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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 46-year-old woman presented to the clinic with a 3- month history of walking difficulty due to worsening knee pain. She had received a diagnosis of rheumatoid arthritis 12 years earlier but had received treatment inconsistently. On physical examination, she had nodular swelling and outward bowing of both knees. She had limited range of motion in her left shoulder and in both wrists and both knees. Anteroposterior radiograph of the knees is shown. What is the diagnosis?

Synovial chondromatosis

Synovial chondrosarcoma

Osteochondritis dissecans

Pigmented villonodular synovitis

Disseminated tuberculosis

Correct! The findings are consistent with synovial chondromatosis, a disorder of the synovium that is characterized by the development of loose cartilaginous bodies. Die Synoviale Chondromatose ist eine seltene Erkrankung der Synovialis großer Gelenke. Es handelt sich um eine knorpelbildende Metaplasie (Chondromatose). Die ersten Kasuistiken stammen von Paul Friedrich Reichel, Melvin Starkey Henderson (1918) und Hugh Toland Jones (1924). Die Ursache ist nach wie vor unklar. Pathologisch-anatomisch handelt es sich um eine Metaplasie mesenchymaler Zellen in umschriebene Knorpelareale. Bei Männern kommt das seltene Krankheitsbild etwa doppelt so häufig wie bei Frauen vor, bei Kindern nur vereinzelt. „Häufig“ befallen sind Knie-, Hüft-, Schulter- und Ellbogengelenk. Auch das Kiefergelenk kann betroffen sein. Die meisten Patienten sind lange relativ beschwerdefrei. Schließlich erfordern Einklemmungserscheinungen, Bewegungsbehinderung oder Schmerzen durch freie Gelenkkörper und synoviale Chondrome, sowie die mögliche Schädigung von Gelenkstrukturen durch Abrieb (Sekundärarthrose) eine Abklärung. Die synoviale Chondromatose ist eine radiologische Blickdiagnose. Als gefürchtete Komplikation ist die Entstehung eines sekundären Chondrosarkoms zu sehen. In einer größeren Studie mit 53 Fällen in 30 Jahren wurden drei Chondrosarkome diagnostiziert. Bei dieser Unterform verschmelzen viele einzelne Chondrome, so dass sich ein solider Tumor bis zu einem Durchmesser von 20 cm ausbilden kann. Auch eine entsprechende Vergrößerung eines einzelnen Chondroms wird für möglich erachtet. Histologisch und radiologisch ist die Abgrenzung von einem Chondrosarkom schwierig. Die Osteochondrosis dissecans, kurz OD, ist eine aseptische, meist traumatisch bedingte Knochennekrose eines umschriebenen Gelenkflächenareals, die mit der Abstoßung eines Gelenkflächenfragmentes einhergehen kann. Die Osteochondrosis dissecans wird im ICD10 den Chondropathien zugeordnet. Alle Gelenke des menschlichen Körpers können betroffen sein, am häufigsten ist jedoch das Kniegelenk in der Wachstumsphase erkrankt. Die Ätiologie ist oftmals unbekannt. Mögliche Ursachen können Mikro- oder Makrotraumata sowie Ischämie oder Störungen der Schilddrüsenfunktion sein. Dauer- und Überbelastung der Gelenkflächen bei Sportlern erhöht vermutlich das Risiko. Eine subchondrale Vaskularisationsstörung führt zur Demarkierung des betroffenen Knochenareals und zur anschließenden Osteolyse oder Sklerosierung an der Gelenkfläche. Der sich darauf befindende Knorpelbereich verfärbt sich anfangs gelb und zeigt erste degenerative Veränderungen. Im weiteren Verlauf löst sich das geschädigte Knorpel-Knochenareal als Dissekat (sogenannte Gelenkmaus) aus der Gelenkoberfläche und hinterlässt eine Defektstelle. Der Gelenkflächendefekt wird später mit fibrösem Gewebe ausgekleidet. Die Colitis Ulcerosa (CU, englisch ulcerative colitis) gehört zur Gruppe der chronisch-entzündlichen Darmerkrankungen. Sie ist durch einen entzündlichen Befall des Dickdarms bzw. des Colons gekennzeichnet. Im Gegensatz zum Morbus Crohn ist von der Entzündung nur der Dickdarm kontinuierlich betroffen und diese ist auf die Darmschleimhaut (Mukosa und Submukosa) beschränkt. Die Ursache der Erkrankung ist unbekannt. Ähnlich wie beim Morbus Crohn nimmt man eine genetisch prädisponierte, krankhaft gesteigerte Immunreaktion gegen die Darmflora an. Es konnten mehrere Genmutationen identifiziert werden, die mit dem Auftreten von chronisch-entzündlichen Darmerkrankungen in Verbindung stehen. Wie bei Morbus Crohn steht der NF-κB-Transkriptionsfaktor im Verdacht, durchgängig aktiv zu sein. Umweltfaktoren wie Hygienestandard und Ernährung sollen eine ebenso wichtige Rolle spielen. Stress und Belastungen können wesentlich zu einem schwierigen Verlauf beitragen und aktive Schübe der Krankheit auslösen. Colitis ulcerosa wurde über einen langen Zeitraum ähnlich wie Morbus Crohn zu den psychosomatischen Krankheiten gezählt, sie gehört zu den Holy Seven. Mittlerweile ist allerdings klar, dass die Colitis ulcerosa durch die genannten organischen Ursachen hervorgerufen wird, und dass die Psychosomatik allenfalls Begleit- und Folgeerscheinungen beeinflusst Ustekinumab ist ein Arzneistoff, der in der Behandlung der Psoriasis eingesetzt wird. Ustekinumab ist ein humaner monoklonaler Antikörper gegen die Zytokine Interleukin-12 (IL- 12) und Interleukin-23 (IL-23). Ustekinumab ist für die Behandlung der mittelschweren bis schweren Plaque-Psoriasis bei Erwachsenen und Jugendlichen ab dem 12. Lebensjahr zugelassen, bei denen andere Therapien nicht angesprochen haben, kontraindiziert sind oder nicht vertragen wurden.[ Zu den häufigsten Nebenwirkungen unter Ustekinumab zählen Infektionen, insbesondere der oberen Atemwege (> 10 %). Häufig (1–10 %) treten auch Depressionen, Schwindel, Kopfschmerz, Durchfall, Juckreiz, Rücken- und Muskelschmerz und Müdigkeit auf. Darüber hinaus können Reaktionen an der Injektionsstelle beobachtet werden. Es gibt auch Hinweise auf mögliche kardiovaskuläre Risiken. Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an IL12B (IL-12p40) subunit (that is shared with IL12) and the IL23A (IL-23p19) subunit.[1] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL- 23R. IL-23 is a proinflammatory cytokine. IL-23 has been shown to be a key cytokine for Th17 maintenance and expansion. Th17 are polarised by IL-6 and TGF-β which activate Th17 transcription factor RORγt. IL-23 stabilises RORγt and thus enables Th17 to properly function and release their effector cytokines such as IL- 17, IL-21, IL-22 and GM-CSF which mediate protection against extracellular parasites (fungi and bacteria) and participate in barrier immunity. Similar effects as IL-23 has on Th17 cells were described on type 3 innate lymphoid cells which actively secrete Th17 cytokines upon IL-23 stimulation. NK cells express IL-23 receptor too. They respond with increased IFN-γ secretion and enhanced antibody-dependent cellular cytotoxicity. IL- 23 also induces proliferation of CD4 memory T cells (not naïve cells). Along with mentioned proinflammatory effects IL-23 promotes angiogenesis. IL-23 heterodimer binds the receptor complex - p19 subunit binds IL-23R while p40 subunit binds IL-12RB1 which leads to recruitment of Janus kinase 2 and Tyrosine kinase 2 kinases. Janus kinase 2 and Tyrosine kinase 2 transduce the signal and phosphorylate STAT3 and STAT4. STATs dimerise and activate transcription of target genes in nucleus. STAT3 is responsible for key Th17 development attributes like RORγt expression or transcription of Th17 cytokines.[ Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight- range–based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). Patients with Clinical Remission, Endoscopic Improvement, Clinical Response, or Histo-Endoscopic Mucosal Healing at Week 8 in the Induction Trial. Weight-range–based doses of ustekinumab approximating 6 mg per kilogram were as follows: 260 mg (weight, ≤55 kg), 390 mg (weight, >55 kg and ≤85 kg), and 520 mg (weight, >85 kg). Patients who had a prohibited change in concomitant medication for ulcerative colitis or who had undergone an ostomy or colectomy before week 8 were considered not to have met the end point. Clinical remission was defined as a total score of 2 or less on the Mayo scale (range, 0 to 12, with higher scores indicating more severe disease) and no subscore greater than 1 (range, 0 to 3) on any of the four Mayo scale components. Endoscopic improvement was defined as a Mayo endoscopic subscore of 0 or 1. Clinical response was defined as a decrease in the total Mayo score of at least 30% and of at least 3 points from baseline, with an accompanying decrease of at least 1 point on the Mayo rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. Histo-endoscopic mucosal healing required both histologic improvement (defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue) and endoscopic improvement. Patients with missing data on all four Mayo subscores at week 8 were considered not to be in clinical remission or not to have a clinical response at week 8. Patients who had a missing Mayo endoscopic subscore at week 8 were considered not to have endoscopic improvement. Patients who were missing any Geboes score components pertaining to histologic improvement at week 8 were considered not to have histologic improvement. The analyses for histologic improvement and histo- endoscopic mucosal healing excluded data from patients whose status with respect to these end points could not be determined at week 8 owing to a biopsy sample that could not be evaluated (i.e., a biopsy sample was obtained but could not be assessed owing to technical issues, such as errors during sample collection, preparation, or both). Patients’ Responses to Maintenance Therapy. Patients who had a clinical response to intravenous ustekinumab during the induction trial were randomly assigned to receive subcutaneous injections of placebo or one of two doses of ustekinumab on entry to the maintenance trial. Patients who had a prohibited change in medication for ulcerative colitis, had undergone an ostomy or colectomy, or had used a rescue medication after a clinical flare or who had discontinued ustekinumab or placebo owing to lack of therapeutic effect or owing to an adverse event of worsening of ulcerative colitis before the week 44 visit were considered not to have met the dichotomous end points or had their value at baseline in the induction trial carried forward from the time of the event onward for continuous end points. Patients with missing data on all four Mayo subscores at week 44 were considered not to have clinical remission, clinical response, or corticosteroid-free clinical remission at week 44. Patients who did not have clinical remission or clinical response at any time before week 44 were considered not to be in clinical remission among patients in clinical remission at week 0 in the maintenance trial or not to have maintenance of clinical response through week 44. Patients who had a missing value for corticosteroid use at week 44 had their last value carried forward. Patients who had a missing Mayo endoscopic subscore at week 44 were considered not to have endoscopic improvement. The percentages of patients in these groups with at least one serious adverse event were 3.7%, 3.4%, and 6.9%, respectively. Through week 44 in the maintenance trial, the percentages of randomly assigned patients who reported at least one adverse event in the groups receiving 90 mg of ustekinumab every 12 weeks, 90 mg of ustekinumab every 8 weeks, and placebo were 69.2%, 77.3%, and 78.9%, respectively. The percentages of patients with at least one serious adverse event were 7.6%, 8.5%, and 9.7%, respectively; the percentages of patients with a serious infection were 3.5%, 1.7%, and 2.3%, respectively. Findings in the nonrandomized population were consistent with those in the randomized population Discussion In this phase 3 trial of an antagonist of interleukin-12 and interleukin-23 involving patients with moderate-to-severe ulcerative colitis, ustekinumab was more effective than placebo in achieving induction of clinical remission at 8 weeks. This effect was observed in patients with or without previous treatment failure with biologic agents, including those who had not received biologics. Among patients who had a response to induction therapy with intravenous ustekinumab and who underwent a second randomization, those assigned to either regimen of subcutaneous ustekinumab were more likely to be in clinical remission at 44 weeks than those assigned to placebo. For all prespecified major secondary end points in the induction and maintenance trials, the percentages of patients were significantly higher in the ustekinumab groups than in the placebo group, except for the major secondary end point of maintenance of clinical remission through week 44 among patients in clinical remission at baseline. For that end point, the percentage of patients in the group receiving ustekinumab every 12 weeks was higher than in the placebo group for both remission definitions, but the percentage in the group receiving ustekinumab every 8 weeks was higher than in the placebo group only for the alternative definition of clinical remission that was used to support the FDA submission. Cancers developed in seven patients who received ustekinumab (including three cases of nonmelanoma skin cancer) and in one patient who received placebo. Potential opportunistic infections developed in four patients who received ustekinumab. There were no cases of anaphylaxis or serious hypersensitivity reactions in patients who received ustekinumab. In conclusion, in this trial involving patients with moderate-to-severe ulcerative colitis despite current or previous treatment with conventional or biologic therapy, ustekinumab was more effective than placebo for inducing and maintaining remission. Vedolizumab ist ein humanisierter monoklonaler Antikörper aus der Gruppe der Integrin-Antagonisten. Er dient der Behandlung von Erwachsenen mit Colitis ulcerosa oder Morbus Crohn. Vedolizumab wird zur Behandlung von mittelschweren bis schweren Erkrankungen verwendet, bei denen sich eine konventionelle Therapie oder TNF-α-Antagonisten als unwirksam oder nicht länger wirksam erwiesen haben bzw. von dem Patienten nicht vertragen werden. Colitis ulcerosa - Vedolizumab ist indiziert für die Behandlung von erwachsenen Patienten mit mittelschwerer bis schwerer aktiver Colitis ulcerosa, die entweder auf konventionelle Therapie oder einen der Tumornekrosefaktor-alpha (TNFα)-Antagonisten unzureichend angesprochen haben, nicht mehr darauf ansprechen oder eine Unverträglichkeit gegen eine entsprechende Behandlung aufweisen. Morbus Crohn - Vedolizumab ist indiziert für die Behandlung von erwachsenen Patienten mit mittelschwerem bis schwerem aktiven Morbus Crohn, die entweder auf konventionelle Therapie oder einen der Tumornekrosefaktor-alpha (TNFα)-Antagonisten unzureichend angesprochen haben, nicht mehr darauf ansprechen oder eine Unverträglichkeit gegen eine entsprechende Behandlung aufweisen.

Vedolizumab targets the α4β7 integrin, preventing leucocyte translocation from the blood into the inflamed gut tissue. MadCAM-1: Mucosal addressin cell adhesion molecule. Adalimumab ist ein therapeutischer humaner monoklonaler Antikörper gegen den Tumornekrosefaktor-α und wird daher auch als TNF- Blocker bezeichnet. Adalimumab wird zur Behandlung von rheumatoider Arthritis, Psoriasis-Arthritis, Spondylitis ankylosans, Uveitis und der chronisch entzündlichen Darmerkrankungen Morbus Crohn und Colitis ulcerosa eingesetzt. Adalimumab ist in der Europäischen Union und der Schweiz zugelassen in folgenden Anwendungsgebieten: für Erwachsene zur Behandlung von mäßiger bis schwerer rheumatoider Arthritis in Kombination mit Methotrexat, bei Unverträglichkeit gegenüber Methotrexat auch als Monotherapie, aktiver und progressiver Psoriasis-Arthritis bei Erwachsenen, bei denen eine Basistherapie nicht erfolgreich war, schwerer aktiver ankylosierender Spondylitis bei Erwachsenen, bei denen eine konventionelle Therapie nicht erfolgreich war, schwergradigem, aktiven Morbus Crohn bei Patienten, bei denen eine Therapie mit einem Glukokortikoid oder einem Immunsuppressivum nicht erfolgreich war, mittelschwerer bis schwergradiger, aktiver Colitis ulcerosa, bei Patienten, die auf eine konventionelle Therapie, einschließlich Glukokortikoiden und 6- Mercaptopurin oder Azathioprin, nicht oder nicht ausreichend angesprochen haben, Schuppenflechte vom Plaque-Typ bei Erwachsenen, die auf eine andere systemische Therapie nicht angesprochen haben. Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis

Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking. In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52. Efficacy Outcomes at Week 52 in the Full-Analysis Set and in Subgroups Defined According to Previous Treatment with a TNF Inhibitor. Shown are the percentages of patients who had clinical remission at week 52 (Panel A), endoscopic improvement at week 52 (Panel B), and corticosteroid-free remission at week 52 (Panel C). Efficacy was analyzed according to treatment randomization group in the full-analysis set, which included all patients who underwent randomization and received at least one dose of a trial drug. The subgroup of patients with no previous tumor necrosis factor (TNF) inhibitor therapy included those who had not previously used a TNF inhibitor and had no response or loss of response to conventional treatments; the subgroup of patients with previous TNF inhibitor therapy included those who had previous exposure to a TNF inhibitor other than adalimumab and had a documented reason for discontinuation of the therapy other than safety. The analysis of corticosteroid-free clinical remission was performed only in the subgroup of patients who were receiving corticosteroids at baseline (as determined from the electronic case report form). Point estimates, 95% confidence intervals, and P values were calculated with the use of the Cochran–Mantel–Haenszel chi-square test, with adjustment for the randomization stratification factors, or with the use of Fisher’s exact method if the numerator was five patients or fewer. Histologic Remission at Week 52 in the Full-Analysis Set. Shown are the percentages of patients who had histologic remission as indicated by a Geboes score lower than 2.0 (on a scale from 0 to 5.4, with higher scores indicating more severe disease activity) (Panel A) or by a Robarts Histopathology Index score lower than 3 (on a scale from 0 to 33, with higher scores indicating more severe disease activity) (Panel B). Patients with missing data on histologic remission status were considered not to have had a response. Clinical Response in the Full-Analysis Set. The assessment of clinical response was based on the change in the partial score on the Mayo scale from baseline to trial visit. The partial Mayo score provides an assessment of ulcerative colitis disease activity and is calculated as the combined subscores on three of the four Mayo components (stool frequency, rectal bleeding, and physician’s global assessment, with the exclusion of endoscopy). The partial Mayo score ranges from 0 to 9, with higher scores indicating greater severity. A clinical response was defined as a reduction in the partial Mayo score of at least 2 points and of at least a 25% from baseline, with an accompanying decrease of at least 1 point on the rectal bleeding component of the Mayo scale or a rectal bleeding subscore of 0 or 1. Patients with missing data on clinical response status were considered not to have had a response. � bars indicate 95% confidence intervals. Adverse events occurred in 62.7% of the patients (240 of 383) in the vedolizumab group and in 69.2% (267 of 386) in the adalimumab group. Exposure-adjusted incidence rates of infections and serious infections showed that both occurred less frequently with vedolizumab than with adalimumab (infections, 23.4 vs. 34.6 events per 100 patient-years; serious infections, 1.6 vs. 2.2 events per 100 patient-years). Herpes zoster infection was less frequent with vedolizumab than with adalimumab (0.5 vs. 4.2 per 100 patient-years), although Clostridium difficile infection was more frequent (1.1 vs. 0.6 per 100 patient-years). No patient received a diagnosis of progressive multifocal leukoencephalopathy. One patient in the vedolizumab group died because of an exacerbation of ulcerative colitis and postoperative complications that were considered by the trial site investigator to be unrelated to vedolizumab or adalimumab. Discussion In this comparative clinical trial of two biologic agents involving patients with moderately to severely active ulcerative colitis, clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission, were observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group. In the Ulcerative Colitis Long-term Remission and Maintenance with Adalimumab 2 (ULTRA2) placebo-controlled trial, clinical remission at week 52 occurred in 17.3% of the patients in the adalimumab group and in 8.5% in the placebo group.15 As in the VARSITY trial, the ULTRA2 trial maintained blinding and randomization throughout the treatment period. In the GEMINI 1 placebo-controlled trial of vedolizumab, the percentages of patients who had clinical remission at week 52 were higher (41.8% of the patients in the vedolizumab group vs. 15.9% in the placebo group). The higher percentages of patients who had a response to active therapy in the GEMINI 1 trial than in the ULTRA2 trial and our trial may have reflected differences in trial design; patients who had a clinical response underwent an additional randomization at week 6 in the GEMINI 1 trial, but the patients in the ULTRA2 trial and our trial underwent randomization only at baseline. In addition, the ULTRA2 trial and the GEMINI 1 trial included a higher percentage of patients who had previously received treatment with a TNF inhibitor than the VARSITY trial. Direct comparisons of efficacy between the clinical trials are difficult and further highlight the need for direct head-to-head trials such as the VARSITY trial. In conclusion, the results of our trial involving patients with moderately to severely active ulcerative colitis show the superiority of vedolizumab over adalimumab in terms of clinical remission and endoscopic improvement but not of corticosteroid-free clinical remission. Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. Percentage of Black Children (5 to 11 Years of Age) with Asthma Who Had a Superior Response to Specific Treatments, According to the Composite Outcome, at 14 Weeks. Shown are the five prespecified comparisons of the percentages of patients with a superior response among those receiving twice-daily treatment with a low- dose inhaled glucocorticoid (fluticasone propionate) at a dose of 50 μg (FP100, the double-fluticasone group); a dose of fluticasone doubled to 100 μg with the addition of a LABA (salmeterol) at a dose of 50 μg (FP100/SM50, the salmeterol–double-fluticasone group); a dose of fluticasone quintupled to 250 μg (FP250, the quintuple-fluticasone group); or a dose of fluticasone quintupled to 250 μg with the addition of salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–quintuple-fluticasone group) with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and change in the forced expiratory volume in 1 second (FEV1). The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment, as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The P value reflects a test of the coprimary null hypothesis that the probability of a superior response to each treatment would not differ. T bars indicate 95% confidence intervals. Percentage of Black Adolescents and Adults with Asthma Who Had a Superior Response to Specific Treatments, According to the Composite Outcome, at 14 Weeks. Shown are all the comparisons of the percentages of patients with a superior response among those receiving twice-daily treatment with fluticasone propionate at a dose of 100 μg plus salmeterol at a dose of 50 μg (FP100/SM50, the salmeterol–fluticasone group); a dose of fluticasone increased by a factor of 2.5 to 250 μg (FP250, the 2.5-fluticasone group); a dose of fluticasone quintupled to 500 μg (FP500, the quintuple-fluticasone group); or a dose of fluticasone increased by a factor of 2.5 to 250 μg with the addition of salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–2.5-fluticasone group) with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and the absolute change in the percentage of the predicted FEV1. The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment, as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The P values reflect a test of the coprimary null hypotheses that the probability of a superior response to each treatment would not differ. T bars indicate 95% confidence intervals. Comparison of the Primary Composite Outcome in the Trial involving Adolescents and Adults and the Trial involving Children. Shown are the prespecified comparisons of the percentages of patients with a superior response. Each panel shows a comparison of a similar step-up in therapy for children and for adolescents and adults. Shown are responses at 14 weeks in adolescents and adults and in children who at baseline had poorly controlled asthma while receiving twice-daily treatment with a low-dose inhaled glucocorticoid (fluticasone propionate) (50 μg in children and 100 μg in adolescents and adults). In children, the step-up trial treatments included doubling the dose of fluticasone to 100 μg (FP100, the double-fluticasone group); doubling the dose of fluticasone to 100 μg and adding salmeterol at a dose of 50 μg (FP100/SM50, the salmeterol–double-fluticasone group); quintupling the dose of fluticasone to 250 μg (FP250, the quintuple-fluticasone group); or quintupling the dose of fluticasone to 250 μg and adding salmeterol at a dose of 50 μg (FP250/SM50, the salmeterol–quintuple-fluticasone group). In adolescents and adults, the step-up interventions included adding salmeterol to the baseline dose of fluticasone (FP100/SM50, the fluticasone– salmeterol group), increasing the dose of fluticasone by a factor of 2.5 (FP250, the 2.5-fluticasone group), increasing the dose of fluticasone by a factor of 2.5 and adding salmeterol (FP250/SM50, the salmeterol–2.5-fluticasone group), or quintupling the dose of fluticasone (FP 500). A superior response was determined with respect to the hierarchical composite outcome that incorporated asthma exacerbations, asthma-control days, and the change in the FEV1. The numbers in each bar represent the percentage of patients who had a superior response to that specific treatment as compared with the alternative treatment. Gray bars indicate the percentage of patients in whom one treatment was not superior to the other. The two groups of patients (patients from the trial involving children and those from the trial involving adolescents and adults) were compared to identify interactions between the two groups and the composite superiority outcome. T bars indicate 95% confidence intervals. Discussion Studies involving children and adults with asthma have been conducted primarily in white populations; these studies have shown that when escalating asthma therapy, the addition of a LABA is more likely to produce a superior response than an increase in the dose of an inhaled glucocorticoid. These data have influenced guidelines regarding escalation of therapy when patients present with asthma that is not well controlled; however, black patients with asthma have not been included in the clinical trials on which the guidelines were based. In the current trials, almost half the children who had at least one grandparent who identified as black and who had poorly controlled asthma (46%) had improved asthma outcomes when the dose of inhaled glucocorticoid was increased rather than with the addition of a LABA. Furthermore, we discovered that in contrast to both black adults and white adults and white children, black children had a response to stepped increases in the dose of inhaled glucocorticoid. Our results are all the more striking in that in our parallel trial we confirmed that adolescents and adults who had at least one grandparent who identified as black had responses similar to those reported in white adults — that is, the addition of a LABA in adults was more likely to lead to superior responses in a larger group of patients than an increase in the dose of an inhaled glucocorticoid. These findings suggest that data cannot be extrapolated from clinical trials involving mixed populations to specific subgroups, including those of different ages and races. We found evidence of adrenal axis suppression in young children (<8 years of age) (Table S9 in the Supplementary Appendix) at the highest dose of inhaled glucocorticoid we tested (fluticasone propionate at a dose of 250 μg). Kids are Kids and LABAs beat SABAs. African ancestry, as determined by patterns of genetic markers, has been associated with asthma-related phenotypes including low lung function and exacerbations, However, we did not find that African ancestry was associated with differential responses in adolescents and adults or with differential responses in children. Nevertheless, the absence of a global ancestral effect does not exclude potential effects of either asthma severity loci or pharmacogenetic loci differentially inherited among persons across varying ancestral backgrounds.21-27 We were also not able to detect phenotypic or biomarker characteristics that were associated with a differential response to a specific therapy. A larger trial might have the power to determine which phenotypic or specific pharmacogenetic variant panels could have the power to detect such differences. In conclusion, our prospective, randomized BARD trials comparing several strategies of treatment escalation for asthma in children and in adolescents and adults who had at least one grandparent who identified as black showed that outcomes differed in children and adults, and the results in these children differed from those previously reported in studies involving white children. In contrast to black adults and white persons of all ages, almost half the children who had at least one grandparent who identified as black and who had poorly controlled asthma had a superior response to an increased dose of an inhaled glucocorticoid over the addition of a LABA. A larger, more simplified trial should be undertaken to determine the best treatment approach for black children with poorly controlled asthma despite the use of standard doses of an inhaled glucocorticoid. CCR5 oder C-C-Motiv-Chemokin-Rezeptor 5 ist – neben CD195 und weiteren Synonymen – die Bezeichnung für ein Rezeptorprotein aus der Familie der Chemokinrezeptoren, das vom Gen CCR5 codiert wird, welches beim Menschen auf Chromosom 3 (Genlocus 3p21.31) liegt, und in Zellen des Immunsystems wie T-Zellen und Makrophagen exprimiert wird. Eine besondere Bedeutung hat CCR5 dadurch, dass ein HI-Virus 1 diesen als Corezeptor gebraucht (nach Bindung an CD4), um sich an eine Zelle so anzuheften, dass sie infiziert werden kann. Der Chemokinrezeptor CCR5 ist als Transmembranprotein auf der Oberfläche verschiedener Leukozyten zu finden, beispielsweise bei Makrophagen, CD4+-Zellen, CD8+-Zellen und NKT-Zellen. CCR5 wird durch unterschiedliche Liganden wie CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES) und CCL8 (MCP-2) aktiviert, ermöglicht eine chemotaktische Zellbewegung und ist damit in Entzündungsreaktionen involviert. Der Rezeptor CCR5 stellt einen Co-Rezeptor für die HIV-Infektion dar und macht das Andocken von HI-Viren an Makrophagen wie auch verschiedene T-Lymphozyten möglich, das Eindringen in die Zellen und somit deren Infektion. Daher ist die Entwicklung von Arzneistoffen, welche die Anbindung von HIV an CCR5 hemmen, von großem Interesse und führte beispielsweise zum ersten zugelassenen Entry-Inhibitor Maraviroc. Timothy Ray Brown (* 1966 in Seattle, Washington) ist ein US-amerikanischer Übersetzer. Er wurde unter dem Namen The Berlin Patient (übersetzt: Berliner Patient) als erster Mensch, der vom Humanen Immundefizienz- Virus (HIV) geheilt wurde, bekannt. Er gründete im Juli 2012 die Stiftung cure for AIDS (Timothy Ray Brown Foundation) mit dem erklärten Ziel, eine Heilung für AIDS zu finden. 1995 wurde er in Berlin positiv auf HIV getestet. Elf Jahre lang erhielt Brown eine hochaktive antiretrovirale Therapie (HAART). 2006 wurde bei ihm eine akute myeloische Leukämie (AML) festgestellt. In der Charité Campus Benjamin Franklin (CBF) in Berlin- Lichterfelde setzte der Hämatologe Gero Hütter zunächst eine Chemotherapie an. Als sie nicht den gewünschten Erfolg brachte, setzte er im Februar 2007 auf eine allogene Stammzelltransplantation. Er verwendete dazu Knochenmark mit einem veränderten CCR5-Gen, der Mutation CCR5Δ32. Anschließend war das HI-Virus bei Brown nicht mehr nachweisbar. Anthony S. Fauci, Leiter des US-amerikanischen National Institute of Allergy and Infectious Diseases (NIAID), hält den Fall Browns für einen Proof of Concept, dass es möglich ist, den Kampf gegen AIDS weit über die antivirale Therapie hinaus zu treiben. Bislang gibt es noch sechs weitere HIV- Patienten, die eine Chemotherapie und dann eine Knochenmarkspende bekamen und keinerlei Spuren des Virus mehr in ihrem Körper haben. Nur einer der sechs erhielt eine Spende von einem Menschen mit CCR5 Mutation, deshalb wird spekuliert, ob eine Nebenwirkung der Knochenmarkspende das Virus ausgelöscht haben könnte. CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia The safety of CRISPR (clustered regularly interspaced short palindromic repeats)–based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing–related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral- therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR- edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. Case report A 27-year-old man received diagnoses of HIV–AIDS (acquired immunodeficiency syndrome) and acute lymphoblastic leukemia (T-cell type) on May 14 and May 30, 2016, respectively. At diagnosis, the HIV viral load was 8.5×106 copies per milliliter, and the CD4+ cell count was 528×106 per liter. Antiretroviral drugs (lamivudine at a dose of 300 mg daily, tenofovir at a dose of 300 mg daily, and lopinavir–ritonavir at a dose of 400 mg of lopinavir and 100 mg of ritonavir twice daily) were immediately administered, which resulted in control of HIV-1 infection and undetectable virus RNA in the serum (<40 copies per milliliter) after 1 year. CD34+ HSPCs (2.36×108 cells) were sorted with magnetic beads from mobilized peripheral-blood mononuclear cells from the donor and subsequently subjected to CRISPR editing of the CCR5 locus. During the transplantation, the antiretroviral drug lopinavir–ritonavir was replaced by raltegravir (at a dose of 400 mg every 12 hours) to avoid drug interaction with cyclosporine. For prophylaxis against graft-versus-host disease, the patient received cyclosporine, a short course of methotrexate, basiliximab (an anti-CD25 antibody), and mycophenolate mofetil. Glucocorticoids and tacrolimus were used continuously for the treatment of graft- versus-host disease. Engraftment of CCR5-Modified Cells. The cell counts of white cells, neutrophils, and lymphocytes in peripheral blood over time are shown on the left y axis of Panel A, and the fluctuation in the hemoglobin level and platelet count are shown on the right y axis. The main preconditioning regimen contained cyclophosphamide (on days −4 and −3) and total- body irradiation (on days −2 and −1). The immunosuppression treatment included methotrexate (on days 1, 3, and 6), basiliximab (on days 0, 4, and 8), mycophenolate mofetil (initiated on day 0 and tapered from day 31 to 47), and cyclosporine (administered intravenously [IV] from day −1 to day 30 and orally from day 31 to 74). Graft-versus-host disease was treated with glucocorticoids (methylprednisolone or prednisone, administered intravenously from day 32 to day 124 and orally tapered from day 125 to 185) and tacrolimus (administered orally from day 75 to 156 and tapered from day 157 to 185). Antiretroviral therapy (ART) was interrupted from day 221 to day 249. The checkerboard design represents the tapering period. Panel B shows the CCR5 gene-disruption efficiency in bone marrow karyocytes detected by means of deep sequencing at different time points after transplantation. Panel C shows the CCR5 gene- disruption efficiency in various types of cells from peripheral-blood samples obtained 19 months after transplantation. Lymphocyte counts and T-lymphocyte subsets increased after transplantation, accompanied by the recovery of the CD4+ cell count to 592.94×106 per liter in month 6 and its stabilization in a normal range. Full donor chimerism was achieved at week 4 after transplantation and persisted through the most recent time point, 19 months after transplantation. The acute lymphoblastic leukemia was in morphologic complete remission at week 4 after transplantation; this remission continued over the 19-month follow-up period. In addition, minimal residual disease remained undetectable for leukemia-associated phenotypes on the basis of flow cytometry. The expression level of the Wilms’ tumor gene (WT1) normalized to the Abelson gene (ABL) — an increase in which predicts relapse — was less than 0.5% after transplantation, which was a level unchanged from before transplantation Clinical Outcomes during and after the Interruption of Antiretroviral Therapy. Shown are the results of assessments for viral load (Panel A), the CD4+ cell counts and the ratio of CD4+ cells to CD8+ cells (Panel B), and the CCR5 gene-disruption efficiency in CD4+ cells (Panel C) from month 3 to month 12 after transplantation. Antiretroviral therapy was interrupted from day 221 to day 249. Discussion We report a successful allogeneic transplantation and long-term engraftment of CRISPR–Cas9–edited, CCR5- ablated HSPCs in a patient with HIV-1 infection and acute lymphoblastic leukemia. The donor cells engrafted with full chimerism, and the acute lymphoblastic leukemia was in complete remission for 19 months after transplantation, during which time the cells with the modified CCR5 gene persisted, and the CCR5 disruption ranged from 5.20 to 8.28% in bone marrow cells. These results show the proof of principle that transplantation and long-term engraftment of CRISPR-edited allogeneic HSPCs can be achieved; however, the efficiency of the response was not adequate to achieve the target of cure of HIV-1 infection. When antiretroviral therapy was interrupted at 7 months after transplantation, a small increase in the percentage of CCR5 indels was observed 2 weeks after the initiation of the interruption. The low efficiency of gene editing in the patient may be due to the competitive engraftment of the coinfused HSPCs in CD34-depleted cells and the persistence of donor T cells. To further clarify the anti-HIV effect of CCR5-ablated HSPCs, it will be essential to increase the gene-editing efficiency of our CRISPR–Cas9 system and improve the transplantation protocol. A recent study showed that homozygosity for CCR5-Δ32 mutation is associated with a reduced life expectancy, which highlights the potential deleterious effect of CCR5 mutation at the individual level. However, unlike other gene-editing strategies that have been proposed for the management of HIV infection, CCR5 ablation within the hematopoietic system of infected persons will not alter expression in nonhematopoietic tissues. In conclusion, our study described the long-term engraftment of CCR5 CRISPR-edited CD34+ cells after allogeneic stem-cell transplantation, which gave rise to less than 8% gene disruption in the genome of circulating bone marrow cells, and off-target effects of the gene editing were not noted. A recent study showed that homozygosity for CCR5-Δ32 mutation is associated with a reduced life expectancy, which highlights the potential deleterious effect of CCR5 mutation at the individual level. However, unlike other gene-editing strategies that have been proposed for the management of HIV infection, CCR5 ablation within the hematopoietic system of infected persons will not alter expression in nonhematopoietic tissues. In conclusion, our study described the long-term engraftment of CCR5 CRISPR-edited CD34+ cells after allogeneic stem-cell transplantation, which gave rise to less than 8% gene disruption in the genome of circulating bone marrow cells, and off-target effects of the gene editing were not noted. COPD ist eine Abkürzung für "Chronic Obstructive Pulmonary Disease", zu deutsch: "chronisch obstruktive Lungenerkrankung". COPD ist eine Sammelbezeichnung für chronische Erkrankungen der Atemwege, die mit einer zunehmenden Einschränkung der Lungenventilation (Airflow) einhergehen. Sie gehört zur Gruppe der obstruktiven Ventilationsstörungen und beinhaltet die Kombination aus chronisch-obstruktiver Bronchitis und Lungenemphysem. GOLD-Definition Nach der Definition der Global Initiative For Chronic Obstructive Lung Disease (GOLD) ist die COPD durch eine nicht reversible Einschränkung der Lungenventilation gekennzeichnet, die normalerweise progredient ist und mit einer überschießenden Entzündungsreaktion auf schädliche Partikel oder Gase einhergeht. Nach Ansicht der GOLD muss bei jedem Patienten an eine COPD gedacht werden, der Symptome wie Husten, Auswurf und Dyspnoe aufweist oder Risikofaktoren (z.B. Rauchen) ausgesetzt ist. Die Diagnose wird durch Spirometrie gesichert. Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease For almost 50 years, since Fletcher and Peto reported their seminal observations in young working men in London, chronic obstructive pulmonary disease (COPD) has been widely accepted as a self-inflicted condition caused by tobacco smoking. The classic concept was that in susceptible persons, smoking elicits an abnormal inflammatory response2 that damages the airways (bronchitis–bronchiolitis) and alveoli (emphysema), accelerates the physiologic decline of lung function with age, and leads to airflow limitation and chronic respiratory symptoms, which are difficult to reverse and may periodically be manifested as exacerbations. As a result, today the diagnosis of COPD relies on the presence of airflow limitation in smokers that is difficult to reverse, and treatment is largely directed toward improving airflow and ameliorating symptoms and exacerbations with the use of bronchodilators with or without inhaled glucocorticoids. Several recent observations, however, challenge this traditional and seemingly straightforward pathogenic paradigm. First, although tobacco smoking is the key environmental risk factor for COPD, about a third of affected patients worldwide are nonsmokers; other environmental pollutants, such as smoke from biomass fuel used for cooking and heating, are also major environmental risk factors for COPD in many places around the globe.

Lung-Function Trajectories from Birth to Death. Two main biologic mechanisms can lead to chronic obstructive pulmonary disease (COPD) in adulthood: abnormal lung development and an increased rate of lung-function decline with age. These mechanisms can coexist. In some persons with below-normal lung function in childhood, a catch-up phase may occur during puberty. Persons with supranormal lung function in early adulthood may lose lung function over time (e.g., by smoking) but nonetheless in late adulthood may have pseudonormal spirometric findings (i.e., findings that appear normal despite the presence of symptoms or evidence of structural lung damage such as emphysema). Smoking-Induced Lung Injury It is difficult to imagine a better way to deliver chronic, repetitive inhalational injury to lung tissue than smoking 20 or more cigarettes a day for many years. A puff of cigarette smoke contains millions of water droplets with a median aerodynamic diameter of 0.45 μm, each containing a complex mixture of toxic chemicals derived from the various types of raw tobacco plus toxic chemicals added to achieve the blend of aroma and taste that defines a particular brand of cigarette.

Pathological Features of COPD According to the Severity of Airflow Limitation. Shown are the proportion of airways containing polymorphonuclear neutrophils (PMNs), macrophages, and eosinophils (Panel A) and the proportion containing CD4 cells, CD8 cells, and B cells (Panel B) in patients with different GOLD (Global Initiative for Chronic Obstructive Lung Disease) grades of airflow limitation. GOLD grade 0 (no longer in use) identifies persons with chronic respiratory symptoms but normal spirometric findings. GOLD grades 1, 2, 3, and 4 identify patients with COPD who have mild, moderate, severe, and very severe airflow limitation, respectively. In Panels A and B, GOLD grades 2 and 3 have been combined so that there is a similar number of patients in each group. In Panel C, the inverse relationship between total wall thickness, measured as the ratio of the volume to the surface area (V:SA), and forced expiratory volume in 1 second (FEV1) is shown. The solid circles denote GOLD 4, the solid squares GOLD 3, the triangles GOLD 2, the open squares GOLD 1, and the diamonds GOLD 0; the dotted lines indicate the boundaries of the GOLD grades. Panel D shows the mean (±SE) volume of epithelium, lamina propria, smooth muscle, and adventitia expressed per unit of V:SA (left y axis) and the percentage of airways containing lymphoid follicles (right y axis); in the inset, Movat’s staining highlights a lymphoid follicle containing a germinal center (GC) surrounded by a rim of darker-staining lymphocytes that extend to the epithelium of both the small airway and the alveolar surface. Asterisks indicate P<0.001 for the comparison with GOLD grade 0, daggers indicate P<0.001 for the comparison with GOLD grade 1, and double daggers indicate P<0.001 for the comparison with GOLD grade 2. Number of Small Airways According to Severity of Airflow Limitation and Amount of Emphysema. Panel A shows that the number of airways measuring 2.0 to 2.5 mm in diameter per lung pair is lower in patients with COPD than in smokers with normal spirometric findings (control smokers), in proportion to the severity of airflow limitation (GOLD grade 1, 2, 3, or 4); P values are for the comparison with control smokers. Panel B shows that the number of terminal bronchioles is reduced in patients with COPD in relation to the amount of emphysema present (as determined by the mean linear intercept), both in patients with panlobular emphysema (PLE) and in those with centrilobular emphysema (CLE). This reduction also occurs in patients with COPD but without emphysema (mean linear intercept, <489 μm). The � bars indicate standard errors. Genetic Loci Associated with COPD. Shown is a Manhattan plot of P values (−log10) for associations between COPD and genetic loci in 22 chromosomes. The 18 gene names in gray indicate genes previously identified as associated with COPD or lung function, and the 4 names in black indicate loci newly identified in a recent study. The horizontal dashed line shows the threshold for genomewide significance (P<5×10−8). Conclusions Once believed to be a single disease caused by smoking and characterized by a progressive loss of lung function with age, COPD should currently be considered a clinical syndrome with many causes in addition to smoking. This does not mean that health care professionals should refrain from encouraging all their patients who smoke to quit, but it does mean that the pathogenic mechanisms in mild-to-moderate COPD may differ from those in severe-to-very- severe cases of airflow limitation. In fact, the assumption that COPD is always a progressive disease also requires careful reconsideration. Currently available evidence indicates that COPD is the end result of a series of dynamic, interactive, and cumulative gene–environment interactions from conception to death that determine the development, maintenance, and function of the lungs, as well as other systemic organs. This realization inevitably leads to the conclusion that the pathogenesis of COPD is complex and heterogeneous and that several mechanisms coexist and interact. It is therefore imperative to identify and validate biomarkers associated with specific endotypes (i.e., mechanisms of disease) that underlie the various lung- function trajectories in patients and rigorously evaluate them to determine which ones are causative. This approach could represent the first step toward the development of specific, effective, and safe preventive and therapeutic strategies, which most likely will have to be implemented earlier in life. Update on Clinical Aspects of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide; COPD led to 3.2 million deaths in 2017, a toll expected to reach 4.4 million yearly by 2040.1,2 With a worldwide prevalence of 10.1%, COPD afflicts many people in low-income, middle-income, and wealthy countries, and years of life lost prematurely increased 13.2% between 2007 and 2017. Although COPD has traditionally been considered a disease that affects men, in some countries, the prevalence and associated mortality are higher among women than among men. In this review, we update the clinical face of COPD, concentrating on the pulmonary aspects of the disease, which also affects many other organ systems. The pathogenesis of COPD is discussed in a companion article by Agustí and Hogg in this issue of the Journal,3 and the review of muco-obstructive lung diseases in a recent issue of the Journal4 complements this article. Prevalence of Chronic Obstructive Pulmonary Disease (COPD) in Selected Countries, 1990–2016. COPD is currently the third leading cause of death and an important cause of complications worldwide. Although COPD is a substantial problem everywhere, China and India account for more than 50% of all cases of COPD in the world. Algorithm for the Evaluation and Treatment of Persons with COPD or at Risk for COPD. Most patients with mild symptoms (green) and no exacerbations per year do well with exposure control, increased physical activity, vaccinations, and use of long-acting bronchodilators. The green and yellow pathways are usually the domain of primary care practitioners. The brown pathways are best managed by health care professionals with experience in COPD management. The darker shades of yellow and brown indicate more severe disease or more complex therapy than the lighter shades. Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 1 indicates mild disease, and GOLD grade 4 very severe disease. The BODE index consists of the integration of body-mass index, the degree of airflow obstruction, the severity of dyspnea, and exercise capacity (6-minute walking distance [6MWD]). CAT denotes COPD Assessment Test, DLco diffusing capacity of the lung for carbon dioxide, FEV1 forced expiratory volume in 1 second, FVC forced vital capacity, IC inspiratory capacity, LVR lung-volume reduction, mMRC modified Medical Research Council dyspnea scale, RV residual volume, and TLC total lung capacity. Algorithm for Pharmacotherapy in Patients with a Confirmed Diagnosis of COPD. Integration of the lung-function compromise, severity of symptoms, and risk of exacerbations helps determine disease severity. Milder disease may benefit from a single inhaled, long-acting bronchodilator, preferably a long-acting muscarinic antagonist (LAMA). In patients with more compromised lung function and infrequent exacerbations of moderate intensity, a LAMA combined with a long-acting beta2-agonist (LABA) in a single inhaler or dual inhalers may be used. A history of asthma, allergies, or rhinitis or an elevated blood eosinophil count (>300 per cubic millimeter) favors the initial use of an inhaled glucocorticoid (IGC) combined with a LABA. If the symptoms and exacerbations persist (more than two exacerbations per year or one hospitalization for COPD), triple therapy consisting of a LAMA, a LABA, and an IGC is useful. An array of systemic therapies (azithromycin, roflumilast, xanthines, and antioxidants) may be considered as third-line agents. The use of biologic agents requires further studies to validate their efficacy. PDE4i denotes phosphodiesterase-4 inhibitor, and SABD short-acting bronchodilator. Future Directions A COPD exacerbation is clinically defined as “an increase in dyspnea, cough, or sputum purulence with or without symptoms of upper respiratory infection.”63 In pharmacologic trials, an exacerbation of COPD is defined as “an acute event characterized by worsening of the patient’s respiratory symptoms that is beyond the day-to-day variation and that leads to a change in medications.” Exacerbations are considered to be mild when only worsening symptoms are reported; moderate when the patient receives antibiotics, systemic glucocorticoids, or both; and severe when the patient visits an emergency department or is hospitalized.65 Exacerbations increase the risk of myocardial infarction, stroke, pulmonary embolism, and death. Myocardial infarction and pulmonary embolism should be ruled out in patients presenting with symptoms of a COPD exacerbation. Frequent exacerbations are associated with worsening health status and a rapid decline in lung function and are a driver of health care costs, accounting for more than 20% of all readmissions occurring within 30 days after a hospitalization for the same diagnosis.

How about stop smoking and vaping (although the later is perferred to the former? We now understand that COPD is more a syndrome than a single disease. The recognition of pre-COPD and early COPD as targetable entities should help guide the development of specific therapies for these stages of disease, which may significantly reduce the incidence of severe COPD. The revolution brought about by chest CT and a better understanding of the multidimensional nature of COPD and coexisting conditions has resulted in widespread use of pulmonary rehabilitation and the development of bronchoscopic techniques to reduce lung volumes in selected patients with emphysema. Therapies that improve lung structure, such as replacement therapy in patients with alpha1-antitrypsin deficiency, indicate that it is possible to modify the course of COPD. More potent and longer-acting bronchodilator agents have become the cornerstone of therapy. A rational approach to the use of inhaled glucocorticoids, with lower doses and avoidance of systemic administration, and the benefits accrued with systemic antiinflammatory agents, have paved the way for precise therapies. These advances hold out promise for effective treatment of COPD. A 14-year-old girl living in Nepal presented to the emergency department with a 3-day history of neck swelling, fever, throat pain, and difficulty swallowing. She appeared sick and had a swollen neck (Panel A), and examination of the oropharynx revealed a grayish-white membrane (Panel B). According to her mother, the patient had received three doses of the diphtheria–pertussis–tetanus vaccine during her first year of life, with no additional doses. Diphtheria was suspected, and treatment with penicillin G and antidiphtheria serum was initiated. A throat culture grew Corynebacterium diphtheriae. On the third day of hospitalization, chest discomfort, palpitations, and elevated troponin I levels developed, along with electrocardiographic abnormalities, including a prolonged PR interval, ectopic beats, and ST-segment depression; these signs and symptoms aroused concern about diphtheria-associated myocarditis. Wide complex tachycardia subsequently developed. The patient continued to have ventricular arrhythmias despite receiving treatment in the pediatric intensive care unit, and she died 2 days later. Isolates that had been sent to the Centers for Disease Control and Prevention in the United States were confirmed by culture to be C. diphtheriae, and polymerase chain reaction confirmed the presence of the toxin gene. A 70-year-old woman presented to an outpatient clinic with a 1-week history of dizziness and a generalized rash after the onset of a viral respiratory tract infection 2 weeks earlier. On physical examination, she had a generalized, macular, nonblanching rash in a reticular pattern with purplish discoloration consistent with livedo reticularis (Panel A). Because of the spontaneous agglutination of the blood (Panel B), the blood samples were warmed in a saline bath at 37°C (Panel C, showing agglutinated blood on the left and warmed blood on the right). Laboratory evaluation revealed a hematocrit of 14% (reference range, 34 to 46), an indirect bilirubin level of 7.6 mg per deciliter (reference value, <1.0), and a lactate dehydrogenase level of 1298 U per liter (reference range, 100 to 190). The direct antiglobulin test was positive for the complement component C3, and the test for cold agglutinins was positive at a 1:2048 dilution at 4°C. A diagnosis of cold agglutinin disease, a form of acquired autoimmune hemolytic anemia, was made, a condition that may have been exacerbated by the patient’s recent viral infection along with the cold weather in upstate New York, where the temperature was 15°F (−9°C) at the time of her presentation. The patient was warmed and treated with blood transfusions and rituximab for 1 week. At the time of hospital discharge, she had a hematocrit of 30% and a reduction in dizziness, but the rash persisted. A 65-Year-Old Woman with Lung Cancer and Chest Pain Six months before the current presentation, the patient presented to a hospital affiliated with this hospital with a 4-day history of acute pain in the lower back, left paraspinal muscles, and right flank. The pain worsened with movement and, to a lesser extent, with inspiration. Imaging studies were obtained. There were bone lesions in the thoracic skeleton, including a lytic lesion (2.3 cm in diameter) at the level of the ninth thoracic vertebra. There was no evidence of pulmonary embolism. Positron-emission tomography and CT (PET-CT) revealed foci of 18F-fluorodeoxyglucose (FDG) avidity in the mass in the left upper lobe, as well as in mediastinal and hilar lymph nodes, the eighth transverse process, the ninth thoracic vertebral body, and the right ninth rib. A biopsy specimen of the lung mass showed evidence of lung adenocarcinoma with a mutation in KRAS. Magnetic resonance imaging (MRI) of the head and spine did not reveal cerebral metastases but confirmed the presence of a lytic lesion at the level of the eighth and ninth thoracic vertebrae; a compression fracture was also observed. Initial Imaging Studies of the Chest, Obtained before the Lung Cancer Diagnosis. A frontal radiograph (Panel A) shows a nodule in the left midlung zone (arrow), with left hilar prominence. A transverse CT image (Panel B) confirms the presence of an irregular nodule in the left upper lobe (arrowhead) and left hilar lymphadenopathy (arrow). A transverse positron-emission tomographic and CT image (Panel C) shows a high level of 18F-fluorodeoxyglucose (FDG) avidity in the nodule in the left upper lobe (white arrowhead) and in the region of left hilar lymphadenopathy (arrow). There is also intense FDG uptake in the eighth thoracic vertebra that is suggestive of bony metastatic disease (black arrowhead). External-beam radiation therapy was administered during the next 2 weeks, followed by four cycles of carboplatin and pemetrexed that were completed during the next 3 months. A repeat PET-CT scan obtained 2 weeks after completion of chemotherapy showed that the FDG-avid foci in had increased in size. Palliative external-beam radiation therapy was administered. Two weeks later, the patient was readmitted to the other hospital with increased back pain. CT of the chest, performed without the administration of intravenous contrast material, revealed atelectasis in the left upper lobe. The patient was treated with external-beam radiation therapy, prednisone, supplemental oxygen, ipratropium in combination with albuterol, and salmeterol in combination with fluticasone, and she was discharged home 2 days later. Two days after discharge, the patient presented to the other hospital with dyspnea and hypoxemia. CT of the chest, performed after the administration of intravenous contrast material, revealed complete collapse of the left upper lobe due to an obstructing endobronchial lesion. The patient received prednisone, inhaled albuterol, tiotropium, salmeterol in combination with fluticasone, and five treatments of external-beam radiation therapy during a 7-day hospitalization. One week after discharge, the immune checkpoint inhibitor nivolumab (3 mg per kilogram of body weight) was administered for the treatment of non–small-cell lung cancer (NSCLC) in the outpatient oncology clinic of the other hospital. After 2 days of chest pain, she was evaluated at the emergency department of the other hospital. Treatment with sublingual nitroglycerin did not reduce the chest pain.

Medications included inhaled salmeterol in combination with fluticasone, tiotropium, morphine sulfate (controlled release), brimonidine, latanoprost, cholecalciferol, senna, docusate, omeprazole, oxycodone, and acetaminophen as needed for pain. Treatment with erythromycin caused stomach upset. She had smoked 1.5 packs of cigarettes per day from 30 years of age until the diagnosis of lung cancer was made, 6 months before the current presentation; she did not drink alcohol or use illicit drugs. She was retired from working as an administrator. She was widowed, had three adult children, and was serving as a caregiver for her mother. Her father had had coronary artery disease, and her mother had lung cancer, osteoporosis for which she had undergone kyphoplasty, and spinal stenosis for which she had undergone laminectomy. Electrocardiogram Obtained at This Presentation. An electrocardiogram shows sinus tachycardia at a rate of 112 beats per minute with borderline right-axis deviation and nonspecific ST-segment and T-wave flattening.

Imaging Studies of the Chest Obtained at This Presentation. A frontal radiograph (Panel A) shows an elevated left hilum (arrow) with adjacent opacity, findings that are consistent with a collapsed left upper lobe. A transverse CT image (Panel B), obtained after the administration of intravenous contrast material, shows a left hilar lesion (asterisk) causing complete obstructive collapse of the left upper lobe.

Atorvastatin, levofloxacin, metoprolol, and intravenous hydromorphone and morphine were administered, and the patient was admitted to the cardiology service. A transthoracic echocardiogram showed a left ventricular ejection fraction of 57%; there was subtle hypokinesis in the mid-inferior, basal inferior, and basal inferoseptal walls, mild-to-moderate tricuspid regurgitation, and no evidence of pericardial effusion, and the size and function of the right ventricle were normal. Myocardial Ischemia The first step in the evaluation of this patient is to determine whether the chest pain and elevated troponin T level are due to myocardial ischemia that is causing an acute coronary syndrome. The manifestations of acute coronary syndrome may be different in women than in men, and therefore, a thorough evaluation of this patient’s history, risk factors, and findings on physical examination is critical to establish this diagnosis. The most common cause of troponin release is low-level injury to the myocardium. Pericarditis This patient’s history and examination findings indicate that she probably does not have pleuritic pain. If she had pleuritic pain on the left side and lay on her left side, the pain would feel somewhat better. Instead, we are told that her pain increases in this position. There is also no history of classic pericarditic pain, which is characterized by an increase in pain when the patient is in a reclined position and a decrease in pain when the patient is seated upright. Pulmonary Embolism Cancer is a risk factor for venous thromboembolism, and this patient presents with chest pain, dyspnea, and unexplained tachycardia. In the context of cancer, an elevated d-dimer level can indicate activation of the clotting cascade. Elevation of the d-dimer level does not necessarily imply thrombosis, and in fact, no evidence of pulmonary embolism is identified on CT. Parenchymal Lung Disease This patient has diminished breath sounds in the left lung, which suggests a pathologic process between the aerated lung and the stethoscope. This finding could indicate a pleural effusion or damage of the lung from cancer or pneumonia. The crackles present at the left apex on lung auscultation arouse concern about further obstruction of the bronchus of the left upper lobe. The examination findings correlate with the known obstruction of the left upper lobe, and pain associated with an obstruction in such a location would typically be pleuritic. Myocarditis One possible explanation to account for this patient’s elevated troponin T level is the treatment she received to control her cancer. Nivolumab, a monoclonal antibody directed against programmed death 1 (PD-1) receptor, is an immune checkpoint inhibitor; it functions by blocking immune-suppressing ligands PD-L1 and PD-L2 from interacting with PD-1 (or the PD-1 receptor) to restore T-cell function and an effective immune response. However, activation of the immune system may be associated with an immune-related adverse event such as myocarditis, although this event would be uncommon. On hospital days 2 through 6, the chest and back pain persisted, and the patient was unable to undergo cardiac MRI because of pain. The troponin T level continued to rise, reaching 1.08 ng per milliliter. On the sixth hospital day, ST-segment depressions were more pronounced in the inferolateral leads, and coronary angiography was performed; there was minimal nonobstructive coronary artery disease. Treatment with methylprednisolone was initiated at a dose of 1 mg per kilogram; however, on the eighth hospital day, complete atrioventricular block developed, with an idioventricular escape rhythm, and the troponin T level reached 1.68 ng per milliliter. An endomyocardial biopsy was performed on the 10th hospital day. Shortly after the patient had received the diagnosis of metastatic NSCLC, she had begun first-line, platinum- based, doublet chemotherapy. After disease progression, Endomyocardial-Biopsy Specimen. Hematoxylin and her treatment was switched to nivolumab, a PD-1 immune eosin staining of the endomyocardial-biopsy specimen checkpoint inhibitor. (Panel A) shows an inflammatory infiltrate that appears Within the past 5 years, inhibition of the PD-1 pathway has to be attacking and killing myocytes (arrows). Immunohistochemical staining shows that the become a standard therapeutic option for patients with inflammatory infiltrate is composed primarily of CD68- advanced NSCLC. Successful targeting of PD-1 and its expressing macrophages (Panel B, in brown) and CD3- ligand, PD-L1, was first reported in the context of second- expressing lymphocytes (Panel C, in brown). A high line treatment of NSCLC, with studies showing the proportion of the lymphocytes are CD8-expressing superiority of an immune checkpoint inhibitor — including cytotoxic T cells (Panel D, in brown). nivolumab — over single-agent docetaxel. Anatomical Diagnosis The first case of myocarditis related to the use of an Active myocarditis consistent with myocarditis related to immune checkpoint inhibitor was reported in 2014. After immune checkpoint inhibition. The patient died suddenly this patient underwent endomyocardial biopsy, the dose of at home less than 1 month after discharge. An autopsy methylprednisolone was increased to 1000 mg per day, was declined by her family. and the troponin T level subsequently decreased to 0.51 ng per milliliter. Axel Ullrich (* 19. Oktober 1943 in Lauban) ist ein deutscher Biochemiker. Er war bis 2016 Direktor der Abteilung für Molekularbiologie am Max-Planck-Institut für Biochemie in Martinsried bei München. Ullrich klonierte den Insulinrezeptor, den EGF-Rezeptor und andere Wachstumsfaktor-Rezeptoren. Er entwickelte den humanisierten Anti-EGFR-Antikörper Trastuzumab (Herceptin®) und den Anti-Angiogenese-Blocker Sunitinib (Sutent®), beides Krebsmedikamente. Ullrich absolvierte das Ludwig-Wilhelm-Gymnasium in Rastatt und studierte bis 1971 Biochemie an der Universität Tübingen. Nach dem Diplom wechselte er an die Universität Heidelberg, an der er 1975 über die „Translation virusspezifischer Ribonukleinsäuren in homologen und heterologen zellfreien Systemen“ promoviert wurde. 1975 ging Ullrich als Postdoktorand und Forschungsassistent an die Abteilung für Biochemie und Biophysik der University of California. Ab 1979 arbeitete er in der 1976 gegründeten Biotechnologiefirma Genentech. 1988 kehrte er nach Deutschland zurück, um Direktor der Abteilung für Molekularbiologie am Max-Planck-Institut für Biochemie in Martinsried zu werden. Außerdem ist Ullrich Honorarprofessor der Second Military Medical University in Shanghai und der Universität Tübingen. Ferner ist Ullrich neben seiner Tätigkeit in München seit 2004 auch Direktor des Singapore Onco Genome Laboratory, einer Kooperation der Max-Planck-Gesellschaft und der Agency for Science, Technology and Research (A*STAR) in Singapur. HER2 and Breast Cancer — A Phenomenal Success Story During the past three decades, the risk of dying from breast cancer in the United States has declined by nearly half, thanks to a combination of screening and early therapy as well as more treatments that are effective with fewer side effects, especially in the adjuvant setting. Therefore, it should come as no surprise, but rather with a great deal of satisfaction and happiness, that the 2019 Lasker– The Human Epidermal Receptor (HER) System and Ways to DeBakey Clinical Medical Target It. As shown in Panel A, the HER system consists of four Research Award goes to three family members, designated HER1 (also known as epidermal scientists — Axel Ullrich, growth factor receptor [EGFR]), HER2 (encoded by ERBB2, Dennis Slamon, and Michael formerly known as neu), HER3, and HER4. At least 11 known Shepard — whose work on peptide growth factors bind to HER1 (epidermal growth factor the human epidermal growth [EGF], heparin-binding EGF-like growth factor [HBEGF], β- cellulin, transforming growth factor α [TGF-α], amphiregulin, factor receptor 2 (HER2) in epigen, and epiregulin), HER3 (neuregulins 1 and 2), and HER4 breast cancer launched a new (neuregulins 1, 2, 3, and 4; β-cellulin; HBEGF; and epiregulin). era in clinical research and the HER2 has no ligand-binding domain but appears to act as a practice of oncology. gatekeeper for the mechanism of action of the family. Binding of HER1, HER3, or HER4 induces dimerization with itself or one of the other three receptors. EGFR, HER2, and HER3 each has a tyrosine kinase domain that is activated on dimerization and transmits a signal cascade to a receptive gene, which induces cell proliferation, invasion, migration, or survival, the hallmarks of cancer. Oncologic dogma maintains that women who have metastatic breast cancer will not be cured. However, my colleagues and I who specialize in the treatment of this disease all have a few such patients who have been rendered disease-free for prolonged periods of time — challenging that dogma. Regardless, even for the many patients who have HER2-positive metastatic breast cancer who are not cured, anti-HER2 therapy results in considerable and long-lasting improvement in quality of life and overall survival. In this regard, even newer advances in the field of anti-HER2 therapy are being tested. Novel antibody–drug conjugates and tyrosine kinase inhibitors are in clinical trials, as are innovative combinations of anti-HER2 therapies with other strategic approaches, such as immune checkpoint inhibitors. Moreover, trastuzumab has now been shown to be active in other, nonbreast HER2-positive cancers, particularly gastric cancers. However, to sing a familiar tune in oncology, these treatments are expensive and require some expertise in delivery, factors that limit their availability for patients without adequate health insurance and those in lower-income countries. Ongoing investigations are leading to more widespread availability of anti-HER2 therapies, including use of generic biosimilar anti-HER2 antibodies and subcutaneous, rather than intravenous, delivery of trastuzumab. The oncologic medical community and, more importantly, our patients owe Drs. Ullrich, Shepard, and Slamon and the numerous other laboratory, translational, and clinical investigators who have played a role in this remarkable story a great debt of appreciation. We must also acknowledge the courageous women who have participated, and continue to do so, in the clinical trials that have gotten us where we are in the treatment of HER2-positive cancers. The ongoing and planned areas of research in this field will continue to lead us into the future in which even more women with HER2-positive breast cancer will live longer or even be cured. The terms “game changer” and “blockbuster” are worn, but in this case the ingenuity, vision, and persistence of these collaborators justify these superlatives. A Study of Telecontraception Telecontraception — the provision of contraception through a website or smartphone app — has recently emerged as an alternative to provision at clinic visits. Telecontraception companies advertise the convenience of their services, which allow patients to complete an online questionnaire and receive a prescription for contraception at a local pharmacy or by mail. Although telecontraception may improve access, there are concerns regarding the quality of these services, including the potential for gaps in the online questionnaires used to screen patients for contraindications. We conducted a “secret shopper” study to assess the process and safety of telecontraception for patients.

These findings suggest that telecontraception may reduce barriers to contraception because vendors are convenient and accessible. In addition, adherence to guidelines among telecontraception vendors may be higher than it is among clinics that provide in-person visits. Telecontraception vendors could increase the quality of their services by improving screening for patient adherence to the regimen of ingesting a pill daily and for rare contraindications to oral contraceptives. Vendors should also make sure that patients are aware of more effective, long-acting, reversible contraceptives.

Ticagrelor ist ein reversibler P2Y12-Antagonist, der über die Interaktion mit Verstärkungs-mechanismen der Thrombozytenaktivierung in die Thrombozytenaggregation eingreift. Eine vergleichbare Wirkung zeigt der Wirkstoff Cangrelor. Der Arzneistoff ist mit Adenosin verwandt und gehört zur Klasse der Cyclopentyltriazolopyramidine. Ticagrelor hemmt den ADP-Rezeptor P2Y12 der Thrombozyten und reduziert damit deren Aggregation. Man nimmt an, dass der Wirkstoff eine eigene Bindungsstelle am Rezeptor hat und somit nicht an die ADP- Bindungsstelle andockt. Die Bindung erfolgt reversibel und ist nicht-kompetitiv. Im Verhältnis zu Clopidogrel bietet Ticagrelor einen schnellen Wirkeintritt und eine stärkere Thrombozytenaggregationshemmung bezogen auf die therapeutische Dosis. Etwa 35% des Wirkstoffs sind oral bioverfügbar. Die Metabolisierung findet hauptsächlich über das CYP3A4- System statt. Neben der eigenen pharmakologischen Aktivität wird über die Verstoffwechselung ein aktiver Metabolit gebildet. Die Elimination läuft überwiegend hepatisch ab. Die Plasmaeiweißbindung von Ticagrelor ist hoch. Die Halbwertszeit beträgt zirka 8 Stunden. Die klinische Wirksamkeit ist im Wesentlichen vergleichbar mit der von Clopidogrel. In klinischen Studien verminderte Ticagrelor/ASS verglichen mit Clopidogrel/ASS innerhalb von 12 Monaten die kardiovaskuläre Mortalität und Gesamtmortalität um gut 1%. In Kombination mit Acetylsalicylsäure wird Ticagrelor bei Auftreten eines akuten Koronarsyndroms oder STEMI angewendet. Das Risiko für atherothrombotische Ereignisse soll bei einer Dauertherapie gemindert werden.