The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients.

OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.

The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 266 AAV patients.

OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.

Breastfeeding Rates During the COVID-19 Pandemic in Germany: Data from the CRONOS Registry.

SARS-CoV-2 infection and COVID-19 disease are thought to have an impact on breastfeeding rate - besides other known peripartal issues. Data of the national CRONOS registry regarding breastfeeding behavior in 6,746 women was analyzed regarding the time window between maternal SARS-CoV-2 infection and time of delivery. In addition, other influencing factors like the predominant viral variant, maternal disease severity, and gestational age at delivery were taken into account. Our data suggest that within the variables analyzed, in the case of acute maternal infection (<14 days before birth), breastfeeding behavior improved with increasing gestational age at birth (p<0.0001), with less severe maternal illness (p<0.0001) and as the pandemic progressed with less virulent viral variants (p=0.01). When adjusting for COVID-19-associated and non-associated factors, rooming-in remains the most important factor positively influencing breastfeeding behavior. With regards to the benefits for mother and infants from breastfeeding, a separation of mother and child even in case of infectious settings should be avoided.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.

The long term vaccine-induced anti-SARS-CoV-2 immune response is impaired in quantity and quality under TNFα blockade.

The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor-α (TNF-α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti-TNF-α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease-modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS-CoV-2-specific B- and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti-SARS-CoV-2 IgG levels, IgG avidity and anti-pre-VOC NA titres were significantly reduced in anti-TNF-α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti-TNF-α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS-CoV-2-specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti-BA.2 NA titres compared to both other groups. We show a reduced SARS-CoV-2 neutralizing capacity in patients under TNF-α blockade. In this cohort, the plasma cell response appears to be less specific and shows stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced.

Updated recommendations of the German Society for Rheumatology for the care of patients with inflammatory rheumatic diseases in times of SARS-CoV-2-methodology, key messages and justifying information.

A few days after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled the first group of recommendations for the care of patients with inflammatory rheumatic diseases in light of SARS-CoV-2/coronavirus disease 2019 (COVID-19). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registries, cross-sectional studies, case reports and case series are available, the DGRh has developed a timely update. This update is based on a literature search of publications available through 15 June 2020 and addresses preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. Driven by the commitment to let patients benefit from these new evidence-based recommendations as quickly as possible, the DGRh published the update in German on its homepage and in the Zeitschrift für Rheumatologie immediately after completion. Here we report the key recommendations to make them available to the international community, provide the scientific methodology used to develop the recommendations, give additional thoughts and advice for the management of patients with rheumatic diseases during the COVID-19 pandemic and discuss our recommendations in the context of other international recommendations.

Secondary research use of personal medical data: patient attitudes towards data donation.

BACKGROUND: The SARS-CoV-2 pandemic has highlighted once more the great need for comprehensive access to, and uncomplicated use of, pre-existing patient data for medical research. Enabling secondary research-use of patient-data is a prerequisite for the efficient and sustainable promotion of translation and personalisation in medicine, and for the advancement of public-health. However, balancing the legitimate interests of scientists in broad and unrestricted data-access and the demand for individual autonomy, privacy and social justice is a great challenge for patient-based medical research. METHODS: We therefore conducted two questionnaire-based surveys among North-German outpatients (n = 650) to determine their attitude towards data-donation for medical research, implemented as an opt-out-process. RESULTS: We observed a high level of acceptance (75.0%), the most powerful predictor of a positive attitude towards data-donation was the conviction that every citizen has a duty to contribute to the improvement of medical research (> 80% of participants approving data-donation). Interestingly, patients distinguished sharply between research inside and outside the EU, despite a general awareness that universities and public research institutions cooperate with commercial companies, willingness to allow use of donated data by the latter was very low (7.1% to 29.1%, depending upon location of company). The most popular measures among interviewees to counteract reservations against commercial data-use were regulation by law (61.4%), stipulating in the process that data are not sold or resold (84.6%). A majority requested control of both the use (46.8%) and the protection (41.5%) of the data by independent bodies. CONCLUSIONS: In conclusion, data-donation for medical research, implemented as a combination of legal entitlement and easy-to-exercise-right to opt-out, was found to be widely supported by German patients and therefore warrants further consideration for a transposition into national law.

[German registry www.Covid19-Rheuma.de : Status report after 1 year of the pandemic]. / Deutsches Register www.Covid19-Rheuma.de : Statusbericht nach 1 Jahr der Pandemie.

The COVID-19 registry ( www.covid19-rheuma.de ) of the German Society of Rheumatology was the first registry for the acquisition and systemic evaluation of viral infections in patients with inflammatory rheumatic diseases (IRD). This has enabled rapid generation of scientific data that will help to improve the care of patients with IRD in the context of the pandemic. In addition to confirming general risk factors, such as patient age and comorbidities (e.g. cardiovascular, chronic lung and kidney diseases), the use of glucocorticoids and the disease activity of the rheumatic disease could be identified as disease-specific independent risk factors for the need of hospitalization due to COVID-19. Evaluations of the continuously growing cohort of patients with IRD and COVID-19 enable recommendations for patient care to be based on better evidence. Cooperation with international rheumatology registries (e.g. European COVID-19 registry for IRD) enables analyses of aggregated cohorts of patients with IRD and COVID-19 for international comparisons and statistically even more reliable statements.

[Recommendations of the German Society for Rheumatology for management of patients with inflammatory rheumatic diseases in the context of the SARS-CoV-2/COVID-19 pandemic - Update July 2020]. / Handlungsempfehlungen der Deutschen Gesellschaft für Rheumatologie e. V. für die Betreuung von Patienten mit entzündlich rheumatischen Erkrankungen im Rahmen der SARS-CoV-2/COVID-19-Pandemie ­ Update Juli 2020.

A few days after the SARS-CoV-2 infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled first recommendations for the care of patients with inflammatory rheumatic diseases (IRD). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registers, cross-sectional studies, case reports and case series are available, the present update is intended to update the previous recommendations and to add new findings. The current recommendations are based on a literature search of publications available up to 15 June 2020 and address preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. An important goal of the current recommendations is also to prevent harm to patients with IRD through unjustified restriction of care. The DGRh will continue to update its recommendations in the case of new aspects and will publish them as well as further information on the COVID-19 pandemic on its homepage ( www.dgrh.de ) in an ongoing process.

US Time-Harmonic Elastography for the Early Detection of Glomerulonephritis.

Background Glomerulonephritis refers to renal diseases characterized by glomerular and tubulointerstitial fibrosis. Multifrequency US time-harmonic elastography enables the noninvasive quantification of tissue elasticity. Purpose To assess the diagnostic performance of US time-harmonic elastography for the early detection of glomerulonephritis. Materials and Methods From August 2016 through May 2017, study participants with biopsy-proven glomerulonephritis were prospectively examined with US time-harmonic elastography. Participants were subdivided according to chronic kidney disease (CKD) stage. All participants underwent elastography of both kidneys to generate full-field-of-view maps of renal shear wave speed (SWS). SWS was determined separately for the whole renal parenchyma, cortex, and medulla and was correlated with quantitative B-mode findings such as renal length and parenchymal thickness. Diagnostic performance of renal elastography was assessed with receiver operating characteristic curve analysis. Results Fifty-three participants with glomerulonephritis (mean age ± standard deviation, 49 years ± 14) and 30 healthy volunteers (mean age, 37 years ± 11) were evaluated. Age-adjusted renal SWS was lower in participants with glomerulonephritis than in healthy volunteers in the parenchyma, cortex, and medulla, with mean values of 1.55 m/sec (95% confidence interval [CI]: 1.51 m/sec, 1.59 m/sec) and 1.69 m/sec (95% CI: 1.64 m/sec, 1.74 m/sec; P < .001), respectively, in parenchyma, 1.80 m/sec (95% CI: 1.75 m/sec, 1.84 m/sec) and 2.08 m/sec (95% CI: 2.02 m/sec, 2.13 m/sec; P < .001) in cortex, and 1.25 m/sec (95% CI: 1.21 m/sec, 1.29 m/sec) and 1.33 (95% CI: 1.27 m/sec, 1.38 m/sec; P = .03) in medulla. Age-adjusted renal cortex SWS was lower in participants with glomerulonephritis and stage 1 CKD (preserved renal function) than in healthy volunteers (mean, 1.88 [95% CI: 1.81, 1.96] vs 2.08 [95% CI: 2.02, 2.13]; P < .001). In participants with CKD, renal cortex SWS values showed a positive association with estimated glomerular filtration rate (n = 39; r = 0.56; P < .001). Exploratory diagnostic performance of US time-harmonic elastography (area under the receiver operating characteristic curve [AUC], 0.89; 95% CI: 0.82, 0.97) outperformed that of B-mode parameters such as parenchymal thickness (AUC, 0.64; 95% CI: 0.51, 0.77; P < .001) and renal length (AUC, 0.55; 95% CI: 0.40, 0.68; P < .001) in identifying glomerulonephritis. Conclusion US time-harmonic elastography depicts abnormal renal stiffness in glomerulonephritis, particularly among patients with early disease and preserved renal function. Advanced chronic kidney disease is associated with further cortical softening. Time-harmonic elastography outperforms B-mode-based size quantification. © RSNA, 2019 Online supplemental material is available for this article.

Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo.

In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.

'Status Quo' on Different Aspects of Gender Distribution in Rheumatology in Germany-Results from a Nationwide Online Survey among Physicians.

OBJECTIVES: Despite the increasing number of female medical students and fellows in Europe, women are still under-represented in higher academic careers and positions in medicine. The aim of this survey was to assess the 'status quo' on gender distribution among rheumatologists in Germany. METHODS: A web-based anonymous survey (21 questions with multiple answers and free text) using QuestionPro® was distributed among rheumatologists in Germany via newsletters, social media and personal contact, including questions regarding hierarchical positions and work characteristics. RESULTS: Among the total of 170 respondents (72% women, 28% men, 1% diverse), 48% were rheumatologists in training, 35% were trained rheumatologists and 7% were heads of rheumatology departments. Regarding the gender ratio at different hierarchical levels, 74% of respondents reported more men than women in leadership positions. Part-time work was possible in the departments of 86% of respondents, with more women working part-time (56%) compared to men (29%). Most respondents stated their impression that employees working part-time did not have the same career chances as full-time workers in their departments. In total, 66% agreed that activities to improve gender equity are necessary. The highest need was seen in reconciling work and family through, e.g., part-time models, flexible childcare options at work and a higher acceptance of part-time work in leadership positions. CONCLUSIONS: According to our results, a gender imbalance is prevalent among rheumatologists in Germany, with lower numbers of women evident at higher hierarchical levels. Traditional role assignments are still represented by a higher proportion of part-time work in women. The establishment of structural changes to achieve better gender equity is needed.

Characteristics and outcomes of SARS-CoV-2 breakthrough infections among double-vaccinated and triple-vaccinated patients with inflammatory rheumatic diseases.

OBJECTIVE: To analyse the clinical profile of SARS-CoV-2 breakthrough infections in at least double-vaccinated patients with inflammatory rheumatic diseases (IRDs). METHODS: Data from the physician-reported German COVID-19-IRD registry collected between February 2021 and July 2022 were analysed. SARS-CoV-2 cases were stratified according to patients' vaccination status as being not vaccinated, double-vaccinated or triple-vaccinated prior to SARS-CoV-2 infection and descriptively compared. Independent associations between demographic and disease features and outcome of breakthrough infections were estimated by multivariable logistic regression. RESULTS: In total, 2314 cases were included in the analysis (unvaccinated n=923, double-vaccinated n=551, triple-vaccinated n=803, quadruple-vaccinated n=37). SARS-CoV-2 infections occurred after a median of 151 (range 14-347) days in patients being double-vaccinated, and after 88 (range 14-270) days in those with a third vaccination. Hospitalisation was required in 15% of unvaccinated, 8% of double-vaccinated and 3% of triple-vaccinated/quadruple-vaccinated patients (p<0.001). Mortality was 2% in unvaccinated, 1.8% in the double-vaccinated and 0.6% in triple-vaccinated patients. Compared with unvaccinated patients, double-vaccinated (OR 0.43, 95% CI 0.29 to 0.62) and triple-vaccinated (OR 0.13, 95% CI 0.08 to 0.21) patients showed a significant lower risk of COVID-19-related hospitalisation. Using multivariable analysis, the third vaccination was significantly associated with a lower risk for COVID-19-related death (OR 0.26; 95% CI 0.01 to 0.73). CONCLUSIONS: Our cross-sectional data of COVID-19 infections in patients with IRD showed a significant reduction of hospitalisation due to infection in double-vaccinated or triple-vaccinated patients compared with those without vaccination and even a significant reduction of COVID-19-related deaths in triple-vaccinated patients. These data strongly support the beneficial effect of COVID-19 vaccination in patients with IRD. TRIAL REGISTRATION NUMBER: EuDRACT 2020-001958-21.

Association Between Tumor Necrosis Factor Inhibitors and the Risk of Hospitalization or Death Among Patients With Immune-Mediated Inflammatory Disease and COVID-19.

Importance: Although tumor necrosis factor (TNF) inhibitors are widely prescribed globally because of their ability to ameliorate shared immune pathways across immune-mediated inflammatory diseases (IMIDs), the impact of COVID-19 among individuals with IMIDs who are receiving TNF inhibitors remains insufficiently understood. Objective: To examine the association between the receipt of TNF inhibitor monotherapy and the risk of COVID-19-associated hospitalization or death compared with other commonly prescribed immunomodulatory treatment regimens among adult patients with IMIDs. Design, Setting, and Participants: This cohort study was a pooled analysis of data from 3 international COVID-19 registries comprising individuals with rheumatic diseases, inflammatory bowel disease, and psoriasis from March 12, 2020, to February 1, 2021. Clinicians directly reported COVID-19 outcomes as well as demographic and clinical characteristics of individuals with IMIDs and confirmed or suspected COVID-19 using online data entry portals. Adults (age ≥18 years) with a diagnosis of inflammatory arthritis, inflammatory bowel disease, or psoriasis were included. Exposures: Treatment exposure categories included TNF inhibitor monotherapy (reference treatment), TNF inhibitors in combination with methotrexate therapy, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, and Janus kinase (Jak) inhibitor monotherapy. Main Outcomes and Measures: The main outcome was COVID-19-associated hospitalization or death. Registry-level analyses and a pooled analysis of data across the 3 registries were conducted using multilevel multivariable logistic regression models, adjusting for demographic and clinical characteristics and accounting for country, calendar month, and registry-level correlations. Results: A total of 6077 patients from 74 countries were included in the analyses; of those, 3215 individuals (52.9%) were from Europe, 3563 individuals (58.6%) were female, and the mean (SD) age was 48.8 (16.5) years. The most common IMID diagnoses were rheumatoid arthritis (2146 patients [35.3%]) and Crohn disease (1537 patients [25.3%]). A total of 1297 patients (21.3%) were hospitalized, and 189 patients (3.1%) died. In the pooled analysis, compared with patients who received TNF inhibitor monotherapy, higher odds of hospitalization or death were observed among those who received a TNF inhibitor in combination with azathioprine/6-mercaptopurine therapy (odds ratio [OR], 1.74; 95% CI, 1.17-2.58; P = .006), azathioprine/6-mercaptopurine monotherapy (OR, 1.84; 95% CI, 1.30-2.61; P = .001), methotrexate monotherapy (OR, 2.00; 95% CI, 1.57-2.56; P < .001), and Jak inhibitor monotherapy (OR, 1.82; 95% CI, 1.21-2.73; P = .004) but not among those who received a TNF inhibitor in combination with methotrexate therapy (OR, 1.18; 95% CI, 0.85-1.63; P = .33). Similar findings were obtained in analyses that accounted for potential reporting bias and sensitivity analyses that excluded patients with a COVID-19 diagnosis based on symptoms alone. Conclusions and Relevance: In this cohort study, TNF inhibitor monotherapy was associated with a lower risk of adverse COVID-19 outcomes compared with other commonly prescribed immunomodulatory treatment regimens among individuals with IMIDs.

Blood dendritic cells in systemic lupus erythematosus exhibit altered activation state and chemokine receptor function.

BACKGROUND: Dendritic cells (DCs) have a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). Reduced numbers of blood DCs and the accumulation of DCs at inflammatory sites have been observed in SLE. One crucial feature of DCs is their ability to migrate. OBJECTIVE: To analyse the maturation/activation state and the migratory capacity of different DC precursor subsets in SLE to further elucidate their role in autoimmunity. METHODS: Plasmacytoid DCs (pDCs), myeloid DCs (mDCs) and monocytes from patients with SLE, healthy volunteers and healthy volunteers immunised with tetanus/diphtheria were examined by flow cytometry for expression of subset-specific antigens (BDCA-2, CD11c, CD14, HLA-DR), activation/maturation markers (CD83, CD86, CD40, BLyS) and chemokine receptors (CCR1, CCR5, CCR7, ChemR23). Additionally, migratory capacity to chemokine receptors was investigated in vitro using the chemokines RANTES, CCL19 and chemerin. RESULTS: SLE monocytes and mDCs had higher CD86 and B-lymphocyte stimulatory factor (BLyS) expression levels. ChemR23 expression was lower in SLE pDCs and mDCs. Basal and CCL19-specific migration levels were higher in SLE pDCs. Altered DC function in SLE had no correlative changes in chemokine receptor expression, whereas immunisation-induced blood DC migration patterns in healthy donors were accompanied by changes in chemokine receptor expression. CONCLUSIONS: The phenotypic and migratory disturbances observed in SLE blood DCs could result in altered distribution of DCs in peripheral tissues, contributing to dysregulated immune responses and autoimmunity.

Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-κB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells.

The persistence of long-lived memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, which are provided in niches organized by stromal cells. Using an ex vivo system in which we supply the known survival signals, direct cell contact to stromal cells, and the soluble cytokine a proliferation-inducing ligand (APRIL), we have elucidated the critical signaling pathways required for the survival of long-lived plasma cells. Integrin-mediated contact of bone marrow plasma cells with stromal cells activates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, leading to critical inactivation of Forkhead-Box-Protein O1/3 (FoxO1/3) and preventing the activation of mitochondrial stress-associated effector caspases 3 and 7. Accordingly, inhibition of PI3K signaling in vivo ablates bone marrow plasma cells. APRIL signaling, by the nuclear factor κB (NF-κB) pathway, blocks activation of the endoplasmic-reticulum-stress-associated initiator caspase 12. Thus, stromal-cell-contact-induced PI3K and APRIL-induced NF-κB signaling provide the necessary and complementary signals to maintain bone marrow memory plasma cells.