Levosimendan as a calcium-sensitizer is a promising innovative therapeutical option for the treatment of severe cardiac dysfunction (CD) and pulmonary hypertension (PH) in preterm infants, but no data are available analyzing levosimendan in cohorts of preterm infants. The design/setting of the evaluation is in a large case-series of preterm infants with CD and PH. Data of all preterm infants (gestational age (GA) < 37 weeks) with levosimendan treatment and CD and/or PH in the echocardiographic assessment between 01/2018 and 06/2021 were screened for analysis. The primary clinical endpoint was defined as echocardiographic response to levosimendan. Preterm infants (105) were finally enrolled for further analysis. The preterm infants (48%) were classified as extremely low GA newborns (ELGANs, < 28 weeks of GA) and 73% as very low birth weight infants (< 1500 g, VLBW). The primary endpoint was reached in 71%, without difference regarding GA or BW. The incidence of moderate or severe PH decreased from baseline to follow-up (24 h) in about 30%, with a significant decrease in the responder group (p < 0.001). The incidence of left ventricular dysfunction and bi-ventricular dysfunction decreased significantly from baseline to follow-up (24 h) in the responder-group (p = 0.007, and p < 0.001, respectively). The arterial lactate level decreased significantly from baseline (4.7 mmol/l) to 12 h (3.6 mmol/l, p < 0.05), and 24 h (3.1 mmol/l, p < 0.01).  Conclusion: Levosimendan treatment is associated with an improvement of both CD and PH in preterm infants, with a stabilization of the mean arterial pressure during the treatment and a significant decrease of arterial lactate levels. Future prospective trials are highly warranted. What is Known: • Levosimendan as a calcium-sensitizer and inodilator is known to improve the low cardiac output syndrome (LCOS), and improves ventricular dysfunction, and PH, both in pediatric as well as in adult populations. Data related to critically ill neonates without major cardiac surgery and preterm infants are not available. What is New: • This study evaluated the effect of levosimendan on hemodynamics, clinical scores, echocardiographic severity parameters, and arterial lactate levels in a case-series of 105 preterm infants for the first time. Levosimendan treatment in preterm infants is associated with a rapid improvement of CD and PH, an increase of the mean arterial pressure, and a significant decrease in arterial lactate levels, as surrogate marker for a LCOS. • How this study might affect research, practice, or policy. As no data are available regarding the use of levosimendan in this population, our results hopefully animate the research community to conduct future prospective trails analyzing levosimendan in randomized controlled trials (RCT) and observational control studies. Additionally, our results potentially motivate clinicians to introduce levosimendan as second second-line therapy in cases of severe CD and PH in preterm infants without improvement using standard treatment strategies.

BackgroundRare diseases (RD) in rheumatology are heterogeneous and thus lack a systemic classification. By definition, prevalences of RD range up to 5/10 000 in Europe. Clinical courses comprise a vast variety of musculoskeletal symptoms such as arthritis, myositis, vasculitis, autoimmune organ involvement and bone diseases. The impact of RD for health care systems is widely unknown and individual patients are prone to unsatisfactory diagnoses and/or treatments.ObjectivesThe objective of this study was to identify and classify RD in rheumatology and estimate their combined prevalence. The data may give a better understanding for this area of rheumatology, may aid specified centers for RD, and perhaps sharpen the overall perception of health care systems.MethodsDatabases (pubmed.org, abstract archives of the European League Against Rheumatism and the American College of Rheumatology, and Orpha.net) were searched for the following terms: rare in combination with arthritis, arteritis, connective tissue disease, rheumatic and vasculitis. Furthermore, terms were used in various combinations including arthralgia, autoimmune, fever, inflammation, joint pain, muscle pain, myalgia and swollen joint. Identified syndromes were then classified according to the following terms and data: differential diagnosis, etiology, genetics, prevalence, principal symptom, prognosis, and therapy. The overall total point prevalence for all RD in rheumatology was estimated by adding up all single point prevalences available.ResultsA total of 82 syndromes and diseases were identified. Classification was as follows: arthritis (n=17) and vasculitis (n=18), fever syndromes (n=13), collagen diseases (n=10), myositis (n=9), and overlaps/others (n=15). Fifty-two diseases showed a chronic progressive course. The mortality was variable in many diseases and thus could not be determined precisely. Point prevalence data were available for 49 syndromes and diseases, and added up to a total point prevalence of 49/ 10 000. Forty-nine of these in part pathophysiologically quite distinct RD are treated with corticosteroids.ConclusionsRare diseases in rheumatology are most often chronic or progressive. Symptoms are variable, they include arthritis, organ and skin involvement. The estimated combined prevalence of all RD in rheumatology is significant with 49/10 000: it is double or more than that of ankylosing spondylitis with 18/10 000 (1). Treatment options are often restricted to corticosteroids presumably because of the scarcity of randomized controlled trials. Health care systems should assign RD the same importance as any other common disease in rheumatology.ReferencesExarchou S, Lindström U, Askling J, Eriksson JK, Forsblad-d'Elia H, Neovius M, Turesson C, Kristensen LE, Jacobsson LT. The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study. Arthritis Res Ther 2015; 201; 17(1):118.Disclosure of InterestNone declared

Background Rare diseases (RDs) in rheumatology as a group have a high prevalence, but randomized controlled trials are hampered by their heterogeneity and low individual prevalence. To survey the current evidence of pharmacotherapies for rare rheumatic diseases, we conducted a systematic review and meta-analysis. Randomized controlled trials (RCTs) of RDs in rheumatology for different pharmaco-interventions were included into this meta-analysis if there were two or more trials investigating the same RD and using the same assessment tools or outcome parameters. The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PUBMED were searched up to April 2nd 2020. The overall objective of this study was to identify RCTs of RDs in rheumatology, evaluate the overall quality of these studies, outline the evidence of pharmacotherapy, and summarize recommended therapeutic regimens. Results We screened 187 publications, and 50 RCTs met our inclusion criteria. In total, we analyzed data of 13 different RDs. We identified several sources of potential bias, such as a lack of description of blinding methods and allocation concealment, as well as small size of the study population. Meta-analysis was possible for 26 studies covering six RDs: Hunter disease, Behçet’s disease, giant cell arteritis, ANCA-associated vasculitis, reactive arthritis, and systemic sclerosis. The pharmacotherapies tested in these studies consisted of immunosuppressants, such as corticosteroids, methotrexate and azathioprine, or biologicals. We found solid evidence for idursulfase as a treatment for Hunter syndrome. In Behçet’s disease, apremilast and IF-α showed promising results with regard to total and partial remission, and Tocilizumab with regard to relapse-free remission in giant cell arteritis. Rituximab, cyclophosphamide, and azathioprine were equally effective in ANCA-associated vasculitis, while mepolizumab improved the efficacy of glucocorticoids. The combination of rifampicin and azithromycin showed promising results in reactive arthritis, while there was no convincing evidence for the efficacy of pharmacotherapy in systemic sclerosis. Conclusion For some diseases such as systemic sclerosis, ANCA-associated vasculitis, or Behcet's disease, higher quality trials were available. These RCTs showed satisfactory efficacies for immunosuppressants or biological drugs, except for systemic sclerosis. More high quality RCTs are urgently warranted for a wide spectrum of RDs in rheumatology.

To explore the image quality and radiation dose of dual source high-pitch cardiac computed tomography with tailored contrast injection protocols for pediatric congenital heart disease patients (CHD). In total, 27 infants with CHD (median age 109 days [IQR 6–199]) were retrospectively analyzed regarding dose length product (DLP) and effective dose (ED) after undergoing cardiothoracic CT imaging. Scan parameters were adjusted on a dual source/detector CT (DSCT) to minimize radiation dose while maintaining adequate quality. Image acquisition was performed at 70% of the R–R interval. Dose reducing measures included prospective electrocardiogram gating, utilizing slow injection velocities and foregoing bolus tracking during contrast injection. Image quality was assessed for artefacts, vessel definition, and noise on a 5-point scale (1 non-diagnostic, 5 excellent). Series were scored on a 0-to-3-point scale regarding answered clinical questions (0 non-diagnostic, 3 all clinical questions could be answered). The median DLP was 5.2 mGy*cm (IQR 3.5–7.8) leading to a median ED of 0.20 mSv (IQR 0.14–0.30). On average the acquired images scored 13.3 ± 2.1 (SD) out of a maximum 15 points with an intraclass correlation coefficient (ICC) of 0.94. All acquired series were able to fully answer all clinical questions scoring maximum points (ICC 1.0). Dual source high pitch CT protocols combined with custom contrast agent injection protocols in pediatric patients with CHD delivered sufficiently high diagnostic imaging quality combined with low submilisievert radiation doses. Prospective high pitch imaging is a reliable method for depiction of cardiac anatomy even in very young pediatric CHD patients with elevated heart rates.

IntroductionPulmonary hypertension (PH) is one of the major contributing factors to the high morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). The severity and duration of postnatal PH are an established risk factor for patient outcome; however, the early postnatal dynamics of PH have not been investigated. This study aims to describe the early course of PH in CDH infants, and its relation to established prognostic markers and outcome measures.MethodsWe performed a monocentric retrospective review of neonates with prenatally diagnosed CDH, who received three standardized echocardiographic examinations at 2–6 h, 24, and 48 h of life. The degree of PH was graded as one of three categories: mild/no, moderate, or severe PH. The characteristics of the three groups and their course of PH over 48 h were compared using univariate and correlational analyses.ResultsOf 165 eligible CDH cases, initial PH classification was mild/no in 28%, moderate in 35%, and severe PH in 37%. The course of PH varied markedly based on the initial staging. No patient with initial no/mild PH developed severe PH, required extracorporeal membrane oxygenation (ECMO)-therapy, or died. Of cases with initial severe PH, 63% had persistent PH at 48 h, 69% required ECMO, and 54% died. Risk factors for any PH included younger gestational age, intrathoracic liver herniation, prenatal fetoscopic endoluminal tracheal occlusion (FETO)-intervention, lower lung to head ratio (LHR), and total fetal lung volume (TFLV). Patients with moderate and severe PH showed similar characteristics, except liver position at 24- (p = 0.042) and 48 h (p = 0.001), mortality (p = 0.001), and ECMO-rate (p = 0.035).DiscussionTo our knowledge, this is the first study to systematically assess the dynamics of PH in the first postnatal 48 h at three defined time points. CDH infants with initial moderate and severe PH have a high variation in postnatal PH severity over the first 48 h of life. Patients with mild/no PH have less change in PH severity, and an excellent prognosis. Patients with severe PH at any point have a significantly higher risk for ECMO and mortality. Assessing PH within 2–6 h should be a primary goal in the care for CDH neonates.

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