Standardization of interstitial lung disease assessment by ultrasound: results from a Delphi process and web-reliability exercise by the OMERACT ultrasound working group.

OBJECTIVES: Over the last years ultrasound has shown to be an important tool for evaluating lung involvement, including interstitial lung disease (ILD) a potentially severe systemic involvement in many rheumatic and musculoskeletal diseases (RMD). Despite the potential sensitivity of the technique the actual use is hampered by the lack of consensual definitions of elementary lesions to be assessed and of the scanning protocol to apply. Within the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group we aimed at developing consensus-based definitions for ultrasound detected ILD findings in RMDs and assessing their reliability in dynamic images. METHODS: Based on the results from a systematic literature review, several findings were identified for defining the presence of ILD by ultrasound (i.e., Am-lines, B-lines, pleural cysts and pleural line irregularity). Therefore, a Delphi survey was conducted among 23 experts in sonography to agree on which findings should be included and on their definitions. Subsequently, a web-reliability exercise was performed to test the reliability of the agreed definitions on video-clips, by using kappa statistics. RESULTS: After three rounds of Delphi an agreement >75 % was obtained to include and define B-lines and pleural line irregularity as elementary lesions to assess. The reliability in the web-based exercise, consisting of 80 video-clips (30 for pleural line irregularity, 50 for B-lines), showed moderate inter-reader reliability for both B-lines (kappa = 0.51) and pleural line irregularity (kappa = 0.58), while intra-reader reliability was good for both B-lines (kappa = 0.72) and pleural line irregularity (kappa = 0.75). CONCLUSION: Consensus-based ultrasound definitions for B-lines and pleural line irregularity were obtained, with moderate to good reliability to detect these lesions using video-clips. The next step will be testing the reliability in patients with ILD linked to RMDs and to propose a consensual and standardized protocol to scan such patients.

Tenderness and radiographic progression in rheumatoid arthritis and psoriatic arthritis.

OBJECTIVE: The aim of this study was to assess the predictive value of tenderness in the absence of swelling with consideration of other potential risk factors for subsequent radiographic progression in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Clinical and sonographic (grey scale and power Doppler (PD)) examination of 22 joints of the hand were performed in patients with RA and PsA. The impact of tenderness on progression after 2 years was analysed in non-swollen joints for RA and PsA separately with multilevel mixed logistic regression analysis. RESULTS: We included 1207 joints in 55 patients with RA and 352 joints in 18 patients with PsA. In RA, tenderness was associated with radiographic progression after 2 years (model 2: OR 1.85 (95% CI 1.01 to 3.27), p=0.047), although the association of PD (OR 2.92 (95% CI 1.71 to 5.00), p<0.001) and erosions (OR 4.74 (95% CI 2.44 to 9.23), p<0.001) with subsequent structural damage was stronger. In PsA, we found a positive but not significant association between tenderness and radiographic progression (OR 1.72 (95% CI 0.71 to 4.17), p=0.23). In contrast, similarly to RA, erosions (OR 4.62 (95% CI 1.29 to 16.54), p=0.019) and PD (OR 3.30 (95% CI 1.13 to 9.53), p=0.029) had a marked effect on subsequent structural damage. CONCLUSION: Our findings imply that tenderness in non-swollen joints in RA is associated with subsequent damage. In both diseases, additional risk factors, such as sonographic signs for synovitis and baseline radiographic damage are associated with radiographic progression.

Development and validation of an OMERACT ultrasound scoring system for the extent of calcium pyrophosphate crystal deposition at the joint level and patient level.

BACKGROUND: The Calcium Pyrophosphate Deposition (CPPD) subgroup of the Outcome Measures in Rheumatology (OMERACT) Ultrasound working group was established to validate ultrasound as an outcome measure instrument for CPPD, and in 2017 has developed and validated standardised definitions for elementary lesions for the detection of calcium pyrophosphate crystals in joints. The aim of this study was to develop and evaluate the reliability of a consensus-based ultrasound scoring system for CPPD extent, representing the next phase in the OMERACT methodology. METHODS: In this study the novel scoring system for CPPD was developed through a stepwise process, following an established OMERACT ultrasound methodology. Following a previous systematic review to gather available evidence on existing scoring systems for CPPD, the novel scoring system was developed through a Delphi survey based on the expert opinion of the members of the OMERACT Ultrasound working group-CPPD subgroup. The reliability of the scoring system was then tested on a web-based and patient-based exercise. Intra-reader and inter-reader reliability of the new scoring system was assessed using weighted Light's κ coefficients. FINDINGS: The four-grade semiquantitative scoring system consisted of: grade 0 (no findings consistent with CPPD), grade 1 (≤3 single spots or 1 small deposit), grade 2 (>3 single spots or >1 small deposit or ≥1 larger deposit occupying ≤50% of the structure under examination in the reference image-ie, the scanning view with the highest grade of depositions), and grade 3 (deposits that occupy more than 50% of the structure under examination in the reference image). The score should be applied to the knee (menisci and hyaline cartilage) and the triangular fibrocartilage complex of the wrist. The intra-reader and inter-reader reliabilities on static images were almost perfect (κ 0·90 [95% CI 0·79-1·00] and κ 0·84 [0·79-0·88]), and on the eight patients recruited (four [50%] female and four [50%] male) were substantial (κ 0·72 [95% CI 0·47 to 0·96] and 0·66 [0·61 to 0·71]). INTERPRETATION: This OMERACT ultrasound scoring system for CPPD was reliable on both static images and patients. The scoring system might be a valuable tool for ensuring valid and comparable results in clinical trials and could help monitor the extent of crystal deposition in patients with CPPD in clinical practice. FUNDING: The Italian Ministry of Health - Ricerca Corrente.

Sonographic assessment of cartilage damage at the metacarpal head in rheumatoid arthritis: qualitative versus quantitative methods.

OBJECTIVE: To test the validity of the OMERACT semi-quantitative score by comparing with a quantitative method in the US assessment of hyaline cartilage at the metacarpal head (MH) in patients with RA and healthy controls (HCs). METHODS: The hyaline cartilage from the second to fifth MHs of both hands was scanned. Hyaline cartilage was scored semi-quantitatively and quantitatively by measuring cartilage thickness and comparing with reference values. In RA patients, radiographic joint space narrowing (JSN) was scored on the same joints using the Simple Erosion Narrowing Score (SENS). RESULTS: A total of 408 MHs in 51 RA patients and 320 MHs in 40 HSs were evaluated. The OMERACT semi-quantitative score was quicker to perform than the quantitative method [6.0 min (s.d. 0.5) vs 8.0 (1.5); P < 0.01]. A significant correlation between the US scores (R = 0.68) and between the US scores and the JSN-SENS (R = 0.61 and R = 0.63 for the semi-quantitative and quantitative method, respectively) was found. The frequency of cartilage abnormalities was similar between the two US methods in RA patients (58.8% and 51.0% of RA patients for the semi-quantitative and quantitative method, respectively; P = 0.46), while the former revealed more abnormalities in HCs (27.5% and 7.5% of HCs; P = 0.02). CONCLUSION: The higher feasibility of the OMERACT semi-quantitative score suggests its use as a first-choice method in the evaluation of cartilage damage. However, despite its limits, the quantitative assessment of HCs, providing patient-tailored information with age- and sex-corrected cut-off values, may represent a valid supplement for optimizing the evaluation of cartilage damage in selected cases.

Conventional ultrasound and elastography as imaging outcome tools in autoimmune myositis: A systematic review by the OMERACT ultrasound group.

AIMS: To analyze whether there is sufficient data from published literature to demonstrate that ultrasound, including elastography, present good metric properties (truth, discrimination and feasibility) in autoimmune myositis (AIM). METHODS: A population, intervention, comparator and outcome-structured (PICO) search was performed in Medline, Cochrane Library and Embase database from 01/01/1973 to 08/05/2019. The inclusion criteria required original research involving adult humans, reported in English, assessing ultrasound and elastography in patients with an AIM. Conference abstracts and computer-assisted diagnostics that focused on technique and not ultrasound domains were excluded. RESULTS: Approximately 2670 articles were identified. Forty-one full-text articles were included in the final analysis. There were 551 AIM patients studied. Eighteen studies (43.9%) had a control group, of which 15 (63.3%) were healthy controls. The age of participants (including controls) varied from 18 to 86 years, and most were females (59%). Diagnosis of AIM was largely biopsy-proven, although some were derived through clinical presentation, positive clinical imaging (ultrasound or otherwise) and/or electromyography and steroid responsiveness. The features examined with ultrasound in the 41 included articles consisted of: muscle echogenicity, bulk, atrophy, architecture, power Doppler, perfusion characteristics, shear wave modulus, shear wave velocity, elasticity index and fasciculations. Twelve studies (29.2%) used quantitative methods to assess these characteristics, whilst others used semi-quantitative, dichotomous/binary and descriptive scoring systems. Criterion validity was met in 14 studies (12/14, 85.7%) and construct validity in 22 studies (22/25, 88.0%). Most published articles reported Level 3b to Level 5 evidence with varying degrees of bias. There was only one longitudinal study examining discrimination. Reliability and feasibility were under-reported. CONCLUSION: This is the first systematic review studying the utility of ultrasound, including elastography, in AIM. There is some evidence for criterion and construct validity, suggesting that ultrasound may be a promising outcome measurement instrument in AIM. Agreement on the standardization of acquisition, and the definitions of target domains, is required. Additionally, further validation studies are required to determine discrimination, reliability and feasibility.

Role of joint damage, malalignment and inflammation in articular tenderness in rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

OBJECTIVES: To determine whether clinical tenderness can be considered a sign of inflammatory joint activity in patients with rheumatoid arthritis (RA), osteoarthritis (OA) or psoriatic arthritis (PsA) and to assess other possible factors associated with tenderness. METHODS: Patients diagnosed with RA, PsA and OA underwent clinical and ultrasound examination of wrists and finger joints. Radiographs of the hands were scored for erosions, joint space narrowing (JSN), osteophytes and malalignment. A binary damage score (positive if ≥1 erosion, JSN and/or presence of malalignment) was calculated. Differences in grey scale signs of synovitis and power Doppler (PD) between tender non-swollen (TNS) versus non-tender non-swollen (NTNS) joints were calculated. Disease duration was assessed,<2 years was regarded as early and >5 years as long-standing arthritis. RESULTS: In total, 34 patients (9 early and 14 long-standing) from patients with RA, 31 patients (7 early and 15 long-standing) with PsA and 30 with OA were included. We found equal frequencies of PD signal between TNS and NTNS joints in RA (p=0.18), PsA (p=0.59) or OA (p=0.96). However, PD had a significant association with tenderness in early arthritis both in RA (p=0.02) and in PsA (p=0.02). The radiographic damage score showed significant association with tenderness in RA (p<0.01), PsA (p<0.01) and OA (p=0.04). CONCLUSION: Tenderness might not always be a sign of active inflammation in RA, PsA and OA. While tenderness in early arthritis may be more related to inflammation, established disease is better explained by joint damage and malalignment.

Performance of magnetic resonance imaging in the diagnosis of axial spondyloarthritis: a systematic literature review.

OBJECTIVES: To summarize the evidence on the performance of MRI for the diagnosis of axial SpA. METHODS: This was a systematic literature review of all studies from January 2013 to March 2017 including adult patients with clinically suspected axial SpA undergoing MRI. Studies from a previously published systematic literature review up to January 2013 were also included. RESULTS: Thirty-one studies were included. Six studies demonstrated good sensitivity and specificity for SI joint (SIJ) bone marrow oedema (BMO). Specificity was increased by the presence of other structural lesions alongside BMO, particularly erosions or fat infiltration. Four studies addressed the utility of SIJ fat infiltration, finding good sensitivity but poor specificity. SIJ erosions showed good specificity in five studies. Studies addressing high T1 signal in the SIJ, fluid signal in the SIJ, ankylosis, sclerosis, capsulitis, backfill and vacuum phenomenon reported limited diagnostic value. In the spine, four studies reported moderate sensitivity and specificity for corner inflammatory lesions, and four reported poor sensitivity and specificity for spinal fat infiltration. Five studies evaluated the added value of spinal MRI over SIJ MRI alone, with variable results depending on the cohort. Six studies addressed the effect of acquisition parameters on diagnostic accuracy: fat-saturated T2-weighted imaging and short tau inversion recovery (STIR) imaging showed comparable utility in identifying BMO. Three studies showed that gadolinium was of minimal added value in the detection of BMO. CONCLUSIONS: These results confirmed the diagnostic utility of MRI in axial SpA. Performance varied according to the characteristics of the cohort and the number and combination of MRI lesions considered.

One year in review 2018: ultrasonography in rheumatoid arthritis and psoriatic arthritis.

Ultrasound is playing an increasingly important role in the differential diagnosis and monitoring of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This technique is more sensitive and specific than clinical examination to detect active synovitis, and the identification of specific synovitis patterns enable differentiation of PsA from RA and other entities. Ultrasound verified inflammation changes along with clinical improvement during therapy, and ultrasound was shown to predict future clinical and structural outcomes thus complementing the clinical risk assessment of patients. In the present review, we summarised the scientific evidence published in 2017 focussing on the use of ultrasonography for clinically relevant and pragmatic aspects of diagnosis and management of RA and PsA.

Loss of phosphatase and tensin homolog (PTEN) in myeloid cells controls inflammatory bone destruction by regulating the osteoclastogenic potential of myeloid cells.

OBJECTIVE: Local bone destruction in rheumatic diseases, which often leads to disability and severely reduced quality of life, is almost exclusively mediated by osteoclasts. Therefore, it is important to understand pathways regulating the generation of osteoclasts. Here, we analysed the impact of the Phosphoinositide-3-Kinase (PI3K)/Phosphatase and tensin homolog (PTEN) axis on osteoclast generation and bone biology under basal and inflammatory conditions. METHODS: We analysed osteoclastogenesis of wildtype (wt) and PTEN(-/-) cells in vitro and in vivo, pit resorption and qPCR of osteoclasts in vitro. Mice with a myeloid cell-specific deletion of PTEN and wt littermate mice were investigated by bone histomorphometry and clinical and histological assessment in the human tumour necrosis factor (TNF)-transgenic (hTNFtg) arthritis model. RESULTS: We show that myeloid-specific PTEN(-/-) mice display increased osteoclastogenesis in vitro and in vivo compared to wt mice. Loss of PTEN did not affect the generation or survival of osteoclast precursor cells. However, PTEN deficiency greatly enhanced receptor activator of nuclear factor κ-B ligand (RANKL)-induced expression of the master transcription factor of osteoclastogenesis, nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), resulting in markedly increased terminal differentiation of osteoclasts in vitro. We also observed increased osteoclastogenesis under inflammatory conditions in the hTNFtg mouse model of arthritis, where hTNFtg/myeloid-specific PTEN(-/-) mice displayed enhanced local bone destruction as well as osteoclast formation in the inflamed joints. The extent of synovial inflammation, however, as well as recruitment of osteoclast precursor cells was not different between wt and myeloid-specific PTEN(-/-) mice. CONCLUSIONS: These data demonstrate that loss of PTEN and, therefore, sustained PI3-Kinase signalling in myeloid cells especially, elevates the osteoclastogenic potential of myeloid cells, leading to enhanced inflammatory local bone destruction. Therefore, although our study allows no direct translational conclusion since we used a conditional knockout approach, the therapeutic targeting of the PI3-Kinase pathway may be of benefit in preventing structural joint damage.

Insulin induced translocation of Na+/K+ -ATPase is decreased in the heart of streptozotocin diabetic rats.

AIM: To investigate the effect of acute insulin administration on the subcellular localization of Na(+)/K(+)-ATPase isoforms in cardiac muscle of healthy and streptozotocin-induced diabetic rats. METHODS: Membrane fractions were isolated with subcellular fractionation and with cell surface biotinylation technique. Na(+)/K(+)-ATPase subunit isoforms were analysed with ouabain binding assay and Western blotting. Enzyme activity was measured using 3-O-methylfluorescein-phosphatase activity. RESULTS: In control rat heart muscle alpha1 isoform of Na(+)/K(+) ATPase resides mainly in the plasma membrane fraction, while alpha2 isoform in the intracellular membrane pool. Diabetes decreased the abundance of alpha1 isoform (25 %, P<0.05) in plasma membrane and alpha2 isoform (50%, P<0.01) in the intracellular membrane fraction. When plasma membrane fractions were isolated by discontinuous sucrose gradients, insulin-stimulated translocation of alpha2- but not alpha1-subunits was detected. Alpha1-subunit translocation was only detectable by cell surface biotinylation technique. After insulin administration protein level of alpha2 increased by 3.3-fold, alpha1 by 1.37-fold and beta1 by 1.51-fold (P<0.02) in the plasma membrane of control, and less than 1.92-fold (P<0.02), 1.19-fold (not significant) and 1.34-fold (P<0.02) in diabetes. The insulin-induced translocation was wortmannin sensitive. CONCLUSION: This study demonstrates that insulin influences the plasma membrane localization of Na(+)/K(+)-ATPase isoforms in the heart. alpha2 isoform translocation is the most vulnerable to the reduced insulin response in diabetes. alpha1 isoform also translocates in response to insulin treatment in healthy rat. Insulin mediates Na(+)/K(+)-ATPase alpha1- and alpha2-subunit translocation to the cardiac muscle plasma membrane via a PI3-kinase-dependent mechanism.

Relationship between obsessive-compulsive symptoms and smoking habits amongst schizophrenic patients.

The rate of smoking is especially high among patients with schizophrenia (SCH) and schizoaffective disorder (SCHAFF). Patients with obsessive-compulsive disorder (OCD) smoke less than the general population. OCD symptoms are more frequent among patients with SCH or SCHAFF than in the general population, but it is still unclear whether schizophrenia patients with OC symptoms suffer from SCH and comorbid OCD, or whether they represent a unique subgroup of SCH with presenting OC symptoms. In our study we hypothetised that the current smoking rate of schizophrenia patients with OC symptoms is lower than in schizophrenia patients without OC symptoms. We assessed OC symptoms with the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), general state with the Brief Psychiatric Rating Scale (BPRS) and smoking habits with a questionnaire among 66 patients with SCH or SCHAFF. We formed two groups by dividing patients according to their Y-BOCS score. Group I consisted of patients with Y-BOCS scores under 16, while group II consisted of patients with Y-BOCS scores above 16, and we compared the current smoking rates of the two groups. We found that the rates did not differ significantly, so we came to the conclusion that OC symptoms are not in a tight relationship with smoking habits among patients with SCH/SCHAFF.