Autophagy in the Pathogenesis of Disease

Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

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Targeting autophagy in cancer

A 52-year-old female presented with an 8-month history of dyspnea, fever, muscle weakness, and arthralgia. Her past medical history was unremarkable. The patient did not report pruritus or a history of atopic disease or allergy. On clinical examination, we noted hyperkeratosis and fissures of the lateral aspects of fingers and fingertips consistent with mechanic’s hands (MH) (Figure 1a, b). She had symmetrically swollen and tender finger joints. The creatine kinase level and electrophysiological tests were normal. Testing for antinuclear antibodies (ANAs) revealed a speckled pattern with a titer of 1 : 320 and showed additional cytoplasmic fluorescence. Serological testing for antibodies yielded positive results for anti-Ro52 antibodies. Other antibodies to extractable nuclear antigens (ENAs), including anti-Ro60 (SS-A) antibodies as well as antisynthetase antibodies (anti-Jo1, anti-EJ, anti-OJ, anti-PL7 and anti-PL12) were negative on repeat testing. Computed tomography of the chest showed signs of interstitial lung disease (ILD) (Figure 1c, red arrowheads). Nailfold video capillaroscopy showed megacapillaries, elongations, and tortuosities consistent with a myositis pattern Clinical Letter

Mechanic's hands in a patient with isolated anti-Ro52 antibodies: antisynthetase syndrome without antisynthetase antibodies.

Inflammatory myopathies are a heterogeneous group of acquired systemic diseases, which include dermatomyositis (DM), polymyositis (PM), necrotising myopathy (NM) and inclusion body myositis (IBM). All four disease entities share certain clinical characteristics, such as progressive muscle weakness and elevated muscle enzymes. Other characteristic-associated features such as skin involvement in DM or the detection of myositis-specific antibodies, may be indicative of a particular subtype. However, muscle biopsy is still essential for the diagnosis and shows distinct histopathological characteristics for each subtype of myositis. Treatment of inflammatory myopathies is still based on clinical experience, since placebo-controlled trials are scarce. While DM, PM and NM respond well to immunosuppressive treatment, IBM is usually resistant to immunotherapy. This review aims to give a concise overview and provide guidance for general management of myositis.

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Current essentials in inflammatory myopathies

Entzündliche Erkrankungen der Muskulatur sind wichtige, zum Teil schwer verlaufende Erkrankungen, die oft zu einer erheblichen Beeinträchtigung der Lebensqualität führen. Neben der Muskelschwäche gibt es oft eine Mitbeteiligung anderer Organe wie Herz, Lunge oder Speiseröhre mit Symptomen wie Atemnot oder Schluckstörung. Nur durch eine frühe und zuverlässige Diagnosestellung, die den aktuellen nationalen und internationalen Standards entspricht, ist eine schnelle und effektive Therapie möglich. Zum diagnostischen Repertoire gehören u. a. Autoantikörperbestimmung, Bildgebung, Muskelbiopsie, Erfassung extramuskulärer Manifestationen z. B. durch eine hochauflösende Lungencomputertomographie und eine individualisierte Tumorsuche. Nur durch eine gute Kooperation von Fächern wie Neurologie bzw. Pädiatrie, Rheumatologie, Dermatologie, Neuropathologie sowie Pulmonologie oder Kardiologie ist eine optimale Therapie und die Vermeidung irreversibler Schäden wie etwa ein Verlust der Gehfähigkeit möglich. Neben der Standardimmunsuppression mit Glukokortikosteroiden, Azathioprin oder Methotrexat ist eine Eskalationstherapie mit Rituximab mittlerweile sehr gut etabliert. Zur interdisziplinären Therapie gehört die Vorstellung an einem entsprechend qualifizierten Zentrum und die Orientierung an nationalen und internationalen Standards wie Leitlinien zur Myositis. Als hilfreiche Ressource steht das MYOSITIS NETZ e. V. ( www.myositis-netz.de ) und die International Myositis Society (iMyoS; www.imyos.org ) zur Verfügung. 

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Myositis: von der Diagnose zur Therapie

/pdf/myositis-from-diagnosis-to-treatment-1srsjth0.pdf

[Myositis: from diagnosis to treatment].

eine 52-jährige Patientin stellte sich mit seit acht Monaten bestehender Dyspnoe, Fieber, Muskelschwäche und Gelenkschmerzen vor. Sie berichtete keinen Juckreiz, keine Allergien und keine atopische Diathese. Die Eigenanamnese war unauffällig. In der klinischen Untersuchung zeigten sich Hyperkeratosen und Fissuren der lateralen Finger und Fingerspitzen mit dem typischen Bild von „Mechanikerhänden“ (MH) (Abbildung 1a, b). Weiterhin ließen sich symmetrisch geschwollene und schmerzhafte Fingergelenke palpieren. Laborchemisch ergaben sich keine Auffälligkeiten, insbesondere die Kreatinkinase war normwertig. Die elektrophysiologische Testung fiel ebenfalls unauffällig aus. In der serologischen Testung auf antinukleäre Antikörper (ANA) beobachteten wir ein gesprenkeltes Muster mit einem Titer von 1 : 320 und zusätzlich bestehender zytoplasmatischer Immunfluoreszenz. Die weiterführende Untersuchung ergab ein stark positives Ergebnis für anti-RO52-Antikörper (AK). Antikörper gegen andere extrahierbare nukleäre Antigene (ENA), inklusive anti-Ro60 (SS-A) und gegen häufige Antisynthetase-AK (anti-Jo1, anti-EJ, anti-OJ, anti-PL7, anti-PL12) waren auch nach wiederholter Bestimmung negativ. Die Computertomographie des Thorax zeigte interstitielle Infiltrate (ILD) (Abbildung 1c, rote Pfeilspitzen). Die Nagelfalzkapillarmikroskopie war auffällig für Megakapillaren, Elongationen und Torquierungen. Die Befunde waren vereinbar mit einem Myositis-Muster (Abbildung 1d, weiße Pfeilspitzen). Eine Lungenbiopsie erfolgte und ergab den Befund einer unspezifischen interstitiellen Pneumonie (non-specific interstitial pneumonia; NSIP). Wir leiteten eine Therapie mit hochdosierten Glukokortikoiden und Azathioprin (AZA) ein. Dies führte zu einer klinischen Verbesserung. Nach Glukokortikoidtapering kam es jedoch zu einem Rezidiv mit Muskelschmerzen und Arthritis. Die MH verschwanden unter Therapie jedoch schnell und kehrten nicht wieder. Da eine insgesamt bessere Prognose nach früher Behandlung mit Rituximab (RTX) [1], insbesondere bei Patienten mit ILD, berichtet wurde, initiierten wir die Therapie mit 2 × 1 g im Abstand von 14 Tagen, gefolgt von AZA. AZA wurde in der Folge bei erneutem Rezidiv mit Muskelschmerzen, Arthritis und Steroidabhängigkeit gegen Mycophenolatmofetil (MMF) getauscht. Die Patientin erhält aktuell RTX als Erhaltungstherapie in einer Dosis von 1 g alle sechs Monate. Das klinische Bild war vereinbar mit dem Antisynthetase-Syndrom (ASS), welches charakterisiert ist durch Fieber, English online version on Wiley Online Library DOI: 10.1111/ddg.13985_g Mechanikerhände bei einer Patientin mit isolierten anti-RO52-Antikörpern: AntisynthetaseSyndrom ohne Antisynthetase-Antikörper

https://onlinelibrary.wiley.com/doi/pdf/10.1111/ddg.13985_g

Jens Schmidt

Papers

Mechanic's hands in a patient with isolated anti-Ro52 antibodies: antisynthetase syndrome without antisynthetase antibodies.

Current essentials in inflammatory myopathies

Myositis: von der Diagnose zur Therapie

[Myositis: from diagnosis to treatment].

Mechanikerhände bei einer Patientin mit isolierten anti‐RO52‐Antikörpern: Antisynthetase‐Syndrom ohne Antisynthetase‐Antikörper