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.

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.

Minimally invasive ultrasound-guided parotid gland biopsy in cadavers performed by rheumatologists.

Introduction: Surgical biopsy of minor salivary glands is routinely performed for the diagnosis of Sjögren syndrome. However, surgical biopsies of the minor labial glands may result in various complications in up to 6% of patients. On the other hand, adverse events following core needle biopsies of the parotid gland in non-rheumatological settings have been reported as very rare. Aim: The objective of this study was to assess the feasibility and determine the presence of parotid gland tissue in ultrasound-guided parotid gland biopsies performed by rheumatologists in cadavers. Material and method: Two senior rheumatologists obtained, under direct ultrasound visualization in in-plane technique, biopsies of 8 parotid glands from 4 different cadavers using a core biopsy needle. One biopsy per gland was taken. Results: All histological exams showed typical parotid gland tissue without any neuronal or vascular tissue. Conclusion: In conclusion, we demonstrated that minimally invasive, ultrasound-guided core needle biopsy of the parotid gland is a highly precise and easy method to obtain salivary gland tissue.Introduction: Surgical biopsy of minor salivary glands is routinely performed for the diagnosis of Sjögren syndrome. However, surgical biopsies of the minor labial glands may result in various complications in up to 6% of patients. On the other hand, adverse events following core needle biopsies of the parotid gland in non-rheumatological settings have been reported as very rare. Aim: The objective of this study was to assess the feasibility and determine the presence of parotid gland tissue in ultrasound-guided parotid gland biopsies performed by rheumatologists in cadavers. Material and method: Two senior rheumatologists obtained, under direct ultrasound visualization in in-plane technique, biopsies of 8 parotid glands from 4 different cadavers using a core biopsy needle. One biopsy per gland was taken. Results: All histological exams showed typical parotid gland tissue without any neuronal or vascular tissue. Conclusion: In conclusion, we demonstrated that minimally invasive, ultrasound-guided core needle biopsy of the parotid gland is a highly precise and easy method to obtain salivary gland tissue.

High prevalence of hip involvement and decrease in inflammatory ultrasound lesions during tumour necrosis factor-α blocking therapy in ankylosing spondylitis.

OBJECTIVES: To assess the prevalence of clinical, US and radiographic hip involvement in AS patients with active disease and to explore the associations between these assessments. Furthermore, to evaluate the effect of 6 months of TNF-α blocking therapy on tender and inflammatory power Doppler US lesions of hip joints. METHODS: Consecutive AS patients starting TNF-α blocking therapy were evaluated for hip joint involvement. At baseline, patient-reported history of hip involvement was assessed and radiographic evaluation (BASRI-hip) was performed. Clinical examination (tender hip joints) and US examination took place before and after 6 months of treatment. RESULTS: Of the 111 included patients, 20% reported a history of hip involvement. At baseline, tender hip joints were present in 23% of patients. US examination showed inflammatory lesions in 17% of patients, of which 74% had positive power Doppler. Structural lesions were present in 20% of patients, of which 55% had osteophytes. Structural radiographic damage was seen in 10% of patients. Highest concordance was found between history of hip involvement and radiographic hip involvement (phi coefficient 0.333). After 6 months of TNF-α blocking therapy, significant decrease was found in tender hip joints (from 29 to 11), total number of inflammatory US lesions (from 29 to 9) and positive power Doppler (from 22 to 6). CONCLUSION: The prevalence rate of hip involvement in AS patients varies from 10 to 23%, depending on the type of hip assessment. TNF-α blocking therapy significantly improved tender hip joints, and inflammatory US lesions including positive power Doppler.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

Soft tissue pathology: regional pain syndromes, nerves and ligaments.

Musculoskeletal ultrasonography (MSUS) is a useful imaging technique in the diagnosis of various soft tissue pathologies. High-frequency linear array transducers provide excellent resolution of soft tissue pathology. Pathological changes in subcutaneous tissue, including soft tissue tumours, abscesses, tenosynovitis, ligamentous and tendinous abnormalities, and peripheral nerve lesions, including carpal tunnel syndrome, can be identified. This review addresses the role of US in diagnosing regional pain syndrome, ligament lesions and nerve lesions.

Can simple ultrasonography predict the clinical effect of intra-articular injection therapy of the knee joint?

To investigate whether ultrasonographic joint assessment can predict the clinical response to intra-articular injection therapy of the knee. Patients with persistent gonarthritis intra-articularly received in a randomized double-blinded crossover fashion radiation synovectomy or a glucocorticoid injection, both followed by clinical bed rest. Prior to treatment and 3 months afterwards, grey-scale ultrasonography (US) of the knee was performed, measuring synovial thickness and extent of effusion. The final clinical effect of these two treatments was assessed at 3 months and finally at 6 months using a composite index. Ninety-seven patients, mainly suffering from undifferentiated arthritis (40%) or rheumatoid arthritis (31%), received 165 injections (including crossovers). Clinical effect at 6 months was not related to the baseline ultrasonographic extent of effusion or synovial thickness, nor with ultrasonographic decrease of effusion after the first 3 months. Nevertheless, it was associated with ultrasonographic decrease of synovial thickness within the first 3 months. Simple baseline US measurements fail to predict the final clinical effect of intra-articular treatment of the knee at 6 months, in contrast to early US changes of synovial thickness 3 months after therapy.

Prevention of glucocorticoid induced osteoporosis with alendronate or alfacalcidol: relations of change in bone mineral density, bone markers, and calcium homeostasis.

OBJECTIVE: To explore the relation of changes in measures of bone turnover and changes in bone mineral density (BMD) of the lumbar spine and total hip over 18 months in a double-blinded, randomized trial, comparing the effect of alfacalcidol (101 patients) versus alendronate (100 patients) on BMD in patients who recently started treatment with glucocorticoids for various rheumatic diseases. METHODS: Associations between changes in serum procollagen type I C-propeptide (P1CP), fasting urine N-terminal telopeptide of type I collagen (NTx), serum calcium, parathyroid hormone (PTH), osteocalcin, and change from baseline in BMD over 18 months were explored with regression and correlation analyses. RESULTS: In both treatment groups, there was a statistically significant decrease in NTx. In the alfacalcidol group there was also a significant increase in P1CP and osteocalcin, in contrast to the alendronate group, but BMD in the alfacalcidol decreased versus an increase in the alendronate group (p < 0.001). In neither treatment group were changes in biochemical measures correlated with the change in BMD, with the exception of a negative correlation in the alendronate group between changes in total hip BMD and NTx. Use of alendronate resulted in an increased PTH in 27 patients, but the increase in BMD of these patients was not statistically significantly different compared to patients taking alendronate with normal PTH levels. CONCLUSION: Changes in BMD were not associated with changes in bone measures, with the exception of NTx in the alendronate group. For the patient taking glucocorticoids in clinical practice, the value of serial assessment of bone markers is low; changes in markers are no substitute for changes in BMD. ClinicalTrials.gov number: NCT00138983.

Is radiation synovectomy for arthritis of the knee more effective than intraarticular treatment with glucocorticoids? Results of an eighteen-month, randomized, double-blind, placebo-controlled, crossover trial.

OBJECTIVE: To compare the clinical efficacy and safety of radiation synovectomy (RSO) with intraarticular (IA) yttrium-90 plus glucocorticoids (GCs) with the efficacy and safety of IA placebo yttrium plus GCs and to identify parameters that predict efficacy. METHODS: The knees of 97 patients with persistent arthritis despite outpatient treatment with IA GCs (n = 113 knees), were treated with either IA (90)Y plus GCs (50%) or IA placebo yttrium plus GCs (50%), followed by 3 days of bed rest in the hospital clinic, with splinting of the treated knee. Predominant diagnoses were undifferentiated arthritis (39%) and rheumatoid arthritis (32%). The clinical effect of therapy was assessed at 6 months using a composite change index (CCI; range 0-12). The primary outcome measure was the response rate (i.e., the percentage of joints with a CCI > or =6). Knees with persistent arthritis after 6 months underwent crossover therapy (51% of the (90)Y plus GCs group versus 45% of the placebo plus GCs group). Adverse effects and radiologic damage during followup were documented. RESULTS: Neither the response rate (48% in both groups), the mean CCI, nor the duration of remission was significantly different between groups. No clinically relevant short-term adverse effects were observed, except for progression of radiologic damage in 34% of the (90)Y plus GCs group versus 28% of the placebo plus GCs group (knee prosthesis placement in 8% versus 1%). The functional and radiologic status at study entry predicted the clinical effect. CONCLUSION: Treatment with (90)Y plus GCs with bed rest and splinting is not superior to IA GCs with bed rest and splinting. Over the short term, both treatments appeared to be safe, although a negative effect of (90)Y on cartilage and bone cannot be ruled out. Thus, it appears that RSO with (90)Y should no longer be considered the treatment of first choice for persistent arthritis of the knee.