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Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
Objective: Biologics have an important role in the treatment of juvenile idiopathic arthritis (JIA). Long‐term safety data are limited. Direct comparison of different agents regarding occurrence of adverse events (AEs), especially of rare events, requires large quantities of patient years. In this analysis, long‐term safety with regard to AE of special interest (AESI) was compared between different biologics.
Methods: Patients with nonsystemic JIA were selected from the German BIKER registry. Safety assessments were based on AE reports. Number of AEs, serious AEs, and 25 predefined AESIs, including medically important infection, uveitis, inflammatory bowel disease, cytopenia, hepatic events, anaphylaxis, depression, pregnancy, malignancy, and death, were analyzed. Event rates and relative risks were calculated using AEs reported after first dose through 70 days after last dose.
Results: A total of 3873 patients entered the analysis with 7467 years of exposure to biologics. The most common AESIs were uveitis (n = 231) and medically important infections (n = 101). Cytopenia and elevation of transaminases were more frequent with tocilizumab (risk ratio [RR] 8.0, 95% confidence interval [CI] 4.2‐15, and RR 4.7, 95% CI 1.8‐12.2, respectively). Anaphylactic events were associated with intravenous route of administration. In patients ever exposed to biologics, eight malignancies were reported. Six pregnancies have been documented in patients with tumor necrosis factor inhibitors. No death occurred in this patient cohort during observation.
Conclusion: Surveillance of pharmacotherapy as provided by the BIKER registry is an import approach, especially for long‐term treatment of children. Overall, tolerance was acceptable. Differences between biologics were noted and should be considered in daily patient care.
Because it is associated with central nervous changes, and olfactory dysfunction has been reported with increased prevalence among persons with diabetes, this study addressed the question of whether the risk of developing diabetes in the next 10 years is reflected in olfactory symptoms. In a cross-sectional study, in 164 individuals seeking medical consulting for possible diabetes, olfactory function was evaluated using a standardized clinical test assessing olfactory threshold, odor discrimination, and odor identification. Metabolomics parameters were assessed via blood concentrations. The individual diabetes risk was quantified according to the validated German version of the “FINDRISK” diabetes risk score. Machine learning algorithms trained with metabolomics patterns predicted low or high diabetes risk with a balanced accuracy of 63–75%. Similarly, olfactory subtest results predicted the olfactory dysfunction category with a balanced accuracy of 85–94%, occasionally reaching 100%. However, olfactory subtest results failed to improve the prediction of diabetes risk based on metabolomics data, and metabolomics data did not improve the prediction of the olfactory dysfunction category based on olfactory subtest results. Results of the present study suggest that olfactory function is not a useful predictor of diabetes.
Inflammatory diseases including psoriasis are associated with metabolic and cardiovascular comorbidities, including obesity and metabolic syndrome. Obesity is associated with greater psoriasis disease severity and reduced response to treatment. Therefore, targeting metabolic comorbidities could improve patients’ health status and psoriasis-specific outcomes. METABOLyx is a randomized controlled trial evaluating the combination of a lifestyle intervention program with secukinumab treatment in psoriasis. Here, the rationale, methodology and baseline patient characteristics of METABOLyx are presented. A total of 768 patients with concomitant moderate to severe plaque psoriasis and metabolic syndrome were randomized to secukinumab 300 mg, or secukinumab 300 mg plus a tailored lifestyle intervention program, over 24 weeks. A substudy of immunologic and metabolic biomarkers is ongoing. The primary endpoint of METABOLyx is PASI90 response at week 24. Other endpoints include patient-reported outcomes and safety. METABOLyx represents the first large scale clinical trial of an immunomodulatory biologic in combination with a standardized lifestyle intervention.
Einleitung: Für die meisten Patienten mit HCC ist die LTX die einzige kurative Behandlungsoption. Bei diesen Patienten scheint eine Kontrolle der Erkrankung durch lokale Verfahren im Intervall bis zur LTX zu erreichen zu sein. Als das beste Verfahren gilt die transarterielle Chemoembolisation (TACE). Die Effektivität ist jedoch umstritten. Möglicherweise kann sie aber Patienten startifizieren, die ein hohes Rezidivrisiko haben.
Material und Methoden: Im Zeitraum zwischen 1995 und 2005 wurden n=27 Patienten mit HCC im Alter zwischen 22 und 69 Jahren transplantiert. Hiervon erhielten n=15 Patienten eine Vorbehandlung in Form einer alleinigen TACE oder kombiniert mit PEI [n=1] bzw. LITT [n=1]. Retrospektiv wurde das Gesamtüberleben sowie das „Event-free-survival“ (Rezidiv, Reinfektion und Tod) analysiert.
Ergebnisse: Die mittlere Wartezeit betrug bei Patienten in der TACE-Gruppe 214 Tage, bei Patienten ohne Vorbehandlung 133 Tage. Bei einem mittleren Nachbeobachtungszeitraum von 1097 ± 1193 Tagen für TACE-Patienten und 1674 ± 966 Tagen für non-TACE-Patienten betrug das Überleben für Patienten, die mit TACE vorbehandelt wurden 83,3%, für Patienten, die keine TACE erhielten 86.7% (p=0,5693). Gleiches fand sich für das Event-free-survival (p=0,8823). Das Gesamtüberleben der Patienten, die auf der Warteliste einen Tumorprogress hatten lag bei 77%, während Patienten mit stabiler Tumorgröße oder Regredienz der Tumore ein Überleben von 93% aufwiesen (p=0,0153). Unter TACE-Behandlung zeigten 5/15 Patienten eine zunehmende Anzahl an Herden im histologischen Präparat verglichen mit der Ausgangsbildgebung. Nur bei einem Patienten zeigte sich der Progress der Erkrankung bereits in der präoperativen Bildgebung. Patienten mit einem Progress der Erkrankung hatten ein Gesamtüberleben von 60%, während Patienten mit „stable disease“ oder Rückgang der Herde ein Gesamtüberleben von 100% hatten (p=0,0180).
Schlussfolgerung: Unseren Ergebnisse zufolge ist der Effekt der TACE als Bridgingverfahren auf das Überleben der Patienten fraglich. Allerdings scheint die TACE zur Riskostratifizierung geeignet zu sein. In unserem Patientenkollektiv hatten Patienten, die eine Progredienz der Erkrankung auf der Warteliste zeigten ein signifikant schlechteres Gesamtüberleben. Dies gilt auch bei ausschließlicher Betrachtung der Patienten mit TACE.
Background: Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
Methods: The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.
Results: Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
Conclusions: The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/− irinotecan in stage II/III colorectal cancer.
The present guidelines comprise relevant aspects of the use of compression therapy with medical compression stockings (MCS), phlebological compression bandages (PCB), and medical adaptive compression systems (MAC) based on an extensive literature search based on the state of scientific knowledge as of December 2018.
These guidelines were prepared by experts within the framework of an electronic consensus process and a consensus conference which took place in Bielefeld, Germany, on September 27, 2018, on the initiative of the German Society of Phlebology (DGP) and the Professional Association of Phlebologists (BVP). The guidelines were adopted by the boards and advisory councils of the DGP and the BVP, and of the participating professional associations, after preparation by the group of experts and extensive debate, on December 31, 2018.
These guidelines do not cover compression therapy with medical thrombosis prophylaxis stockings (MTPS) or with intermittent pneumatic compression (IPC), which are treated in other guidelines (AWMF 003-001, S3; AWMF 037-001, S1).
The recommendations of the AWMF guidelines “Diagnostics and Treatment of Lymphedema” (registration number 058-001) and “Lipedema” (registration number 037-012) shall also be taken into account where appropriate: https://www.awmf.org/uploads/tx_szleitlinien/058-001l_S2k_Diagnostik_und_Therapie_der_Lymphoedeme_2017-05.pdf, https://www.awmf.org/uploads/tx_szleitlinien/037-012l_S1_Lipoedem_2016-01.pdf.
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.
Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM.
Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements.
Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease.
Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.