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Improved understanding of the immunopathogenesis of systemic lupus erythematosus (SLE) has paved the way for new selective treatment strategies for these inflammatory systemic diseases, similarly to diseases such as rheumatoid arthritis and the spondylarthritides. New specific biologics were developed or are being developed and open up new treatment options for patients. Belimumab is particularly important in this respect. The monoclonal antibody that blocks the cytokine BAFF/BLyS is the first medicament approved for the treatment of serologically active SLE in the last decade and also the first biologic approved for this disease. A number of other biologics for the treatment of SLE are in clinical development. This article addresses the promising new drugs currently under development for the treatment of SLE.

Summary Background Patients with primary systemic vasculitis or polymyalgia rheumatica might be at a high risk for poor COVID-19 outcomes due to the treatments used, the potential organ damage cause by primary systemic vasculitis, and the demographic factors associated with these conditions. We therefore aimed to investigate factors associated with COVID-19 outcomes in patients with primary systemic vasculitis or polymyalgia rheumatica. Methods In this retrospective cohort study, adult patients (aged ≥18 years) diagnosed with COVID-19 between March 12, 2020, and April 12, 2021, who had a history of primary systemic vasculitis (antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis, giant cell arteritis, Behcet's syndrome, or other vasculitis) or polymyalgia rheumatica, and were reported to the COVID-19 Global Rheumatology Alliance registry were included. To assess COVID-19 outcomes in patients, we used an ordinal COVID-19 severity scale, defined as: (1) no hospitalisation; (2) hospitalisation without supplemental oxygen; (3) hospitalisation with any supplemental oxygen or ventilation; or (4) death. Multivariable ordinal logistic regression analyses were used to estimate odds ratios (ORs), adjusting for age, sex, time period, number of comorbidities, smoking status, obesity, glucocorticoid use, disease activity, region, and medication category. Analyses were also stratified by type of rheumatic disease. Findings Of 1202 eligible patients identified in the registry, 733 (61·0%) were women and 469 (39·0%) were men, and their mean age was 63·8 years (SD 17·1). A total of 374 (31·1%) patients had polymyalgia rheumatica, 353 (29·4%) had ANCA-associated vasculitis, 183 (15·2%) had giant cell arteritis, 112 (9·3%) had Behcet's syndrome, and 180 (15·0%) had other vasculitis. Of 1020 (84·9%) patients with outcome data, 512 (50·2%) were not hospitalised, 114 (11·2%) were hospitalised and did not receive supplemental oxygen, 239 (23·4%) were hospitalised and received ventilation or supplemental oxygen, and 155 (15·2%) died. A higher odds of poor COVID-19 outcomes were observed in patients who were older (per each additional decade of life OR 1·44 [95% CI 1·31–1·57]), were male compared with female (1·38 [1·05–1·80]), had more comorbidities (per each additional comorbidity 1·39 [1·23–1·58]), were taking 10 mg/day or more of prednisolone compared with none (2·14 [1·50–3·04]), or had moderate, or high or severe disease activity compared with those who had disease remission or low disease activity (2·12 [1·49–3·02]). Risk factors varied among different disease subtypes. Interpretation Among patients with primary systemic vasculitis and polymyalgia rheumatica, severe COVID-19 outcomes were associated with variable and largely unmodifiable risk factors, such as age, sex, and number of comorbidities, as well as treatments, including high-dose glucocorticoids. Our results could be used to inform mitigation strategies for patients with these diseases. Funding American College of Rheumatology and the European Alliance of Associations for Rheumatology.

IntroductionSeveral risk factors for severe COVID-19 specific for patients with inflammatory rheumatic and musculoskeletal diseases (RMDs) have been identified so far. Evidence regarding the influence of different RMD treatments on outcomes of SARS-CoV-2 infection is still poor.MethodsData from the German COVID-19-RMD registry collected between 30 March 2020 and 9 April 2021 were analysed. Ordinal outcome of COVID-19 severity was defined: (1) not hospitalised, (2) hospitalised/not invasively ventilated and (3) invasively ventilated/deceased. Independent associations between demographic and disease features and outcome of COVID-19 were estimated by multivariable ordinal logistic regression using proportional odds model.Results2274 patients were included. 83 (3.6%) patients died. Age, male sex, cardiovascular disease, hypertension, chronic lung diseases and chronic kidney disease were independently associated with worse outcome of SARS-CoV-2 infection. Compared with rheumatoid arthritis, patients with psoriatic arthritis showed a better outcome. Disease activity and glucocorticoids were associated with worse outcome. Compared with methotrexate (MTX), TNF inhibitors (TNFi) showed a significant association with better outcome of SARS-CoV-2 infection (OR 0.6, 95% CI0.4 to 0.9). Immunosuppressants (mycophenolate mofetil, azathioprine, cyclophosphamide and ciclosporin) (OR 2.2, 95% CI 1.3 to 3.9), Janus kinase inhibitor (JAKi) (OR 1.8, 95% CI 1.1 to 2.7) and rituximab (OR 5.4, 95% CI 3.3 to 8.8) were independently associated with worse outcome.ConclusionGeneral risk factors for severity of COVID-19 play a similar role in patients with RMDs as in the normal population. Influence of disease activity on COVID-19 outcome is of great importance as patients with high disease activity—even without glucocorticoids—have a worse outcome. Patients on TNFi show a better outcome of SARS-CoV-2 infection than patients on MTX. Immunosuppressants, rituximab and JAKi are associated with more severe course.

BackgroundWe describe the early experiences of adults with systemic rheumatic disease who received the COVID-19 vaccine.MethodsFrom 2 April to 30 April 2021, we conducted an online, international survey of adults with systemic rheumatic disease who received COVID-19 vaccination. We collected patient-reported data on clinician communication, beliefs and intent about discontinuing disease-modifying antirheumatic drugs (DMARDs) around the time of vaccination, and patient-reported adverse events after vaccination.ResultsWe analysed 2860 adults with systemic rheumatic diseases who received COVID-19 vaccination (mean age 55.3 years, 86.7% female, 86.3% white). Types of COVID-19 vaccines were Pfizer-BioNTech (53.2%), Oxford/AstraZeneca (22.6%), Moderna (21.3%), Janssen/Johnson & Johnson (1.7%) and others (1.2%). The most common rheumatic disease was rheumatoid arthritis (42.3%), and 81.2% of respondents were on a DMARD. The majority (81.9%) reported communicating with clinicians about vaccination. Most (66.9%) were willing to temporarily discontinue DMARDs to improve vaccine efficacy, although many (44.3%) were concerned about rheumatic disease flares. After vaccination, the most reported patient-reported adverse events were fatigue/somnolence (33.4%), headache (27.7%), muscle/joint pains (22.8%) and fever/chills (19.9%). Rheumatic disease flares that required medication changes occurred in 4.6%.ConclusionAmong adults with systemic rheumatic disease who received COVID-19 vaccination, patient-reported adverse events were typical of those reported in the general population. Most patients were willing to temporarily discontinue DMARDs to improve vaccine efficacy. The relatively low frequency of rheumatic disease flare requiring medications was reassuring.

Background: The impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide. Methods: Survey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis. Findings: 12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjogren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514). Interpretation: People with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity. Funding: American College of Rheumatology.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ., Objectives: To determine factors associated with COVID-19-related death in people with rheumatic diseases. Methods: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. Results: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. Conclusion: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants.

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.

OBJECTIVE Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. METHODS Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of

Objectives To evaluate the influence of the SARS-CoV-2 pandemic on the adherence of patients with inflammatory rheumatic diseases (IRD) to their immunomodulatory medication during the three-month lockdown in Germany. Methods From 16th March until 15th June 2020, IRD patients from private practices and rheumatology departments were asked to answer a questionnaire addressing their behaviour with respect to their immunomodulating therapy. Eight private practices and nine rheumatology departments that included rheumatology primary care centres and university hospitals participated. A total of 4252 questionnaires were collected and evaluated. Results The majority of patients (54%) were diagnosed with RA, followed by psoriatic arthritis (14%), ankylosing spondylitis (10%), connective tissue diseases (12%) and vasculitides (6%). Most of the patients (84%) reported to continue their immunomodulatory therapy. Termination of therapy was reported by only 3% of the patients. The results were independent from the type of IRD, the respective immunomodulatory therapy and by whom the patients were treated (private practices vs rheumatology departments). Younger patients ( Conclusion The data show that most of the patients continued their therapy in spite of the pandemic. A significant change in behaviour with regard to their immunomodulatory therapy was not observed during the three months of observation. The results support the idea that the immediate release of recommendations of the German Society of Rheumatology were well received, supporting the well-established physician–patient relationship in times of a crisis.

Background/objectives The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria. Methods We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE. Results Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia Conclusions Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.

IntroductionWhether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated. Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation.MethodsPatients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated. Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19.ResultsData from 468 patients with RMD with SARS-CoV-2 infection were reported. Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died. Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation. Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91).ConclusionAge was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs. Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic.

Background Vasculitides comprise a group of rare diseases which affect less than 5 in 10.000 individuals. Most types of vasculitis can become organ- and life-threatening and are characterized by chronicity, high morbidity and relapses, altogether resulting in significant morbidity and mortality. Previous studies have been either monocentric or mainly retrospective – studies with a prospective design mostly consisted of rather small cohorts of 100 to 200 patients. The aim of the Joint Vasculitis Registry in German-speaking countries (GeVas) is to record all patients who have been recently diagnosed with vasculitis or who have changed their treatment due to a relapse (inception cohort). In GeVas, data are collected prospectively in a multicenter design in Germany, Austria and Switzerland. By this approach, courses of vasculitis and their outcomes can be monitored over an extended period. Methods GeVas is a prospective, web-based, multicenter, clinician-driven registry for the documentation of organ manifestations, damage, long-term progress and other outcomes of various types of vasculitis. The registry started recruiting in June 2019. As of October 2020, 14 centers have been initiated and started recruiting patients in Germany. Involvement of sites in Austria and the German-speaking counties of Switzerland is scheduled in the near future. Discussion In June 2019, we successfully established a prospective multicenter vasculitis registry being the first of its kind in German-speaking countries. The participating centers are currently recruiting, and systematic analysis of long-term vasculitis outcomes is expected in the ensuing period. Trial registration German Clinical Trials Register (Deutsches Register Klinischer Studien): DRKS00011866. Registered 10 May 2019.

Background:Patients with rheumatic and musculoskeletal diseases (RMD) might have an increased risk for infection due to their immunomodulatory treatment, secondary to their disease and comorbidities. Recent studies suggest a decreased risk of severe COVID-19 in RMD-patients treated with biologics.Objectives:The aim of this study was to assess courses of RMD patients treated with TNF-inhibitors (TNF-I) included in the German COVID-19 registry.Methods:In the German physician-reported COVID-19-RMD registry, patients with an RMD and confirmed SARS-CoV-2-infection were documented (data entered between March 30, 2020 and January 30, 2021). We analysed TNF-I treated patients, their course and outcome of the infection. Data were compared to RMD-patients treated with other immunomodulatory drugs (OID) than TNF-I.Results:A total of 269 patients were treated with a TNF-I (57% female) compared to 874 patients who were treated with OID (68% female). Median age was 52 years (range: 19-87) in the TNF-I-group versus 58 years (range: 18-91) in the OID-group. Rheumatoid arthritis was the most common diagnosis (38% in TNF-I-group vs. 52% in the OID-group), followed by ankylosing spondylitis (32% vs. 6%), psoriatic arthritis (22% vs. 11%) and other RMD (9% vs. 31%). Adalimumab (35%) and etanercept (35%) were the most frequently used TNF-I (tab. 1). Glucocorticoids (GC) were used in 22% of TNF-I-treated patients and in 42% of the OID-group.Under TNF-I, stable disease was reported prior to the SARS-CoV-2-infection in 53% of the patients (OID-group: 47%), followed by low disease activity in 35% (OID: 34%), moderate disease activity in 6% (OID: 12%) and high disease activity in 4% (OID: 3%). Most frequent comorbidities were arterial hypertension (29% under TNF-I vs. 35% under OID), diabetes (8% vs. 11%) and cardiovascular diseases (7% vs. 12%).The most common reported COVID-19 symptoms were dry cough (57% vs. 55%), fever (53% vs. 61%) and fatigue (50% vs. 49%). Hospitalization due to SARS-CoV infection was required in only 12% of the TNF-I-treated cases vs. in 29% in the OID-group. Oxygen treatment was necessary in 5% of the patients under TNF-I compared to 22% under OID and invasive ventilation in 2% in the TNF-I-group compared to 6% under OID. Most notably, no fatal courses of COVID-19 were reported among the 269 RMD-patients treated with TNF-I versus 49 deaths in the 874 cases (5.6%) treated with OID. Focussing on the hospitalizated TNF-I patients, the rate of concomitant GC use (pConclusion:High or moderate RMD-disease activity is an important factor associated with severity of COVID-19 including mortality. In this large cohort RMD patients treated with TNF-I show a low hospitalisation rate and no fatal course. This is reassuring for patients and treating rheumatologists to use TNF-I to control RMD disease activity. The use of glucocorticoids and high disease activity seem to counteract possible protective effects of TNF-I.Table 1.TNF inhibition (269)Other immunomodulation (874)Total patientsRate (%)Total patientsRate (%)Disease activitystable1415340847low933529934Moderate15610812High104293Comorbiditiescardiovascular diseases18710412arterial hypertension772930335bronchial asthma124657COPD/interstitial lung disease1148610chronic renal failure93779Osteoporosis135678Diabetes2289211COVID-19 related symptomsFever1425347855dry cough1525753061Expectoration3112839muscular pain973628032Fatigue1355042449Headache1013823727shortness of breath491824528no symptoms239566COVID-19 outcomeOutpatients2378861971Inpatients321225529need of oxygen treatment18718922invasive ventilation52496fatal course00496TNF inhibitorsAdalimumab9535Infliximab239Certolizumab3312Golimumab249Etanercept9435GC and disease activity in TNF-I treated patientsTNF-I inpatients treated with GC18/3256p< 0.001TNF-I outpatients treated with GC42/23718TNF-I inpatients with high disease activity4/3213TNF-I outpatients with high disease activity6/2376p= 0.005Acknowledgements:The authors would like to thank all physicians and personnel involved in the documentation of the cases in our registry.Disclosure of Interests:None declared

Funder: American College of Rheumatology Research and Education Foundation; FundRef: http://dx.doi.org/10.13039/100000960, Funder: National Institute of Arthritis and Musculoskeletal and Skin Diseases; FundRef: http://dx.doi.org/10.13039/100000069, Funder: European League Against Rheumatism; FundRef: http://dx.doi.org/10.13039/501100008741, OBJECTIVES: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 Classification Criteria for systemic lupus erythematosus (SLE) have been validated with high sensitivity and specificity. We evaluated the performance of the new criteria with regard to disease duration, sex and race/ethnicity, and compared its performance against the Systemic Lupus International Collaborating Clinics (SLICC) 2012 and ACR 1982/1997 criteria. METHODS: Twenty-one SLE centres from 16 countries submitted SLE cases and mimicking controls to form the validation cohort. The sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated. RESULTS: The cohort consisted of female (n=1098), male (n=172), Asian (n=118), black (n=68), Hispanic (n=124) and white (n=941) patients; with an SLE duration of 1 to

ObjectivesPatients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany.MethodsUsing an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters—for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection—are documented.ResultsUntil 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course.ConclusionsIn a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.

Background:Patients with inflammatory rheumatic diseases (IRD) and infection with SARS-CoV-2 may be at risk to develop a severe course of COVID-19. To gather knowledge about SARS-CoV-2 infections in IRD patients, a national registry was established to elucidate IRD specific profiles of COVID-19.Objectives:To identify risk factors for hospitalisation.Methods:Patients from the German registry on SARS-CoV-2 infection in IRD were analysed. Patients are enrolled with a pre-existing IRD and a positive lab-result for a SARS-CoV-2 infection. The main outcome parameter was hospitalisation versus non-hospitalisation. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Covariates included in the model were age group, gender, key comorbidities (cardiovascular, lung diseases, chronic renal insufficiency), prior and/or current use of glucocorticosteroids (GC) or NSAIDs and remission.Results:Until May 17th, 2020, data from 192 IRD patients with SARS-CoV-2 infection were reported (67 males; 124 females; 1 diverse). 64 patients were hospitalised, 21 patients were ventilated non-invasively/invasively and 15 patients died.Baseline characteristics are shown in table 1, stratified into the patient groups non-hospitalisation, hospitalisation without ventilation, and hospitalisation with ventilation. Non-hospitalised patients were younger, had less comorbidities and were less often treated with GC. In the group of hospitalised patients compared to non-hospitalised patients more patients were male (42% vs 32% male) with an even higher proportion in the ventilated patient group (57% male).In the multivariable logistic regression model, age>65 years (OR 5.1; 95%CI 2.3-11.4), cardiovascular comorbidity (OR 2.3; 95%CI 1.0-5.0), and prior and/or current treatment with GC (OR 2.6; 95%CI 1.2-5.4) were independently associated with hospitalisation.Parameter, N (%)Non-hospitalisation128 (66.7)Hosp. without ventilation42 (22.4)Hosp. with ventilation21 (10.9)Age [years], mean (SD)53.8 (13.4)65.2 (15.5)69.7 (9.9)Female87 (68.5)28 (65.1)9 (42.9)RA60 (46.9)24 (55.8)12 (57.1)Psoriasis23 (18)3 (7)3 (14.3)Axial spondyloarthritis14 (10.9)2 (4.7)0Lupus7 (5.5)1 (2.3)0Remission of IRD67 (52.3)23 (53.5)4 (19)Number of comorbidities, mean (SD)1 (1.2)1.8 (1.4)2.4 (1.5)Cardiovascular disease42 (32.8)25 (58.1)16 (76.2)Pulmonary disease16 (12.5)8 (18.6)8 (38.1)Chronic renal insufficiency5 (3.9)7 (16.3)4 (19)Cancer2 (1.6)4 (9.3)2 (9.5)Obesity (BMI>30)23 (18)5 (11.6)3 (14.3)Diabetes3 (2.3)7 (16.3)4 (19)Other comorbidities20 (15.6)9 (20.9)6 (28.6)csDMARD (without HCQ)59 (46.1)25 (58.1)8 (38.1)HCQ13 (10.2)1 (2.3)2 (9.5)bDMARD48 (37.5)15 (34.9)8 (38.1)tsDMARD5 (3.9)1 (2.3)1 (4.8)Glucocorticosteroids47 (37)29 (67.4)13 (61.9)NSAIDs21 (16.4)5 (11.6)1 (4.8)Conclusion:As has been described for COVID-19 in general, also in IRD male gender may be associated with a more severe course of the infection as the descriptive analysis of data shows. Risk factors for SARS-CoV-2 infection-dependent hospitalisation in IRD patients include age (>65 years), cardiovascular comorbidities, and prior and/or current treatment with GC.Disclosure of Interests:Anne Regierer Speakers bureau: Novartis, Celgene, Janssen-Cilag, Rebecca Hasseli Grant/research support from: Pfizer, Consultant of: Pfizer, Gilead, Novartis, Celgene, Abbvie, Medac, Bimba Hoyer: None declared, Andreas Krause: None declared, Hanns-Martin Lorenz Grant/research support from: Consultancy and/or speaker fees and/or travel reimbursements: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly. Scientific support and/or educational seminars and/or clinical studies: Abbvie, MSD, BMS, Pfizer, Celgene, Medac, GSK, Roche, Chugai, Novartis, UCB, Janssen-Cilag, Astra-Zeneca, Lilly, Baxter, SOBI, Biogen, Actelion, Bayer Vital, Shire, Octapharm, Sanofi, Hexal, Mundipharm, Thermo Fisher., Consultant of: see above, Alexander Pfeil Grant/research support from: This study Investigator Initiated Study “Automatic assessment of joint space narrowing in rheumatoid arthritis based on the Post-hoc analysis” (number: IIS-2016-110818) is a part of the of the Investigator Initiated Study “The quantification of inflammatory related periarticular bone loss in certolizumab pegol treated patients with rheumatoid arthritis” (number: IIS-2014-101458) which is supported by UCB Pharma GmbH, Monheim, Germany., Jutta Richter Grant/research support from: Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Tim Schmeiser Speakers bureau: Actelion, UCB, Pfizer, Christof Specker Consultant of: Abbvie, Boehringer Ingelheim, Chugai, Lilly, Novartis, Sobi, UCB, Celgene, Janssen-Cilag, MSD, Pfizer, Roche, UCB, Toshiba, Anja Strangfeld Speakers bureau: AbbVie, BMS, Pfizer, Roche, Sanofi-Aventis, Reinhard Voll: None declared, Hendrik Schulze-Koops: None declared, Ulf Müller-Ladner Speakers bureau: Biogen

Background The European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) embarked on a project to re-evaluate classification criteria for systemic lupus erythematosus (SLE). The first phase of the classification project involved generation of a broad set of items potentially useful for classification of SLE and their selection for use in a subsequent forced-choice decision analysis. Methods A large international group of expert lupus clinicians was invited to participate in a 2-step process to generate, rate and select items based on their importance in diagnosing early and established SLE, respectively, via a web-based survey. Results 135 and 147 experts were invited to participate in the item generation and item reduction process, respectively. Out of 145 items generated, item reduction resulted in 40 candidate items moving forward to the next phase. Key features for classifying both early and established SLE included characteristic autoantibodies, specific renal features, and skin manifestations. A small majority (51%) stated that one organ system would be sufficient for classifying SLE, but that additional typical laboratory features (ANA, dsDNA) would be required. Notably, 85% of the expert group would positively classify SLE if renal pathology alone showed lupus nephritis. Conclusion The Delphi exercise resulted in a set of 40 candidate criteria for the classification of SLE for subsequent assessment. This study comprised the largest panel ever involved in the development of SLE classification criteria, providing a broadly representative view of the current approach to classification SLE. This article is protected by copyright. All rights reserved.

Key Points Question Is receipt of tumor necrosis factor (TNF) inhibitor monotherapy at the time of COVID-19 diagnosis associated with adverse COVID-19 outcomes compared with other treatment regimens among patients with immune-mediated inflammatory diseases (IMIDs)? Findings In this cohort study of 6077 patients with IMIDs and COVID-19, TNF inhibitors in combination with azathioprine/6-mercaptopurine therapy, methotrexate monotherapy, azathioprine/6-mercaptopurine monotherapy, or Janus kinase inhibitor monotherapy were each associated with significantly higher odds of hospitalization or death compared with TNF inhibitor monotherapy. Meaning This study’s findings support the continued use of TNF inhibitor monotherapy among individuals with IMIDs during the pandemic., 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, This cohort study uses data from 3 international registries to examine the association between the receipt of tumor necrosis factor monotherapy and the risk of COVID-19–associated hospitalization or death among adult patients with immune-mediated inflammatory diseases.

Background:The current pandemic constitutes an entirely new situation for patients as well as physicians. The insecurity of the early phase, shutdowns, increasing infection rate and appearing SARS-CoV2 mutations have created a situation that makes live difficult especially for chronic diseases i.e. patients with rheumatic and musculoskeletal diseases (RMD) and their treating physicians. The psychosocial burden that is created by this special situation is completely unknown and is estimated to be higher in patients than in the general population.Objectives:In order to measure the impact on our patients, the German COVID19-Rheuma patient survey was set up in April 2020, during Germany’s first shut down.Methods:The German COVID19-Rheuma patient survey is a patient reported longitudinal online survey where patients with RMD who registered between April and July 2020 are asked on a monthly base using an online survey on social, personal, medical factors, whether a COVID19 infection occurred, isolation measures were changed and scores regarding stress and anxiety are recorded. Between April and July 2020, 637 patients registered and completed a first survey. Up to January 2021, about 400 patients are still enrolled.Here we present an interim analysis of the first 6 months regarding patients that were enrolled in April and May during the first shut-down. This first analysis compares the situation in the first lockdown to July, a phase with very low infection numbers in Germany, and to November, the beginning of the second lockdown.Results:150 patients (87% female) were enrolled in April/early May 2020. Mean age was 48 years (range 11-89). The majority of patients suffered from rheumatoid arthritis (51%), followed by psoriatic arthritis (17%), other spondyloarthropathies (10%) and connective tissue diseases (10%).The majority of patients received antirheumatic therapies: 32% glucocorticoids (GC), 31% cDMARDs, 21% TNF inhibitors, 7% Jak inhibitors, and 9% other biologicals. Of the patients treated with GC, 25% were on GC monotherapy.In the first lockdown, 26% of patients were working remotely and 24% were self-isolating (doubles included). Additionally, 48% were using masks that were not mandatory at that time and 41% were using disinfection in a regular manner. The rates for remote work and self-isolation did not change significantly over time while the mask use increased to 98% with the official obligation to do so. The use of disinfectants increased to 88% in November.Regarding disease activity, no change in patient global assessment could be observed over time (4.3 ± 2.5 vs. 4.0 ±2.6 and 4.0 ± 2.5). Self-reported pain was also stable over time as were sleep disturbances. While 48.2% of patients who were receiving physiotherapy paused in April, only 10 and 14% did so in July and November, respectively. 11% of the patients paused their medication in the first lockdown, whereas only 2.75% did so in July and 3.4% in November. Contact with the treating rheumatologist was maintained over time in the majority of cases.Conclusion:While in the beginning of the pandemic the insecurity was considerable and the concern that the fear for infection would lead to inadequately treated patients with RMDs, we here show for the first time that on the one hand our patients were timely in taking adequate measures to keep themselves safe (e.g. self-isolating, mask use) and adapted to the clinical situation in not pausing their medication. Altogether, in this alert cohort, the pandemic did not lead to an increase of patient-reported disease activity in the first six months.Acknowledgements:Thanks goes to all patients who participated in the study.Disclosure of Interests:None declared

Objective To analyze the composition of known plasmacytosis in SLE to obtain further insight into the nature of underlying mechanisms. Methods Plasmablasts of active and inactive/treated SLE patients, and of healthy controls were characterized by flow cytometry, EliSpot and transwell migration assays, and results were compared to characteristics of vaccination-induced plasmablasts. Serum cytokine levels were analyzed by a Luminex assay, and kidney biopsies by histology. Results We here demonstrate the expression of markers of mucosal immune reactions by circulating plasmablasts in SLE. IgA, CCR10, and β7 integrin were expressed by 48%, 40% and 38% of plasmablasts, respectively, with varying co-expression patterns. Consistent with mucosal homing, some SLE plasmablasts migrated towards the mucosal chemokine CCL28 and secreted polymeric IgA. SLE plasmablasts shared phenotypic characteristics with antigen-specific plasmablasts induced by oral, but not parenteral vaccinations. Autoreactive antibody-secreting cells were detectable of the IgG and the IgA isotype, but only the emergence of phenotypically mucosal plasmablasts were positively associated with serum IL-2 and PDGF-BB levels. Conclusion Our data suggest that distinct plasmablast differentiation pathways jointly contribute to peripheral plasmacytosis in SLE, i.e. a cytokine-amplified mucosal ‗steady state‘ plasmablast response, and an autoreactive plasmablast response, representing conventional autoimmunity. Our results indicate an overly activated mucosal immune system in patients with SLE, with both immunological and clinical implications. This article is protected by copyright. All rights reserved.

An improved understanding of the immune pathology that contributes to the development of systemic lupus erythematosus (SLE) has led to the development and introduction of new selective therapies in this disease over the last years after the introduction of biologicals in diseases, such as rheumatoid arthritis (RA), spondyloarthritis, and anti-neutrophil cytoplasmic antibodies (ANCA) vasculitides. Beyond that, studies with biologicals in SLE patients have provided new insights into this disease based on failures and successes while further treatment options are explored to improve patient outcomes in SLE. There are two cornerstones of the immune mechanisms driving SLE: enhanced B-cell/plasma cell abnormalities and cytokine disturbances. In this context, the antibody against the cytokine BAFF/BLyS (belimumab) directed against a B-cell survival cytokine has been the first approved drug for SLE in recent decades and is also the first biological for this disease. Other biological drugs targeting T cells, T- and B-cell collaboration, type I interferons, and intracellular signaling pathways for the treatment of SLE patients are in advanced clinical development.

ObjectiveTo develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).MethodsThis international initiative had four phases. (1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort and a patient survey. (2) Criteria reduction by Delphi and nominal group technique exercises. (3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. (4) Refinement of weights and threshold scores in a new derivation cohort of 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 subjects.ResultsThe 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.ConclusionThese new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered and weighted criteria reflect current thinking about SLE and provide an improved foundation for SLE research.

Background:IgG4-related disease (IgG4-RD) is a polymorphic autoimmune disease leading to tumourous swelling and/or fibrosis of affected organs. Riedel’s thyroiditis is – besides chronic periaortitis, Mikulicz Syndrome and many others – an organ manifestation of IgG4-RD that has been thought to be an independent disease for a long time. About 40% of patients have single organ IgG4-RD while the others suffer from multisystemic disease [1].Objectives:Glucocorticoids, sometimes combined with other immunosuppressives are the standard treatment of IgG4-RD, in some situations (e.g. mechanical complications or suspected malignancy) surgery may be necessary but little is known about the management of fully resected single-organ IgG4-RD [1].Methods:We report a case of single-organ IgG4-RD (Riedel’s thyroiditis) after complete resection and perform a brief review of the literature to guide clinical management in this situation.Results:A woman (51 y) with pre-existing Hashimoto’s thyroiditis (thyroid peroxidase antibody positive) developed a rapidly growing struma with very firm consistency (not allowing fine needle biopsy). Besides slightly increased C-reactive protein (5,3 mg/l) there was no laboratory sign suggestive for IgG4-RD (normal serum IgG4, complement, eosinophils and IgE). Within 4 months the patient suffered from hoarseness and progredient dyspnea. Surgical thyroidectomy was performed and histopathology revealed IgG4-related Riedel’s thyroiditis with extensive (storiform) fibrosis, a dense lymphoplasmacytic infiltrate, obliterative phlebitis, eosinophilia and 13 IgG4-positive plasma cells per high power field.After referral to our department a comprehensive work-up showed no signs of other manifestations of IgG4-RD. Treatment with glucocorticoids is clearly recommended for patients with symptomatic IgG4-RD in an international consensus statement, whereas “watchful waiting” may be appropriate in some cases of asymptomatic or mild disease. While some highly fibrotic lesions may not respond well to glucocorticoids and may require surgical intervention, no clear guidance is available for the management of fully resected single organ IgG4-RD [2].A brief review of the literature revealed that few cases of single-organ IgG4-RD remaining in remission after resection without medical treatment have been reported e.g. IgG4-related cholecystitis, autoimmune-pancreatitis, tumours of the intestinal tract, lung, thymus, meninges, paravertebral space and others [3–9].After discussion of the options with the patient no systemic immunosuppression was given under close follow up without signs of relapse in clinical examinations, laboratory or imaging during the first 6 months.Conclusion:Limited evidence from case reports suggests that a “watchful waiting” strategy without systemic immunosuppressive treatment may be reasonable in some cases of single-organ IgG4-RD after the affected organ was completely resected (e.g. due to mechanical complications or suspected malignoma). However, close follow-up monitoring should be applied due to the risk of relapse or development of new organ manifestations.References:[1]Brito-Zerón et al.Best Pract. Res. Clin. Rheumatol.2016[2]Khosroshahi et al.Arthritis Rheumatol.2015[3]Takahashi et al.Surg. Case Rep.2015[4]Akbari et al.ACG Case Rep. J.2018[5]Oda et al.Thorac. Cancer2019[6]Nambirajan et al.Childs Nerv. Syst. ChNS Off. J. Int. Soc. Pediatr. Neurosurg.2019[7]Uchida et al.Asian J. Endosc. Surg.2018[8]Hart et al.Mod. Pathol. Off. J. U. S. Can. Acad. Pathol. Inc2015[9]Kim et al.Tuberc. Respir. Dis.2014Disclosure of Interests:Jan Schirmer: None declared, Marcus Seeger: None declared, Dominik Schulte Paid instructor for: Ferring, Speakers bureau: Amgen, Astra Zeneca, Braun, Fresenius, Ipsen, Johnson & Johnson, Lilly, MSD, Novartis, Novo Nordisk, Sanofi, Matthias Laudes Speakers bureau: Roche, Sanofi, Chugai, Stefan Schreiber Consultant of: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, provention Bio, Protagonist and Falk, Bimba F. Hoyer: None declared

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.

Ein verbessertes Verstandnis der Pathomechanismen, die beim systemischen Lupus erythematodes (SLE) beteiligt sind, hat zu neuen selektiven Therapiestrategien bei dieser entzundlichen Systemerkrankung gefuhrt. Dabei ergeben sich Analogien zu Erkrankungen wie der rheumatoiden Arthritis und den Spondylarthriden. Neue Biologika wurden auf dieser Basis entwickelt oder befinden sich in der klinischen Entwicklung und eroffnen neue Therapieoptionen fur die Patienten. In diesem Zusammenhang ist vor allem Belimumab zu nennen. Dieser Antikorper gegen das Zytokin BAFF/BLyS ist das erste zugelassene Medikament fur die Therapie des SLE und zugleich das erste fur diese Erkrankung zugelassene Biologikum. Andere biologische Medikamente gegen weitere Zytokine oder zellulare Strukturen zur Behandlung von SLE-Patienten sind in der Entwicklung. In diesem Beitrag werden neben den Erfahrungen mit Belimumab bei SLE auch die aktuellen Entwicklungen anderer Biologika fur die Therapie des SLE diskutiert.

ObjectivesTo 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).MethodsTwelve patients received a median of two (range 1–4) 21-day cycles of intravenous bortezomib (1.3 mg/m2) 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.ResultsUpon 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.ConclusionsThese 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.

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., Highlights • Th1 cells expressing miR-148a mediate colitis in a murine model of IBD. • Antagomir-148a inhibits colitis by selectively depleting Th1 cells from the colon. • Antagomir-148a does not affect the protective immunological memory.

ObjectivesWe have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus.MethodsSplenic CD138+ antibody-secreting cells (ASCs) from >6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1−/− mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed.ResultsThe adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1−/− mice. Rag1−/− mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer.ConclusionsThese findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.

Systemic lupus erythematosus (SLE) is a chronic systemic intermittent autoimmune disease, which can affect nearly all organ systems. The disease is characterized by the detection of more than 100 different auto-antibodies. For the clinical practice as well as in controlled clinical studies it is absolutely necessary to define target criteria which allow the evaluation of the effectiveness of therapy. Many instruments are available for measuring the activity of the disease, the quality of life, the extent of irreversible damage and the individual manifestation in organs. There are also now various biomarkers to characterize the pathophysiologic aspects, clinical activity, therapeutic effectiveness and prognosis.

Erdheim–Chester disease is a rare form of non-Langerhans cell histiocytosis characterized by foamy histiocyte infiltration of the skeleton and viscera. A case of Erdheim–Chester disease that was initially mistaken for Ormond's disease is presented with a discussion of the tests required to differentiate between the two diagnoses. Background A 54-year-old man presented with fever, abdominal pain, anemia, elevated C-reactive protein level and decreased renal function. Idiopathic retroperitoneal fibrosis (Ormond's disease) had been diagnosed in the past, leading to surgical ureterolysis. Re-evaluation of the CT scans and histological biopsy samples revealed unusual sclerosis of the long bones and diffuse infiltrates of foamy histiocytes in the bone marrow and the retroperitoneum. Investigations Physical examination, laboratory tests including hemoglobin concentration, erythrocyte sedimentation rate, C-reactive protein level, β2-microglobulin level, creatinine level, CT of the chest and abdomen, bone scintigraphy, bone marrow and soft tissue biopsies and immunohistochemistry. Diagnosis Erdheim–Chester disease with retroperitoneal fibrosis and bone sclerosis. Management Treatment with glucocorticoids failed. The patient's symptoms improved significantly after initiation of interferon-α therapy.

Long-lived plasma cells (LLPCs) are an unmet therapeutic challenge, and developing strategies for their targeting is an emerging goal of autoantibody-mediated diseases such as systemic lupus erythematosus (SLE). It was previously shown that plasma cells can be depleted by agents such as bortezomib (Bz) or by blocking LFA-1 and VLA-4 integrins. However, they regenerate quickly after depletion due to B cell hyperactivity in autoimmune conditions. Therefore, we compared different therapies for the elimination of LLPCs combined with selective B-cell targeting in order to identify the most effective treatment to eliminate LLPCs and prevent their regeneration in lupus-prone NZB/W F1 mice. Methods NZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti-CD20 plus bortezomib and anti-LFA-1/anti-VLA4 blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease. Results Short-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice. Conclusions These findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody-mediated diseases.

The current view holds that chronic autoimmune diseases are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressants, the production of autoantibodies may persist and contribute to the autoimmune pathology. We recently demonstrated in autoimmune mice that both short-lived plasmablasts and long-lived plasma cells are involved in autoantibody production. While anti-proliferative immunosuppressive therapy and monoclonal anti-CD20 antibody deplete short-lived plasmablasts, long-lived plasma cells survive and continue to produce (auto)antibodies. Thus, strategies for targeting long-lived plasma cells may provide potent new treatment modalities.

Haematopoietic stem cell transplantation (HSCT) is an effective treatment for severe autoimmune diseases such as systemic lupus erythematosus (SLE).1 However, it is increasingly recognised that these patients have an added propensity to develop secondary autoimmune disorders.2 ,3 Here, we report on a 21-year-old male patient who received a CD34-selected autologous HSCT following conditioning with antithymocyte-globulin and cyclophosphamide (CYC) after written informed consent for refractory, severe SLE with renal, haematological, mucocutaneous and musculoskeletal manifestations (SLEDAI 19).1 Clinical remission was achieved for SLE within 3 months after HSCT and anti-double-stranded DNA (anti-dsDNA) antibodies disappeared despite immunosuppressive drug withdrawal. Eight months after HSCT, the patient presented with spontaneous joint and skin bleeding and was diagnosed with factor VIII (FVIII) inhibitor haemophilia with an activated partial thromboplastin time >100 s, FVIII activity

Background Current SLE classification criteria may not classify patients with early SLE well. SLE mimickers can have an initial presentation similar to SLE and need to be distinguished from early SLE patients by classification criteria. Objectives To describe the clinical and serological presenting manifestations of SLE at disease onset and those of SLE mimickers. Methods We collected clinical and laboratory data on patients newly presenting with potential SLE (symptoms Results Of 616 patients, 389 were diagnosed with SLE (89% female) and 227 were given other diagnoses (97% female). A smaller proportion of SLE patients than patients with mimicking conditions were White (55% vs. 90%). Mimickers included UCTD, Sjogren9s syndrome, rheumatoid arthritis, scleroderma, and fibromyalgia. Clinical and autoantibodes presenting manifestations in new onset SLE and mimickers are represented in table 1. In univariable analyses, the following autoantibodies profiles were associated with SLE vs. mimickers: Profile 1 (ANA, anti-Sm, anti-Ro and anti-RNP; OR 3.49, 95% confidence interval [CI] 2.29–5.31) and Profile 2 (ANA, anti-cardiolipin IgG/IgM, Beta2 and lupus anticoagulant; OR 2.82, 95% CI 1.75–4.55). In multivariable analyses, the following autoantibodies profiles were associated with SLE vs. mimickers: Profile 1 (OR 3.02, 95% CI 1.90–4.80) and Profile 2 (OR 3.11, 95% CI 1.80–5.36). Adding hypocomplementemia to Profile 1 and 2 showed a high association with SLE [OR 3.40, 95%CI 2.21–5.22 and OR 2.41, 95%CI 1.53–3.80] respectively. Conclusions We identified clinical manifestations and autoantibodies more commonly associated with SLE than with mimickers at initial presentation. Autoantibody profiles particularly including ANA and especially in the presence of hypocomplementemia, showed associations with SLE. Acknowledgement New SLE classification criteria for clinical research are being developed, sponsored by EULAR and ACR. Disclosure of Interest None declared

Antibodies contribute to the pathogenesis of many chronic inflammatory diseases, including autoimmune disorders and allergies. They are secreted by proliferating plasmablasts, short-lived plasma cells and non-proliferating, long-lived memory plasma cells. Memory plasma cells refractory to immunosuppression are critical for the maintenance of both protective and pathogenic antibody titers. Here, we studied the response of plasma cells in spleen, bone marrow and inflamed kidneys of lupus-prone NZB/W mice to high-dose dexamethasone and/or cyclophosphamide. BrdU+, dividing plasmablasts and short-lived plasma cells in the spleen were depleted while BrdU- memory plasma cells survived. In contrast, all bone marrow plasma cells including anti-DNA secreting cells were refractory to both drugs. Unlike bone marrow and spleen, which showed a predominance of IgM-secreting plasma cells, inflamed kidneys mainly accommodated IgG-secreting plasma cells, including anti-DNA secreting cells, some of which survived the treatments. These results indicate that the bone marrow is the major site of memory plasma cells resistant to treatment with glucocorticoids and anti-proliferative drugs, and that inflamed tissues and secondary lymphoid organs can contribute to the autoreactive plasma cell memory. Therefore, new strategies targeting autoreactive plasma cell memory should be considered. This could be the key to finding a curative approach to the treatment of chronic inflammatory autoantibody-mediated diseases.

IntroductionTakayasu arteritis (TA) is a large vessel vasculitis involving the aorta and its major branches. T cell-mediated autoimmunity is thought to play a major role in its pathogenesis, while the role of B cells is still unclear.MethodsB cell subsets in the peripheral blood of 17 patients with TA were analysed and compared with nine patients with active systemic lupus erythematosus (SLE) and nine healthy controls by flow cytometry. Based on these findings, three patients with active refractory TA were treated with B cell depletion therapy (BCDT) using monoclonal anti-CD20 antibodies (rituximab).ResultsThe absolute number and frequency of peripheral blood CD19+/CD20−/CD27high antibody-secreting cells in patients with active TA was significantly higher than in healthy donors. As in active SLE, the majority of these cells are newly generated plasmablasts which significantly correlated with TA activity. Three patients with active refractory TA and expansion of plasmablasts were successfully treated with BCDT, which resulted in remission.ConclusionDisturbances of B cell homeostasis may be critical in TA. Circulating plasmablasts could be a useful biomarker of disease activity and a tool for selecting appropriate candidates for BCDT. B cells and plasmablasts/plasma cells may therefore represent novel targets for effective therapies for TA.

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.

Recently, it has been shown that plasma cells secreting antibodies can be long lived and as such constitute an independent component of immunological memory. They are generated in the context of memory immune reactions and migrate to the bone marrow, where they persist for years and decades. Their survival is dependent on receiving distinct signals provided by cells forming a plasma cell survival niche. They also can migrate to, and survive in, inflamed tissue. In autoimmune diseases long-lived plasma cells secreting autoantibodies provide an as yet unmet therapeutic challenge, because they are resistant to conventional treatments, in particular to immunosuppression and anti-inflammatory drugs. They are eliminated by immunoablation with antithymocyte globulin. This may be the reason why immunoablation followed by reconstitution of the patient's immune system from haematopoietic stem cells induces long-term remissions in many patients with autoimmune diseases. However, more specific treatments for the elimination of autoreactive, long-lived plasma cells are needed, to avoid the complete temporary immunoincomptence induced by immunoablation, and to decipher the role of long-lived autoreactive plasma cells in human autoimmune diseases in more detail.

B-cells and antibody-secreting plasma cells are key players in protective immunity, but also in autoimmune disease. To understand their various functions in the initiation and maintenance of autoimmune pathology, a detailed dissection of their functional diversity is mandatory. This requires a detailed phenotypic classification of the diversity of B-cells. Here, technologies of immunocytometry and ELISpot are described in detail, and their value for phenotypic characterization of cells of the B lineage, as well as for preparative cell sorting, to further characterize them functionally and on the molecular level are described.

Background and objectives Long-lived plasma cells (LLPCs) producing pathogenic antibodies are an important factor in autoimmune diseases maintenance and relapse. The therapeutic options available so far for targeting these cells (e.g. autologous stem cell transplantation, bortezomib) have the major disadvantage of eliminating the protective humoral immunity with the obvious caveats regarding a higher risk of infection. Therefore the development of new therapeutic tools for the selective depletion of LLPCs secreting pathogenic antibodies would be a great step forward. Material and methods We synthetized an antigen affinity matrix (AM) conjugating a plasma cell specific antibody (i.e. anti-CD138) with the antigen/autoantigen-of-interest (i.e. Ovalbumin or Acetylcholine-Receptor, AChR). We performed proof-of-concept experiments using the anti-CD138-ovalbumin using: 1) anti-ovalbumin secreting hybridoma cells and 2) spleen cells from ovalbumin-immunised mice. Moreover, we used the anti-CD138-AChR AM for the ex-vivo depletion of splenic pathogenic plasma cells isolated from mice with experimental autoimmune myasthenia gravis (EAMG). Results Antibodies secreted by ovalbumin-specific plasma cells could bind the ovalbumin delivered at surface of the plasma cell by the AM. In this way, anti-ovalbumin-specific hybridoma cells and splenic plasma cells were induced to commit suicide in presence of complement. Conversely, unrelated plasma cells (i.e. secreting antibodies against other antigens) were not lysed confirming the specificity of the method. Importantly, pathogenic plasma cells secreting anti-AChR-autoantibodies from the spleen of mice with EAMG can be eliminated using an anti-CD138-AChR-construct, suggesting that the AM technology can be used for the specific depletion of autoantibodies secreting plasma cells. Conclusion Here we show that the AM technology could represent the first available tool for the depletion of (auto)antigen-specific plasma cells without affecting the protective plasma cells. We are currently testing the therapeutic efficacy of this AM in murine models of autoimmune disease.

Background and objectives Plasma cell depletion with bortezomib can prevent the development of lupus nephritis and prolong survival in NZB/W mice. Here, we studied the effect of the immunisation with OVA in combination with bortezomib on the disease in NZB/W mice. Methods NZB/W F1 female mice 16 week-old (early disease stage) were divided into 3 groups as follows: 1. Non-immunised mice as a control group, 2. Immunised mice; mice immunised with alum-precipitated OVA i.p and boosted 3 weeks after primary immunisation, 3. Immunised mice as group 2 receiving two shots of bortezomib (0.75 mg/kg, i.v) at 48 and 12 h before secondary immunisation. The numbers of anti-dsDNA antibody secreting cells (ASCs) were assessed in spleen and bone marrow by ELISPOT one month after secondary immunisation. Moreover we investigated serologic parameters including anti-OVA and anti-dsDNA antibody levels by ELISA as well as proteinuria and survival rate. Results Immunised mice (group 2) developed proteinuria, which occurred earlier and stronger than in the non-immunised mice and in mice additionally treated with Bz before booster immunisation (group 3). Survival rate of immunised mice was reduced in comparison to group 3 treated with Bz while group 1 showed the longest survival. Autoantibody levels in group 2 and 3 were higher than in the control group 1. Mice immunised with OVA showed a tendency to higher numbers of IgM anti-dsDNA ASCs in the bone marrow and spleen than in non-immunised mice while IgG anti-dsDNA ASCs counts analysed in mice immunised with OVA and treated with Bz, were comparable with their counts in non-immunised mice. The Bz treatment before the secondary OVA immunisation resulted in lower anti-OVA antibody levels than in immunised mice without Bz treatment. Conclusion Immunisation with alum-precipitated OVA accelerates autoimmunity in NZB/W mice. This effect can be ameliorated by plasma cell depletion with bortezomib.

Objectives The proteasome inhibitor bortezomib, approved for the therapy of multiple myeloma, depletes plasma cells (PCs) and ameliorates nephritis in mouse models of systemic lupus erythematosus (SLE). Here, we analyzed the efficacy of bortezomib as induction therapy in patients with refractory SLE. Methods Twelve patients with active SLE were included in this prospective multicentre cohort study. The patients received one to four cycles of intravenous bortezomib (Velcade®) 1.3mg/m 2 as “off-label” treatment. Disease activity was evaluated using the SELENA-SLEDAI score. We determined serum concentrations of anti–double-stranded DNA (anti-dsDNA) and protective antibodies. Multicolor flow cytometry was performed to analyze peripheral blood B and PC subsets as well as Siglec-1 expression on monocytes as surrogate marker for type I interferon (IFN) activity. Results The disease activity significantly decreased upon induction therapy with bortezomib and remained stable for the following 3 months under maintenance therapies. Treatment-related adverse events were mild or moderate. During proteasome inhibition, serum antibody concentrations significantly declined with greater reductions in anti-dsDNA (∼60%) than protective (∼30%) antibodies. Upon bortezomib treatment, numbers of HLA-DR + short-lived (p=0.024) and HLA-DR – long-lived (p=0.038) peripheral blood PCs were strongly decreased, whereas circulating B cells remained virtually unaffected. Notably, PC numbers significantly increased in-between cycles. Siglec-1 expression on monocytes significantly declined (p Conclusions Bortezomib targeting PCs and type I IFN activation may represent an effective treatment option with rather low toxicity in refractory SLE patients. Bortezomib efficiently induces short-term remissions but requires maintenance treatment inhibiting PC regeneration for sustained efficacy. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5884

Background The proteasome inhibitor bortezomib, approved for the treatment of multiple myeloma, has been demonstrated to deplete short- and long-lived plasma cells (PCs) and ameliorate nephritis in murine models of systemic lupus erythematosus (SLE). Here, we aimed to analyse the effect of bortezomib in refractory SLE patients. Methods In this single-centre cohort study, eight SLE patients with active disease despite immunosuppressive treatment received up to four 21-day cycles of bortezomib 1.3mg/m 2 , on days 1, 4, 8, and 11 by intravenous injection as an “off-label” treatment. Multicolor flow cytometry was performed to analyse peripheral blood B and PC subsets as well as Siglec-1 expression on monocytes. Autoantibody and vaccine titres as well as B cell activating factor (BAFF) levels in serum were analysed with ELISA. Results From 2009 until 2012, eight SLE patients received a median of two bortezomib cycles (range one to four). Under proteasome inhibition, disease activity significantly improved with a median SLEDAI reduction from 13 to 4 (p>0.001). Bortezomib treatment had profound effects on antibody titers, with greater reduction in pathogenic (anti-dsDNA-abs. 58.7%) than protective antibody titers (e.g. anti-Tetanus-abs. 29.2%). In addition, total immunoglobulin levels and Siglec-1 expression on monocytes (as surrogate for type I interferon) significantly decreased (p = 0.016), whereas BAFF and complement levels significantly increased. While circulating B-cell numbers remained unaffected, bortezomib treatment resulted in a significant depletion of both HLA-DR + short-lived (55.5% reduction, p = 0.024) and HLA-DR- long-lived (53.5% reduction, p = 0.038) peripheral blood PCs. Also IgA secreting PCs were depleted (61.8% reduction). Nevertheless, PCs were rapidly regenerated with a median increase of 268.8% within 10 days from the last bortezomib application. Conclusion Proteasome inhibition with bortezomib has beneficial effects on disease manifestations in SLE by PC depletion and inhibition of type I interferon but regeneration of PCs is not prevented. Overall, proteasome inhibition has demonstrated the therapeutic relevance of targeting autoreactive memory plasma cells as such, and it constitutes a new therapeutic option. Nevertheless, fur sustained efficacy, proteasome inhibition needs to be combined with therapeutic approaches targeting B cell activation and differentiation to inhibit PC regeneration.

Background B cells are important players in granulomatosis with polyangiitis (GPA) as suggested by the presence of autoantibodies reacting with specific neutrophil granular enzymes ANCA) in a vast majority of patients as well as the success of B cell depleting therapies in GPA. Renal manifestations in GPA are considered to be directly ANCA – mediated whereas the granulomatous inflammation appears to be mediated by CD4 T cells. Objectives For a better understanding of the possible role of B cells in ANCA-associated vasculitis we analyzed the B cell subsets in the peripheral blood of patients with GPA and found marked changes correlating with disease activity as measured by the BVAS (Birmingham vasculitis activity score) as well as ANCA-levels. Methods 17 patients with GPA (10 with active disease, 7 with inactive disease) were analyzed by flow cytometry as compared to 20 healthy donors. Staining for CD27, CD20, CD19, MHCII, CD3, 4 and 8 was analyzed using flowjo software. Statistical analysis was performed using graph pad prism, and p-values of Results Marked differences (p=0,0018) could be observed in plasma cell counts as well as frequencies in GPA patients (6,5 ±5,06/µl) with a BVAS-score > 0 as compared to those with a BVAS-score =0 (2,5± 1,6/µl) or healthy persons (2,3±1,15/µl). Plasma cell numbers as well as the frequency of plasma cells within all B cells correlated with the BVAS (r= 0,91, p Regarding T cells, there was a significant reduction of CD3 (p=0,01) and CD4 T (p=0,012) cells in patients with active GPA as compared to patients in remission, whereas CD8 T cells did not show any significant changes. Conclusions Plasma cell numbers are increased in patients with active GPA which implies a role for plasma cell mediated effects in active GPA. Presumably, their main role is the production of autoantibodies, but also cytokine production. Independent of their direct contribution to the disease, they may serve as a biomarker of disease activity as they highly correlate with the BVAS. References Hoyer et al, ARD 2012 Disclosure of Interest None Declared

Background Takayasu arteritis and giant cell vasculitis are two forms of large vessel disease mostly affecting women. One of their main differences is the age at onset this being around 20 years for Takayasu’s (TA) and largely above 50 for giant cell vasculitis (GCA). In some patients the affected vessels also differ with a focus on the temporal artery in the aged patients and a stronger focus on the aorta in TA.Until recently T cells were believed to be the major player in those fomrs of large vessel vasculitis. We could show recently that B cell disturbances ca be found in Takayasu arteritis correlating with dsease activity. For giant cell vasculitis data is still lacking about B cell disturbances. Objectives In this study we compare the frequency and absolute number of B cell subsets in the peripheral blood of patients suffering from TA, GCA and Systemic lupus erythematosus (SLE) as compared to healthy controls. Methods Peripheral blood mononuclear cells were analysed ex vivo by flow cytometry according to their expression of CD19, CD20, CD27, IgD and MHCII. Samples from 14 with active GCA, 10 with inactive GCA, 8 with active SLE, 5 with active TA and 25 healthy controls were analysed. Plasma cells were characterized by being CD19 pos, CD27 high, CD20 neg. Switched memory B cells were characterized by being CD19pos, CD27pos IgD neg, Naive B cells were characterized as being CD27 neg IgD pos. Double neg cells were CD19 pos CD27 neg IgD neg. Calculations were done using Graph Pad prism using Mann-Whitney-test and p- values of less than 0.05 were taken as significant. Results Overall B cell numbers are comparable in GCA, TA and healthy donors whereas they were found to be reduced in SLE as was reported previously. Regarding plasma cells frequency we could detect a significant increase in patients with active GCA, active TA and obviously SLE as compared to healthy controls whereas frequency in patients with inactive disease were only slightly increased. Regarding absolut numbers this change was only detecable for patients with active GCA. For MHCII-high plasma cells a reduction as compared to healthy controls could be observed that did not reach significance. In the other B cell subsets a significant reduction could be found between healthy donors and patients with active GCA regarding the naive B cells (frequency and absolute numbers p=0,01 and p=0,005). In Takayasu patients a similar change could be observed but not being significant. For the frequency a significant increase could be observed regarding the switched memory B cells (p=0,003) that was nearly as pronounced in inactive GCA but was not observed in TA and SLE. Conclusions Here we show for the first time that disturbances in B cell subsets in the peripheral blood can be observed not only in TA but also in patients with GCA. The observed changes differ between giant cell vasculitis and TA and are only to some extend comparable to the ones described in SLE. Therefore the flowcytometric analysis of B cell substes in the blood could be a tool to differentiate between thoses diseases and are another hint for a different B-cell-pathomechanism for TA and GCA. In addition B cells might represent an interesting therapeutic target for new drugs. Disclosure of Interest None Declared

Backgroundand objectives Long-lived memory plasma cells secreting pathogenic autoantibodies are resistant to conventional immunosuppression and B cell targeting therapies. Bortezomib, an approved drug for relapsing multiple myeloma, efficiently depletes short- and long-lived plasma cells and ameliorates nephritis in murine lupus models. Therefore, the authors studied the efficacy of bortezomib in refractory SLE patients in a case series. Materials and methods At three university centers, 13 SLE patients refractory or intolerant to cyclophosphamide, MMF and/or rituximab were treated with bortezomib intravenously at a dose of 1.3 mg/m2 body surface area on days 1, 4, and 8 and, in some cases, on day 11. Most patients received 20mg of dexamethasone together with bortezomib. Treatment cycles were repeated up to four times with an interruption of usually 10 to 14 days between cycles. The following clinical and laboratory parameters were monitored: SLEDAI disease activity score, 24 h proteinuria, creatinine clearance, circulating plasma cells, complement C3 and C4, IgG, IgA, IgM, antibodies to dsDNA and ENA, and vaccine titers. Results SLEDAI and antibody levels significantly decreased under bortezomib while complement levels increased. In seven patients with active nephritis, proteinuria declined within 6 weeks of treatment, and normalised after four months in one case. Anti-dsDNA antibodies decreased by up to 90%, anti-ENA and protective vaccine titers by up to 50%, and immunoglobulin levels by up to 30%. Circulating plasmablasts dropped substantially. Serious side effects were not observed. One patient experienced myalgia, fever and headache 1 day after the first 3 bortezomib doses. Three of five patients treated with four bortezomib injections per cycle developed polyneuropathies, which were reversible upon discontinuation of treatment. One patient developed reversible thrombocytopenia after four treatment cycles. Conclusions The proteasome inhibitor bortezomib may effectively reduce disease activity in refractory SLE patients by depleting plasma cells. The data encourage initiation of clinical trials with bortezomib in refractory SLE and support the relevance of plasma cells in the pathogenesis of this autoimmune disease.

Background Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are an inflammation of the large arteries and their major branches. They have been considered distinct disorders based on their clinical features, age of onset and ethnic distribution. But the histopathology of arterial lesions and imaging studies suggest similar pathogenetic mechanisms in these diseases. Since the authors have recently shown disturbances in the B cell homeostasis in patients with active TAK the aim of this study was to analyse circulating B cell subpopulations in patients with GCA as compared to those with TAK. Methods Peripheral blood mononuclear cells from six patients with active TAK and six with inactive disease, 16 patients with GCA (eight with active and eight with inactive disease) and 12 healthy controls were analysed by flow cytometry for the expression of CD27, CD19, CD20, MHCII, CD3, CD8 and CD4. Plasma cell population is considered CD20−/CD19+/CD27+++. Newly generated plasmablasts express additionally MHC class II. CD19+/CD20+/CD27+ cells were considered as memory B cells and their CD27 low counterpart as naive B cells. Results Patients with active TAK and GCA showed significantly higher frequencies of plasma cells (among all CD19+ B cells) than in inactive patients (p=0.02 and 0.029, respectively) and healthy controls. The absolute plasma cell numbers were increased in TAK patients (p=0.0015) but not in GCA. Active TAK patients showed also elevated circulating plasmablasts in comparison with patients in remission (p=0.0053). The frequency of plasma cells in the blood correlated significantly with the disease activity according to the NIH criteria (r=0.73 and p=0.069). In contrast to TAK, active GCA patients exhibited a significant reduction of the memory B cell subset versus inactive patients (p=0.028). Disturbances of T cell subset were not observed. Conclusions The findings suggest different roles of B cells in the pathogenesis of TAK versus GCA. Circulating plasma cells/plasmablasts may serve as biomarker of disease activity in TAK and provide indication for a B cell and plasma cell directed therapy.

When activated, B cells can differentiate either into memory B cells, or into plasma cells, which secrete the B cells antibody at high rates. Plasma cells can be short-lived or long-lived. Long-lived plasma cells are maintained mostly in the bone marrow, in privileged survival niches, which are organised by dedicated stroma cells [1]. Long-lived plasma cells constitute a discrete type of immunological memory cells, providing humoral protection to recurrent pathogens. In immune-mediated diseases, like allergy or inflammatory rheumatic diseases, however, memory plasma cells can turn detrimental, constantly providing pathogenic antibodies. In systemic lupus erythematosus (SLE), autoreactive memory plasma cells, secreting antibodies against self antigens such as DNA, are readily detectable. These cells represent a therapeutic challenge. While short-lived plasma cells, respectable their precursors and their generation, are targeted by conventional immunosuppression with drugs such as cyclophosphamide, memory plasma cells do not respond, continue to secrete antibodies, and thus sustain persistence of disease [2,3]. New therapies, targeting memory plasma cells, have to be developed, to meet this challenge. Several different therapeutic strategies have been proposed so far.One of the more promising strategies aims at the inhibition of proteasomes, since this strategy has been shown to be effective to eliminate multiple myeloma cells, i.e. transformed plasma cells. In a first study, Neubert and collegues could show in 2008 that in the NZB/W mouse model of SLE, memory plasma cells are depleted from spleen and bone marrow by the proteasome inhibitor bortezomib (Velcade) [4]. Clinically, treated mice showed reduced nephritis and prolonged survival. Consequently, the groups of ReinhardVoll and our group initiated a clinical trial of bortezomib for the treatment of patients with SLE. Those patients had not responded to other treatments earlier and showed persistent autoantibody titers, indicating the presence of autoreactive memory plasma cells. Four patients with active SLE, previously treated with cyclophosphamide, received bortezomib (Velcade®) at doses of 1.3mg/m2 on days +1, 4, 8, 11 followed by a 10 days treatment-free interval for four cycles along with 20mg dexamethasone according to the approved myeloma protocol. Under proteasome inhibition, a significant clinical improvement was achieved in all patients associated with a reduction in lupus-specific autoantibodies. In addition, protective, vaccine-specific antibodies and total immunoglobulin levels dropped significantly, suggesting a depletion of bone marrow memory plasma cells secreting these antibodies.In all patients, like in the NZB/W mice, repeated treatment was needed for sustained efficacy, indicating that autoreactive memory plasma cells are continuously generated in chronic disease. Thus, a therapeutic regimen combining B cell depletion with memory plasma cells depletion might be preferable. First experiments in NZB/W mice showed a sustained effect of combination therapies depleting plasma cell precursors as well as fully differentiated plasma cells. In conclusion proteasome inhibition in SLE has demonstrated the therapeutic relevance of autoreactive memory plasma cells as such, and it constitutes a new therapeutic option, which has to be developed with respect to sustained effectivity, minimization of side effects and reduction of risk of infection.

Takayasu's arteritis (TA) is a large vessel vasculitis of unknown origin involving the aorta and its major branches. T cell mediated autoimmunity …

According to the current view, chronic AID are driven by the continuous activation of autoreactive B and T lymphocytes. However, despite the use of potent immunosuppressive drugs, these patients exhibit continued autoantibody production, which often contributes to progression of the AID. To elucidate this problem, we analyzed the lifespan of cells secreting (auto)antibodies (Ab) in NZB/W mice. The number of Ab-secreting cells in splenic tissue increased from ages 1 to 5 months and became stable thereafter. Later, some 60% of the total Ab-secreting cell compartment consisted of dividing, short-lived plasmablasts (SLPB), whereas 40% consisted of nondividing, long-lived plasma cells (LLPC) with a half-life of more than 6 months. Although high-dose cyclophosphamide eliminated SLPB, LLPC survived and continued to produce (auto)Ab. This explains why treatment with cyclophosphamide (CY) does not result in the complete disappearance of antinuclear Ab. Pathogenic anti-dsDNA Ab usually vanish after this treatment, indicating that they are generated by proliferating SLPB. However, anti-dsDNA Ab can be resistant to CY in refractory SLE. We treated six refractory SLE patients by autologous stem cell transplantation (ASCT) using CY and ATG as the mobilization regimen. ASCT was performed using purified CD34+ stem cells. The patients have now been followed for 5–70 months. Initially, persistent anti-dsDNA disappeared within 3 months. Likewise, the ANA became negative except in one case. That patient continued to exhibit anti-Ro/SSA and anti-La/SSB, the titers of which decreased continuously and were undetectable after 17 months. This emphasizes the enormous lifespan of residual plasma cells after interrupting the supply of new cells from the dividing SLPB compartment. In conclusion, the aforementioned ASCT protocol can lead to depletion of autoreactive LLPC. Since ASCT may not always be able to eliminate autoreactive LLPC, these cells are potential targets for autoimmune disease therapy.