H. Cypers

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.

An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series

Background In inflammatory bowel disease (IBD), a new biological therapy has recently been approved. Vedolizumab is a humanised IgG1 monoclonal antibody to α4β7 integrin that modulates gut lymphocyte trafficking. Although an exclusively local effect of vedolizumab could be expected based on the restricted presence of the α4β7–mucosal vascular addressin cell adhesion molecule 1 complex in the gut, past combined success with anti-tumour necrosis factor, and previous demonstration of α4β7 integrin in the joint, led to the expectation of a therapeutic efficacy in spondyloarthritis. Nonetheless, the effect of vedolizumab on extraintestinal manifestations—and especially the joint—has not been reported so far. Case report A series of five patients with IBD who were treated with vedolizumab and promptly developed new onset or exacerbation of sacroiliitis or arthritis are reported. Conclusions Vedolizumab therapy does not seem to show any efficacy in and might even induce arthritis and/or sacroiliitis. However, larger cohort studies are needed to provide information on the prevalence, the evolution and underlying mechanism.

Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis

Introduction Microscopic bowel inflammation is present in up to 50% of patients with spondyloarthritis (SpA) and is associated with more severe disease. Currently no reliable biomarkers exist to identify patients at risk. Calprotectin is a sensitive marker of neutrophilic inflammation, measurable in serum and stool. Objectives To assess whether serum and faecal calprotectin in addition to C-reactive protein (CRP) can be used to identify patients with SpA at risk of microscopic bowel inflammation. Methods Serum calprotectin and CRP were measured in 125 patients with SpA. In 44 of these patients, faecal samples were available for calprotectin measurement. All 125 patients underwent an ileocolonoscopy to assess the presence of microscopic bowel inflammation. Results Microscopic bowel inflammation was present in 53 (42.4%) patients with SpA. Elevated serum calprotectin and CRP were independently associated with microscopic bowel inflammation. Faecal calprotectin was also significantly higher in patients with microscopic bowel inflammation. Patients with CRP and serum calprotectin elevated had a frequency of bowel inflammation of 64% vs 25% in patients with low levels of both. When either CRP or serum calprotectin was elevated, the risk was intermediate (40%) and measuring faecal calprotectin provided further differentiation. Hence we suggest a screening approach where initially serum calprotectin and CRP are assessed and, if necessary, faecal calprotectin. The model using this scenario provided an area under the ROC curve of 74.4% for detection of bowel inflammation. Conclusions Calprotectin measurements in stool and serum, in addition to CRP, may provide a promising strategy to identify patients with SpA at risk of bowel inflammation and could play a role in overall patient stratification.

Dysbiosis and zonulin upregulation alter gut epithelial and vascular barriers in patients with ankylosing spondylitis

Background Dysbiosis has been recently demonstrated in patients with ankylosing spondylitis (AS) but its implications in the modulation of intestinal immune responses have never been studied. The aim of this study was to investigate the role of ileal bacteria in modulating local and systemic immune responses in AS. Methods Ileal biopsies were obtained from 50 HLA-B27+ patients with AS and 20 normal subjects. Silver stain was used to visualise bacteria. Ileal expression of tight and adherens junction proteins was investigated by TaqMan real-time (RT)-PCR and immunohistochemistry. Serum levels of lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), intestinal fatty acid-BP (iFABP) and zonulin were assayed by ELISA. Monocyte immunological functions were studied in in vitro experiments. In addition the effects of antibiotics on tight junctions in human leukocyte antigen (HLA)-B27 transgenic (TG) rats were assessed. Results Adherent and invasive bacteria were observed in the gut of patients with AS with the bacterial scores significantly correlated with gut inflammation. Impairment of the gut vascular barrier (GVB) was also present in AS, accompanied by significant upregulation of zonulin, and associated with high serum levels of LPS, LPS-BP, iFABP and zonulin. In in vitro studies zonulin altered endothelial tight junctions while its epithelial release was modulated by isolated AS ileal bacteria. AS circulating monocytes displayed an anergic phenotype partially restored by ex vivo stimulation with LPS+sCD14 and their stimulation with recombinant zonulin induced a clear M2 phenotype. Antibiotics restored tight junction function in HLA-B27 TG rats. Conclusions Bacterial ileitis, increased zonulin expression and damaged intestinal mucosal barrier and GVB, characterises the gut of patients with AS and are associated with increased blood levels of zonulin, and bacterial products. Bacterial products and zonulin influence monocyte behaviour.

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.

Spondyloarthritis and inflammatory bowel disease

Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) are chronic, idiopathic inflammatory disorders of the axial and peripheral joints and the intestinal tract, respectively, affecting up to 1 % of the population. There is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of these two entities. Nevertheless, their treatment is at times conflicting. NSAIDs, although useful in SpA, are considered to be possible risk factors for flares in IBD. Moreover, etanercept, a soluble TNF receptor blocker used in SpA, is ineffective in IBD. As patients with SpA often develop microscopic gut inflammation, it is important to understand the impact on disease progression or even therapeutic response. Further research is mandatory in this regard.ZusammenfassungSpondylarthritiden (SpA) und chronisch entzündliche Darmerkrankungen (CED) sind chronische, idiopathische inflammatorische Störungen der axialen und peripheren Gelenke bzw. des Intestinaltrakts und betreffen etwa 10% der Bevölkerung. Es gibt klinische und genetische Hinweise auf Überlappungen in der Pathogenese dieser beiden nosologischen Entitäten, doch ihre Behandlungen konfligieren bisweilen. Nichtsteroidale Antiphlogistika sind zwar hilfreich in der Behandlung der SpA, doch sie werden auch als mögliche Risikofaktoren für CED-Schübe angesehen. Ferner ist Etanercept, ein bei SpA gegebener löslicher TNF-Rezeptorblocker, nicht wirksam bei CED. Da SpA-Patienten häufig mikroskopisch sichtbare Darmentzündungen entwickeln, ist es wichtig, den Einfluss auf den Erkrankungsprogress oder sogar auf das Therapieansprechen zu verstehen. In diesem Zusammenhang ist weitere Forschung unbedingt erforderlich.

Brief Report: Six-Week Treatment of Axial Spondyloarthritis Patients With an Optimal Dose of Nonsteroidal Antiinflammatory Drugs: Early Response to Treatment in Signal Intensity on Magnetic Resonance Imaging of the Sacroiliac Joints.

To evaluate the early effect of full‐dose nonsteroidal antiinflammatory drugs (NSAIDs) on the extent and intensity of bone marrow edema of the sacroiliac (SI) joints on magnetic resonance imaging (MRI) in axial spondyloarthritis (SpA).

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.

Spondyloarthritis and inflammatory bowel disease. Comorbidity and treatment implications.

Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) are chronic, idiopathic inflammatory disorders of the axial and peripheral joints and the intestinal tract, respectively, affecting up to 1 % of the population. There is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of these two entities. Nevertheless, their treatment is at times conflicting. NSAIDs, although useful in SpA, are considered to be possible risk factors for flares in IBD. Moreover, etanercept, a soluble TNF receptor blocker used in SpA, is ineffective in IBD. As patients with SpA often develop microscopic gut inflammation, it is important to understand the impact on disease progression or even therapeutic response. Further research is mandatory in this regard.ZusammenfassungSpondylarthritiden (SpA) und chronisch entzündliche Darmerkrankungen (CED) sind chronische, idiopathische inflammatorische Störungen der axialen und peripheren Gelenke bzw. des Intestinaltrakts und betreffen etwa 10% der Bevölkerung. Es gibt klinische und genetische Hinweise auf Überlappungen in der Pathogenese dieser beiden nosologischen Entitäten, doch ihre Behandlungen konfligieren bisweilen. Nichtsteroidale Antiphlogistika sind zwar hilfreich in der Behandlung der SpA, doch sie werden auch als mögliche Risikofaktoren für CED-Schübe angesehen. Ferner ist Etanercept, ein bei SpA gegebener löslicher TNF-Rezeptorblocker, nicht wirksam bei CED. Da SpA-Patienten häufig mikroskopisch sichtbare Darmentzündungen entwickeln, ist es wichtig, den Einfluss auf den Erkrankungsprogress oder sogar auf das Therapieansprechen zu verstehen. In diesem Zusammenhang ist weitere Forschung unbedingt erforderlich.