Non-invasive biomarkers of disease activity and organ damage in ANCA-associated vasculitis: a systematic review.

BACKGROUND: In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), histopathological assessment of affected tissue is often necessary for diagnosis and assessment of disease extent. There is a requirement for validated non-invasive biomarkers to avoid the need for serial tissue biopsies. METHODS: A systematic review of scientific databases from 2012 until present was performed to identify studies fulfilling the inclusion criteria. Studies were assessed for quality using the Strengthening the Reporting of Observational Studies in Epidemiology checklist for cohort, case-control and cross-sectional studies and the Risk of Bias Assessment tool for Non-randomised Studies, or the Cochrane Risk of Bias tool 2.0 for randomised controlled trials. A descriptive synthesis of the data for non-invasive (blood-based or urinary) biomarkers of AAV-related disease activity and organ damage was performed. RESULTS: Twenty-two high quality studies were included. These articles reported the value of blood-based and urinary biomarkers including anti-neutrophil cytoplasmic antibodies, immune cells, complement factors, gene expression profiles, cytokines, chemokines and other proteins in the assessment of disease activity and/or organ damage in patients with AAV. Many of these biomarkers involve the alternative complement pathway, neutrophil activation and macrophage activation. CONCLUSION: This is the first contemporary systematic review synthesising the value of non-invasive biomarkers of AAV-related disease activity and organ damage. The incorporation of individual markers in combined biomarker profiles might enhance clinical decision-making. Many unmet needs were identified; few studies involve oeosinophilic granulomatosis with polyangiitis and patients with childhood-onset AAV. Further validation of the candidate biomarkers is warranted in large prospective studies to bridge the existing knowledge gaps and apply precision health to systemic vasculitis.

Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment.

BACKGROUND: Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU. METHODS: A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab. RESULTS: Adalimumab trough levels were significantly higher in complete responders 11.8 µg/mL (range 6.9-33.0) compared to partial or non-responders 9,2 µg/mL (range 0-13.6) (p = 0,004). Receiver-operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561-0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%). CONCLUSIONS: A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.

Structural ultrasound of joints and tendons in healthy children: development of normative data.

BACKGROUND: Musculoskeletal ultrasound is a well accessible technique to assess disease activity in children with juvenile idiopathic arthritis. Knowledge of reference values of joint structures is indispensable to differentiate between physiological and pathological finding. The aim of this study was to assess the structural sonographic features of joints and tendons in healthy children from several age groups (0.2-18 year), and develop a set of normative data. METHODS: Greyscale ultrasound was performed in 500 healthy children (age 0.2-18 years) according to a predefined scanning protocol (Additional file 1) including the shoulder, elbow, wrist, second metacarpophalangeal joint, hip, knee, ankle, and first metatarsophalangeal joint). Demographic data and values of cartilage thickness, tendon diameters, and the degree of capsular distention measured by bone-capsular distance (BCD) were collected. Differences according to the sex were assessed by unpaired t-test. Single and multiple regression analyses were performed between the ultrasound outcomes and covariates such as age, height, weight and body mass index. Growth charts and tables were developed with respect to age. Nonparametric quantile regression was applied using the R-packages quantreg and quantregGrowth. RESULTS: A total of 195 male and 305 female volunteers were included between the age of 0 and 18 years (mean age 8.9; range: 0.2-17.9 years). Cartilage diminished markedly as children aged, and cartilage of the boys was significantly thicker compared to the girls in all joints (p < 0.001). In addition, cartilage became thinner as children's height and weight increased (beta regression coefficients between - 0.27 and - 0.01, p < 0.0001). Capsular distention (i.e., BCD > 0 mm) was uncommon in the ankle, wrist and MCP2 (resp. in 3, 6, and 3% of cases). It was more common in the suprapatellar and parapatellar knee, MTP1 and posterior recess of the elbow (resp. in 34, 32, 46, and 39% of cases). In the hip, some capsular distention was always present. Age was found to be the best predictor for BCD (beta regression coefficients between 0.05 and 0.13, p < 0.0001). Height was, in addition to age, a good predictor of tendon diameter (beta regression coefficients between 0.03 and 0.14, p < 0.0001). Growth curves and tables for each variable were developed. CONCLUSIONS: Reference values of sonographic cartilage thickness, BCD and diameters of tendons at several joints were established from 500 healthy children, aged between 0.2 and 18 years. Growth charts and tables were developed to distinguish normal findings from pathology in children with complaints suspicious of arthritis.

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.

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.

Distinct phenotypes of multisystem inflammatory syndrome in children: a cohort study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a severe disease with an unpredictable course and a substantial risk of cardiogenic shock. Our objectives were to (a) compare MIS-C phenotypes across the COVID-19 pandemic, (b) identify features associated with intensive care need and treatment with biologic agents. METHODS: Youth aged 0-18 years, fulfilling the World Health Organization case definition of MIS-C, and admitted to the Alberta Children's Hospital during the first four waves of the COVID-19 pandemic (May 2020-December 2021) were included in this cohort study. Demographic, clinical, biochemical, imaging, and treatment data were captured. RESULTS: Fifty-seven MIS-C patients (median age 6 years, range 0-17) were included. Thirty patients (53%) required intensive care. Patients in the third or fourth wave (indicated as phase 2 of the pandemic) presented with higher peak ferritin (µg/l, median (IQR) = 1134 (409-1806) vs. 370 (249-629), P = 0.001), NT-proBNP (ng/l, median (IQR) = 12,217 (3013-27,161) vs. 3213 (1216-8483), P = 0.02) and D-dimer (mg/l, median (IQR) = 4.81 (2.24-5.37) vs. 2.01 (1.27-3.34), P = 0.004) levels, and higher prevalence of liver enzyme abnormalities (n(%) = 17 (68) vs. 11 (34), P = 0.02), hypoalbuminemia (n(%) = 24 (100) vs. 25 (81), P = 0.03) and thrombocytopenia (n(%) 18 (72) vs. 11 (34), P = 0.007) compared to patients in the first two waves (phase 1). These patients had a higher need of non-invasive/mechanical ventilation (n(%) 4 (16) vs. 0 (0), P = 0.03). Unsupervised clustering analyses classified 47% of the patients in the correct wave and 74% in the correct phase of the pandemic. NT-proBNP was the only significant contributor to the need for intensive care in all applied multivariate regression models. Treatment with biologic agents was significantly associated with peak CRP (mg/l (median, IQR = 240.9 (132.9-319.4) vs. 155.8 (101.0-200.7), P = 0.02) and ferritin levels (µg/l, median (IQR) = 1380 (509-1753) vs. 473 (280-296)). CONCLUSIONS: MIS-C patients in a later stage of the pandemic displayed a more severe phenotype, reflecting the impact of distinct SARS-CoV-2 variants. NT-proBNP emerged as the most crucial feature associated with intensive care need, underscoring the importance of monitoring.

Blurring and Irregularity of the Subchondral Cortex in Pediatric Sacroiliac Joints on T1 Images: Incidence of Normal Findings That Can Mimic Erosions.

OBJECTIVE: To determine prevalence of variations of subchondral bone appearance that may mimic erosions on T1-weighted magnetic resonance imaging (MRI) of pediatric sacroiliac (SI) joints according to age and sex. METHODS: With ethics committee approval and informed consent, SI joint MRIs of 251 children (132 girls), mean age 12.4 years (range 6.1-18.0 years), were obtained in 2 cohorts: 127 children imaged for nonrheumatic reasons, and 124 children with low back pain but no features of sacroiliitis at initial clinical MRI review. MRIs were reviewed by 3 experienced radiologists, blinded from each other, for 3 features of the cortical black line representing the subchondral bone plate on T1-weighted MRI: visibility, blurring, and irregularity. RESULTS: Based on agreement from 2 or more readers, the cortical black line was partially absent in 88.4% of the children, blurred in 34.7%, and irregular in 41.4%. All these features were most common on the iliac side of SI joints and at the first sacral vertebra level. Clearly visualized, sharply delineated SI joints with none of these features were seen in only 8.0% of children, or in 35.1% if we conservatively required agreement of all 3 readers to consider a feature present. There was no significant difference between sexes or cohorts; findings were similar across pediatric age groups. CONCLUSION: Understanding the normal MRI appearance of the developing SI joint is necessary to distinguish physiologic findings from disease. At least two-thirds (65%) of normal pediatric SI joints showed at least 1 feature that is a component of the adult definition of SI joint erosions, risking overdiagnosis of sacroiliitis.

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.

Performance of an MRI scoring system for inflammation of joints and entheses in peripheral SpA: post-hoc analysis of the CRESPA trial.

OBJECTIVES: The aim of this study was to investigate the reliability, validity, and sensitivity to change of a novel MRI scoring system in early peripheral SpA (pSpA). METHODS: MRI of the pelvis and lower extremities was performed before initiation of the TNF inhibitor golimumab in 56 patients and repeated in 46 patients who achieved sustained clinical remission after 24, 36 or 48 weeks. Three readers applied a semi-quantitative MRI scoring system for lower-extremity joint and entheseal inflammation. Four lesion types were assessed: entheseal osteitis, entheseal soft-tissue inflammation, joint osteitis, and joint synovitis/effusion. MRI response was defined as a decrease in MRI lower-extremity inflammation index (sum of scores from 75 sites, each scored 0-3) above the smallest detectable change (SDC). RESULTS: At follow-up, the MRI index decreased in 34 of 46 patients (74%), and 15 (33%) patients achieved MRI response, i.e. a decrease above SDC of 2.8. When restricting the analysis to patients with clinical involvement of lower-extremity sites that were assessed by MRI, 13 of 28 (46%) achieved MRI response. Interreader reliability was very good, with an average-measure intraclass correlation coefficient of 0.92 (95% CI: 0.85-0.95) for status scores and 0.89 (0.80-0.94) for change in scores. The MRI index correlated with other measures of disease activity, including CRP [Spearman's rho 0.41 (0.23-0.56)], swollen joint count of 6 joints [0.47 (0.27-0.63)], tender enthesis count of 14 entheses [0.32 (0.12-0.50)] and pain score [0.28 (0.08-0.46)], all P < 0.05. CONCLUSION: The proposed MRI lower-extremity inflammation index demonstrated reliability, validity, and sensitivity to change in patients with early pSpA. TRIAL REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov, NCT01426815.

Central nervous system manifestations of monogenic autoinflammatory disorders and the neurotropic features of SARS-CoV-2: Drawing the parallels.

Central nervous system (CNS) involvement in monogenic autoinflammatory disorders (AID) is increasingly recognized and can be life threatening. Therefore, a low threshold to consider CNS disease should be maintained in patients with systemic inflammation. Hyperinflammation is also a key feature of severe acute COVID-19 and post COVID-19 entities such as multisystem inflammatory syndrome in children. Like AID, COVID-19 patients can present with severe CNS involvement. The impact of COVID-19 on AID and CNS involvement in particular is still obscure, nevertheless dreaded. In the current review, we synthesize the spectrum of CNS manifestations in monogenic AID. We explore common pathophysiological and clinical features of AID and COVID-19. Moreover, we assess the impact of immune dysregulation associated with SARS-CoV-2 infections and post COVID-19 hyperinflammation in AID. The striking commonalities found between both disease entities warrant caution in the management of AID patients during the current pandemic.

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.

Magnetic resonance imaging findings in the normal pediatric sacroiliac joint space that can simulate disease.

BACKGROUND: Magnetic resonance imaging (MRI) features of active sacroiliac joint inflammation include joint space fluid and enhancement, but it is unclear to what extent these are present in normal children. OBJECTIVE: To describe normal MRI appearances of pediatric sacroiliac joint spaces in boys and girls of varying ages. MATERIALS AND METHODS: In this ethics-approved prospective study, 251 children (119 boys, 132 girls; mean age: 12.4 years, range: 6.1-18.0 years), had both oblique-coronal T1-weighted and short tau inversion recovery (STIR) sacroiliac joint MRI. Of these, 127 were imaged for other reasons and had asymptomatic sacroiliac joints ("normal cohort") while 124 had low back pain with no features of sacroiliitis on initial clinical MRI review ("low-back-pain cohort"). Post-gadolinium T1-weighted sequences were available in 16/127 normal and 124/124 low-back-pain subjects. Three experienced radiologists scored high signal in the sacroiliac joint space on STIR (score 0=absent; 1=high signal compared to normal bone marrow present anywhere in the joint but not as bright as fluid [compared to vessels, cerebrospinal fluid]; 2=definite fluid signal in part of the joint; 3=definite fluid signal, entire vertical height, majority of slices) and, when available, joint space post-contrast enhancement (0=no high signal/enhancement; 1=thin, symmetrical, mildly increased linear high signal present in the joint space; 2=focal, thick or intense enhancement). Associations between joint signal scores, age, gender and sacral apophyseal closure were analysed. RESULTS: Increased signal on STIR (score 1-3) was present in 74.7% of pediatric sacroiliac joint spaces, as intense as fluid in 18.4%. There was no significant difference in proportion by gender, side or cohort, but girls showed peak signal earlier than boys (10 years old vs. 12 years old, respectively). On post-gadolinium T1-weighted sequences, a thin rim of increased signal was nearly universally seen in sacroiliac joint spaces without focal, intense or thick post-contrast enhancement. CONCLUSION: Sacroiliac joint spaces of most children demonstrate mildly increased signal on STIR, compared to normal bone marrow, and thin rim-like enhancement on post-contrast T1 images, likely related to cartilage. These findings should not be confused with sacroiliitis.

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.

TNFi-induced sustained clinical remission in peripheral spondyloarthritis patients cannot be maintained with a step-down strategy based on methotrexate.

OBJECTIVES: Treatment with golimumab monotherapy in early peripheral SpA (pSpA) results in higher rates of clinical remission compared with treatment in more longstanding disease. When reaching remission, treat-to-target recommendations suggest tapering of treatment. We therefore explored whether addition of MTX would permit discontinuation of golimumab in patients with pSpA in sustained clinical remission. METHODS: After a 2-year extension phase with golimumab treatment, patients with pSpA reaching clinical remission in the CRESPA trial were offered a tapering strategy leading to discontinuation of golimumab and replacement by MTX monotherapy. Patients were prospectively followed to assess the rate of sustained biologic-free clinical remission. In case of relapse of arthritis, enthesitis or dactylitis under MTX monotherapy, golimumab was restarted. RESULTS: Of the original 60 pSpA patients, 25 entered the step-down strategy. Currently, only 4 patients (16%) are still in sustained remission under MTX monotherapy. In 21 patients (84%), golimumab was reinstalled because of relapse of disease activity (n = 19) or development of adverse events related to MTX (n = 2). Restarting golimumab treatment promptly restored clinical remission in all patients within 12 weeks. CONCLUSION: In patients with early pSpA achieving clinical remission after 2 years of golimumab treatment, step-down therapy to monotherapy with MTX led to high rates of clinical relapse. This underscores the overall weak efficacy of MTX in maintaining clinical remission in pSpA. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01426815.

Normal subchondral high T2 signal on MRI mimicking sacroiliitis in children: frequency, age distribution, and relationship to skeletal maturity.

OBJECTIVES: To determine patterns of variation of subchondral T2 signal changes in pediatric sacroiliac joints (SIJ) by location, age, sex, and sacral apophyseal closure. METHODS: MRI of 502 SIJ in 251 children (132 girls), mean age 12.4 years (range 6.1-18.0), was obtained with parental informed consent. One hundred twenty-seven out of 251 had asymptomatic joints and were imaged for non-rheumatologic reasons, and 124 had low back pain but no sign of sacroiliitis on initial clinical MRI review. After calibration, three subspecialist radiologists independently scored subchondral signal changes on fat-suppressed fluid-sensitive sequences from 0 to 3 in 4 locations, and graded the degree of closure of sacral segmental apophyses. Associations between patient age, sex, signal changes, and apophyseal closure were analyzed. RESULTS: Rim-like subchondral increased T2 signal or "flaring" was much more common at sacral than iliac SIJ margins (72% vs 16%, p < 0.001) and was symmetrical in > 90% of children. Iliac flaring scores were always lower than sacral, except for 1 child. Signal changes decreased as sacral apophyses closed, and were seen in < 20% of subjects with fully closed apophyses. Signal changes were more frequent in boys, and peaked in intensity later than for girls (ages 8-12 vs. 7-10). Subchondral signal in iliac crests was high throughout childhood and did not correlate with other locations. CONCLUSIONS: Subchondral T2 "flaring" is common at SIJ of prepubertal children and is generally sacral-predominant and symmetrical. Flaring that is asymmetrical, greater in ilium than sacrum, or intense in a teenager with closed apophyses, is unusual for normal children and raises concern for pathologic bone marrow edema. KEY POINTS: • A rim of subchondral high T2 signal is commonly observed on MRI at pediatric sacroiliac joints, primarily on the sacral side before segmental apophyseal closure, and should not be confused with pathology. • Unlike subchondral signal changes elsewhere, high T2 signal underlying the iliac crest apophyses is a near-universal normal finding in children that usually persists throughout adolescence. • The following patterns are unusual in normal children and are suspicious for pathology: definite iliac flaring, iliac flaring more intense than sacral flaring, left-right difference in flaring, definite flaring of any pattern in teenagers after sacral apophyseal closure.

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.