of IBD with immunosuppressive therapies that also reduce joint inflammation. Diagnoses using New York criteria and failure or delays in referrals to a rheumatologist also contribute to delays in an essential diagnosis of ESpA.24

The impact of incorrect or delayed diagnosis can be significant to the disease course, as it results in delays in treatment that contribute to poorer quality of life and greater progression of joint damage.25  Longer disease duration at the time of treatment has also been associated with poorer outcomes and a lessened response to interferon therapy.24,26

ESpA Treatment

Treatment of IBD/ESpA is dependent on the constellation of overlapping symptoms.  In cases of type 1 arthropathies involving inflammation of the peripheral joints occurring as a feature of IBD exacerbation, treatment is directed to resolution of the intestinal symptoms, which can also reduce joint pain. 

Type 2 arthritis manifests as inflammation of the axial joints, independent of the course of concomitant IBD, and is frequently treated with NSAIDS. Concern over the potential of NSAIDs to contribute to IBD flares has not been supported in limited studies.27,28

An alternative is selective cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be safe for short-term treatment in a placebo-controlled clinical trial and several smaller trials.29-31 Standard analgesic medications may also be used, and physiotherapy and corticosteroid injections are also used as adjunctive therapies. 

In cases of high disease activity that are resistant to conventional treatments, the Assessment in SpondyloArthritis International Society/European League Against Rheumatism (ASAS/EULAR)  guidelines recommend the use of anti-TNF inhibitors infliximab, etanercept, and adalimumab to relieve axial and peripheral joint pain and stiffness of AS and improve flexibility and motion.32

Summary and Clinical Applicability

Enteropathic spondyloarthritis encompasses a group of rheumatic disorders that share overlapping pathophysiology with other immune system disorders, particular those of the gut. Therefore, a multidisciplinary approach is important to recognizing the varied manifestations of ESpA in patients with IBD in order to achieve a prompt and accurate diagnosis leading to the comprehensive care required to manage these diseases effectively.

Clinical goals are to maximize long-term quality of life through the management and control of inflammation of the gut and joints, manage peripheral involvement of the eyes and skin, and prevent progression to structural damage.


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