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 Table of Contents  
Year : 2020  |  Volume : 15  |  Issue : 5  |  Page : 52-56

Colitis in spondyloarthritis

Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication23-May-2020

Correspondence Address:
Prof. Vikas Agarwal
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-3698.284752

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Inflammatory bowel disease (IBD) is seen in up to 14% of patients with spondyloarthritis (SpA) with a lower prevalence seen in the Asian population. Conversely, SpA is the most common extraintestinal manifestation in IBD, with prevalence ranging from 10% to 39%. Apart from the strong Class I human leukocyte antigen B27 link for both diseases, several new shared genetic risk loci are identified from genome-wide association studies. Demonstrable mucosal inflammation of gut is present in most of the patients with SpA, even in the absence of clinically overt IBD. Mucosal inflammation leads to disruption of the epithelial barrier and activation of antigen-presenting cells and T-helper cells, which then home to synovium to cause inflammation maintaining the gut synovial axis. Several putative gut bacteria are implicated in the pathogenesis of SpA. IBD must be suspected in all patients of SpA presenting with abdominal pain, diarrhea, unexplained weight loss, anemia, or other malabsorption features. Fecal calprotectin is emerging as a noninvasive screening tool for detecting clinically silent IBD in patient with SpA. Several therapeutic targets have emerged in the last few years based on the understanding of the pathogenic mechanism and have considerably changed the management of both IBD and SpA.

Keywords: Ankylosing spondylitis, colitis, fecal calprotectin, gut microbiome, mucosal inflammation, spondyloarthropathy

How to cite this article:
Hafis M, Agarwal V. Colitis in spondyloarthritis. Indian J Rheumatol 2020;15, Suppl S1:52-6

How to cite this URL:
Hafis M, Agarwal V. Colitis in spondyloarthritis. Indian J Rheumatol [serial online] 2020 [cited 2023 Feb 2];15, Suppl S1:52-6. Available from:

  Introduction Top

The term spondyloarthritis (SpA) represents a group of disorders, including ankylosing spondylitis (AS), nonradiographic axial SpA (nr-axSpA), undifferentiated peripheral SpA, reactive arthritis (ReA), psoriatic arthritis (PsA), and inflammatory bowel disease (IBD)-associated arthritis. These are not mutually exclusive diagnoses and considerable overlap occurs between the phenotype of these disorders. The common features of these disorders include predominant axial involvement, asymmetric lower limb predominant oligoarthritis, dactylitis, enthesitis, male predominance, and a strong association with human leukocyte antigen (HLA)-B27 allele.

The association between IBD, both Crohn's disease (CD) and ulcerative colitis (UC), and SpA is well described in the literature. In this review, we provide an overview of epidemiology, shared genetic risk factors, pathogenesis, and treatment of IBD in SpA.

  Epedemiology Top

The prevalence of IBD in AS ranges from 6% to 14% across studies.[1],[2],[3],[4] A meta-analysis of 156 studies showed a pooled prevalence of 6.8% (95% confidence interval [CI]: 6.1–7.7%).[1] Pooled analysis of studies from Asia showed a lesser prevalence of IBD in SpA (2.9%, 95% CI: 1.9–4.4%).[1] A large population-based matched cohort study from the United Kingdom (UK) showed that 3.4% of patients had IBD at the time of diagnosis of SpA.[2] The cumulative incidence of IBD rose to 7.5% after 20 years of diagnosis of SpA. The risk for IBD was more pronounced in the 1st year of SpA.[2] A meta-regression analysis showed no association between disease duration and the prevalence and IBD. A meta-analysis addressing the prevalence of peripheral and extra-articular disease manifestations in patients with AS and nr-axSpA showed that the pooled prevalence of IBD was similar in AS (4.1%, 95% CI: 2.3–6.5%) and nr-axSpA (6.4%, 95% CI: 3.6–9.7%).[3] In the outcome in the AS international study cohort of 279 patients with 12 years follow-up, age, gender, HLA B27 status, pattern of articular involvement or level of inflammatory markers at diagnosis of SpA did not predict the development of IBD on follow-up.[4]

Microscopic gut inflammation can occur in up to 70% of patients with SpA.[5] In patients with axSpA, male sex (odds ratio [OR] =8.9), high disease activity measured by the bath AS disease activity index (OR = 2.05), restricted spinal mobility measured by the bath AS metrology index (OR = 1.94), and younger age (OR = 0.85) were independently associated with microscopic gut inflammation.[6] The significance of microscopic inflammation lies in the fact that up to 7% of them can progress to clinically overt IBD in 5 years.[7]

SpA is the most common extraintestinal manifestation in IBD, with prevalence ranging from 10% to 39%.[8] A meta-analysis of available studies showed that peripheral arthritis occurred in 13% of IBD patients.[9] In contrast, AS was seen in only 3% of patients. Two distinct forms of peripheral arthritis are described in IBD. Type I arthritis is self-limited nonerosive pauci articular asymmetric arthritis-like ReA. Type II arthritis involves more than five joints, is erosive and destructive, and has more association with HLA B27. A recent observational data from Italy, which enrolled 347 patients with enteropathic SpA showed that Type 1 (Pauci articular asymmetric peripheral arthritis) was the most frequent form.[10] CD was more associated with arthritis than UC.[10] IBD was inactive in most patients at the time of the development of arthritis. Most of the patients required biologic therapy.[10] Patients with a family history of IBD, history of appendicectomy, smoking, and the presence of any other extraintestinal manifestations are more likely to develop peripheral arthritis.[8] Erythema nodosum and pyoderma gangrenosum were also commonly observed in patients with peripheral arthritis than patients who did not.[8]

  Genetics Top

Both IBD and SpA are associated with HLA B27 allele. About 25%–78% of patients with both IBD and SpA are positive for HLA B27 allele.[11],[12],[13] Other MHC genes having an association with both IBD and SpA include HLA DRB 0103, HLA B35, and HLA B44.[8] A genome-wide association study, which did high-density genotyping of immune-related loci in a large number of AS patients, identified substantial overlap of risk gene polymorphism for AS with that of IBD.[14] AS-associated loci were associated with the same single nucleotide polymorphism at 12 loci shared with CD, at 11 loci shared with UC. The common risk polymorphism genes from this study included IL23R, ERAP, CARD9, ICOSLG, and NKX2-3.[14]

  Pathogenesis Top

The exact immunologic mechanisms that link the gut inflammation to synovial inflammation are not yet fully understood. Various theories are proposed to explain the gut-synovial axis. Demonstrable mucosal inflammation of the gut is present in most of the patients with SpA, even in the absence of clinically overt IBD.[5] In addition, there is a considerable alteration in gut microbiota in AS patients compared to rheumatoid arthritis patients and healthy controls.[15] Studies suggest that patients with AS have a highly permeable gut mucosa, which increases exposure to microbes.[16] HLA B27 transgenic rats that had been raised in a germ-free environment did not develop features of SpA.[17] Persistent inflammation and constant antigenic stimulation can activate T-cells, and this might be responsible for chronic bowel inflammation.

Many putative bacteria are implicated in the pathogenesis of SpA, including Klebsiella pneumoniae, Ruminococcus gnavus, Lachnospiraceae, Prevotellaceae, Rikenellaceae, Porphyromonadaceae, and Bacteroidaceae.[15],[18] The loss of architectural and functional integrity in the intestinal epithelium allows for the passage of microbiota or their metabolites into the submucosa and the systemic circulation. It was earlier believed that bacterial antigens may translocate from gut to synovium via the bloodstream to initiate synovial inflammation and arthritis.[19] However, there is little evidence to suggest that actual pathogens themselves home to synovium to produce an inflammatory response.[19]

CARD15 is a susceptibility gene for both CD. Certain CARD15 polymorphisms predispose to subclinical mucosal inflammation in patients with SpA.[20] The protein product of CARD 15 is NOD2. NOD2 is expressed on the surface of the intestinal antigen presenting cells (APC). The ligand for NOD2 (MDP) is universal molecule present in the cell wall component in many bacteria.[21] On binding to MDP, NOD2 gets activated and results in downstream activation of transcription factor nuclear factor-κB and mediates cytokine release (including tumor necrosis factor-α, [TNF-α]) and inflammation.[21] Mutations in NOD2 result in a peculiar syndrome characterized by uveitis and inflammatory arthritis (autosomal dominant Blaus syndrome).[22] Together these observations suggest that NOD2 may be a common link between joint and gut inflammation.

Local intestinal inflammation leads to damage in the epithelial lining. This facilitates contact of gut flora to antigen-presenting cells located in sub-mucosa leading to activation of Th1 and Th17 cells.[19] Homing of lymphocyte to Peyer's patches is brought about interaction between integrins on lymphocyte, and mucosal addressin cell adhesion molecule-1 expressed on the high endothelial venules. Activation of T cells results in the release of inflammatory cytokines, which include TNF-α and interleukin-17 (IL-17). TNF-α can activate apoptosis of intestinal epithelial cells and contributes to further mucosal damage.[23],[24],[25]

Activated T-cells and macrophages then home to synovium through bloodstream. Homing of cells to synovium requires adhesion molecules such as integrins and intercellular adhesion molecule-1 (CD54).[19] Experimental data supports this theory of homing of immune cells activated from gut mucosa to synovium. Clonal T-cell expansions have been shown in the colonic mucosa and the synovium of patients with SpA.[26] Both synovium and gut mucosa of patients with SpA are enriched with CD 163 + macrophage cells.[27] It has also been shown that macrophages can selectively bind with P-selectin molecules expressed by synovial cells.[28] These macrophages may the source of persistent antigenic stimulation in the synovium.

Cytokines IL-17 and IL-22 also act in synergy to maintain the integrity of the gut mucosal epithelium against microorganisms by inducing the production of anti-microbial peptides.[29] This explains the higher incidence of IBD flares in the anti-IL-17-treated SpA patients in trials.[29] Interestingly, a recent study done to characterize the ecological effects of biologic therapies on the gut bacterial and fungal microbiome of PsA SpA patients showed that the initiation of IL-17A blockade corresponded with features of subclinical gut mucosal inflammation and dysbiosis of certain fungal and bacterial taxa, particularly Candida albicans.[30]

  Diagnosis Top

IBD must be suspected in all patients of SpA presenting with abdominal pain, diarrhea, unexplained weight loss, anemia, or other malabsorption features. Routine screening of all patients of SpA with colonoscopy is not yet recommended. Fecal calprotectin could serve as a screening test for IBD/subclinical mucosal inflammation.[31] A recent study has shown that elevated C-reactive protein and calprotectin together can predict subclinical mucosal inflammation.[32] Fecal calprotectin reports should be interpreted cautiously in patients who are taking nonsteroidal anti-inflammatory drugs (NSAIDs).

Colonoscopy is the gold standard for the diagnosis of UC. Intubation of terminal ileum helps in detecting ileocolonic CD.[8] Proximal ileal lesions can be missed in CD. Results from a recent study suggest capsule endoscopy may be superior to conventional colonoscopy.[33] Alternatives to visualizing small bowel include computed tomography with small bowel enterography and magnetic resonance imaging with small bowel enterography.

  Treatment Top

Shared genetic and pathogenic mechanisms of SpA and IBD is also reflected in therapeutic strategies in both diseases. However, certain differences in the treatment of both diseases are striking. NSAIDs, even though it is the first-line treatment in SpA, is generally avoided in IBD owing to the risk of exacerbation associated with it.[34] Similarly, while systemic corticosteroid forms part of the early management of IBD, have little role in the management of axSpA.[34]

Methotrexate and sulfasalazine have demonstrated efficacy in peripheral SpA, while their role in axSpA is controversial. Both these medicines are effective in the select group of IBD even though these are not the preferred first-line agents.[35],[36],[37] With the current evidence available, anti-TNF agents are the ideal choice for initial treatment in a patient with co-existing SpA and IBD with inadequate response to initial management.[34],[35] Among the anti-TNF, both infliximab and adalimumab have demonstrated efficacy in both CD and UC while all five are approved in the treatment of SpA.[35] Etanercept, on the other hand, is not effective in IBD and can cause IBD flares in SpA patients.[38],[39]

Understanding of the IL-23/IL-17 axis in the pathogenesis of SpA has led to the use of anti-IL17 agents in axSpA, PsA, and skin psoriasis. The efficacy and relative safety of secukinumab and Ixekizumab are established in axSpA (MEASURE1, MEASURE2, COAST-V trials).[40],[41] However, the use of secukinumab was associated with exacerbation of IBD.[29] Blocking of IL-12/23 (Ustekinumab) while effective against CD is not found to be efficacious in axSpA.[42],[43] This dichotomy despite the proven role of the IL23/17 axis in both SpA and IBD is perplexing. Recent evidence show that Th17 activation can occur in SpA independent of IL23 through direct interaction with mesenchymal cells.[44] Alternatively, ILC3 and γδ T-cells also can produce IL-17 without the requirement of IL-23.[44] These redundant pathways in IL17 production explain basal level 17 production in SpA despite blocking IL-23. IL-17 is required for the defense against pathogens in the gut micro milieu. This regulation becomes defective and leads to flare in IBD when treated with IL17 blockers. However, the basal IL-17 production is not affected by IL-23 blocking as explained above, and thus no increased risk of IBD flare.[8]

Several Janus kinase (JAK) inhibitors are being evaluated in the treatment of SpA. Tofacitinib inhibits JAK3 and JAK1, to a lesser extent JAK2. Tofacitinib, while demonstrated efficacy in SpA, was not shown to be effective in CD.[45],[46] Selective JAK1 inhibitors, filgotinib, and upadacitinib have shown efficacy in both axSpA and favorable results in IBD.[47],[48],[49],[50] While newer therapeutic options emerge in both SpA and IBD, hierarchical positions of these agents, the therapeutic algorithm is yet to be defined.

  Conclusion Top

IBD is an extra-articular manifestation of SpA in a small subset of patients. We do not have accurate predictors to determine which SpA patients will develop IBD. Based on shared genetic predisposition and immunologic features, current and future therapeutics are likely to change the landscape of therapeutics in this disease.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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