Rhekiss-The German Register for Child Wish and Pregnancies in Inflammatory Rheumatic Diseases.

In pharmacoepidemiology, robust data are needed to judge the impact of drug treatment on pregnancy, pregnancy outcomes and breast-fed infants. As pregnant and breastfeeding women are usually excluded from randomised clinical trials, observational studies are required. One of those data sources are pregnancy registers specifically developed to focus on certain diseases or disease groups. The German Rhekiss register investigates pregnancies in women with chronic inflammatory rheumatic diseases (IRD). Rhekiss is a nationwide, multicentre, longitudinal study, in which women aged 18 years or older with an underlying IRD can be enrolled by a rheumatologist either when planning a pregnancy or in the first half of pregnancy. Data are collected prospectively at regular follow-up visits. Rheumatologists and patients provide information in a web-based system before conception (if enrolment was at the time of pregnancy planning), during and after pregnancy. A smartphone app is available for patients. Maternal and clinical information, general laboratory markers, treatment with antirheumatic and other drugs, adverse events, items related to course and outcome of pregnancy and the health of the child are uniformly assessed for all diseases. Individual information on the IRD includes classification criteria, diagnosis-specific laboratory parameters, clinical parameters and validated instruments to measure disease activity or damage. Furthermore, patient-reported outcome measures are captured. A total of 2013 individual patients have been enrolled in the register, and data on 1801 completed pregnancies are available. In summary, Rhekiss is a comprehensive and complex register that can answer various research questions about pregnancy in women with chronic IRDs.

Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP).

OBJECTIVE: To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. METHODS: Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. RESULTS: In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. CONCLUSIONS: Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.

Health-related quality of life in patients with mixed connective tissue disease: a comparison with matched systemic sclerosis patients.

OBJECTIVES: Health-Related Quality of Life (HRQoL) in adult patients with mixed connective tissue disease (MCTD) has not been described so far. Therefore, we performed an explorative study to evaluate HRQoL in MCTD patients. METHODS: MCTD patients fulfilling the Kahn criteria and participating in the prospective follow-up cohort for MCTD of the Leiden University Medical Center were included; and matched to systemic sclerosis (SSc) patients based on age, sex and disease duration. Data on disease characteristics and HRQoL (SF36 and EQ-5D) were collected annually. HRQoL was compared between MCTD and SSc patients at baseline. Factors associated with HRQoL in MCTD were identified using linear regression and change in HRQoL over 3 years using linear mixed models. RESULTS: Thirty-four MCTD patients (121 visits) and 102 SSc patients (424 visits) were included. At baseline, MCTD patients presented with interstitial lung disease, cardiac involvement, synovitis and myositis more frequently compared to SSc patients, while use of immunosuppressive medication was less frequent. In both groups, mean SF36 scores were lower than in the general Dutch population. The SF36 subscore "general health perception" was impacted most in both groups (MCTD: 38.5 [SD:7.0], SSc: 39.9 [SD:8.9]). During follow-up, SF36 scores improved in MCTD patients, while EQ5DNL remained stable. No specific characteristics were identified that associated with baseline HRQoL or change in HRQol over time. CONCLUSIONS: Like in SSc, HRQoL in MCTD is significantly impaired, especially the general health perception of patients. Evaluation in larger prospective cohorts is needed to identify characteristics that impact HRQol most.

The added value of a European Reference Network on rare and complex connective tissue and musculoskeletal diseases: insights after the first 5 years of the ERN ReCONNET.

In order to address the main challenges related to the rare diseases (RDs) the European Commission launched the European Reference Networks (ERNs), virtual networks involving healthcare providers (HCPs) across Europe. The mission of the ERNs is to tackle low prevalence and RDs that require highly specialised treatment and a concentration of knowledge and resources. In fact, ERNs offer the potential to give patients and healthcare professionals across the EU access to the best expertise and timely exchange of lifesaving knowledge, trying to make the knowledge travelling more than patients. For this reason, ERNs were established as concrete European infrastructures, and this is particularly crucial in the framework of rare and complex diseases in which no country alone has the whole knowledge and capacity to treat all types of patients.It has been five years since their kick-off launch in Vilnius in 2017. The 24 ERNs have been intensively working on different transversal areas, including patient management, education, clinical practice guidelines, patients' care pathways and many other fundamental topics. The present work is therefore aimed not only at reporting a summary of the main activities and milestones reached so far, but also at celebrating the first 5 years of the ERN on Rare and Complex Connective Tissue and Musculo-skeletal Diseases (ReCONNET), in which the members of the network built together one of the 24 infrastructures that are hopefully going to change the scenario of rare diseases across the EU.

EULAR recommendations for a core data set for pregnancy registries in rheumatology.

BACKGROUND AND OBJECTIVE: There is an urgent need for robust data on the trajectories and outcomes of pregnancies in women with inflammatory rheumatic diseases (IRD). In particular when rare outcomes or rare diseases are to be investigated, collaborative approaches are required. However, joint data analyses are often limited by the heterogeneity of the different data sources.To facilitate future research collaboration, a European League Against Rheumatism (EULAR) Task Force defined a core data set with a minimum of items to be collected by pregnancy registries in rheumatology covering the period of pregnancy and the 28-day neonatal phase in women with any underlying IRD. METHODS: A stepwise process included a two-round Delphi survey and a face-to-face meeting to achieve consensus about relevant items. RESULTS: A total of 64 multidisciplinary stakeholders from 14 different countries participated in the two rounds of the Delphi process. During the following face-to-face meeting of the EULAR Task Force, consensus was reached on 51 main items covering 'maternal information', 'pregnancy' and 'treatment'. Generic instruments for assessment are recommended for every item. Furthermore, for the five most frequent IRDs rheumatoid arthritis, spondyloarthritis, juvenile idiopathic arthritis, systemic lupus erythematosus and other connective tissue diseases, disease-specific laboratory markers and disease activity measurements are proposed. CONCLUSION: This is the first consensus-based core data set for prospective pregnancy registries in rheumatology. Its purpose is to stimulate and facilitate multinational collaborations that aim to increase the knowledge about pregnancy course and safety of treatment in women with IRDs during pregnancy.

Are remission and low disease activity state ideal targets for pregnancy planning in systemic lupus erythematosus? A multicentre study.

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.

Factors detrimental to work productivity and daily activities in systemic lupus erythematosus patients - Analysis of the German LuLa study.

OBJECTIVE: The aim of this study was to identify factors associated with impaired work productivity and impaired daily activities in patients with systemic lupus erythematosus (SLE). METHODS: The LuLa study is a longitudinal patient-reported study. Beyond sociodemographic data, work productivity, daily activities and fatigue, several other clinical outcome parameters (e.g. mental health-related quality of life and physical functioning, disease activity, damage and pain) were surveyed with validated questionnaires. The effects of confounders on work productivity (WPAI 2) and daily activity domains (WPAI 4) were studied by multivariate regression analysis. RESULTS: A total of 585 patients completed the questionnaire of whom 259 were employed and analysed. The median impairment in work productivity (WPAI 2) was 20% (Q1-3 0-40), and the median impairment in daily activities (WPAI 4) was 30% (Q1-3 10-50%). Multivariate regression analysis revealed that fatigue, pain, disease activity and health-related quality of life affected WPAI 2 and 4. Furthermore, we observed distinct synergistic effects of fatigue, disease activity and pain on both work productivity and daily activities: a higher impact of fatigue was associated with the reported extent of pain or disease activity. CONCLUSION: In employed patients with SLE, impaired work productivity and impaired daily activities were frequently reported. Fatigue, pain, disease activity and health-related quality of life demonstrated a detrimental impact, with a synergistic effect of fatigue, disease activity and pain. Hence, both optimized pain management and targeted immunomodulatory therapy are important for preserving active participation in life among patients with fatigue.

Delayed diagnosis adversely affects outcome in systemic lupus erythematosus: Cross sectional analysis of the LuLa cohort.

OBJECTIVE: Despite increased physician's awareness and improved diagnostic and serological testing in the recent years, the interval between the initial symptoms and the diagnosis of Systemic lupus erythematosus (SLE) is still very long. Our aim was to study this delay and its association to the outcome of the disease. METHODS: Information on demographics, onset of first symptoms, first physicians visit and time of diagnosis was assessed by self-reported questionnaires among SLE patients in Germany (LuLa cohort, n = 585) in the year 2012. Disease activity (Systemic Lupus Activity Questionnaire; SLAQ), disease related damage (Brief Index of Lupus Damage; BILD), health related quality of life (Short Form 12) and fatigue (FSS) were chosen as proxies for outcome. Linear regression analysis was used to analyze the association of the delay in diagnosis to the outcome, adjusted for age, disease duration and sex. RESULTS: Mean duration between the onset of symptoms and the diagnosis of SLE was 47 months (SD 73). The longer the time to diagnosis, the higher the disease activity (ß = 0.199, p < 0.0001), the disease-related damage (ß = 0.137, p = 0.002) and fatigue (ß 0.145, p = 0.003) and the lower the health-related quality of life (physical ß = -0.136, p = 0.004, mental ß = -0.143, p = 0.004). CONCLUSION: In systemic lupus erythematosus, longer time to diagnosis was associated with worse outcome. Concepts in care with the intention to shorten the time to diagnosis are needed to improve the long-term outcome of the disease.

[State of the art: fertility and pregnancy in rheumatic diseases]. / State of the Art: Fertilität und Schwangerschaft bei rheumatischen Erkrankungen.

Inflammatory rheumatic diseases often affect women of childbearing age, for whom pregnancy is still associated with increased risks. At the same time, we are gaining more and more insights into risk factors and preventive strategies, enabling almost all women to have successful pregnancies with few adverse outcomes. The cornerstones are planning of the pregnancy under effective disease control and the modification of individual risk factors. Hydroxychloroquine is once again coming into focus as a compound with multiple positive effects. Recommendations published by the American College of Rheumatology (ACR) provide a practical overview of the evidence. Based on the current state of knowledge, rheumatologists can make a lasting contribution to a positive pregnancy outcome for mother and child.

[Deescalation and glucocorticoid-free treatment in SLE]. / Deeskalation und glukokortikoidfreie Therapie bei SLE.

Treatment of systemic lupus erythematosus (SLE) without permanent glucocorticoid therapy is inconceivable for most patients and their physicians. Although we have significantly improved the prognosis of SLE, management remains constrained by a lack of effective, targeted therapies and the lack of evidence-based approaches to the use of existing compounds. For example, for glucocorticoids (GC), which are used continuously in a majority of patients, there are no evidence-based recommendations for initiation, tapering, and cessation in the treatment of SLE. Even today, GC are without alternatives in acute situations, especially organ- or life-threatening ones. However, due to the known long-term adverse effects, the role of GC is viewed increasingly critically. Long-term data from cohorts show that the use of GC actually contributes to morbidity and mortality in SLE. Strategies to reduce the use of GC in SLE are therefore urgently needed and are proposed in this paper.

Pregnancy outcomes in DMARD-exposed patients with juvenile idiopathic arthritis-results from a JIA biologic registry.

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.

[Antiphospholipid syndrome : Update on diagnostics and management]. / Antiphospholipidsyndrom : Update zu Diagnostik und Therapie.

Antiphospholipid syndrome (APS) was first identified in patients with systemic lupus erythematosus (SLE) and frequent occurrence of thromboembolic complications and miscarriages accompanied by detection of anticardiolipin antibodies (aCL). When APS was also later found without an underlying SLE, the so-called primary APS was distinguished from its secondary form with SLE. Even more specific than aCL are the lupus anticoagulant (LA) and antibodies against beta­2 glycoprotein I (aB2GP I). In recent years, it has become evident that the risk of (further) thromboembolic and obstetric complications is markedly increased if all three serological criteria of APS (aCL, aB2GP I and LA), the so-called triple positivity, are present (high-risk profile). Immunosuppression is not effective in preventing further thromboembolic complications of APS. Low-dose aspirin (LDA), heparin and vitamin K antagonists are used in primary and secondary prophylaxis. The direct oral anticoagulants have an increased risk of complications compared to these treatments and should not be used in cases of high-risk APS.

What factors could influence physicians' management of women of childbearing age with chronic inflammatory disease? A systematic review of behavioural determinants of clinical inertia.

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.

Vaccination coverage in systemic lupus erythematosus-a cross-sectional analysis of the German long-term study (LuLa cohort).

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.

High diagnostic accuracy of histone H4-IgG autoantibodies in systemic lupus erythematosus.

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.

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).

OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation.

A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The level of agreement among experts in regard to statements and propositions of use in clinical practice was established by Delphi voting. The task force defined 4 overarching principles and 11 points to consider for use of antirheumatic drugs during pregnancy and lactation. Compatibility with pregnancy and lactation was found for antimalarials, sulfasalazine, azathioprine, ciclosporin, tacrolimus, colchicine, intravenous immunoglobulin and glucocorticoids. Methotrexate, mycophenolate mofetil and cyclophosphamide require discontinuation before conception due to proven teratogenicity. Insufficient documentation in regard to fetal safety implies the discontinuation of leflunomide, tofacitinib as well as abatacept, rituximab, belimumab, tocilizumab, ustekinumab and anakinra before a planned pregnancy. Among biologics tumour necrosis factor inhibitors are best studied and appear reasonably safe with first and second trimester use. Restrictions in use apply for the few proven teratogenic drugs and the large proportion of medications for which insufficient safety data for the fetus/child are available. Effective drug treatment of active inflammatory rheumatic disease is possible with reasonable safety for the fetus/child during pregnancy and lactation. The dissemination of the data to health professionals and patients as well as their implementation into clinical practice may help to improve the management of pregnant and lactating patients with rheumatic disease.