Upadacitinib in Active Non-radiographic Axial Spondyloarthritis: 1-Year Data From a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial.

OBJECTIVE: Upadacitinib improved the signs and symptoms of non-radiographic axial spondyloarthritis (nr-axSpA) versus placebo over 14 weeks in the primary analysis of the SELECT-AXIS 2 nr-axSpA study. Here, we evaluated the efficacy and safety of upadacitinib through 1 year in patients with nr-axSpA in SELECT-AXIS 2. METHODS: Patients aged at least 18 years diagnosed with nr-axSpA who fulfilled the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria and were receiving stable background therapy were randomized to upadacitinib 15 mg once daily or placebo for the 52-week double-blind period. Efficacy was assessed using non-responder imputation incorporating multiple imputation (NRI-MI) and as-observed analyses for binary endpoints, and mixed-effects model repeated measures for continuous endpoints. RESULTS: Of 314 randomized patients, 259 (upadacitinib, n = 129; placebo, n = 130) completed 52 weeks of treatment. More patients receiving upadacitinib versus placebo achieved ≥40% improvement in ASAS at week 52 (63% vs 43%, NRI-MI; nominal P < 0.001). Similar treatment effects were observed for the achievement of axSpA Disease Activity Score inactive disease (33% v 11%, NRI-MI; nominal P < 0.001). Overall, patients receiving upadacitinib versus placebo showed greater improvement in disease activity, inflammation, pain, function, enthesitis, and quality of life through 52 weeks. Adverse events were generally comparable between the treatment groups. No opportunistic infections, malignancies, major adverse cardiovascular events, venous thromboembolic events, inflammatory bowel disease, or deaths were reported in those receiving upadacitinib. CONCLUSION: Treatment with upadacitinib showed sustained efficacy versus placebo with no new safety findings identified through 1 year. These results support the continued favorable benefit-risk profile of upadacitinib treatment for nr-axSpA.

Adding ultrasound to treat-to-target shows no benefit in achieving clinical remission nor in slowing radiographic progression in rheumatoid arthritis: results from a multicenter prospective cohort.

OBJECTIVE: To assess whether using ultrasound (US) in addition to clinical information versus only clinical information in a treat-to-target (T2T) strategy leads to more clinical remission and to less radiographic progression in RA. METHODS: Patients with RA from the 2-year prospective BIODAM cohort were included. Clinical and US data (US7-score) were collected every 3 months and hands and feet radiographs every 6 months. At each visit, it was decided whether patients were treated according to the clinical definition of T2T with DAS44 remission as benchmark (T2T-DAS44). T2T-DAS44 was correctly applied if: (i) DAS44 remission had been achieved or (ii) if not, treatment was intensified. A T2T strategy also considering US data (T2T-DAS44-US) was correctly applied if: (i) both DAS44 and US remission (synovitis-score < 2, Doppler-score = 0) were present; or (ii) if not, treatment was intensified. The effect of T2T-DAS44-US on attaining clinical remission and on change in Sharp-van der Heijde score compared to T2T-DAS44 was analysed. RESULTS: A total of 1016 visits of 128 patients were included. T2T-DAS44 was correctly followed in 24% of visits and T2T-DAS44-US in 41%. DAS44 < 1.6 was achieved in 39% of visits. Compared to T2T-DAS44, using the T2T-DAS44-US strategy resulted in a 41% lower likelihood of DAS44 remission [OR (95% CI): 0.59 (0.40;0.87)] and had no effect on radiographic progression [ß(95% CI): 0.11 (- 0.16;0.39)] assessed at various intervals up to 12 months later. CONCLUSION: Our results do not suggest a benefit of using the US7-score in addition to clinical information as a T2T benchmark compared to clinical information alone. Key Points • Ultrasound has a valuable role in diagnostic evaluation of rheumatoid arthritis, but it is unclear whether adding ultrasound to the clinical assessment in a treat-to-target (T2T) strategy leads to more patients achieving remission and reduction in radiographic progression. • Our data from a real-world study demonstrated that adding information from ultrasound to the clinical assessment in a T2T strategy led to a lower rather than a higher likelihood of obtaining clinical remission as compared to using only clinical assessment. • Our data demonstrated that adding ultrasound data to a T2T strategy based only on clinical assessment did not offer additional protection against radiographic progression in patients with RA. • Adding US to a T2T strategy based on clinical assessment led to far more treatment intensifications (with consequences for costs and exposure to adverse events) without yielding a meaningful clinical benefit.

Exploring the Effects of Ixekizumab on Pain in Patients with Ankylosing Spondylitis Based on Objective Measures of Inflammation: Post Hoc Analysis from a Large Randomized Clinical Trial.

INTRODUCTION: The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). METHODS: The COAST-V 52-week, double-blind, placebo-controlled, randomized phase III trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. RESULTS: In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = - 3.9, p < 0.001, adalimumab mean = - 2.6, p < 0.05) compared to placebo (mean = - 1.6) at week 16. When inflammation was controlled as assessed by MRI + CRP, ixekizumab and adalimumab had numerically greater reductions at week 16 in SP-N versus placebo. All ixekizumab groups had further improvements at week 52. When inflammation was persisting as assessed by MRI + CRP, ixekizumab-treated patients had significant reduction in SP-N (mean = - 3.7, p < 0.001) versus placebo (mean = - 1.7), improvement with adalimumab did not reach significance (mean = - 2.6, p = 0.06). In the pathway analysis at week 16, ixekizumab had a greater effect on pain outcomes compared to adalimumab. CONCLUSION: This post hoc analysis is supportive of the hypothesis that ixekizumab reduces pain in AS by additional mechanisms other than the reduction of measurable inflammation. TRIAL REGISTRATION NUMBER: NCT02696785.

The OMERACT whole-body MRI scoring system for inflammation in peripheral joints and entheses (WIPE) in spondyloarthritis - reference image atlas for the knee region.

OBJECTIVE: To develop a reference image atlas for the Outcome Measures in Rheumatology whole-body MRI scoring system for inflammation in peripheral joints and entheses (OMERACT MRI-WIPE) of the knee region. METHODS: Image examples of each pathology, location and grade, were collected and discussed at web-based, interactive meetings within the OMERACT MRI in Arthritis Working Group. Subsequently, reference images were selected by consensus. RESULTS: Reference images for each grade, pathology and location are depicted, along with definitions, reader rules and recommended MRI-sequences. CONCLUSION: The atlas guides scoring whole-body MRIs for inflammation in joints and entheses of the knee region according to MRI-WIPE methodology in clinical trials and cohorts.

Hip and pelvis region MRI reference image atlas for scoring inflammation in peripheral joints and entheses according to the OMERACT-MRI WIPE scoring system in patients with spondyloarthritis.

OBJECTIVE: To develop a reference image atlas for scoring the hip/pelvis region according to the OMERACT whole-body MRI scoring system for inflammation in peripheral joints and entheses (MRI-WIPE). METHODS: We collected image examples of each pathology, location and grade, discussed them at web-based, interactive meetings and, finally, selected reference images by consensus. RESULTS: Reference images for each grade and location of osteitis, synovitis and soft tissue inflammation are provided, as are definitions, reader rules and recommended MRI-sequences. CONCLUSION: A reference image atlas was created to guide scoring whole-body MRIs for arthritis and enthesitis in the hip/pelvis region in spondyloarthritis/psoriatic arthritis clinical trials and cohorts.

OMERACT validation of a deep learning algorithm for automated absolute quantification of knee joint effusion versus manual semi-quantitative assessment.

OBJECTIVE: To begin evaluating deep learning (DL)-automated quantification of knee joint effusion-synovitis via the OMERACT filter. METHODS: A DL algorithm previously trained on Osteoarthritis Initiative (OAI) knee MRI automatically quantified effusion volume in MRI of 53 OAI subjects, which were also scored semi-quantitatively via KIMRISS and MOAKS by 2-6 readers. RESULTS: DL-measured knee effusion correlated significantly with experts' assessments (Kendall's tau 0.34-0.43) CONCLUSION: The close correlation of automated DL knee joint effusion quantification to KIMRISS manual semi-quantitative scoring demonstrated its criterion validity. Further assessments of discrimination and truth vs. clinical outcomes are still needed to fully satisfy OMERACT filter requirements.

Erosions on T1-Weighted Magnetic Resonance Imaging Versus Radiography of Sacroiliac Joints in Recent-Onset Axial Spondyloarthritis: 2-Year Data (EMBARK Trial and DESIR Cohort).

OBJECTIVE: (1) To compare the capacity to detect sacroiliac joint (SIJ) erosions and baseline-to-week 104 change in erosions between magnetic resonance imaging (MRI) and radiographs in recent-onset axial spondyloarthritis (axSpA); and (2) to compare treatment-discriminatory capacities of MRI and radiographic scores for erosion detection in patients receiving etanercept in the Effect of Etanercept on Symptoms and Objective Inflammation in Nonradiographic axSpA (EMBARK) trial vs controls in the DESIR (Devenir des Spondylarthropathies Indifférenciées Récentes) cohort. METHODS: Anonymized SIJ MRI and radiographs were assessed at patient and joint surface levels. Three readers evaluated MRI; 3 different readers evaluated radiographs. Final scores for comparison of radiographs and MRI for detection of erosions were assigned based on agreement of ≥ 2 of 3 readers' assessments. RESULTS: At baseline, discordance in erosion detection between imaging methods was more frequent for MRI erosions in the absence of radiographic erosions (48/224 [21.4%] patients) than for radiographic erosions in the absence of MRI erosions (14/224 [6.3%] patients; P < 0.001). After 104 weeks, a decrease in erosions was observed on MRI but not radiographs in 49/221 (22.2%) patients, and on radiographs but not MRI in 6/221 (2.7%) patients (P < 0.001). In the treatment-discriminant capacity analysis, the largest standardized differences between etanercept and control cohorts at week 104 were changes in Spondyloarthritis Research Consortium of Canada MRI erosion discrete score, changes in erosion average score, and meeting the modified New York criteria on radiographs, with unadjusted/adjusted Hedges G effect sizes of 0.40/0.50, 0.40/0.56, and 0.40/0.43, respectively. CONCLUSION: In recent-onset axSpA, SIJ erosions and erosion change were observed more frequently on MRI than radiography. The significance of interval improvement of MRI erosions warrants further research. [ClinicalTrials.gov: NCT01258738, NCT01648907].

Thresholds for unacceptable work state in radiographic axial Spondyloarthritis of four presenteeism and two clinical outcome measurement instruments.

OBJECTIVES: To a) identify threshold values of presenteeism measurement instruments that reflect unacceptable work state in employed r-axSpA patients; b) determine whether those thresholds accurately predict future adverse work outcomes (AWO) (sick leave or short/long-term disability); c) evaluate the performance of traditional health-outcomes for r-axSpA; d) explore whether thresholds are stable across contextual factors. METHODS: Data from the multinational AS-PROSE study was used. Thresholds to determine whether patients consider themselves in an 'unacceptable work state' were calculated at baseline for four instruments assessing presenteeism and two health-outcomes specific for r-axSpA. Different approaches derived from the receiver operating characteristic methodology were used. Validity of the optimal thresholds was tested across contextual factors and for predicting future AWO over 12 months. RESULTS: Of 366 working patients, 15% reported an unacceptable work state; 6% experienced at least one AWO in 12 months. Optimal thresholds were: WPAI-presenteeism ≥40 (AUC 0.85), QQ-method <97 (0.76), WALS ≥0.75 (AUC 0.87), WLQ-25 ≥ 29 (AUC 0.85). BASDAI and BASFI performed similarly to the presenteeism instruments: ≥4.7 (AUC 0.82) and ≥3.5 (AUC 0.79), respectively. Thresholds for WALS and WLQ-25 were stable across contextual factors, while for all other instruments they overestimated unacceptable work state in lower educated persons. Proposed thresholds could also predict future AWO, although with lower performance, especially for QQ-method, BASDAI and BASFI. CONCLUSIONS: Thresholds of measurement instruments for presenteeism and health status to identify unacceptable work state have been established. These thresholds can help in daily clinical practice to provide work related support to r-axSpA patients at risk for AWO.

Systematic calibration reduces sources of variability for the preliminary OMERACT juvenile idiopathic arthritis MRI- sacroiliac joint score (OMERACT JAMRIS-SIJ).

OBJECTIVE: To determine whether systematic calibration enhances scoring proficiency of the OMERACT juvenile idiopathic arthritis MRI-Sacroiliac Joint score (JAMRIS-SIJ) and whether contrast-enhancement enhances its performance. METHODS: MRI SIJ scans of 50 cases with juvenile spondyloarthritis were scored by 7 raters after calibration with 3 different knowledge transfer tools. RESULTS: Calibrated readers achieved greater reliability for scoring certain inflammatory and structural lesions. Sensitivity and reliability for scoring inflammatory lesions was greater on fluid-sensitive compared to contrast-enhanced sequences. CONCLUSION: Systematic calibration should be implemented prior to the use of JAMRIS-SIJ for clinical trials. It is unlikely that contrast-enhanced MRI will improve the performance of this method.

Bimekizumab treatment in patients with active axial spondyloarthritis: 52-week efficacy and safety from the randomised parallel phase 3 BE MOBILE 1 and BE MOBILE 2 studies.

OBJECTIVES: Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated superior efficacy versus placebo in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) at Week 16. Here, the objective is to report the efficacy and safety of BKZ at Week 52. METHODS: BE MOBILE 1 (nr-axSpA; NCT03928704) and BE MOBILE 2 (r-axSpA; NCT03928743) comprised a 16-week, double-blind, placebo-controlled period, then a 36-week maintenance period. From Week 16, all patients received subcutaneous BKZ 160 mg every 4 weeks. RESULTS: Improvements versus placebo in Assessment of SpondyloArthritis International Society ≥40% response (primary endpoint), Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels and MRI inflammation of the sacroiliac joints/spine at Week 16 were sustained to Week 52 in BKZ-randomised patients. At Week 52, responses of patients switching from placebo to BKZ at Week 16 were comparable to BKZ-randomised patients. At Week 52, ≥1 treatment-emergent adverse events (TEAEs) were reported in 183 (75.0%) and 249 (75.5%) patients with nr-axSpA and r-axSpA, respectively. Serious TEAEs occurred in 9 (3.7%) patients with nr-axSpA and 20 (6.1%) patients with r-axSpA. Oral candidiasis was the most frequent fungal infection (nr-axSpA: 18 (7.4%); r-axSpA: 20 (6.1%)). Uveitis occurred in three (1.2%) and seven (2.1%) patients with nr-axSpA and r-axSpA, and inflammatory bowel disease in two (0.8%) and three (0.9%). CONCLUSIONS: At Week 52, dual inhibition of IL-17A and IL-17F with BKZ resulted in sustained efficacy across the axSpA spectrum; the safety profile was consistent with the known safety of BKZ. TRIAL REGISTRATION NUMBER: NCT03928704; NCT03928743.

A novel biomarker of MMP-cleaved cartilage intermediate layer protein-1 is elevated in patients with rheumatoid arthritis, ankylosing spondylitis and osteoarthritis.

Rheumatic joints have an altered cartilage turnover. Cartilage intermediate layer protein 1 (CILP-1) is secreted from articular chondrocytes and deposited into the cartilage extracellular matrix. We developed an immunoassay targeting a Matrix Metalloproteinase (MMP)-generated neo-epitope of CILP-1, named CILP-M. Human articular cartilage was cleaved with proteolytic enzymes and CILP-M levels were measured. We also quantified CILP-M in two studies from patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and osteoarthritis (OA) and explored the monitoring and prognostic potential of CILP-M in TNF-α inhibitory treatment and modified Stoke AS Spine Score (mSASSS) progression. CILP-M was generated by MMP-1, -8 and -12. In the discovery study, CILP-M was significantly higher in patients with RA, AS and OA than healthy donors (p < 0.01, p < 0.001, p < 0.05) with an area under the curve (AUC) between the diseased groups and healthy donors > 0.95 (p < 0.001). In the validation study, patients with RA and AS had significantly higher CILP-M levels than healthy controls (p < 0.001) and AUC > 0.90 (p < 0.001). Patients with AS treated with TNF- α inhibitory treatment in the validation study had significantly lower CILP-M levels after treatment (p = 0.004). CILP-M may provide useful insights into cartilage degradation processes in rheumatic diseases.

The bone marrow side of axial spondyloarthritis.

Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFß) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.

Comparative validation of the knee inflammation MRI scoring system and the MRI osteoarthritis knee score for semi-quantitative assessment of bone marrow lesions and synovitis-effusion in osteoarthritis: an international multi-reader exercise.

Background: Bone marrow lesions (BMLs) and synovitis on magnetic resonance imaging (MRI) are associated with symptoms and predict degeneration of articular cartilage in osteoarthritis (OA). Validated methods for their semiquantitative assessment on MRI are available, but they all have similar scoring designs and questionable sensitivity to change. New scoring methods with completely different designs need to be developed and compared to existing methods. Objectives: To compare the performance of new web-based versions of the Knee Inflammation MRI Scoring System (KIMRISS) with the MRI OA Knee Score (MOAKS) for quantification of BMLs and synovitis-effusion (S-E). Design: Retrospective follow-up cohort. Methods: We designed web-based overlays outlining regions in the knee that are scored for BML in MOAKS and KIMRISS. For KIMRISS, both BML and S-E are scored on consecutive sagittal slices. The performance of these methods was compared in an international reading exercise of 8 readers evaluating 60 pairs of scans conducted 1 year apart from cases recruited to the OA Initiative (OAI) cohort. Interobserver reliability for baseline status and baseline to 1 year change in BML and S-E was assessed by intra-class correlation coefficient (ICC) and smallest detectable change (SDC). Feasibility was assessed using the System Usability Scale (SUS). Results: Mean change in BML and S-E was minimal over 1 year. Pre-specified targets for acceptable reliability (ICC ⩾ 0.80 and ⩾ 0.70 for status and change scores, respectively) were achieved more frequently for KIMRISS for both BML and synovitis. Mean (95% CI) ICC for change in BML was 0.88 (0.83-0.92) and 0.69 (0.60-0.78) for KIMRISS and MOAKS, respectively. KIMRISS mean SUS usability score was 85.7 and at the 95th centile of ranking for usability versus a score of 55.4 and 20th centile for MOAKS. Conclusion: KIMRISS had superior performance metrics to MOAKS for quantification of BML and S-E. Both methods should be further compared in trials of new therapies for OA.

Advances in the Evaluation of Peripheral Enthesitis by Magnetic Resonance Imaging in Patients With Psoriatic Arthritis.

Enthesitis is a key disease manifestation in patients with psoriatic arthritis (PsA) that considerably contributes to pain, lower physical function, and reduced quality of life. Clinical assessment of enthesitis lacks sensitivity and specificity, and therefore better methods are urgently needed. Magnetic resonance imaging (MRI) allows detailed assessment of the components of enthesitis, and consensus-based validated MRI scoring systems exist. These include the Outcome Measures in Rheumatology (OMERACT) Heel Enthesitis MRI Scoring System (HEMRIS) method, which assesses the entheses of the heel region in a detailed manner, and the OMERACT MRI Whole-Body Score for Inflammation in Peripheral Joints and Entheses (MRI-WIPE) method, which provides an overall assessment of the inflammatory burden in the peripheral entheses and joints in the entire body using whole-body MRI. At an MRI workshop at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 meeting in Brooklyn, the MRI appearances of peripheral enthesitis were described, as were the scoring methods. The utility of MRI for improved assessment of enthesitis was demonstrated with examples of patient cases. Clinical trials in PsA that evaluate enthesitis by MRI as a key endpoint should include the presence of MRI enthesitis as an inclusion criterion, and apply validated MRI outcomes to assess the effect of therapeutics on enthesitis are recommended.

Tofacitinib Reduces Spinal Inflammation in Vertebral Bodies and Posterolateral Elements in Ankylosing Spondylitis: Results from a Phase 2 Trial.

INTRODUCTION: This post hoc analysis of phase 2 trial data assessed the efficacy of tofacitinib on magnetic resonance imaging (MRI) outcomes with the detailed anatomy-based Canada-Denmark (CANDEN) MRI scoring system and evaluated tofacitinib suppression of spinal inflammation in patients with active ankylosing spondylitis (AS). METHODS: Patients with active AS (per modified New York criteria) were randomized 1:1:1:1 to receive tofacitinib 2, 5, or 10 mg twice daily (BID), or placebo, in a 16-week, phase 2, double-blind clinical trial. Spine MRI assessments were performed at baseline and week 12. For post hoc analysis, MRI images from patients receiving tofacitinib 5 or 10 mg BID, or placebo, were re-evaluated by two readers blinded to time point/treatment and assessed by the CANDEN MRI scoring system. Least squares mean changes from baseline to week 12 were reported for CANDEN-specific MRI outcomes, with analysis of covariance used for comparisons of pooled tofacitinib and tofacitinib 5 or 10 mg BID versus placebo. p values without multiplicity adjustment were reported. RESULTS: MRI data from 137 patients were analyzed. At week 12, CANDEN spine inflammation score and vertebral body, posterior elements, corner, non-corner, facet joint, and posterolateral inflammation subscores were significantly reduced with pooled tofacitinib versus placebo (p < 0.0001; except non-corner subscore, p < 0.05). Total spine fat score was numerically increased with pooled tofacitinib versus placebo. CONCLUSIONS: In patients with AS, tofacitinib treatment was associated with significant reductions in MRI scores of spinal inflammation versus placebo, as assessed by the CANDEN MRI scoring system. Tofacitinib reduced inflammation in posterolateral elements of the spine and facet joints, which has not been described previously. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT01786668).

Consensus-Driven Definition for Unequivocal Sacroiliitis on Radiographs in Juvenile Spondyloarthritis.

OBJECTIVE: Radiography is still used worldwide for the detection of sacroiliitis in juvenile spondyloarthritis (JSpA), despite its low sensitivity and reliability. We aimed to define unequivocal evidence of sacroiliitis on pelvic radiography in skeletally immature youth for use in classification criteria when magnetic resonance imaging (MRI) is unavailable. METHODS: Subjects were a retrospective cohort of juvenile patients with spondyloarthritis with a radiograph and MRI as part of a diagnostic evaluation for axial disease. Six musculoskeletal imaging experts underwent an iterative consensus process to define unequivocal sacroiliitis on radiography in skeletally immature youth. Radiographs were graded using the modified New York (mNY) criteria and the unequivocal sacroiliitis criteria. Interrater agreement was assessed with the Fleiss [Formula: see text] statistic. Specificity, area under the receiver operator characteristic curve (AUROC), and sensitivity of the 2 measures were tested using 2 MRI reference standards. RESULTS: A total of 112 subjects, with a median age of 14.9 (range 6.7-20.1) years, were included. The Fleiss [Formula: see text] was fair for the mNY criteria (0.54, 95% CI 0.42-0.67) and the unequivocal sacroiliitis criteria (0.58, 95% CI 0.46-0.69). The unequivocal sacroiliitis criteria achieved > 90% specificity using both MRI reference standards. Sensitivity (59.26 and 57.14 vs 44.83 and 43.33) and AUROC (0.76 and 0.76 vs 0.71 and 0.71) were higher, for both reference standards, for the unequivocal sacroiliitis in youth definition than for the mNY criteria, respectively. CONCLUSION: In this study, we propose the first consensus-derived definition to our knowledge of unequivocal sacroiliitis by radiography in skeletally immature youth. This definition achieved excellent specificity and had higher AUROC and sensitivity values than the mNY criteria using both MRI reference standards. This definition has applicability to the JSpA axial disease classification imaging criterion when MRI is unavailable.

Evidence in support of the bone marrow as the primary lesion in axial spondyloarthritis.

PURPOSE OF REVIEW: Over the past several decades, the concept that the primary lesion accounting for the development of axSpA is an enthesopathy has been widely accepted. However, the hallmark abnormality of axSpA occurs in the sacroiliac joint at the interface of cartilage and bone at a location remote from any anatomical enthesis. Both imaging and histopathological data from the sacroiliac joint point to immunopathogenetic events in the bone marrow as being of primary importance. Here, we discuss new developments in our understanding of immune events in the bone marrow relevant to axSpA that reinforce the need for a change in our conceptual paradigm for the pathogenesis of axSpA. RECENT FINDINGS: Human spinal enthesis samples contain myeloperoxidase-expressing cells, a marker of neutrophils, and mucosal-associated invariant T cells in the perientheseal bone marrow, which may be activated by stromal cells and circulating microbial products to express IL-17A and IL-17F and tumor necrosis factor (TNF). Evaluation of transcriptomes of monocytes from patients with axSpA demonstrates a lipopolysaccharide/TNF signature characterized by the expression of genes associated with granulocytopoietic bone marrow cells. This neutrophil-like phenotype is more evident in established and more severe axSpA and may be activated by microbial products from the gut. A similar expansion of granulocyte-monocyte progenitor-driven hematopoiesis occurs in the SKG mouse driven by granulocyte-macrophage colony-stimulating factor. Mesenchymal stem cells (MSCs) from ankylosing spondylitis patients are more likely to exhibit osteogenic differentiation than MSCs from healthy donors, which may be mediated by the formation of specific clusters of transcriptional factors, super enhancers, regulated by axSpA-associated single nucleotide polymorphisms located mostly in noncoding regions. TNF-α may enhance directional migration of AS-MSC compared with MSC from healthy controls from the bone marrow to entheseal soft tissue, which is mediated by increased expression of engulfment and cell motility protein 1 (ELMO1). TNF and IL-17A display differential effects on adipogenesis and osteogenesis of MSC in perientheseal bone marrow and soft tissue. SUMMARY: Bone marrow has the capacity to undergo rapid adaptation in terms of cell composition, differentiation, and immune function, resulting in inflammation and osteogenesis in axSpA.

Sustained low functional impairment in axial spondyloarthritis (axSpA): which are the primary outcomes that should be targeted to achieve this?

OBJECTIVES: To (i) determine whether sustained disease activity states, as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS), impact function, and (ii) evaluate characteristics predicting sustained low functional impairment in a prospective axial spondyloarthritis (axSpA) cohort. METHODS: Biologic Treatment Registry Across Canada (BioTRAC) was a multi-center, prospective registry that collected real-world data on axSpA patients receiving infliximab or golimumab between 2006 and 2017. Generalized estimating equations (GEE) were used to test baseline characteristics, treatment, and duration (at 6 and 12 months vs. only at 6 or 12 months vs. neither) of low BASDAI (< 3), ASDAS-inactive disease (ID)(< 1.3), and ASDAS-low disease activity (LDA) in predicting sustained low Bath Ankylosing Spondylitis Functional Index (BASFI)(< 3) between 12 and 18 months. The adjusted impact of achieving low disease state at 6 and/or 12 months on BASFI at 18 months was analyzed by generalized linear models. RESULTS: Eight hundred ten patients were enrolled. 33.7%, 13.4%, and 24.7% achieved sustained low BASDAI, ASDAS-ID, and ASDAS-LDA, respectively. In univariable GEE of baseline variables, age and baseline BASDAI, BASFI, and ASDAS significantly predicted sustained low BASFI. In multivariable GEE, sustained low BASDAI (p < 0.001), low BASDAI only at 6 or 12 months (p = 0.001), and baseline BASFI (p < 0.001) were the only predictors of sustained low BASFI. Sustained ASDAS-ID (p = 0.040) and ASDAS-LDA (p < 0.001) were also predictors when forced into the model. Similar results were obtained when evaluating the BASFI score at 18 months. CONCLUSION: Sustained BASDAI < 3 may be a valid and feasible target for a treat-to-target strategy in axSpA having function as treatment goal.

Stricter treat-to-target in RA does not result in less radiographic progression: a longitudinal analysis in RA BIODAM.

OBJECTIVES: To investigate whether meticulously following a treat-to-target (T2T)-strategy in daily clinical practice will lead to less radiographic progression in patients with active RA who start (new) DMARD-therapy. METHODS: Patients with RA from 10 countries starting/changing conventional synthetic or biologic DMARDs because of active RA, and in whom treatment intensification according to the T2T principle was pursued, were assessed for disease activity every 3 months for 2 years (RA-BIODAM cohort). The primary outcome was the change in Sharp-van der Heijde (SvdH) score, assessed every 6 months. Per 3-month interval DAS44-T2T could be followed zero, one or two times (in a total of two visits). The relation between T2T intensity and change in SvdH-score was modelled by generalized estimating equations. RESULTS: In total, 511 patients were included [mean (s.d.) age: 56 (13) years; 76% female]. Mean 2-year SvdH progression was 2.2 (4.1) units (median: 1 unit). A stricter application of T2T in a 3-month interval did not reduce progression in the same 6-month interval [parameter estimates (for yes vs no): +0.15 units (95% CI: -0.04, 0.33) for 2 vs 0 visits; and +0.08 units (-0.06; 0.22) for 1 vs 0 visits] nor did it reduce progression in the subsequent 6-month interval. CONCLUSIONS: In this daily practice cohort, following T2T principles more meticulously did not result in less radiographic progression than a somewhat more lenient attitude towards T2T. One possible interpretation of these results is that the intention to apply T2T already suffices and that a more stringent approach does not further improve outcome.