Dissertation committee:
Δημήτριος Πεκτασίδης, Ομότιμος Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Πέτρος Σφηκάκης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Μπούμπας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ιωάννης Μπολέτης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Δημήτριος Βασιλόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Μαρία Τεκτονίδου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αιμιλία Χατζηγιάννη, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Background
Despite the progress in the therapeutics of ANCA-associated vasculitides (AAV), mortality and relapse rates remain high. Among complications, serious infections are common, real-life data regarding their incidence and predisposing factors—after the introduction of B-cell depleting agents—are limited while data quantifying the risk per treatment modality and year of the disease are missing. Regarding the AAV pathogenesis, the complement system has been recently proposed to play an important role. Moreover, the application of advanced next generation sequencing techniques could offer a deeper understanding of the underlying mechanisms of disease. Here, we aim to describe in details the natural course of AAV, the incidence and the risk factors for SI in a contemporary cohort, the value of serum and kidney deposited C3 in predicting renal outcomes and to compare the shared mechanisms and differences between AAV and infection with the use of RNA sequencing.
Methods
Multicenter, observational, retrospective study of 162 AAV patients followed in three tertiary referral centers. Mortality, relapse and serious infection rates were estimated. A subgroup of 47 patients with AAV were categorized according to their serum C3 levels and to those with positive or negative kidney biopsy immunofluorescence (IF) for C3 and baseline characteristics as well as progression to end-stage renal disease (ESRD) between the 2 groups were compared. Finally, the transcriptomic profile of 30 AAV patients was compared with respective published data of patients with sepsis due to community-acquired pneumonia.
Results
We included 162 patients with GPA (63%) and MPA (37%), males 51.9%, mean age 60.9 years, ΑΝCA+ 86%, and generalized disease 80%. Mortality was 9.2% (15/162) and was numerically lower in GPA compared to MPA (5.9% vs 15%, p=0.053). Fifty-two percent of patients had at least one relapse. Compared to those without relapse, they were younger (57.7 ± 14.9 vs 64.4 ± 16, p=0.006), more likely to have eGFR >30 ml/min at diagnosis (84.5% vs 67.9%, p=0.013) and more likely to be cANCA/PR3+ (50.6% vs 37.2%, p=0.09), nevertheless this last finding was not statistically significant. Regarding treatments, patients treated with RTX for induction and/or maintenance had lower rates of relapses compared to those not receiving RTX (24.5% vs 63.7%, p<0.001).
During follow-up (891.2 patient-years, mean 5.4 years), 67 SI were recorded in 50 patients at an incidence rate of 7.5 per 100 patient-years. The SI incidence rate was higher during induction with cyclophosphamide (CYC) compared to rituximab (RTX, 19.3 vs. 11.3 per 100 patient-years, respectively) while it was lower and comparable between RTX and other regimens (5.52 vs. 4.54 per 100 patient-years, respectively) in the maintenance phase. By multivariate analysis, plasmapheresis (PLEX) and/or dialysis was a strong predictor for an SI during the 1st year after diagnosis (OR = 3.16, 95% CI 1.001–9.96) and throughout the follow-up period (OR = 5.21, 95% CI 1.93–14.07). In contrast, a higher baseline BVAS (OR = 1.11, 95% CI 1.01–1.21) was associated with SI only during the 1st year.
In the subgroup of 47 patients, 23% (11/47) were hypo-complementemic; these patients were older (74 vs. 65 years, p = 0.013), had higher creatinine levels (4.9 vs. 2.2 mg/dL, p = 0.006), were more often hemodialysis dependent (64% vs. 19%, p = 0.009) and progressed more often to ESRD (55% vs. 11%, p = 0.01) compared to normo-complementemic patients (n = 36). On multivariate analysis, serum creatinine at diagnosis (HR = 16.8, 95%CI: 1.354–208.62, p = 0.028) and low serum C3 (HR = 2.492; 95% CI: 1.537–11.567; p = 0.044) were independent predictors for ESRD. Among 25 patients with an available kidney biopsy, 56% had C3 deposition by IF and displayed more often a mixed histological pattern (72% vs. 27%, p = 0.033), low serum C3 levels (42% vs. 18%, p < 0.001) and serious infections during follow-up (57% vs. 18%, p = 0.047) compared to those with negative (n = 11) IF staining.
RNA sequencing results showed a small ovelap in the DEGs between groups (2.3%). After gene ontology analysis, common pathways between AAV and sepsis included the transmembrane and intracellular signaling, interferon and immune response.
Conclusions
In this real-life study of patients with AAV, mortality was approximately 10% and half of the patients experienced at least one relapse. The SI incidence was higher during CYC compared to RTX induction while there was no difference between RTX and other agents used for maintenance therapy. Higher disease activity at baseline and need for PLEX and/or dialysis were independent factors associated with an SI. Almost one of four patients with AAV has low C3 levels at diagnosis which is associated with more severe renal disease and worse renal outcomes (ESRD). This should be taken into account in therapeutic and monitoring strategies. Given the frequently common findings between AAV and infection, RNA sequencing revealed that transcriptomics could be a useful tool for the differential diagnosis between the two syndromes.
