Die Rolle des Metabolismus und metabolisch relevanter Faktoren in der Pathophysiologie rheumatischer Erkrankungen

Zusammenfassung

Bei der Entstehung und dem Verlauf rheumatischer Erkrankungen spielen Adipositas, Metabolisches Syndrom (MetS) und Stoffwechselerkrankungen wie Diabetes eine wichtige Rolle. Wichtige Faktoren sind hierbei Fettgewebshormone wie z. B. Adiponektin und Leptin, aber auch andere biologisch aktive Faktoren des Metabolismus, wie die freien und gebundenen Fettsäuren im Blut und die Cholesterinwerte, welche den Krankheitsverlauf von Patienten mit rheumatischen Erkrankungen beeinflussen. Sowohl für Patienten mit rheumatoider Arthritis (RA) und Psoriasis-Arthritis (PsA) als auch für die nicht autoimmun beeinflusste Arthrose stellt Adipositas einen anerkannten Risikofaktor dar und ist somit von pathophysiologischer Bedeutung. Ein Einfluss auf das Ansprechen auf Medikamente wurde ebenso beobachtet. So erreichen übergewichtige PsA-Patienten, v. a. bei vermehrtem abdominalem Fett, unter TNFα-Blocker-Therapie mit geringerer Wahrscheinlichkeit eine minimale Krankheitsaktivität. In der Pathophysiologie rheumatischer Erkrankungen ist Fettgewebe außerdem wichtig als IL-6-Produzent, da IL-6 zu etwa einem Drittel im Fettgewebe produziert wird und eine Reduktion des Körpergewichts auch zur Reduktion des Serum-IL-6-Spiegels führt. Die Interaktion zwischen Immunsystem und biologisch aktiven Faktoren aus dem Metabolismus bei entzündlichen Erkrankungen funktioniert in beide Richtungen, wodurch die Wirknetzwerke sehr komplex werden. Der Entzündungsmarker C-reaktives Protein (CRP) bspw. bindet im Serum an Leptin und verhindert dadurch dessen Wirkung bzw. die Signalweiterleitung an die Zielzellen. Gleichzeitig fördert Leptin in der Leber die Bildung von CRP. Über diese gegenseitigen Einflüsse kann vermutlich CRP die Adipositas und deren Komorbiditäten beeinflussen. Der CRP-Spiegel korreliert aber auch negativ mit den HDL-Werten, und die Lipidwerte im Blut werden durch akute oder chronische Entzündung signifikant verändert. Auch die neuen Therapieansätze mit „Small Molecules“ wie z. B. Tofacitinib wirken sich nicht nur auf die Entzündung, sondern auch auf den Metabolismus aus. So wurde gezeigt, dass Patienten mit RA signifikant niedrigere Werte an Gesamtcholesterin, HDL-C, LDL-C und Apo-A1 im Vergleich zu gesunden Kontrollen aufweisen. Diese werden aber unter Behandlung mit Tofacitinib signifikant erhöht und nähern sich somit den Werten der gesunden Kontrollgruppe an.

Abstract

Obesity, metabolic syndrome (MetS) and other metabolic diseases such as diabetes play an important role in the onset and progression of rheumatic diseases. Hormones of the adipose tissue, e. g. adiponectin or leptin, as well as other metabolic factors including free fatty acids or cholesterol may influence the disease progression of patients with rheumatic diseases. For patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) as well as patients with the non-autoimmune disease osteoarthritis, obesity represents a risk factor with pathophysiological importance. The response to drugs is also affected by obesity. For example, in PsA patients on anti-TNF treatment, there is a negative correlation between the amount of abdominal fat and the likelihood of achieving minimal disease activity. Within the pathophysiology of rheumatic diseases, adipose tissue is one of the most important sources of IL-6 as it produces up to one third of systemic IL-6, and a reduction of body weight leads to a reduction of IL-6 serum levels. The interaction between the immune system and biologically active metabolic factors is bidirectional, which leads to a highly complex network of interactions. C-reactive protein (CRP), for example, an inflammatory marker protein, binds to leptin, thus inhibiting its signal transduction and effects on target cells. At the same time, leptin promotes the secretion of CRP in the liver. This mechanism is possibly one of many pathways by which inflammation and metabolism influence each other. In addition, CRP serum levels inversely correlate with HDL levels, and serum lipid profiles change significantly in case of acute or chronic inflammation. New therapeutic approaches with “small molecules” such as tofacitinib not only lower inflammation, but also affect parts of the metabolism. RA patients, for example, have significantly lower serum levels of total cholesterol, HDL-C, LDL-C and Apo-A1 compared with healthy individuals. However, these levels increase in response to tofacitinib treatment and approximate those of healthy individuals.

Schlüsselwörter

Arthritis - Adipokine - Arthrose - Adipositas

Key words

obesity - adipokines - osteoarthritis - rheumatoid arthritis

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