Spine and Sacroiliac Joint Involvement in Newly Diagnosed Patients With Inflammatory Bowel Disease: Clinical and MRI Findings From a Population-Based Cohort.

INTRODUCTION: In patients with inflammatory bowel disease (IBD), co-occurring spondyloarthritis (SpA) leads to poorer outcomes and impaired quality of life, highlighting the importance of early detection and effective treatment. This is the first study to assess the prevalence and distribution of axial symptoms and magnetic resonance imaging (MRI)-detected involvement of the spine and sacroiliac joints (SIJs) in early IBD. METHODS: Newly diagnosed patients with IBD from a prospective, population-based cohort were consecutively recruited. Rheumatological interview, clinical, ultrasound, and MRI assessment for SIJ and spine inflammatory and structural lesions were made using validated scoring methods and consensus definitions of axial SpA (axSpA). RESULTS: Of 110 patients (ulcerative colitis: 70, Crohn's disease: 40, mean age of 42 years, and 40% male), 48 (44.9%) reported back and/or buttock pain, and 10 (9.1%) had inflammatory back pain. Seventeen (16.7%) patients had MRI findings indicative of axSpA; only 10 of these patients had axial symptoms. Inflammatory MRI lesions were present in SIJs and the spine of 27 (26.5%) and 30 (30.3%) patients, respectively. The Assessment of SpondyloArthritis International Society classification criteria for axSpA were met in 11 (10%) cases. MRI findings typical of axSpA were associated with peripheral joint and entheseal inflammation detected by ultrasound ( P = 0.04). No differences in clinical or imaging findings were found between patients with ulcerative colitis and Crohn's disease. DISCUSSION: One-in-6 newly diagnosed patients with IBD had MRI findings indicative of axSpA. As 40% of these patients were asymptomatic, this suggests that axSpA is underdiagnosed in early IBD. Multidisciplinary collaboration is essential to ensure early detection of axial inflammation and to enable optimal therapy preventing future structural damage and disability.

MRI-based synthetic CT: a new method for structural damage assessment in the spine in patients with axial spondyloarthritis - a comparison with low-dose CT and radiography.

OBJECTIVE: To investigate the ability of MRI-based synthetic CT (sCT), low-dose CT (ldCT) and radiography to detect spinal new bone formation (NBF) in patients with axial spondyloarthritis (axSpA). METHODS: Radiography of lumbar and cervical spine, ldCT and sCT of the entire spine were performed in 17 patients with axSpA. sCT was reconstructed using the BoneMRI application (V.1.6, MRIGuidance BV, Utrecht, NL), a quantitative three-dimensional MRI-technique based on a dual-echo gradient sequence and a machine learning processing pipeline that can generate CT-like MR images. Images were anonymised and scored by four readers blinded to other imaging/clinical information, applying the Canada-Denmark NBF assessment system. RESULTS: Mean scores of NBF lesions for the four readers were 188/209/37 for ldCT/sCT/radiography. Most NBF findings were at anterior vertebral corners with means 163 on ldCT, 166 on sCT and 35 on radiography. With ldCT of the entire spine as reference standard, the sensitivity to detect NBF was 0.67/0.13 for sCT/radiography; both with specificities >0.95. For levels that were assessable on radiography (C2-T1 and T12-S1), the sensitivity was 0.61/0.48 for sCT/radiography, specificities >0.90. For facet joints, the sensitivity was 0.46/0.03 for sCT/radiography, specificities >0.94. The mean inter-reader agreements (kappa) for all locations were 0.68/0.58/0.56 for ldCT/sCT/radiography, best for anterior corners. CONCLUSION: With ldCT as reference standard, MRI-based sCT of the spine showed very high specificity and a sensitivity much higher than radiography, despite limited reader training. sCT could become highly valuable for detecting/monitoring structural spine damage in axSpA, not the least in clinical trials.

Detection of structural lesions of the sacroiliac joints in patients with spondyloarthritis: A comparison of T1-weighted 3D spoiled gradient echo MRI and MRI-based synthetic CT versus T1-weighted turbo spin echo MRI.

OBJECTIVES: To investigate the detection of erosion, sclerosis and ankylosis using 1 mm 3D T1-weighted spoiled gradient echo (T1w-GRE) MRI and 1 mm MRI-based synthetic CT (sCT), compared with conventional 4 mm T1w-TSE. MATERIALS AND METHODS: Prospective, cross-sectional study. Semi-coronal 4 mm T1w-TSE and axial T1w-GRE with 1.6 mm slice thickness and 0.8 mm spacing between overlapping slices were performed. The T1w-GRE images were processed into sCT images using a commercial deep learning algorithm, BoneMRI. Both were reconstructed into 1 mm semi-coronal images. T1w-TSE, T1w-GRE and sCT images were assessed independently by 3 expert and 4 non-expert readers for erosion, sclerosis and ankylosis. Cohen's kappa for inter-reader agreement, exact McNemar test for lesion frequencies and Wilcoxon signed-rank test for confidence in lesion detection were used. RESULTS: Nineteen patients with axial spondyloarthritis were evaluated. T1w-GRE increased inter-reader agreement for detecting erosion (kappa 0.42 vs 0.21 in non-experts), increased detection of erosion (57 vs 43 of 152 joint quadrants) and sclerosis (26 vs 17 of 152 joint quadrants) among experts, and increased reader confidence for scoring erosion and sclerosis. sCT increased inter-reader agreement for detecting sclerosis (kappa 0.69 vs 0.37 in experts) and ankylosis (0.71 vs 0.52 in non-experts), increased detection of sclerosis (34 vs 17 of 152 joint quadrants) and ankylosis (20 vs 13 of 76 joint halves) among experts, and increased reader confidence for scoring erosion, sclerosis and ankylosis. CONCLUSION: T1w-GRE and sCT increase sensitivity and reader confidence for the detection of erosion, sclerosis and ankylosis, compared with T1w-TSE. CLINICAL RELEVANCE STATEMENT: These methods improve the detection of sacroiliac joint structural lesions and might be a useful addition to SIJ MRI protocols both in routine clinical care and as structural outcome measures in clinical trials.

Translocation of non-lytic antimicrobial peptides and bacteria penetrating peptides across the inner membrane of the bacterial envelope.

The increase in multidrug-resistant pathogenic bacteria has become a problem worldwide. Currently there is a strong focus on the development of novel antimicrobials, including antimicrobial peptides (AMP) and antimicrobial antisense agents. While the majority of AMP have membrane activity and kill bacteria through membrane disruption, non-lytic AMP are non-membrane active, internalize and have intracellular targets. Antimicrobial antisense agents such as peptide nucleic acids (PNA) and phosphorodiamidate morpholino oligomers (PMO), show great promise as novel antibacterial agents, killing bacteria by inhibiting translation of essential target gene transcripts. However, naked PNA and PMO are unable to translocate across the cell envelope of bacteria, to reach their target in the cytosol, and are conjugated to bacteria penetrating peptides (BPP) for cytosolic delivery. Here, we discuss how non-lytic AMP and BPP-PMO/PNA conjugates translocate across the cytoplasmic membrane via receptor-mediated transport, such as the cytoplasmic membrane transporters SbmA, MdtM/YjiL, and/or YgdD, or via a less well described autonomous process.

Tapering of TNF inhibitors in axial spondyloarthritis in routine care - 2-year clinical and MRI outcomes and predictors of successful tapering.

OBJECTIVES: In a 2-year follow-up study of patients with axial spondyloarthritis (axSpA) in clinical remission who tapered TNF inhibitor (TNFi) treatment according to a clinical guideline, we aimed to investigate the proportion who successfully tapered/discontinued therapy and baseline predictors thereof. The proportion regaining clinical remission after flare and the progression on MRI/radiography were also assessed. METHODS: One-hundred-and-nine patients (78 [72%]/31 [28%] receiving standard and reduced dose, respectively) in clinical remission (BASDAI < 40, physician global score < 40) and no signs of disease activity the previous year tapered TNFi as follows: to two-thirds of standard dose at baseline, half at week 16, one-third at week 32 and discontinuation at week 48. Patients experiencing clinical, BASDAI or MRI flare (predefined criteria) stopped tapering and escalated to previous dose. Prediction analyses were performed by multivariable regression. RESULTS: One hundred and six patients (97%) completed 2 years' follow-up; 55 patients (52%) had successfully tapered: 23 (22%) receiving two-thirds, 15 (14%) half, 16 (15%) one-third dose and 1 (1%) discontinued. In patients at standard dose at baseline (n = 78), lower physician global score was the only independent predictor of successful tapering (odds ratio [OR] = 0.79 [95% CI: 0.64, 0.93]; P = 0.003). In the entire patient group lower physician global score (OR = 0.86 [0.75, 0.98]; P = 0.017), lower Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Erosion score (OR = 0.78 [0.57, 0.98]; P = 0.029) and current smoker (OR = 3.28 [1.15, 10.57]; P = 0.026) were independent predictors of successful tapering. At 2 years, 97% of patients were in clinical remission. Minimal changes in imaging findings were observed. CONCLUSION: After 2 years following a clinical guideline, 52% of patients with axSpA in clinical remission had successfully tapered TNFi, only 1% discontinued. Baseline physician global score was an independent predictor of successful tapering.

Do tender joints in active psoriatic arthritis reflect inflammation assessed by ultrasound and magnetic resonance imaging?

OBJECTIVE: To investigate the association between clinical joint tenderness and intra- and periarticular inflammation as assessed by ultrasound and MRI in patients with active PsA and to explore if the associations differ according to patient-reported outcomes (PROs) and structural damage. METHODS: Forty-one patients with active PsA and hand involvement had 76/78 joints examined for swelling/tenderness and ultrasound and MRI of 24 and 12 finger joints, respectively. Synovitis, tenosynovitis, periarticular inflammation and erosions were assessed using OMERACT definitions and scoring systems. Correlation between imaging inflammation sum-scores (intra-and periarticular) and tender/swollen joint counts were calculated using Spearman's rho, agreement at joint level was examined using prevalence and bias adjusted kappa (PABAK). Subgroup analyses explored the influence of PROs and radiographic erosive disease on these associations. RESULTS: No significant correlations were found between tender or swollen joint counts and imaging inflammation sum-scores (rho = -0.31-0.38). In patients with higher level of overall pain, disability and lower self-reported mental health, a tendency towards negative correlations were found. At joint level, intra- and periarticular imaging inflammatory lesions had slight agreement with joint tenderness (PABAK = 0.02-0.19) and slight to moderate with swelling (PABAK = 0.16-0.54). For tender joints, agreement with imaging inflammation was even weaker in patients with either high overall pain scores, high disability scores, and/or non-erosive disease. CONCLUSION: Joint tenderness had low association with imaging signs of inflammation in PsA patients, particularly in patients with high self-reported pain, disability and low mental health, indicating that tenderness is influenced by other parameters than local inflammation.

Arresting chromosome replication upon energy starvation in Escherichia coli.

Most organisms possess several cell cycle checkpoints to preserve genome stability in periods of stress. Upon starvation, the absence of chromosomal duplication in the bacterium Escherichia coli is ensured by holding off commencement of replication. During normal growth, accumulation of the initiator protein DnaA along with cell cycle changes in its activity, ensure that DNA replication starts only once per cell cycle. Upon nutrient starvation, the prevailing model is that an arrest in DnaA protein synthesis is responsible for the absence of initiation. Recent indications now suggest that DnaA degradation may also play a role. Here we comment on the implications of this potential new layer of regulation.

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

OBJECTIVE: To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological DMARDs (bDMARDs) at the 2-year follow-up in RA patients in sustained remission. METHODS: Patients in sustained remission (DAS28-CRP ≤ 2.6) and with no radiographic progression the previous year tapered bDMARDs according to a standardized regime. A total of 119 of these patients were included in this ultrasound substudy. 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 OMERACT scoring system at the joint level for both grey-scale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at the patient level. The final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at the 2-year follow-up was assessed via logistic regression analyses. RESULTS: Negative IgM-RF [odds ratio (OR) = 0.29, 95% CI: 0.10-0.85; P = 0.024] and lower Doppler sum score of 24 joints (OR = 0.44, 95% CI: 0.15, 0.87; P = 0.014) were independent predictors for successful discontinuation of bDMARDs at the 2-year follow-up. The predictive value of the Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR = 0.58, 95% CI: 0.35, 0.91; P = 0.018), whereas ultrasound was not. Clinical parameters were not predictive of successful tapering/discontinuation. CONCLUSION: Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at the 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.

Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission.

OBJECTIVES: To study if clinical, radiographic and MRI markers can predict MRI and radiographic damage progression and achievement of stringent remission in patients with established RA in clinical remission followed by a targeted treatment strategy. METHODS: RA patients (DAS28-CRP <3.2, no swollen joints) receiving conventional synthetic DMARDs were randomized to conventional or MRI-targeted treat-to-target strategies with predefined algorithmic treatment escalations. Potentially predictive baseline variables were tested in multivariate logistic regression analyses. RESULTS: In the 171 patients included, baseline MRI osteitis independently predicted progression in MRI erosion [odds ratio (OR) 1.13 (95% CI 1.06, 1.22)], joint space narrowing [OR 1.15 (95% CI 1.07, 1.24)] and combined damage [OR 1.23 (95% CI 1.13, 1.37)], while tenosynovitis independently predicted MRI erosion progression [OR 1.13 (95% CI 1.03, 1.25)]. A predictor of radiographic erosion progression was age, while gender predicted progression in joint space narrowing. Following an MRI treat-to-target strategy predicted stringent remission across all remission definitions: Clinical Disease Activity Index remission OR 2.94 (95% CI 1.25, 7.52), Simplified Disease Activity Index remission OR 2.50 (95% CI 1.01, 6.66), ACR/EULAR Boolean remission OR 5.47 (95% CI 2.33, 14.13). Similarly, low tender joint count and low patient visual analogue scale pain and global independently predicted achievement of more stringent remission. CONCLUSION: Baseline MRI osteitis and tenosynovitis were independent predictors of 2 year MRI damage progression in RA patients in clinical remission, while independent predictors of radiographic damage progression were age and gender. Following an MRI treat-to-target strategy, low scores of patient-reported outcomes and low tender joint count predicted achievement of stringent remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01656278.

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

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.

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

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.

DNA Replication Control Is Linked to Genomic Positioning of Control Regions in Escherichia coli.

Chromosome replication in Escherichia coli is in part controlled by three non-coding genomic sequences, DARS1, DARS2, and datA that modulate the activity of the initiator protein DnaA. The relative distance from oriC to the non-coding regions are conserved among E. coli species, despite large variations in genome size. Here we use a combination of i) site directed translocation of each region to new positions on the bacterial chromosome and ii) random transposon mediated translocation followed by culture evolution, to show genetic evidence for the importance of position. Here we provide evidence that the genomic locations of these regulatory sequences are important for cell cycle control and bacterial fitness. In addition, our work shows that the functionally redundant DARS1 and DARS2 regions play different roles in replication control. DARS1 is mainly involved in maintaining the origin concentration, whether DARS2 is also involved in maintaining single cell synchrony.

Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial.

Importance: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. Objective: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. Design, Setting, and Participants: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. Interventions: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. Main Outcomes and Measures: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde-modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. Results: Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde-modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, -4.8% [1-sided 95% CI, -13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, -7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. Conclusions and Relevance: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. Trial Registration: ClinicalTrials.gov Identifier: NCT01656278.

Control of bacterial chromosome replication by non-coding regions outside the origin.

Chromosome replication in Eubacteria is initiated by initiator protein(s) binding to specific sites within the replication origin, oriC. Recently, initiator protein binding to chromosomal regions outside the origin has attracted renewed attention; as such binding sites contribute to control the frequency of initiations. These outside-oriC binding sites function in several different ways: by steric hindrances of replication fork assembly, by titration of initiator proteins away from the origin, by performing a chaperone-like activity for inactivation- or activation of initiator proteins or by mediating crosstalk between chromosomes. Here, we discuss initiator binding to outside-oriC sites in a broad range of different taxonomic groups, to highlight the significance of such regions for regulation of bacterial chromosome replication. For Escherichia coli, it was recently shown that the genomic positions of regulatory elements are important for bacterial fitness, which, as we discuss, could be true for several other organisms.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. TRIAL REGISTRATION NUMBER: NCT00660647.

Oxidative DNA damage is instrumental in hyperreplication stress-induced inviability of Escherichia coli.

In Escherichia coli, an increase in the ATP bound form of the DnaA initiator protein results in hyperinitiation and inviability. Here, we show that such replication stress is tolerated during anaerobic growth. In hyperinitiating cells, a shift from anaerobic to aerobic growth resulted in appearance of fragmented chromosomes and a decrease in terminus concentration, leading to a dramatic increase in ori/ter ratio and cessation of cell growth. Aerobic viability was restored by reducing the level of reactive oxygen species (ROS) or by deleting mutM (Fpg glycosylase). The double-strand breaks observed in hyperinitiating cells therefore results from replication forks encountering single-stranded DNA lesions generated while removing oxidized bases, primarily 8-oxoG, from the DNA. We conclude that there is a delicate balance between chromosome replication and ROS inflicted DNA damage so the number of replication forks can only increase when ROS formation is reduced or when the pertinent repair is compromised.

Enthesitis in patients with psoriatic arthritis, axial spondyloarthritis and healthy subjects assessed by 'head-to-toe' whole-body MRI and clinical examination.

OBJECTIVES: To investigate the ability of whole-body MRI (WBMRI) to detect axial and peripheral enthesitis in patients with psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), and in healthy subjects (HS). Furthermore, to develop MRI enthesitis indices based on WBMRI and validate these by use of clinical measures of disease activity. METHODS: Prospective cross-sectional study of patients with PsA (n=18) and axSpA (n=18) with moderate to high disease activity, and HS (n=12). Enthesitis at 35 individual sites located at upper and lower limbs, chest and pelvis were evaluated by WBMRI and clinical examination, and compared. Three new WBMRI enthesitis indices were developed. RESULTS: WBMRI allowed evaluation of 888 (53%) of 1680 sites investigated, and 19 (54%) of 35 entheses had a readability >70%. The percentage agreement between WBMRI and clinical enthesitis was 49-100%, when compared at the level of the individual entheses. Enthesitis on WBMRI was observed in 148 (17%) of the entheseal sites, and was frequently present at greater trochanters (55%) and Achilles (43%) and supraspinate (23%) tendon insertions in patients and HS. At the first mentioned two locations enthesitis often appeared without clinical signs of enthesitis. Patients and HS differed significantly in one of the new WBMRI enthesitis scores. Patients and HS differed significantly in one of the new WBMRI enthesitis scores, and this score correlated weakly with BASDAI question 4 (tenderness in relation to entheses), BASDAI and patient global (ρ=0.29-0.31, p<0.05). CONCLUSIONS: WBMRI is a promising new imaging modality for evaluation of enthesitis in patients with PsA and axSpA, but requires further investigation before clinical use.

A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial.

OBJECTIVES: To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. METHODS: In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. RESULTS: Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months' follow-up, with mean change scores of -3.7 (median -3.0), -2.2 (-1) and -5.3 (-4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann-Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months' follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001-0.002 and p=0.062-0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. CONCLUSIONS: A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

Head-to-toe whole-body MRI in psoriatic arthritis, axial spondyloarthritis and healthy subjects: first steps towards global inflammation and damage scores of peripheral and axial joints.

OBJECTIVES: By whole-body MRI (WBMRI), we aimed to examine the frequency and distribution of inflammatory and structural lesions in PsA patients, SpA patients and healthy subjects (HSs), to introduce global WBMRI inflammation/damage scores, and to assess WBMRI's reproducibility and correlation with conventional MRI (convMRI). METHODS: WBMRI (3.0-T) of patients with peripheral PsA (n = 18) or axial SpA (n = 18) and of HS (n = 12) was examined for proportion of evaluable features (readability) and the presence and pattern of lesions in axial and peripheral joints. Furthermore, global WBMRI scores of inflammation and structural damage were constructed, and WBMRI findings were compared with clinical measures and convMRI (SpA/HS: spine and SI joints; PsA/HS: hand). RESULTS: The readability (92-100%) and reproducibility (intrareader intraclass correlation coefficient: 0.62-1.0) were high in spine/SI joint, but lower in the distal peripheral joints. Wrists, shoulders, knees, ankles and MTP joints were most commonly involved, with frequency of synovitis > bone marrow oedema (BMO) > erosion. WBMRI global BMO scores of peripheral and axial joints were higher in PsA {median 7 [interquartile range (IQR) 3-15]} and SpA [8 (IQR 2-14)] than in HSs [2.5 (IQR 1-4.5)], both P < 0.05. WBMRI global structural damage scores (erosion, fat infiltration and ankylosis) were higher in SpA [7 (IQR 3-12)] than HSs [1.5 (IQR 0-4.5)], P = 0.012. Correlations between WBMRI and convMRI spine and SI joint scores were ρ = 0.20-0.78. CONCLUSION: WBMRI allows simultaneous assessment of peripheral and axial joints in PsA and SpA, and the distribution of inflammatory and structural lesions and global scores can be determined. The study strongly encourages further development and longitudinal testing of WBMRI techniques and assessment methods in PsA and SpA.

Influence of field strength, coil type and image resolution on assessment of synovitis by unenhanced MRI--a comparison with contrast-enhanced MRI.

OBJECTIVES: To explore if the reliability of synovitis assessment by unenhanced MRI is influenced by different MRI field-strengths, coil types and image resolutions in RA patients. METHODS: Forty-one RA patients and 12 healthy controls underwent hand MRI (wrist and 2(nd)--5(th) metacarpophalangeal joints) at 4 different field-strengths (0.23 T/0.6 T/1.5 T/3.0 T) on the same day. Seven protocols using a STIR sequence with different field-strengths, coils (flex coils/dedicated phased-array extremity coils) and resolution were applied and scored blindly for synovitis (OMERACT-RAMRIS method). A 1.5 T post-contrast T1-weighted sequence was used as gold standard reference. RESULTS: Fair-good agreement (ICC=0.38--0.72) between the standard reference and the different STIR protocols (best agreement with extremity coil and small voxel size at 1.5 T). The accuracy for presence/absence of synovitis was very high per person (0.80--1.0), and moderate-high per joint (0.63--0.85), whereas exact agreements on scores were moderate (0.50--0.66). The intrareader agreement (15 patients and 3 controls) on presence/absence of synovitis was very high (0.87--1.0). CONCLUSIONS: Unenhanced MRI using STIR sequence is only moderately reliable for assessing hand synovitis in RA, when contrast-enhanced MRI is considered the gold standard reference. Contrast injection, field strength and coil type influence synovitis assessment, and should be considered before performing MRI in clinical trials and practice. KEY POINTS: • STIR is only moderately reliable for synovitis assessment, compared with post-contrast-T1-w. • Contrast injection, field strength, and coil type influence synovitis assessment. • Contrast injection is recommended for reliable and reproducible hand synovitis assessment.