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Abstract Background Patient-reported outcomes (PROs) play a crucial role in assessing rheumatic diseases, offering insights into disease evaluation and treatment efficacy. This study focuses on PRO assessment in large vessel vasculitides, including Takayasu Arteritis and Giant Cell Arteritis (GCA). Methods We retrospectively analyzed routine data from patients treated at our rheumatology clinic over a 10-year span. Patient and physician-rated global disease activity scale (G-DAS) scores, measured on a numeric rating scale (0–10 points), were collected at each visit. Clinical variables like age, sex, body mass index (BMI), disease duration, lab values, pain perception, and questionnaire responses were recorded. Linear regression and generalized additive linear regression (GAM analysis) examined associations between PROs and these factors. Results The study included 138 patients, primarily diagnosed with GCA (94.4%). Mean follow-up was 2.5 years (0-7.7). Patient and physician G-DAS exhibited a moderate correlation (Pearson R 0.19, CI 0.14–0.24, p

Objective: To compare physician and patient assessments of global disease activity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and to identify associated factors., Methods: Global disease activity scores (0-10 points) were retrospectively analyzed from physicians and patients with AAV at each outpatient visit from 2010 to 2020. We compared the scores and performed a linear regression with a random effects to identify associated factors., Results: Patients ( n  = 143, 1,291 pairs, 52% female) had a mean 64 (±15) years of age and a mean disease duration of 9 (±7) years. Patients and physicians global disease activity assessments showed a moderate correlation (Pearson R 0.31, CI [0.23-0.52], p  < 0.001). Linear regression showed a strong association between the physician-documented disease activity scores and serum CRP levels (β = 0.22, CI [0.18, 0.28]), disease duration (β = -0.022, CI [-0.04,-0.01]) and patients' assessment of disease activity (β = 0.08, CI [0.04, 0.12]). By contrast, patient assessments were strongly associated with the degree of pain (β = 0.30, CI [0.25, 0.35]), functional limitations in daily living (HAQ, β = 0.49, CI [0.21, 0.78]) and the global physical well-being (NRS, β = 0.39, CI [0.32, 0.46])., Conclusion: Patients' and physicians' assessments of disease activity correlated. High CRP levels and disease duration were associated with physician-assessed disease activity scores, while subjective limitations were associated with higher patient-assessed disease activity scores. These findings highlight and support the need to develop and evaluate patient-reported outcomes to assess disease activity in patients diagnosed with AAV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rohde, Kernder, Acar, Düsing, Fischer-Betz, Haase, Mucke, Sander, Richter, Filla, Schneider and Chehab.)

Objective: It is still a matter of debate whether low-dose acetylsalicylic acid (LDASA) should be prescribed to all patients with SLE during pregnancy. This study aimed at investigating the impact of LDASA on pregnancy outcomes in patients with SLE without history of renal involvement and without antiphospholipid antibodies (aPL)., Methods: This is a retrospective analysis of prospectively monitored pregnancies at seven rheumatology centres. Previous/current renal involvement and aPL positivity were the exclusion criteria. Adverse pregnancy outcome (APO) is the composite outcome of the study and included proteinuric pre-eclampsia, preterm delivery <37 weeks, small-for-gestational age infant, low birth weight <2500 g, intrauterine growth restriction and intrauterine fetal death after 12 weeks of gestation of a morphologically normal fetus., Results: 216 pregnancies in 187 patients were included; 82 pregnancies (38.0%) were exposed to LDASA treatment. No differences in terms of age at conception, disease duration, clinical manifestations, comorbidities and disease flare during pregnancy were observed between patients taking LDASA and those who did not take LDASA during pregnancy. APO was observed in 65 cases (30.1%), including 13 cases (6.1%) of pre-eclampsia. The incidence of all complications was similar in the two groups. However, it is interesting to note that pre-eclampsia had lower frequency in patients taking LDASA versus those not taking LDASA (2.4% vs 8.3%, p=0.14)., Conclusions: In pregnant patients with SLE without renal involvement and were aPL-negative, there is a low risk of severe obstetric complications, such as early pre-eclampsia. LDASA treatment does not provide a statistically significant advantage over these complications. However, a careful individual risk-benefit balance is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Chronic inflammatory diseases (CIDs), including rheumatic diseases and other inflammatory conditions, often affect women of reproductive age. Tumor necrosis factor inhibitors (TNFi) are widely used to treat CID, but there is limited information on outcomes of TNFi-exposed pregnancies. We evaluated pregnancy outcomes from 1392 prospectively reported pregnancies exposed to certolizumab pegol (CZP), a PEGylated, Fc-free TNFi with no to minimal placental transfer., Methods: CZP-exposed pregnancies in patients with CID from the UCB Pharmacovigilance global safety database were reviewed from the start of CZP clinical development (July 2001) to 1 November 2020. To limit bias, the analysis focused on prospectively reported cases with known pregnancy outcomes., Results: In total, 1392 prospective pregnancies with maternal CZP exposure and known pregnancy outcomes ( n  = 1425) were reported; 1021 had at least first-trimester CZP exposure. Live birth was reported in 1259/1425 (88.4%) of all prospective outcomes. There were 150/1425 (10.5%) pregnancy losses before 20 weeks (miscarriage/induced abortion), 11/1425 (0.8%) stillbirths, and 5/1392 (0.4%) ectopic pregnancies. Congenital malformations were present in 30/1259 (2.4%) live-born infants, of which 26 (2.1%) were considered major according to the Metropolitan Atlanta Congenital Defects Program criteria. There was no pattern of congenital malformations., Discussion and Conclusion: No signal for adverse pregnancy outcomes or congenital malformations was observed in CZP-exposed pregnancies. Although the limitations of data collected through this methodology (including underreporting, missing information, and absence of a comparator group) should be considered, these data provide reassurance for women with CID who require CZP treatment during pregnancy, and their treating physicians., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.C.: Consultancy fees from UCB Pharma; grant/research support from GSK, Janssen, and Pfizer. R.F.-B.: Consultancy fees from AbbVie, BMS, Celgene, Chugai, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, and UCB Pharma. C.N.-P.: Consultancy fees from Alliance Pharma and UCB Pharma; speakers bureau for Alexion, Janssen, Sanofi, and UCB Pharma. A.E.S.: Consultancy fees for Antiretroviral Pregnancy Registry, Harmony Biosciences, IQVIA, PPD, Sanofi-Genzyme, Syneos, UCB Pharma, and ViiV. B.S.: Lecture fees from AbbVie and UCB Pharma. M.D.: Consultancy fees from AbbVie, Arena, BMS, Celgene, Eli Lilly, Gilead, Janssen, Pfizer, Takeda, and UCB Pharma. T.K.: Employee and shareholder of UCB Pharma. R.K.: Employee and shareholder of UCB Pharma; shareholder of Biogen. B.L.: Employee and shareholder of UCB Pharma. F.F.: Grant/research support from UCB Pharma; speakers bureau for Mepha, Roche, and UCB Pharma., (© The Author(s), 2022.)

Background: Pregnancies in women with chronic disease are on the rise. This pertains to autoimmune diseases in particular since these tend to affect women of childbearing age. The interaction between pregnancy and autoimmune disease may increase the risk of maternal, fetal, and obstetric complications; additional care may be required., Methods: This review is based on a selective literature search in PubMed (2015-2020)., Results: In women with autoimmune diseases, the course of pregnancy is highly variable. Some autoimmune diseases tend to improve during pregnancy and do not to result in any serious obstetric complications. Others may worsen during pregnancy, with deterioration of the maternal condition as well as obstetric and perinatal complications. In systemic lupus erythematosus and myasthenia gravis, placental transfer of specific autoantibodies may cause fetal or neonatal disease., Conclusion: The care of pregnant women with chronic diseases requires collaboration between specialists of the pertinent levels of care. A stable course of disease before conception, close interdisciplinary care, and pregnancy-compatible medication contribute to a reduction in maternal and perinatal complications.

Objective: Multiple guidelines recommend continuing hydroxychloroquine (HCQ) for SLE during pregnancy based on observational data. The goal of this individual patient data meta-analysis was to identify the potential benefits and harms of HCQ use within lupus pregnancies., Methods: Eligible studies included prospectively collected pregnancies in women with lupus. After a systematic literature search, seven datasets meeting inclusion criteria were obtained. Pregnancy outcomes and lupus activity were compared for pregnancies with a visit in the first trimester in women who did or did not take HCQ throughout pregnancy. Birth defects were not systematically collected. This analysis was conducted in each dataset, and results were aggregated to provide a pooled OR., Results: Seven cohorts provided 938 pregnancies in 804 women. After selecting one pregnancy per patient with a first trimester visit, 668 pregnancies were included; 63% took HCQ throughout pregnancy. Compared with pregnancies without HCQ, those with HCQ had lower odds of highly active lupus, but did not have different odds of fetal loss, preterm delivery or pre-eclampsia. Among women with low lupus activity, HCQ reduced the odds of preterm delivery., Conclusions: This large study of prospectively-collected lupus pregnancies demonstrates a decrease in lupus activity among woman who continue HCQ through pregnancy and no harm to pregnancy outcomes. Like all studies of HCQ in lupus pregnancy, this study is confounded by indication and non-adherence. As this study confirms the safety of HCQ and diminished SLE activity with use, it is consistent with current recommendations to continue HCQ throughout pregnancy., Competing Interests: Competing interests: MC: Funding: AHRQ, Arthritis Foundation; Grants: GSK; Consulting and Advisory Board: UCB. AE: Grant funding: NIH NCATS Award 1KL2TR002554. SB: Grants: NIH, US FDA, PCORI, RRF, CARRA; Consulting: UCB; Travel: FDA; Leadership: CARRA Assistant Scientific Director. DDG: Grants and/or consulting fees from AstraZeneca; Leadership: Member of the Systemic Lupus International Collaborating Clinics group; served on the Medical advisory board of the Lupus foundation of America. MAP: Grant NIH RO-1 AR069572., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The German pregnancy register Rhekiss is designed as a nationwide, web-based longitudinal observational cohort established in 2015. The register follows women with inflammatory rheumatic disease prospectively from child wish or early pregnancy until 2 years post-partum. Information on clinical and laboratory parameters, drug treatment, and (adverse) pregnancy outcomes are documented in pre-specified intervals. Physicians and patients report data for the same time periods via separated accounts and forms into a web-based application (app). As data entry on mobile devices might improve response rates of patients, a responsive app as a further convenient documentation option was developed. Methods: The Rhekiss-app is available for self-reported data retrieval since August 2017 from the App stores. For the current analysis, Rhekiss register data were used from the start of the register until 30 September 2020. The analyses were performed for forms containing information on devices. Outcome parameters were compared for mobile and desktop users for the quantity and quality of filled forms. Results: In total, 5,048 forms were received and submitted by 966 patients. About 57% of forms were sent from mobile devices with the highest numbers in patients with child wishes (63%). Users of mobile devices were slightly younger and often had less high-education level (62 vs. 79%) compared with desktop users. The proportion of forms submitted via mobile devices increased steadily from 48% in the fourth quarter of 2018 to 64% in the third quarter of 2020. The proportion of forms received before and after the Rhekiss-app implementation increased with the highest increase of 12% for forms filled at time point 12 months post-partum. Mobile users submitted significantly more forms than desktop users (2.9 vs. 2.1), data sent via desktops were more often complete (88 vs. 86%). Conclusion: The responsive app is a valuable additional tool for data collection and is well-accepted by patients as indicated by its increasing use in Rhekiss. Apart from desktop/browser developments, the technological adoptions within observational cohorts and registries should take smartphone requirements and developments into account, especially when patient-reported data in young, mobile patients are collected, bearing in mind that data quality could be compromised and concepts for improving data quality should be implemented., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Richter, Weiß, Bungartz, Fischer-Betz, Zink, Schneider and Strangfeld.)

Background: Uncontrolled inflammatory disease activity can impact pregnancy outcomes and the health of the mother and child. This retrospective claims database analysis assessed treatment patterns before, during, and after pregnancy among women with inflammatory rheumatic disease (IRD; axial spondyloarthritis [axSpA], psoriatic arthritis [PsA], and rheumatoid arthritis [RA]) or psoriasis (PSO) in Germany., Methods: Data were extracted from the BARMER sickness fund (2013-2017). Pregnant women (18-45 years) with documented IRD or PSO diagnoses were compared with age-matched controls from the same database for the analysis of patient characteristics, healthcare resource utilization, and pharmacological treatment during pregnancy. Reported measures included the proportion of women with pharmacological prescriptions or hospitalization/new prescription of corticosteroids or biologics in the 180 days before pregnancy, during pregnancy, and 180 days after delivery. Pre-specified prescription categories (such as disease-specific drugs [not including biologics]) were identified by anatomical therapeutic chemical classification codes. Extrapolated values to the German statutory health insurance population are reported., Results: Overall, 2702 pregnant women with IRD (axSpA: 1063; PsA: 660; RA: 979) and 6527 with PSO were identified. The proportion of women with IRD receiving prescriptions for disease-specific drugs reduced during pregnancy and remained stable after delivery (before: 15.0%; during: 9.0%; after: 9.7%). The proportion of women with PSO receiving prescriptions for disease-specific drugs was low (before: 0.6%; during: 0.3%; after: 0.1%). The proportion of women with hospitalization/new prescription of corticosteroids or biologics decreased during pregnancy, compared with pre-pregnancy, and increased after delivery in women with IRD (before: 9.0%; during: 5.1%; after: 11.1%) and PSO (before: 3.5%; during: 1.9%; after: 2.7%)., Conclusions: A reduction in pharmacological treatment during pregnancy was observed for women with IRD in Germany. Many women with IRD did not return to pre-pregnancy treatments after delivery, despite signs of disease exacerbation, such as hospitalization and initiation of treatment with corticosteroids/biologics, in this period., (© 2021. The Author(s).)

Objectives: To determine whether disease remission or low disease activity state at the beginning of pregnancy in SLE patients is associated with better pregnancy outcome., Methods: Pregnancies in SLE patients prospectively monitored by pregnancy clinics at four rheumatology centres were enrolled. Patient demographics and clinical information were collected at baseline (pregnancy visit before 8 weeks of gestation) including whether patients were in remission according to the Definition of Remission in SLE (DORIS) criteria and and/or Lupus Low Disease Activity State (LLDAS). Univariate and multivariate analysis were performed to determine predictors of disease flare and adverse pregnancy outcomes (APOs) including preeclampsia, preterm delivery, small for gestational age infant, intrauterine growth restriction and intrauterine fetal death., Results: A total of 347 pregnancies were observed in 281 SLE patients. Excluding early pregnancy losses, 212 pregnancies (69.7%) occurred in patients who were in remission at baseline, 33 (10.9%) in patients in LLDAS, and the remainder in active patients. Seventy-three flares (24%) were observed during pregnancy or puerperium, and 105 (34.5%) APOs occurred. Multivariate analysis revealed that patients in disease remission or taking HCQ were less likely to have disease flare, while a history of LN increased the risk. The risk of APOs was increased in patients with shorter disease duration, while being on HCQ resulted a protective variable. An almost significant association between complete remission and a decreased risk of APOs was observed., Conclusions: Prenatal planning with a firm treat-to-target goal of disease remission is an important strategy to reduce the risk of disease flares and severe obstetric complications in SLE pregnancies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: The main study objective was to identify challenges and barriers experienced by dermatologists and rheumatologists when engaging women of reproductive age in shared decision-making (SDM) related to treatment and management of chronic inflammatory disease (CID) before, during and after pregnancy., Design: A mixed-methods study was conducted, employing (1) semistructured interviews, (2) an online survey and (3) triangulation of findings., Participants: 524 dermatologists and rheumatologists entered the study; 495 completed it; 388 met inclusion criteria for analysis. Participants were included if actively practising in Germany (GER), the UK or the USA; had a minimum 5% caseload of female patients of reproductive age with either axial spondyloarthritis, psoriasis, psoriatic arthritis or rheumatoid arthritis; and had experience prescribing biologics., Results: 48 interviews and 340 surveys were analysed. Interviews underscored dermatologists and rheumatologists' suboptimal integration of SDM in clinical practice. In the survey, 90% (n=305) did not know about SDM models. A perceived lack of competency counselling patients on pregnancy and family planning was also identified during interviews. Among the survey sample, 44% (n=150) of specialists agreed they preferred leaving pregnancy-related discussions to obstetricians and/or gynaecologists and 57% (n=189) reported having suboptimal skills discussing contraceptive methods with patients. Another finding that emerged from interviews was the perception that all biologics are strictly contraindicated during pregnancy. Suboptimal knowledge was noted among 57% (n=95) of dermatologists and 48% (n=83) of rheumatologists surveyed in that regard, with a statistically significant difference by country among dermatologists (GER: 42% vs UK: 71% vs USA: 57%, p=0.015)., Conclusions: This study identified low levels of knowledge, skill and confidence, as well as attitudinal issues, that explain why SDM is not fully integrated in dermatology and rheumatology clinical practice. Blended-learning interventions are recommended to assist CID specialists in developing effective communication and patient engagement competencies., Competing Interests: Competing interests: JEM has worked as a paid consultant to lead advisory boards and non-branded talks on the management of psoriasis in women for UCB BioPharma. RF has worked as a paid consultant for UCB BioPharma, and speaker for AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, GSK, Janssen, Lilly, Medac, MSD, Novartis, Roche, UCB BioPharma and Pfizer. CN-P has worked as a paid consultant and speaker for UCB BioPharma. IV has worked as a paid consultant and speaker for UCB BioPharma and speaker for Novartis, Boehringer Ingelheim. IV was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration (ARC) West Midlands. SM is the CEO and founder of AXDEV Group, AXDEV Global and AXDEV Europe. MA and MP are employees of AXDEV Group., (© 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.)

Despite promising candidates for new therapeutic options in the treatment of systemic lupus erythematosus (SLE), many clinical trials have failed in the past few years. The disappointing results have been at least partly be attributed to trial designs. With the aim of stimulating new developments in SLE trial design, an international open space meeting was held on occasion of the European Lupus Meeting 2018 in Duesseldorf, Germany about 'What are the topics you care about for making trials in lupus more effective?'. The Open Space is a participant-driven technology, where the discussion topics and schedule are selected during the meeting by all participants and discussion rounds are led by the people attending encouraging active contributions. Eleven topics were selected for further discussion, of which 6 were voted to be more intensively discussed in two consecutive rounds. Major topics were the optimal handling of glucocorticoids in clinical trials, the improvement of outcome measures, reducing or controlling the placebo response and the identification of biomarkers and stratification parameters. Further, the importance of local and international networks was emphasised. By networking, collaborations are facilitated, patient recruitment is more efficient and treatment can be harmonised thus lead to more successful SLE trials. Further discussions are needed to substantiate the results and develop new trial designs., Competing Interests: Competing interests: None declared., (© 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 investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs., Methods: In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis., Results: The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively., Conclusion: Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Pregnancy represents a complex challenge to clinicians treating women with chronic inflammatory disease. Many clinicians face a situation of heightened sensitivity to the potential risks and uncertainties associated with the effect of pharmacological treatment on pregnancy outcomes. This may create an environment vulnerable to clinical inertia, whereby behavioural factors such as cognitive heuristics and biases, and other factors such as attitudes to risk and emotion can contribute. This systematic review was undertaken to assess if clinical inertia has been investigated/identified in this setting and took a behavioural science approach to identify and understand the potential determinants of clinical inertia in this treatment setting., Methods: A systematic literature search was conducted to identify publications which investigated or described clinical inertia or its determinants (e.g. heuristics, biases etc.). Results were coded for thematic analysis using two inter-related behavioural models: the COM-B model and the Theoretical Domains Framework., Results: Whilst studies investigating or describing clinical inertia in this treatment setting were not identified, the behavioural analysis revealed a number of barriers to the pharmacological management of women of fertile age affected by chronic inflammatory disease. Factors which may be influencing clinician's behaviour were identified in all domains of the COM-B model. The primary factors identified were a lack of knowledge of treatment guidelines and fears concerning the safety of medications for mother and fetus. Lack of experience of treating pregnant patients was also identified as a contributing factor to undertreatment., Conclusion: Using a behavioural approach, it was possible to identify potential factors which may be negatively influencing clinician's behaviour in this treatment setting, although specific research was limited.

Background: The collaborative initiative of the European Network of Pregnancy Registers in Rheumatology (EuNeP) aims to combine data available in nationwide pregnancy registers to increase knowledge on pregnancy outcomes in women with inflammatory rheumatic diseases (IRD) and on drug safety during pregnancy and lactation. The objective of this study was to describe the similarities and differences of the member registers., Methods: From all registers, information about their structure and design was collected, as well as which parameters regarding demographics, maternal outcomes, treatment, course and outcome of pregnancy, and development of the child were available in the respective datasets. Furthermore, the current recruitment status was reported., Results: The four registers (EGR2 (France), RePreg (Switzerland), RevNatus (Norway), and Rhekiss (Germany)) collect information prospectively and nationwide. Patients can be enrolled before conception or during pregnancy. To date, more than 3500 patients in total have been included, and data on 2200 pregnancies with an outcome are available. The distribution of diagnoses in the respective registers varies considerably, and only three entities (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) are captured by all the registers. Broad consistency was found in non-disease-specific data items, but differences regarding instruments and categories as well as frequency of data collection were revealed. Disease-specific data items are less homogeneously collected., Conclusion: Although the registers in this collaboration have similar designs, we found numerous differences in the variables collected. This survey of the status quo of current pregnancy registers is the first step towards identifying data collected uniformly across registers in order to facilitate joint analyses., Trial Registration: Not applicable.

Purpose: Since the launch of belimumab in 2011, the BLyS antibody has been increasingly used in the therapy of systemic Lupus erythematosus (SLE). Comparative studies showed that the intravenous (i.v.) and subcutaneous (s.c.) administration forms do not differ in their efficacy. Since the approval of the s.c. therapy, many patients have been switched from i.v. to s.c. administration. The clinical course of these patients and their satisfaction regarding the drug have not yet been investigated., Methods: A total of 9 patients with SLE were switched from i.v. to s.c. belimumab between 12/2017 and 03/2018. We assessed a self-developed questionnaire on drug satisfaction, disease activity (SLEDAI-2k), serological activity (leukocytes, DNA antibodies, complement), disease damage (SLICC/ACR damage index) and functional status (health-assessment questionnaire) at switching (T0) and after 6 months (T1). Association of the questionnaires with the form of administration (i.v. vs s.c.) was analyzed for each variable separately by linear regression analyses, adjusted for age, gender and disease duration., Results: At switching, disease activity of all patients was well controlled (median SLEDAI-2k = 2 [Interquartile range 0-4]) and the patients were mainly satisfied with their therapy. No evidence for any difference in disease activity, disease damage or patient satisfaction 6 months after switching was found. In tendency, patients were more satisfied with the s.c. administration., Conclusion: The switch from i.v. to s.c. belimumab was successful in all cases and had no effect on disease activity or patient satisfaction. Despite the small sample size, s.c. belimumab seems to offer a good alternative to i.v. application., Competing Interests: RFB, MS and GC have received consulting fees and research support (investigator initiated study; LuLa-study) from GlaxoSmithKline, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2019 Mucke et al.)

Objective: To investigate the role of epitope spreading in established systemic lupus erythematosus (SLE)., Methods: IgG autoantibody reactivity with 398 distinct recombinant proteins was measured over a period of 6 years in 69 SLE patients and compared to that in 45 controls. Changes in mean fluorescence intensity (MFI), number of autoantibodies to distinct antigens, and reactivity with distinct clones of established antigenic targets (e.g., U1 RNP, Sm, and ribosomal P) representing epitope fine mapping were assessed. Linear mixed modeling, adjusted with Bonferroni correction for age and sex, was applied., Results: The total number of autoantibodies, mean MFI, and number of autoantibodies in epitope fine mapping were higher in SLE patients compared to controls (P < 0.0001). The total number of antibodies to distinct autoantigens remained stable over time, while the mean MFI decreased over time in SLE (P < 0.021). SLE patients showed variable recognition of epitopes in fine mapping over time. In particular, in SLE patients, more clones of the U1 RNP complex were recognized at the time of new organ involvement (+0.65) (P = 0.007). Mean MFI was higher in patients with lupus nephritis (P = 0.047). The time-averaged MFIs of 22 individual autoantibodies (including double-stranded DNA [dsDNA]) were higher, after Bonferroni correction, in SLE (P < 0.0001). The MFIs of dsDNA and histone cluster 2 H3c were associated with scores on the Systemic Lupus Activity Measure (P < 0.0001)., Conclusion: Longitudinal surveillance of the IgG autoantibody repertoire in established SLE reveals evidence of sustained breadth of autoantibody repertoire without significant expansion. Associations of disease activity with dsDNA and with histone H3 autoantibodies were confirmed., (© 2018, American College of Rheumatology.)

Mixed connective tissue disease (MCTD) is a complex overlap disease with features of different autoimmune connective tissue diseases (CTDs) namely systemic sclerosis, poly/dermatomyositis and systemic lupus erythematous in patients with antibodies targeting the U1 small nuclear ribonucleoprotein particle. In this narrative review, we summarise the results of a systematic literature research which was performed as part of the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases project, aimed at evaluating existing clinical practice guidelines (CPGs) or recommendations. Since no specific CPGs on MCTD were found, other CPGs developed for other CTDs were taken into consideration in order to discuss what can be applied to MCTD even if designed for other diseases. Three major objectives were proposed for the future development of CPGs: MCTD diagnosis (diagnostic criteria), MCTD initial and follow-up evaluations, MCTD treatment. Early diagnosis, epidemiological data, assessment of burden of disease and QOL aspects are among the unmet needs identified by patients., Competing Interests: Competing interests: None declared.

Objectives: Vaccinations are an important measure to prevent infections in immunocompromised patients. The knowledge of vaccination coverage and reasons for non-vaccination in patients with SLE is scarce. The aim of this study was to assess coverage rates of selected vaccinations in a representative sample of SLE patients and to identify predictors for non-vaccination., Methods: In 2013, information on selected vaccinations (coverage, application and reservations) and on demographics, clinical parameters and health beliefs was assessed by means of a self-reported questionnaire among a representative sample of SLE patients in Germany (LuLa cohort)., Results: Five hundred and seventy-nine patients participated. Vaccination status was primarily checked by their general practitioner (57.3%). Of all the patients, 24.9% did not get their vaccination status checked at all, 16.1% had generally been advised against the use of vaccinations by a physician, and 37.5% stated that they had rejected vaccinations themselves. Their main reasons were fears of developing a lupus flare (21.8%) or adverse events (13.5%). A greater belief by patients in the doctor controlling one's health and the general benefit of medication prevented the rejection of vaccines. Vaccination coverage was low for all recorded vaccinations (tetanus 65.8%, influenza 45.2%, pneumococcus 32.2% and meningococcus 6.1%). Older age was predictive of receiving influenza and pneumococcal vaccination. The same applies for CSs >7.5 mg for receiving influenza vaccination., Conclusion: Vaccination coverage in SLE patients is poor and reflects insufficient implementation of national and international recommendations. Rheumatologists need to recognize patients' reservations against vaccinations, to communicate their importance and safety and to give individual recommendations to patients and their health-care providers., Trial Registration: German Clinical Trials Register, www.germanctr.de, DRKS00011052.

Background: Recurrent miscarriage, also referred to as recurrent spontaneous abortion (RSA), affects 1 - 5% of couples and has a multifactorial genesis. Acquired and congenital thrombophilia have been discussed as hemostatic risk factors in the pathogenesis of RSA., Method: This review article was based on a selective search of the literature in PubMed. There was a special focus on the current body of evidence studying the association between RSA and antiphospholipid syndrome and hereditary thrombophilia disorders., Results: Antiphospholipid syndrome (APS) is an acquired autoimmune thrombophilia and recurrent miscarriage is one of its clinical classification criteria. The presence of lupus anticoagulant has been shown to be the most important serologic risk factor for developing complications of pregnancy. A combination of low-dose acetylsalicylic acid and heparin has shown significant benefits with regard to pregnancy outcomes and APS-related miscarriage. Some congenital thrombophilic disorders also have an increased associated risk of developing RSA, although the risk is lower than for APS. The current analysis does not sufficiently support the analogous administration of heparin as prophylaxis against miscarriage in women with congenital thrombophilia in the same way as it is used in antiphospholipid syndrome. The data on rare, combined or homozygous thrombophilias and their impact on RSA are still insufficient., Conclusion: In contrast to antiphospholipid syndrome, the current data from studies on recurrent spontaneous abortion do not support the prophylactic administration of heparin to treat women with maternal hereditary thrombophilia in subsequent pregnancies. Nevertheless, the maternal risk of thromboembolic events must determine the indication for thrombosis prophylaxis in pregnancy.

Objective: Diagnosis of SLE relies on the detection of autoantibodies. We aimed to assess the diagnostic potential of histone H4 and H2A variant antibodies in SLE., Methods: IgG-autoantibodies to histones H4 (HIST1H4A), H2A type 2-A (HIST2H2AA3) and H2A type 2-C (HIST2H2AC) were measured along with a standard antibody (SA) set including SSA, SSB, Sm, U1-RNP and RPLP2 in a multiplex magnetic microsphere-based assay in 153 SLE patients [85% female, 41 (13.5) years] and 81 healthy controls [77% female, 43.3 (12.4) years]. Receiver operating characteristic analysis was performed to assess diagnostic performance of individual markers. Logistic regression analysis was performed on a random split of samples to determine the additional value of histone antibodies in comparison with SA by likelihood ratio test and determination of diagnostic accuracy in the remaining validation samples., Results: Microsphere-based assay showed good interclass correlation (mean 0.85, range 0.73-0.99) and diagnostic performance in receiver operating characteristic analysis (area under the curve (AUC) range 84.8-93.2) compared with routine assay for SA parameters. HIST1H4A-IgG was the marker with the best individual diagnostic performance for SLE vs healthy (AUC 0.97, sensitivity 95% at 90% specificity). HIST1H4A-IgG was an independent significant predictor for the diagnosis of SLE in multivariate modelling (P < 0.0001), and significantly improved prediction of SLE over SA parameters alone (residual deviance 45.9 vs 97.1, P = 4.3 × 10-11). Diagnostic accuracy in the training and validation samples was 89 and 86% for SA, and 95 and 89% with the addition of HIST1H4A-IgG., Conclusion: HIST1H4A-IgG antibodies improve diagnostic accuracy for SLE vs healthy., (© The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. [br]For Permissions, please email: journals.permissions@oup.com)

Objective: To provide an estimate of age-specific incidence rate of physician-diagnosed systemic lupus erythematosus (SLE) for German men and women., Methods: The age-specific and sex-specific prevalence of diagnosed SLE in claims data is used to estimate the incidence in the German male and female population. The claims data set stems from a representative sample of the statutory health insurance in 2002 and comprises 2.3 million people. The statutory health insurance covers >85% of the German population., Results: The estimated incidence rates are 0.9 (95% CI 0.7 to 1.1) per 100 000 person-years for men and 1.9 (95% CI 1.7 to 2.2) per 100 000 person-years for women. The age-specific incidence rate of SLE in the male population has a maximum of 2.2 (95% CI 1.0 to 3.4) per 100 000 person-years at the age of 65-70 years. In women, the incidence is peaking at the rate of 3.6 (95% CI 2.9 to 4.3) cases per 100 000 person-years at the age of 20-25 years, but has a second local maximum (2.6, 95% CI 1.5 to 3.8) at menopausal age., Conclusions: For the first time, representative data on the incidence of SLE in Germany are provided. The estimated incidence rates of SLE for men and women in Germany are at the lower end of other estimates from comparable European countries., Competing Interests: Conflicts of Interest: None declared.

Background: The aim was to identify novel diagnostic autoantibody candidates for rheumatoid arthritis (RA) by comprehensive screening for autoreactivity., Method: We incubated 5892 recombinant proteins coupled to fluorescent beads, with patients' sera for the detection of IgG-autoantibodies in three independent patient cohorts: A (n = 72 patients with established RA); B/B- (n = 116 patients with early RA (B) and n = 51 CCP-negative patients with early RA from B (B-)); and C (n = 184 patients with early seronegative RA), in comparison to matched healthy controls. Intersects of significantly increased autoantibodies as determined by the Mann-Whitney test were sought., Result: Screening of 5892 antigens in RA cohorts A and B, or the seronegative cohorts B- and C revealed intersects of 23 and 13 significantly increased autoantibodies, respectively. Reactivity to three antigens was increased in all cohorts tested: N-acetylglucosamine-1-phosphate transferase, gamma subunit (GNPTG), heterogeneous nuclear ribonucleoprotein A1-like 2 (HNRNPA1), and insulin-like growth factor binding protein 2 (IGFBP2)., Conclusions: Comprehensive sequential screening for autoantibodies reveals novel candidates for diagnostic markers in both seropositive and seronegative RA and suggests new fields of research into the pathogenesis of RA.

Objective: The aim of this study was to identify factors associated with pain coping and catastrophising in patients with systemic lupus erythematosus., Methods: All patients were participants of the lupus erythematosus long-term study, which is based on patient-reported data assessed among members of the German Lupus Erythematosus Self-Help Organization. Assessments were performed by means of a questionnaire. Among self-reported clinical data the Pain-Related Self Statements Scale (PRSS) was included. To depict significant differences univariable analyses were carried out using non-parametrical rank tests. To examine factors influencing our outcome variables, we performed a multivariable stepwise regression model including variables that presented significantly in the univariable analysis., Results: 447 cases (94.9% female) were analysed showing a mean catastrophising score of 1.1 (SD 0.8) and a mean coping score of 2.8 (SD 0.9) in the PRSS subscales. Higher catastrophising quartiles went along with higher experienced pain, lupus activity, fatigue, damage and decreased health related quality of life, whereas they presented inversely for coping. In our multivariable model, factors associated with catastrophising were: number of lupus-specific drugs (p value 0.004), pain in the last 7 days (p value 0.034), the Short Form 12 Health Survey Mental Component Summary (p value <0.001) and disease activity measured by the Systemic Lupus Activity Questionnaire (p value 0.042). Social participation reflected by performed leisure activities such as dancing or bowling had a positive association with coping (p value 0.006). In contrast, other health related physical activities and their extent had no impact on coping. A direct association between the amount of pain coping and catastrophising, as well as a great impact of the catastrophising, respectively, coping level on physical and mental functioning could be shown., Conclusions: Reduction or increase of detected factors might lead to a modification of pain coping and catastrophising and offer an approach to more effective care in patients with SLE.

Objectives: Disease activity accounts for damage, overall mortality and co-morbidities in SLE and should frequently be assessed to adapt therapeutic patient management. The Systemic Lupus Activity Questionnaire (SLAQ) is a patient-reported instrument for the assessment of disease activity derived from the Systemic Lupus Erythematosus Activity Measure (SLAM) and was originally developed in English. Our aim was to validate the SLAQ in German and evaluate its use in a large cohort., Methods: We translated and adapted the SLAQ questionnaire in German. It was applied to SLE outpatients at a tertiary centre (n=328) and compared to the SLAMnolab and other SLE outcome parameters. Internal consistency, criterion validity, inter-rater and test-retest reliability as well as construct validity were examined. Correlation, Cronbach's alpha, Mann-Whitney U-test or the Kruskal-Wallis one-way analysis of variance test were ascertained where appropriate. Levels of statistical significance were defined at 5% (p<0.05). All reported p-values are two-tailed., Results: The German SLAQ showed a comparable strong correlation with the SLAMnolab (r=0.632, p<0.0001) as the original version of the SLAQ and presented a good to excellent internal consistency reliability (Cronbach's alpha=0.89). Accrued damage as well as low disease activity are factors possibly influencing the score. Amongst others, scores were higher in patients with more reported flares, lower self-reported overall health, lower functional status and higher daily doses of prednisolone., Conclusions: Our German version of the SLAQ shows a comparable validity as the original SLAQ and is a promising instrument to survey disease activity in clinical routine as well as in clinical and epidemiological studies. Possible interacting factors need to be considered when applying.

Chronic diseases impose a tremendous global health problem of the 21st century. Epidemiological and public health models help to gain insight into the distribution and burden of chronic diseases. Moreover, the models may help to plan appropriate interventions against risk factors. To provide accurate results, models often need to take into account three different time-scales: calendar time, age, and duration since the onset of the disease. Incidence and mortality often change with age and calendar time. In many diseases such as, for example, diabetes and dementia, the mortality of the diseased persons additionally depends on the duration of the disease. The aim of this work is to describe an algorithm and a flexible software framework for the simulation of populations moving in an illness-death model that describes the epidemiology of a chronic disease in the face of the different times-scales. We set up a discrete event simulation in continuous time involving competing risks using the freely available statistical software R. Relevant events are birth, the onset (or diagnosis) of the disease and death with or without the disease. The Lexis diagram keeps track of the different time-scales. Input data are birth rates, incidence and mortality rates, which can be given as numerical values on a grid. The algorithm manages the complex interplay between the rates and the different time-scales. As a result, for each subject in the simulated population, the algorithm provides the calendar time of birth, the age of onset of the disease (if the subject contracts the disease) and the age at death. By this means, the impact of interventions may be estimated and compared.

Objective: MMF is teratogenic and needs to be replaced before pregnancy. This change may lead to flares. Our aim was to determine the risk of renal flares in women with LN who switched treatment from MMF to AZA before conception and to evaluate the outcome of their pregnancies., Methods: Medical records of women with LN counselled for pregnancy wish were reviewed. Women receiving treatment with either MMF or AZA (control group), with inactive lupus (SLEDAI ≤ 4) and quiescent LN (serum creatinine <1.5 mg/dl, inactive sediment and proteinuria <1 g/24 h for the preceding 6 months) were eligible for this study., Results: We identified 54 women [23 treated with MMF (group 1) and 31 treated with AZA (group 2)]. MMF dosage was tapered and subsequently transferred to AZA, which was maintained throughout pregnancy. Three (13%) patients (group 1) vs none (group 2) developed a renal flare 3-6 months after transitioning from MMF to AZA (P = 0.14) before pregnancy ensued. The only parameter with a significant difference in those with flare compared with those without was younger age (median 27 vs 30 years; P = 0.03). Risk for adverse outcome within 48 pregnancies (pre-eclampsia 9%, preterm delivery 20.5%) increased with every milligramme of prednisone dosage [odds ratio (OR) 2.03] and every single unit of SLEDAI score (OR 3.92). Renal flares occurred post-partum in two women. No patient developed worsening of renal function., Conclusion: Replacing MMF with AZA in patients with quiescent LN for pregnancy planning rarely leads to renal flares. Pregnancy outcome was favourable.

Objectives: To analyse if defensins, immunomodulatory peptides involved in angiogenesis and elevated in the sera of systemic lupus erythematosus (SLE) patients, relate to cardiovascular disease in SLE., Methods: Serum levels of the defensins human beta defensin 2 (hBD2) and human neutrophil peptide (HNP) of 72 SLE patients were determined by ELISA at baseline. Cardiovascular risk factors and the occurrence of cardiovascular events (CVE: stroke, claudication, angina pectoris, myocardial infarction) were recorded over 6 years. Intima media thickness of the carotid arteries (CIMT) was measured by ultrasound in 42 patients at baseline and at 4 years. Normally distributed log-transformed defensin levels (log-hBD2 and log-HNP) were used for statistical analysis., Results: SLE patients who experienced a CVE had significantly higher log-hBD2 values and a likelihood-ratio for CVE of 2.23 when levels increased above 3.3 log(ng/ml). Using binary logistic regression analysis, log-hBD2 significantly contributed to a model also incorporating the number of traditional cardiovascular risk factors (dyslipidemia, hypertension, positive family history, age, smoking) as explanatory variables for the incidence of cardiovascular events. Moreover, SLE patients with progressive CIMT showed increased log-hBD2 and log-HNP values. Both defensin-levels also showed some correlation to the plaque stadium at baseline (hBD2: r2 0.10; HNP r2 0.12). Neither log-hBD2 nor log-HNP were correlated to traditional cardiovascular risk factors., Conclusions: HNP and especially hBD2 may be indicators of progressive cardiovascular disease in SLE.

Adult onset Still's disease (AOSD) is an uncommon, systemic, inflammatory disorder of unknown etiology, characterised by spiking fevers, skin rash, and arthritis. Treatment consists of glucocorticosteroids and immunosuppressive drugs. Over the last few years it has become increasingly evident that treatment with the IL-1 receptor antagonist (IL-1RA) anakinra is highly effective even in patients with intractable disease. So far, there are scant data available on the effects of anakinra in pregnancy. We report two patients with AOSD who successfully gave birth while treated with anakinra during pregnancy.

Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting., Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators., Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm)., Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Systemic connective tissue diseases (CTDs) are disease entities characterized by a systemic and heterogeneous spectrum of clinical symptoms. The treatment of CDTs has improved substantially, but with the developments of new and probably more expensive targeted therapies, there will be a need of rigorous evaluation in patient-oriented research. Proposed domains for outcome measurement of CTDs are activity, damage by disease and/or medications and quality of life. To evaluate the overall disease activity in CTDs, scores are developed that include typical signs and symptoms. For example, in systemic lupus erythematosus (SLE), various activity instruments have been developed and validated. Recently, a definition for significant reduction in activity based on these scores was proposed and has now to be validated in clinical trials. In addition, the American College of Rheumatology has framed recommendations for response criteria of major target organs. Besides, the rarity of CTDs other than SLE and the rare therapeutic options, especially the heterogeneous disease expression, has prevented development of instruments scoring the disease activity. In individual patients, there is need for a more organ-specific evaluation, and non-disease-specific and/or global health instruments may be used in evaluating the response of individual treatment regimen.

Objective: To evaluate a novel specific psychological intervention aimed at improving coping in patients with systemic lupus erythematosus (SLE)., Methods: 34 community living SLE patients were recruited for the study. Intervention was undertaken in groups of up to eight patients and in two blocks over six months each. Eight patients were enrolled as a waiting list group. The 18 group sessions focused on information about the disease and specific problems of SLE patients, combining psychoeducative and psychotherapeutic elements. Psychological and medical evaluations were conducted at baseline and after three, six, and 12 months, using validated instruments., Results: The 34 SLE patients (91% female, mean age 42 years) improved significantly over a six month period on most of the psychological measuring instruments applied, such as depression, anxiety, and overall mental burden. The waiting list group showed no significant changes., Conclusions: Conceptualised psychoeducational support may produce a significant and sustained improvement in coping skills of SLE patients and hence in their quality of life.

Background: The heteropolymer technology was developed to remove pathogens from the circulation., Objectives: To evaluate the safety and tolerability of a single administration and to establish proof of principle for ETI-104 in normal healthy volunteers (NHV) and patients with systemic lupus erythematosus (SLE) METHODS: The drug was given intravenously to 11 NHV and six patients with SLE. Over 28 days, vital signs were noted, a haematological and chemical analysis of blood and urine was carried out, and adverse events were recorded. CR1 receptor numbers, the ability of antigen based heteropolymers to bind to red blood cells (RBCs), and the clearance of high avidity and total anti-dsDNA antibodies were measured by Farr assays and FACS analysis., Results: No safety measure differed significantly from normal in both groups; no drug related serious adverse events occurred. ETI-104 rapidly bound to RBCs in NHV and patients with SLE. Binding of the drug to RBCs of patients with SLE also caused a rapid reduction of circulating anti-dsDNA antibodies in the plasma 15 minutes after administration, with a maximum reduction of 55% (range 43-62). At 28 days statistically significant decreases were maintained in three patients, while in the other three the values had returned to baseline levels., Conclusion: These clinical trials established the safety and the proof of principle of the new immunoconjugate ETI-104. This provides the basis for further development of this technology for numerous indications-for example, therapeutic options for autoimmune diseases or viral and bacterial infections.