Lipidome profiling of neutrophil-derived extracellular vesicles unveils their contribution to the ensemble of synovial fluid-derived extracellular vesicles during joint inflammation.

The molecular signature of cell-derived extracellular vesicles (EVs) from synovial fluid (SF) offers insights into the cells and molecular processes associated with joint disorders and can be exploited to define biomarkers. The EV-signature is determined by cargo molecules and the lesser-studied lipid bilayer. We here investigated the lipidome of SF-EVs in inflamed joints derived from Rheumatoid Arthritis (RA) and Spondyloarthritis (SpA) patients, two autoimmune-driven joint diseases, and compared these signatures to the lipid profile of equine SF-EVs obtained during induced acute synovitis. Since neutrophils are primary SF-infiltrating cells during these inflammatory joint diseases, we also analyzed how inflammatory stimuli alter the lipidomic profile of human and equine neutrophil-derived EVs (nEVs) in vitro and how these signatures relate to the lipidome signatures of SF-EVs from inflamed joints. We identified neutrophil stimulation intensity-dependent changes in the lipidomic profile of nEVs with elevated presence of dihexosylceramide (lactosylceramide), phosphatidylserine, and phosphatidylethanolamine ether-linked lipid classes in human nEVs upon full neutrophil activation. In horses, levels of monohexosylceramide (glucosylceramide) increased instead of dihexosylceramide, indicating species-specific differences. The lipid profiles of RA and SpA SF-EVs were relatively similar and showed a relative resemblance with stimulated human nEVs. Similarly, the lipidome of equine synovitis-derived SF-EVs closer resembled the one of stimulated equine nEVs. Hence, lipidome profiling can provide insights into the contribution of nEVs to the heterogeneous pool of SF-EVs, deepening our understanding of inflammatory joint diseases and revealing molecular changes in joint homeostasis, which can lead to the development of more precise disease diagnosis and treatment strategies.

HIF-1α and MIF enhance neutrophil-driven type 3 immunity and chondrogenesis in a murine spondyloarthritis model.

The hallmarks of spondyloarthritis (SpA) are type 3 immunity-driven inflammation and new bone formation (NBF). Macrophage migration inhibitory factor (MIF) was found to be a key driver of the pathogenesis of SpA by amplifying type 3 immunity, yet MIF-interacting molecules and networks remain elusive. Herein, we identified hypoxia-inducible factor-1 alpha (HIF1A) as an interacting partner molecule of MIF that drives SpA pathologies, including inflammation and NBF. HIF1A expression was increased in the joint tissues and synovial fluid of SpA patients and curdlan-injected SKG (curdlan-SKG) mice compared to the respective controls. Under hypoxic conditions in which HIF1A was stabilized, human and mouse neutrophils exhibited substantially increased expression of MIF and IL-23, an upstream type 3 immunity-related cytokine. Similar to MIF, systemic overexpression of IL-23 induced SpA pathology in SKG mice, while the injection of a HIF1A-selective inhibitor (PX-478) into curdlan-SKG mice prevented or attenuated SpA pathology, as indicated by a marked reduction in the expression of MIF and IL-23. Furthermore, genetic deletion of MIF or HIF1A inhibition with PX-478 in IL-23-overexpressing SKG mice did not induce evident arthritis or NBF, despite the presence of psoriasis-like dermatitis and blepharitis. We also found that MIF- and IL-23-expressing neutrophils infiltrated areas of the NBF in curdlan-SKG mice. These neutrophils potentially increased chondrogenesis and cell proliferation via the upregulation of STAT3 in periosteal cells and ligamental cells during endochondral ossification. Together, these results provide supporting evidence for an MIF/HIF1A regulatory network, and inhibition of HIF1A may be a novel therapeutic approach for SpA by suppressing type 3 immunity-mediated inflammation and NBF.

CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis.

HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human ß2m (hß2m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (Ddit3-/-), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated Il23a overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced Il23a expression in immune cells isolated from the colon of B27+ rats, Il17a levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including Il1a, Ifng and Tnf in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized Il17a mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with Cd3e (CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.

Validation of SPARCC MRI-RETIC e-tools for increasing scoring proficiency of MRI sacroiliac joint lesions in axial spondyloarthritis

BACKGROUND: The Spondyloarthritis Research Consortium of Canada (SPARCC) developers have created web-based calibration modules for the SPARCC MRI sacroiliac joint (SIJ) scoring methods. We aimed to test the impact of applying these e-modules on the feasibility and reliability of these methods. METHODS: The SPARCC-SIJ RETIC e-modules contain cases with baseline and follow-up scans and an online scoring interface. Visual real-time feedback regarding concordance/discordance of scoring with expert readers is provided by a colour-coding scheme. Reliability is assessed in real time by intraclass correlation coefficient (ICC), cases being scored until ICC targets are attained. Participating readers (n=17) from the EuroSpA Imaging project were randomised to one of two reader calibration strategies that each comprised three stages. Baseline and follow-up scans from 25 cases were scored after each stage was completed. Reliability was compared with a SPARCC developer, and the System Usability Scale (SUS) assessed feasibility. RESULTS: The reliability of readers for scoring bone marrow oedema was high after the first stage of calibration, and only minor improvement was noted following the use of the inflammation module. Greater enhancement of reader reliability was evident after the use of the structural module and was most consistently evident for the scoring of erosion (ICC status/change: stage 1 (0.42/0.20) to stage 3 (0.50/0.38)) and backfill (ICC status/change: stage 1 (0.51/0.19) to stage 3 (0.69/0.41)). The feasibility of both e-modules was evident by high SUS scores. CONCLUSION: The SPARCC-SIJ RETIC e-modules are feasible, effective knowledge transfer tools, and their use is recommended before using the SPARCC methods for clinical research and tria.

The value of a repeat MRI examination of the sacroiliac joints following an inconclusive initial examination.

OBJECTIVE: Assess the diagnostic utility of repeat sacroiliac joint (SIJ) magnetic resonance imaging (MRI) examinations following an inconclusive initial examination performed for suspected sacroiliitis. METHOD: Subjects with > 1 SIJ MRI examinations, an inconclusive first scan and at least 6 months interval between scans, were included. All scans were evaluated for the presence of structural/active SIJ lesions as well as any other pathology. Clinical data was extracted from the patients' clinical files, and any missing data was obtained by a telephone interview. Diagnosis and active/structural scores were compared between first and follow-up examinations (t test). RESULTS: Seventy-one subjects were included in the study, 77.4% females, mean age 41.0 ± 15 years, mean time interval between exams 30.4 ± 25.24 months. Twelve subjects performed > 2 scans. In only two subjects (2.81%), both females, MRI diagnosis changed from inconclusive to definite sacroiliitis. None of the subjects with > 2 scans had evidence of sacroiliitis in any of the following MRI examinations. Significant differences were observed between the scores of active SIJ lesion of the first and follow-up MRI (1.51/1.62, p = 0.02) but not for scores of structural lesions (1.22/1.68, p = 0.2). CONCLUSIONS: Repeat SIJ MRI when the first MRI is inconclusive for sacroiliitis is more valuable in ruling out than in securing diagnosis of sacroiliitis. We suggest that when MRI findings are inconclusive, decision-making should be based on clinical data.

Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis.

OBJECTIVE: Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. METHODS: Experiments in SKG, Card9-/-SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4+ T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. RESULTS: Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4+ T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27+ AS patients expanded autologous Th17 cells in vitro, and the AS-associated CARD9S12N variant increased IL-17A. CONCLUSIONS: These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .

Artificial intelligence for the detection of sacroiliitis on magnetic resonance imaging in patients with axial spondyloarthritis.

Background: Magnetic resonance imaging (MRI) is important for the early detection of axial spondyloarthritis (axSpA). We developed an artificial intelligence (AI) model for detecting sacroiliitis in patients with axSpA using MRI. Methods: This study included MRI examinations of patients who underwent semi-coronal MRI scans of the sacroiliac joints owing to chronic back pain with short tau inversion recovery (STIR) sequences between January 2010 and December 2021. Sacroiliitis was defined as a positive MRI finding according to the ASAS classification criteria for axSpA. We developed a two-stage framework. First, the Faster R-CNN network extracted regions of interest (ROIs) to localize the sacroiliac joints. Maximum intensity projection (MIP) of three consecutive slices was used to mimic the reading of two adjacent slices. Second, the VGG-19 network determined the presence of sacroiliitis in localized ROIs. We augmented the positive dataset six-fold. The sacroiliitis classification performance was measured using the sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). The prediction models were evaluated using three-round three-fold cross-validation. Results: A total of 296 participants with 4,746 MRI slices were included in the study. Sacroiliitis was identified in 864 MRI slices of 119 participants. The mean sensitivity, specificity, and AUROC for the detection of sacroiliitis were 0.725 (95% CI, 0.705-0.745), 0.936 (95% CI, 0.924-0.947), and 0.830 (95%CI, 0.792-0.868), respectively, at the image level and 0.947 (95% CI, 0.912-0.982), 0.691 (95% CI, 0.603-0.779), and 0.816 (95% CI, 0.776-0.856), respectively, at the patient level. In the original model, without using MIP and dataset augmentation, the mean sensitivity, specificity, and AUROC were 0.517 (95% CI, 0.493-0.780), 0.944 (95% CI, 0.933-0.955), and 0.731 (95% CI, 0.681-0.780), respectively, at the image level and 0.806 (95% CI, 0.729-0.883), 0.617 (95% CI, 0.523-0.711), and 0.711 (95% CI, 0.660-0.763), respectively, at the patient level. The performance was improved by MIP techniques and data augmentation. Conclusion: An AI model was developed for the detection of sacroiliitis using MRI, compatible with the ASAS criteria for axSpA, with the potential to aid MRI application in a wider clinical setting.

Sex-specific diagnostic efficacy of MRI in axial spondyloarthritis: challenging the 'One Size Fits All' notion.

OBJECTIVES: Sex-specific differences in the presentation of axial spondyloarthritis (axSpA) may contribute to a diagnostic delay in women. The aim of this study was to investigate the diagnostic performance of MRI findings comparing men and women. METHODS: Patients with back pain from six different prospective cohorts (n=1194) were screened for inclusion in this post hoc analysis. Two blinded readers scored the MRI data sets independently for the presence of ankylosis, erosion, sclerosis, fat metaplasia and bone marrow oedema. Χ2 tests were performed to compare lesion frequencies. Contingency tables were used to calculate markers for diagnostic performance, with clinical diagnosis as the standard of reference. The positive and negative likelihood ratios (LR+/LR-) were used to calculate the diagnostic OR (DOR) to assess the diagnostic performance. RESULTS: After application of exclusion criteria, 526 patients (379 axSpA (136 women and 243 men) and 147 controls with chronic low back pain) were included. No major sex-specific differences in the diagnostic performance were shown for bone marrow oedema (DOR m: 3.0; f: 3.9). Fat metaplasia showed a better diagnostic performance in men (DOR 37.9) than in women (DOR 5.0). Lower specificity was seen in women for erosions (77% vs 87%), sclerosis (44% vs 66%), fat metaplasia (87% vs 96%). CONCLUSION: The diagnostic performance of structural MRI markers is substantially lower in female patients with axSpA; active inflammatory lesions show comparable performance in both sexes, while still overall inferior to structural markers. This leads to a comparably higher risk of false positive findings in women.

[Computed tomography versus magnetic resonance imaging : Pros and cons in axial spondyloarthritis]. / Computertomographie versus Magnetresonanztomographie : Pro und Kontra in der axialen Spondyloarthritis.

The diagnosis of axial spondyloarthritis depends on direct visualization of the sacroiliitis in addition to clinical assessment and determination of the histocompatibility antigen HLA-B27. While the value of conventional radiographic images has meanwhile been described in many studies as insufficient to diagnose the disease at an early stage, magnetic resonance imaging and also computed tomography now offer the possibility to visualize findings, such as bone marrow edema, erosion, fat metaplasia, backfill and ankylosis. Thus, it is necessary to decide which procedure should be used and when. Furthermore, both cross-sectional imaging techniques are currently undergoing major changes, and technical advancements are making great strides every year. This article provides an overview of which future technologies will be included in the rheumatological diagnostics of the sacroiliac joints. This overview also illustrates which standard methods are established in the diagnostics of axial spondyloarthritis and how they are used.

Current Role of Conventional Radiography of Sacroiliac Joints in Adults and Juveniles with Suspected Axial Spondyloarthritis: Opinion from the ESSR Arthritis and Pediatric Subcommittees.

This opinion article by the European Society of Musculoskeletal Radiology Arthritis and Pediatric Subcommittees discusses the current use of conventional radiography (CR) of the sacroiliac joints in adults and juveniles with suspected axial spondyloarthritis (axSpA). The strengths and limitations of CR compared with magnetic resonance imaging (MRI) and computed tomography (CT) are presented.Based on the current literature and expert opinions, the subcommittees recognize the superior sensitivity of MRI to detect early sacroiliitis. In adults, supplementary pelvic radiography, low-dose CT, or synthetic CT may be needed to evaluate differential diagnoses. CR remains the method of choice to detect structural changes in patients with suspected late-stage axSpA or established disease and in patients with suspected concomitant hip or pubic symphysis involvement. In children, MRI is the imaging modality of choice because it can detect active as well as structural changes and is radiation free.

Comparison of sacroiliac CT findings in patients with and without ankylosing spondylitis aged over 50 years.

Diagnosis of axial spondyloarthritis (axSpA) is nowadays commonly made with the help of pelvic radiography or magnetic resonance imaging (MRI). However, there is an important inter-observer variability in radiography, and MRI is subject to possible false positives and is not the best modality for studying structural lesions. Conversely, pelvic computed tomography (CT) has excellent specificity and appears to be more effective than radiography for the diagnosis of ankylosing spondylitis (AS). However, its findings in patients over 50 years of age have not yet been studied. The objectives of this study were to describe the CT characteristics of sacro-iliac joints (SIJ) and the presence of intra-articular gas in patients with AS aged over 50 years and to compare them with controls of the same age and sex. This two-center, cross-sectional, observational study was performed using the medical records of the rheumatology departments of two University Hospitals. We included patients with a clinical diagnosis of axSpA, who had both definite radiographic sacroiliitis according to the modified New York criteria and met the ASAS 2009 criteria for axSpA (that is, AS), and who had undergone any CT scan including the whole SIJ. Each patient was matched for age and sex to a control randomly selected on the Picture Archiving and Communication System (PACS), symptomatic or asymptomatic, and without spondyloarthritis. For each individual, CT scans were interpreted blindly by two independent rheumatologists and scored for joint space narrowing (JSN), erosions, sclerosis, intra-articular gas, and diffuse idiopathic skeletal hyperostosis (DISH). Ninety patients and 90 controls were included in the study. The rates of positive JSN, erosion, and sclerosis scores were higher in the AS group (91% vs. 21%, p < 0.0001; 31% vs. 2%, p < 0.0001; 27% vs. 13%, p = 0.03, respectively), but the rates of intra-articular gas and DISH were higher in the control group (24% vs. 68%, p < 0.0001; 7% vs. 33%, p < 0.0001, respectively). 58% of patients had complete bilateral ankylosis. A total of 83 (92.2%) patients had a CT scan considered positive for AS, compared with only seven controls (7.8%). Sclerosis and erosions were predominantly on the anterosuperior part and iliac side of the joint in controls and were more diffuse in patients with AS. CT findings in patients with AS over 50 years of age are mostly represented by changes in the joint space; patients with AS have more erosions and sclerosis changes, but less intra-articular gas than controls.

Role of Patrick-FABER test in detecting sacroiliitis and diagnosing spondyloarthritis in subjects with low back pain.

OBJECTIVES: To evaluate sensitivity, specificity, and predictive value of Patrick-FABER test in assessing magnetic resonance imaging (MRI) sacroiliitis and addressing the diagnosis of spondyloarthritis (SpA) in subjects with low back pain (LBP). METHODS: Subjects with LBP were consecutively enrolled. The assessors were blinded to patients' clinical, laboratory, or imaging data. All subjects underwent sacroiliac joint MRI to detect presence of sacroiliac oedema or structural changes. RESULTS: One hundred and ten subjects were included in the study [males (61.8%); median age of 45 (21-69) years; LBP duration of 78 (3-240) months]. Patrick-FABER test sign's sensitivity was 76.2% (95% CI: 60.5-87.9%), specificity was 66.2% (95% CI: 53.6-77.2%), positive predictive value (PPV) was 58.1% (95% CI: 44.1-71.3%) and negative predictive value (NPV) was 81.8% (95% CI: 69.1-90.9%) for the diagnosis of sacroiliitis, with an overall diagnostic accuracy of 70%. At the univariate and multivariate analysis, Patrick-FABER test sign was associated with inflammatory lesions of sacroiliitis at MRI and SpA diagnosis. Univariate and multivariate analysis showed an association between smoking status (p=0.01), sacroiliitis, and SpA diagnosis. The odds of having sacroiliitis was 2.7 higher in smokers (OR: 2.7; 95% CI: 1.1-7) as compared to non-smokers and 6.3 higher in those with a positive Patrick-FABER test sign (OR: 6.3; 95%CI: 2.5-15.6) as compared to those with a negative sign. CONCLUSIONS: Our study shows that Patrick-FABER test positivity could represent a useful clinical test for addressing the use of sacroiliac joints MRI and SpA diagnosis in subjects with LBP. Further, smoking habit could represent an associate anamnestic element for addressing the use of sacroiliac MRI.

Sacroiliac joint MRI for diagnosis of ax-SpA: algorithm to improve the specificity of the current ASAS MRI criteria.

OBJECTIVE: To compare sacroiliac joint (SIJ) lesions on MRI in women with versus without axial spondyloarthritis (ax-SpA) and establish an algorithm to determine whether such lesions are due to ax-SpA. METHODS: This retrospective comparative study assessed bone marrow edema (BME), sclerosis, erosions, osteophytes, and ankylosis at the SIJ in two groups of women, one with and another without ax-SpA. Sensitivity and specificity were calculated for combinations/characteristics of lesions, using rheumatologists' assessment with assessment of spondyloarthritis international society (ASAS) criteria as the gold standard for diagnosis of ax-SpA. RESULTS: Compared to women without ax-SpA, women with ax-SpA had more BME (61% vs 17%, p < 0.001), sclerosis (40% vs 22%, p < 0.001), erosions (35% vs 5%, p < 0.001), and ankylosis (2% vs 0%, p = 0.007), but less osteophytes (5% vs 33%, p < 0.001). The ASAS MRI criteria yielded 59% sensitivity and 88% specificity, while a new algorithm achieved 56% sensitivity and 95% specificity using the following criteria: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. CONCLUSIONS: We recommend the following pragmatic algorithm for MRI diagnosis of ax-SpA in women: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. The false positive rate when using the new algorithm (3.3%) is less than half than when using the ASAS MRI criteria (7.7%); thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA. CLINICAL RELEVANCE STATEMENT: The developed algorithm has a false-positive rate that is less than half than when using the ASAS MRI criteria (3.3% vs 7.7%), thus its application in clinical practice could reduce overdiagnosis and prevent overtreatment of axial spondyloarthritis. KEY POINTS: • Compared to women without axial spondyloarthritis (ax-SpA), women with ax-SpA had a significantly higher prevalence of bone marrow edema (BME), sclerosis, erosions, and ankylosis, but a significantly lower prevalence of osteophytes. • A new algorithm for positive ax-SpA based on sacroiliac joint MRI was developed: no osteophytes at the sacroiliac joint (SIJ) and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. • We recommend this new algorithm for diagnosis of ax-SpA in women, as it has a significantly better specificity than the assessment of spondyloarthritis international society (ASAS) MRI criteria and less than half the false positive rate; thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA.

T cells in the pathogenesis of axial spondyloarthritis.

Axial spondyloarthritis (axSpA) is the prototype of the spondyloarthritis spectrum. The involvement of T cells in its pathogenesis has long been suspected on the basis of the association with the major histocompatibility complex I molecule HLA-B27 and the pivotal role of interleukin 17 in the inflammatory mechanisms associated with the disease. Moreover, the presence of unconventional or "innate-like" T cells within the axial enthesis suggests an important role for these cells in the pathophysiology of the disease. In this review, we describe the characteristics and the interleukin 17 secretion capacity of the T-cell subsets identified in axSpA. We discuss the genetic and epigenetic mechanisms that support the alteration of T-cell functions and promote their activation in axSpA. We also discuss recent data on T cells that could explain the extra-articular manifestations of the SpA spectrum.

Machine Learning Pipeline for Predicting Bone Marrow Edema Along the Sacroiliac Joints on Magnetic Resonance Imaging.

OBJECTIVE: We aimed to develop and validate a fully automated machine learning (ML) algorithm that predicts bone marrow edema (BME) on a quadrant level in sacroiliac (SI) joint magnetic resonance imaging (MRI). METHODS: A computer vision workflow automatically locates the SI joints, segments regions of interest (ilium and sacrum), performs objective quadrant extraction, and predicts presence of BME, suggestive of inflammatory lesions, on a quadrant level in semicoronal slices of T1/T2-weighted MRI scans. Ground truth was determined by consensus among human readers. The inflammation classifier was trained using a ResNet18 backbone and five-fold cross-validated on scans of patients with spondyloarthritis (SpA) (n = 279), postpartum individuals (n = 71), and healthy subjects (n = 114). Independent SpA patient MRI scans (n = 243) served as test data set. Patient-level predictions were derived from aggregating quadrant-level predictions, ie, at least one positive quadrant. RESULTS: The algorithm automatically detects the SI joints with a precision of 98.4% and segments ilium/sacrum with an intersection over union of 85.6% and 67.9%, respectively. The inflammation classifier performed well in cross-validation: area under the curve (AUC) 94.5%, balanced accuracy (B-ACC) 80.5%, and F1 score 64.1%. In the test data set, AUC was 88.2%, B-ACC 72.1%, and F1 score 50.8%. On a patient level, the model achieved a B-ACC of 81.6% and 81.4% in the cross-validation and test data set, respectively. CONCLUSION: We propose a fully automated ML pipeline that enables objective and standardized evaluation of BME along the SI joints on MRI. This method has the potential to screen large numbers of patients with (suspected) SpA and is a step closer towards artificial intelligence-assisted diagnosis and follow-up.

The correlations between C-reactive protein and MRI-detected inflammation in patients with axial spondyloarthritis: a systematic review and meta-analysis.

BACKGROUND: C-reactive protein (CRP) and magnetic resonance imaging (MRI) are widely used to monitor inflammation in patients with axial spondyloarthritis (axSpA), but the relationship between CRP and MRI-detected inflammation is incompletely understood. The present study was undertaken to assess correlations between CRP and MRI-detected inflammation in axSpA. MATERIALS AND METHODS: A systematic literature search was performed (Medline, Embase, and Cochrane Library) to identify relevant studies concerning CRP and MRI-detected inflammation in axSpA patients. The MRI-detected inflammation was evaluated by MRI-based disease activity score (DAS). The correlation between CRP and MRI-based DAS was integrated by random-effect models. RESULTS: Eighteen studies reported a total of 1392 axSpA patients which were included in this meta-analysis. CRP was significantly associated with spinal MR DAS (r=0.226, 95%CI [0.149, 0.291], p<0.001, I2=23%). We also found a moderate correlation between CRP change and spinal MR DAS change (r[ASspiMRI-a]=0.354, 95%CI [0.282, 0.422], p<0.001, I2=48%; r[SPARCC]=0.544, 95%CI [0.345, 0.701], p<0.001, I2=19%). CRP at baseline was negatively associated with improvement in spinal MR DAS (r= - 0.327, 95%CI [-0.397, -0.264], p<0.001, I2=0%). However, no significant association was found between CRP and sacroiliac joint (SIJ) MR DAS. CONCLUSIONS: In axSpA patients, CRP is associated with MRI-detected inflammation in the spine but not in SIJ. We speculate that CRP could be a reasonable index to reflect spinal inflammation. Therefore, we suggest it is not essential to repeat spinal MRI in a short term, while SIJ MRI may be necessary to provide additional information on inflammation. Key Points • CRP is associated with MRI-detected inflammation in the spine but not in sacroiliac joints. • CRP at baseline was negatively associated with improvement in spinal MR DAS. • It was not essential to repeat spinal MRI frequently, while SIJ MRI may be necessary to provide additional information on inflammation.

Two-year imaging outcomes from a phase 3 randomized trial of secukinumab in patients with non-radiographic axial spondyloarthritis.

BACKGROUND: Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. METHODS: In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0-8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0-72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0-24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0-69). RESULTS: Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, - 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase ≤ smallest detectable change) in SI joint score (87.7% and 85.6%) and mSASSS score (97.5% and 97.1%) in the secukinumab and placebo-secukinumab groups. Only 3.3% (n = 7) and 2.9% (n = 3) of patients in the secukinumab and placebo-secukinumab groups, respectively, who were mNY-negative at baseline were scored as mNY-positive at week 104. Overall, 1.7% and 3.4% of patients with no syndesmophytes at baseline in the secukinumab and placebo-secukinumab group, respectively, developed ≥ 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], - 1.23 [2.81] vs - 0.37 [1.90] with placebo) was sustained through week 104 (- 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). CONCLUSION: Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02696031.

New bone formation at the sacroiliac joint in axial spondyloarthritis: characterization of backfill in MRI and CT.

OBJECTIVE: MRI findings of the SI joint space in axial SpA (axSpA) include inflammation and fat metaplasia inside an erosion; the latter is also termed 'backfill'. We compared such lesions with CT to better characterize whether they represent new bone formation. METHODS: We identified patients with axSpA who underwent both CT and MRI of the SI joints in two prospective studies. MRI datasets were jointly screened by three readers for joint space-related findings and grouped into three categories: type A-high short tau inversion recovery (STIR) and low T1 signal; type B-high signal in both sequences; type C-low STIR and high T1 signal. Image fusion was used to identify MRI lesions in CT before we measured Hounsfield units (HU) in each lesion and surrounding cartilage and bone. RESULTS: Ninety-seven patients with axSpA were identified and we included 48 type A, 88 type B, and 84 type C lesions (maximum 1 lesion per type and joint). The HU values were 73.6 (s.d. 15.0) for cartilage, 188.0 (s.d. 69.9) for spongious bone, 1086.0 (s.d. 100.3) for cortical bone, 341.2 (s.d. 96.7) for type A, 359.3 (s.d. 153.5) for type B and 446.8 (s.d. 123.0) for type C lesions. Lesion HU values were significantly higher than those for cartilage and spongious bone, but lower than those for cortical bone (P < 0.001). Type A and B lesions showed similar HU values (P = 0.93), whereas type C lesions were denser (P < 0.001). CONCLUSION: All joint space lesions show increased density and might contain calcified matrix, suggesting new bone formation, with a gradual increase in the proportion of calcified matrix towards type C lesions (backfill).

Osteonecrosis of the Tarsal Navicular: Not Always Spontaneous!

BACKGROUND: Mueller-Weiss disease, a rare and complex foot condition, is defined as spontaneous and progressive navicular fragmentation leading to midfoot pain and deformity. However, its exact etiopathogenesis remains unclear. We report a case series of tarsal navicular osteonecrosis to describe the clinical and imaging characteristics and etiologic profile of the disease. METHODS: This retrospective study included five women diagnosed as having tarsal navicular osteonecrosis. The following data were extracted from medical records: age, comorbidities, alcohol and tobacco consumption, history of trauma, clinical presentation, imaging modalities performed, treatment protocol, and outcomes. RESULTS: Five women with a mean age of 51.4 years (range, 39-68 years) were enrolled in the study. Mechanical pain and deformity over the dorsum of the midfoot was the main clinical presentation. Rheumatoid arthritis, granulomatosis with polyangiitis, and spondyloarthritis were reported by three patients. Radiographs revealed bilateral distribution in one patient. Three patients underwent computed tomography. It showed a fragmentation of the navicular bone in two cases.Magnetic resonance imaging was performed in one patient showing flattening of the lateral aspect of the navicular bone with signal abnormalities. Talonaviculocuneiform arthrodesis was performed in all of the patients. CONCLUSIONS: Mueller-Weiss disease-like changes may occur in patients with an underlying inflammatory disease such as rheumatoid arthritis and spondyloarthritis.

Can radiomics replace the SPARCC scoring system in evaluating bone marrow edema of sacroiliac joints in patients with axial spondyloarthritis?

OBJECTIVES: To develop an objective and efficient method based on radiomics to evaluate bone marrow edema (BMO) of sacroiliac joints (SIJs) by magnetic resonance imaging (MRI) in patients with axial spondyloarthritis (axSpA) and to compare with the Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. METHODS: From September 2013 to March 2022, patients with axSpA who underwent 3.0T SIJ-MRI were included and were randomly divided into training and validation cohorts at a ratio of 7:3. The optimal radiomics features selected from the SIJ-MRI in the training cohort were included to generate the radiomics model. The performance of the model was evaluated by ROC analysis and decision curve analysis (DCA). Rad scores were calculated using the radiomics model. The responsiveness was compared for Rad scores and SPARCC scores. We also assessed the correlation between the Rad score and SPARCC score. RESULTS: A total of 558 patients were finally included. The radiomics model showed favorable discrimination of a SPARCC score <2 or ≥2 both in the training (AUC, 0.90; 95% CI: 0.87-0.93) and validation cohorts (AUC, 0.90; 95% CI, 0.86-0.95). DCA confirmed that the model was clinically useful. Rad score showed higher responsiveness to treatment-related change than SPARCC score. Furthermore, a significant correlation was noted between the Rad score and SPARCC score when scoring the status of BMO (rs=0.80, P < 0.001), and a strong correlation was noted when scoring the change in BMO (r=0.70, P < 0.001). CONCLUSION: The study proposed a radiomics model to accurately quantify the BMO of SIJs in patients with axSpA, providing an alternative to the SPARCC scoring system. Key Points • The Rad score is an index with high validity for the objective and quantitative evaluation of bone marrow edema (BMO) of the sacroiliac joints in axial spondyloarthritis. • The Rad score is a promising tool to monitor the change of BMO upon treatment.