Dear editor,

Recently Henes et al reported that serum levels of the proinflammatory mediator high mobility group box-1 protein (HMGB1) were elevated and showed a significant correlation with the burden of granulomatous inflammation in patients with Granulomatosis with polyangiitis (GPA or Wegener) (1). The same group has previously published data suggesting that HMGB1 is a marker of GPA and that HMGB1 is not detected in patients with Microscopic polyangiitis (MPA) (2). We have recently studied AAV-patients with biopsy-proven renal involvement. We found elevated serum HMGB1 levels in active disease compared with remission in GPA, MPA and Churg-Strauss syndrome (CSS) and have also demonstrated HMGB1 in active renal lesions in tissue stainings irrespective of AAV subtype (3). This may reflect necrosis-induced inflammation in the kidneys although systemic inflammation is also likely to be important. Furthermore we have previously demonstrated elevated levels of serum HMGB1 in other inflammatory diseases such as RA in which granulomatosis is not a key finding (4). Our HMGB1 serum samples have been analyzed with a Western Blot method whereas Henes et al utilized a commercial ELISA. This methodological issue may be of importance as there seems to be a discrepancy between Western Blot and ELISA results. Urbonaviciute et al reported that serum/plasma components bind to HMGB1 and may interfere with its detection by ELISA systems and similar findings were reported in a more recent cohort of patients with systemic lupus erythematosus (5,6). After reanalyzing our AAV-data (3) looking specifically at lung involvement in addition to renal involvement we found that there was a significant correlation between HMGB1 levels in 11 patients with lung manifestations (Rho 0.37, p=0.02). However again we could not differentiate between HMGB1 and ANCA subtypes as there were 7 GPA patients, 3 MPA and 1 MPO-positive CSS patient. The current study utilizes a new CT volumetry method to measure granulomata in the lungs. As no follow-up remission data was presented it is however not completely evident that HMGB1 levels correlate with granuloma size in the individual patient. Henes et al raise the question whether circulating HMGB1 reflects the burden of granulomatous inflammation. Considering these and our results it would be interesting to study HMGB1 as a marker of disease activity in a wide range of disease manifestations and as a possible indicator of total AAV disease burden. Moreover we interestingly found that even though HMGB1 was significantly lower in remission compared to active AAV renal disease it still remained elevated compared to healthy controls. This may reflect a persistent low-grade inflammatory activity or tissue damage despite an appearance of clinical and histopathological remission. We would propose investigating larger cohorts with serum and tissue staining with and without a granulomatous phenotype in both active phase and in remission to further elucidate the role of HMBG1 in vasculitidies. This may clarify whether HMGB1 is a reliable predictor of disease activity and outcome in AAV and a possible target for pharmacological modulation.

References

1. Henes FO, Chen Y, Bley TA, et al. Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis 2011;70(11):1926-9.

2. Wibisono D, Csernok E, Lamprecht P, et al. Serum HMGB1 levels are increased in active Wegener's granulomatosis and differentiate between active forms of ANCA-associated vasculitis. Ann Rheum Dis 2010;69(10):1888-9.

3. Bruchfeld A, Wendt M, Bratt J, et al. High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. Mol Med 2011;17(1-2):29-35.

4. Goldstein RS, Bruchfeld A, Yang L, et al. Cholinergic Anti-Inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis. Mol Med 2007;13:210-5.

5. Urbonaviciute V, Furnrohr BG, Weber C, et al. Factors masking HMGB1 in human serum and plasma. J Leukoc Biol 2007;81:67-74.

6. Deena A Abdulahad, Johanna Westra, Johannes Bijzet, et al. High mobility group box 1 (HMGB1) and anti-HMGB1 antibodies and their relation to disease characteristics in systemic lupus erythematosus. ART 2011;13:R71.