Peripheral manifestations are major determinants of disease phenotype and outcome in new onset spondyloarthritis.

OBJECTIVES: To delineate the impact of peripheral musculoskeletal manifestations on stratification of disease phenotype and outcome in new-onset spondyloarthritis (SpA), using a prospective observational nationwide inception cohort, the BelGian Inflammatory Arthritis and spoNdylitis cohorT (Be-Giant). METHODS: Newly diagnosed adult SpA patients, fulfilling the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral SpA, were included in Be-Giant and prospectively followed every six months. Peripheral involvement (defined as arthritis, enthesitis and/or dactylitis) was determined in relation to clinically similar patient subsets at baseline and disease activity patterns during two-year follow-up, identified through K-means cluster analysis and latent class growth analysis. RESULTS: From November 2010 to March 2020, 367 patients were enrolled in Be-Giant, of whom 162 (44%) had peripheral manifestations. Two patient clusters [A, axial predominant (n = 248) and B, peripheral predominant (n = 119)] were identified at diagnosis. Longitudinal analysis (n = 115) revealed two trajectories of disease activity in each cluster: one with persistently high disease activity over time ('High'), the other rapidly evolving to low disease activity ('Low'). In cluster A patients, peripheral manifestations predisposed to the 'High' trajectory [odds ratio (OR) = 2.0, 95% CI: 1.3, 3.1, P = 0.001], despite more rapid initiation of biologics compared with patients without peripheral manifestations (hazard ratio (HR) = 2.1, 95% CI: 1.0, 4.4, P = 0.04 - Cox proportional-hazards model). CONCLUSION: Peripheral musculoskeletal manifestations are major determinants of phenotypical diversity in new-onset SpA. Intriguingly, stratification of axial SpA according to concomitant peripheral involvement identified an endotype with an unfavorable outcome despite more prompt therapeutic intensification with biologics. These observations justify an endotype-tailored approach beyond current ASAS/EULAR management recommendations.

Pitfalls in the detection of myositis specific antibodies by lineblot in clinically suspected idiopathic inflammatory myopathy.

OBJECTIVES: Today, the contribution of myositis-specific autoantibodies (MSA) in the diagnostic workup of idiopathic inflammatory myopathies (IIM) is on the rise. The aim of this study was to document MSA frequency as detected by lineblot in a set of consecutive MSA requests and to correlate the results with clinical diagnosis, IIM subtype and indirect immunofluorescence (IIF) findings. Additionally, a comparison between two lineblots was performed. METHODS: A total of 118 consecutive samples of patients with suspicion of IIM were analysed on IIF and two lineblots. A total of 107 patients with autoimmune rheumatic diseases served as controls. RESULTS: MSA were detected in 55% of IIM patients (n=31) and 7.9% (n=12) of patients without clinical diagnosis of IIM or myositis overlap syndrome. All the IIM patients had a MSA-compatible clinical subtype. There was no to fair agreement between both lineblots for the individual antibodies, with most discrepancies observed for anti-TIF1γ (κ=-0.021), anti-SRP (κ=-0.006) and anti-SAE (κ=0.395). Differences between both assays were mostly observed in the non-IIM patients, also showing signi cantly lower blot signal intensities compared to IIM patients (p=0.0013). MSA in the non-IIM patients frequently showed an incompatible IIF pattern. CONCLUSIONS: Lineblot seems to be an interesting tool for MSA detection in a clinical context, allowing the identification of clinical subtypes. However, considerable caution must be exercised in interpreting the results in case of low positive MSA signal intensity, discordant lineblot results and/or an incompatible IIF pattern.

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.

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

OBJECTIVE: 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 Crohn's 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. METHODS: Gene analysis by 16S ribosomal RNA amplicon sequencing was used to compare the microbial composition in ileal and colonic biopsy specimens from 27 patients with SpA (14 with microscopic bowel inflammation, 13 without) and 15 healthy control subjects (ileal samples from all 15 subjects and colonic samples from 6). Spearman's rank correlation tests were used to assess correlations of the microbial composition with disease activity measures. RESULTS: The intestinal inflammation status (histologically normal versus acute or chronic inflammation) was strongly associated with the mucosal microbiota profile of patients with SpA. In inflamed biopsy tissue, the detected bacterial community composition clustered separately from that in noninflamed biopsy tissue (P < 0.05 by permutational multivariate analysis of variance, using hierarchical clustering on Bray-Curtis distances). Interestingly, abundance of the genus Dialister was found to be positively correlated with the Ankylosing Spondylitis Disease Activity Score (Spearman's rho = 0.62, false discovery rate-corrected q < 0.01). This finding was further supported by the low frequency of Dialister observed in noninflamed ileal and colonic biopsy tissue from patients with SpA and healthy controls. CONCLUSION: These findings demonstrate a significant difference in the intestinal microbial composition in patients with SpA who have microscopic gut inflammation compared to those without microscopic gut inflammation. Moreover, Dialister may represent a potential microbial marker of disease activity in SpA.

Scintigraphic detection of TNF-driven inflammation by radiolabelled certolizumab pegol in patients with rheumatoid arthritis and spondyloarthritis.

BACKGROUND: Biologicals are the cornerstone for many treatment algorithms in inflammatory arthritis. While tumour necrosis factor (TNF) inhibitors may achieve important responses in ∼50% of patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA), a significant fraction of patients are partial or non-responders. We hypothesised that in vivo assessment of TNF by scintigraphy with 99mTc-radiolabelled certolizumab pegol (CZP) might lead to a more 'evidence-based biological therapy'. OBJECTIVES: Our goal was to perform a proof-of-concept study of in vivo detection of TNF by immunoscintigraphy of a radiolabelled TNF inhibitor in RA and SpA, and correlate this with clinical, imaging findings and therapeutic outcome. METHODS: CZP was conjugated with succinimidyl-6-hydrazino-nicotinamide and subsequently radiolabelled with Tc99m. Whole body and static images of hands, feet and sacroiliac joints of 20 patients (5 RA; 15 SpA) were acquired at 3 time points. Immunoscintigraphic findings were scored semiquantitatively. Subsequently, all patients were treated with CZP. RESULTS: In peripheral joints, clinically affected joints or abnormal ultrasound findings were observed more frequently (p<0.001) in the scintigraphic-positive group. In patients with axial SpA, bone marrow edema on MRI was detected more frequently (p<0.001) in quadrants with tracer uptake. At the patient level, the odds of a joint remaining tender despite 24 weeks of CZP treatment was significantly smaller in joints with clear tracer uptake as compared with those with no uptake (OR=0.42, p=0.04). CONCLUSIONS: Immunoscintigraphy with radiolabelled CZP demonstrated both axial and peripheral inflammation, and displayed good correlation with clinical features, conventional imaging and therapy response. TRIAL REGISTRATION NUMBER: NCT01590966; Results.

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

PURPOSE OF REVIEW: Thirty 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 FINDINGS: The 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 Crohn's disease versus SpA. SUMMARY: Microscopic 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.

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.

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 (P(combined)= 3.9×10(-5) and P(combined)= 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 (P(combined)= 9.08×10(-4)), including AS and non-AS (P(combined)=6.16×10(-4) and P(combined)=0.049, respectively), whereas the -TTC haplotype was associated with reduced risk of SpA, including AS and non-AS (P(combined)=2.36×10(-7), P(combined)= 5.69×10(-6) and P(combined)= 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.

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.

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.

Therapy for spondyloarthritis: the role of extra-articular manifestations (eye, skin).

Spondyloarthritis can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. Extra-articular manifestations are all the medical conditions and symptoms that are not directly related to the locomotor system. Besides inflammatory bowel diseases, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations regarding the treatment of spondyloarthritis.

Peripheral manifestations in spondyloarthritis: relevance for diagnosis, classification and follow-up.

PURPOSE OF REVIEW: The field of spondyloarthritis (SpA) has evolved enormously over the last few years, starting with the advent of biological therapies at the end of the previous millenium. A lot of work has been done to construct valid outcome measures and treatment guidelines based upon the results of pivotal studies with Tumor necrosis factor (TNF)-blocking agents. Most of these trials were performed in well described populations, such as patients suffering from ankylosing spondylitis (AS) or psoriatic arthritis. RECENT FINDINGS: Over recent years a reappraisal has been done with regard to considering again the full spectrum of diseases belonging to the SpA concept, especially in early disease stages. This effort culminated in the construction of new classification criteria for axial and peripheral SpA. Around the same time, a number of patient registries were set up, allowing the follow-up of patients in order to study the natural evolution of patients classified early. The first data from these cohorts provide interesting information on peripheral joint manifestations such as arthritis, enthesitis or dactylitis. Recognition and monitoring of these manifestations are essential for clinicians in order to provide comprehensive patient care. SUMMARY: There is a growing interest in the field of SpA to move from rather restricted and longstanding diseases such as AS to a more comprehensive view, encompassing not only inflammatory back pain, but also peripheral arthritis and enthesitis, as well as extra-articular manifestations. The new classification criteria and guidelines for follow-up are applied now in a number of prospective patient registries, and provide us with valuable information on the early disease stages 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 Crohn's 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.