Serum calprotectin: a better biomarker in ANCA-associated vasculitis? Save

Flares in ANCA-associated vasculitis are difficult to predict, but serum calprotectin may help predict relapse and renal failure, according to data presented at the EULAR 2020 virtual meeting this week.

New analyses from the MAINRITSAN trial suggest that, in ANCA-associated vasculitis patients achieving complete remission with cyclophosphamide and maintained with either rituximab or azathioprine, increases in serum calprotectin from baseline to six months were able to predict patients who would go on to relapse in the following year, as well as those who incurred renal function decline. Notably, this association appeared to extend across disease characteristics, opening up the possibility of a genuine improvement to standard care in this disease.

ANCA-associated vasculitis has long been in need of better ways to predict impending relapses, and the damage that they entail, including decline in renal function. The maintenance phase of ANCA-associated vasculitis often presents a fraught balance between the rationalization of maintenance therapy and the omnipresent risk of flare with subsequent intensification of therapy. Since the establishment of ANCA-associated vasculitis as a disease entity, the potential for a biomarker of relapse has been vigorously explored, often with disappointing results. Most notably, the use of ANCA autoantibody titres in predicting disease flare remains attractive in theory but confounded in practice, with the close correlation between titres in flares in some patients belying the complete absence of predictive value in others.

Calprotectin, a sensitive marker of inflammation, is more familiar to most clinicians when fecally tested to screen for inflammatory bowel disease, but has come under increasing scrutiny as a serum marker of disease activity across a variety of different inflammatory disease processes. Its potential for heightened sensitivity to inflammation makes it particularly appealing for the prediction of emerging inflammatory disease, a concept previously explored in early rheumatoid arthritis. Notably, it is highly expressed in active ANCA-associated vasculitis, including at the site of glomerular lesions. The idea that detecting subclinical inflammation during remission might identify patients on the path to relapse is always an enticing one, but is particularly so given the clinical need in this disease.

Xavier Roland and colleagues from Universite Grenoble Alpes in France, examined this potential in patients from the MAINRITSAN trial, which compared rituximab and azathioprine maintenance in patients receiving cyclophosphamide induction therapy. They identified 96 patients who achieved complete remission following induction, and then looked at serum calprotectin levels from baseline as well as at six months, when remission was defined. While absolute levels of serum calprotectin at both of these time points did not predict relapse, increases in serum calprotectin between these two time points correlated with subsequent flare over the following twelve months. Notably, this change appeared independent of age and disease characteristics such as disease subtype, ANCA subtype, maintenance therapy, and extent of disease. This was further noted to predict renal function decline in both the whole study group, as well as in the PR3-ANCA positive group.

This builds on previous work, from Ruth Pepper and colleagues in the RAVE-ITN multicentre research group, showing similar increases in serum calprotectin in patients in the RAVE trial, which compared cyclophosphamide and azathioprine to rituximab in induction of remission, with this association noted specifically in PR3-ANCA positive patients. While it remains necessary to examine this relationship prospectively to determine its full potential, in serum calprotectin the hope for a practically useful biomarker in ANCA-associated vasculitis may be closer than ever before.

Roland X et al, ‘OP0031 An increase in serum calprotectin level in ANCA-associated vasculitides patients during maintenance therapy is associated with more relapse and accelerated renal function decline’. Doi: 10.1136/annrheumdis-2020-eular.4083 https://ard.bmj.com/content/79/Suppl_1/22.3

Pepper RJ et al, ‘The association of serum calprotectin (S100A8/S100A9) levels with disease relapses in PR3-ANCA-associated vasculitis’, Arthritis Rheumatol. 2017 Jan; 69(1): 185–193. doi: 10.1002/art.39814 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839649/