Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients

Abstract

Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such ‘double-positive’ cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies.

Anti-Glomerular Basement Membrane Disease

“…The authors hypothesize that MPO-ANCA recognizing linear and conformational epitopes may arise sequentially, via a process of inter-and intramolecular epitope spreading (87). We recently analyzed the outcomes of a large cohort of these "doublepositive" patients from four centers in Europe, and found that they experience the early morbidity and mortality of anti-GBM disease, with severe kidney and lung disease at presentation, requiring aggressive immunosuppressive therapy and plasma exchange (88). During long-term follow-up, they relapsed at a frequency comparable to a parallel cohort of patients with AAV, suggesting they warrant more careful long-term follow-up and maintenance immunosuppression, unlike patients with single-positive anti-GBM disease.…”

Vasculitis

“…ELISA invariably shows the presence of anti-GBM antibodies in serum of these patients. One-third of the patients can have circulating ANCA, mainly MPO-ANCA, in addition to anti-GBM antibody [43]. ANCA can precede the development of anti-GBM antibody by months or years.…”

“…ANCA can precede the development of anti-GBM antibody by months or years. The patients can be doubly positive for anti-GBM and C-ANCA or P-ANCA [43]. Double-positive patients have characteristics similar to those of ANCA-associated vasculitis including older age and longer symptom duration before diagnosis and features of anti-GBM disease such as kidney and lung involvement at presentation [43].…”

“…43 A lobular panniculitis is noted at low magnification (×40) 44 Large zone of caseous necrosis is noted in addition to the granulomatous vasculitis (×200) (continued)…”

Was sind die Indikationen für Rescue-Verfahren?

“…In einer der bis dato größten Kohortenstudien zur Anti-GBM-Erkrankung war bei Patienten mit einer additiven Plasmapheresebehandlung kein relevanter Langzeitbenefit im Vergleich zur Standardimmunsuppression mit CYC und GC erkennbar, es bestand allerdings ein erheblicher Selection-Bias zum Einsatz der Plasmapherese [15]. Andere Kohortenstudien konnten zeigen, dass eine bereits bestehen- Bis zu 50 % Patienten mit Anti-GBM-Erkrankung sind auch MPO-oder PR3-ANCA-positiv [44]. Die Daten zur Prognose von ANCA-positiven Patienten mit Anti-GBM-Erkrankung sind uneinheitlich -es wurden sowohl eine höhere als auch niedrige Wahrscheinlichkeit eines Erhalts der Nierenfunktion bei positivem ANCA berichtet [3,15,44].…”