Dokument: Multimodale Magnetresonanztomografie entzündlicher und degenerativer Gelenkerkrankungen

Titel:	Multimodale Magnetresonanztomografie entzündlicher und degenerativer Gelenkerkrankungen
Weiterer Titel:	Multimodal Magnetic Resonance Imaging of Inflammatory and Degenerative Joint Disease
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=61199
URN (NBN):	urn:nbn:de:hbz:061-20221123-130500-2
Kollektion:	Publikationen
Sprache:	Deutsch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Habilitation
Medientyp:	Text
Autor:	Abrar, Daniel Benjamin [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 7,55 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 15.11.2022 / geändert 15.11.2022
Dewey Dezimal-Klassifikation:	600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibungen:	Erkrankungen des Bewegungsapparates gehören zu den häufigsten Gründen für den Arztbesuch und sind weltweit die führende Ursache für Schmerz und Behinderung. In der Folge ergeben sich zusätzlich zum individuellen Leidensdruck der Patienten enorme wirtschaftliche Kosten für die Gesellschaft. So belaufen sich die Kosten für Erkrankungen des Bewegungsapparates alleine in den USA jährlich auf nahezu eine Billion US-Dollar. Die verschiedenen Erkrankungen des Bewegungsapparates unterscheiden sich dabei sowohl hinsichtlich ihres zeitlichen Verlaufes und der betroffenen Körperregion als auch im Hinblick auf ihre Ätiologie. So tragen zum einen akute Verletzungen, wie Frakturen, Bandrisse oder Knorpelschäden, zum anderen chronische Erkrankungen, wie Arthrose (osteoarthritis, OA) , Arthritiden oder Lumbago zum bunten Strauß möglicher Erkrankungen des Bewegungsapparates bei. Dabei nimmt die Vielseitigkeit der Behandlungsmöglichkeiten dieser Erkrankungen stetig zu, insbesondere das weite Feld entzündlicher Gelenkerkrankungen, wie der rheumatoiden Arthritis (RA) oder der Psoriasis-Arthritis (PsA), wurde durch die Entwicklung der biologischen und gezielt synthetischen erkrankungsmodifizierenden Arzneimittel (biological und targeted-synthesized disease modifying drugs, bDMARD und tsDMARD) revolutioniert. Durch die frühzeitige Behandlung mit diesen DMARDs kann durch stetige Therapiekontrolle (sog. treat-to-target Prinzip, T2T) häufig eine dauerhafte Remission erreicht werden. Um eine derartige Erkrankung des Bewegungsapparates rechtzeitig behandeln zu können, ist eine möglichst frühzeitige Diagnose entscheidend. Seit ihrer Etablierung finden bildgebende Verfahren breite Anwendung in der Diagnostik muskuloskelettaler Erkrankungen. Konventionelle Radiografie, Computertomografie und Magnetresonanztomografie (MRT) erlauben die sensitive, häufig sofortige und nahezu ubiquitär verfügbare Diagnose und Therapiekontrolle typischer traumatischer, degenerativer oder entzündlicher Erkrankungen des Bewegungsapparates. Seit ihrer Entwicklung in den 1980er Jahren nimmt dabei die Bedeutung der MRT stetig zu. Ihre hohe Ortsauflösung, der exzellente Weichteilkontrast und die fehlende Anwendung ionisierender Strahlung machen die MRT zum Stützpfeiler muskuloskelettaler Bildgebung. Entzündliche Weichteilveränderungen von Synovialis, Sehnen, Muskeln, Faszien und Subkutis lassen sich dabei ebenso detailliert abbilden wie knöcherne Pathologien wie Erosionen, Frakturen und Tumore. Über diese strukturell-morphologischen Möglichkeiten der MRT hinaus, gibt es inzwischen moderne MRT-Verfahren, die auf molekularer Ebene unter anderem den Gelenkknorpel kompositionell analysieren können. So erlaubt beispielsweise die Glykosaminoglykan (GAG) Chemical Exchange Saturation Transfer (CEST) Bildgebung den Nachweis von Proteoglykanen im hyalinen Gelenkknorpel und in Bandscheiben. Da der Proteoglykanverlust ein frühes Zeichen von Knorpelschäden ist, wie sie im Rahmen degenerativer oder entzündlicher Gelenkveränderungen auftreten, können so potentielle Gelenkerkrankungen biochemisch-sensitiv erkannt werden, bevor diese strukturell manifest werden. In der vorliegenden Habilitationsschrift wird die multimodale MRT entzündlicher und degenerativer Gelenkerkrankungen untersucht. Dabei kommen nicht-invasive Methoden der kompositionellen Knorpelbildgebung bei entzündlichen Gelenkerkrankungen des peripheren und Achsenskeletts sowie bei Patienten mit unspezifischen Rückenschmerzen und Leistungssportlern zum Einsatz. Außerdem wird der Stellenwert hochauflösender MRT mit speziellen Empfangsspulen für die Detektion, Unterscheidung und Therapiekontrolle typischer rheumatischer Gelenkerkrankungen näher beleuchtet. Die erste Arbeit untersucht den diagnostischen Stellenwert der hochauflösenden MRT von Ringbändern bei Patienten mit PsA im Vergleich zu Patienten mit RA und gesunden Kontrollpersonen. Im Rahmen dessen wurden die Finger D2-5 der obigen Studienpopulation mittels 3 Tesla (T) MRT und einer speziellen 16-Kanalhandspule untersucht, um so entzündliche und strukturelle Veränderungen der Ringbänder zu detektieren. Dabei zeigte sich, dass Patienten mit PsA ausgeprägtere Veränderungen der Ringbänder als die Vergleichskohorte aus RA-Patienten und Gesunden aufweisen. Ringbandveränderungen sind daher als für die PsA typisch anzusehen und können bei der Unterscheidung zwischen RA und PsA hilfreich sein. Die zweite Arbeit befasst sich mit der Etablierung und Optimierung eines gagCEST Untersuchungsprotokolls, das mit einer klinisch-anwendbaren Untersuchungsdauer von unter acht Minuten bei einer Magnetfeldstärke von 3 T anwendbar ist. Dazu wurden zunächst Bloch-Mc-Connell Simulationsexperimente durchgeführt, um ein optimales gagCEST-Protokoll zu etablieren. Anschließend wurde der tibiotalare Gelenkknorpel von Patienten nach osteochondraler Läsion des Talus sowie von gesunden Kontrollpersonen mit dem optimierten Protokoll untersucht. Dabei zeigten sich sowohl eine gute Reproduzierbarkeit der Ergebnisse als auch signifikante Unterschiede zwischen Patienten und Kontrollpersonen. Somit konnte diese Machbarkeitsstudie die Durchführbarkeit von gagCEST am tibiotalaren Gelenkknorpel bei 3 T belegen. In der dritten Arbeit wurden die symptomatischen Hände von Patienten mit RA und PsA mit einer dezidierten Handspule und 3 T MRT untersucht, um systematisch erkrankungsassoziierte Veränderungen zu erfassen und mögliche Unterschiede zwischen beiden Entitäten herauszuarbeiten. Zur exakten Analyse wurden die standardisierten und validierten Scores für RA und PsA, der RA MRI und PsA MRI Score (RAMRIS und PsAMRIS) erhoben. Diese bilden typische erkrankungsassoziierte Veränderungen, wie Synovialitis, Tenovaginitis, Osteoödem und Erosionen ab. In der Studienpopulation konnte gezeigt werden, dass die PsA signifikant häufiger mit extraartikulär gelegenen, entzündlichen Veränderungen einhergeht als die RA und mit diesem Merkmal eine Differenzierung beider Entitäten erleichtert werden kann. Die vierte Arbeit analysierte systematisch den GAG-Gehalt lumbaler Bandscheiben (intervertebral disks, IVDs) von Patienten mit radiografisch nachgewiesener axialer Spondyloarthropathie (r-axSpA) im Vergleich zu altersgleichen Kontrollpersonen. Zudem wurden typische erkrankungsassoziierte Veränderungen der Wirbelsäule, wie beispielsweise Syndesmophyten und Spondylitis, mittels morphologischer Standard-MRT erfasst. Dabei zeigten sich signifikant niedrigere IVD-gagCEST-Werte bei Patienten. Zudem zeigte sich ein Zusammenhang zwischen niedrigen IVD-gagCEST-Werten und dem Vorliegen von Syndesmophyten. In der fünften Arbeit wurde untersucht, ob und inwieweit Knorpeldegeneration mit Entzündung des Synovialis in den Fingergelenken von Patienten mit PsA assoziiert ist. Dazu wurde der Proteoglykangehalt des Gelenkknorpels der Fingergelenke mittels delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) analysiert. Die Methode ist ein biochemisch-sensitives Verfahren zur Evaluation der Knorpelzusammensetzung. Zudem wurde mittels dynamic contrast-enhanced (DCE) MRT, der sogenannten Perfusionsbildgebung, die Durchblutung der Synovialis und somit letztlich die Ausprägung bestehender Synovialitis betrachtet. Dabei zeigte sich ein Zusammenhang zwischen Proteoglykanverlust und Ausprägung der Synovialitis. Die sechste Arbeit evaluiert eine vereinfachte Version des PsAMRIS, den sogenannten sPsAMRIS, der eine schnellere Analyse erkrankungsassoziierter Veränderungen an den Fingergelenken von Patienten mit PsA erlaubt und dabei eine gleichwertige Sensitivität für Veränderungen wahrt. In der siebten Arbeit wurden die Fingergelenke von Patienten mit RA und PsA mittels dGEMRIC hinsichtlich der Zusammensetzung des Gelenkknorpels, also dem Proteoglykangehalt, untersucht. Hier zeigte sich, dass kein signifikanter Unterschied zwischen beiden Armen der Studienpopulation besteht. Somit ist von einer Beteiligung des Gelenkknorpels im Erkrankungsverlauf beider Entitäten auszugehen. Die Arbeiten acht bis zehn untersuchten den Proteoglykangehalt lumbaler Bandscheiben in unterschiedlichen Kollektiven mittels gagCEST Bildgebung. Dabei konnte gezeigt werden, dass Patienten mit unspezifischer Lumbago, Radikulopathie und juveniler idiopathischer Skoliose (adolescent idiopathic scoliosis, AIS) signifikant niedrigere IVD-gagCEST-Werte aufweisen als gesunde Kontrollpersonen. Zudem weisen IVDs, die unmittelbar an Bandscheibenherniationen oder an die Endpunkte einer skoliotischen Hauptkrümmung grenzen, niedrige gagCEST-Werte auf als entferntere IVDs. Die zehnte Arbeit untersuchte Elite-Ruderer aus der deutschen Nationalmannschaft im Verlauf ihres jährlichen Trainingszyklus. Dabei wurde festgestellt, dass in lumbalen IVDs ein belastungsabhängiges Remodeling stattfindet. So wurden in der Belastungsphase höhere IVD-gagCEST-Werte als in der Ruhephase festgestellt. Zusammenfassend zeigen die zehn Arbeiten neue und vertiefende Erkenntnisse über moderne MRT-Verfahren, die zum einen hochauflösende Bilder feiner Gelenkstrukturen und zum anderen kompositionelle Informationen über Gelenkknorpel und Bandscheiben vermitteln. So können degenerative und entzündliche Gelenkveränderungen sowohl strukturell als auch ultrastrukturell sichtbar gemacht werden, was als Ansatzpunkt für zukünftige Implementierung in Diagnostik und Therapiekontrolle entzündlicher und degenerativer Gelenkerkrankungen dienen kann. Musculoskeletal disorders are among the most common reasons for visiting a doctor and are the leading cause of pain and disability worldwide. As a result, in addition to the individual suffering of patients, there are enormous economic costs to society. For example, the cost of musculoskeletal disorders in the U.S. alone is nearly one trillion U.S. dollars annually. The various diseases of the musculoskeletal system differ in terms of their time course and the region of the body affected, as well as in terms of their etiology. Acute injuries, such as fractures, torn ligaments or cartilage damage, on the one hand, and chronic diseases, such as osteoarthritis (OA), arthritis or lumbago, on the other, contribute to the colorful bouquet of possible diseases of the musculoskeletal system. In particular, the broad field of inflammatory joint diseases, such as rheumatoid arthritis (RA) or psoriatic arthritis (PsA), has been revolutionized by the development of biological and targeted-synthesized disease modifying drugs (bDMARD and tsDMARD). Early treatment with these DMARDs can often achieve a durable remission through steady therapy control (so-called treat-to-target principle, T2T). In order to be able to treat such a musculoskeletal disease in time, early diagnosis is crucial. Since their establishment, imaging techniques have been widely used in the diagnosis of musculoskeletal diseases. Conventional radiography, computed tomography, and magnetic resonance imaging (MRI) allow sensitive, often immediate, and almost ubiquitously available diagnosis and therapy monitoring of typical traumatic, degenerative, or inflammatory diseases of the musculoskeletal system. Since its development in the 1980s, the importance of MRI has been steadily increasing. Its high spatial resolution, excellent soft tissue contrast, and lack of use of ionizing radiation make MRI the mainstay of musculoskeletal imaging. Inflammatory soft tissue changes of synovium, tendons, muscles, fascia, and subcutis can be imaged in as much detail as bony pathologies such as erosions, fractures, and tumors. Beyond these structural-morphological possibilities of MRI, there are now modern MRI techniques that can analyze articular cartilage compositionally at the molecular level, among other things. For example, glycosaminoglycan (GAG) chemical exchange saturation transfer (CEST) imaging allows detection of proteoglycans in hyaline articular cartilage and intervertebral discs. Since proteoglycan loss is an early sign of cartilage damage as it occurs in the context of degenerative or inflammatory joint changes, potential joint diseases can thus be detected biochemically-sensitively before they become structurally manifest. In the present postdoctoral thesis, multimodal MRI of inflammatory and degenerative joint diseases is investigated. Non-invasive methods of compositional cartilage imaging are used in inflammatory joint diseases of the peripheral and axial skeleton as well as in patients with non-specific back pain and competitive athletes. In addition, the value of high-resolution MRI with special receiving coils for the detection, differentiation, and therapy monitoring of typical rheumatic joint diseases is further elucidated. The first paper investigates the diagnostic value of high-resolution MRI of annular ligaments in patients with PsA compared to patients with RA and healthy controls. As part of this, fingers D2-5 of the above study population were examined using 3 Tesla (T) MRI and a dedicated 16-channel hand coil to detect inflammatory and structural changes in the annular ligaments. This showed that patients with PsA had more pronounced changes in the annular ligaments than the comparison cohort of RA patients and healthy individuals. Ring ligament changes can therefore be considered typical for PsA and may be helpful in distinguishing between RA and PsA. The second work deals with the establishment and optimization of a gagCEST examination protocol that is applicable with a clinically applicable examination time of less than eight minutes at a magnetic field strength of 3 T. To this end, Bloch-Mc-Connell simulation experiments were first performed to establish an optimal gagCEST protocol. Subsequently, the tibiotalar articular cartilage of patients after osteochondral lesion of the talus as well as of healthy control subjects was examined with the optimized protocol. The results showed good reproducibility as well as significant differences between patients and control subjects. Thus, this feasibility study was able to demonstrate the feasibility of gagCEST on tibiotalar articular cartilage at 3 T. In the third paper, the symptomatic hands of patients with RA and PsA were examined with a dedicated hand coil and 3 T MRI to systematically detect disease-associated changes and to highlight potential differences between the two entities. For accurate analysis, the standardized and validated scores for RA and PsA, the RA MRI and PsA MRI Score (RAMRIS and PsAMRIS) were collected. These map typical disease-associated changes, such as synovialitis, tenovaginitis, osteoedema, and erosions. In the study population, PsA was shown to be significantly more frequently associated with extra-articular inflammatory changes than RA, and this feature can be used to facilitate differentiation of the two entities. The fourth paper systematically analyzed the GAG content of lumbar intervertebral discs (IVDs) from patients with radiographically proven axial spondyloarthropathy (r-axSpA) compared to age-matched controls. In addition, typical disease-associated changes of the spine, such as syndesmophytes and spondylitis, were assessed by standard morphological MRI. This showed significantly lower IVD gagCEST values in patients. In addition, a correlation between low IVD-gagCEST values and the presence of syndesmophytes was shown. The fifth paper investigated whether and to what extent cartilage degeneration is associated with synovial inflammation in the finger joints of patients with PsA. For this purpose, the proteoglycan content of the articular cartilage of the finger joints was analyzed using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC). This method is a biochemically sensitive method for the evaluation of cartilage composition. In addition, dynamic contrast-enhanced (DCE) MRI, so-called perfusion imaging, was used to assess synovial blood flow and ultimately the extent of existing synovitis. This showed a correlation between proteoglycan loss and the expression of synovitis. The sixth paper evaluates a simplified version of the PsAMRIS, the so-called sPsAMRIS, which allows a faster analysis of disease-associated changes in the finger joints of patients with PsA while maintaining an equivalent sensitivity for changes. In the seventh paper, finger joints of patients with RA and PsA were examined by dGEMRIC with respect to articular cartilage composition, i.e., proteoglycan content. Here, it was shown that there was no significant difference between the two arms of the study population. Thus, the involvement of articular cartilage in the disease process of both entities can be assumed. Papers eight through ten examined the proteoglycan content of lumbar intervertebral discs in different collectives using gagCEST imaging. They demonstrated that patients with nonspecific lumbago, radiculopathy, and adolescent idiopathic scoliosis (AIS) have significantly lower IVD gagCEST values than healthy controls. In addition, IVDs immediately adjacent to disc herniations or to the endpoints of a scoliotic major curve have low gagCEST values than more distant IVDs. The tenth paper examined elite rowers from the German national team during their annual training cycle. It was found that load-dependent remodeling occurs in lumbar IVDs. Thus, higher IVD gagCEST values were found in the loading phase than in the resting phase. In summary, the ten papers reveal new and in-depth insights into modern MRI techniques that provide both high-resolution images of fine articular structures and compositional information about articular cartilage and intervertebral discs. Thus, degenerative and inflammatory joint changes can be visualized both structurally and ultrastructurally, which can serve as a starting point for future implementation in diagnostics and therapy control of inflammatory and degenerative joint diseases.
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