Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate-like T Cell Signature.

OBJECTIVE: Patients with spondyloarthritis (SpA) often present with microscopic signs of gut inflammation, a risk factor for progressive disease. We investigated whether mucosal innate-like T cells are involved in dysregulated interleukin-23 (IL-23)/IL-17 responses in the gut-joint axis in SpA. METHODS: Ileal and colonic intraepithelial lymphocytes (IELs), lamina propria lymphocytes (LPLs), and paired peripheral blood mononuclear cells (PBMCs) were isolated from treatment-naive patients with nonradiographic axial SpA with (n = 11) and without (n = 14) microscopic gut inflammation and healthy controls (n = 15) undergoing ileocolonoscopy. The presence of gut inflammation was assessed histopathologically. Immunophenotyping of innate-like T cells and conventional T cells was performed using intracellular flow cytometry. Unsupervised clustering analysis was done by FlowSOM technology. Serum IL-17A levels were measured via Luminex. RESULTS: Microscopic gut inflammation in nonradiographic axial SpA was characterized by increased ileal intraepithelial γδ-hi T cells, a γδ-T cell subset with elevated γδ-T cell receptor expression. γδ-hi T cells were also increased in PBMCs of patients with nonradiographic axial SpA versus healthy controls and were strongly associated with Ankylosing Spondylitis Disease Activity Score. The abundance of mucosal-associated invariant T cells and invariant natural killer T cells was unaltered. Innate-like T cells in the inflamed gut showed increased RORγt, IL-17A, and IL-22 levels with loss of T-bet, a signature that was less pronounced in conventional T cells. Presence of gut inflammation was associated with higher serum IL-17A levels. In patients treated with tumor necrosis factor blockade, the proportion of γδ-hi cells and RORγt expression in blood was completely restored. CONCLUSION: Intestinal innate-like T cells display marked type 17 skewing in the inflamed gut mucosa of patients with nonradiographic axial SpA. γδ-hi T cells are linked to intestinal inflammation and disease activity in SpA.

Ultrasound-guided core needle biopsy and incisional biopsy of the parotid gland are comparable in diagnosis of primary Sjögren's syndrome.

OBJECTIVES: Salivary gland lymphocytic infiltrates are a hallmark of primary SS (pSS), but traditional biopsy techniques hold several disadvantages. Ultrasound-guided core needle (US-guided CN) parotid gland biopsy is minimally invasive and reliable for diagnosis of lymphoma in pSS. This proof-of-concept study aimed to explore this technique in the diagnostic work-up of pSS and is the first to address its value in a consecutive cohort independently of the presence of salivary gland swelling. METHODS: Combined incisional and US-guided CN parotid biopsy was performed in 20 patients with suspected or confirmed pSS from the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). Surface area and presence of a focus score (FS) of at least one, germinal centres and lymphoepithelial lesions were recorded. RESULTS: Salivary gland tissue was interpretable in 19 patients. Fourteen patients had ≥4 mm2 salivary gland tissue by both techniques, in four US-guided CN biopsies salivary gland tissue was <4 mm2. Paired biopsies ≥4 mm2 displayed a concordance of 90% for FS ≥ 1. Presence of lymphoepithelial lesions and germinal centres showed absolute concordance. Of four US-guided CN biopsies <4 mm2, three interpretable incisional biopsies were available, 2/3 with perfect concordance. When including biopsies of <4 mm2 salivary gland tissue, presence of FS ≥ 1 or germinal centres gave a sensitivity of 70% in incisional and of 69% in US-guided CN biopsy. CONCLUSIONS: US-guided CN biopsy of the parotid gland is at least equivalent to incisional biopsy of the parotid gland in the diagnostic work-up of pSS.

Work participation is unaffected in Belgian spondyloarthritis patients: data from the BelGian Inflammatory Arthritis and SpoNdylitis cohorT.

OBJECTIVES: This study aimed to (i) investigate actual work participation in Belgian spondyloarthritis (SpA) patients compared with the general population, and (ii) identify determinants of work-related outcomes. MATERIAL AND METHODS: Adult SpA patients from the Ghent University Hospital based Be-GIANT cohort (fulfilling ASAS classification criteria) were cross-sectionally questioned on their socio-economic status and completed a Work Productivity and Activity Impairment questionnaire (May 2018 to May 2019). Results were compared with national and regional data on the general population using indirect standardization. Associations between clinical and job characteristics and work-related outcomes were analysed with logistic regression (having a paid job) and negative binomial hurdle models (sick leave and presenteeism, i.e. restrictions while at work). RESULTS: A total of 215/262 (82%) patients of working age (<65 y/o) had a paid job, corresponding to an age- and sex-adjusted employment ratio of 1.00 (95% CI 0.88, 1.14). Patients worked 39.6h (10.5h)/week, and 49% (95% CI 42, 56%) reported sick leave in the previous year, similar to the general population (39.7h/week, 42%). In total, 56% reported presenteeism of median (IQR) 10% (0-20%). In multivariate analysis, functional impairment (BASFI) and health-related quality of life (HRQoL, EuroQoL-VAS) were associated with each work-related outcome, while contextual factors (education, physically demanding job) were positively associated with, respectively, having a paid job and presenteeism. Clinical characteristics showed no independent association with any of these outcomes. CONCLUSIONS: Evidence from this academic cohort study does not support a work participation gap between SpA patients and the general population, but confirms the role of physical function, overall HRQoL, and education or job type as risk factors for adverse work outcomes.

The value of separate detection of anti-Ro52, anti-Ro60 and anti-SSB/La reactivities in relation to diagnosis and phenotypes in primary Sjögren's syndrome.

OBJECTIVES: Autoantibody detection is an essential step in pSS diagnosis. However, the value of separate anti-Ro52, anti-Ro60 and anti-SSB/La detection in pSS diagnosis and phenotyping has not been extensively studied. This study aimed to explore disease characteristics of anti-SSA/Ro positive, suspected and definite pSS patients, in relation to serological profiles based on anti-Ro52, anti-Ro60 and anti-SSB/La reactivity. METHODS: Of 187 anti-SSA/Ro positive patients included in the Belgian Sjögren's Syndrome Transition Trial (BeSSTT), 155 were considered definite pSS patients, due to fulfilment of the 2016 ACR-EULAR classification criteria, and 32 suspected, due to reactivity against SSA/Ro without presence of other criteria. None of the patients met any of the ACR-EULAR exclusion criteria for pSS. Patients were grouped based on the presence of anti-Ro52, anti-Ro60 and anti-SSB/La antibodies. RESULTS: Mono-reactivity against Ro60 or Ro52, double reactivity against Ro52/Ro60 and triple reactivity against Ro52/Ro60 and SSB was detected in respectively 30, 23, 70 and 60 patients. Mono-anti-Ro60 positive patients showed the least pSS features. Mono-anti-Ro52 positive patients reported a significantly higher dryness burden (p=0.016) and tended toward more salivary gland ultrasound (SGUS) abnormalities (p=0.054) than mono-anti-Ro60 positives. Double positive patients showed similar characteristics as mono-anti-Ro52 positive patients, whereas triple positive patients showed lowest unstimulated salivary flow rates (p=0.002) and Schirmer tests (p=0.002), highest ocular staining scores (p<0.001), most positive labial salivary gland biopsies (p=0.039), most laboratory abnormalities compatible with B-cell hyperactivity and highest SGUS scores (p<0.001) compared to other patient groups. CONCLUSIONS: These data indicate that separate detection of anti-Ro52, anti-Ro60 and anti-SSB/La reactivity is not only relevant towards pSS diagnosis, but markedly aids in patient stratification and evaluation of disease burden. Our results suggest a stepwise model in which mono-reactivity against Ro60 displayed the least objective and subjective glandular pSS features, whereas glandular abnormalities and signs of B-cell hyperactivity were most present in patients showing triple reactivity against Ro60, Ro52 and SSB/La.

Selection of study endpoints and patients for clinical trials in primary Sjögren's syndrome.

In the last decade, many randomised controlled trials (RCTs) with biological DMARDs (bDMARDs) have been performed in patients with primary Sjögren's syndrome (pSS). Unfortunately, no bDMARD has yet been approved for systemic treatment of pSS. The heterogeneity of disease manifestations raises two essential questions: 1) which outcome measure is valid, reliable and responsive to demonstrate treatment efficacy and should be used as primary study endpoint? and 2) which pSS patients should be included in clinical trials? Both the selection of the primary study endpoint and the selection of patients are crucial and evolving issues in clinical trial design in pSS. This article summarises the history and comments the selection of primary study endpoints including the novel development of composite endpoints. Furthermore, this article gives an overview of inclusion criteria used for phase II and III trials, and illustrates by data-analysis based on two prospective observational cohorts that each additional selection criterion will (largely) decrease the number of eligible patients in daily clinical practice.

Discriminative power of salivary gland ultrasound in relation to symptom-based endotypes in suspected and definite primary Sjögren's Syndrome.

OBJECTIVES: Salivary gland ultrasound (SGUS) is emerging as essential tool in primary Sjögren's Syndrome (pSS), but its link to symptom-based endotypes is unknown. Therefore, we explored SGUS outcomes in relation to endotypes in patients with definite and suspected pSS. METHODS: Definite pSS patients (n = 171) fulfilling the 2016 ACR/EULAR classification criteria, and suspected pSS patients (n = 119), positive for at least one criterion, were included in the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). Stratification into endotypes according to the Newcastle Sjögren's Stratification Tool resulted in low symptom burden (LSB), pain dominant with fatigue (PDF), dryness dominant with fatigue (DDF) and high symptom burden (HSB). SGUS was assessed with Hocevar score (0-48). The dataset was randomly divided into a discovery (n = 203) and replication (n = 87) cohort. RESULTS: SGUS had strong discriminative power for pSS classification (AUC=0.74), especially in DDF (AUC=0.89). In definite pSS, Hocevar scores in DDF were high compared to other endotypes (38 (20-44) versus 18 (9-33); p < 0.001). Patients with highest SGUS-scores showed more sicca and laboratory abnormalities. Moreover, a subset of young, anti-SSA/Ro positive patients not fulfilling classification criteria showed clear SGUS abnormalities. Replication showed similar results. CONCLUSIONS: SGUS-scores were significantly higher in definite pSS with DDF endotype, providing the first evidence of imaging abnormalities in salivary glands matching distinct biological profiles ascribed to pSS endotypes. Additionally, a subset of patients with potential early disease was detected based on presence of anti-SSA antibodies and high SGUS-scores. These results underscore the role of SGUS as powerful tool both in pSS classification and stratification.

Progressive Increase in Sacroiliac Joint and Spinal Lesions Detected on Magnetic Resonance Imaging in Healthy Individuals in Relation to Age.

OBJECTIVE: Magnetic resonance imaging (MRI) plays a pivotal role in spondyloarthritis (SpA) diagnosis. However, a detailed description of MRI findings of the sacroiliac (SI) joints and spine in healthy individuals is currently lacking. This study was undertaken to evaluate the occurrence of MRI-detected SI joint and spinal lesions in healthy individuals in relation to age. METHODS: Ninety-five healthy subjects (ages 20-49 years) underwent MRI of the SI joints and spine. Bone marrow edema (BME) and structural lesions of the SI joints were scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Spinal inflammatory and structural lesions were evaluated using the SPARCC MRI spine inflammation index and the Canada-Denmark MRI scoring system, respectively. Fulfillment of the Assessment of SpondyloArthritis international Society definition of a positive MRI for sacroiliitis/spondylitis was reviewed. Findings were compared to MRIs of axial SpA patients from the Belgian Inflammatory Arthritis and Spondylitis cohort. RESULTS: Of the subjects ≥30 years old, 17.2% fulfilled the definition of a positive MRI for sacroiliitis, but this occurred rarely in younger subjects. SI joint erosions (20.0%) and fat metaplasia (13.7%) were detected across all age groups. Erosions were more frequently visualized in subjects ages ≥40 years (39.3%). Spinal BME (35.7%) and fat metaplasia (28.6%) were common in subjects older than 40 years. Nonetheless, only 1 subject had ≥3 corner inflammatory lesions. SI joint and spinal SPARCC scores and total structural lesions scores increased progressively with age. CONCLUSION: Contrary to what is commonly believed, structural MRI-detected SI joint lesions are frequently seen in healthy individuals. Especially in older subjects, the high occurrence of inflammatory and structural MRI-detected lesions impacts their specificity for SpA, which has important implications for the interpretation of MRIs in patients with a clinical suspicion of SpA.

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.

The Value of Magnetic Resonance Imaging for Assessing Disease Extent and Prediction of Relapse in Early Peripheral Spondyloarthritis.

OBJECTIVE: This study was undertaken to assess the inflammatory burden in peripheral spondyloarthritis (SpA) by magnetic resonance imaging (MRI) of the legs in an early remission-induction strategy study of tumor necrosis factor (TNF) blockade. Furthermore, we sought to determine the value of MRI to predict disease relapse versus sustained remission after treatment discontinuation. METHODS: Thirty-two patients with early peripheral SpA with involvement of the legs determined on clinical examination and confirmed by ultrasonography (US) participated in a remission-induction trial of a TNF inhibitor (TNFi). Patients underwent MRI of the joints and entheses of the legs at baseline and at clinical remission, after which TNFi treatment was withdrawn. Images were evaluated for joint effusion, joint osteitis, entheseal soft tissue inflammation, and entheseal osteitis. RESULTS: Joint effusion and enthesitis on clinical examination and US correlated well with MRI abnormalities. In addition, a substantial amount of subclinical involvement was seen on MRI, mainly in the ankle joints and heel entheses. Inflammation scores were markedly lower in the subclinically involved joints and entheses versus those that were clinically involved (P values ranged from 0.01 to <0.001). Inflammatory load on MRI decreased significantly upon TNFi treatment (P < 0.001). Whereas 80% of the joints that were clinically involved at baseline showed no effusion on remission MRI, 2 of 3 entheses involved at baseline showed residual inflammation. In addition, patients who experienced a relapse after treatment discontinuation displayed more entheseal soft tissue inflammation on remission MRI compared to those who maintained drug-free remission (P = 0.028). CONCLUSION: Our findings delineate a differential response of synovitis and enthesitis, with enthesitis on MRI being less responsive to TNFi treatment. Furthermore, residual entheseal inflammation might be indicative of the need for continuous therapy.

Axial involvement in patients with early peripheral spondyloarthritis: a prospective MRI study of sacroiliac joints and spine.

OBJECTIVES: To assess axial involvement on MRI in early peripheral spondyloarthritis (pSpA) and to evaluate whether axial inflammation predicts relapse on treatment withdrawal. METHODS: Fifty-six patients with early, active, newly diagnosed pSpA underwent MRI of the sacroiliac joints (SIJs) and spine prior to golimumab initiation. At sustained clinical remission of pSpA, treatment was withdrawn and a second MRI was performed. Bone marrow oedema (BME) was scored by three readers according to the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Scores were compared with an axial spondyloarthritis cohort (Belgian Arthritis and Spondylitis cohort). Structural lesions were assessed using a similar method. Furthermore, fulfilment of the Assessment of Spondyloarthritis International Society (ASAS) definition of a positive MRI for sacroiliitis was assessed. Spinal images were evaluated for BME and structural lesions using the Canada-Denmark MRI spine scoring system by two readers. RESULTS: Thirty-six per cent showed SIJ BME at baseline, all fulfilling the ASAS definition of sacroiliitis. No association with back pain was found. Twenty-one per cent displayed SIJ structural lesions. Spinal BME was limited: the median inflammation scores were low and no patients had ≥5 inflammatory corner lesions. On clinical remission, a significant decrease in SIJ SPARCC scores was detected. On clinical remission, no significant differences in SIJ SPARCC scores were noted between patients relapsing and those maintaining remission after treatment discontinuation. CONCLUSION: In patients with early pSpA, a surprisingly high prevalence of sacroiliitis on MRI was observed; SPARCC scores decreased significantly on tumour necrosis factor inhibition. Residual inflammation on MRI was not predictive of relapse of peripheral manifestations. No relevant inflammatory spinal involvement was detected. Collectively, our findings suggest a higher inflammatory burden in patients with early pSpA than anticipated.

High prevalence of spondyloarthritis-like MRI lesions in postpartum women: a prospective analysis in relation to maternal, child and birth characteristics.

OBJECTIVES: Bone marrow oedema (BMO) on MRI of sacroiliac joints (SIJs) represents a hallmark of axial spondyloarthritis (SpA), yet such lesions may also occur under augmented mechanical stress in healthy subjects. We therefore sought to delineate the relationship between pregnancy/delivery and pelvic stress through a prospective study with repeated MRI. Results were matched with maternal, child and birth characteristics. METHODS: Thirty-five women underwent a baseline MRI-SIJ within the first 10 days after giving birth. MRI was repeated after 6 months and, if positive for sacroiliitis according to the Assessment of SpondyloArthritis International Society (ASAS) definition, after 12 months. BMO and structural lesions were scored by three trained readers using the Spondyloarthritis Research Consortium of Canada (SPARCC) method. RESULTS: Seventy-seven per cent of the subjects (27/35) displayed sacroiliac BMO immediately postpartum, 60% fulfilled the ASAS definition of a positive MRI. After 6 months, 46% of the subjects (15/33) still showed BMO, representing 15% (5/33) with a positive MRI. After 12 months, MRI was still positive in 12% of the subjects (4/33). Few structural lesions were detected. Intriguingly, in this study, the presence of BMO was related to a shorter duration of labour and lack of epidural anaesthesia. CONCLUSION: A surprisingly high prevalence of sacroiliac BMO occurs in women immediately postpartum. Our data reveal a need for a waiting period of at least 6 months to perform an MRI-SIJ in postpartum women with back pain. This study also underscores the importance of interpreting MRI-SIJ findings in the appropriate clinical context.

Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis.

OBJECTIVES: Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up. RESULTS: Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p < 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p < 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication. CONCLUSIONS: This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc.