Maria Stoenoiu

Corticosteroids induce expression of aquaporin-1 and increase transcellular water transport in rat peritoneum.

The water channel aquaporin-1 (AQP1) is the molecular counterpart of the ultrasmall pore responsible for transcellular water permeability during peritoneal dialysis (PD). This water permeability accounts for up to 50% of ultrafiltration (UF) during a hypertonic dwell, and its loss can be a major clinical problem for PD patients. By analogy with the lung, the hypothesis was tested that corticosteroids may increase AQP1 expression in the peritoneal membrane (PM) and improve water permeability and UF in rats. First, the expression and distribution of the glucocorticoid receptor (GR) in the PM and capillary endothelium was documented. Time-course and dose-response analyses showed that a daily IM injection of dexamethasone (1 or 4 mg/kg) for 5 d induced an approximately twofold increase in the expression of AQP1 at the mRNA and protein levels. The GR antagonist RU-486 completely inhibited the dexamethasone effect. The functional counterpart of the increased AQP1 expression was a significant increase in sodium sieving and net UF across the PM, contrasting with a lack of effect on the osmotic gradient and permeability for small solutes. The latter observation reflected the lack of effect of corticosteroids on nitric oxide synthase (NOS) activity and endothelial NOS isoform expression in the PM. In conclusion, corticosteroids induce AQP1 expression in the capillary endothelium of the PM, which is reflected by increased transcellular water permeability and UF. These data emphasize the critical role of AQP1 during PD and suggest that pharmacologic regulation of AQP1 may provide a target for manipulating water permeability across the PM.

Repeat kidney biopsies fail to detect differences between azathioprine and mycophenolate mofetil maintenance therapy for lupus nephritis: data from the MAINTAIN Nephritis Trial

BACKGROUND In the MAINTAIN Nephritis Trial, azathioprine (AZA) and mycophenolate mofetil (MMF) were compared as maintenance immunosuppressive treatment of proliferative lupus nephritis (LN) after a short-course of intravenous cyclophosphamide. Here, we compare the pathological findings on repeat kidney biopsies between the two groups. METHODS Per protocol, repeat renal biopsies were obtained in 30 patients (16 AZA and 14 MMF) at 2 years (±6 months). Baseline and follow-up biopsies were graded according to the International Society of Nephrology/Renal Pathological Society (ISN/RPS) classification. The activity and chronicity indices (AI, CI) were calculated using two different semiquantitative scoring systems (Morel-Maroger and National Institutes of Health). Statistics were performed by non-parametric tests. RESULTS The clinical characteristics of the 30 re-biopsied patients only marginally differ from the entire MAINTAIN cohort (105 patients). Clinical baseline and follow-up characteristics of AZA- and MMF-treated re-biopsied patients did not differ. Time (SD) to repeat renal biopsy was 25.0 (2.0) and 26.5 (3.3) months in AZA and MMF patients, respectively. More patients had normal renal biopsies or Classes I/II/V LN at follow-up compared to baseline and conversely, less patients had Class IV LN at follow-up. In both groups, the AI statistically decreased at follow-up compared to baseline, while the CI slightly, but significantly, increased. No differences could be detected between the groups. CONCLUSION Centralized pathological analyses, including ISN/RPS classification and comparisons of AI/CI, failed to find differences between MMF and AZA at 2 years, a result well in line with the absence of difference in long-term clinical outcome reported elsewhere.

Tendon friction rubs in systemic sclerosis: a possible explanation—an ultrasound and magnetic resonance imaging study

OBJECTIVE To assess the tendon and joint involvement at wrists and ankles of patients suffering from diffuse SSc and to identify the morphological substrate of tendon friction rubs (TFRs). METHODS Fifteen consecutive patients suffering from diffuse SSc were included. All patients had two musculoskeletal US (MSUS) examinations of the wrists and ankles. MRI was performed at the most affected joints as detected by MSUS and in all sites in which TFRs were present. RESULTS No clinically overt arthritis or tenosynovitis was detected in the wrists and/or ankles prior to MSUS. Synovitis, tenosynovitis and tendon tear were identified in 8, 4 and 2 of 15 patients, respectively, by both MSUS and MRI. At entry, 5 patients had palpable TFRs (4 bilateral and 1 unilateral) and 10 patients did not. Tenosynovitis was more frequently found in ankles with TFRs (3/9) than in those without TFRs (3/21), although the difference was not statistically different (P = 0.3). Using MRI, deep connective tissue infiltrates surrounding tendons were present in all sites with TFRs but in only one patient without TFRs. CONCLUSION Both MSUS and MRI are effective in detecting synovitis and tenosynovitis in diffuse SSc patients. Tenosynovitis, synovitis and thickened retinacula are not infrequently seen in these patients. Our data suggest that juxta-tendinous connective tissue infiltrates might be the morphological substrate of tendon friction rubs, which may thus be a misnomer for tissue friction rubs.

The Increasing Spectrum of Indications of Whole-Body MRI Beyond Oncology: Imaging Answers to Clinical Needs

Whole-body coverage using MRI was developed almost 2 decades ago. The first applications focused on the investigation of the skeleton to detect neoplastic disease, mainly metastases from solid cancers, and involvement by multiple myeloma and lymphoma. But the extensive coverage of the whole musculoskeletal system, combined with the exquisite sensitivity of MRI to tissue alteration in relation to different pathologic conditions, mainly inflammation, has led to the identification of a growing number of indications outside oncology. Seronegative rheumatisms, systemic sclerosis, inflammatory diseases involving muscles or fascias, and multifocal osseous, vascular, or neurologic diseases represent currently validated or emerging indications of whole-body MRI (WB-MRI). We first illustrate the most valuable indications of WB-MRI in seronegative rheumatisms that include providing significant diagnostic information in patients with negative or ambiguous MRI of the sacroiliac joints and the lumbar spine, assessing disease activity in advanced (ankylosed) central disease, and evaluating the peripherally dominant forms of spondyloarthropathy. Then we review the increasing indications of WB-MRI in other rheumatologic and nonneoplastic disorders, underline the clinical needs, and illustrate the role of WB-MRI in the positive diagnosis and evaluation of disease burden, therapeutic decisions, and treatment monitoring.

Patient-reported outcomes and safety in patients undergoing synovial biopsy: comparison of ultrasound-guided needle biopsy, ultrasound-guided portal and forceps and arthroscopic-guided synovial biopsy techniques in five centres across Europe

Background We present a European multicenter study, comparing safety data and patient-reported outcomes (PRO) from patients undergoing synovial biopsy using ultrasound-guided needle biopsy (US-NB), ultrasound-guided portal and forceps (US-P&F) or arthroscopic-guided (AG) procedures. Objectives To describe safety and PRO data on joint indices of pain, stiffness and swelling before and after biopsy, procedural discomfort, joint status compared with before biopsy and willingness to undergo a second biopsy for each technique and compare the three techniques. To evaluate the impact on PRO and safety data of corticosteroid therapy as part of the biopsy procedure and sequential biopsy procedures. Methods Data were collected on the day of biopsy and 7–14 days postprocedure. Joint pain, swelling and stiffness indices were recorded as 0–100  mm Visual Analogue Scale; qualitative outcome variables on five-point Likert scales. Groups were compared with linear regression, adjusting for disease activity, corticosteroid therapy and prebiopsy PRO value and accounting for repeated measurements. Results A total of 524 synovial biopsy procedures were documented (402 US-NB, 65 US-P&F and 57 AGSB). There were eight adverse events (1.5%) with no difference between biopsy methods (p=0.55). All PROs were improved 2  weeks postprocedure, and there were no differences in postbiopsy change in PROs between biopsy methods. Corticosteroid administration, whether intramuscular (n=62) or intra-articular (n=38), did not result in more adverse events (p=0.81) and was associated with reduction in postbiopsy swelling (p<0.01). Sequential biopsy procedures (n=103 patients) did not result in more adverse events (p=0.61) or worsening in PRO data. Conclusion Overall, our results do not suggest a significant difference in safety or patient tolerability between US-NB, US-P&F and AGSB sampling. Further, corticosteroid therapy as part of the biopsy procedure and sequential biopsies is safe and well tolerated in patients.

Fasciae of the musculoskeletal system: normal anatomy and MR patterns of involvement in autoimmune diseases

The fascial system is a three-dimensional continuum of connective tissues present everywhere throughout the body, from the head to the toes and from the skin to the bone. The current article aims to review the normal anatomy of the fasciae of the musculoskeletal system with macroscopic and microscopic correlations and to describe their appearance at MRI in normal subjects and in patients with autoimmune diseases of the musculoskeletal system.Key Points• The fascial system is a three-dimensional continuum of connective tissues.• It is present everywhere throughout the body, from the head to the toes and from the skin to the bone.• The normal fascial system is barely visible at MRI.• MR patterns of fascial involvement in autoimmune diseases reflect the complex anatomy of the fasciae of the musculoskeletal system.

Whole body MRI in spondyloarthritis (SpA): Preliminary results suggest that DWI outperforms STIR for lesion detection

PurposeTo compare the diagnostic accuracy of DWI and STIR sequences in Whole body (WB) MRI of SpA patients.Materials and methodsTwenty consecutive patients with confirmed active SpA and 20 controls were investigated with identical WB MRI protocols, including DWI and STIR images. Two observers recorded ‘lesions’ (high signal intensity foci on STIR and high b-value DWI) in 17 anatomical areas, making a 17-point ‘area score’ and a 40-point ‘lesion score’. ROC performance, inter-observer agreement, correlation with clinical parameters and spine and sacro-iliac joints (SIJ) MRI scores were assessed.ResultsSpA patients had significantly higher lesion scores on DWI than on STIR (p<0.025). The lesion score area under the curve was significantly higher with DWI (99.9) than with STIR (95.8, p=0.02). DWI lesion score ≥5 had both sensitivity and specificity ≥85 %. With STIR the best threshold ≥3 yielded sensitivity ≥85 % and specificity ≥60 %. DWI area score ≥3 yielded sensitivity ≥85 % and specificity ≥80 %. With STIR the best threshold ≥4 yielded sensitivity ≥70 % and specificity ≥80 %. Inter-observer agreement was strong for both sequences. In patients, the lesion score was positively correlated with ASDAS-CRP, log(CRP), and local MRI scores.ConclusionsDWI is a promising alternative to STIR in WB MRI to detect active SpA lesions.Key Points• DWI is a robust alternative to STIR in WBMRI in SpA.• DWI might be superior in discriminating relevant inflammatory and degenerative changes.• Positive correlations exist between WB MRI, clinical, biological, local MRI data.• Distribution and frequency of abnormal MRI findings in SpA are highlighted.

Whole Body MRI: Non-oncological Musculoskeletal Applications

Purpose of the ReviewWhole-body MRI is an emerging imaging technique on continuous evolution, used in many oncologic indications and introduced more recently in rheumatologic and systemic disorders. In this article, we review the recent musculoskeletal applications of this technique outside the field of cancer.Recent FindingsWhole-body MRI, with its high sensitivity to bone marrow and soft-tissue alterations, and ability of extensive body coverage, is progressively regarded as an effective and powerful imaging tool for the detection, staging, and monitoring under treatment of many rheumatic diseases and systemic pathologies affecting the musculoskeletal system. Disease specific imaging protocols have been designed.SummaryWhole-body MRI is an appealing, non-irradiating tool emerging in musculoskeletal imaging. It is becoming the imaging of choice in several non-oncologic indications, and its application field is on continuous expansion.

AB1172 Does ultrasound-scored synovitis depend on the pharmacokinetics of intravenous infliximab in patients with rheumatoid arthritis?

Background Musculoskeletal ultrasound (US) was developed more than four decades ago and gradually made its way to daily rheumatological practice. This dynamic, non-irradiating and relatively inexpensive technique allows detection of synovitis/tenosynovitis as well as quantification of joint inflammation. However, several external factors, such as, joint position, machine settings, sonographer expertise and certain medications can influence the results of the US examination. Objectives The aim of this study was to investigate whether the pharmacokinetics of intravenous (i.v.) infliximab (IFX) influences the grade of US detected synovitis, measured by gray-scale (GS) and colour Doppler (CD) in rheumatoid arthritis (RA) patients. Methods Inclusion criteria were RA patients with at least one swollen joint, being treated with i.v. IFX, who had neither, changes in DMARD therapy nor local corticosteroid injections in the previous 3 months. Patients underwent clinical, laboratory and US assessment at three time points: at trough, peak plasma drug concentration and at mid-cycle. US assessments were performed blindly to the clinical and laboratory data. Twenty-four joints were assessed for the presence and grade (0–3) of GS synovitis and synovial CD signal: elbows, wrists, 2nd-5th metacarpophalangeal (MCP) joints, knees, ankles, 2nd-5th metatarsophalangeal (MTP) joints. A global OMERACT-EULAR synovitis score (GLOESS) as well as the sum of GS and CD scores were calculated for the 24-joint set, for the 12-joint set (Naredo score) and for wrists-MCP-ankles-MTP joints. Several disease activity scores (DAS) [28-joint DAS (DAS28-CRP), Simplified Disease Activity Index (SDAI)] and health assessment questionnaire (HAQ) were assessed in all patients. Trough plasma IFX concentrations were available in 20 patients. Results Twenty-two RA patients were prospectively recruited from the biologic therapy unit of our hospital. Two thirds of patients were female and mean age was 61 years. The majority of them had long-standing seropositive RA and over 90% had radiographic damage. The median of IFX treatment duration was 9 years. There were no significant differences between the GS, CD and GLOESS scores at IFX peak time and trough time. US-joint count, GS, CD and GLOESS scores did not significantly differ between peak time and trough time. Patients with long-lasting RA treated with IFX had relatively stable US-detected synovitis and slightly lower clinical scores at 4 weeks after IFX administration as compared to baseline. The DAS28CRP, 28 and 44 swollen joint counts did not correlate with trough serum IFX concentrations. US scores (GS and GLOESS) significantly correlate with trough serum IFX concentrations (Spearman correlation coefficient, r=−0.55, p=0.01, n=20). Patients with low trough IFX levels, especially ≤1 µg/ml, had higher US joint count as well as US scores (p<0.01). Reference [1] US-scored synovitis is not significantly influenced by pharmacokinetics of IFX in RA patients. US examination can be conducted independently of time of IFX administration i.e. before or after IFX administration in clinical trials. Although there was no correlation with clinical scores, low trough IFX concentration correlated with the degree of US-detected synovitis. Disclosure of Interest None declared

OP0121 Safety, Tolerability and Feasibility of Minimally Invasive Ultrasound-Guided Synovial Biopsy of Wrist and Metacarpophalangeal Joints - An Ultrasound Follow-Up Study

Background Synovitis is the common feature of patients suffering from inflammatory arthropathies (IA). The development of ultrasound (US)-guided synovial biopsy will enable synovial tissue collection from small joints and will facilitate molecular studies, thus improving the understanding of mechanisms of IA as small joints are frequently involved in these diseases. Objectives To assess the safety, tolerability and feasibility to perform synovial biopsies from wrist and metacarpophalangeal (MCP) joints, using a minimally invasive US-guided technique in patients suffering from rheumatoid arthritis (RA), spondylarthropathies (SA) or undifferentiated arthritis (UA). Methods Two target joints (TJ) were biopsied: wrist and MCP. Patients with at least one clinically swollen joint at these levels, suffering from RA, SA, or UA underwent a US examination. The TJ chosen for the biopsy was the joint with the most important inflammatory changes on gray-scale (GS) US. GS synovitis and power-Doppler (PD) activity were assessed by OMERACT scores, on the day of the biopsy, as well as 2 weeks (w), 6w and 6 months (m) after the biopsy. In addition, tendon tears, hematoma, paratenonitis and tenosynovitis were searched by US. Patient-reported outcomes (PRO) included a standard questionnaire given to all patients on the day of the biopsy as well as 1w, 2w, and 6w after the biopsy. Tolerability and the patient-reported willingness to repeat the procedure was assessed using the 5-point Likert scale. Results Forty-one patients suffering from RA (27), SA (7) and UA (7) underwent US-guided biopsy of the wrists (20) and MCP (21) joints. A non-significant increase in pain was reported 24 h after the procedure. No difference in PRO of the biopsied joints was reported 2w and 6w after the biopsy, as compared to assessment before the biopsy. No infection or haemorrhage was observed after the biopsy. PRO did not differ significantly among patients suffering from RA, SA or UA. At the TJ, US scores tended to decrease 2w after the procedure. At 6w and 6m follow-up, no safety concerns were reported. Treatment response at the TJ was similar to the response of non-biopsied joints matched for the baseline US parameters. Conclusions With the exception of study of Kelly et al (Ann Rheum Dis. 2015;74:611–6117), data on safety, tolerability, feasibility and PRO using the minimally invasive US-guided biopsy technique are lacking. In this work, we confirm that US-guided biopsy of wrist and MCP joints is feasible, safe and well tolerated by RA patients. At 2w, 6w and 6m follow-up, no safety concerns were reported. Furthermore, no differences in PRO between RA, SA and UA were observed. This technique is therefore a promising approach to assess the presence and persistency of synovial inflammatory processes in patients with early and refractory IA, and to facilitate patients stratification according to transcriptomic profiles. Acknowledgement We acknowledge Pr C. Pitzalis and S. Kelly for giving us the opportunity to learn and further disseminate minimally invasive ultrasound-guided technique, and for fruitful discussions. Disclosure of Interest None declared