Anti-proteinase 3 antineutrophil cytoplasmic antibody reflects disease activity and predicts the response to steroid therapy in ulcerative colitis

Abstract

Background Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin. Methods This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission. Results Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5–9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54–17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023). Conclusions PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC. Trial registration: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.

Case Report: Proteinase 3 Antineutrophil Cytoplasmic Antibody-Associated Ulcerative Colitis Presenting as Recurrent Intestinal Pseudo-Obstruction in a Teenage Patient With in situ Proteinase 3 Immunohistochemical Staining

“…The serum PR3-ANCA positivity and MPO-ANCA negativity in our patient are consistent with the findings for pediatric patients with UC in other studies ( 6 , 7 ). PR3-ANCA titers increased after the patient discontinued oral prednisolone and decreased after infliximab treatment, which appeared to correlate with the disease activity reported previously ( 3 , 5 ). Moreover, co-occurrence of other immune-mediated inflammatory diseases—most commonly with psoriasis or asthma and rarely with other gastrointestinal diseases—was associated with poorer outcomes ( 17 ).…”

“…Although the levels of PR3-ANCA in UC are lower than those in AAV ( 13 ), serum PR3-ANCA, which is more prevalent in UC than in CD, has emerged as a potential marker for accurately discriminating UC from CD ( 11 ), particularly when detection is performed using chemiluminescent immunoassays with an appropriate cut-off value ( 14 ). Furthermore, PR3-ANCA positivity can serve as a marker of disease activity and correlates with nonresponse to steroid therapy in moderate-to-severe UC and with primary nonresponse to antitumor necrotizing factor-α agents ( 3 , 15 ). In our patient with nonvasculitic UC, PR3-ANCA with the highest titer of 30-fold the cut-off value was present in serum (measured through fluorescence enzyme immunoassay [FEIA], Phadia® 250, Thermo Fisher Scientific Inc., Waltham, MA, USA), and PR3 antigen was detected in situ in the inflamed bowels (measured through immunohistochemical staining labeled with rabbit monoclonal anti-PR3 antibody [EPR6277] (ab133613, abcam®, Cambridge, UK) to human PR3 at 1/100 dilution in formalin-fixed paraffin-embedded sections according to the user instruction).…”

“…In Western countries, MPO-ANCA has been reported to be useful in differentiating UC from Crohn's disease (CD) due to its 65% positivity rate in patients with UC compared with a <10% positivity rate in patients with CD ( 4 ). However, in Japanese patients with UC, PR3-ANCA was found to be more commonly positive (39.2%−53.5%) than MPO-ANCA ( 3 , 5 ). The positivity rate of PR3-ANCA in pediatric patients with UC was higher (57.6%) than that in adult patients with UC ( 6 ).…”

“…However, the involvement of the upper gastrointestinal (UGI) tract in UC is rare and has nonspecific endoscopic and microscopic characteristics ( 2 ); for diagnosis of UC, clinical, laboratory, radiological, endoscopic, and histopathological criteria must be met. Antineutrophil cytoplasmic antibodies (ANCAs), including proteinase 3 (PR3)-ANCA (or cytoplasmic ANCA [c-ANCA]) and myeloperoxidase (MPO)-ANCA (or perinuclear ANCA [p-ANCA]) ( 3 ), have been investigated as potential serum biomarkers to aid in making diagnoses, correlating disease activity, and predicting therapeutic responses. In Western countries, MPO-ANCA has been reported to be useful in differentiating UC from Crohn's disease (CD) due to its 65% positivity rate in patients with UC compared with a <10% positivity rate in patients with CD ( 4 ).…”

PR3-ANCAs Detected by Third-Generation ELISA Predicts Severe Disease and Poor Survival in Primary Sclerosing Cholangitis

“…In the context of the serological diagnosis of rapidly progressive glomerulonephritis, PR3-ANCAs are included in the recommended specific autoantibody (autoAb) testing [ 17 , 18 ]. Later, PR3-ANCAs were reported as serological markers for ulcerative colitis (UC), an IBD closely related to PSC, and were suggested to be useful for the differential serological diagnosis of IBD [ 19 , 20 , 21 , 22 , 23 ]. However, in contrast to PSC and UC, PR3-ANCAs did not show an association with disease activity in GPA [ 24 , 25 ].…”