...remission was defined in accordance to Multinational Interdisciplinary Working Group for Uveitis in Childhood 2. ...patients with insidious onset of disease being ANA positive are at particular ...risk of developing JIA, as uveitis onset may occur before arthritis onset. Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany.
To investigate whether bortezomib, a proteasome inhibitor approved for treatment of multiple myeloma, induces clinically relevant plasma cell (PC) depletion in patients with active, refractory ...systemic lupus erythematosus (SLE).
Twelve patients received a median of two (range 1-4) 21-day cycles of intravenous bortezomib (1.3 mg/m(2)) with the coadministration of dexamethasone (20 mg) for active SLE. Disease activity was assessed using the SLEDAI-2K score. Serum concentrations of anti-double-stranded DNA (anti-dsDNA) and vaccine-induced protective antibodies were monitored. Flow cytometry was performed to analyse peripheral blood B-cells, PCs and Siglec-1 expression on monocytes as surrogate marker for type-I interferon (IFN) activity.
Upon proteasome inhibition, disease activity significantly declined and remained stable for 6 months on maintenance therapies. Nineteen treatment-emergent adverse events occurred and, although mostly mild to moderate, resulted in treatment discontinuation in seven patients. Serum antibody levels significantly declined, with greater reductions in anti-dsDNA (∼60%) than vaccine-induced protective antibody titres (∼30%). Bortezomib significantly reduced the numbers of peripheral blood and bone marrow PCs (∼50%), but their numbers increased between cycles. Siglec-1 expression on monocytes significantly declined.
These findings identify proteasome inhibitors as a putative therapeutic option for patients with refractory SLE by targeting PCs and type-I IFN activity, but our results must be confirmed in controlled trials.
Treatment of systemic onset juvenile idiopathic arthritis JIA (sJIA), although dramatically improved, remains a challenge. Experience from clinical practice will be presented using data from the ...German Biologics register (BiKeR) for evaluation of efficacy and safety of treatment with etanercept (ETA), tocilizumab (TOC) and the interleukin-1 inhibitors anakinra and canakinumab (IL-1i) in sJIA.
Patients with sJIA documented in the BIKeR register, who were exposed to ETA, TOC or IL-1i were identified. Baseline demographics, clinical characteristics and disease activity parameters have been documented. Efficacy was determined using the JIA-American College of Rheumatology (ACR) response criteria and the Juvenile Disease Activity Score 10 (JADAS10). An intention-to-treat analysis was performed and patients who discontinued due to inefficacy or intolerance were analysed as non-responders. Safety assessments were based on adverse events (AEs) reports.
Since 2000, 245 sJIA patients (50.3% male) exposed to biologic agents have been identified: 143 patients treated with ETA, 71 with TOC and 60 with IL-1i (anakinra 38, canakinumab 22). All patients received systemic steroids for pre-treatment but less frequently with TOC and IL-1i than with ETA for concomitant treatment. At baseline, the ETA cohort had fewer systemic disease manifestations but more active joints. The JIA-ACR 30/50/70/90 response over a period of 24 months was reached more often in the IL-1i and TOC cohort than with ETA. ETA/TOC/IL1i JADAS-remission (JADAS ≤1) was reached in 20%/37%/52%, minimal disease activity (JADAS ≤3.8 in 35%/61%/68% and ACR inactive disease in 24%/33%/56%). As compared to ETA, rates of AEs were significantly higher in the TOC cohort (risk ratio (RR) 5.3/patient-year; p < 0.0001) and serious AE were observed more frequently with TOC (RR 2.5; p < 0.5) and IL1i (2.9; p < 0.01).
A large proportion of patients gained significant response to treatment especially with TOC or IL-1is. After 6 months on treatment, JADAS remission was reached by up to half of patients while up to two thirds reached JADAS minimal disease activity. ETA has been used in the past but it is clearly less effective and its use in systemic JIA has markedly decreased in Germany.
Antibody‐secreting cells (ASCs), including short‐lived plasmablasts and long‐lived memory plasma cells (LLPCs), contribute to autoimmune pathology. ASCs, particularly LLPCs, refractory to ...conventional immunosuppressive drugs pose a major therapeutic challenge. Since stromal cells expressing C‐X‐C motif chemokine‐12 (CXCL12) organize survival niches for LLPCs in the bone marrow, we investigated the effects of CXCL12 and its ligand CXCR4 (C‐X‐C chemokine receptor 4) on ASCs in lupus mice (NZB/W). Fewer adoptively transferred splenic ASCs were retrieved from the bone marrow of recipient immunodeficient Rag1−/− mice when the ASCs were pretreated with the CXCR4 blocker AMD3100. CXCR4 blockade also significantly reduced anti‐OVA ASCs in the bone marrow after secondary immunization with OVA. In this study, AMD3100 efficiently depleted ASCs, including LLPCs. After two weeks, it decreased the total number of ASCs in the spleen and bone marrow by more than 60%. Combination with the proteasome inhibitor bortezomib significantly enhanced the depletion effect of AMD3100. Continuous long‐term (five‐month) CXCR4 blockade with AMD3100 after effective short‐term LLPCs depletion kept the number of LLPCs in the bone marrow low, delayed proteinuria development and prolonged the survival of the mice. These findings identify the CXCR4‐CXCL12 axis as a potential therapeutic target likely due to its importance for ASC homing and survival.
The highly specific CXCR4 antagonist AMD3100 blocks the interaction of CXCR4 expressed on antibody‐secreting cells (ASCs) with CXCL12 resulting in their reduced homing and survival in bone marrow as well as enhanced depletion in combination with bortezomib in NZB/W F1 mice. AMD3100 long‐term treatment delays proteinuria and prolongs survival.
The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic ...pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline.
Six hundred twenty-three IPF patients with available QoL data (St George's Respiratory Questionnaire SGRQ, UCSD Shortness-of-Breath Questionnaire SoB, EuroQol visual analogue scale and index EQ-5D, Well-being Index WHO-5) were analysed. Mean age was 69.6 ± 8.7 years, 77% were males, mean disease duration 2.0 ± 3.3 years, FVC pred was 67.5 ± 17.8%, DL
pred 35.6 ± 17%.
Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms (NYHA; p < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity (as measured by GAP score, CPI, FVC and 6-min walk test; p < 0.05 each). Multivariate analyses showed a significant association between QoL (by SGRQ total) and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment.
Overall, IPF patients under real-life conditions have lower QoL compared to those in clinical studies. There is a meaningful relationship between QoL and various patient characteristics.
The INSIGHTS-IPF registry is registered at Clinicaltrials.gov ( NCT01695408 ).
The aim of this study was to develop a patient-reported questionnaire that is suitable to detect periodontitis (PD) in patients with rheumatoid arthritis (RA).
A self-reported questionnaire ...containing 12 items potentially relevant to PD and dentists' semiquantitative assessment of PD (no/mild/moderate/severe) was obtained from 353 patients from an early arthritis cohort. Available radiographs (n = 253) and blinded assessment of 3 independent dentists were used for validation. By defining the dentists' assessment as the reference standard, relevant questionnaire items were identified with factor analysis methods. Receiver operator characteristic (ROC) plots were used to determine sensitivities and specificities to detect PD in varying severity. Ordinal regression models were used to determine the coefficients for the final score.
Seventy percent had at least mild PD. The items from the questionnaire correlating best with the dentists' assessment were selected for a final 6-item score (number of teeth, gum pockets, receding gums, loose teeth, receding jaw bone and tooth extractions and age). For the detection of any/moderate/severe PD, the bias-corrected areas under the curve (AUC) were 0.81/0.83/0.90. Sensitivity to detect mild PD was 85% and specificity 57%. Very high specificity was achieved for the detection of severe PD with 99% at the cost of low sensitivity (28%).
This patient-reported six-item score has moderate diagnostic properties to study PD in RA patients in epidemiological settings. We propose to use the score as a measure of periodontitis without applying cut-off values.
To assess the first-year features of patients with chronic nonbacterial osteomyelitis (CNO).
Patients with a diagnosis of CNO, disease duration of under 13 months, and first registration in the ...German National Pediatric Rheumatologic Database (NPRD) between 2009 and 2018 were included in this cross-sectional analysis.
Of 774 documented patients, 62.8% were female, and all patients had a median age of 11 years. The most affected clinical sites were the tibia (29.7%), pelvis (28.0%), and femur (27.8%). HLA-B27 was positive in 48 of 314 analyzed patients (15.3%). In 406 patients, an X-ray was performed at the first visit; X-ray results showed osteosclerosis/-lysis in 34.0% and hyperostosis in 14.5% of the patients. MRI scans (focal and whole-body scans) were performed in 648 patients, and 81.5% showed a positive TIRM/STIR signal. A total of 84.7% of the patients were administered nonsteroidal anti-inflammatory drugs, 9.6% were administered oral glucocorticoids, 10.8% were administered disease-modifying anti-rheumatic drugs (DMARDs), and 6.1% were administered bisphosphonates. An evaluation of the patient's questionnaire showed an overall well-being (NRS 0-10) of 2.0. The PedCNO disease "activity" score revealed a 70% improvement in variables in 43% of patients in the initial 1-year follow-up. Copresentation with diagnostic criteria of pediatric enthesitis-related arthritis was rare.
To our knowledge, the NPRD cohort seemed to be the largest cohort of children and adolescents suffering from CNO worldwide. Most patients were treated effectively with NSAIDs, and only a small group of patients was administered additional medication. The patient-defined measures of disease activity had a moderate impact on patients' daily lives.
Not applicable.
EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study in patients with pulmonary hypertension treated with riociguat. Patients were followed for 1–4 ...years, and the primary outcomes were adverse events (AEs) and serious AEs (SAEs), including embolic/thrombotic and hemorrhagic events. Here we report data on patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving a vitamin K antagonist (VKA; n = 683) or a non-vitamin K antagonist oral anticoagulant (NOAC; n = 198) at baseline. AEs and SAEs were reported in 438 patients (64.1%) and 257 patients (37.6%), respectively, in the VKA group, and in 135 patients (68.2%) and 74 patients (37.4%) in the NOAC group. Exposure-adjusted hemorrhagic event rates were similar in the two groups, while exposure-adjusted embolic and/or thrombotic event rates were higher in the NOAC group, although the numbers of events were small. Further studies are required to determine the long-term effects of anticoagulation strategies in CTEPH.
Context: To date, it is unclear which measure of obesity is the most appropriate for risk stratification.
Objective: The aim of the study was to compare the associations of various measures of ...obesity with incident cardiovascular events and mortality.
Design and Setting: We analyzed two German cohort studies, the DETECT study and SHIP, including primary care and general population.
Participants: A total of 6355 (mean follow-up, 3.3 yr) and 4297 (mean follow-up, 8.5 yr) individuals participated in DETECT and SHIP, respectively.
Interventions: We measured body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and waist-to-hip ratio (WHR) and assessed cardiovascular and all-cause mortality and the composite endpoint of incident stroke, myocardial infarction, or cardiovascular death.
Results: In both studies, we found a positive association of the composite endpoint with WHtR but not with BMI. There was no heterogeneity among studies. The relative risks in the highest versus the lowest sex- and age-specific quartile of WHtR, WC, WHR, and BMI after adjustment for multiple confounders were as follows in the pooled data: cardiovascular mortality, 2.75 (95% confidence interval, 1.31–5.77), 1.74 (0.84–3.6), 1.71 (0.91–3.22), and 0.74 (0.35–1.57), respectively; all-cause mortality, 1.86 (1.25–2.76), 1.62 (1.22–2.38), 1.36 (0.93–1.69), and 0.77 (0.53–1.13), respectively; and composite endpoint, 2.16 (1.39–3.35), 1.59 (1.04–2.44), 1.49 (1.07–2.07), and 0.57 (0.37–0.89), respectively. Separate analyses of sex and age groups yielded comparable results. Receiver operating characteristics analysis yielded the highest areas under the curve for WHtR for predicting these endpoints.
Conclusions: WHtR represents the best predictor of cardiovascular risk and mortality, followed by WC and WHR. Our results discourage the use of the BMI.
Measures of abdominal obesity but not body mass index predict cardiovascular risk and mortality.
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.
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