https://www.mdc-berlin.de/de/veroeffentlichungstypen/clinical- journal-club

Als gemeinsame Einrichtung von MDC und Charité fördert das Experimental and Clinical Research Center die Zusammenarbeit zwischen Grundlagenwissenschaftlern und klinischen Forschern. Hier werden neue Ansätze für Diagnose, Prävention und Therapie von Herz-Kreislauf- und Stoffwechselerkrankungen, Krebs sowie neurologischen Erkrankungen entwickelt und zeitnah am Patienten eingesetzt. Sie sind eingelanden, um uns beizutreten. Bewerben Sie sich! A 29-year-old man with a history of aplastic anemia, who was being treated with cyclosporine, presented to the emergency department with a 4-day history of fever, cough, and difficulty breathing at rest. One day before the onset of symptoms, a pruritic rash had developed on his face, trunk, and limbs. On physical examination, he had a diffuse rash at different stages of development, including papules, vesicles (Bläschen), pustules, and crusted vesicles. What is the diagnosis?

Eosinophilic granulomatosis with polyangiitis

Disseminated varicella infection

Disseminated intravascular coagulation

Drug-induced hypersensitivity syndrome

Immune thrombocytopenia purpura

A chest radiograph showed multiple nodules coalescing to form nodular consolidation and infiltrates in both lungs. A clinical diagnosis of disseminated varicella infection was made, based on his history of contact with a person who had chickenpox, along with the appearance of lesions and pulmonary symptoms in the context of immunosuppression. Zuranolone (INN; developmental code SAGE-217) is an investigational medication, which is under development by SAGE Therapeutics for the treatment of major depressive disorder, , , Parkinson's disease, , and seizures. It is a synthetic, orally active, inhibitory pregnaneneurosteroid, and acts as a positive of the GABAA receptor. The drug was developed as an improvement of (brexanolone) with high oral bioavailability and a biological half-life suitable for once-daily administration. Trial of SAGE-217 in Patients with Major Depressive Disorder Altered neurotransmission of γ-aminobutyric acid (GABA) has been implicated in the pathogenesis of depression. Whether SAGE-217, an oral, positive allosteric modulator of GABA type A receptors, is effective and safe for the treatment of major depressive disorder is unknown. In this double-blind, phase 2 trial, we enrolled patients with major depression and randomly assigned them in a 1:1 ratio to receive 30 mg of SAGE-217 or placebo once daily. The primary end point was the change from baseline to day 15 in the score on the 17-item Hamilton Depression Rating Scale (HAM-D; scores range from 0 to 52, with higher scores indicating more severe depression). Secondary efficacy end points, which were assessed on days 2 through 8 and on days 15, 21, 28, 35, and 42, included changes from baseline in scores on additional depression and anxiety scales, a reduction from baseline of more than 50% in the HAM-D score, a HAM-D score of 7 or lower, and a Clinical Global Impression of Improvement score of 1 (very much improved) or 2 (much improved) (on a scale of 1 to 7, with a score of 7 indicating that symptoms are very much worse). The mean HAM-D score at baseline was 25.2 in the SAGE-217 group and 25.7 in the placebo group. On day 15, the least-squares mean change from baseline in HAM-D score was −17.4±1.3 points in the SAGE-217 group and −10.3±1.3 points in the placebo group (least-squares mean difference in change, −7.0; 95% confidence interval [CI], −10.2 to −3.9; P<0.001). At each time point from day 2 through day 28, the unadjusted 95% confidence intervals for the between-group difference in the change from baseline in HAM-D scores did not include zero, and the differences were generally in the same direction as those of the primary outcome, but the unadjusted 95% confidence intervals for days 35 and 42 included zero. At day 15, the least-squares mean change from baseline in the Bech-6 score was −40.7±3.3 points in the SAGE-217 group and −25.7±3.4 points in the placebo group (least-squares mean difference in change, −15.1 points; unadjusted 95% CI, −23.3 to −6.8). At day 15, the least-squares mean change from baseline in the MADRS score was −22.5±1.9 in the SAGE-217 group and −15.0±1.9 in the placebo group (least-squares mean difference in change, −7.6 points; unadjusted 95% CI, −12.3 to −2.8). Efficacy End Points. Scores on the 17-item Hamilton Depression Rating Scale (HAM-D) range from 0 to 52, with higher scores indicating more severe depression. The primary end point was the change in HAM-D score from baseline to day 15 (Panel A). � bars indicate ±1 SE. The percentage of patients who had a reduction from baseline in HAM-D score of more than 50% (Panel B) and the percentage of patients who had a HAM-D score of 7 or lower (Panel C) were secondary end points. The most common adverse events that occurred in at least 5% of patients in the SAGE-217 group were headache, dizziness, nausea, and somnolence Among patients with moderate-to-severe major depressive disorder, treatment with SAGE- 217 for 14 days resulted in a reduction in depressive symptoms, as assessed on the basis of the change in the HAM-D score from baseline to day 15 and of changes in secondary end-point assessments that also were generally in the same direction as those of the primary outcome. The trial was not designed to confirm findings beyond the 15-day assessment period. One patient reported euphoria as an adverse event, which suggests that in most patients the effect of SAGE-217 on alleviation of depressive symptoms was not related to a temporary feeling of euphoria. The assessment of scores on the Bech-6 subscale showed improvement in all core symptoms of depression among patients who received SAGE-217. The effect of SAGE-217 was similar among patients who received adjunctive treatment with conventional antidepressants and those who received SAGE-217 as monotherapy, although the number of patients in these groups was small, and the trial was not powered to assess this comparison. These findings may support a role for GABAA receptors in the pathophysiology of depression. On the basis of the pharmacologic properties of SAGE-217 as a positive allosteric modulator of GABAA receptors, somnolence and sedation may be expected adverse events, and these were among the most common adverse events in the trial.

In conclusion, in this trial of SAGE-217, an oral, synthetic positive allosteric modulator of

GABAA receptors, patients who received SAGE-217 had a greater reduction in depressive symptoms at day 15 than patients who received placebo. Larger and longer trials are necessary to determine the durability and safety of SAGE-217 in the treatment of depression. Krampfadern (von althochdeutsch krimpfan ‚krümmen‘; fremdwortlich Varix und Varize, Plural Varizen, von lateinisch varix) sind knotig-erweiterte (oberflächliche) Venen (Blutadern). Die Krankheit beim Vorliegen von Varizen heißt in der Fachsprache Varikose oder auch Varikosis. Betroffen sind die oberflächlichen Venen der Beine inklusive deren Hauptstämmen, der Vena saphena magna und Vena saphena parva. Die Ursache der idiopathischen Varikose liegt in einer angeborenen Venenwand- bzw. Bindegewebsschwäche. Keine Rolle spielen Sonne, Wärme, Übereinanderschlagen (Verschränken) der Beine. Das Blut wird durch die Muskelpumpe gegen die Schwerkraft zum Herzen transportiert. Bei Bewegung, z. B. dem Spazierengehen, verkürzen sich die Beinmuskeln und pumpen das Blut in Richtung Herz. Ein Rückfluss wird durch Segelklappen verhindert. Wenn durch Veranlagung die Venenwände schwach sind, das umgebende Gewebe wenig Druck aufbaut und die Bewegung der Beine fehlt, z. B. durch Tätigkeiten, die langes Stehen oder Sitzen erfordern, bleibt mehr Blut in den Beinen. Die Venen werden gedehnt, bis sie so weit sind, dass die Venenklappen sie nicht mehr verschließen – vergleichbar einem Tor mit zu großem Rahmen. An diesem Punkt kommt es zur Strömungsumkehr, auch Blow-out genannt: Das Blut fließt der Schwerkraft folgend Richtung Fuß, statt zum Herzen. Das Phänomen setzt sich über Jahre immer schneller, da mit jeder undichten Klappe mehr Blut in den Beinvenen steht, Richtung Fuß fort. Die Krampfadern entstehen durch einen Abfluss des Blutes über die oberflächlichen Beinvenen, die bei einer Varikosis gefüllter sind. Die Adern selbst sind ungefährliche Zeichen der venösen Überlastung, die auf Schlimmeres hinweisen: eine chronisch-venöse Insuffizienz mit den unten beschriebenen Symptomen. Im Vordergrund der operativen Therapie stehen heute minimalinvasive operative Verfahren, wobei zwischen Methoden der Unterbindung, der Entfernung und der Sklerosierung (Verklebung) von Venen unterschieden werden kann. Bei der endovenösen Lasertherapie, der endovenösen Radiofrequenztherapie und der Sklerotherapie wird die Innenauskleidung der betroffenen Venen (das Endothel) thermisch oder chemisch zerstört, so dass der Blutstrom unterbunden ist. Die Venen selbst werden nicht entfernt. Dabei gibt es im Wesentlichen drei grundlegende Verfahren. Einmal die endoluminalen Verfahren mit Laser (hier gibt es mehrere Anbieter, die alle mit einem ähnlichen System arbeiten) und dann das sogenannte VNUS-Closure-Fast-Verfahren, bei dem ein schlauchartiger Heizdraht in der Vene mit Strom erhitzt wird und so im direkten Kontakt die Venenwände thermisch schädigt. Das dritte Verfahren ist die Celon-FITT-Radiofrequenzmethode (RFITT = Radiofrequenz-induzierte Thermo-Therapie). Dabei wird Radiofrequenz-Energie in die Venenwände eingekoppelt, was direkt dort zur Verödung, dem Verschweißen und dem dauerhaften Verschluss der krankhaften Vene, sprich der Krampfader führt. Bei der wenig verbreiteten CHIVA-Methode werden Venen gezielt an einzelnen Stellen abgebunden, so dass die für die Krampfadern verantwortlichen krankhaften Rückflüsse vermieden werden. Bereits bestehende Krampfadern können sich so innerhalb einiger Wochen wieder zurückbilden. Idealerweise werden in spezialisierten Einrichtungen mehrere oder alle der oben angeführten Verfahren angeboten, um dem Patienten eine möglichst auf seine Form der Varikose zugeschnittene ideale Therapie zukommen zu lassen, denn nicht jedes Verfahren kann bei jedem Patienten in gleicher Weise angewendet werden. Five-Year Outcomes of a Randomized Trial of Treatments for Varicose Veins

Endovenous laser ablation and ultrasound-guided foam sclerotherapy are recommended alternatives to surgery for the treatment of primary varicose veins, but their long-term comparative effectiveness remains uncertain. In a randomized, controlled trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of laser ablation, foam sclerotherapy, and surgery. Primary outcomes at 5 years were disease-specific quality of life and generic quality of life, as well as cost-effectiveness based on models of expected costs and quality-adjusted life- years (QALYs) gained that used data on participants’ treatment costs and scores on the EuroQol EQ-5D questionnaire.

In the two-way comparison of foam sclerotherapy with surgery, surgery cost an additional £737 ($1,048) per patient, for a mean QALY gain of 0.042, resulting in an incremental cost-effectiveness ratio of £17,554 ($24,956). At the willingness-to-pay threshold of £20,000 ($28,433) per QALY, 54.5% of the model iterations favored surgery. At 5 years, 58% of the patients who had undergone laser ablation, 54% who had undergone surgery, and 47% who had undergone foam sclerotherapy reported having no varicose veins (odds ratio for foam sclerotherapy vs. laser ablation, 0.59; 95% CI, 0.41 to 0.85). Overall, 11% of the patients in the laser ablation group, 14% in the foam sclerotherapy group, and 7% in the surgery group had further treatment. Markov-Model–Based Analysis of the Cost-Effectiveness of the Three Treatments at 5 Years. Costs were converted to U.S. dollars with the use of the Organization for Economic Cooperation and Development (OECD) purchasing power parities for 2017 (£0.703402 equivalent to $1). With this conversion, the equivalent value for £10,000 is $14,217; for £20,000 is $28,433; for £30,000 is $42,650; for £40,000 is $56,867; and for £50,000 is $71,083. In this large, multicenter trial comparing surgery, laser ablation, and foam sclerotherapy for the treatment of primary varicose veins, quality of life was better at 5 years than at baseline in all groups. Five years after treatment, there were significant differences between the treatments with respect to disease-specific quality of life. The AVVQ scores were better among participants treated with laser ablation or surgery than among those treated with foam sclerotherapy, with effect sizes of 2.86 and 2.60, respectively. Quality of life was similar in the laser ablation and surgery groups. The 5-year cost-effective analyses were generally in keeping with our previously reported model-based estimates — namely, laser ablation performed under a local anesthetic in a treatment-room setting had a 77% probability of being cost-effective up to a willingness-to-pay maximum of £20,000 ($28,433). There was considerable uncertainty in the two-way cost- effective analysis comparing foam sclerotherapy with surgery. In summary, this large, multicenter trial comparing the clinical effectiveness of laser ablation, foam sclerotherapy, and surgery for the treatment of varicose veins showed that in all three groups, quality of life 5 years after treatment was improved from baseline. However, there were clinically important between-group differences in disease-specific quality of life that favored laser ablation and surgery over foam sclerotherapy. Laser ablation was similar to surgery with respect to quality of life and of the three treatments had the highest chance of being cost-effective. Der Pyruvatkinasemangel (PK), genauer Pyruvatkinase- Mangel der Erythrozyten oder Hämolytische Anämie durch Mangel der erythrozytären Pyruvatkinase ist eine seltene angeborene Störung der Glykolyse mit dem Hauptmerkmal einer hämolytischen Anämie. Die Erkrankung gilt als die häufigste Ursache einer angeborenen, nicht-sphärozytären hämolytischen Anämie. Die Erstbeschreibung stammt aus dem Jahre 1961 durch die US-Amerikaner William N. Valentine und Mitarbeiter. Der Erkrankung liegen Mutationen im PKLR-Gen auf Chromosom 1 Genort q22 zugrunde, welches die Aktivität der Pyruvatkinase in den Erythrozyten stört mit vermindertem ATP- und erhöhten 2,3-Diphosphoglycerat (2,3-DPG)-Spiegel im Erythrozyten und wohl infolge Ausfilterung (selektiver Sequestrierung) der nicht regulären jungen Erythrozyten, besonders der Retikulozyten, in der Milz zu einer chronischen hämolytischen Anämie führt. Manifestation bereits beim Neugeborenen. sehr breites klinisches Spektrum von schwerer Neugeborenengelbsucht mit lebensbedrohlicher Anämie bei Geburt bis kompensierter Hämolyse ohne erkennbare Anämie häufig chronischer Ikterus, Blässe, Gallensteine und Splenomegalie, Gedeihstörung, beim Erwachsenen Ulcus cruris. Der Schweregrad der Anämie ist variabel und kann zur Transfusionspflichtigkeit führen. In anderen Fällen entsteht eine kompensierte Hämolyse ohne Anämie, die erst im Rahmen von Infektionen oder während der Schwangerschaft zu hämolytischen Krisen führt. Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency

Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells. In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase. The most common adverse events were headache (in 24 patients), insomnia (in 22 patients), and nausea (in 21 patients). These events resolved within 7 days after the initiation of treatment in 60 of 65 episodes (92%) of headache, in 16 of 34 episodes (47%) of insomnia, and in 25 of 32 episodes (78%) of nausea. Headache and insomnia most often occurred within 2 weeks after drug initiation. Of the 52 patients, 19 (37%) had adverse events of grade 3 or higher, as reported by the investigator. Of these patients, 9 (17%) had 11 events that were deemed by the investigator to be possibly or probably related to mitapivat, including hypertriglyceridemia (in 4 patients [6%]), hemolytic anemia (in 2 [4%]), and hemolysis, dizziness, headache, renal-cell carcinoma in the left kidney, and insomnia (in 1 each [2%]).23 The patient with renal-cell carcinoma had a kidney lesion that had been present at the time of enrollment and was identified retrospectively. Change in Hemoglobin According to PKLR Genotype and Hemoglobin Response According to Pyruvate Kinase Protein Level at Baseline. Panel A shows the mean change from baseline in the hemoglobin level during the 24 weeks of the core period, according to the patient’s PKLR genotype category. Of the 52 patients who received mitapivat, 20 (38%) — all of whom had at least one missense mutation — had a mean increase of more than 1.0 g per deciliter in the hemoglobin level (indicated by a thick gray line); 19 patients had a mean increase of at least 1.5 g per deciliter (thin gray line).

A mean increase of more than 1.0 g per deciliter in the hemoglobin level did not occur in any of the 5 patients who were homozygous for the R479H mutation (as indicated by an asterisk) or in any of the 10 patients who were homozygous for non-missense mutations (as indicated by a red bar). Panel B shows the patients who had a hemoglobin response (defined as an increase from baseline of >1.0 g per deciliter in the hemoglobin level at >50% of the assessments during the core period) and those who did not have a response, according to the baseline level of pyruvate kinase protein in red cells, a value that has been normalized to the hemoglobin level (an approximation of the total red-cell protein level) and to the pyruvate kinase protein level measured in a sample obtained from a healthy control (to allow for interassay comparisons). Patients with an increased baseline level of pyruvate kinase protein were more likely to have a hemoglobin response to mitapivat. However, since there were exceptions to this observation, the baseline level of pyruvate kinase protein is not a consistent predictor of hemoglobin response. Patients who were homozygous for the R479H mutation are indicated by asterisks. In 1 patient, the baseline level of red-cell pyruvate kinase protein was not available, so the day 15 sample was used.

Hematologic Measures in Patients with and Those without a Hemoglobin Response. Shown are the mean levels of hemoglobin (Panel A), the absolute reticulocyte count (Panel B), indirect bilirubin (Panel C), and haptoglobin (Panel D) during the 24-week core period, according to whether the patients had a hemoglobin response or no hemoglobin response. The hemoglobin response was sustained during nearly 3 years of follow-up in the extension phase. The indirect bilirubin levels decreased in all the patients. However, the lactate dehydrogenase levels. Thus, there may be an independent effect of mitapivat on bilirubin metabolism. The � bars indicate 95% confidence intervals. In Panel B, the values for the reticulocyte count per cubic millimeter are presented at 0.001 of the actual value. Mitapivat is a small-molecule, allosteric activator of pyruvate kinase in red cells with a side-effect profile that allowed continued administration in 46 of 52 patients (88%) with pyruvate kinase deficiency in this phase 2 study. Treatment with mitapivat was associated with a rapid, clinically significant increase in the hemoglobin level in approximately half the treated patients. The hemoglobin response was sustained for up to 35 months with ongoing mitapivat administration and was associated with improvement in laboratory markers of hemolysis. This study establishes proof of concept for a molecular therapy targeting the underlying enzymatic defect of a hereditary enzymopathy. Grade 3 or greater adverse effects that were considered by the investigator to be related to mitapivat were seen in 17% of patients who were treated daily for up to 35 months. The most commonly reported adverse events occurred soon after drug initiation and were transient. Doses of mitapivat that were significantly lower than the initial doses were associated with hemoglobin responses. Changes in sex hormone levels stayed mainly within normal ranges and did not correlate with adverse events or changes in bone mineral density. Since mitapivat directly binds and activates residual mutant red-cell pyruvate kinase enzyme, it is hypothesized that a minimal level of full-length red-cell pyruvate kinase protein may be required for pyruvate kinase activation by mitapivat. In this study, a hemoglobin response was associated with the residual level of pyruvate kinase protein in red cells at baseline. This finding is consistent with previous ex vivo observations and provides further evidence that mitapivat is working by means of its proposed mechanism of action. Nevertheless, differing degrees of hemoglobin response in patients with equivalent levels of red-cell pyruvate kinase protein suggest that this protein level is not a reliable predictor of hemoglobin response. The data from this study indicate that the adverse-event profile for mitapivat at the adjusted dose aimed at increasing the hemoglobin level appears to allow for long-term administration of the drug. In addition to finding that 88% of the patients could continue to receive mitapivat without unacceptable adverse events, we showed that the subsequent pyruvate kinase activation resulted in clinically significant hemoglobin increases and improvement in hemolytic markers in approximately half the patients with pyruvate kinase deficiency, particularly those with a PKLR genotype that included at least one missense mutation. Die Alveolarproteinose wird auch als pulmonal-alveoläre Proteinose oder als Phospholipoproteinose bezeichnet. Die englische Bezeichnung lautet pulmonary alveolar proteinosis (PAP). Die Erkrankung ist selten und hat eine großenteils unbekannte Ätiologie. Es liegt eine Füllung des Alveolarraums mit zellfreiem, amorphem, eosinophilem, lipidreichem Material vor, bedingt durch eine Störung des Surfactantmechanismus. Männer erkranken häufiger als Frauen, meist im mittleren Erwachsenenalter. Die Erkrankung kann klinisch unerkannt auftreten, Spontanremissionen sind möglich. Sie tritt kongenital, im Kindesalter, oder auch im mittleren Erwachsenenalter auf. Ursächlich für die Erkrankung sind Stoffwechselstörungen, die zur Anhäufung von Surfactant führen, indem eine pathologische Wiederaufnahme der Phospholipide über den Alveolarfilm besteht und die Phagozytosefähigkeit der Alveolarmakrophagen übe rlastet ist. Angeborene Formen gehen auf genetische Neumutationen zurück und sind in der Regel im Säuglingsalter tödlich. Beschrieben sind Mutationen des Surfactant-Protein-B-Gens sowie für GM-CSF. Erworbene Störungen des Surfactantmetabolismus werden als sekundäre Alveolarproteinosen bezeichnet. Sie entstehen bei pulmonalen Infekten, immunologischen Erkrankungen. Bei Tumorerkrankungen und auch chronischer Staubbelastung (Aluminium, Quarz) können auch sekundäre Alveolarproteinosen auftreten. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte– macrophage colony-stimulating factor (GM- CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to- moderate disease remains unclear. Changes in the Alveolar–Arterial Oxygen Gradient. Panel A shows changes in the alveolar–arterial oxygen gradient from baseline to week 25 in the GM-CSF group (33 patients) and placebo group (30 patients) during the 24-week randomized intervention period. The middle solid horizontal lines show the median values, the upper solid horizontal lines show the 75th percentiles, and the lower solid horizontal lines show the 25th percentiles. Each circle represents an individual patient. Panel B shows high- resolution computed tomographic (CT) images of the chest in a representative patient from the GM-CSF group at baseline and at week 25, with a reduction in ground- glass opacity during treatment. The distribution of numbers of pixels with various CT density values for the same patient is shown.

In this randomized, controlled trial involving patients with mild-to-moderate autoimmune pulmonary alveolar proteinosis, the change in the alveolar–arterial oxygen gradient was better with inhaled GM-CSF than with placebo. The effect of spontaneous remission, which occurs in approximately 20% of patients, and the placebo effect may have played a role in the earlier open- label phase 2 study. The effects of spontaneous remission on the reduction in symptoms of pulmonary alveolar proteinosis were obviated by the present randomized trial design. The difference between current or former smokers and patients who had never smoked with respect to the increase in the alveolar–arterial oxygen gradient suggests that cigarette smoking may affect the pathway of antibody production and thus stimulate GM-CSF neutralization. We speculate that long-term cigarette smoking may cause minimal remodeling of small airways, leading to changes in mucus production that affect the distribution of inhaled GM-CSF in the lung. In addition, alveolar macrophages in smokers may be functionally impaired beyond the defects caused by GM-CSF autoantibodies; this impairment may be responsible for the poor response to inhaled GM-CSF in smokers with autoimmune pulmonary alveolar proteinosis. During the trial, we observed an increase in serum levels of autoantibodies against GM-CSF in the GM-CSF group but not in the placebo group. However, the neutralizing capacity did not differ between the groups, probably because of the duration of inhalation. Administration of subcutaneous, long-term, intermittent recombinant human GM-CSF can cause a transient induction of autoantibodies against GM-CSF in patients with metastatic colon cancer. The results of our randomized, controlled trial showed that inhaled GM-CSF had a significant but very modest effect on the alveolar–arterial oxygen gradient in patients with pulmonary alveolar proteinosis. At the dose used, there were changes in some laboratory measures, but no clinically important changes in outcomes were noted. Immune Thrombocytopenia A 72-year-old woman who is receiving apixaban for atrial fibrillation but otherwise does not have a clinically significant medical history presents to the hospital with lower gastrointestinal bleeding. On admission, her hemoglobin level is 8.5 g per deciliter, platelet count 2000 per cubic millimeter, and white-cell count 5300 per cubic millimeter. She receives a transfusion of packed red cells and platelets that results in an increase in the hemoglobin level and a decrease in bleeding, but only a transient increase in the platelet count. The examination is unremarkable. A peripheral-blood smear shows no abnormalities other than thrombocytopenia; these findings are consistent with a diagnosis of immune thrombocytopenia. How should this case be managed?

Pathophysiological Features of Immune Thrombocytopenia. Although the pathophysiology of immune thrombocytopenia (ITP) is incompletely understood, the key event is considered to be the production of antiplatelet autoantibodies. These autoantibodies target platelets for destruction by macrophages in the spleen, liver, or both through activation of Fcγ receptors; this process is controlled by spleen tyrosine kinase (Syk). Autoantibodies may also destroy platelets through other mechanisms and inhibit platelet production by megakaryocytes. Antigens from phagocytosed platelets are thought to be presented by the major histocompatibility complex class II (MHCII) to T-cell receptors (TCRs), stimulating autoreactive T cells. T-cell changes seen in ITP and hypothesized to be pathogenic include skewing of T helper (Th) cells toward a type 1 T helper (Th1) and type 17 T helper (Th17) phenotype, reduction of regulatory T-cell activity, and an increase in cytotoxic T cells. A few studies suggest that cytotoxic T cells can also directly destroy or inhibit the production of platelets. Peripheral-Blood Smear and Bone Marrow Aspirate from a Patient with ITP. Panel A shows thrombocytopenia (only one platelet [arrow] is observed in the field) and normal erythrocytes in a peripheral-blood smear. Panel B shows bone marrow in a patient with ITP, with good cellularity, normal development of erythroid and myeloid cells, and an increased number of megakaryocytes.

Glucocorticoids Glucocorticoid treatment is the standard initial therapy for patients with ITP. Two commonly used regimens are pulsed high-dose dexamethasone and a more prolonged course of oral prednisone or prednisolone. Adverse events such as weight gain and cushingoid appearance were more prevalent with prednisone or prednisolone. Although 60 to 80% of patients with ITP have an initial response to glucocorticoids, only 30 to 50% of adults have a sustained response after glucocorticoids are discontinued. Thrombopoietin-Receptor Agonists Eltrombopag and romiplostim are thrombopoietin-receptor agonists that are approved by the Food and Drug Administration (FDA) for patients with ITP that is refractory to other treatment and with disease lasting more than 6 months (eltrombopag) or 12 months (romiplostim). In randomized, placebo-controlled trials of each of these agents involving patients with chronic ITP in whom at least one previous therapy has failed, 70 to 95% of patients had an increased platelet count with initial treatment and 40 to 60% had durable responses with ongoing treatment. Immunomodulators Rituximab is the most widely used immunomodulator in patients with ITP, although it is not approved by the FDA for this indication. A systematic review of single-group studies showed a response in 60% of patients, with a complete response in 40% of patients. A meta-analysis including five randomized, controlled trials showed a significantly higher incidence of complete response at 6 months with rituximab than with glucocorticoids or placebo. Fostamatinib, an oral spleen tyrosine kinase (Syk) inhibitor, was approved by the FDA in 2018 for patients with ITP in whom one previous therapy has failed. In pooled randomized trials, a stable response (defined as a platelet count ≥50,000 per cubic millimeter on at least four of six visits twice a week during weeks 14 to 24) was achieved in 18% of patients receiving fostamatinib and in 2% of those receiving placebo. Splenectomy A systematic review showed that splenectomy, which remains the most effective therapy for ITP, induced long-lasting remissions in 60 to 70% of patients. Splenectomy is generally not performed in frail elderly patients because of increased surgical complications in this group. It is generally not performed in patients with secondary ITP owing to a lower incidence of response and more adverse events in these cohorts than in others. A 56-year-old man presented to the emergency department with pain in his right hand after he hit a desk in frustration during an argument at work. On physical examination, there was swelling at the base of the fifth digit, with no open wound. A plain radiograph of the right hand showed a fracture at the neck of the fifth metacarpal (arrow). Sometimes called a boxer’s fracture, this injury typically occurs when a person punches an object with a closed fist. Despite its name, the fracture is uncommon among professional boxers and typically occurs among untrained persons punching without proper technique. In our patient, because the fracture had created an angulation of greater than 30 degrees and the injury was to his dominant hand, he was treated with percutaneous intramedullary nail fixation and cast immobilization. At follow-up 5 months after surgery, he had regained full use of his right hand. A 49-year-old man was referred to the otorhinolaryngology clinic with a 3-month history of progressive voice changes and pain with swallowing. He had a history of hypertension and type 2 diabetes mellitus and was a current smoker. He had no recent weight loss or other systemic symptoms. Fiberoptic laryngoscopy revealed a 2-cm lesion at the level of the vocal cords (Panel A). The laryngeal lesion was excised, and findings on histologic examination were consistent with metastasis of a clear-cell carcinoma. Computed tomography of the abdomen and chest were subsequently performed and revealed a mass measuring 7.0 cm by 6.4 cm by 6.6 cm at the superior pole of the right kidney (Panel B), several pulmonary lesions, and enlarged mediastinal lymph nodes — findings consistent with metastatic disease. Laparoscopic radical nephrectomy of the right kidney was performed, and oral sunitinib was initiated for the treatment of metastatic renal-cell carcinoma. At 1 year of follow-up, the patient had stable mediastinal lesions and complete remission (disappearance) of some of the pulmonary lesions. A Terminal Event A 54-year-old man presented to a primary care clinic with worsening pain in the lower back. Two years earlier, sudden-onset, sharp, constant, nonradiating lumbar pain had developed, in the absence of inciting trauma. Over the 6 months before the current presentation, severe back pain frequently awakened him from sleep. He described morning stiffness in his lower back lasting 1 to 2 hours, which was alleviated by activity and by nonsteroidal antiinflammatory drugs (NSAIDs). He reported having had neck, right shoulder, and sternal pain for the past year. He had no fevers, chills, weight loss, or gastrointestinal or urinary symptoms but did report fatigue, as well as weakness in his arms (more so in his right arm than in his left) and legs (symmetric). Over the past year, he had used a cane and an abdominal binder to aid his walking. The reports from two lumbar and cervical magnetic resonance imaging (MRI) studies performed at outside facilities 1 year and 2 years before this presentation described multilevel degenerative changes, with disk bulges at L4–L5 and C4–C7, a disk bulge and osteophyte complex at C5–C6 causing moderate-to-severe canal stenosis, and multilevel neuroforaminal stenosis. No cord signal abnormalities or inflammatory changes were noted in the report of either MRI. His medical history included diabetes mellitus, hypertension, and gastroesophageal reflux disease. His medications were aspirin, naproxen, gabapentin, oxycodone with acetaminophen, metformin, benazepril, and famotidine. He was born in Korea, immigrated to the United States at the age of 26, and traveled to Korea annually. He was a current tobacco smoker with a smoking history of 30 pack-years; he did not drink and never used illicit drugs. His temperature was 36.8°C, blood pressure 134/65 mm Hg, heart rate 61 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation 100% while he was breathing ambient air. He appeared uncomfortable from pain. Head, neck, cardiopulmonary, abdominal, and skin examinations were normal. He had reduced cervical and lumbar range of motion, lumbar spinal tenderness, an antalgic gait, and normal strength, sensation, and reflexes in both arms and both legs. The white-cell count was 8400 per cubic millimeter, hemoglobin 10.5 g per deciliter, mean corpuscular volume 91 fl, and platelet count 325,000 per cubic millimeter. Serum electrolyte levels, liver-function test results, and uric acid levels were normal. The ferritin level was 34 μg per liter (normal range, 22 to 322), iron level 9 μg per deciliter (1.6 μmol per liter) (normal range, 42 to 175 μg per deciliter [7.5 to 31.3 μmol per liter]), transferrin level 192 mg per deciliter (normal range, 182 to 360), transferrin saturation 3% (normal range, 10 to 47), and reticulocyte count 27.1×109 per liter (normal range, 29×109 to 121.4×109). The glycated hemoglobin level was 7.5%. MRI and CT Images of Disk and Vertebral Erosion. T1-weighted sagittal MRI of the lumbar spine (Panel A) shows multiple erosions of the vertebral bodies. A gadolinium-enhanced sagittal sequence (Panel B) reveals increased signal in the L4 and L5 vertebral bodies and the intervertebral disk space, and an epidural fluid collection (arrow). A sagittal computed tomographic (CT) image (Panel C) shows similar structural changes in the vertebral bodies. Tests for human immunodeficiency virus (HIV) MRI of Pelvis. A T1-weighted (fat- antibodies were negative. The erythrocyte sensitive) coronal oblique view (Panel sedimentation rate was more than 100 mm per A) of the pelvis identifies a hypodensity hour (normal range, 0 to 20). The C-reactive and erosion around the left sacroiliac protein level was 61.2 mg per liter (normal range, 0 joint (arrow). This corresponds to the to 6.3). Serum and urine protein electrophoresis hyperintensity (bone marrow edema) on results and a prostate-specific antigen level were the fluid-sensitive sequence (Panel B). normal. Human leukocyte antigen B27 (HLA-B27) The short-tau inversion recovery coronal was not present. A tuberculin skin test was oblique view of the pelvis (Panel B) positive, with 30 mm of induration. Computed suppresses signals from fat. The tomography (CT) of the chest, abdomen, and increased signal intensity around the left pelvis revealed three centrilobular nodules sacroiliac joint (arrow) is bone marrow measuring 2 mm each in the right upper lobe. edema, which is suggestive of active Extensive vertebral body erosions were again sacroiliitis. noted Tests for human immunodeficiency virus (HIV) antibodies were negative. The erythrocyte sedimentation rate was more than 100 mm per hour (normal range, 0 to 20). The C-reactive protein level was 61.2 mg per liter (normal range, 0 to 6.3). Serum and urine protein electrophoresis results and a prostate-specific antigen level were normal. Human leukocyte antigen B27 (HLA-B27) was not present. A tuberculin skin test was positive, with 30 mm of induration. Empirical rifampin, isoniazid, pyrazinamide, and ethambutol were prescribed. CT-guided biopsies of the left posterior iliac crest, L2–L3 disk, and L3 end plate revealed no evidence of neoplasm. Staining of bone and epidural fluid specimens for bacteria, fungus, and mycobacteria, as well as a Mycobacterium tuberculosis complex polymerase-chain-reaction (PCR) assay, were negative. All bacterial, fungal, and mycobacterial cultures were negative. Given that the patient’s symptoms were not alleviated with antituberculous therapy, that therapy was discontinued after 4.5 months. Esophagogastroduodenoscopy revealed mild chronic gastritis with a 4-mm erosion on the lesser curve and helicobacter organisms; the duodenal mucosa appeared normal. Colonoscopy revealed one diminutive hyperplastic polyp and otherwise normal-appearing ileum and colon, which were not biopsied. The patient was treated with pantoprazole, clarithromycin, and amoxicillin for 2 weeks. Celecoxib was substituted for naproxen. Etanercept was prescribed for suspected ankylosing spondylitis. After 1 month, the patient’s back pain decreased, and he resumed exercise. Over the next 8 months, the erythrocyte sedimentation rate decreased, the C-reactive protein level normalized, and MRI of the total spine showed interval reduction of bone marrow edema. On repeat testing, the hemoglobin level was 12.1 g per deciliter, with mean corpuscular volume of 91 fl. Although the patient had no gastrointestinal symptoms, a fecal calprotectin level was measured to evaluate for inflammatory bowel disease, given the persistent anemia and atypical presentation of ankylosing spondylitis; the level was 103 μg per gram (normal value at our institution at that time, <163). After 14 months of etanercept therapy, the patient was admitted for severe odynophagia. He described 10 years of self-limited oral ulcers; he reported no history of genital ulcers. Results of repeat HIV testing were negative. Oral examination and laryngoscopy showed diffuse white plaques on the tongue and multiple tender, shallow ulcers up to 2 cm in size on the tongue, uvula, palate, epiglottic folds, and false vocal cords. Oral Examination Showing Shallow Ulcers on the Uvula and Palate. Scrapings from the tongue plaques did not show fungi, and a direct immunofluorescence assay for herpes simplex virus (HSV) was negative. His symptoms were not alleviated with fluconazole.

CT of the abdomen and pelvis showed thickening of the terminal ileal wall and bilateral erosions of the sacroiliac joint. Bacterial, fungal, and mycobacterial cultures of sputum specimens and bronchoalveolar fluid were negative. Over this 2-year period of evaluation, the patient’s weight decreased from 62 kg to 55 kg. This patient has spondylodiskitis, bilateral sacroiliitis, oral ulcerations, ileal wall thickening, scattered pulmonary nodules, and systemic inflammation that have lasted more than 2 years without the discovery of an infection and with an incomplete response to etanercept. The ileum is rich in lymphoid tissue, and wall thickening could occur with many diseases, including tuberculosis, lymphoma, Crohn’s disease, and Whipple’s disease. The patient was discharged with an appointment for outpatient colonoscopy. The colonoscopy was delayed because the patient was readmitted for recurrent severe odynophagia from oral ulcerations. During that hospitalization, sudden abdominal pain on the right side and melena developed. CT of the abdomen revealed free air and extravasation of extraluminal contrast material. Exploratory laparotomy revealed a pinpoint perforation 15 cm proximal to the ileocecal valve and a thickened, strictured, and chronically inflamed ileocecal valve and distal ileum. An ileocecectomy with ileocolonic anastomosis was performed. Ileum Specimen. A specimen from the ileum with hematoxylin and eosin staining shows multiple neutrophils within the surface epithelium (Panel A, arrow), indicating active ileitis, and focal pseudopyloric metaplasia (Panel B, arrows), indicating chronicity. There were no granulomas or dysplasia. Six weeks after surgery, treatment with adalimumab and methotrexate was initiated. Over the next 6 months, the patient’s back pain decreased substantially. The erythrocyte sedimentation rate and the C-reactive protein level normalized, and MRI showed resolution of the bone marrow edema of the spine and the area around the sacroiliac joints. CT of the chest showed that the pulmonary nodules had resolved. The patient was able to exercise regularly, and his weight increased to the baseline level. Commentary Spondyloarthritis describes a family of diseases that are characterized by chronic inflammation affecting the axial joints (spine, pelvis, and thoracic cage), peripheral joints (arms and legs), or both. When the axial joints are predominantly involved, the condition is called axial spondyloarthritis; its prototype is ankylosing spondylitis, which is characterized by radiographic evidence of sacroiliitis. The most common extraarticular manifestation of axial spondyloarthritis is anterior uveitis, which is typically associated with HLA-B27. Peripheral spondyloarthritis primarily involves peripheral joints; its prototype is psoriatic arthritis, which is characterized by psoriatic skin lesions, synovitis, enthesitis, and dactylitis. Reactive arthritis, which is triggered by antecedent infection, is another spondyloarthritis that is typically peripheral. Spondyloarthritis in patients with inflammatory bowel disease (Crohn‘s disease) can be predominantly axial or peripheral.

Aplasia cutis congenita in monozygotic twins

Die Aplasia cutis congenita (ACC) ist eine intrauterin erworbene oder angeborene Erkrankung, eine meist lokal begrenzte kongenitale Aplasie der Kutis, häufig am Kopf. Häufig finden sich weitere Auffälligkeiten an den Augen, an Hals, Nase oder Ohren oder der Gliedmaßen. Die Erkrankung wurde erstmals im Jahre 1767 durch M. Cordon beschrieben. Die Häufigkeit wird mit 1–5 / 10 000 angegeben, bei den familiären Formen erfolgt die Vererbung autosomal-rezessiv oder häufiger autosomal-dominant. Als Ursache kommen Infektionen, Gefäß- Fehlbildungen, Amniondefekte, teratogene Medikamente (z. B. ACE-Hemmer, Carbimazol, Methimazol oder Valproinsäure) infrage. Es besteht eine Assoziation mit schweren Fehlbildungen wie Omphalozele, Gastroschisis oder Spina bifida. Seltenen familiären Formen liegen Mutationen im BMS1-Gen am Genort 10q11.21 zugrunde.

NCBI This gene likely encodes a ribosome assembly protein. A similar protein in yeast functions in 35S-rRNA processing, which includes a series of cleavage steps critical for formation of 40S ribosomes. Related pseudogenes exist on chromosomes 2, 9, 10, 15, 16, and 22.