Liesbet Van Praet

Microscopic gut inflammation in axial spondyloarthritis: a multiparametric predictive model

Objective To assess the rates and explore predictors of microscopic gut inflammation in a cohort of patients with axial and peripheral spondyloarthritis (SpA). Methods Ileocolonoscopy was performed in 65 patients with axial and peripheral SpA from the Gent Inflammatory Arthritis and spoNdylitis cohorT. Histopathological analysis and scoring were performed by an experienced pathologist. Results Overall, 46.2% of the patients with SpA showed microscopic gut inflammation. In axial SpA, the following parameters were independently associated with gut involvement: male sex (OR=8.9, p=0.035); high disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (OR=2.05, p=0.032); restricted spinal mobility measured by the Bath Ankylosing Spondylitis Metrology Index (OR=1.94, p=0.009); and younger age (OR=0.85, p=0.013). No clear association was found for human leucocyte antigen-B27 status, presence of peripheral arthritis, enthesitis, uveitis, psoriasis, intake of non-steroidal anti-inflammatory drugs and family history of SpA. The prevalence of gut inflammation in non-radiographic axial SpA and ankylosing spondylitis was comparable. Conclusions The prevalence of microscopic gut inflammation in SpA remains unaltered over time. Younger age (shorter symptom duration), progressive disease, male sex and higher disease activity are independently associated with microscopic gut inflammation in axial SpA.

Degree of bone marrow oedema in sacroiliac joints of patients with axial spondyloarthritis is linked to gut inflammation and male sex: results from the GIANT cohort

Introduction Bone marrow oedema (BMO) of the sacroiliac joints (SIJs) is a hallmark of axial spondyloarthritis (SpA). However, the relationship between the extent of BMO and disease phenotype is poorly understood. Objective To assess the link between BMO of the SIJs and gut inflammation. We have also evaluated the correlation between BMO and established disease activity parameters. Methods Sixty-eight patients with axial SpA from the Gent Inflammatory Arthritis and spoNdylitis cohorT underwent ileocolonoscopy and MRI of the SIJs. Histopathological analysis and SPondyloArthritis Research Consortium of Canada (SPARCC) scores were performed. Results A significant higher SPARCC score (median (range)) was observed in axial SpA patients showing chronic gut inflammation (16.9 (3.8–68.3)) compared with axial SpA patients showing normal gut histology (9.8 (0.0–45.0); p<0.05). In a multiple linear regression model, we identified, besides chronic gut inflammation (effect size of 11.3, 95% CI (2.1 to 20.4)), male sex (effect size of 10.5, 95% CI (3.3 to 17.8)) to be independently associated to the extent of BMO. There was a low to moderate correlation between the degree of BMO and C-reactive protein(r=0.39, p=0.002) and Ankylosing Spondylitis Disease Activity Score (r=0.35, p=0.007). Conclusions Higher degrees of BMO were observed in patients showing chronic gut inflammation. These data solidify a link between mucosal inflammation and progressive disease in axial SpA.

Brief Report: Dialister as a Microbial Marker of Disease Activity in Spondyloarthritis

Dysbiosis of the intestinal microbiota has been widely established in inflammatory bowel disease (IBD). There is significant clinical and genetic overlap between spondyloarthritis (SpA) and IBD, and up to 50% of all patients with SpA exhibit microscopic signs of bowel inflammation, often bearing particular resemblance to early Crohns disease, a subtype of IBD. This study was undertaken to assess the relationship between intestinal microbial composition, gut histology, and disease activity markers in SpA.

Investigating the genetic association between ERAP1 and spondyloarthritis

Objective A robust association between polymorphisms in the non-major histocompatibility complex gene ERAP1 and ankylosing spondylitis (AS) in several populations was recently identified. The aim of the current study was to determine the level of association of ERAP1 polymorphisms with spondyloarthritis (SpA) in French/Belgian populations with particular attention to genotype–phenotype correlations. Methods We studied 734 independent SpA cases and 632 controls from two European cohorts. Five single-nucleotide polymorphisms (SNPs), rs27044, rs17482078, rs10050860, rs30187 and rs2287987 were genotyped, and case-control association analyses were carried using PLINK 1.07 software. Linkage disequilibrium and haplotypes were estimated with Haploview. Analysis was first carried out in SpA as a whole group, and then separately in AS and non-radiographic SpA (non-AS) patients. Results Consistent with previous studies conducted in AS, rs30187 was the most significantly associated SNP with SpA (p=0.008 in the French, and p=6.46×10−4 in the Belgian cohorts). In the combined cohorts, this SNP was associated with both AS and non-AS (Pcombined= 3.9×10−5 and Pcombined= 0.005, respectively). A similar trend was observed with other SNPs. The rs17482078/rs10050860/rs30187-CCT haplotype was significantly associated with increased risk of SpA in both cohorts (Pcombined= 9.08×10−4), including AS and non-AS (Pcombined=6.16×10−4 and Pcombined=0.049, respectively), whereas the -TTC haplotype was associated with reduced risk of SpA, including AS and non-AS (Pcombined=2.36×10−7, Pcombined= 5.69×10−6 and Pcombined= 2.13×10−4, respectively). Conclusions This is the first study to show an association between several polymorphisms located in ERAP1 and SpA as a whole. Our findings demonstrate consistent association of the same SNPs and haplotypes with both AS and non-AS subtypes of SpA.

The transition of acute to chronic bowel inflammation in spondyloarthritis

That gut and joint inflammation are linked in spondyloarthritis (SpA) has been recognized for almost three decades. Intriguingly, microscopic gut inflammation, which occurs frequently in patients with SpA, is an important risk factor for clinically overt Crohns disease and ankylosing spondylitis. This Review describes current insights into the underlying mechanisms that lead to chronic gut inflammation in patients with SpA. We propose that the development of chronic bowel inflammation in these individuals occurs through a transition phase, in which inflammation evolves from an acute into a chronic state. Our transition model implies that different cell types are involved at different stages during disease progression, with stromal cells having an important role in chronicity. In addition, deficient regulatory feedback mechanisms or genetically determined alterations in antigen presentation, endoplasmic reticulum stress, autophagy or cytokine signaling might also favor a transition from self-limiting acute inflammation to chronic inflammation. We anticipate that this transition phase might be an important window for therapeutic intervention.

Mucosal Inflammation in Spondylarthritides: Past, Present, and Future

Spondylarthritides (SpA) and inflammatory bowel disease (IBD) are idiopathic, chronic inflammatory disorders. Although they are very distinct and well-defined entities, there is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of the two. Subclinical gut inflammation is present in up to two thirds of all SpA patients and can evolve into IBD. This subclinical gut inflammation has been shown to be strongly associated with joint inflammation, providing a clue for a common pathophysiologic background. Despite extensive research progress in the field over the past few years, many questions remain unanswered. In this paper, we focus on the clinical, genetic, and pathophysiologic overlap of SpA and IBD. Furthermore, we discuss some of the targets that may influence therapeutic decision making.

Pathophysiology and Role of the Gastrointestinal System in Spondyloarthritides

Inflammatory bowel disease (IBD) is a well-known extra-articular manifestation in spondyloarthritis (SpA); about 6.5% of patients with ankylosing spondylitis develop IBD during the course of the disease. The pathogenesis of both SpA and IBD is considered to be the result of a complex interplay between the host (genetic predisposition), the immune system and environmental factors, notably microorganisms, leading to a disturbed immune system and chronic inflammation. Over the past decade, the role of tumor necrosis factor inhibition (infliximab, etanercept, adalimumab, golimumab) in improving signs and symptoms and overall quality of life has been well documented in various forms of SpA. Future research will clarify the role of other potential targets.

Relevance of the gut/joint axis for the management of spondyloarthritis in daily clinical practice.

Purpose of reviewThirty years ago, the concept of microscopic gut inflammation in spondyloarthritis (SpA) was established. Over the past decade, there has been tremendous progress in the earlier diagnosis of SpA. In addition, it has been suggested that, because of improved hygiene over the past years, exposure to microorganisms has changed, leading to a shift in diseases, for example, a decreased incidence of reactive arthritis. It is therefore necessary to re-establish the role of gut inflammation in SpA. Recent findingsThe prevalence of microscopic gut inflammation could be confirmed in c. 50% of patients with early axial and/or peripheral SpA. More importantly, a predictive model could be developed linking gut inflammation with clinical factors, that is, higher disease activity, extensive sacroiliac bone marrow edema, and progressive disease. In addition, there is increasing evidence indicating that the presence or absence of gut inflammation in SpA may influence therapeutic decision-making in the future. A clear demonstration of this is the different efficacy of IL-17 blockade in Crohns disease versus SpA. SummaryMicroscopic gut inflammation is present in almost 50% of SpA patients and appears relevant for prognosis and therapeutic decision-making. SpA patients with the chronic type of gut inflammation seem to have a less favorable disease course. It is therefore conceivable that assessment of gut inflammation should be included in future models for risk stratification of SpA.

Senescence marker killer cell lectin-like receptor G1 (KLRG1) contributes to TNF-α production by interaction with its soluble E-cadherin ligand in chronically inflamed joints

Objectives Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1+ T cells to synovitis. Methods Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-α/IFN-γ production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE-cadherin levels in our paired samples were determined. Moreover, TNF-α/IFN-γ production by antigen-specific T cells was evaluated in the presence of sE-cadherin. Results KLRG1+ T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1+ T cells were more functionally active as opposed to KLRG1− T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1+ CD4+ T cells able to produce TNF-α but not IFN-γ. Conclusions sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-α production by KLRG1+ CD4+ T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis.

Anti-TNF-induced remission in very early peripheral spondyloarthritis: the CRESPA study

Objective To evaluate the efficacy and safety of golimumab to induce clinical remission in patients with very early, active peripheral spondyloarthritis (pSpA). Methods Clinical REmission in peripheral SPondyloArthritis is a monocentric study of golimumab treatment in patients with pSpA. All patients fulfilled the Assessment of SpondyloArthritis international Society classification criteria for pSpA, with a symptom duration ≤12 weeks. Patients were randomised 2:1 to receive golimumab 50 mg every 4 weeks or matching placebo for 24 weeks. The primary end point was the percentage of patients achieving clinical remission at week 24, defined as absence of arthritis, enthesitis and dactylitis. Secondary end points included joint and enthesis counts, patient-reported outcomes, erythrocyte sedimentation rate and C reactive protein. From week 12, non-responders were allowed to receive rescue medication with golimumab. Adverse events were recorded. Results 60 patients were randomised with similar baseline characteristics. At week 24, a significantly higher percentage of patients receiving golimumab achieved clinical remission compared with placebo (75% (30/40) vs 20% (4/20); p<0.001). At week 12, similar results were observed (70% (28/40) vs 15% (3/20); p<0.001). All secondary end points were met at week 24. Rescue medication was necessary in 50% in the placebo group opposed to only 10% in the golimumab arm. Rates of adverse events were low and similar in both groups. Conclusions Markedly high remission induction rates were noted with golimumab in very early pSpA. Of interest, in placebo-treated patients, very low spontaneous remission rates were observed. Trial registration number NCT01426815; Results.