Risikostratifizierung bei ANCA-assoziierten Vaskulitiden

Zusammenfassung

ANCA-assoziierte Vaskulitiden (AAV) sind nekrotisierende Vaskulitiden der kleinen bis mittelgroßen Gefäße, welche die Granulomatose mit Polyangiitis (GPA), die mikroskopische Polyangiitis (MPA) und die Eosinophile Granulomatose mit Polyangiitis (EGPA) umfassen. AAV gehen häufig mit Organfunktion-bedrohenden Manifestationen und einer entsprechend erhöhten Mortalität einher. Für die Planung von Diagnostik, Therapie und Langzeitbetreuung ist daher eine Risikostratifizierung im Hinblick auf Mortalität, Entwicklung schwerer Organinsuffizienzen, insbesondere einer terminalen Niereninsuffizienz, mögliche Therapieresistenz, Rezidive, Infektionen und Malignome erforderlich. Wichtige Risikofaktoren für erhöhte Mortalität und/oder terminale Niereninsuffizienz sind neben der renalen Beteiligung per se eine bereits zum Zeitpunkt der Diagnose deutlich eingeschränkte renale Funktion einschliesslich initialer Dialysepflichtigkeit, eine hohe initiale Aktivität der AAV gemessen am Birmingham Vaskulitis Activity Score, aber auch kardiale und gastrointestinale Manifestationen, Infektionen, Anämie sowie ein Alter von>65 Jahren. Histologisch ist der Nachweis chronischer irreversibler glomerulärer und tubulärer Läsionen in der Nierenbiopsie mit einer schlechten Prognose im Hinblick auf die Nierenfunktion assoziiert. Basierend auf der histopathologischen Klassifikation der ANCA-assoziierten Glomerulonephritis (GN) ist der Befund einer sklerosierenden GN mit einer besonders ungünstigen Prognose assoziiert, während die fokale GN sehr selten zur terminalen Niereninsuffizienz führt. MPO-ANCA zeigen eine Assoziation mit chronischen Läsionen in der Nierenbiopsie sowie erhöhter Mortalität und erhöhtem Risiko für terminale Niereninsuffizienz. Im Hinblick auf die pulmonale Beteiligung sind alveoläre Hämorrhagie und interstitielle Lungenerkrankung mit einer erhöhten Mortalität assoziiert. Bei EGPA wird die Prognose entscheidend durch die Kardiomyopathie bestimmt. Risikofaktoren für Rezidive weichen erheblich von denen für Mortalität und terminale Niereninsuffizienz ab. Ein erhöhtes Rezidivrisiko besteht bei Nachweis von PR3-ANCA, GPA und pulmonaler Beteiligung. Auch bei granulomatösen Läsionen, Beteiligung des oberen Respirationstraktes und kardiovaskulären Manifestationen wird ein erhöhtes Rezidivrisiko beschrieben. Im Gegensatz zur Assoziation einer initial schlechten Nierenfunktion mit Mortalität und terminaler Niereninsuffizienz, wurde für Patienten mit initial guter Nierenfunktion ein erhöhtes Rezidivrisiko gezeigt. Weitere Risikofaktoren für Rezidive sind Staphylokokken-Besiedelung der Nase, frühere Rezidive und ANCA-Positivität nach Remissionsinduktion. Titeranstieg oder Wiederauftreten von ANCA zeigen nur eine moderate Beziehung zum Rezidivrisiko. Der prädiktive Wert für Rezidive ist offenbar bei bestimmten Subgruppen, wie bei Patienten mit renaler Beteiligung und pulmonaler Hämorrhagie sowie bei mit Rituximab-behandelten Patienten besser als bei Patienten mit granulomatösen Manifestationen. Daher ist eine Therapieentscheidung allein auf Basis der Entwicklung der ANCA-Titer nicht möglich. Risikofaktoren für schwere Infektionen sind höher dosierte und prolongierte Glukokortikoidtherapie, Leuko- und Lymphopenie, höheres Lebenalter, Niereninsuffizienz und pulmonale Beteiligung. Die Malignomrate insbesondere für Nicht-Melanom-Hauttumoren, Harnblasenkarzinome und Leukämie ist bei AAV erhöht und zeigt eine Assoziation mit hohen kumulativen Cyclophosphamiddosen. Da insbesondere frühzeitige irreversible Organschäden die Prognose bestimmen und Rezidive die Entwicklung irreversibler Schäden treiben, sind frühestmögliche Diagnose und Therapie sowie rasches Erkennen und Vermeiden von Rezidiven essentiell für die Risikominimierung.

Abstract

ANCA-associated vasculitides (AAV) are necrotising vasculitides of small and medium blood vessels involving granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). AAV are frequently associated with manifestations that threaten organ function and are associated with increased mortality. For the planning of diagnosis, therapy and long-term management, risk stratification is required with respect to mortality, development of severe organ failures, especially end-stage renal disease (ESRD), possible resistance to therapy, relapses and infections. Important risk factors for mortality and/or ESRD include renal involvement itself, reduction in renal function at the time of diagnosis, including initial need for renal replacement therapy, high disease activity at baseline measured by the Birmingham Vasculitis Activity Score, but also cardiovascular and gastrointestinal involvement, infections, anaemia and age>65 years. Histological evidence of chronic irreversible glomerular and tubulointerstitial lesions in renal biopsy are associated with a poor prognosis with respect to renal function. On the basis of the histopathological classification of ANCA-associated glomerulonephritis (GN), the finding of sclerosing GN is associated with a particularly poor prognosis, whereas focal GN rarely results in ESRD. MPO-ANCA is associated with chronic lesions in renal biopsy as well as with increased mortality and increased risk for ESRD. With respect to pulmonary involvement, alveolar haemorrhage and interstitial lung disease are associated with increased mortality. In EGPA, prognosis is significantly determined by cardiomyopathy. Risk factors for relapses are quite different from those for mortality and ESRD. There is an increased risk for relapses in patients with PR3-ANCA, GPA and those with pulmonary involvement. Increased risk for relapse has also been described in the case of granulomatous lesions, involvement of the upper respiratory tract and cardiovascular manifestations. In contrast to the association of reduced renal function at baseline with mortality and ESRD, in patients with a normal renal function at baseline an increased risk for relapse has been shown. Further risk factors for relapse are nasal carriage of staphylococcus aureus, previous relapses and ANCA positivity at time of completion of induction therapy. An increase in ANCA titres or reappearance of ANCA show only a modest association with the risk for relapse, The predictive value for relapses is obviously better in certain subgroups, such as patients with renal involvement and alveolar haemorrhage as well as in patients treated with rituximab in comparison to patients with granulomatous manifestations. Therefore therapeutic decision cannot only be based on ANCA. Risk factors for severe infections are prolonged treatment with glucocorticoids with a high cumulative dose, leukopenia and lymphopenia, older age, renal failure and pulmonary involvement. The rate of malignancy – especially for non-melanoma skin cancer, bladder cancer and leukaemia is increased in AAV and associated with high cumulative cyclophosphamide doses. Because early irreversible organ damage determines a poor prognosis and relapses drive irreversible organ damage, diagnosis and initiation of therapy must be as soon as possible and early recognition and the avoidance of relapses are essential for risk minimisation.

Schlüsselwörter

Risikostratifizierung - ANCA - Vaskulitis

Key words

Risk stratification - ANCA - Vasculitis

Publication History

Article published online:
08 April 2021

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