Publications by authors named "Simon Krabbe"

37 Publications

Joint and entheseal inflammation in the knee region in spondyloarthritis - reliability and responsiveness of two OMERACT whole-body MRI scores.

Semin Arthritis Rheum 2021 Aug 17;51(4):933-939. Epub 2021 Jun 17.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Objective: To perform region-based development of whole-body MRI through validation of knee region scoring systems in spondyloarthritis (SpA).

Methods: Assessment of knee inflammatory pathologies using 2 systems, OMERACT MRI Whole-body score for Inflammation in Peripheral joints and Entheses (MRI-WIPE) and Knee Inflammation MRI Scoring System (KIMRISS), in 4 iterative multi-reader exercises.

Results: In the final exercise, reliability was mostly good for readers with highest agreement in previous exercise. Median pairwise single-measure ICCs for osteitis and synovitis/effusion status/change were 0.71/0.48 (WIPE-osteitis), 0.48/0.77 (WIPE-synovitis/effusion), 0.59/0.91 (KIMRISS-osteitis) and 0.92/0.97 (KIMRISS-synovitis/effusion). SRMs were 0.74 (WIPE-synovitis/effusion) and 0.78 (KIMRISS-synovitis/effusion).

Conclusion: MRI-WIPE and KIMRISS may both be useful in SpA whole-body evaluation studies.
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http://dx.doi.org/10.1016/j.semarthrit.2021.05.013DOI Listing
August 2021

Arthritis and enthesitis in the hip and pelvis region in spondyloarthritis - OMERACT validation of two whole-body MRI methods.

Semin Arthritis Rheum 2021 Aug 21;51(4):940-945. Epub 2021 May 21.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

Objective: To validate reliability, correlation and responsiveness of two whole-body MRI scores for the hip/pelvis region in spondyloarthritis.

Methods: Assessment of hip/pelvis inflammation in 4 multi-reader exercises using the OMERACT MRI Whole-body score for Inflammation in Peripheral joints and Entheses (MRI-WIPE) and Hip Inflammation Magnetic Resonance Imaging Scoring System (HIMRISS).

Results: In exercises 3-4 (11/20 cases, respectively; 9 readers) reliability was mostly good for the 3 best calibrated readers. Median pairwise single-measure ICC for status were 0.58-0.65 (WIPE-osteitis), 0.10-0.88 (HIMRISS-osteitis) and for status/change 0.38-0.72/0.52-0.60 (WIPE-synovitis/effusion) and 0.68-0.89/0.78-0.85 (HIMRISS-synovitis/effusion). SRM was 1.23 for WIPE-osteitis, while lower for WIPE-synovitis/effusion and HIMRISS.

Conclusion: MRI-WIPE and HIMRISS may after further validation be useful in future spondyloarthritis trials.
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http://dx.doi.org/10.1016/j.semarthrit.2021.05.006DOI Listing
August 2021

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

Arthritis Rheumatol 2021 May 13. Epub 2021 May 13.

VIB Center for Inflammation Research, Ghent University, and Ghent University Hospital, Ghent, Belgium.

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.
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http://dx.doi.org/10.1002/art.41783DOI Listing
May 2021

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

RMD Open 2021 04;7(2)

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1136/rmdopen-2020-001516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061801PMC
April 2021

Doppler ultrasound predicts successful discontinuation of biological DMARDs in rheumatoid arthritis patients in clinical remission.

Rheumatology (Oxford) 2021 Mar 20. Epub 2021 Mar 20.

Center for Rheumatology and Spine Diseases, Center of Head and Orthopedics, Glostrup, Rigshospitalet, Capital Region, Denmark.

Objective: To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological disease-modifying anti-rheumatic drugs (bDMARDs) at 2-year follow-up in rheumatoid arthritis (RA) patients in sustained remission.

Methods: Patients in sustained remission (DAS28-CRP≤2.6) and no radiographic progression the previous year tapered bDMARD according to a standardized regime. One-hundred-and-nineteen of these patients were included in this ultrasound sub-study. At baseline, clinical assessment, MRI, x-ray and ultrasound of 24 joints were performed. Ultrasound-detected synovitis was defined and scored 0-3 using the Outcome in Rheumatology (OMERACT) scoring system at joint level for both greyscale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at patient level. Final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at 2-year follow-up was assessed via logistic regression analyses.

Results: Negative IgM-RF (OR = 0.29; 95% Confidence Interval (CI)=0.10-0.85; p = 0.024) and lower Doppler sum score of 24 joints (OR(95%CI)=0.44;(0.15-0.87); p = 0.014) were independent predictors for successful discontinuation of bDMARD at 2-year follow-up. The predictive value of Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR(95% CI)=0.58(0.35-0.91); p = 0.018), whereas ultrasound was not. Clinical parameters were not predictive for successful tapering/discontinuation.

Conclusions: Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at 2-year follow-up - the odds for achieving successful discontinuation decreased by 56% per one-unit increase in Doppler sum score. Ultrasound could not predict successful tapering.
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http://dx.doi.org/10.1093/rheumatology/keab276DOI Listing
March 2021

Using a DAS28-CRP-steered treat-to-target strategy does not eliminate subclinical inflammation as assessed by ultrasonography in rheumatoid arthritis patients in longstanding clinical remission.

Arthritis Res Ther 2021 02 1;23(1):48. Epub 2021 Feb 1.

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Glostrup, Copenhagen, Denmark.

Background: Subclinical synovitis by ultrasound is a frequent finding in rheumatoid arthritis (RA) patients in remission and has been shown to be related to erosive progression, risk of flare and unsuccessful drug tapering, but it has not been investigated how a DAS28 T2T-steered strategy in routine care affects the presence of subclinical synovitis in RA patients in remission. The aim of the current study was to investigate the presence of ultrasound-detected subclinical inflammation in RA patients in long-term remission receiving either biological or conventional disease-modifying anti-rheumatic drugs (bDMARD/csDMARD) and, finally, to investigate the presence of ultrasound remission using different ultrasound remission criteria.

Methods: Eighty-seven RA patients (42 patients receiving bDMARD and 45 csDMARD) received DAS28-CRP-steered treatment in routine care and had achieved DAS28-CRP-remission for > 1 year without radiographic progression. Twenty-four joints were scored 0-3 by ultrasound (elbows, wrists, knees, ankles, metacarpophalangeal and metatarsophalangeal joints 2-5) for grey-scale synovial hypertrophy (GS) and colour Doppler activity (CD) using the OMERACT scoring system. Ultrasound remission was defined as strict (GS score = 0 and CD score = 0), semi-strict (GS score < 1 and Doppler score = 0) and Doppler remission (Doppler score = 0).

Results: No differences between treatment groups were found for GS sum score and Doppler sum score (median (range) 6 (0-19) and 0 (0-12), respectively). A Doppler score > 0 in at least 1 joint was seen in 44%, a GS score > 1 in at least 1 joint in 93% and a GS score > 2 in at least 1 joint in 54% of patients. Strict ultrasound remission was only observed in bDMARD patients (7%; p = 0.01). Thirty-seven per cent were in semi-strict ultrasound remission and 56% in Doppler remission (no significant difference between groups) with similar results across the subgroups of patients who also fulfilled the ACR-EULAR Boolean-, CDAI- and SDAI-remission criteria.

Conclusions: Ultrasound frequently detected subclinical synovitis in RA patients in longstanding DAS28-remission obtained through a DAS28-CRP-steered strategy. This was independent of treatment and applied ultrasound remission criteria. Strict ultrasound remission was rare.
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http://dx.doi.org/10.1186/s13075-021-02426-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849184PMC
February 2021

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

Rheumatology (Oxford) 2021 08;60(8):3834-3844

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1093/rheumatology/keaa876DOI Listing
August 2021

Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial.

BMJ 2020 12 2;371:m4328. Epub 2020 Dec 2.

Department of Rheumatology, Ålesund Hospital, Ålesund, Norway.

Objective: To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.

Design: Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.

Setting: Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.

Participants: Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.

Interventions: Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.

Main Outcome Measures: The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.

Results: 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval -5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and -0.6% (-10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.

Conclusions: All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.

Trial Registration: EudraCT2011-004720-35, NCT01491815.
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http://dx.doi.org/10.1136/bmj.m4328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708829PMC
December 2020

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

Eur J Radiol Open 2020 5;7:100285. Epub 2020 Nov 5.

Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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 (ADC) was 230 μmm/s (standard deviation [SD] = 120). This was significantly lower ( < 0.01) than the means of the lesion-based ROI ADC (ADC = 420 μmm/s, SD = 210) and index-lesion ROI ADC (ADC = 471 μmm/s, SD = 278), which did not differ. ADC correlated with SPARCC-BME scores at baseline ( < 0.01) as did changes over time in ADC- and SPARCC-BME (<0.05). At all follow-up time points, responsiveness was high for ADC (SRM > 0.92) and ADC (SRM > 0.87) while moderate for ADC (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.
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http://dx.doi.org/10.1016/j.ejro.2020.100285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649611PMC
November 2020

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

Ann Rheum Dis 2021 01 28;80(1):103-108. Epub 2020 Oct 28.

Internal Medicine and Pediatrics, Ghent University Faculty of Medicine and Health Sciences, Ghent, Belgium.

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.
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http://dx.doi.org/10.1136/annrheumdis-2020-218480DOI Listing
January 2021

Folinic acid alleviates side effects of methotrexate in arthritis patients with side effects despite folic acid supplementation: an observational cohort study.

Rheumatology (Oxford) 2020 Nov;59(11):3566-3568

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet Glostrup, Glostrup Town.

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http://dx.doi.org/10.1093/rheumatology/keaa277DOI Listing
November 2020

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

RMD Open 2020 02 11;6(1). Epub 2020 Feb 11.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Glostrup, Denmark.

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.
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http://dx.doi.org/10.1136/rmdopen-2019-001150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046972PMC
February 2020

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

J Rheumatol 2021 02 15;48(2):198-206. Epub 2020 Jun 15.

A.E. Poulsen, MD, S. Krabbe, MD, M. Østergaard, MD, PhD, DMSc, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

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.
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http://dx.doi.org/10.3899/jrheum.200084DOI Listing
February 2021

Novel whole-body magnetic resonance imaging response and remission criteria document diminished inflammation during golimumab treatment in axial spondyloarthritis.

Rheumatology (Oxford) 2020 11;59(11):3358-3368

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.

Objectives: To investigate criteria for treatment response and remission in patients with axial SpA as assessed by whole-body magnetic resonance imaging (WB-MRI) of axial and peripheral joints and entheses during treatment with golimumab.

Methods: We performed an investigator-initiated cohort study of 53 patients who underwent WB-MRI at weeks 0, 4, 16 and 52 after initiation of golimumab. Images were assessed according to the Spondyloarthritis Research Consortium of Canada MRI SI joint inflammation index, Canada-Denmark MRI spine inflammation score and the MRI peripheral joints and entheses inflammation index.

Results: At weeks 4, 16 and 52, WB-MRI demonstrated an at least 50% reduction of MRI inflammation of the sacroiliac joints in 16, 29 and 32 (30%, 55% and 60%) patients, of the spine in 20, 30 and 31 (38%, 57% and 58%) patients and of peripheral joints and entheses in 8, 17 and 15 (15%, 32% and 28%) patients, respectively. The BASDAI50 response was achieved by 29, 31 and 31 (55%, 58% and 58%) patients, while ASDAS clinically important improvement (ASDAS-CII) was achieved by 37, 40 and 34 (70%, 75% and 64%) patients. WB-MRI remission criteria for spine, sacroiliac joints and peripheral joints and entheses were explored; total WB-MRI remission was attained by 2, 6 and 3 (4%, 11% and 6%) patients. At week 16, among 35 patients with an at least 50% reduction in the MRI Axial Inflammation Index (sacroiliac joint and spine inflammation), 29 (83%) achieved BASDAI50 and 35 (100%) achieved ASDAS-CII; among 16 patients with MRI axial inflammation non-response, 14 (88%) were BASDAI50 non-responders and 11 (69%) did not achieve ASDAS-CII.

Conclusion: WB-MRI demonstrated a significant reduction of inflammation in both the spine, sacroiliac joints and peripheral joints and entheses during golimumab treatment. Few patients achieved total WB-MRI remission. Combining spinal and sacroiliac joint inflammation in an MRI Axial Inflammation Index increased the ability to capture response.

Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02011386.
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http://dx.doi.org/10.1093/rheumatology/keaa153DOI Listing
November 2020

Association between MRI findings and patient-reported outcomes in patients with rheumatoid arthritis in clinical remission and at relapse.

Int J Rheum Dis 2020 Apr 28;23(4):488-498. Epub 2020 Jan 28.

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark.

Objective: To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse.

Methods: Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests.

Results: Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P < .01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P < .03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse.

Conclusion: Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.
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http://dx.doi.org/10.1111/1756-185X.13790DOI Listing
April 2020

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.

RMD Open 2019 13;5(2):e001057. Epub 2019 Oct 13.

Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, Alberta, Canada.

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.
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http://dx.doi.org/10.1136/rmdopen-2019-001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803003PMC
April 2020

High versus standard magnetic resonance image resolution of the cervical spine in patients with axial spondyloarthritis.

Acta Radiol 2020 Apr 3;61(4):471-479. Epub 2019 Sep 3.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.

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http://dx.doi.org/10.1177/0284185119872689DOI Listing
April 2020

Whole-body Magnetic Resonance Imaging Inflammation in Peripheral Joints and Entheses in Axial Spondyloarthritis: Distribution and Changes during Adalimumab Treatment.

J Rheumatol 2020 01 1;47(1):50-58. Epub 2019 Apr 1.

From the Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; Center for Rheumatology and Spine Diseases, Frederiksberg Hospital, Frederiksberg; Department of Radiology, Herlev and Gentofte Hospital, Herlev; Center for Rheumatology and Spine Diseases, and Gentofte Hospital, Hellerup, Denmark; Department of Diagnostic Imaging, Sheba Medical Center, affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: To investigate the distribution of whole-body magnetic resonance imaging (WB-MRI) inflammatory lesions of peripheral joints and entheses, and their response to adalimumab (ADA) treatment and agreement with clinical measures of disease activity in patients with axial spondyloarthritis (axSpA).

Methods: Explorative analysis of an investigator-initiated randomized controlled trial of ADA. WB-MRI was performed at weeks 0, 6, 24, and 48. Detailed analyses of WB-MRI lesions in peripheral joints and entheses were performed, including agreement with clinical measures of disease activity.

Results: WB-MRI inflammatory lesions were most frequently observed in the acromioclavicular, metatarsophalangeal, and wrist joints (> 10% of joints), and at the greater trochanter, calcaneal insertion of the Achilles tendon, and ischial tuberosity (> 15% of entheses). Inflammation resolved in ≥ 2/3 of involved sternoclavicular, metacarpophalangeal, first carpometacarpal, hip, and tarsometatarsal joints, and pubic symphyses and medial femoral condyles. In contrast, inflammation resolved in ≤ 1/6 of involved acromioclavicular joints, knee joints, and supraspinatus tendon insertions at humerus. Tenderness of joints and entheses agreed poorly with WB-MRI inflammation (κ < 0.40). Joint tenderness resolved more frequently in MRI-positive than MRI-negative joints (8/13, 62% vs 9/34, 26%) after 6 weeks of active treatment.

Conclusion: Inflammatory lesions of peripheral joints and entheses in patients with predominantly axSpA, and changes therein, can be mapped using WB-MRI, and it may contribute to differentiate between inflammatory and noninflammatory joint tenderness. (Trial registration: ClinicalTrials NCT01029847).
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http://dx.doi.org/10.3899/jrheum.181159DOI Listing
January 2020

Development and Validation of an OMERACT MRI Whole-Body Score for Inflammation in Peripheral Joints and Entheses in Inflammatory Arthritis (MRI-WIPE).

J Rheumatol 2019 09 15;46(9):1215-1221. Epub 2019 Feb 15.

From the Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Diagnostic Imaging, Sheba Medical Center, Affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; University Pierre et Marie Curie - Paris 6, Sorbonne Universités, GRC-08 (EEMOIS); AP-HP, Rheumatology Department, Pitié Salpêtrière University Hospital, Paris, France; Division of Medicine, University of New South Wales, Sydney, Australia; Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, India; Department of Radiology and Diagnostic Imaging, and Department of Medicine, University of Alberta; CaRE Arthritis, Edmonton, Canada; Department of Rheumatology, Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels; Department of Radiology, Ghent University Hospital, Ghent, Belgium; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds; National Institute for Health Research (NIHR) Leeds Biomedical Research Centre, Leeds Teaching Hospital National Health Service (NHS) Trust, UK; Department of Radiology, Arthritis Imaging Research Group, University Hospital Charité, Berlin, Germany; Spire Sciences Inc., Boca Raton, Florida, USA.

Objective: To develop a whole-body magnetic resonance imaging (MRI) scoring system for peripheral arthritis and enthesitis.

Methods: After consensus on definitions/locations of MRI pathologies, 4 multireader exercises were performed. Eighty-three joints were scored 0-3 separately for synovitis and osteitis, and 33 entheses 0-3 separately for soft tissue inflammation and osteitis.

Results: In the last exercise, reliability was moderate-good for musculoskeletal radiologists and rheumatologists with previously demonstrated good scoring proficiency. Median pairwise single-measure/average-measure ICC were 0.67/0.80 for status scores and 0.69/0.82 for change scores; κ ranged 0.35-0.77.

Conclusion: Whole-body MRI scoring of peripheral arthritis and enthesitis is reliable, which encourages further testing and refinement in clinical trials.
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http://dx.doi.org/10.3899/jrheum.181084DOI Listing
September 2019

The OMERACT MRI in Enthesitis Initiative: Definitions of Key Pathologies, Suggested MRI Sequences, and a Novel Heel Enthesitis Scoring System.

J Rheumatol 2019 09 1;46(9):1232-1238. Epub 2019 Feb 1.

From the Department of Clinical Immunology and Rheumatology, Christian Medical College, Vellore, India; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark; Department of Diagnostic Imaging, Sheba Medical Center, Affiliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Hôpitaux Universitaires Pitié Salpêtrière; Paris 6 University, GRC-UPMC 08, Pierre Louis Institute of Epidemiology and Public Health; Service de Radiologie, Hôpital Lariboisière, AP-HP and Université Paris-Diderot, Paris, France; Division of Medicine, University of New South Wales, Sydney, Australia; Cliniques Universitaires Saint-Luc, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels; Department of Rheumatology, Ghent University Hospital, Ghent, Belgium; Department of Radiology and Diagnostic Imaging, and CaRE (Canadian Research Education) Arthritis and Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Radiology, Arthritis Imaging Research Group, University Hospital Charité, Berlin, Germany; Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway; Faculty of Medicine and Health, University of Leeds, Leeds, UK.

Objective: To develop and validate an enthesitis magnetic resonance imaging (MRI) scoring system for spondyloarthritis/psoriatic arthritis, using the heel as model.

Methods: Consensus definitions of key pathologies and 3 heel enthesitis multireader scoring exercises were done, separated by discussion, training, and calibration.

Results: Definitions for bone and soft tissue pathologies were agreed. In the final exercise, median pairwise single-measures intraclass correlation coefficients (ICC; patient-level) for entheseal inflammation status/change scores were 0.83/0.82 for all readers. For radiologists and selected rheumatologists, ICC were 0.91/0.84 and quadratic-weighted κ (lesion-level) 0.57-0.91/0.45-0.81.

Conclusion: The proposed definitions and Heel Enthesitis Scoring System (HEMRIS) are reliable among trained readers and promising for clinical trials.
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http://dx.doi.org/10.3899/jrheum.181093DOI Listing
September 2019

Utility of Magnetic Resonance Imaging in Diagnosis and Monitoring Enthesitis in Patients with Spondyloarthritis: An OMERACT Systematic Literature Review.

J Rheumatol 2019 09 1;46(9):1207-1214. Epub 2019 Feb 1.

From the Department of Clinical Immunology and Rheumatology, Christian Medical College; Cochrane South Asia, Christian Medical College, Vellore, India; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen; Copenhagen Center for Arthritis Research (COPECARE), Copenhagen; Center for Rheumatology and Spine Diseases, Rigshospitalet Glostrup, Glostrup, Denmark; UK National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals National Health Service (NHS) Trust; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK; Division of Medicine, University of New South Wales, Sydney, Australia.

Objective: A systematic literature review was performed to document published magnetic resonance imaging (MRI) lesion definitions and scoring systems for enthesitis in spondyloarthritis (SpA).

Methods: PubMed, Embase, and Cochrane Library databases were searched for original publications involving adult patients with SpA undergoing MRI of axial/peripheral joints. Selected articles were assessed for quality using a standardized assessment tool and metric indices.

Results: Considering the heterogeneous design, quality, and outcome measures of studies, statistical data pooling was considered inappropriate. A qualitative narrative of results was undertaken based on study designs.

Conclusion: Lack of a comprehensive, validated score warrants additional research to develop an MRI enthesitis scoring system. PROSPERO registration number: CRD42018090537.
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http://dx.doi.org/10.3899/jrheum.181083DOI Listing
September 2019

Human adipose glycerol flux is regulated by a pH gate in AQP10.

Nat Commun 2018 11 12;9(1):4749. Epub 2018 Nov 12.

University of Copenhagen, Department of Biomedical Sciences, Nørre Allé 14, DK-2200, Copenhagen N, Denmark.

Obesity is a major threat to global health and metabolically associated with glycerol homeostasis. Here we demonstrate that in human adipocytes, the decreased pH observed during lipolysis (fat burning) correlates with increased glycerol release and stimulation of aquaglyceroporin AQP10. The crystal structure of human AQP10 determined at 2.3 Å resolution unveils the molecular basis for pH modulation-an exceptionally wide selectivity (ar/R) filter and a unique cytoplasmic gate. Structural and functional (in vitro and in vivo) analyses disclose a glycerol-specific pH-dependence and pinpoint pore-lining His80 as the pH-sensor. Molecular dynamics simulations indicate how gate opening is achieved. These findings unravel a unique type of aquaporin regulation important for controlling body fat mass. Thus, targeting the cytoplasmic gate to induce constitutive glycerol secretion may offer an attractive option for treating obesity and related complications.
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http://dx.doi.org/10.1038/s41467-018-07176-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232157PMC
November 2018

Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care - 2-year outcomes and predictors.

Rheumatology (Oxford) 2019 01;58(1):110-119

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark.

Objectives: A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation.

Methods: One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level.

Results: One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation.

Conclusion: By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.
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http://dx.doi.org/10.1093/rheumatology/key244DOI Listing
January 2019

Inflammatory and structural changes in vertebral bodies and posterior elements of the spine in axial spondyloarthritis: construct validity, responsiveness and discriminatory ability of the anatomy-based CANDEN scoring system in a randomised placebo-controlled trial.

RMD Open 2018 16;4(1):e000624. Epub 2018 Mar 16.

Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup, Denmark.

Background: The Canada-Denmark (CANDEN) definitions of spinal MRI lesions allow a detailed anatomy-based evaluation of inflammatory and structural lesions in vertebral bodies and posterior elements of the spine in patients with axial spondyloarthritis (axSpA). The objective was to examine the reliability, responsiveness and discrimination of scores for spinal inflammation, fat, bone erosion and new bone formation based on the CANDEN system and to describe patterns of inflammatory and structural lesions and their temporal development.

Methods: 49 patients with axSpA from an investigator-initiated, randomised, placebo-controlled trial of adalimumab underwent spinal MRI at weeks 0/6/24/48. MR images were scored according to the CANDEN system and the Spondyloarthritis Research Consortium of Canada (SPARCC) method. Total scores, and various subscores, were created by summing individual lesion scores.

Results: The CANDEN spine inflammation score had high responsiveness, similar to the SPARCC MRI spine index (Guyatt's responsiveness index 1.88 and 1.67, respectively), and discriminated between adalimumab and placebo treatment already at 6 weeks' follow-up (P=0.03). Anterior/posterior corner inflammation subscores showed similar responsiveness. Inter-reader reliability for the CANDEN spine inflammation and fat scores was good to very good for status and change scores (intraclass correlation coefficient (ICC)=0.71-0.92). Reliability for CANDEN new bone formation and erosion scores was good to very good for status scores (ICC=0.61-0.75) but, due to minimal progression, poor for change scores (ICC≤0.40).

Conclusions: The CANDEN spine inflammation score showed good responsiveness, discrimination between active treatment and placebo and reliability. The CANDEN spine structural scores had good cross-sectional reliability, but longer studies are needed to investigate their sensitivity to change.

Trial Registration Number: NCT01029847; Results.
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http://dx.doi.org/10.1136/rmdopen-2017-000624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856914PMC
March 2018

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

J Rheumatol 2018 05 15;45(5):621-629. Epub 2018 Feb 15.

From the Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, and Department of Clinical Biochemistry, Rigshospitalet, Glostrup; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen; Center for Rheumatology and Spine Diseases, Frederiksberg Hospital, Frederiksberg; Department of Radiology, Copenhagen University Hospital Herlev, Herlev; Center for Rheumatology and Spine Diseases, Copenhagen University Hospital Gentofte, Hellerup; Department of Rheumatology, Zealand University Hospital, Køge; Odense Patient Data Explorative Network (OPEN), Odense University Hospital/Institute of Clinical Research, Odense, Denmark; Department of Diagnostic Imaging, Sheba Medical Center (affiliated with the Sackler School of Medicine, Tel Aviv University), Ramat Gan, Israel.

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.
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http://dx.doi.org/10.3899/jrheum.170408DOI Listing
May 2018

Purification and functional comparison of nine human Aquaporins produced in Saccharomyces cerevisiae for the purpose of biophysical characterization.

Sci Rep 2017 12 4;7(1):16899. Epub 2017 Dec 4.

Department of Biology, Faculty of Science, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, OE, Denmark.

The sparse number of high-resolution human membrane protein structures severely restricts our comprehension of molecular physiology and ability to exploit rational drug design. In the search for a standardized, cheap and easily handled human membrane protein production platform, we thoroughly investigated the capacity of S. cerevisiae to deliver high yields of prime quality human AQPs, focusing on poorly characterized members including some previously shown to be difficult to isolate. Exploiting GFP labeled forms we comprehensively optimized production and purification procedures resulting in satisfactory yields of all nine AQP targets. We applied the obtained knowledge to successfully upscale purification of histidine tagged human AQP10 produced in large bioreactors. Glycosylation analysis revealed that AQP7 and 12 were O-glycosylated, AQP10 was N-glycosylated while the other AQPs were not glycosylated. We furthermore performed functional characterization and found that AQP 2, 6 and 8 allowed flux of water whereas AQP3, 7, 9, 10, 11 and 12 also facilitated a glycerol flux. In conclusion, our S. cerevisiae platform emerges as a powerful tool for isolation of functional, difficult-to-express human membrane proteins suitable for biophysical characterization.
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http://dx.doi.org/10.1038/s41598-017-17095-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715081PMC
December 2017

Infection Mimicking Progression of Scleroderma.

Case Rep Rheumatol 2017 27;2017:4029271. Epub 2017 Sep 27.

Center for Rheumatology and Spine Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.

This case report describes a patient with scleroderma who developed infection, which for more than a year mimicked worsening of her connective tissue disorder. The patient was diagnosed with scleroderma based on puffy fingers that developed into sclerodactyly, abnormal nail fold capillaries, interstitial lung disease, Raynaud's phenomenon, esophageal dysmotility, and positivity for rheumatoid factor and anti-SSA antibodies. She developed massive inflammatory changes of the cutis, the subcutis, and the muscle fasciae of the right leg, that after several failed attempts of immunosuppressive treatments were found to be caused by . While she was receiving high-dose prednisolone, as worsening of her connective tissue disease was suspected to be the cause of the inflammatory changes, she had meningitis and was hospitalized for several weeks, but she recovered from this without sequelae. After infection was diagnosed, she was treated with clarithromycin and rifampicin. Her skin manifestations, arthralgias, and fatigue improved considerably, and the wounds of the right leg healed, unfortunately with significant scarring. Immunodeficiency testing was unremarkable. In summary, an infection with was mistaken for an unusually severe progression of scleroderma.
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http://dx.doi.org/10.1155/2017/4029271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635288PMC
September 2017

Whole-body Magnetic Resonance Imaging in Inflammatory Arthritis: Systematic Literature Review and First Steps Toward Standardization and an OMERACT Scoring System.

J Rheumatol 2017 11 15;44(11):1699-1705. Epub 2017 Jun 15.

From the Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Rigshospitalet, Glostrup; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark; Department of Diagnostic Imaging, The Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Arthritis Imaging Research Group, Department of Radiology, Charité Medical School, Berlin; Radiology, Diagnostic and Interventional Radiology, University Hospital Heidelberg, Heidelberg, Germany; Department of Radiology and Diagnostic Imaging, and Division of Rheumatology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada; Spire Sciences Inc., Boca Raton, Florida, USA; St. James' University and Chapel Allerton Hospitals; Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds; UK National Institute for Health Research (NIHR) Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK; University of New South Wales (NSW), Sydney, Australia.

Objective: Whole-body magnetic resonance imaging (WB-MRI) is a relatively new technique that can enable assessment of the overall inflammatory status of people with arthritis, but standards for image acquisition, definitions of key pathologies, and a quantification system are required. Our aim was to perform a systematic literature review (SLR) and to develop consensus definitions of key pathologies, anatomical locations for assessment, a set of MRI sequences and imaging planes for the different body regions, and a preliminary scoring system for WB-MRI in inflammatory arthritis.

Methods: An SLR was initially performed, searching for WB-MRI studies in arthritis, osteoarthritis, spondyloarthritis, or enthesitis. These results were presented to a meeting of the MRI in Arthritis Working Group together with an MR image review. Following this, preliminary standards for WB-MRI in inflammatory arthritides were developed with further iteration at the Working Group meetings at the Outcome Measures in Rheumatology (OMERACT) 2016.

Results: The SLR identified 10 relevant original articles (7 cross-sectional and 3 longitudinal, mostly focusing on synovitis and/or enthesitis in spondyloarthritis, 4 with reproducibility data). The Working Group decided on inflammation in peripheral joints and entheses as primary focus areas, and then developed consensus MRI definitions for these pathologies, selected anatomical locations for assessment, agreed on a core set of MRI sequences and imaging planes for the different regions, and proposed a preliminary scoring system. It was decided to test and further develop the system by iterative multireader exercises.

Conclusion: These first steps in developing an OMERACT WB-MRI scoring system for use in inflammatory arthritides offer a framework for further testing and refinement.
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http://dx.doi.org/10.3899/jrheum.161114DOI Listing
November 2017

Toxic Epidermal Necrolysis-Like Lesions and Systemic Lupus Erythematosus Possibly Triggered by Sulfasalazine.

Case Rep Rheumatol 2016 12;2016:4501937. Epub 2016 Jul 12.

Center for Rheumatology and Spine Diseases, Rigshospitalet, 2100 Copenhagen, Denmark.

This case report describes a patient with arthritis of the large joints, bilateral sacroiliitis, and positive anti-SSA and anti-dsDNA antibody, who received sulfasalazine and shortly thereafter became critically ill. He developed toxic epidermal necrolysis, hemolytic anemia, lymphopenia, markedly elevated ferritin, and muscle wasting. A diagnosis of systemic lupus erythematosus was made, and mycophenolate mofetil and systemic glucocorticoids brought this severe disease under control. Toxic epidermal necrolysis-like lesions and hemophagocytic syndrome have been reported as manifestations of systemic lupus erythematosus. This patient possibly had spondyloarthritis or an undifferentiated connective tissue disease at presentation, and we suggest, based on the timing of events, that sulfasalazine may have acted as a trigger of the severe disease manifestations.
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http://dx.doi.org/10.1155/2016/4501937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960340PMC
August 2016
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