HMGB1 in ANCA-associated vasculitis: A longitudinal study

Introduction.- Extra-cellular high mobility group box 1 (HMGB1) acts as an alarmin and has been shown to be a biomarker of disease activity in systemic lupus erythematosus (SLE). This study aims to assess anti- HMGB1 antibodies and HMGB1 levels as biomarkers for disease activity and predictors of relapsing disease in ANCA-associated vasculitis (AAV). Methods.- AAV patients with active disease and healthy controls (HC) were evaluated for anti-HMGB1 antibodies by an in house ELISA while serum HMGB1 levels were measured longitudinally in AAV patients at presentation, during remission, prior to and at relapses by a commercial ELISA kit. Results.- HMGB1 levels were similar between AAV patients at presentation (n = 52) and HC (n = 35) (2.64 ± 1.80 ng/ml vs. 2.39 ± 1.09 ng/ml; P = 0.422). AAV patients with renal involvement had lowerHMGB1 levels than patients without renal involvement at presentation (2.35 ± 1.48 ng/ml vs. 3.52 ± 2.41 ng/ml; P = 0.042). A negative correlation was observed between HMGB1 levels and 24-hour proteinuria (P = -0.361, P = 0.028). Forty-nine AAV patients were evaluated for HMGB1 levels during follow-up and no differences were observed between relapsing and non-relapsing patients (P = 0.350). No significant increase in HMGB1 levels was observed prior to a relapse comparing to the remission period and changes in HMGB1 levels were not associated with an increased risk for relapse in AAV. Positivity for anti-HMGB1 antibodies was low in patients with active AAV (3 out of 24 patients). Conclusion.- Serum HMGB1 levels at presentation are lower in patients with renal involvement. Relapses are not preceded or accompanied by significant rises in HMGB1 levels and changes in HMGB1 levels are not related to ensuing relapses. Anti-HMGB1 antibodies are present in only a few patients in AAV. In contrast to SLE, HMGB1 does not seem to be a useful biomarker for disease activity and relapses in AAV

HMGB1 in ANCA-associated vasculitis: A longitudinal study

Background High mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunologic competent cells. Higher levels of HMGB1 have been found in ANCA-associated vasculitis (AAV), especially in patients with granulomatosis with polyangiitis (GPA) and active disease. HMGB1 has been associated with granulomatous manifestations of GPA and with biopsy-proven renal involvement in AAV. Objectives To measure HMGB1 levels longitudinally in a cohort of patients with AAV in order to evaluate the association with disease activity, remission, relapses, and specific organ involvement. Methods HMGB1 levels were tested by ELISA at diagnosis, at least twice during the remission period and during a disease flare. Disease activity was ascertained using the Birmingham Vasculitis Activity Score (BVAS). Results 50 patients with AAV and 35 age and sex matched healthy controls (HC) (58.5±14.1 years vs. 55.1±11.7 years at baseline; P=0.256), frequency of females (44.0% vs. 51.4%; P =0.499) were included. The frequency of each AAV subgroup was as follows: GPA (62%), microscopic polyangiitis (MPA) (20%), isolated necrotizing glomerulonephritis (iNGN) (16%) and Churg-Strauss syndrome (CSS) (2%). Localized disease was found in 16% and renal involvement in 74% at disease onset. Patients and HC had similar mean levels of HMGB1 at baseline (2.61±1.83 vs. 2.34±0.94 ng/mL; P=0.389). Patients with localized disease presented higher median levels of HMGB1 than those with generalized disease but this difference was not significant [3.14 (0.50-9.03) vs. 1.97 (0.46-7.54) ng/mL; P=0.233] whereas patients with renal involvement had lower levels of HMGB1 in comparison to those without renal involvement at baseline (2.29±1.48 vs. 3.52±2.41 ng/mL; P=0.035). Negative correlations were found between serum HMGB1 and 24 hours proteinuria levels (ρ = -0.352; P=0.038) and between HMGB1 and serum creatinine at baseline (ρ = -0.287; P=0.045). The mean follow-up period was 53.4 months and at least one relapse was observed in 34.0% of patients. Among relapsing patients, at least one relapse was found in 64.7% and 2 relapses in 35.3%. At baseline, relapsing patients presented significantly higher mean BVAS when compared to non-relapsing patients (20.2±8.8 vs. 15.3±5.8; P=0.038) while other baseline features were similar between relapsing and non-relapsing patients including age, gender, ANCA specificity, HMGB1 and C-reactive protein (CRP) levels. Median HMGB1 levels were as follows: 2.12 ng/mL at baseline, 1.44 ng/mL and 1.90 ng/mL in patients in remission 3 and 11 months after commencing therapy (P=0.029). Median HMGB1 levels were 2.26 ng/mL and 2.04 ng/mL in the first and in the second relapse, respectively. Conclusions Serum HMGB1 levels were similar between patients with AAV and controls at baseline and renal involvement may account for unexpectedly lower levels of HMGB1 in patients with AAV at baseline, possibly due to urinary loss in patients with proteinuria. No clear relation between HMGB1 levels and disease activity could be found. Nonetheless, a significant decrease in HMGB1 levels was observed in AAV patients from baseline to remission