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MRI of the joints and entheses of the legs at baseline and at clinical remission, after which TNFi treatment was withdrawn.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.

Application of the OMERACT Grey-scale Ultrasound Scoring System for salivary glands in a single-centre cohort of patients with suspected Sjögren's syndrome.

AIM: To describe salivary gland involvement in patients suspected of Sjögren's syndrome (SS) using the OMERACT Ultrasound Scoring System for SS. Next, using different ultrasound cut-offs, to assess the performance of the scoring system for diagnosis and fulfilment of 2016 ACR/EULAR SS classification criteria. METHODS: All patients referred to our department with a suspicion of SS in a 12-month period were included. All underwent grey-scale ultrasound of the parotid and submandibular glands prior to clinical examination, Schirmer's test, unstimulated salivary flow, blood samples including autoantibody analysis. Labial biopsy was performed according to clinicians' judgement. Images of the four glands were scored 0-3 according to the scoring system and a consensus score was obtained using a developed ultrasound atlas. RESULTS: Of the 134 patients included in the analysis, 43 were diagnosed with primary SS (pSS) and all fulfilled the 2016 American College of Rheumatology (ACR)/EULAR classification criteria. More patients with pSS compared with non-pSS had score ≥2 in at least one gland (72% vs 13%; p<0.001). In patients with score ≥2 in any gland, significantly more had positive autoantibodies, sialometry, Schirmer's test and positive labial biopsy compared with those with scores ≤1. The best ultrasound cut-off value for diagnosing pSS was ≥1 gland with a score ≥2 (sensitivity=0.72, specificity=0.91). CONCLUSION: The OMERACT Ultrasound Scoring System showed good sensitivity (0.72) and excellent specificity (0.91) for fulfilling 2016 ACR/EULAR criteria using cut-off score >2 in at least one gland. Our data supports the use of ultrasound for diagnosing pSS and supports incorporation of ultrasound in the classification criteria.

Risk of serious infections in arthritis patients treated with biological drugs: a matched cohort study and development of prediction model.

OBJECTIVES: Serious infection is a concern for patients with inflammatory joint diseases treated with biological drugs (bDMARDs). The objectives were to compare risk of serious infection, defined as infection leading to hospitalization, in patients initiating bDMARD treatment with that in the general population and, second, to develop a simple clinical prediction model and to obtain risk estimates for individual patients. METHODS: This was a matched-cohort study based on nationwide registries in Denmark. Patients with RA, axial SpA and PsA initiating first bDMARD monitored in the DANBIO registry were matched 1:10 by age, gender and postal code with controls from the general population. The risk of serious infection during 12 months' follow-up was assessed with Cox regression. Prediction models were developed using logistic regression and compared using area under the receiver operating characteristic curve (AUC). RESULTS: We included 11 372 patients and 113 715 controls. During follow-up, 522 patients (4.6%) and 1434 controls (1.3%) developed a serious infection (hazard ratio 3.7, 95% CI 3.4, 4.1). Age-stratified risk was largely similar across diagnoses. A simple prediction model, the 'DANBIO infection risk score', based on age and a count of six clinical risk factors had moderate discriminative power (internal validation: AUC 0.69) that was comparable to that of the existing RABBIT (Rheumatoide Arthritis Beobachtung der BIologika-Therapie) Risk Score (external validation: AUC 0.68). CONCLUSION: Patients with inflammatory joint diseases initiating bDMARD treatment had a four times increased risk of serious infection compared with the general population. A simple prediction model, feasible for shared decision-making, was developed to obtain risk estimates for individual patients.

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.

Whole-body Magnetic Resonance Imaging in Psoriatic Arthritis, Rheumatoid Arthritis, and Healthy Controls: Interscan, Intrareader, and Interreader Agreement and Distribution of Lesions.

OBJECTIVE: Whole-body MRI (WBMRI) is a promising technique for monitoring patients' global disease activity in inflammatory joint diseases. The validation of WBMRI is limited; no studies have evaluated the test-retest agreement (interscan agreement) and only a few have assessed the intra- and interreader agreement. Therefore, we first examined the interscan agreement of WBMRI in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), and healthy controls (HC); and second, we evaluated the intra- and interreader agreement and agreement with conventional hand MRI and determined the distribution of lesions. METHODS: WBMRI was performed twice at a 1-week interval in 14 patients with PsA, 10 with RA, and 16 HC. Images were anonymized and read in pairs with unknown chronological order by experienced readers according to the Outcome Measures in Rheumatology (OMERACT) WBMRI, Canada-Denmark MRI, and the RA MRI scoring system (RAMRIS) and the PsA MRI scoring system (PsAMRIS). Ten image sets were reanonymized for assessment of intra- and interreader agreement. Agreement was calculated on lesion level by percentage exact agreement (PEA) and Cohen κ, and for sum scores by absolute agreement, single-measure intraclass correlation coefficient (ICC). RESULTS: WBMRI of the spine and peripheral joints and entheses generally showed moderate to almost perfect interscan agreement with PEA ranging from 95% to 100%, κ 0.71-1.00, and ICC 0.95 to 1.00. Intra- and interreader data generally showed moderate to almost perfect agreement. Agreement with conventional MRI varied. More lesions were found in patients than in HC. CONCLUSION: WBMRI showed good interscan agreement, implying that repositioning of the patient between examinations does not markedly affect scoring of lesions. Intra- and interreader agreement were moderate to almost perfect.

Validation of assessment methods for the apparent diffusion coefficient in a clinical trial of axial spondyloarthritis patients treated with golimumab.

PURPOSE: To compare three region-of-interest (ROI) settings in the assessment of ADC in a clinical trial, and to evaluate the effectiveness of ADC in assessing therapy-induced changes and predicting clinical outcomes. METHODS: In a 52-week clinical trial involving patients with axial spondyloarthritis, mean sacroiliac joint (SIJ) ADC measurements using structured, lesion-based, and index-lesion ROI-settings were assessed at baseline and weeks 4, 16, and 52. Variation among the three ROI-settings, correlations with Spondyloarthritis Research Consortium of Canada (SPARCC)-bone marrow edema (BME) SIJ inflammation indices, standardized response means (SRMs), and effectiveness in predicting clinical outcomes were analyzed. RESULTS: Forty of the 53 patients had at least one assessable SIJ lesion on ADC at baseline. The mean of the structured ROI ADC (ADCstruc) was 230 µmm2/s (standard deviation [SD] = 120). This was significantly lower (p < 0.01) than the means of the lesion-based ROI ADC (ADClesion = 420 µmm2/s, SD = 210) and index-lesion ROI ADC (ADCindex = 471 µmm2/s, SD = 278), which did not differ. ADC correlated with SPARCC-BME scores at baseline (p < 0.01) as did changes over time in ADC- and SPARCC-BME (p<0.05). At all follow-up time points, responsiveness was high for ADClesion (SRM > 0.92) and ADCindex (SRM > 0.87) while moderate for ADCstruc (SRM:0.54-0.67). Baseline ADC and changes in ADC did not predict clinical outcomes. CONCLUSIONS: Lesion-based and index-lesion ROI ADC could both be used to evaluate the effectiveness of tumor necrosis factor inhibitor therapy. None of the methods could predict clinical outcomes.

Atlas of the OMERACT Heel Enthesitis MRI Scoring System (HEMRIS).

OBJECTIVE: Assessment of enthesitis, a key feature in spondyloarthritis (SpA) and psoriatic arthritis (PsA), using objective and sensitive methods is pivotal in clinical trials. MRI allows detection of both soft tissue and intra-osseous changes of enthesitis. This article presents an atlas for the Outcome Measures in Rheumatology (OMERACT) Heel Enthesitis Magnetic Resonance ImagingMRI Scoring System (HEMRIS). METHODS: Following a preliminary selection of potential examples of each grade, as per HEMRIS definitions, the images along with detailed definitions and reader rules were discussed at web-based, interactive meetings between the members of the OMERACT MRI in Arthritis Working Group. RESULTS: Reference images of each grade of the MRI features to be assessed using HEMRIS, along with reader rules and recommended MRI sequences are depicted. CONCLUSION: The presented reference images can be used to guide scoring Achilles tendon and plantar fascia (plantar aponeurosis) enthesitis according to the OMERACT HEMRIS in clinical trials and cohorts in which MRI enthesitis is used as an outcome.

Canada-Denmark MRI scoring system of the spine in patients with axial spondyloarthritis: updated definitions, scoring rules and inter-reader reliability in a multiple reader setting.

Objective: To validate the Canada-Denmark (CANDEN) MRI scoring system for the spine in axial spondyloarthritis with updated lesion definitions. Methods: Lesion definitions in the CANDEN system were updated and illustrated by a consensus set of reference images. Sagittal spine MRIs of 40 patients with axial spondyloarthritis obtained at baseline and at week 52 after initiation of treatment with the tumour necrosis factor inhibitor golimumab were evaluated in unknown chronology by seven readers blinded to all other data. Results: CANDEN MRI spine inflammation score had very good reliability for status scores (single-measure intraclass correlation coefficient (ICC) of 21 reader pairs median of 0.91 (IQR 0.88-0.92)) and change scores (ICC 0.88 (0.86-0.92)). CANDEN MRI spine fat score had good to very good reliability for status scores (ICC 0.79 (0.75-0.86)) and moderate to good reliability for detecting change (ICC 0.59 (0.46-0.73)). CANDEN MRI spine bone erosion score and CANDEN MRI spine new bone formation score had slight to moderate reliability for status scores (ICC 0.38 (0.32-0.52) and 0.39 (0.27-0.49), respectively). Conclusion: The CANDEN MRI spine scoring system allows a comprehensive evaluation of inflammation, fat, bone erosion and new bone formation of the spine in patients with axial spondyloarthritis. It demonstrated very good reliability for detecting change in inflammation, moderate to good reliability for detecting change in fat, and slight to moderate reliability for detecting bone erosions and new bone formation. Studies with longer follow-up or patients with more advanced spinal involvement may be needed to reliably detect change in bone erosion and new bone formation scores. Trial registration number: NCT02011386.

Whole-body Magnetic Resonance Imaging in Axial Spondyloarthritis: Reduction of Sacroiliac, Spinal, and Entheseal Inflammation in a Placebo-controlled Trial of Adalimumab.

OBJECTIVE: To investigate whether adalimumab (ADA) reduces whole-body (WB-) magnetic resonance imaging (MRI) indices for inflammation in the entheses, peripheral joints, sacroiliac joints, spine, and the entire body in patients with axial spondyloarthritis (axSpA). METHODS: An investigator-initiated, randomized, placebo-controlled, double-blinded 48-week followup trial included 49 patients with axSpA, who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.0 despite treatment with nonsteroidal antiinflammatory drugs and a clinical indication for tumor necrosis factor inhibitor treatment. Patients were randomized to subcutaneous ADA 40 mg or placebo every other week for 6 weeks; thereafter, all patients received ADA. Conventional MRI and WBMRI were performed at weeks 0, 6, 24, and 48. The primary WBMRI endpoint was the proportion of patients with an improvement in WBMRI total inflammation index above the smallest detectable change (SDC) at Week 6. RESULTS: The primary WBMRI endpoint (improvement of SDC > 2.3) was met in 11 (44%) patients in the ADA group and 3 (13%) patients in the placebo group (p = 0.025, Fisher's exact test). The primary conventional MRI endpoint, the minimally important change in Spondyloarthritis Research Consortium of Canada Spine MRI Inflammation Index at Week 6, was achieved by 9 (36%) patients in the ADA group and 4 (17%) patients in the placebo group (p = 0.20). The primary clinical endpoint, BASDAI reduction > 50% or 2.0 at Week 24, was attained by 32 (65%) patients. CONCLUSION: ADA provided significant reductions in WBMRI indices of peripheral, axial, and whole-body inflammation in patients with axSpA. WBMRI is promising for objective assessment and monitoring of peripheral and axial disease activity in future clinical trials.

Bone marrow oedema assessment by magnetic resonance imaging in rheumatoid arthritis wrist and metacarpophalangeal joints: the importance of field strength, coil type and image resolution.

OBJECTIVE: The aim of this study was to examine the influence of different MRI unit field strengths, coil types and image resolutions on the OMERACT RA MRI scoring system (RAMRIS) of bone marrow oedema (BME) and image quality. METHODS: Forty-one patients and 12 healthy controls participated in this cross-sectional study. Coronal short tau inversion recovery (STIR) and T1-weighted sequences were obtained at 0.23, 0.6, 1.5 and 3T using flex coils (Flex). Additional STIR sequences were obtained with phased array extremity coils (Extr) (at 0.6 and 1.5T) and higher resolution (at 1.5T). In otal, 338 STIR image sets were anonymized and scored according to RAMRIS and parameters of image quality were measured. RESULTS: The BME sum scores were similar overall when comparing the different MRI units, coil types and voxel sizes, yet significantly higher at the higher resolution of 1.5T Extr compared with 0.23T Flex (P = 0.004), 0.6T Flex (P = 0.03), 1.5T Flex (P = 0.05) and 3T Flex (P = 0.001). Mean differences were relatively minor (0-3.5). Intrareader reliability of BME scores was high [intraclass correlation coefficient ≥ 0.90 for all except 0.23T (0.81) and percentage exact agreement 81-88%]. The smallest detectable difference was better at 0.6, 1.5 and 3T (9-29% of maximum value) than at 0.23T (40%). Image quality was lowest at 0.23T. CONCLUSION: No major, consistent differences were found between BME scores using STIR sequences obtained at different field strengths, coil types and image resolutions, suggesting that these are equally suited for assessment of BME in RA. However, parameters of image quality and intrareader reliability (favouring 0.6, 1.5 and 3T) should be considered when selecting the MRI acquisition strategy.

Pancreatic bicarbonate secretion involves two proton pumps.

Pancreas secretes fluid rich in digestive enzymes and bicarbonate. The alkaline secretion is important in buffering of acid chyme entering duodenum and for activation of enzymes. This secretion is formed in pancreatic ducts, and studies to date show that plasma membranes of duct epithelium express H(+)/HCO(3)(-) transporters, which depend on gradients created by the Na(+)/K(+)-ATPase. However, the model cannot fully account for high-bicarbonate concentrations, and other active transporters, i.e. pumps, have not been explored. Here we show that pancreatic ducts express functional gastric and non-gastric H(+)-K(+)-ATPases. We measured intracellular pH and secretion in small ducts isolated from rat pancreas and showed their sensitivity to H(+)-K(+) pump inhibitors and ion substitutions. Gastric and non-gastric H(+)-K(+) pumps were demonstrated on RNA and protein levels, and pumps were localized to the plasma membranes of pancreatic ducts. Quantitative analysis of H(+)/HCO(3)(-) and fluid transport shows that the H(+)-K(+) pumps can contribute to pancreatic secretion in several species. Our results call for revision of the bicarbonate transport physiology in pancreas, and most likely other epithelia. Furthermore, because pancreatic ducts play a central role in several pancreatic diseases, it is of high relevance to understand the role of H(+)-K(+) pumps in pathophysiology.

Purinergic receptors stimulate Na+/Ca2+ exchange in pancreatic duct cells: possible role of proteins handling and transporting Ca2+.

Most purinergic receptors activate intracellular Ca(2+) signalling, and in epithelia they stimulate transport of major ions. Aim of the present study on pancreatic ducts was to find whether P2 receptors also regulate cellular Ca(2+) transport, such as that via the Na(+)/Ca(2+) exchanger (NCX). Since NCX can also be connected with epithelial Ca(2+) transport, we also investigated expression of some Ca(2+)-handling/transporting proteins. Expression analysis revealed that pancreatic ducts of rat and human duct cell line CFPAC-1 (also PANC-1 and Capan-1) express the Na(+)/Ca(2+) exchanger (splice variants NCX1.3 and 1.7), as well as the Ca(2+)-sensing receptor and the Ca(2+)-binding protein calbindin-D 9k. These proteins localize to the luminal and lateral membranes of pancreatic duct epithelia. Ca(2+) imaging experiments showed that activation of purinergic P2Y and P2X receptors stimulated NCX in human and rat duct cells. Application of ATP to CFPAC-1 monolayers also stimulated Ca(2+) transport from the luminal to the basolateral side. Taken together, these results show that pancreatic ducts express a number of Ca(2+)-handling/transporting proteins and we propose that these together with purinergic receptors play a role in regulation of duct lumen Ca(2+) content.