Prophylactic antibodies inhibit spike-specific T and B cell responses after COVID-19 vaccination.

Active and passive immunization is used in high-risk patients to prevent severe courses of COVID-19, but the impact of prophylactic neutralizing antibodies on the immune reaction to the mRNA vaccines has remained enigmatic. Here we show that CD4 T and B cell responses to Spikevax booster immunization are suppressed by the therapeutic antibodies Casirivimab and Imdevimab. B cell and T cell responses were significantly induced in controls but not in antibody-treated patients. The data indicates that humoral immunity, i. e. high levels of antibodies, negatively impacts reactive immunity, resulting in blunted cellular responses upon boosting. This argues for temporal separation of vaccination efforts; with active vaccination preferably applied before prophylactic therapeutic antibody treatment.

[Autoantibody diagnostics in idiopathic inflammatory myopathy]. / Autoantikörperdiagnostik bei idiopathisch inflammatorischen Myopathien.

Idiopathic inflammatory myopathy (IIM) is a group of rare and heterogeneous systemic diseases that manifest not only in the muscles but also in the skin, joints, and lungs. Initial symptoms can be isolated and variable and thus the diagnosis poses challenges to various specialist groups. As autoantibodies are sometimes the only specific findings that lead to the diagnosis and appropriate treatment, basic knowledge of them is essential. This article explains the available test systems, names the clinical indications necessary for the initiation of autoantibody diagnostics, provides information on the etymology, antigens, synonyms, and first descriptors, describes indirect immunofluorescence on HEp­2 cells induced by myositis antibodies, and provides clinical-serological associations. The comparison of the autoantibody findings with the clinical symptoms and laboratory findings enables the identification of false positive or false negative laboratory findings in the sense of a plausibility check.

Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus.

Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).

2022 EULAR points to consider for the measurement, reporting and application of IFN-I pathway activation assays in clinical research and practice.

BACKGROUND: Type I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings. OBJECTIVE: To develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility. METHODS: EULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined. RESULTS: Two overarching principles and 11 PtC were defined. The first set (PtC 1-4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5-11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda. CONCLUSIONS: IFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology.

Improvement of humoral immunity by repeated dose-intensified COVID-19 vaccinations in primary non- to low-responders and B cell deficient rheumatic disease patients.

OBJECTIVE: To determine whether repeated, dose-intensified mRNA vaccinations against COVID-19 increase humoral immunity in previously low-responding patients with autoimmune rheumatic diseases (AIRD), including rituximab-treated and B cell depleted patients. METHODS: Of 308 AIRD patients receiving basic immunization, 98 had a low serological response against SARS-CoV-2 with a neutralizing capacity of < 70% using surrogate neutralization assay. 38 patients received a third vaccination with 30 µg BNT162b2 16 weeks after second vaccination. If neutralizing serum capacity was below 70% four weeks after the last vaccination, then the fourth vaccination (n = 19) and the fifth (n = 4) vaccination with 100 µg mRNA-1273 took place eight weeks after the last vaccination. RESULTS: Each of the three booster vaccinations resulted in a significant increase of mean serum neutralizing capacity (3rd: Δ = 42%, p < 0.001; 4th: Δ = 19%, p = 0.049 and 5th: Δ = 51%, p = 0.043) and produced a significant proportion of high-responders (3rd: 34%; 4th: 32% and 5th: 75%). Low B cell counts (p = 0.047), lower previous antibody response (p < 0.001) and rituximab therapy (p = 0.021) were negatively associated with successful response to the third but not to the fourth vaccination. Remarkably, substantial increases in neutralization capacity of up to 99% were observed after repeated vaccinations in B cell depleted patients. CONCLUSION: AIRD patients with low humoral response benefited from up to three repeated dose-intensified mRNA booster vaccinations - despite low B cell count and previous rituximab therapy. Each additional vaccination substantially reduced the number of low-responding, vulnerable patients.

Self-reported diagnostic confidence predicts diagnostic accuracy in axial spondyloarthritis imaging.

OBJECTIVES: Reporting diagnostic confidence (DC) in axial spondyloarthritis (axSpA) imaging is recommended by the ASAS guidelines. Our aim was to investigate whether self-reported DC predicts diagnostic accuracy in axSpA imaging using X-ray (XR), computed tomography (CT) and magnetic resonance imaging (MRI). METHODS: We performed a post hoc analysis including 163 patients with low back pain (89 axSpA and 56 non-axSpA). Nine blinded readers with different experience levels (inexperienced (< 1 year), semi-experienced (3-8 years) and experienced (> 12 years)) scored the sacroiliac joint images for compatibility with axSpA. DC was reported on a scale from 1 (not sure) to 10 (very sure). Mean DC scores and standard deviations were calculated for correct and incorrect responses using XR, CT, MRI, XR+MRI and CT+MRI. Differences in DC were assessed using the Mann-Whitney U test. RESULTS: DC scores were higher for correct axSpA diagnoses and differed significantly between correct and incorrect responses for all modalities (p< 0.001), with a mean DC of 7.1 ± 2.1 and 6.3 ± 2.1 for XR, 8.3 ± 1.8 and 6.7 ± 2.0 for CT, 8.1 ± 1.9 and 6.2 ± 1.9 for MRI, 8.2 ± 1.8 and 6.7 ± 1.8 for XR+MRI and 8.4 ± 1.8 and 6.8 ± 1.8 for CT+MRI, respectively. This was also the case when looking at the results by experience group, except for XR in the inexperienced group. CONCLUSION: Providing self-reported DC in radiological reports is useful information to predict diagnostic reliability in axSpA imaging.

Choose wisely: imaging for diagnosis of axial spondyloarthritis.

OBJECTIVE: To assess the diagnostic accuracy of radiography (X-ray, XR), CT and MRI of the sacroiliac joints for diagnosis of axial spondyloarthritis (axSpA). METHODS: 163 patients (89 with axSpA; 74 with degenerative conditions) underwent XR, CT and MR. Three blinded experts categorised the imaging findings into axSpA, other diseases or normal in five separate reading rounds (XR, CT, MR, XR +MR, CT +MR). The clinical diagnosis served as reference standard. Sensitivity and specificity for axSpA and inter-rater reliability were compared. RESULTS: XR showed lower sensitivity (66.3%) than MR (82.0%) and CT (76.4%) and also an inferior specificity of 67.6% vs 86.5% (MR) and 97.3% (CT). XR +MR was similar to MR alone (sensitivity 77.5 %/specificity 87.8%) while CT+MR was superior (75.3 %/97.3%). CT had the best inter-rater reliability (kappa=0.875), followed by MR (0.665) and XR (0.517). XR +MR was similar (0.662) and CT+MR (0.732) superior to MR alone. CONCLUSIONS: XR had inferior diagnostic accuracy and inter-rater reliability compared with cross-sectional imaging. MR alone was similar in diagnostic performance to XR+MR. CT had the best accuracy, strengthening the importance of structural lesions for the differential diagnosis in axSpA.

Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease.

OBJECTIVES: Inflammatory rheumatic and musculoskeletal diseases (iRMDs) are associated with increased systemic bone loss that is mediated by chronic inflammation, treatment with glucocorticoids (GCs) and other factors. Our objective was to analyse the impact of variables that influence osteoporosis (OP) in patients with iRMD treated with GC. METHODS: Rh-GIOP (acronyme) is a prospective observational cohort study investigating bone health in consecutive patients with iRMD and current or prior GC treatment. We present an analysis of the patients' baseline data here. Bone mineral density (BMD) measured by dual X-ray absorptiometry was the primary outcome. Multivariable linear regression models were performed to identify variables associated with BMD. RESULTS: Data from 1066 patients with iRMD were analysed. GC doses of <5 mg prednisone equivalent per day, cumulative dose and duration of GC therapy were not associated with negative effects on BMD. Dosages of ≥5 mg/day lost their negative association with BMD after adjustment for confounders. When subanalysing patients with exactly 5 mg/day, no negative effect was seen. For patients with rheumatoid arthritis (RA), GC doses of >7.5 mg/day showed a negative association with BMD overall, but this effect seemed to be specific only to patients with moderate or high disease activity (Disease Activity Score 28-C reactive protein >3.2). CONCLUSIONS: GCs of ≤5 mg/day did not seem to be associated with a reduction of BMD in patients with iRMD and current or prior exposure to GC. This is most likely due to the dampening of inflammation by GC, which exerts a mitigating effect on the risk of OP. In RA, current GC doses of >7.5 mg/day were negatively associated with BMD, but only in patients with moderate to high disease activity. TRIAL REGISTRATION NUMBER: NCT02719314.

Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases.

OBJECTIVE: To study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD). METHODS: In this retrospective study, neutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 patients with AIRD on MTX therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 patients with AIRD without immunosuppressive medication. RESULTS: Patients on MTX showed a significantly lower mean antibody response compared with patients with AIRD without immunosuppressive therapy (71.8% vs 92.4%, p<0.001). For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001). All nine patients with antibody levels below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher mean neutralising antibody levels after second vaccination, compared with patients who continued MTX therapy during both vaccinations (83.1% vs 61.2%, p=0.001). This effect was particularly pronounced in patients older than 60 years (80.8% vs 51.9%, p=0.001). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days. CONCLUSION: MTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age.

Evaluation of SIGLEC1 in the diagnosis of suspected systemic lupus erythematosus.

OBJECTIVES: To evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE). METHODS: SIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020. RESULTS: SLE was confirmed in 76 of 232 patients (32.8 %) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared with patients without SLE (P <0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were >99.9 % and 0.1 %, respectively. Using receiver operating characteristic (ROC) analysis and DeLong testing, the area under the curve (AUC) for SIGLEC1 (AUC = 0.95) was significantly higher than for ANA (AUC = 0.88, P = 0.031), C3 (AUC = 0.83, P = 0.001) and C4 (AUC = 0.83, P = 0.002) but not for anti-dsDNA antibodies (AUC = 0.90, P = 0.163). CONCLUSION: IFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases.

Contrast-enhanced CT techniques and MRI perform equally well in arthritis imaging of the hand: a prospective diagnostic accuracy study.

OBJECTIVES: To investigate the performance of dual-energy CT (DECT)-generated iodine maps (iMap) and CT subtraction (CT-S) in the detection of synovitis, tenosynovitis, and peritendonitis/paratenonitis compared to magnetic resonance imaging (MRI) using musculoskeletal ultrasound (MSUS) as standard of reference. METHODS: This IRB-approved prospective study consecutively investigated patients with undifferentiated arthritis. All patients underwent MSUS, MRI and contrast-enhanced DECT of the hand; from the latter conventional CT-S, image-based iMap (iMap-I) and raw data-based iMap (iMap-RD) were reconstructed. CT and MRI datasets were scored for synovitis and tenosynovitis/paratenonitis applying the modified Rheumatoid Arthritis MRI Score (RAMRIS). Sensitivity, specificity, and diagnostic accuracy were calculated. Non-inferiority was tested using the one-tailed McNemar test. Correlation of sum scores was assessed using Pearson's test. Interreader reliability was assessed using Cohen's kappa. RESULTS: Overall, 33 patients were included. MSUS was positive for synovitis and tenosynovitis/paratenonitis in 28 patients with a sum score of 6.91. Excellent correlation with MSUS was shown for CT-S (sum score 6.38; r = 0.91), iMap-RD (sum score 9.74; r = 0.82), MRI (sum score 12.70; r = 0.85), and iMap-I (sum score 6.94; r = 0.50). CT-S had the highest diagnostic accuracy of 83%, followed by iMap-I (78%), MRI (75%), and iMap-RD (74%). All modalities showed non-inferiority. Reader agreement was good for CT-S and MRI (κ = 0.62; 0.64) and fair for iMap-RD and iMap-I (κ = 0.31; 0.37). CONCLUSION: CT-S and iMap allow highly standardized arthritis imaging and are suitable for clinical practice. MSUS still has the highest availability for arthritis imaging and served as gold standard for this study. KEY POINTS: • CT subtraction, iodine map with dual-energy CT, and MRI showed non-inferiority to musculoskeletal ultrasound. • MRI was the most sensitive but least specific imaging technique compared with CT subtraction and dual-energy CT. • CT subtraction showed the best correlation with musculoskeletal ultrasound.

Nuclear antigen-reactive CD4+ T cells expand in active systemic lupus erythematosus, produce effector cytokines, and invade the kidneys.

Systemic lupus erythematosus is a systemic and chronic autoimmune disease characterized by loss of tolerance towards nuclear antigens with autoreactive CD4+ T cells implicated in disease pathogenesis. However, very little is known about their receptor specificity since the detection of human autoantigen specific CD4+ T cells has been extremely challenging. Here we present an analysis of CD4+ T cells reactive to nuclear antigens using two complementary methods: T cell libraries and antigen-reactive T cell enrichment. The frequencies of nuclear antigen specific CD4+ T cells correlated with disease severity. These autoreactive T cells produce effector cytokines such as interferon-γ, interleukin-17, and interleukin-10. Compared to blood, these cells were enriched in the urine of patients with active lupus nephritis, suggesting an infiltration of the inflamed kidneys. Thus, these previously unrecognized characteristics support a role for nuclear antigen-specific CD4+ T cells in systemic lupus erythematosus.

Quantification of morning stiffness to assess disease activity and treatment effects in rheumatoid arthritis.

OBJECTIVES: The clinical parameter of morning stiffness is widely used to assess the status of RA, but its accurate quantitative assessment in a clinical setting has not yet been successful. This lack of individual quantification limits both personalized medication and efficacy evaluation in the treatment of RA. METHODS: We developed a novel technology to assess passive resistance of the MCP III joint (stiffness) and its passive range of motion (PRoM). Within this pilot study, 19 female postmenopausal RA patients and 9 healthy controls were examined in the evening as well as the morning of the following day. To verify the specificity of the biomechanical quantification, 11 patients with RA were assessed both prior to and ∼3 h after glucocorticoid therapy. RESULTS: While the healthy controls showed only minor changes between afternoon and morning, in RA patients the mean PRoM decreased significantly by 18% (s.d. 22) and stiffness increased significantly by 20% (s.d. 18) in the morning compared with the previous afternoon. We found a significant positive correlation between RA activity and biomechanical measures. Glucocorticoids significantly increased the mean PRoM by 16% (s.d. 11) and reduced the mean stiffness by 23% (s.d. 22). CONCLUSION: This technology allowed mechanical stiffness to be quantified in MCP joints and demonstrated high sensitivity with respect to disease status as well as medication effect in RA patients. Such non-invasive, low-risk and rapid assessment of biomechanical joint stiffness opens a novel avenue for judging therapy efficacy in patients with RA and potentially also in other non-RA inflammatory joint diseases.

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity.

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons.

Perfusion in hand arthritis on dynamic contrast-enhanced computed tomography: a randomized prospective study using MRI as a standard of reference.

OBJECTIVE: To evaluate the performance of dynamic contrast-enhanced CT (DCE-CT) in detecting and quantitatively assessing perfusion parameters in patients with arthritis of the hand compared with dynamic contrast-enhanced MRI (DCE-MRI) as a standard of reference. MATERIALS AND METHODS: In this IRB-approved randomized prospective single-centre study, 36 consecutive patients with suspected rheumatoid arthritis underwent DCE-CT (320-row, tube voltage 80 kVp, tube current 8.25 mAs) and DCE-MRI (1.5 T) of the hand. Perfusion maps were calculated separately for mean transit time (MTT), time to peak (TTP), relative blood volume (rBV), and relative blood flow (rBF) using four different decomposition techniques. Region of interest (ROI) analysis was performed in metacarpophalangeal joints II-V and in the wrist. Pairs of perfusion parameters in DCE-CT and DCE-MRI were compared using a two-tailed t test for paired samples and interpreted for effect size (Cohen's d). According to the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) scoring results, differentiation of synovitis-positive and synovitis-negative joints with both modalities was assessed with the independent t test. RESULTS: The two modalities yielded similar perfusion parameters. Identified differences had small effects (d 0.01-0.4). DCE-CT additionally differentiates inflamed and noninflamed joints based on rBF and rBV but tends to underestimate these parameters in severe inflammation. The total dose-length product (DLP) was 48 mGy*cm with an estimated effective dose of 0.038 mSv. CONCLUSION: DCE-CT is a promising imaging technique in arthritis. In patients with a contraindication to MRI or when MRI is not available, DCE-CT is a suitable alternative to detect and assess arthritis.

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE.

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14++CD16+ monocytes, CD56+ CD16dim natural killer cells, marginal zone-like IgD+CD27+ B cells, and on CD4+ and CD8+ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.

SIGLEC1 (CD169) is a sensitive biomarker for the deterioration of the clinical course in childhood systemic lupus erythematosus.

BACKGROUND: To analyse the validity of membrane-bound SIGLEC1 (CD169) as a sensitive biomarker for monitoring disease activity in pediatric systemic lupus erythematosus (SLE). METHODS: 27 children and adolescents with SLE were followed for a mean of 13.5 months. During consecutive routine visits SLEDAI-2k, C3, C4 and ds-DNA values were determined. Additionally, expression of SIGLEC1 on monocytes was determined by flow cytometry. The amount of PE-labelled CD169 mAb bound per monocyte was analyzed using QuantiBRITE™ PE tubes. Associations between biomarkers and the clinical course were investigated by regression analysis. RESULTS: In general, SIGLEC1 expression is high on SLE-derived monocytes (mean 6 359 (SD 6 056) molecules/monocyte, cut-off 2 500 molecules/monocyte), all patients with newly diagnosed SLE exhibit elevated expression (mean 13366 (SD 7 750) molecules/monocyte). Changes (Δ) in SIGLEC1 levels during the clinical course is the only biomarker that significantly correlates with the change in SLEDAI-2k (betaST = 0.28, p = 0.001). At follow-up visit, a clinically important worsening was experienced by 47.6% of patients with a Δ SIGLEC1 > 2 151 molecules/cell (OR 5.31) and 72.4% with a Δ SIGLEC1 > 756 molecules/cell (OR 8.90). Conversely, 36.4% of patients with a Δ SIGLEC1 < -2 818 molecules/cell (OR 4.16, percentiles as cut-off criteria) and 50.0% of patients with a Δ SIGLEC1 < -1 370 molecules/cell (OR 3.55, application of Youden index) showed clinical improvement. SIGLEC1 expression correlates inversely with the amount of therapeutically applied hydroxychloroquine (p < 0.001). CONCLUSIONS: SIGLEC1 expression on monocytes is a sensitive biomarker for adjusting disease activity in childhood SLE and represents a promising and easily applicable tool for disease monitoring.

Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors.

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.

Ultra-low-dose CT detects synovitis in patients with suspected rheumatoid arthritis.

PURPOSE: To prove the feasibility and measure the diagnostic accuracy of contrast-enhanced ultra-low-dose CT (ULD-CT) for the depiction of inflammatory soft-tissue changes (synovitis, tenosynovitis and peritendonitis) in patients with arthritis of the hand. MATERIALS AND METHODS: In this institutional review board-approved study, 36 consecutive patients over the age of 50 with suspected rheumatoid arthritis underwent ULD-CT (estimated radiation exposure <0.01 mSv) and MRI of the hand with weight-adapted intravenous contrast administration. ULD-CT subtraction and MR images were assessed for synovitis, tenosynovitis and peritendonitis by three readers using a modified Rheumatoid Arthritis MRI Score (RAMRIS). Patients were asked which modality they would prefer for future examinations. Sensitivity and specificity of ULD-CT for detection of inflammatory changes were calculated using MRI as standard of reference. The sum scores were correlated using Pearson's r. RESULTS: All 36 patients showed synovitis in MRI. ULD-CT had 69% sensitivity on the patient level and 65% on the joint level with 87% specificity. Sensitivity was higher in patients with more severe inflammation (80% for MRI RAMRIS >1). There was almost perfect correlation between the modified RAMRIS sum scores of ULD-CT and MRI (Pearson's r=0.94). Regarding preferences for future examinations, 85% preferred ULD-CT over MRI. ULD-CT detected more differential diagnoses than MRI (8 vs 2/12). CONCLUSION: Contrast-enhanced ULD-CT of the hand allows for depiction of soft-tissue inflammation at the hand and can be achieved using very low radiation exposure (<0.01 mSv). ULD-CT may evolve to a fast and comfortable alternative to MRI, although it is not as sensitive as MRI for detecting mild disease.