Serum autoantibody reactivity in bullous pemphigoid is associated with neuropsychiatric disorders and the use of antidiabetics and antipsychotics: a large, prospective cohort study.

BACKGROUND: Bullous pemphigoid (BP), the by far most frequent autoimmune blistering skin disease (AIBD), is immunopathologically characterized by autoantibodies against the two hemidesmosomal proteins BP180 (collagen type XVII) and BP230 (BPAG1 or dystonin). Several comorbidities and potentially disease-inducing medication have been described in BP, yet a systematic analysis of these clinically relevant findings and autoantibody reactivities has not been performed. OBJECTIVE: To determine associations of autoantibody reactivities with comorbidities and concomitant medication. METHODS: In this prospective multicenter study, 499 patients diagnosed with BP in 16 European referral centers were included. The relation between anti-BP180 NC16A and anti-BP230 IgG ELISA values at the time of diagnosis as well as comorbidities and concomitant medication collected by a standardized form were analysed. RESULTS: An association between higher serum anti-BP180 reactivity and neuropsychiatric but not atopic and metabolic disorders was observed as well as with the use of insulin or antipsychotics but not with dipeptidyl peptidase-4 (DPP4) inhibitors, inhibitors of platelet aggregation and L-thyroxine. The use of DPP4 inhibitors was associated with less anti-BP180 and anti-BP230 reactivity compared with BP patients without these drugs. This finding was even more pronounced when compared with diabetic BP patients without DPP4 inhibitors. Associations between anti-BP180 and anti-BP230 reactivities were also found in patients using insulin and antipsychotics, respectively, compared with patients without this medication, but not for the use of inhibitors of platelet aggregation, and L-thyroxine. CONCLUSION: Taken together, these data imply a relation between autoantibody reactivities at the time of diagnosis and both neuropsychiatric comorbidities as well as distinct concomitant medication suggesting a link between the pathological immune mechanisms and clinical conditions that precede the clinically overt AIBD.

Incidence of pemphigoid diseases in Northern Germany in 2016 - first data from the Schleswig-Holstein Registry of Autoimmune Bullous Diseases.

BACKGROUND: Autoimmune bullous diseases (AIBD) are rare disorders characterized by autoantibody formation against components of adhesion molecules; in pemphigoid diseases (PD), these are proteins of hemidesmosomes and basement membrane, important for cell-matrix adhesion in skin and/or mucous membranes. Incidences of these diseases vary considerably between different populations. OBJECTIVES: To establish a registry prospectively recruiting all AIBD patients in a geographically well-defined region in Northern Germany (Schleswig-Holstein). METHODS: Only patients with verified disease (by clinical presentation, histology, direct and/or indirect immunofluorescence and /or ELISA) living in Schleswig-Holstein were included. Incidences of PD were estimated based on the total number of inhabitants in Schleswig-Holstein, stratified by birth year and sex. RESULTS: Of 67 patients with PD [35 male, 32 female, mean age 75 (standard deviation 14.3 years)], 83% were patients with bullous pemphigoid [n = 56, 28 male, 28 female, mean age 78 (SD 9.9)]. The resulting crude incidences were 23.4 patients/million/year for all pemphigoid patients, 19.6 patients/million/year for bullous pemphigoid (age-standardized 16.9 patients/million/year) with a strong increase in bullous pemphigoid patients in the age group of 85-90 years with 262 patients/million/year. Incidences for bullous pemphigoid were higher in urban compared to rural areas. Other PD (mucous membrane pemphigoid, linear IgA disease, anti-p200 pemphigoid) were less frequent with crude incidences of 2.1, 1.0 and 0.7 patients/million/year, respectively. CONCLUSIONS: This study prospectively analyses the incidence of PD in a carefully defined geographical area. The highest incidence among PD patients was found for bullous pemphigoid. The incidence of bullous pemphigoid is considerably increased compared to previous reports and reveals regional differences. Further studies are needed in order to clarify these findings.

Cytokine levels in children and adults with wheezing and asthma show specific patterns of variability over time.

Levels of cytokines are used for in-depth characterization of patients with asthma; however, the variability over time might be a critical confounder. To analyze the course of serum cytokines in children, adolescents and adults with asthma and in healthy controls and to propose statistical methods to control for seasonal effects. Of 532 screened subjects, 514 (91·5%) were included in the All Age Asthma Cohort (ALLIANCE). The cohort included 279 children with either recurrent wheezing bronchitis (more than two episodes) or doctor-diagnosed asthma, 75 healthy controls, 150 adult asthmatics and 31 adult healthy controls. Blood samples were collected and 25 µl serum was used for analysis with the Bio-Plex Pr human cytokine 27-Plex assay. Mean age, body mass index and gender in the three groups of wheezers, asthmatic children and adult asthmatics were comparable to healthy controls. Wheezers (34·5%), asthmatic children (78·7%) and adult asthmatics (62·8%) were significantly more often sensitized compared to controls (4·5, 22 and 22·6%, respectively). Considering the entire cohort, interleukin (IL)-1ra, IL-4, IL-9, IL-17, macrophage inflammatory protein (MIP)-1- α and tumor necrosis factor (TNF)- α showed seasonal variability, whereas IL-1ß, IL-7, IL-8, IL-13, eotaxin, granulocyte colony-stimulating factor (G-CSF), interferon gamma-induced protein (IP)-10, MIP-1 ß and platelet-derived growth factor (PDGF)-BB did not. Significant differences between wheezers/asthmatics and healthy controls were observed for IL-17 and PDGF-BB, which remained stable after adjustment for the seasonality of IL-17. Seasonality has a significant impact on serum cytokine levels in patients with asthma. Because endotyping has achieved clinical importance to guide individualized patient-tailored therapy, it is important to account for seasonal effects.

Prevalence and age distribution of pemphigus and pemphigoid diseases among paediatric patients in Germany.

BACKGROUND: Autoimmune bullous diseases are rare and mostly occur in adults. Several cases and small case series have been described in children, but no systematic study about the prevalence of autoimmune bullous diseases (AIBD) in children is available. PATIENTS AND METHODS: We analysed data of 1.7 million children insured in the largest German health insurance company based on the ICD-10-GM classification for the year 2015. Data were adjusted to the general German population based on the data of the Federal Statistical Office for the year 2015. RESULTS: The prevalence of AIBD was calculated to 101.1/million children in 2015, resulting in about 1351 patients below the age of 18 years in Germany. The highest prevalence of all AIBD was seen for pemphigus vulgaris (30.5/million children) followed by linear IgA disease (24.5/million children) and bullous pemphigoid (4.9/million children). CONCLUSION: Autoimmune bullous diseases in minors are scarce but should be taken into consideration in patients with pruritus and/or blisters and erosions on the skin and/or mucous membranes. Treatment is challenging, and due to the rarity of AIBD in minors, the management of these disorders in this patient population is best performed in specialized centres in a multidisciplinary approach, including paediatric dermatologists or dermatologists and paediatricians.

Upper airway stimulation for obstructive sleep apnea-Can radiological position monitoring predict tongue motion one year after implantation?

BACKGROUND: Tongue motion patterns (TMP) can influence the outcome of upper airway stimulation (UAS) in the treatment of obstructive sleep apnea (OSA). As a postoperative control, the cuff position of the stimulation lead is monitored via X­ray imaging. A multidimensional X­ray assessment system was established and the association between these positional assessments and TMP was investigated 1 year after implantation. MATERIAL AND METHODS: The study on TMP and the X­ray assessments were carried out at a German ear nose and throat clinic as an implantation center. The TMPs were assessed under bipolar electrode configuration and were categorized according to the currently available literature as right-sided protrusion (RP), left-sided protrusion (LP), bilateral protrusion (BP) and mixed activation (MA). The X­ray assessment was carried out in five dimensions: the position relative to the mandible and hyoid, cuff steepness in the lateral view of the neck, the cuff position based on the single electrode, and the lead connection to the cuff in the anterior-posterior view. The analyses were performed by three raters with different medical backgrounds and knowledge regarding TMP. RESULTS: In approximately 60% of patients, the apnea-hypopnea index was reduced to below 15/h 1 year after implantation. The most common TMPs were RP and BP (82.9%). The interrater variability of the X­ray assessment was good except for one category. Furthermore, no relevant associations were found apart from the correlation between a favorable TMP and the cuff position with respect to the lateral position of the stimulation cable. CONCLUSION: Despite good interrater variability and convenient usage of the suggested X­ray assessment system, this approach did not enable the identification of any associations by which a TM and, therefore, a possible straightforward or complicated treatment pathway could be predicted. Attention should possibly be paid to a rotation of the cuff during implantation with a lateral position of the stimulation lead.

[Upper Airway Stimulation for obstructive sleep apnea-Can radiological position monitoring predict tongue motion one year after implantation? German version]. / Die obere Atemwegsstimulation bei obstruktiver Schlafapnoe ­ Kann die radiologische Lage des Stimulation-Cuff die Zungenbewegung vorhersagen?

BACKGROUND: Tongue motion patterns (TMP) can influence the outcome of upper airway stimulation (UAS) in the treatment of obstructive sleep apnea (OSA). As a postoperative control the cuff position of the stimulation lead is monitored via X­ray imaging. A multidimensional X­ray assessment system was established and the association between these positional assessments and TMP was investigated 1 year after implantation. MATERIAL AND METHODS: The study on TMP and the X­ray assessments were carried out at a German ear nose and throat clinic as an implantation center. The TMPs were assessed under bipolar electrode configuration and were categorized according to the currently available literature as right-sided protrusion (RP), left-sided protrusion (LP), bilateral protrusion (BP) and mixed activation (MA). The X­ray assessment was carried out in five dimensions: the position relative to the mandible and hyoid, cuff steepness in the lateral view of the neck, the cuff position based on the single electrode and the lead connection to the cuff in the anterior-posterior view. The analyses were performed by three raters with different medical backgrounds and knowledge regarding TMP. RESULTS: In approximately 60% of the patients the apnea-hypopnea index was reduced to below 15/h, 1 year after implantation. The most common TMPs were RP and BP (82.9%). The interrater variability of the X­ray assessment was good except for one category. Furthermore, no relevant associations were found apart from the correlation between a favorable TMP and the cuff position with respect to the lateral position of the stimulation cable. CONCLUSION: Despite good interrater variability and convenient usage of the suggested X­ray assessment system, this approach did not enable the identification of any associations, by which a TM and therefore a possible straightforward or complicated treatment pathway could be predicted. Attention should possibly be paid to a rotation of the cuff during implantation with a lateral position of the stimulation lead.

Combined-modality 125J-seed-brachytherapy, external beam radiation and androgen deprivation therapy of unfavorable-risk prostate cancer: report of outcomes and side-effects.

PURPOSE: To analyze outcomes and complication rates in an unselected cohort of men with unfavorable (NCCN intermediate and high-risk) PCa receiving combined-modality radiation treatment (CRT). METHODS: Patients received androgen deprivation therapy for 1 year and combined-modality radiation treatment (CRT) consisting of external-beam radiotherapy (EBRT, 59.4 Gy, 33 fractions) and 125J seed-brachytherapy (S-BT, 100 Gy). Subgroups, including WHO group 3-5, and initial PSA (iPSA) < 20 and > 20 ng/ml were identified. Biochemical recurrence-free (BRFS), metastasis-free (MFS), cancer-specific (CSS) and overall survival (OS) were calculated at 5 and 10 years using the Kaplan-Meier method. Subgroups were compared using log-rank test and Cox proportional hazards regression. Urogenital and gastrointestinal side-effects were reported according to the CTCAE classification. RESULTS: After a median of 6.9 years (range 2-13) calculated 5- and 10-year rates for the whole cohort of 425 men were 92.8% and 82.5% for BRFS, 95.1%, and 88.8% for MFS, 98.2%, and 95.1 for CSS, and 95.4%, and 80.1% for OS, respectively. Univariate (UVA) and multivariate analysis (MV) identified a group with unfavorable outcome with iPSA > 20 ng/ml, comprising 24% of all patients, in which 55% of recurrences, 54% of metastases and 71% of cancer-specific deaths occurred. Side-effects were limited, with < 5% of patients complaining of genitourinary and 0.5% of gastrointestinal AEs after 5 years. CONCLUSION: CRT is an excellent treatment option for men with unfavorable PCa. In a subgroup of patients with iPSA > 20 ng/ml further, possibly systemic, treatment options should be identified.

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

Supine position and REM dependence in obstructive sleep apnea : Critical model considerations.

BACKGROUND: When considering supine position and REM dependence, many studies refer to the traditional definition in which obstructive sleep apnea (OSA) severity is at least doubled in the corresponding position/sleep stage (Cartwright index). The lack of consideration of the time spent in that particular sleep situation can lead to clinical bias. PATIENTS AND METHODS: Two cohorts of patients with at least moderate OSA were analyzed retrospectively for anthropometric associations and correlations with OSA severity. One group consisted of 48 patients diagnosed using a polygraph, and the other group of 222 patients underwent polysomnography. First, the conventional Cartwright index was used, and a modified index was later applied to integrate the relative time component for REM sleep and the supine position. RESULTS: Less than a fifth of the patients fulfilled the classic conditions for supine position or REM sleep dependency. There were no definitive cut-offs in the classic or modified Cartwright index with regard to daytime sleepiness. Both indices show there was a correlation between OSA severity and being overweight. CONCLUSION: The modified Cartwright index allowed us to identify borderline cases that were characterized by a very low or high amount of time spent in the supine position or REM sleep situation. Therapy effects that could have been biased only by varying amounts of time spent in the supine position could be better controlled for. Future studies will possibly include various other ratios besides the previously accepted 2:1 ratio when different statistical parameters are considered, such as the reduction of OSA severity or therapy adherence.

[Supine position and REM dependence in obstructive sleep apnea. Critical model considerations. German version]. / Rückenlage- und REM-Bezug bei obstruktiver Schlafapnoe. Kritische Modellbetrachtungen.

BACKGROUND: When considering supine position and REM dependence, many previous studies have referred to the traditional definition in which obstructive sleep apnea (OSA) severity is at least doubled in the corresponding position/sleep stage (Cartwright index). The lack of consideration of the time spent in the particular sleep situation could cause clinical bias. PATIENTS AND METHODS: Two cohorts of patients with at least moderate OSA were analyzed retrospectively for anthropometric associations with OSA severity. One group consisted of 48 patients diagnosed using a polygraph and the other group of 222 patients underwent polysomnography. First, the conventional Cartwright index was used, and a modified index was later applied to integrate the relative time component for REM sleep and the supine position. RESULTS: Less than a fifth of the patients fulfilled the classic conditions for supine position or REM sleep dependency. There were no definitive cutoffs in the classic or modified Cartwright index with regard to daytime sleepiness. Both indices show there was a correlation between OSA severity and being overweight. CONCLUSION: The modified Cartwright index allowed identification of borderline cases that were characterized by a very low or high amount of time spent in the supine position or REM sleep situation. Treatment effects that could have been caused only by other components, e.g., different times spent in the supine position, could be better controlled for. In future studies there will be various other ratios besides the previously accepted 2:1 ratio when different statistical parameters are considered, such as the reduction of OSA severity or adherence to treatment.

Challenges in planning and conducting diagnostic studies with molecular biomarkers.

Biomarkers are of increasing importance for personalized medicine in many areas of application, such as diagnosis, prognosis, or the selection of targeted therapies. In many molecular biomarker studies, intensity values are obtained from large scale ­omics experiments. These intensity values, such as protein concentrations, are often compared between at least two groups of subjects to determine the diagnostic ability of the molecular biomarker. Various prospective or retrospective study designs are available for molecular biomarker studies, and the biomarker used may be univariate or may even consist in a multimarker rule. In this work, several challenges are discussed for the planning and conduct of biomarker studies. The phases of diagnostic biomarker studies are closely related to levels of evidence in diagnosis, and they are therefore discussed upfront. Different study designs for molecular biomarker studies are discussed, and they primarily differ in the way subjects are selected. Using two systematic reviews from the literature, common sources of bias of molecular diagnostic studies are illustrated. The extreme selection of patients and controls and verification bias are specifically discussed. The pre-analytical and technical variability of biomarker measurements is usually expressed in terms of the coefficient of variation, and is of great importance for subsequent validation studies for molecular biomarkers. It is finally shown that the required sample size for biomarker validation quadratically increases with the coefficient of variation, and the effect is illustrated using real data from different laboratory technologies.

Pregnancy risk factors for very premature delivery: what role do hypertension, obesity and diabetes play?

PURPOSE: Very premature delivery is a major cause of infant morbidity and mortality. Obesity, diabetes and pregnancy hypertension are known risk factors for pregnancy complications. The study aimed to scrutinize differences of pregnancy complications in a cohort of very premature deliveries compared to a national group. METHODS: In a multicenter study performed between January 2009 and December 2010 including 1,577 very low birth weight (VLBW) infants, we compared parental reported pregnancy problems of VLBW infants with a national cohort (KIGGS). We compared reported pregnancy complications to reasons for premature delivery and neonatal outcome within the group of VLBW infants. RESULTS: While parents of the national cohort reported pregnancy-induced hypertension in 8 %, parents of VLBW infants reported this complication more frequently (27 %). Mothers of the national cohort were significantly younger (1 year), suffered less from obesity, anaemia, diabetes. Regression analysis showed that hypertension (OR = 5.11) and advanced maternal age (OR = 1.03) increased the risk for premature birth. Women with hypertension were likely to experience a clinically indicated premature delivery, had more VLBW infants with a moderate growth restriction, but less multiples and their infants had less intraventricular haemorrhages grade 3 or 4. Otherwise, neonatal outcome was correlated with gestational age but not with the pregnancy complications diabetes, hypertension or obesity. CONCLUSION: Premature birth seems to be correlated to gestational hypertension and associated problems in about » of VLBW infants. Further studies should focus on preventing and treating gestational hypertension to avoid premature delivery and associated neonatal morbidity.

[Clinical trials with medical devices: lack of quality illustrated for faecal incontinence]. / Therapiestudien mit Medizinprodukten: Mangelnde Qualität illustriert anhand analer Inkontinenz.

BACKGROUND: Medical devices must be safe and functioning states the law. Treatments with medical devices need not be efficacious to be allowed. We investigated special requirements and problems arising from the law. METHODS: The market for medical devices is contrasted with that for drugs. The requirements of relevant laws are discussed. Finally, published clinical studies on anal incontinence are analysed with respect to their methodological quality. RESULTS: Clinical trials of medical devices for treat-ing anal incontinence are of poor methodological quality thus preventing evaluation of the devices' utility. CONCLUSION: Large, high quality clinical studies of the efficacy of medical devices for treating anal incontinence are urgently needed. Only such studies enable health technology assessment and comprehensible decisions on reimbursement by health insurance.

Botulinum toxin for Frey's syndrome: a closer look at different treatment responses.

OBJECTIVE: Botulinum toxin is a widely accepted, effective treatment for Frey's syndrome. While some patients need only one injection, others require repeated treatments. We aimed to describe the clinical features of patients with a more challenging treatment course. DESIGN: Literature review and retrospective analysis of eight consecutive patients treated at a university hospital. SUBJECTS: These patients' treatment responses were categorised (using our own system) and compared with those of 25 published cases. RESULTS: Combined analysis identified no significant correlation between treatment response and age, gender or the extent of primary salivary gland surgery. There was no significant correlation between botulinum toxin dosage and time between treatments. CONCLUSION: Frey's syndrome should be viewed as a dynamic process in which the stimulus for aberrant reinnervation of parasympathetic nerve fibres can be reduced, in some patients, with higher botulinum toxin dose injections to the treated areas. However, responses are unpredictable, and relapses may occur at different time points and in different areas.

[3T-AI: a new treatment algorithm for anal incontinence with a higher evidence level]. / 3T-AI: Ein neuer, mit höherer Evidenz versehener Behandlungsalgorithmus bei analer Inkontinenz.

BACKGROUND: The evidence for conservative treatment of anal incontinence is poor. In our first publication [Schwandner et al. Dis Colon Rectum 2010; 53: 1007-1016] we demonstrated that a novel therapeutic concept, termed triple target treatment (3T), combining amplitude-modulated medium frequency stimulation and electromyography biofeedback (EMG-BF) was superior to EMG-BF alone. Questions about the required treatment duration and the relevant subgroups of patients with sphincter damage and damaged anal sensibility were not addressed. METHODS: We enrolled 158 patients with anal incontinence in this randomized study. Here, we -report on the important subgroup analyses of patients with and without sphincter damage and damaged anal sensibility for the endpoints Cleveland Clinic Score (CCS) and success record. Using the results of this study we propose a novel treatment algorithm which is open for discussion. RESULTS: In patients with sphincter damage, the median difference on the CCS from baseline to 9 months was 5 points higher for 3T than for EMG-BF (95 % confidence interval 0-8; p = 0.0168). While 47 % of the patients with sphincter damage became continent with 3T, only 18 % did with EMG-BF (p = 0.0036). Ten of 17 patients in the 3T group regained anal sensibility after 3 months stimulation. There was tendency towards improved continence in patients with neuropathy upon 3T treatment (p = 0.1219). CONCLUSIONS: 3T is superior to EMG-BF alone for patients with sphincter damage and neuropathic anal incontinence. It is a successful key element within our treatment algorithm, even in patients with sphincter damage and neuropathic anal incontinence.

[Guidelines for research reports: an application of CONSORT 2010 statements]. / Leitlinien für Forschungsberichte: eine Anwendung des CONSORT 2010 Statements.

INTRODUCTION: Reporting guidelines are not only useful for authors in compiling complete and transparent reports but they can use also be used by readers for the critical appraisal of the study. In this study, we apply the CONSORT 2010 reporting guideline to illustrate its value as the first step in the critical appraisal. PATIENTS AND METHODS: We have applied the checklist of the CONSORT 201 statement to the publication of Richter et al. [7]. This has been done by both authors independently. We report for each item of the 25 item checklist whether it was adequately reported, and we comment on each item. RESULTS: The paper of Richter et al. does not comply with the CONSORT 2010 checklist and the CONSORT extension for summaries in all items. CONCLUSION: The most important reporting guidelines are now available in German (https://www.thieme-connect.de/ejournals/toc/dmw/104011). They are useful for authors of research articles to compile complete and transparent reports. Readers can use items of these reporting guidelines for judging the quality of a published study. To this end, there is a need to distinguish between reporting quality and the quality of a specific study.

[A prospective evaluation of psychometric items in patients with nasal deformities]. / Psychosoziale Leistungseinschätzung bei Patienten mit Nasendeformitäten.

BACKGROUND: Patient satisfaction with surgical outcome is essential in plastic reconstructive surgery, yet no German-language psychometrically validated instrument exist for assessing satisfaction with surgery in the head and neck area. Previously, the short form of the "Frankfurter Selbstkonzeptskalen/FSKN" showed mixed results in a sample of patients undergoing correction of microtia. MATERIAL AND METHODS: This short form was tested in 22 patients following septorhinoplasty and in 24 following tonsillectomy, regarding its psychometric characteristics. RESULTS: While showing good practical characteristics and content validity, there were disappointing results in responsiveness to change and known group's discriminant validity. CONCLUSIONS: Beside sample size, different psychological mechanisms in more common malformations of the head neck area, especially in patients with nasal deformities, have to be further explored as they are not sufficiently represented in the short form of FSKN.