Adjuvant treatment of severe/refractory bullous pemphigoid with protein A immunoadsorption.

BACKGROUND: While depletion of circulating autoantibodies using immunoadsorption (IA) is an established therapeutic approach in patients with pemphigus vulgaris, IA has only sporadically been used in other autoimmune bullous disorders. Although bullous pemphigoid (BP) usually responds well to topical and systemic corticosteroids, rapid depletion of serum autoantibodies may be an effective adjuvant treatment option in patients with severe and/or refractory disease. PATIENTS AND METHODS: Case series of 20 patients (13 women, 7 men; mean age 78.6 years; range 56-94 years) with severe or refractory BP. In addition to oral prednisolone (0.25-0.5 mg/kg/day), dapsone (1.0-1.5 mg/kg/day), and clobetasol propionate 0.05 % ointment (lesional application, twice daily), treatment consisted of protein A IA (three sessions on consecutive days). The mean follow-up period was 33.6 months (1-84 months). RESULTS: The majority of patients showed a rapid and sustained response. One month after treatment, eight patients (42 %; 19 patients were included in the follow-up) were in complete remission; at the last follow-up visit (after 1 to 84 months), that number was 13 (68 %). Not only was there an initial drop in anti-BP180 autoantibodies (by 92 %), the effect also continued after one and three months, with mean autoantibody levels at 26 % and 13 % of baseline, respectively (p < 0.001). Both previously treated and treatment-naive patients showed a significant reduction in anti-BP180NC16A antibody levels throughout the observation period. Adverse events occurred in 13 of the 20 patients (65 %). Three were severe of which two were likely or probably related to IA. CONCLUSION: Immunoadsorption is an effective adjuvant treatment option for (the usually elderly) patients with severe and/or refractory BP.

Adjuvante Behandlung des schweren/refraktären bullösen Pemphigoids mit Protein-A-Immunadsorption.

HINTERGRUND: Mittels Immunadsorption (IA) können Immunglobuline und Immunkomplexe aus dem Plasma entfernt werden. Während dieses therapeutische Verfahren beim Pemphigus vulgaris bereits etabliert ist, wird es bei anderen blasenbildenden Autoimmundermatosen bislang nur sporadisch eingesetzt. Das bullöse Pemphigoid (BP) spricht zwar meist gut auf eine Therapie mit topischen und systemischen Kortikosteroiden an, jedoch könnte bei Patienten mit ausgedehnten Läsionen oder bei einem Rezidiv die rasche Reduktion der pathogenen Autoantikörper eine effektive adjuvante Therapie darstellen. PATIENTEN UND METHODIK: Fallserie mit 20 Patienten (13 Frauen, 7 Männer; mittleres Alter 78,6 Jahre; 56-94 Jahre) mit schwerem oder refraktärem BP, die zusätzlich zur Basistherapie bestehend aus Prednisolon (0,25-0,5 mg/kg/d), Dapson (1,0-1,5 mg/kg/d) und Clobetasolpropionat 0,05 % Salbe (läsional 2 x/d) mit Protein-A-IA (3 IAs an aufeinander folgenden Tagen) behandelt wurden. Die durchschnittliche Nachbeobachtungszeit betrug 33,6 Monate (1-84 Monate). ERGEBNISSE: Bei der Mehrzahl der Patienten zeigte sich ein rascher und langandauernder Therapieeffekt. Nach einem Monat befanden sich acht Patienten (von 19 nachbeobachteten, 42 %) und zum Zeitpunkt des letzten Kontakts (nach 1-84 Monaten) 13 Patienten (68 %) in kompletter Remission. Die Anti-BP180-Autoantikörper wurden nicht nur initial (um 92 %) gesenkt, sondern lagen auch nach ein und drei Monaten im Mittel bei 26 % und 13 % des Wertes vor Therapiebeginn (p < 0,001). Bei Differenzierung in vortherapierte bzw. therapienaive Patienten zeigten sich in beiden Subgruppen signifikante Absenkungen der Anti-BP180NC16A-Antikörper-Spiegel zu allen Zeitpunkten. Unerwünschte Ereignisse traten bei dreizehn (65 %) der 20 Patienten auf, Drei der Ereignisse waren schwer und zwei davon wahrscheinlich oder möglicherweise in Zusammenhang mit der IA. SCHLUSSFOLGERUNGEN: Die IA ist eine effektive adjuvante Therapieoption bei den in aller Regel älteren Patienten mit einem schweren und/oder therapierefraktären BP.

Safety Aspects of Immunoadsorption in IgG Removal Using a Single-Use, Multiple-pass Protein A Immunoadsorber (LIGASORB): Clinical Investigation in Healthy Volunteers.

Therapeutic apheresis and immunoadsorption are used to deplete efficiently pathogenic autoantibodies in crises in several acute autoimmune driven diseases. This prospective, non-comparative cohort study was conducted at a single study center under standardized conditions in 10 healthy volunteers. Efficient immunoglobulin G (IgG) removal (-86% versus baseline) was achieved after 3 apheresis treatments on 3 consecutive days. The treatments were well tolerated. Safety laboratory parameters did not show unexpected or pathological changes. The effects were transient, with most parameters exhibiting complete recovery between treatments. Minimal complement activation and moderate transient fibrinogen depletion were observed. Immunoadsorption with LIGASORB® provides a safe and effective treatment alternative to TPE in acute episodes of peripheral neurological diseases mediated by pathogenic IgG autoantibodies.

Hypertension and mild chronic kidney disease persist following severe haemolytic uraemic syndrome caused by Shiga toxin-producing Escherichia coli O104:H4 in adults.

BACKGROUND: Shiga toxin-producing, enteroaggregative Escherichia coli was responsible for the 2011 outbreak of haemolytic uraemic syndrome (HUS). The present single-centre, observational study describes the 1-year course of the disease with an emphasis on kidney function. Outcome data after 1 year are associated with treatment and patient characteristics at onset of HUS. METHODS: Patients were treated according to a standardized approach of supportive care, including a limited number of plasmapheresis. On top of this treatment, patients with severe HUS (n = 35) received eculizumab, a humanized anti-C5 monoclonal antibody inhibiting terminal complement activation. The per-protocol decision--to start or omit an extended therapy with eculizumab accompanied by azithromycin--separated the patients into two groups and marked Day 0 of the prospective study. Standardized visits assessed the patients' well-being, kidney function, neurological symptoms, haematological changes and blood pressure. RESULTS: Fifty-six patients were regularly seen during the follow-up. All patients had survived without end-stage renal disease. Young(er) age alleviated restoring kidney function after acute kidney injury even in severe HUS. After 1 year, kidney function was affected with proteinuria [26.7%; 95% confidence interval (CI) 13.8-39.6], increased serum creatinine (4.4%, CI 0.0-10.4), increased cystatin C (46.7%, CI 32.1-61.3) and reduced (<90 mL/min) estimated glomerular filtration rate (46.7%, CI 32.1-61.3). Nine of the 36 patients without previous hypertension developed de novo hypertension (25%, CI 10.9-39.1). All these patients had severe HUS. CONCLUSIONS: Although shiga toxin-producing Escherichia coli (STEC)-HUS induced by O104:H4 was a life-threatening acute disease, follow-up showed a good recovery of organ function in all patients. Whereas kidney function recovered even after longer duration of dialysis, chronic hypertension developed after severe HUS with neurological symptoms and could not be prevented by the extended therapy.

Glucocorticoid replacement therapy in adrenal insufficiency--a challenge to physicians?

Adrenal insufficiency (AI) is a rare disease caused by destruction of the adrenal glands or dysfunction of the pituitary gland or the hypothalamus. Treatment usually requires lifelong replacement therapy with glucocorticoids. Correct use of glucocorticoids and early dose adjustments are essential to cover the increased glucocorticoid demand in stress. Repeated education of patients and their partners is the best strategy to avoid life-threatening emergencies. However, there is a debate whether physicians' knowledge regarding AI is sufficient, in part due to the rareness of this endocrine disorder. To determine the present specific knowledge of physicians in a large University Department of Internal Medicine with a clinically and scientifically active Division of Endocrinology, all interns, residents / fellows, specialists or senior physicians / consultants were asked to complete a questionnaire with various possible answers on the subject of AI (n=69, median age 30 years, range 23-49 years). The present data suggest that in the investigated University Hospital setting current physicians' knowledge of medical replacement strategies in AI may be insufficient depending on the level of education and experience. Even physicians with training in endocrinology in part demonstrated extensive knowledge gaps. There might be a need for additional structured information and training on AI, even in specialized hospitals.

Heart rate variability and metabolic rate in healthy young adults with low birth weight.

OBJECTIVE: Low birth weight (LBW) is associated with obesity and a higher cardiovascular risk in adult life. Since autonomic dysfunction could be a pathophysiological factor for this association, we assessed the impact of LBW on cardiac autonomic activity and metabolic rate in young adulthood. We hypothesized that the autonomic tone could be coupled with the metabolic rate in subjects with LBW. METHODS: Heart rate variability (HRV) from 24-hour Holter-electrocardiograms was measured in 15 healthy adults aged 20 to 30 years with LBW (<2500g at term) and 15 paired subjects with normal birth weight (NBW). The pairs were closely matched by gender, age, and body mass index. Resting energy expenditure was measured by indirect calorimetry and body composition by bioimpedance. RESULTS: Global HRV parameters were significantly higher in the LBW group and a marked difference was observed in the long wave fluctuations of the frequency domain (very low frequency). These fluctuations were positively correlated with the resting energy expenditure per body weight in the LBW and negatively in the NBW group. Only in the LBW group HRV was closely related to body fat. INTERPRETATION: This case-control study indicates that autonomous nervous function is not generally deteriorated in young adults with LBW and has a significant association with metabolic rate. Thus, it may be a determinant of the body weight regulation in this group. The higher cardiovascular risk in ageing individuals with LBW would therefore rather be a consequence of weight gain than of a primary autonomous nervous dysfunction.

High prevalence of fibromyalgia-associated symptoms in patients with hypothalamic-pituitary disorders.

OBJECTIVES: Various complaints of patients with fibromyalgia often resemble clinical features observed in patients with hypothalamic-pituitary diseases. The aim of this study was to evaluate whether patients with hypothalamic-pituitary diseases are at increased risk for fibromyalgia syndrome (FMS). METHODS: A questionnaire for evaluating fibromyalgia-associated symptoms was sent to 121 patients with hypothalamic-pituitary disorders (HPD) (60 women, 61 men; mean age, 55.4 years; range, 21-83 years) of the endocrine outpatient clinic. 115 patients (57 women, 58 men; mean age 56.9 years; range, 21 to 82 years) with cardiovascular diseases (CD) served as controls. RESULTS: Fibromyalgia-associated symptoms regarding muscular complaints were significantly more frequent in the HPD group than in CD patients (53.7 % vs. 35.7%, p= 0.003). In particular, we found a significant higher prevalence of autonomic symptoms in the HPD group as compared to the CD group regarding several qualities (cold hands, p=0.039; flatulence, p=0.022; tiredness, p=0.017). In addition, swollen and painful finger joints were reported more often in the HPD group than in the CD group (p=0.002). Of note, no differences regarding any fibromyalgia-associated symptom were detected when patients with hypothalamic-pituitary hormone excess syndromes were compared to those with a pituitary pathology without hormonal excess. Similarly, prevalence of fibromyalgia-associated symptoms was not related to the treatment modality of pituitary disease; i.e. surgical vs. conservative or any hormonal replacement therapy. CONCLUSIONS: Our data suggest that patients with hypothalamic-pituitary disorders may be at increased risk of developing fibromyalgia-associated symptoms.

[Impairment of cardiac autonomic nervous system and incidence of arrhythmias in severe hyperglycemia]. / Beeinträchtigung des kardialen autonomen Nervensystems und Arrhythmie-Inzidenz bei schwerer Hyperglykämie.

BACKGROUND AND PURPOSE: Deterioration of cardiac autonomic nervous system in diabetics is associated with increased cardiac and arrhythmogenic mortality. Therefore, the present study engaged in the question how heart rate variability is acutely changed in diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. Moreover was evaluated how blood pressure, heart rate and incidence of arrhythmias can be explained by figures of heart rate variability. PATIENTS AND METHODS: In a prospective observation of time course we investigated in 4 years consecutively 12 intensive care patients with DKA and 2 with HHS (10 male, 4 female, 19-62 years, initial plasma glucose 404-1192 mg/dl). All patients received a standardized treatment to international current guidelines. In addition to hemodynamic and clinical-chemical monitoring HRV analysis was performed continuously for at least 48 hours. Simultaneously, we determined supraventricular and ventricular arrhythmic episodes. RESULTS: HRV was diminished over the whole spectrum in dependence on blood glucose concentration. Thus, sympathovagal balance (LF/HF ratio) was initially sympathetic predominated in blood glucose levels < 600 mg/dl (relatively prevailing LF power) and vagal predominated in blood glucose levels > 600 mg/dl (relatively prevailing HF power). In correlation analysis of HRV parameters with blood glucose rS-coefficients from -0.934 to -0.821 were achieved (p < 0.001). Further, the initial mean blood pressure correlated with the LF/HF ratio in HRV minimum (rS = 0.711, p = 0.004). The initial heart rate in relation to assumed intrinsic frequency correlated with minimal found Total Power (rS = -0.656, p = 0.011). In the period of whole 48 hours, more arrhythmic events occurred in consequence to initial glucose levels (rS = 0.693, p = 0.006). But the maximum of arrhythmic episodes was usually later ascertained than the minimum of HRV (p < 0.001). At the time of each arrhythmic maximum the sympathovagal balance (LF/HF) showed no uniform figures. Only similar in all cases was that the LF/HF ratio was found either > 4 or < 1. CONCLUSION: Clinical complications in high glucose levels must be seen in the context of a nearly complete blockade of sympathetic and parasympathetic activity. Basically to extreme autonomic restriction, sympathetic and vagal predominance can change rapidly into each other. This retarded vulnerable predisposition may declare the arrhythmic potential. An important progress in the monitoring of patients could be achieved by implementation of a continuous HRV measurement because hereby the actual risk potential can be ascertained timely and reliably.

[Continuous analysis of heart rate variability for examination of cardiac autonomic nervous system after alcohol intoxication]. / Kontinuierliche Analyse der Herzfrequenzvariabilität zur Beurteilung des kardialen autonomen Nervensystems nach Alkoholintoxikation.

BACKGROUND: Alcohol intoxication is associated with deterioration of cardiac nervous function and increased mortality. PATIENTS AND METHODS: Therefore, 14 patients (eight male, six female; 24-59 years) with pure ethanol intoxication and toxic levels of 210-520 mg/dl in the blood were prospectively investigated. For evaluation of changes in sympathetic and vagal modulation, an analysis of heart rate variability (HRV) was performed. RESULTS: The results show that HRV in general is suppressed in dependence on blood alcohol levels. Most correlation was found in short-term variability of frequency domain (HF power) after logarithmic transformation (p < 0.001). Also the discrimination of moderate versus severe intoxication was greatest in HF power (p < 0.001). During recovery, all HRV parameters increased to significantly higher figures within 24 h (p < 0.001), but elevated LF/HF ratio as a sign of sympathetic predominance continued over the whole observation period (p < 0.001 to reference). Regarding the danger of possibly life-threatening arrhythmias, the LF/HF ratio showed significantly increased figures in the period of maximal development of supraventricular and ventricular arrhythmias (p = 0.001 to 24-h mean of LF/HF). CONCLUSION: These results underline the longer-lasting hyperadrenergic state during "holiday heart syndrome". The still depressed cardiac autonomic nervous system after 24 h, especially in the vagal activity-describing part, might be basically relevant for later occurrence of cardiovascular complications, if additional trigger factors become present.

Myocardial infarction as an uncommon clinical manifestation of intravascular large cell lymphoma.

Intravascular large cell lymphoma (IVL) is a very rare variant of non-Hodgkin's lymphoma presenting with puzzling clinical manifestations. There is a predilection for the central nervous system, but the tumour often affects also skin, lung, and kidneys while lymphadenopathy and hepatosplenomegaly are usually absent. Myocardial infarction due to IVL has not been reported so far. We here report on a 56-year-old patient who was admitted to our hospital with fever and clinical signs of erysipelas. He had a 6-month history of "collagen vasculitic disease" treated with prednisolone and azathioprine. He received antibiotic treatment, but after transient improvement fever recurred with generalized seizures and myocardial infarction, which required transfer to the intensive care unit where the patient died with signs of an acute cardiogenic shock. Autopsy revealed a generalized high-grade B cell lymphoma of IVL type affecting and obstructing small vessels of a variety of tissues including heart, brain and lungs. The tumorous obliteration of small intramyocardial vessels had led to an acute ischaemia with infarction and subsequent signs of myocardial insufficiency. To the best of the authors' knowledge myocardial infarction as a leading symptom of IVL has not been described.