- Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) (2011)
- 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 vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2440 mg of rituximab over a median (range) of 194 (180 to 1407) 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. Additional file 1: Supplemental tables. Table A1. Duration of follow-up from first rituximab infusion to last control visit by diagnosis. Table A2. Number of rituximab infusions by diagnosis.
- Identification of shared risk loci and pathways for bipolar disorder and schizophrenia (2017)
- 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.
- Superimposed high-frequency jet ventilation combined with continuous positive airway pressure/assisted spontaneous breathing improves oxygenation in patients with H1N1-associated ARDS (2012)
- Background: Numerous cases of swine-origin 2009 H1N1 influenza A virus (H1N1)-associated acute respiratory distress syndrome (ARDS) bridged by extracorporeal membrane oxygenation (ECMO) therapy have been reported; however, complication rates are high. We present our experience with H1N1-associated ARDS and successful bridging of lung function using superimposed high-frequency jet ventilation (SHFJV) in combination with continuous positive airway pressure/assisted spontaneous breathing (CPAP/ASB). Methods: We admitted five patients with H1N1 infection and ARDS to our intensive care unit. Although all patients required pure oxygen and controlled ventilation, oxygenation was insufficient. We applied SHFJV/CPAP/ASB to improve oxygenation. Results: Initial PaO2/FiO2 ratio prior SHFJV was 58-79 mmHg. In all patients, successful oxygenation was achieved by SHFJV (PaO2/FiO2 ratio 105-306 mmHg within 24 h). Spontaneous breathing was set during first hours after admission. SHFJV could be stopped after 39, 40, 72, 100, or 240 h. Concomitant pulmonary herpes simplex virus (HSV) infection was observed in all patients. Two patients were successfully discharged. The other three patients relapsed and died within 7 weeks mainly due to combined HSV infection and in two cases reoccurring H1N1 infection. Conclusions: SHFJV represents an alternative to bridge lung function successfully and improve oxygenation in the critically ill.
- Hyperoxia reversibly alters oxygen consumption and metabolism (2012)
- Aim: Ventilation with pure oxygen (hyperoxic ventilation: HV) is thought to decrease whole body oxygen consumption (VO(2)). However, the validity and impact of this phenomenon remain ambiguous; until now, under hyperoxic conditions, VO(2) has only been determined by the reverse Fick principle, a method with inherent methodological problems. The goal of this study was to determine changes of VO(2), carbon dioxide production (VCO(2)), and the respiratory quotient (RQ) during normoxic and hyperoxic ventilation, using a metabolic monitor. Methods: After providing signed informed consent and institutional acceptance, 14 healthy volunteers were asked to sequentially breathe room air, pure oxygen, and room air again. VO(2), VCO(2), RQ, and energy expenditure (EE) were determined by indirect calorimetry using a modified metabolic monitor during HV. Results: HV reduced VO(2) from 3.4 (3.0/4.0) mL/kg/min to 2.8 (2.5/3.6) mL/kg/min (P < 0.05), whereas VCO(2) remained constant (3.0 [2.6/3.6] mL/kg/min versus 3.0 [2.6/3.5] mL/kg/min, n.s.). After onset of HV, RQ increased from 0.9 (0.8/0.9) to 1.1 (1.0/1.1). Most changes during HV were immediately reversed during subsequent normoxic ventilation. Conclusion: HV not only reduces VO(2), but also increases the respiratory quotient. This might be interpreted as an indicator of the substantial metabolic changes induced by HV. However, the impact of this phenomenon requires further study.
