Seroconversion after a third COVID-19 vaccine is affected by rituximab dose but persistence is not in patients with rheumatoid arthritis.

OBJECTIVES: In patients with RA treated with (ultra-)low-dose rituximab (RTX), we investigated the association of dosing and timing of RTX on seroconversion after a third coronavirus disease 2019 (COVID-19) vaccination and the persistence of humoral response after a two-dose vaccination. MATERIAL AND METHODS: In this monocentre observational study, patients from the COVAC cohort were included in the third vaccine analysis if humoral response was obtained 2-6 weeks after a third vaccination in previous non-responders and in the persistence analysis if a follow-up humoral response was obtained before a third vaccination in previous responders. Dichotomization between positive and negative response was based on the assay cut-off. The association between the latest RTX dose before first vaccination, timing between the latest RTX dose and vaccination and response was analysed with univariable logistic regression. RESULTS: Of the 196 patients in the cohort, 98 were included in the third vaccine analysis and 23 in the persistence analysis. Third vaccination response was 19/98 (19%) and was higher for 200 mg RTX users [5/13 (38%)] than for 500 and 1000 mg users [7/37 (19%) and 7/48 (15%), respectively]. Non-significant trends were seen for higher response with lower dosing [200 vs 1000 mg: odds ratio (OR) 3.66 (95% CI 0.93, 14.0)] and later timing [per month since infusion: OR 1.16 (95% CI 0.97, 1.35)]. Humoral response persisted in 96% (22/23) and 89% (8/9) of patients who received RTX between the two measurements. CONCLUSIONS: Repeated vaccination as late as possible after the lowest RTX dose possible seems the best vaccination strategy. A once positive humoral response after COVID-19 vaccination persists irrespective of intercurrent RTX infusion. Study registration. Netherlands Trial Registry (https://www.trialregister.nl/), NL9342.

Rituximab dose-dependent infection risk in rheumatoid arthritis is not mediated through circulating immunoglobulins, neutrophils or B cells.

OBJECTIVES: Rituximab (RTX) is a safe and effective treatment for RA. A dose-dependent infection risk was found in the REDO trial. Some studies associate RTX use with higher infection risks, possibly explained by low immunoglobulin levels and/or neutropenia. Additionally, a higher infection risk shortly after RTX infusion is reported. The objectives of this study were (i) to compare incidence rates of infections between doses and over time, and (ii) to assess B-cell counts, immunoglobulin levels, neutrophil counts and corticosteroid/disease modifying rheumatic drug use as mediating factors between RTX study dose and infection risk. METHODS: Post hoc analyses of the REDO trial were performed. Infection incidence rates between RTX dosing groups and between time periods were compared using Poisson regression. A step-wise mediation analysis was performed to investigate if any of the factors mentioned above act as a mediator in the observed dose-dependent difference in infection risk. RESULTS: The potential mediators that were investigated (circulating B-cell counts, immunoglobulin levels, neutrophil counts and drug use) did not explain the dose-dependent infection risk observed in the REDO trial. Additionally, a trend towards a time-dependent infection risk was found, with higher infection rates shortly after RTX infusion. CONCLUSIONS: These secondary analyses of the REDO trial confirmed the observed dose-dependent infection risk. Additionally, we found that infection risks were higher shortly after RTX infusion. However, a mediating pathway was not found.

Humoral response to coronavirus disease-19 vaccines is dependent on dosage and timing of rituximab in patients with rheumatoid arthritis.

OBJECTIVES: Humoral response to vaccines in RA patients treated with rituximab (RTX) in standard dosages (≥1000 mg) is decreased. Ultra-low dosages (500 or 200 mg) may have better response. Also, timing after latest RTX infusion may be an important variable. We aimed to investigate the influence of RTX dosage and timing on response to COVID-19 vaccination in RA patients. METHODS: A single-centre observational study (n = 196) investigated the humoral response, measured by total Ig anti-COVID-19 assay (positive response ≥1.1), 2-6 weeks after complete COVID-19 vaccination. A multivariable logistic regression model was built to study the effect of RTX dosage and time between latest rituximab and vaccination on response, adjusting for age and methotrexate use. RESULTS: After two-dose vaccination, the response rate was significantly better for patients receiving 200 mg (n = 31, 45%) rituximab compared with 1000 mg (n = 98, 26%; odds ratio 3.07, 95% CI 1.14-8.27) and for each additional month between latest rituximab and vaccination (OR 1.67, 1.39-2.01). CONCLUSION: Both increased time between latest rituximab infusion and complete vaccination, and 200 mg as latest dose were associated with a better response to COVID-19 vaccination and should be considered when trying to increase vaccine response after rituximab in RA patients. TRIAL REGISTRATION: Netherlands Trial Register, https://www.trialregister.nl/, NL9342.

Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors.

Objective: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.

A comparison between ultrasonographic, surgical and histological assessment of tenosynovits in a cohort of idiopathic carpal tunnel syndrome patients.

Carpal tunnel syndrome (CTS) may be caused by subclinical tenosynovitis which may be detected by ultrasonography (US). The objective of this study is to investigate whether ultrasonography has a place in the workup of idiopathic CTS patients. Therefore, we investigated the prevalence of tenosynovitis and its association with the clinical outcome of surgery. A cohort of 31 consecutive idiopathic CTS patients (33 wrists) who were a candidate for carpal tunnel release (CTR) surgery was assessed using greyscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Peroperatively, tenosynovitis was evaluated macroscopically by the surgeon. Tissue samples from areas macroscopically suspected for tenosynovitis were taken for histological evaluation. The clinical outcome of the operation was assessed after 6 months and if applicable alternative diagnoses for the CTS were proposed. US tenosynovitis (OMERACT) was detected preoperatively in 58 % of the wrists. Peroperatively, macroscopic tenosynovitis was detected visually in 88 % of the wrists. Histological evaluation demonstrated a limited influx of lymphocytes indicative of a mild chronic inflammatory response in 19 %. Non-specific reactive changes were observed in 78 % of the cases. Ultrasonographically defined tenosynovitis was associated with an OR of 2.81 (95 % CI 0.61-13) for responding well to surgery. Most cases of ultrasonographic and peroperatively defined tenosynovitis were classified by histology as reactive changes. The presence of ultrasonographic tenosynovitis might be associated with a better clinical outcome of surgery.

Very different performance of the power Doppler modalities of several ultrasound machines ascertained by a microvessel flow phantom.

INTRODUCTION: In many patients with rheumatoid arthritis (RA) subclinical disease activity can be detected with ultrasound (US), especially using power Doppler US (PDUS). However, PDUS may be highly dependent on the type of machine. This could create problems both in clinical trials and in daily clinical practice. To clarify how the PDUS signal differs between machines we created a microvessel flow phantom. METHODS: The flow phantom contained three microvessels (150, 1000, 2000 microns). A syringe pump was used to generate flows. Five US machines were used. Settings were optimised to assess the lowest detectable flow for each US machine. RESULTS: The minimal detectable flow velocities showed very large differences between the machines. Only two of the machines may be able to detect the very low flows in the capillaries of inflamed joints. There was no clear relation with price. One of the lower-end machines actually performed best in all three vessel sizes. CONCLUSIONS: We created a flow phantom to test the sensitivity of US machines to very low flows in small vessels. The sensitivity of the power Doppler modalities of 5 different machines was very different. The differences found between the machines are probably caused by fundamental differences in processing of the PD signal or internal settings inaccessible to users. Machines considered for PDUS assessment of RA patients should be tested using a flow phantom similar to ours. Within studies, only a single machine type should be used.

Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumatoid arthritis--a systematic review of the literature.

INTRODUCTION: Ultrasonography (US) might have an added value to clinical examination in diagnosing early rheumatoid arthritis (RA) and assessing remission of RA. We aimed to clarify the added value of US in RA in these situations performing a systematic review. METHODS: A systematic literature search was performed for RA, US, diagnosis and remission. Methodological quality was assessed; the wide variability in the design of studies prohibited pooling of results. RESULTS: Six papers on the added value of US diagnosing early RA were found, in which at least bilateral metacarpophalangeal (MCP), wrists and metatarsophalangeal (MTP) joints were scanned. Compared to clinical examination, US was superior with regard to detecting synovitis and predicting progression to persistent arthritis or RA. Eleven papers on assessing remission were identified, in which at least the wrist and the MCP joints of the dominant hand were scanned. Often US detected inflammation in patients clinically in remission, irrespective of the remission criteria used. Power Doppler signs of synovitis predicted X-ray progression and future flare in patients clinically in remission. CONCLUSIONS: US appears to have added value to clinical examination for diagnosing of RA when scanning at least MCP, wrist and MTP joints, and, when evaluating remission of RA, scanning at least wrist and MCP joints of the dominant hand. For both purposes primarily power Doppler US might be used since its results are less equivocal than those of greyscale US.

The most reliable probe position in the ultrasonographic examination of the wrist in rheumatoid arthritis.

OBJECTIVES: This study aims to evaluate the inter-observer reliability of the ultrasonographic examination of the wrist in RA patients between 3 examiners and 3 probe positions. METHODS: Fifty-three RA patients were recruited at the University Clinical Hospital of Santiago de Compostela in Spain for ultrasonographic examination of the wrist. Ultrasonography (US) was performed on both wrists using a GE LOGIQ 9 machine, using three probe positions: Lister's Tubercle to digit II (position 1), Lister's Tubercle to digit III (position 2) and ulnocarpal (position 3), from the anatomic medial orientation. Three examiners (2 experienced ultrasonographers and 1 junior ultrasonographer) scored synovitis according to a 0-3 semiquantitative scoring system. Inter-observer reliability was expressed using the ICC (A,1). RESULTS: For grey-scale ultrasound (GSUS) the inter-observer reliability (ICC(A,1)) (single measure, agreement definition) ranged from 0.35 for the ulnocarpal joint, position 3, to 0.60 in both position 1 for the radiocarpal joint and position 2 for the inter-carpal joint. Using power Doppler ultrasound (PDUS) the inter-observer reliability (ICC(A,1)) ranged from 0.36 in position 3, to 0.52 both in position 1 and 2 for the radiocarpal joint. CONCLUSIONS: The reliability of the GSUS-examination of the wrist joints of RA patients with GSUS shows highest, moderate reliability using the anatomical landmarks Tubercle of Lister and digit III (position 2). The reliability of the PDUS examination was similar and moderate in both position 1 (Lister's Tubercle to digit II) and position 2 (Lister's Tubercle to digit III). The reliability was poorest for position 3 (the anatomic medial view of the ulnocarpal joint) in both the GSUS and PDUS examination. This study suggests that position 2 should be used in clinical trials and daily practice.