Prognosis of ANCA‐associated vasculitis according to long‐term ANCA patterns.
Keywords: anti‐neutrophil cytoplasmic antibodies, prognosis, renal failure, vasculitis
Summary
Long‐term observation of patients with ANCA‐associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow‐up. This study aimed to characterize these patterns and to determine their prognostic significance.
All ANCA determinations performed in two university hospitals during a 2‐year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti‐myeloperoxidase (anti‐MPO) or anti‐proteinase 3 (anti‐PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients’ time–course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow‐up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5–9·1 and HR = 2·9, 95% CI = 1·1–8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti‐MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2–26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti‐MPO‐associated vasculitis.
Introduction
Anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis comprises a heterogeneous group of vasculitides characterized by inflammation and necrosis of small‐ and medium‐sized vessels, usually associated with autoantibodies directed against neutrophil lysosomal enzymes [1].
Consensus statements on testing methods, clinical indications and interpretation of ANCA tests have been published [2, 3]. However, the usefulness of monitoring ANCA levels in the clinical follow‐up of AAV is still a matter of debate [4]. Most studies have focused upon analysing the sensitivity, specificity and predictive value of an increase in ANCA levels to predict clinical relapses. The results of these studies vary widely, probably related to the heterogeneity of the vasculitides included, the criteria used to define an increase in ANCA titers and the criteria used to define a clinical relapse [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]. At present, most clinicians continue to routinely monitor ANCA levels, although several studies have claimed that there is no need to perform such serial measurements, as they have a low sensitivity and specificity to predict a clinical relapse [16, 17, 18, 19].
Long‐term observation of patients with AAV allows the identification of different patterns of ANCA titers during follow‐up. Some patients will display a monophasic pattern, with an initial peak of antibodies that later become negative, while others will present persistent low levels or recurrent peaks, or will remain with persistently high ANCA levels. The present study aimed to characterize these longitudinal patterns and to determine their clinical associations and possible prognostic impact.
Methods
After obtaining the approval of the clinical research ethics committees, we reviewed all ANCA determinations performed by the Immunology Service of Parc Taulí Hospital Universitari (PTHU) and by the Immunology Service at Hospital Universitari Vall d’Hebron (HUVH) from January 2014 to December 2015.
Patients were eligible for inclusion if they met the following three criteria: (1) had a biopsy compatible with the diagnosis of microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) or eosinophilic granulomatosis with polyangiitis (EGPA) [20], or met the American College of Rheumatology classification criteria for GPA [21] or EGPA [22] without an alternative clinical diagnosis; (2) had positive anti‐MPO or anti‐PR3 antibodies with titers ≥ 20 U/ml at least once; and (3) had at least five serial ANCA determinations from the date of diagnosis until December 2017. We excluded patients who did not complete 6 months of follow‐up, patients with vasculitis limited to the skin or associated with cocaine abuse and patients with insufficient clinical information.
Both immunology laboratories used a two‐stage strategy for ANCA testing. First, all ANCA requests were tested by indirect immunofluorescence (IIF) using the commercially available Granulocyte Mosaic 13 kit (Euroimmun, Lübeck, Germany), following the instructions of the manufacturer. This test is a qualitative and semiquantitative IIF assay for determination of ANCA of immunoglobulin (Ig)G, which uses a combination of three biochips per field (one arranged with ethanol‐fixed granulocytes, another with formalin‐fixed human granulocytes and a control arranged with HEp‐2 cells spiked with ethanol‐fixed granulocytes). A serum dilution of 1 : 10 was used and stained slides were read by an experienced clinical immunologist. Secondly, all ANCA‐positive samples by IIF were tested by immunoassays to detect ANCA specificity for PR3 or MPO. During the study period, two different commercially available methods were used: (a) ImmunoCAP® 250 Phadia AB (Thermo Fisher Scientific, Uppsala, Sweden), a capture enzyme‐linked immunosorbent assay (ELISA) technique was used at PTHU; and (b) Quanta Flash® MPO/PR3 (Inova Diagnostics, San Diego, CA, USA); a chemiluminescence assay was used at HUVH.
Full details of the presenting illness, clinical relapses and treatments carried out during follow‐up were collected from case records. We considered a clinical relapse any new or worsened clinical manifestation of AAV that required a change in therapy, independently of ANCA titers. For this purpose, we considered as clinical manifestations of AAV all those included in the Birmingham Vasculitis Activity Score (BVAS) [23].
Worsening renal function was defined as an increase in serum creatinine ≥ 1·5 times from baseline during follow‐up. End‐stage renal disease (ESRD) was defined as the need for sustained renal replacement therapy.
Four longitudinal patterns of ANCA levels were defined: (1) monophasic pattern, initial peak of anti‐PR3 or anti‐MPO antibodies with subsequent negative results; (2) remitting pattern, initial peak of anti‐PR3 or anti‐MPO antibodies followed by persistent low ANCA levels (< 20 U/ml); (3) recurrent ANCA pattern, at least two successive peaks of anti‐PR3 or anti‐MPO antibodies (≥ 20 U/ml) at follow‐up, with periods of negative results; and (4) persistent ANCA pattern, sustained positive anti‐PR3 or anti‐MPO antibodies (> 20 U/ml) throughout follow‐up.
Associations between ANCA patterns and clinical variables were analysed using univariate statistics (Student’s t‐ or Mann–Whitney U‐tests, as appropriate, for continuous variables and χ2 or Fisher’s exact test for dichotomous variables). The association between ANCA patterns and clinical relapses or worsening renal function were analysed using Kaplan–Meier curves and Cox proportional hazards model. P‐values < 0·05 were considered statistically significant. All statistical analyses were carried out using spss version 23.0 for Windows (SPSS, Inc., Chicago, IL, USA).
Results
A total of 121 patients met the inclusion criteria; 18 patients were excluded because of insufficient clinical information (n = 9), early death (n = 5), vasculitis limited to the skin (n = 4), non‐classifiable vasculitis (n = 2) or vasculitis associated with cocaine abuse (n = 2). Thus, 99 patients were finally included in the analyses.
Table 1 summarizes the clinical characteristics of the patients included in the study. Patients’ mean age at diagnosis was 56·5 years and median follow‐up was 9 years. Overall, 55 patients were diagnosed with MPA, 36 with GPA and eight with EGPA. Of 99 patients, 67 (68%) were positive for anti‐MPO antibodies and 32 (32%) for anti‐PR3 antibodies.
Table 1.
Clinical characteristics and outcome of anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis according to antigenic specificity
| Total (n = 99) | Anti‐MPO (n = 67) | Anti‐PR3 (n = 32) | P b | |
|---|---|---|---|---|
| Age, years, mean (s.d.) | 56·5 (16·8) | 61·3 (14·6) | 46·4 (17·0) | < 0·001 |
| Female sex, n (%) | 48 (48·5) | 34 (50·7) | 14 (43·8) | n.s. |
| Diagnosis | ||||
| MPA, n (%) | 55 (55·6) | 54 (80·6) | 1 (3·1) | < 0·001 |
| GPA, n (%) | 36 (36·4) | 5 (7·5) | 31 (96·9) | < 0·001 |
| EGPA, n (%) | 8 (8·1) | 8 (11·9) | 0 (0) | 0·05 |
| Immunofluorescence pattern | ||||
| Cytoplasmic staining | 33 (33·3) | 1 (1·5) | 32 (100) | < 0·001 |
| Perinuclear staining | 66 (66·7) | 66 (98·5) | 0 (0) | |
| Time–course ANCA pattern | ||||
| Monophasic, n (%) | 26 (26·3) | 23 (34·3) | 3 (9·4) | 0·008 |
| Remitting, n (%) | 13 (13·1) | 11 (16·4) | 2 (6·3) | n.s. |
| Persistent, n (%) | 21 (21·2) | 9 (13·4) | 12 (37·5) | 0·006 |
| Recurrent, n (%) | 39 (39·4) | 24 (35·8) | 15 (46·9) | n.s. |
| Clinical features | ||||
| Constitutional symptoms, n (%) | 72 (72·7) | 47 (70·1) | 25 (78·1) | n.s. |
| Fever, n (%) | 54 (54·5) | 36 (53·7) | 18 (56·3) | n.s. |
| Anemia, n (%) | 84 (84·8) | 56 (83·6) | 28 (87·5) | n.s. |
| Microhematuria, n (%) | 68 (68·7) | 52 (77·6) | 16 (50·0) | 0·006 |
| Renal failure, n (%) | 60 (60·6) | 49 (73·1) | 11 (34·4) | < 0·001 |
| Alveolar hemorrhage, n (%) | 28 (28·3) | 19 (28·4) | 9 (28·1) | n.s. |
| Pulmonary infiltrates, n (%) | 22 (22·2) | 11 (16·4) | 11 (34·4) | 0·04 |
| Pulmonary nodules, n (%) | 20 (20·2) | 2 (3·0) | 18 (56·3) | < 0·001 |
| Mononeuritis multiplex, n (%) | 16 (16·2) | 11 (16·4) | 5 (15·6) | n.s. |
| CNS involvement, n (%) | 5 (5·1) | 2 (3·0) | 3 (9·4) | n.s. |
| ENT involvement, n (%) | 33 (33·3) | 9 (13·4) | 24 (75·0) | < 0·001 |
| Purpura, n (%) | 14 (14·1) | 6 (9·0) | 8 (25·0) | 0·03 |
| Arthritis, n (%) | 49 (49·5) | 25 (37·3) | 24 (75·0) | < 0·001 |
| Ocular involvement, n (%) | 10 (10·1) | 4 (6·0) | 6 (18·8) | 0·05 |
| Treatment | ||||
| Corticosteroids, n (%) | 99 (100) | 67 (100) | 32 (100) | n.s. |
| Cyclophosphamide, n (%) | 78 (78·8) | 51 (76·1) | 27 (84·4) | n.s. |
| Azathioprine, n (%) | 39 (39·4) | 24 (35·8) | 15 (46·9) | n.s. |
| Methotrexate, n (%) | 12 (12·1) | 2 (3·0) | 10 (31·3) | < 0·001 |
| Mycophenolic acid, n (%) | 20 (20·2) | 17 (25·4) | 3 (9·4) | n.s. |
| Plasmapheresis, n (%) | 17 (17·2) | 15 (22·4) | 2 (6·3) | 0·05 |
| Rituximab, n (%) | 32 (32·3) | 19 (28·4) | 13 (40·6) | n.s. |
| Outcome | ||||
| Follow‐up, years, median (IQR) | 9·0 (9·22) | 7·6 (7·3) | 12·2 (9·8) | 0·001 |
| Clinical relapse, a n (%) | 59 (59·6) | 32 (47·8) | 27 (84·4) | 0·001 |
| Worsening renal function, n (%) | 26 (26·3) | 21 (31·3) | 5 (15·6) | n.s. |
| End‐stage renal disease, n (%) | 19 (19·2) | 17 (25·4) | 2 (6·3) | 0·02 |
| ESRD at baseline, n (%) | 8 (8·1) | 7 (10·4) | 1 (3·1) | n.s. |
| ESRD during follow‐up, n (%) | 11 (11·1) | 10 (14·9) | 1 (3·1) | n.s. |
| Mortality, n (%) | 29 (29·3) | 24 (35·8) | 5 (15·6) | 0·04 |
| Mortality related to vasculitis, n (%) | 5 (5·1) | 4 (6·0) | 1 (3·1) | n.s. |
≥ 1 clinical relapses during follow‐up;
χ2 (categorical variables) or Student’s t‐test (continuous variables). n.s. = not significant. ANCA = anti‐neutrophil cytoplasmic antibody; anti‐MPO = anti‐myeloperoxidase; anti‐PR3 = anti‐proteinase‐3; MPA = microscopic polyangiitis; GPA = granulomatosis with polyangiitis; EGPA = eosinophilic granulomatosis with polyangiitis; ESRD = end‐stage renal disease; IQR = interquartile range; ENT = ear, nose, throat; CNS = central nervous system; s.d. = standard deviation.
All but one of the patients with anti‐PR3 antibodies were diagnosed with GPA. Compared to patients with anti‐MPO antibodies, those with anti‐PR3 antibodies were younger and had a higher prevalence of purpura, arthritis, pulmonary infiltrates or nodules and ear–nose–throat (ENT) or ocular involvement. Patients with anti‐PR3 antibodies had a higher rate of clinical relapses but lower mortality than patients with anti‐MPO antibodies. Patients with anti‐MPO antibodies were characterized by a higher prevalence of microhematuria, renal failure and ESRD than patients with anti‐PR3 antibodies (Table 1).
Time–course analysis of ANCA levels identified 26 (26·3%) patients with monophasic pattern; 13 patients (13·1%) with remitting pattern; 39 patients (39·4%) with recurrent pattern; and 21 patients (21·2%) with persistent ANCA pattern. Clinical characteristics, diagnosis, ANCA specificity, treatment administered and outcome according to ANCA patterns are shown in Table 2.
Table 2.
Clinical characteristics and outcome of ANCA‐associated vasculitis according to ANCA pattern
| Monophasic (n = 26) | Remitting (n = 13) | Persistent (n = 21) | Recurrent (n = 39) | P b | |
|---|---|---|---|---|---|
| Age, years, mean (s.d.) | 59·0 (14·9) | 57·4 (18·9) | 50·7 (20·6) | 57·7 (15·0) | n.s. |
| Female sex, n (%) | 14 (53·8) | 8 (35·9) | 12 (57·1) | 14 (61·5) | n.s. |
| Diagnosis | |||||
| MPA, n (%) | 17 (65·4) | 10 (76·9) | 9 (42·9) | 19 (48·7) | 0·05 |
| GPA, n (%) | 5 (19·2) | 3 (23·1) | 12 (57·1) | 16 (41·0) | |
| EGPA, n (%) | 4 (15·4) | 0 | 0 | 4 (10·3) | |
| ANCA specificity | |||||
| Anti‐MPO, n (%) | 23 (88·5) | 11 (84·6) | 9 (42·9) | 24 (61·5) | 0·004 |
| Anti‐PR3, n (%) | 3 (11·5) | 2 (15·4) | 12 (57·1) | 15 (38·5) | |
| Clinical features | |||||
| Constitutional symptoms, n (%) | 22 (84·6) | 9 (69·2) | 17 (81·0) | 24 (61·5) | n.s. |
| Fever, n (%) | 15 (57·7) | 5 (38·5) | 11 (52·4) | 23 (59·0) | n.s. |
| Anemia, n (%) | 22 (84·6) | 12 (92·3) | 21 (100) | 29 (74·4) | 0·05 |
| Microhematuria, n (%) | 16 (61·5) | 11 (84·6) | 16 (76·2) | 25 (64·1) | n.s. |
| Renal failure, n (%) | 16 (61·5) | 9 (69·2) | 14 (66·7) | 21 (53·8) | n.s. |
| Alveolar hemorrhage, n (%) | 7 (26·9) | 2 (15·4) | 6 (28·6) | 13 (33·3) | n.s. |
| Pulmonary infiltrates, n (%) | 6 (23·1) | 0 | 5 (23·8) | 11 (28·2) | n.s. |
| Pulmonary nodules, n (%) | 2 (7·7) | 3 (23·1) | 5 (23·8) | 10 (25·6) | n.s. |
| Mononeuritis multiplex, n (%) | 5 (19·2) | 1 (7·7) | 4 (19·0) | 6 (15·4) | n.s. |
| CNS involvement, n (%) | 2 (7·7) | 0 | 1 (4·8) | 2 (5·1) | n.s. |
| ENT involvement, n (%) | 6 (23·1) | 2 (15·4) | 10 (47·6) | 15 (38·5) | n.s. |
| Purpura, n (%) | 2 (7·7) | 3 (23·1) | 5 (23·8) | 4 (10·3) | n.s. |
| Arthritis, n (%) | 13 (50·0) | 3 (23·1) | 14 (66·7) | 19 (48·7) | n.s. |
| Ocular involvement, n (%) | 0 | 1 (7·7) | 3 (14·3) | 6 (15·4) | n.s. |
| Treatment | |||||
| Cyclophosphamide, n (%) | 18 (69·2) | 12 (92·3) | 19 (90·5) | 29 (74·4) | n.s. |
| Azathioprine, n (%) | 10 (38·5) | 6 (46·2) | 9 (42·9) | 14 (35·9) | n.s. |
| Mycophenolic acid, n (%) | 3 (11·5) | 3 (23·1) | 7 (33·3) | 7 (17·9) | n.s. |
| Methotrexate, n (%) | 0 | 0 | 2 (9·5) | 10 (25·6) | 0·007 |
| Plasmapheresis, n (%) | 10 (38·5) | 1 (7·7) | 3 (14·3) | 3 (7·7) | 0·009 |
| Rituximab, n (%) | 10 (38·5) | 2 (15·4) | 6 (28·6) | 14 (35·9) | n.s. |
| Outcome | |||||
| Follow‐up, years, median (IQR) | 5·7 (3·3) | 7·1 (7·5) | 9·6 (7·5) | 8·6 (8·0) | 0·07 |
| Clinical relapse, a n (%) | 6 (23·1) | 4 (30·8) | 15 (71·4) | 34 (87·2) | < 0·001 |
| Worsening renal function, n (%) | 0 | 0 | 2 (9·5) | 3 (7·7) | 0·06 |
| End‐stage renal disease, n (%) | 7 (26·9) | 1 (7·7) | 3 (14·3) | 8 (20·5) | n.s. |
| ESRD at baseline, n (%) | 6 (23·1) | 0 | 0 | 2 (5·1) | 0·01 |
| ESRD during follow‐up, n (%) | 1 (3·8) | 1 (7·7) | 3 (14·3) | 6 (15·4) | n.s. |
| Mortality, n (%) | 6 (23·1) | 4 (30·8) | 5 (23·8) | 14 (35·9) | n.s. |
| Mortality related to vasculitis, n (%) | 2 (7·7) | 3 (23·1) | 8 (38·1) | 13 (33·3) | n.s. |
≥ 1 clinical relapses during follow‐up;
χ2 (categorical variables) or analysis of variance (anova) (continuous variables). ANCA = anti‐neutrophil cytoplasmic antibody; n.s. = not significant; anti‐MPO = anti‐myeloperoxidase; anti‐PR3 = anti‐proteinase‐3; MPA = microscopic polyangiitis; GPA = granulomatosis with polyangiitis; EGPA = eosinophilic granulomatosis with polyangiitis; ESRD = end‐stage renal disease; IQR = interquartile range; ENT = ear, nose, throat; CNS = central nervous system; s.d. = standard deviation.
Patients with a monophasic or remitting ANCA pattern were more commonly diagnosed with MPA and had a higher prevalence of anti‐MPO antibodies. These patients more often presented with ESRD at baseline and had received plasmapheresis more commonly than patients with a recurrent or persistent ANCA pattern (Table 2).
Association between longitudinal ANCA patterns and risk of clinical relapse
The proportion of patients who developed a clinical relapse was similar in patients with recurrent or persistent ANCA patterns (34 of 39; 87·2 versus 15 of 21; 71·4%; P = 0·13). These relapse rates were much higher than those observed in patients with monophasic or remitting ANCA patterns (six of 29; 23·1% and four of 13; 30·8%, respectively) (Table 2). Because of these similarities, in some analyses the four subsets were joined into two groups, the recurrent/persistent (R/P) pattern and the monophasic/remitting (M/R) pattern (Fig. 1).
Fig. 1.
Clinical relapse according to anti‐neutrophil cytoplasmic antibody (ANCA) pattern in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). (a) All ANCA vasculitis; (b) anti‐PR3 vasculitis; (c) anti‐myeloperoxidase (MPO) vasculitis.
In the univariate analysis, other variables associated with an increased risk of clinical relapse were the diagnosis of GPA, anti‐PR3 specificity, presence of arthritis, ENT or ocular involvement and having received treatment with azathioprine, methotrexate or rituximab. Clinical features such as renal failure were associated with a lower risk of clinical relapse (Table 3).
Table 3.
Variables associated with clinical relapses in GPA and MPA (n = 91)
| Univariate analysis | P | |
|---|---|---|
| Hazard ratio (95% CI) | ||
| Age | 0·99 (0·97–1·01) | 0·19 |
| Female sex | 0·94 (0·56–1·56) | 0·82 |
| Diagnosis | ||
| MPA | 1 | |
| GPA | 1·90 (1·12–3·22) | 0·02 |
| Antigenic specificity | ||
| Anti‐MPO | 1 | |
| Anti‐PR3 | 2·34 (1·38–3·97) | 0·002 |
| ANCA pattern | ||
| Monophasic | 1 | |
| Remitting | 0·91 (0·26–3·24) | 0·88 |
| Persistent | 3·36 (1·29–8·79) | 0·01 |
| Recurrent | 4·31 (1·78–10·42) | 0·001 |
| Clinical features | ||
| Constitutional symptoms | 0·65 (0·36–1·16) | 0·15 |
| Fever | 0·63 (0·37–1·09) | 0·1 |
| Anemia | 0·99 (0·40–2·50) | 0·99 |
| Microhematuria | 0·73 (0·42–1·29) | 0·28 |
| Renal failure | 0·58 (0·34–0·98) | 0·04 |
| Alveolar hemorrhage | 1·09 (0·62–1·91) | 0·78 |
| Pulmonary infiltrates | 1·66 (0·90–3·06) | 0·1 |
| Pulmonary nodules | 1·24 (0·67–2·27) | 0·49 |
| Mononeuritis multiplex | 1·40 (0·68–2·87) | 0·36 |
| CNS involvement | 2·83 (0·86–9·29) | 0·09 |
| ENT involvement | 2·36 (1·38–4·03) | 0·002 |
| Purpura | 1·22 (0·57–2·58) | 0·61 |
| Arthritis | 1·82 (1·07–3·12) | 0·03 |
| Ocular involvement | 2·34 (1,10–4·99) | 0·03 |
| Treatment | ||
| Cyclophosphamide | 0·68 (0·32–1·42) | 0·3 |
| Azathioprine | 1·74 (1·02–2·98) | 0·04 |
| Methotrexate | 2·72 (1·38–5·36) | 0·004 |
| Mycophenolic acid | 1·41 (0·77–2·60) | 0·27 |
| Plasmapheresis | 0·50 (0·20–1·27) | 0·15 |
| Rituximab | 2·10 (1·20–3·68) | 0·009 |
ANCA = anti‐neutrophil cytoplasmic antibody; MPA = microscopic polyangiitis; GPA = granulomatosis with polyangiitis; anti‐MPO = anti‐myeloperoxidase; anti‐PR3 = anti‐proteinase; CI = confidence interval.
In the multivariate Cox regression analysis, the recurrent or persistent ANCA patterns together with the presence of arthritis or ocular involvement, the absence of fever or having received rituximab treatment were independently associated with a higher risk of clinical relapse. Neither the clinical diagnosis nor the antigenic specificity were associated with an increased risk of clinical relapse (Table 4).
Table 4.
Variables associated with clinical relapses in GPA and MPA (n = 91), multivariate analysis
| Model 1* | Cox regression | P | Model 2* | Cox regression | P |
|---|---|---|---|---|---|
| Hazard ratio (95% CI) | Hazard ratio (95% CI) | ||||
| ANCA pattern | ANCA pattern | ||||
| Monophasic | Monophasic/remitting | ||||
| Remitting | 0·92 (0·25–3·42) | 0·90 | Persistent/recurrent | 3·55 (1·75–7·21) | < 0·001 |
| Persistent | 2·94 (1·08–7·99) | 0·03 | |||
| Recurrent | 3·67 (1·48–9·06) | 0·005 | |||
| Fever | 0·42 (0·23–0·78) | 0·006 | Fever | 0·42 (0·23–0·79) | 0·006 |
| Arthritis | 2·48 (1·36–4·52) | 0·003 | Arthritis | 2·40 (1·33–4·32) | 0·004 |
| Ocular involvement | 2·80 (1·22–6·44) | 0·015 | Ocular involvement | 2·80 (1·22–6·40) | 0·015 |
| Rituximab treatment | 2·47 (1·39–4·39) | 0·002 | Rituximab treatment | 2·54 (1·43–4·50) | 0·001 |
ANCA = anti‐neutrophil cytoplasmic antibody; MPA = microscopic polyangiitis; GPA = granulomatosis with polyangiitis; CI = confidence interval.
Model 1 was based on the four described ANCA patterns. Hazard ratios of clinical relapse in remitting, persistent or recurrent ANCA patterns were compared to the monophasic pattern. Model 2 was based on two aggregated ANCA patterns. Hazard ratio of clinical relapse in persistent/recurrent ANCA patterns were relative to the monophasic/remitting pattern.
Association between longitudinal ANCA patterns and renal prognosis
In our series, 21 of 26 patients with worsening renal function, 10 of 11 patients with ESRD during follow‐up and seven of eight patients with ESRD at baseline had anti‐MPO antibodies (Table 1).
Due to the scarcity of patients with anti‐PR3 AAV who developed renal failure in our series, we focused our analysis of renal outcomes on patients with anti‐MPO antibodies, regardless of whether they were diagnosed with GPA or MPA. In the univariate analysis, we found that patients with arthritis, fever or constitutional symptoms had a lower risk of worsening renal function than patients without these clinical manifestations (Table 5). In addition, patients with the combined R/P pattern had significantly worse renal prognosis than patients with the combined M/R pattern (Fig 2).
Table 5.
Variables associated with worsening renal failure in anti‐MPO vasculitis, univariate analysis (n = 52) a
| Univariate analysis | P | |
|---|---|---|
| Hazard ratio (95% CI) | ||
| Age | 1·00 (0·97–1·04) | 0·88 |
| Female sex | 0·95 (0·40–2·27) | 0·92 |
| Diagnosis | ||
| GPA | 1 | |
| MPA | 1·83 (0·42–7·96) | 0·42 |
| ANCA pattern | ||
| Monophasic | 1 | |
| Remitting | 1·93 (0·32–11·59) | 0·47 |
| Persistent | 3·45 (0·63–18·87) | 0·15 |
| Recurrent | 4·26 (0·95–19·07) | 0·06 |
| Clinical features | ||
| Constitutional symptoms | 0·33 (0·14–0·78) | 0·01 |
| Fever | 0·33 (0·13–0·86) | 0·02 |
| Anemia | 1·34 (0·18–10·05) | 0·78 |
| Microhematuria | 1·88 (0·44–8·07) | 0·4 |
| Alveolar hemorrhage | 1·18 (0·48–2·94) | 0·71 |
| Pulmonary infiltrates | 0·85 (0·20–3·72) | 0·83 |
| Pulmonary nodules | 1·52 (0·20–11·51) | 0·69 |
| Mononeuritis multiplex | 0·04 (0·00–8·13) | 0·23 |
| ENT involvement | 0·28 (0·04–2·12) | 0·22 |
| Purpura | 0·87 (0·11–6·67) | 0·89 |
| Arthritis | 0·25 (0·08–0·76) | 0·01 |
| Ocular involvement | 1·07 (0·25–4·62) | 0·93 |
| Treatment | ||
| Cyclophosphamide | 0·38 (0·10–1·47) | 0·16 |
| Azathioprine | 0·54 (0·21–1·41) | 0·21 |
| Methotrexate | 0·04 (0·00–141·05) | 0·45 |
| Mycophenolic acid | 0·83 (0·30–2·29) | 0·71 |
| Plasmapheresis | 1·76 (0·50–6·24) | 0·38 |
| Rituximab | 2·18 (0·86–5·52) | 0·1 |
Patients with end‐stage renal disease at baseline and patients diagnosed with eosinophilic granulomatosis with polyangiitis were excluded from this analysis.
MPA = microscopic polyangiitis; GPA = granulomatosis with polyangiitis; ENT = ear, nose, throat; ANCA = anti‐neutrophil cytoplasmic antibody; CI = confidence interval.
Fig. 2.
Worsening renal failure according to anti‐neutrophil cytoplasmic antibody (ANCA) pattern in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) anti‐myeloperoxidase (MPO) vasculitis.
In the multivariate Cox regression analysis, both the recurrent ANCA or the combined R/P ANCA patterns were associated with an increased risk of worsening renal failure. The presence of arthritis or constitutional symptoms were associated with better renal outcomes. Neither the clinical diagnosis nor the antigenic specificity were associated with an increased risk of worsening renal failure (Table 6).
Table 6.
Variables associated with worsening renal failure in anti‐MPO vasculitis (n = 52),a multivariate analysis
| Model 1* | Cox regression | P | Model 2* | Cox regression | P |
|---|---|---|---|---|---|
| Hazard ratio (95% CI) | Hazard ratio (95% CI) | ||||
| ANCA pattern | ANCA pattern | ||||
| Monophasic | Monophasic/remitting | ||||
| Remitting | 1·92 (0·32–11·62) | 0·48 | Persistent/recurrent | 3·10 (1·11–8·64) | 0·03 |
| Persistent | 3·39 (0·62–18·62) | 0·16 | |||
| Recurrent | 5·68 (1·24–26·05) | 0·03 | Constitutional symptoms | 0·40 (0·16–1·00) | 0·05 |
| Arthritis | 0·19 (0·06–0·62) | 0·006 | Arthritis | 0·24 (0·08–0·75) | 0·01 |
Model 1 was based on the four described ANCA patterns. Hazard ratios of worsening renal failure in remitting, persistent or recurrent ANCA patterns are relative to the monophasic pattern. Model 2 was based on two aggregated ANCA patterns. Hazard ratio of worsening renal failure in persistent/recurrent ANCA patterns is relative to the monophasic/remitting pattern.
ANCA = anti‐neutrophil cytoplasmic antibody; CI = confidence interval.
The data that support the findings of this study are available on request from the corresponding author (J. O.).
Discussion
In this study we have defined four time–course ANCA patterns and we observed an increased risk of clinical relapse in patients with a recurrent or persistent ANCA pattern, independently of the clinical diagnosis or the antigenic specificity.
The presence of anti‐PR3 antibodies has long been associated with an increased risk of clinical relapse [1, 15, 24]. However, in our cohort the recurrent or persistent ANCA patterns were associated with an increased risk of relapse, regardless of the ANCA antigenic specificity. These results are in keeping with other studies showing that patients with AAV and recurrent high anti‐MPO antibodies are also at increased risk of clinical relapse [25, 26], and by the observation by Kemna et al., showing that the association of an ANCA rise with a relapse was influenced by persistence of ANCA and not by ANCA antigenic specificity. Our results do not support the opinion of some authors claiming that there is no need in routinely monitoring ANCA titers in patients with ANCA‐associated vasculitis [19].
We have also found that patients with anti‐MPO vasculitis and a recurrent ANCA pattern were more prone to worsening renal function. It is generally accepted that patients with anti‐MPO antibodies have a worse renal prognosis and a higher risk of progression to ESRD than patients with anti‐PR3 antibodies [24, 27, 28, 29, 30, 31, 32, 33], although not all studies have confirmed this association [34, 35, 36]. Patients with anti‐MPO antibodies usually have more glomerulosclerosis and interstitial fibrosis on renal biopsies than patients with anti‐PR3 antibodies [30, 32, 34, 36]. Some authors have suggested that these chronic lesions could result from a more protracted course and a greater diagnostic delay in anti‐MPO AAV patients, meaning that on starting treatment they would have more irreversible chronic renal lesions than anti‐PR3 AAV patients [30, 32, 34]. Our results, showing a lower decline of renal function in anti‐PR3 patients despite being immunologically active, do not support this hypothesis. Conversely, it is likely that inflammatory lesions of patients with anti‐MPO antibodies would have a greater tendency to residual fibrosis, as suggested both in experimental studies [37] and in clinical observations showing an increased risk of lung fibrosis in patients with anti‐MPO antibodies [38, 39].
Other factors that have been associated with renal prognosis in AAV are advanced age [28], renal failure at disease onset [28, 31] and presence of tubular atrophy [28]. The importance of the longitudinal ANCA patterns on renal survival has been scarcely investigated. A small retrospective study by Franssen et al. [40] found similar results to ours, with persistently high anti‐MPO levels leading to chronic renal failure. Our series, with a larger number of patients with anti‐MPO AAV, provides original data in this regard, showing a worse renal prognosis in patients with recurrent or persistent high anti‐MPO‐antibody levels.
The present study provides new information on the prognosis of AAV according to ANCA patterns. This is a clinical study, and does not allow us to ascertain the physiopathological basis that would underlie the observed ANCA patterns. In addition, other limitations should also be mentioned. This is a retrospective observational study, so the clinical follow‐up and treatments administered were not uniform. However, we performed a multivariate analysis and none of the administered treatments had a significant impact on the associations that have been described. Secondly, the number of patients with anti‐PR3 AAV and a monophasic/remitting pattern was too small in our series in order to draw conclusions on renal prognosis according to ANCA patterns in patients with this antigenic specificity.
In conclusion, our study suggests that patients with a recurrent or persistent ANCA pattern have a higher risk of clinical relapse than patients with a monophasic or remitting pattern. In addition, patients with anti‐MPO antibodies and a recurrent ANCA pattern had worse renal prognosis. Our results would suggest that a more aggressive treatment may be needed in these patients in order to preserve their renal function.
Disclosures
The author declare they have no conflicts of interest.
Acknowledgements
The authors thank J. C. O., MStats Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Catalonia.
Data Availability
The data that support the findings of this study are available on request from the corresponding author (J.O).
References
- 1. Cornec D, Cornec‐Le Gall E, Fervenza F, Specks U. ANCA‐associated vasculitis – clinical utility of using ANCA specificity to classify patients. Nat Rev Rheumatol 2016; 12:570–9. [DOI] [PubMed] [Google Scholar]
- 2. Savige J, Gillis D, Benson E et al International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 1999; 111:507–13. [DOI] [PubMed] [Google Scholar]
- 3. Bossuyt X, Cohen Tervaert JW, Arimura Y et al Revised 2017 international consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nature Rev Rheumatol 2017; 13:683–92. [DOI] [PubMed] [Google Scholar]
- 4. Csernok E. The diagnostic and clinical utility of autoantibodies in systemic vasculitis. Antibodies 2019; 8:31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Birck R, Schmitt WH, Kaelsch IA, van der Woude FJ. Serial ANCA determinations for monitoring disease activity in patients with ANCA‐associated vasculitis: systematic review. Am J Kidney Dis 2005; 47:15–23. [DOI] [PubMed] [Google Scholar]
- 6. Boomsma MM, Stegeman CA, van der Leij MJ et al Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000; 43:2025–33. [DOI] [PubMed] [Google Scholar]
- 7. Fussner LA, Hummel AM, Schroeder DR et al Factors determining the clinical utility of serial measurements of antineutrophil cytoplasmic antibodies targeting proteinase 3. Arthritis Rheum 2016; 68:1700–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. De’Oliviera J, Gaskin G, Dash A, Rees AJ, Pusey CD. Relationship between disease activity and anti‐neutrophil cytoplasmic antibody concentration in long‐term management of systemic vasculitis. Am J Kidney Dis 1995; 25:380–9. [DOI] [PubMed] [Google Scholar]
- 9. Gaskin G, Savage COS, Ryan JJ et al Anti‐neutrophil cytoplasmic antibodies and disease activity during long‐term follow‐up of 70 patients with systemic vasculitis. Nephrol Dial Transplant 1991; 6:689–94. [DOI] [PubMed] [Google Scholar]
- 10. Girard T, Mahr A, Noël LH et al Are antineutrophil cytoplasmic antibodies a marker predictive of relapse in Wegener’s granulomatosis? A prospective study. Rheumatology 2001; 40:147–51. [DOI] [PubMed] [Google Scholar]
- 11. Han WK, Choi HK, Roth RM, McCluskey RT, Niles JL. Serial ANCA titers: useful tool for prevention of relapses in ANCA‐associated vasculitis. Kidney Int 2003; 63:1079–85. [DOI] [PubMed] [Google Scholar]
- 12. Jayne DR, Gaskin G, Pusey CD, Lockwood CM. ANCA and predicting relapse in systemic vasculitis. Q J Med 1995; 88:127–33. [PubMed] [Google Scholar]
- 13. Sanders JSF, Huitma MG, Kallenberg CGM, Stegeman CA. Prediction of relapses in PR3‐ANCA‐associated vasculitis by assessing responses of ANCA titres to treatment. Rheumatology 2006; 45:724–9. [DOI] [PubMed] [Google Scholar]
- 14. Kemna MJ, Damoiseaux J, Austen J et al ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol 2015; 26:537–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Kyndt X, Reumaux D, Bridoux F et al Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis. Am J Med 1999; 106:527–33. [DOI] [PubMed] [Google Scholar]
- 16. Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener’s granulomatosis. Arthritis Rheum 1993; 36:365–71. [DOI] [PubMed] [Google Scholar]
- 17. Davenport A, Lock RJ, Wallington T. Clinical significance of the serial measurement of autoantibodies to neutrophil cytoplasm using a standard indirect immunofluorescence test. Am J Nephrol 1995; 15:201–7. [DOI] [PubMed] [Google Scholar]
- 18. Finkielman JD, Lee AS, Hummel AM et al ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med 2007; 120:643.e9–643.e14. [DOI] [PubMed] [Google Scholar]
- 19. Verstockt B, Bossuyt X, Vanderschueren S, Blockmans D. There is no benefit in routinely monitoring ANCA titers in patients with granulomatosis with polyangiitis. Clin Exp Rheumatol 2015; 33:S72–S76. [PubMed] [Google Scholar]
- 20. Jennette JC, Falk RJ, Bacon PA et al 2012 Revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65:1–11. [DOI] [PubMed] [Google Scholar]
- 21. Leavitt RY, Fauci AS, Bloch DA et al The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33:1101–7. [DOI] [PubMed] [Google Scholar]
- 22. Masi AT, Hunder GG, Lie JT et al The American College of Rheumatology 1990 criteria for the classification of Churg–Strauss syndrome. Arthritis Rheum 1990; 33:1094–100. [DOI] [PubMed] [Google Scholar]
- 23. Mukhtyar C, Lee R, Brown D et al Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis 2009; 68:1827–32. [DOI] [PubMed] [Google Scholar]
- 24. Lionaki S, Blyth ER, Hogan SL et al Classification of antineutrophil cytoplasmic autoantibody vasculitides: the role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis. Arthritis Rheum 2012; 64:3452–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Terrier B, Saadoun D, Sène D et al Antimyeloperoxidase antibodies are a useful marker of disease activity in antineutrophil cytoplasmic antibody‐associated vasculitides. Ann Rheum Dis 2009; 68:1564–71. [DOI] [PubMed] [Google Scholar]
- 26. Tomasson G, Grayson PC, Mahr AD, LaValley M, Merkel PA. Value of ANCA measurements during remission to predict a relapse of ANCA‐associated vasculitis – meta‐analysis. Rheumatology 2012; 51:100–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Robson J, Doll H, Suppiah R et al Damage in the ANCA‐associated vasculitides: long‐term data from the European Vasculitis Study group (EUVAS) therapeutic trials. Ann Rheum Dis 2015; 74:177–84. [DOI] [PubMed] [Google Scholar]
- 28. Tanna A, Guarino L, Tam FWK et al Long‐term outcome of anti‐neutrophil cytoplasm antibody‐associated glomerulonephritis: evaluation of the international histological classification and other prognostic factors. Nephrol Dial Transplant 2015; 30:1185–92. [DOI] [PubMed] [Google Scholar]
- 29. Mohammad AJ, Segelmark M. A population‐based study showing better renal prognosis for proteinase 3 antineutrophil cytoplasmic antibody (ANCA)‐associated nephritis versus myeloperoxidase ANCA‐associated nephritis. J Rheumatol 2014; 41:1366–73. [DOI] [PubMed] [Google Scholar]
- 30. Vizjak A, Rott T, Koselj‐Kajtna M, Rozman B, Kaplan‐Pavlovcic S, Ferluga D. Histologic and immunohistologic study and clinical presentation of ANCA‐associated glomerulonephritis with correlation to ANCA antigen specificity. Am J Kidney Dis 2003; 41:539–49. [DOI] [PubMed] [Google Scholar]
- 31. de Joode AAE, Sanders JSF, Stegeman CA. Renal survival in proteinase 3 and myeloperoxidase ANCA‐associated systemic vasculitis. Clin J Am Soc Nephrol 2013; 8:1709–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Quintana LF, Perez NS, De Sousa E et al ANCA serotype and histopathological classification for the prediction of renal outcome in ANCA‐associated glomerulonephritis. Nephrol Dial Transplant 2014; 29:1764–9. [DOI] [PubMed] [Google Scholar]
- 33. Sada KE, Yamamura M, Harigai M et al Different responses to treatment across classified diseases and severities in Japanese patients with microscopic polyangiitis and granulomatosis with polyangiitis: a nationwide prospective inception cohort study. Arthritis Res Ther 2015; 17:305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Franssen CFM, Gans ROB, Arends AJ et al Differences between anti‐myeloperoxidase‐and anti‐proteinase 3 associated renal disease. Kidney Int 1995; 47:193–9. [DOI] [PubMed] [Google Scholar]
- 35. Westman KW, Bygren PG, Olsson H, Ranstam J, Wieslander J. Relapse rate, renal survival, and cancer morbidity in patients with Wegener’s granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol 1998; 9:842–52. [DOI] [PubMed] [Google Scholar]
- 36. Marco H, Draibe J, Villacorta J et al Determinants of renal and patient outcomes in a Spanish cohort of patients with ANCA‐associated vasculitis and renal involvement. Clin Rheumatol 2018; 37:1065–74. [DOI] [PubMed] [Google Scholar]
- 37. Guilpain P, Chereau C, Goulvestre C et al The oxidation induced by antimyeloperoxidase antibodies triggers fibrosis in microscopic polyangiitis. Eur Respir J 2011; 37:1503–13. [DOI] [PubMed] [Google Scholar]
- 38. Tzelepis GE, Kokosi M, Tzioufas A et al Prevalence and outcome of pulmonary fibrosis in microscopic polyangiitis. Eur Respir J 2010; 36:116–21. [DOI] [PubMed] [Google Scholar]
- 39. Comarmond C, Crestani B, Tazi A et al Pulmonary fibrosis in antineutrophil cytoplasmic antibodies (ANCA)‐ associated vasculitis: a series of 49 patients and review of the literature. Medicine 2014; 93:340–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Franssen CFM, Stegeman CA, Oost‐Kort WW et al Determinants of renal outcome in anti‐myeloperoxidase‐associated necrotizing crescentic glomerulonephritis. J Am Soc Nephrol 1998; 9:1915–23. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author (J.O).