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\begin{document}

\title{Relapse rate and renal prognosis in ANCA-associated vasculitis according
to long-term ANCA patterns.}



\author[1]{Joaquim Oristrell}%
\author[2]{José Loureiro-Amigo}%
\author[2]{Roser Solans}%
\author[1]{Mª Pau Valenzuela}%
\author[1]{Víctor Monsálvez}%
\author[3]{Alfons Segarra-Medrano}%
\author[1]{Mª José Amengual}%
\author[3]{Ana Marín}%
\author[1]{Carlos Feijoo}%
\author[1]{Carles Tolosa}%
\affil[1]{Consorci Corporació Sanitària Parc Taulí}%
\affil[2]{Hospital Vall d'Hebron}%
\affil[3]{Vall d’Hebron Hospital Universitari}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Introduction: 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
characterise these patterns and to determine their prognostic
significance. Methods: all ANCA determinations performed in two
university hospitals along 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, they had [?]5 serial ANCA determinations, and
they had AAV diagnosed by biopsy or 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. Results: A total of 99
patients (55 with microscopic polyangiitis {[}MPA{]}, 36 with
granulomatosis with polyangiitis {[}GPA{]}, and 8 with eosino\selectlanguage{ngerman}¬philic
granulomatosis with polyangiitis) 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 (HR
3.7 {[}95\% 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 (OR 5.7 {[}95\% CI
1.2-26.0{]}). Conclusion: 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.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Relapse rate and renal prognosis in ANCA-associated vasculitis
according to long-term ANCA patterns.}

\textbf{Short title:} long-term ANCA patterns and prognosis of systemic
vasculitis

\textbf{Joaquim Oristrell*.} Internal Medicine Service. Parc Tauli
Hospital Universitari. Institut d'Investigaci\selectlanguage{ngerman}ó i Innovació Parc Taulí
I3PT. Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{José Loureiro-Amigo.} Internal Medicine Service. Hospital
Universitari Vall d'Hebrón. Universitat Autònoma de Barcelona.
Barcelona, Catalonia.

\textbf{Roser Solans.} Internal Medicine Service. Hospital Universitari
Vall d'Hebrón. Universitat Autònoma de Barcelona. Barcelona, Catalonia.

\textbf{Mª. Pau Valenzuela.} Nephrology Service. Parc Tauli Hospital
Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT.
Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{Víctor Monsálvez.} Internal Medicine Service. Parc Tauli
Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí
I3PT. Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{Alfons Segarra.} Nephrology Service. Hospital Universitari Vall
d'Hebrón. Universitat Autònoma de Barcelona. Barcelona, Catalonia.

\textbf{Mª. José Amengual.} Immunology Service. Parc Tauli Hospital
Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT.
Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{Ana Marín.} Immunology Service. Hospital Universitari Vall
d'Hebrón. Universitat Autònoma de Barcelona. Barcelona, Catalonia.

\textbf{Carlos Feijoo.} Internal Medicine Service. Parc Tauli Hospital
Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT.
Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{Carles Tolosa.} Internal Medicine Service. Parc Tauli Hospital
Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT.
Universitat Autònoma de Barcelona. Sabadell, Catalonia.

\textbf{*Corresponding author:} Joaquim Oristrell, MD, PhD. Servei de
Medicina Interna. Parc Tauli Hospital Universitari. Institut
d'Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de
Barcelona. Sabadell, Catalonia. mail:\emph{joristrell@tauli.cat}

\textbf{Key words:} antineutrophil cytoplasmic antibodies, vasculitis,
renal failure, prognosis

\textbf{Summary:}

\textbf{Introduction:} 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 characterise these patterns and to determine their prognostic
significance.

\textbf{Methods:} all ANCA determinations performed in two university
hospitals along 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, they had \selectlanguage{english}[?]5 serial ANCA determinations, and
they had AAV diagnosed by biopsy or 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.

\textbf{Results:} A total of 99 patients (55 with microscopic
polyangiitis {[}MPA{]}, 36 with granulomatosis with polyangiitis
{[}GPA{]}, and 8 with eosinophilic granulomatosis with polyangiitis)
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 (HR 3.7 {[}95\% 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 (OR
5.7 {[}95\% CI 1.2-26.0{]}).

\textbf{Conclusion:} 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.

\textbf{Introduction}

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
comprises a heterogeneous group of vasculitides characterised 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). However, the
usefulness of monitoring ANCA levels in the clinical follow-up of AAV is
still a matter of debate. Most studies have focused on 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 titres, and
the criteria used to define a clinical relapse (3). 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 since they have a low sensitivity and specificity to
predict a clinical relapse (4-7).

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 characterise these longitudinal patterns and
to determine their clinical assocations and possible prognostic impact.

\textbf{Methods}

After obtaining the approval of the clinical research ethics committees,
we reviewed all ANCA determinations performed by the Immunology Service
of Parc Tauli Hospital Universitari (PTHU) and by the Immunology Service
at Hospital Universitari Vall d'Hebron (HUVH) from January 2014 through
December 2015.

Patients were eligible for inclusion if they met the following three
criteria: 1) had a biopsy compatible with the diagnosis of MPA, GPA, or
EGPA, or met the American College of Rheumatology classification
criteria for GPA (8) or EGPA (9) without an alternative clinical
diagnosis; 2) had positive anti-MPO or anti-PR3 antibodies with titers
\selectlanguage{english}[?]20 U/ml at least once; and 3) had at least 5 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.

ANCA titers were determined in serum by indirect immunofluorescence both
on ethanol and on formalin-fixed human neutrophils smeared onto glass
slides (Granulocyte Mosaic 13 EUROIMMUN, Lubeck, Germany). All
ANCA-positive samples were analysed for anti-MPO and anti-PR3 antibodies
by capture ELISA techniques (ImmunoCAP(r) 250 Phadia AB, Thermo Fisher
Scientific, Uppsala, Sweden) or chemiluminescence (QUANTA Flash MPO /
PR3, INOVA diagnostics, San Diego, California, USA).

Full details of the presenting illness, clinical relapses, and
treatments carried out during follow-up were collected from case
records. Clinical relapse was defined as a new or worsened manifestation
of AAV that required a change in therapy.

Worsening renal function was defined as an increase in serum creatinine
\selectlanguage{english}[?]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
(\textless{}20 U/ml); 3) Recurrent ANCA pattern: at least two successive
peaks of anti-PR3 or anti-MPO antibodies (\selectlanguage{english}[?]20 U/ml) on follow-up, with
periods of negative results; and 4) Persistent ANCA pattern: sustained
positive anti-PR3 or anti-MPO antibodies (\textgreater{} 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 Chi-square 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
\textless{} 0.05 were considered statistically significant. All
statistical analyses were carried out using SPSS version 23.0 for
Windows (SPSS, Chicago, IL, USA).

\textbf{Results}

A total of 121 patients met the inclusion criteria; Eighteen 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 summarises 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 8 with EGPA. Out of 99 patients, 67 (68\%) were positive
for anti-MPO antibodies and 32 (32\%) for anti-PR3 antibodies.

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 eye-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 characterised 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.

Patients with a monophasic o 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).

\textbf{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 (34/39; 87.2\%
vs. 15/21; 71.4\%; p=0.13). These relapse rates were much higher than
those observed in patients with monophasic or remitting ANCA patterns
(6/29; 23.1\% and 4/13; 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).

In the univariate analysis, other variables associated with an increased
risk of clinical relapse were the diagnosis of GPA, the anti-PR3
specificity, the 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).

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).

\textbf{Association between longitudinal ANCA patterns and renal
prognosis}

In our series, 21 out of 26 patients with worsening renal function, 10
out of 11 patients with ESRD during follow-up, and 7 out of 8 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 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).

In the multivariate Cox regression analysis, both the recurrent ANCA
pattern, or the combined R/P ANCA pattern 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).

\textbf{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 (1,10,11). 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 (12,13), and by the observation of 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
(14). Our results do not support the opinion of some authors claiming
that there is no need in routinely monitoring ANCA titres in patients
with ANCA-associated vasculitis (7).

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 (11,15-21), although not all studies
have confirmed this association (22-24). Patients with anti-MPO
antibodies usually have more glomerulosclerosis and interstitial
fibrosis on renal biopsies than patients with anti-PR3 antibodies
(18,20,22,24). 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 (18,20,22). 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
(25), and in clinical observations showing an increased risk of lung
fibrosis in patients with anti-MPO antibodies (26,27).

Other factors that have been associated with renal prognosis in AAV are
advanced age (16), renal failure at disease onset (16,19), and presence
of tubular atrophy (16). The importance of the longitudinal ANCA
patterns on renal survival has been scarcely investigated. A small
retrospective study by Franssen et al (28) 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, but several limitations should be mentioned.
This is a retrospective observational study, so the clinical follow-up
and treatments administered were not uniform. However, we performed a
multivariate analyses and none of the administered treatments had a
significant impact on the associations that have been described.

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.

\textbf{Aknowledgements:}

Joan Carles Oliva, MStats Institut d'Investigacio i Innovacio Parc Tauli
I3PT. Universitat Autonoma de Barcelona. Sabadell, Catalonia.

\textbf{Conflict of interest:}

The author declare they have not any conflict of interest.

\textbf{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;12:570-579.

2.-Bossuyt X, Cohen Tervaert JW, Arimura Y, Blockmans D, Flores-Suarez
LF, Guillevin L et al. Revised 2017 international consensus on testing
of ANCAs in granulomatosis with polyangiitis and microscopic
polyangiitis. Nature Rev Rheumatol 2017;13:683-692.

3.-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.

4.-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;36:365-371.

5.-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--207.

6.-Finkielman JD, Lee AS, Hummel AM, Viss MA, Jacob GL, Homburger HA, et
al. ANCA are detectable in nearly all patients with active severe
Wegener's granulomatosis. Am J Med 2007;120:643.e9--643.e14.

7.-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.

8.-Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et
al. The American College of Rheumatology 1990 criteria for the
classification of Wegener's granulomatosis. Arthritis Rheum
1990;33:1101-1107.

9.-Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The
American college of rheumatology 1990 criteria for the classification of
Churg-Strauss syndrome. Arthritis Rheum 1990;33:1094-1100.

10.-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--533.

11.-Lionaki S, Blyth ER, Hogan SL, Hu Y, Senior BA, Jennette CE 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;64:3452-3462.

12.-Terrier B, Saadoun D, Sene D, Ghillani P, Amoura Z, Deray G et al.
Antimyeloperoxidase antibodies are a useful marker of disease activity
in antineutrophil cytoplasmic antibody-associated vasculitides. Ann
Rheum Dis 2009;68:1564--1571.

13.-Tomasson G, Grayson PC, Mahr AD, LaValley M, Merkel PA. Value of
ANCA measurements during remission to predict a relapse of
ANCA-associated vasculitis---a meta-analysis. Rheumatology 2012; 51:
100-109.

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--542.

15.-Robson J, Doll H, Suppiah R, Flossmann O, Harper L, Hoglund P 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--184.

16.-Tanna A, Guarino L, Tam FWK, Rodriquez-Cubillo B, Levy JB, Cairns TD
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--1192.

17.-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--1373

18.-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;41:539-549.

19.-de Joode AAE, Sanders J SF, Stegeman CA. Renal survival in
proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis.
Clin J Am Soc Nephrol 2013; 8:1709-1717.

20.-Quintana LF, Perez NS, De Sousa E, Rodas LM, Griffiths MH, Sole M et
al. ANCA serotype and histopathological classification for the
prediction of renal outcome in ANCAassociated glomerulonephritis.
Nephrol Dial Transplant 2014; 29:1764-1769.

21.-Sada KE, Yamamura M, Harigai M, Fujii T, Takasaki Y, Amano K, 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.

22.-Franssen CFM, Gans ROB, Arends AJ, Hageluken C, ter Wee PM, Gerlag
PGG et al. Differences between anti-myeloperoxidase-and anti-proteinase
3 associated renal disease. Kidney Int 1995; 47:193--199.

23.-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;9:842-852.

24.-Marco H, Draibe, Villacorta J, Quintana LF, Martin N, Garcia-Osuna N
et al. Determinants of renal and patient outcomes in a Spanish cohort of
patients with ANCA-associated vasculitis and renal involvement. Clinical
Rheumatology. doi.org/10.1007/s10067-017-3973-3982.

25.-Guilpain P, Chereau C, Goulvestre C, Servettaz A, Montani D, Tamas N
et al. The oxidation induced by antimyeloperoxidase antibodies triggers
fibrosis in microscopic polyangiitis. Eur Respir J 2011; 37: 1503--1513

26.Tzelepis GE, Kokosi M, Tzioufas A, Toya SP, Boki KA, Zormpala A et
al. Prevalence and outcome of pulmonary fibrosis in microscopic
polyangiitis. Eur Respiratory J 2010 36: 116-121.

27.-Comarmond C, Crestani B, Tazi A, Hervier B, Adam-Marchand S, Nunes H
et al. Pulmonary fibrosis in antineutrophil cytoplasmic antibodies
(ANCA)- associated vasculitis: a series of 49 patients and review of the
literature. Medicine (Baltimore) 2014;93:340--349.

28.-Franssen CFM, Stegeman CA, Oost-Kort WW, Kallenberg CGM, Limburg PC,
Tiebosch A et al. Determinants of renal outcome in
anti-myeloperoxidase-associated necrotizing crescentic
glomerulonephritis. J Am Soc Nephrol 1998;9:1915-1923.

Table 1. Clinical characteristics and outcome of ANCA-associated
vasculitis according to antigenic specificity.

Table 2. Clinical characteristics and outcome of ANCA-associated
vasculitis according to ANCA pattern

Table 3. Variables associated with clinical relapses in GPA amd MPA

Table 4. Variables associated with clinical relapses in GPA and MPA.
Multivariate analysis.

Table 5. Variables associated with worsening renal failure in anti-MPO
vasculitis. Univariate analysis.

Table 6. Variables associated with worsening renal failure in anti-MPO
vasculitis. Multivariate analysis

Fig 1. Clinical relapse according to ANCA pattern in GPA and MPA. A: all
ANCA vasculitis; B: anti-PR3 vasculitis; C: anti-MPO vasculitis.

Fig 2. Worsening renal failure according to ANCA pattern in GPA or MPA
anti-MPO vasculitis.



\textbf{Table 1. Clinical characteristics and outcome of ANCA-associated
vasculitis according to antigenic specificity}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Total} (n=99)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Anti-MPO} (n=67)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Anti-PR3} (n=32)\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{p} \textsuperscript{b}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Age,} yrs, mean (SD) \textbf{Female sex,} n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
56.5 (16.8) 48 (48.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
61.3 (14.6) 34 (50.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
46.4 (17.0) 14 (43.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001 NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Diagnosis} MPA, n (\%) GPA, n (\%) EGPA, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
55 (55.6) 36 (36.4) 8 (8.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
54 (80.6) 5 (7.5) 8 (11.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (3.1) 31 (96.9) 0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textless{}0.001 \textless{}0.001 0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Time-course ANCA pattern} Monophasic, n (\%) Remitting, n (\%)
Persistent, n (\%) Recurrent, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
26 (26,3) 13 (13,1) 21 (21,2) 39 (39,4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23 (34.3) 11 (16.4) 9 (13.4) 24 (35.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 (9.4) 2 (6.3) 12 (37.5) 15 (46.9)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.008 NS 0.006 NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Clinical features} Constitutional symptoms, n (\%) Fever, n (\%)
Anemia, n (\%) Microhaematuria, n (\%) Renal failure, n (\%) Alveolar
haemorrhage, n (\%) Pulmonary infiltrates, n (\%) Pulmonary nodules, n
(\%) Mononeuritis multiplex, n (\%) CNS involvement, n (\%) ENT
involvement, n (\%) Purpura, n (\%) Arthritis, n (\%) Ocular
involvement, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
72 (72.7) 54 (54.5) 84 (84.8) 68 (68.7) 60 (60.6) 28 (28.3) 22 (22.2) 20
(20.2) 16 (16.2) 5 (5.1) 33 (33.3) 14 (14.1) 49 (49.5) 10 (10.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47 (70.1) 36 (53.7) 56 (83.6) 52 (77.6) 49 (73.1) 19 (28.4) 11 (16.4) 2
(3.0) 11 (16.4) 2 (3.0) 9 (13.4) 6 (9.0) 25 (37.3) 4 (6.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
25 (78.1) 18 (56.3) 28 (87.5) 16 (50.0) 11 (34.4) 9 (28.1) 11 (34.4) 18
(56.3) 5 (15.6) 3 (9.4) 24 (75.0) 8 (25.0) 24 (75.0) 6 (18.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NS NS NS 0.006 \textless{}0.001 NS 0.04 \textless{}0.001 NS NS
\textless{}0.001 0.03 \textless{}0.001 0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Treatment} Corticosteroids, n (\%) Cyclophosphamide, n (\%)
Azathioprine, n (\%) Methotrexate, n (\%) Mycophenolic acid, n (\%)
Plasmapheresis , n (\%) Rituximab, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
99 (100) 78 (78.8) 39 (39.4) 12 (12.1) 20 (20.2) 17 (17.2) 32
(32.3)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
67 (100) 51 (76.1) 24 (35.8) 2 (3.0) 17 (25.4) 15 (22.4) 19 (28.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
32 (100) 27 (84.4) 15 (46.9) 10 (31.3) 3 (9.4) 2 (6.3) 13 (40.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
NS NS NS \textless{}0.001 NS 0.05 NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Outcome} Follow-up, yrs, median (IQR) Clinical
relapse\textsuperscript{a}, n (\%) Worsening renal function, n (\%)
End-stage renal disease, n (\%) -ESRD at baseline, n (\%) -ESRD during
follow-up, n (\%) Mortality, n (\%) Mortality related to vasculitis, n
(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9.0 (9.22) 59 (59.6) 26 (26.3) 19 (19.2) 8 (8.1) 11 (11.1) 29 (29.3) 5
(5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
7.6 (7.3) 32 (47.8) 21 (31.3) 17 (25.4) 7 (10.4) 10 (14.9) 24 (35.8) 4
(6.0)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
12.2 (9.8) 27 (84.4) 5 (15.6) 2 (6.3) 1 (3.1) 1 (3.1) 5 (15.6) 1
(3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.001 0.001 NS 0.02 NS NS 0.04 NS\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} [?]1 clinical relapses during
follow-up.\textsuperscript{b}Chi square (categoric variables) or
Student's t (continuous variables). NS: 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.

\textbf{Table 2. Clinical characteristics and outcome of ANCA-associated
vasculitis according to ANCA pattern}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Monophasic (n=26)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Remitting (n=13)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Persistent (n=21)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
Recurrent (n=39)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
p \textsuperscript{b}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Age,} yrs, mean (SD) \textbf{Female sex,} n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
59.0 (14.9) 14 (53.8)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
57.4 (18.9) 8 (35.9)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50.7 (20.6) 12 (57.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
57.7 (15.0) 14 (61.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NS NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{Diagnosis} MPA, n (\%) GPA, n (\%) EGPA, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
17 (65.4) 5 (19.2) 4 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
10 (76.9) 3 (23.1) 0\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
9 (42.9) 12 (57.1) 0\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
19 (48.7) 16 (41.0) 4 (10.3)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.05\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
\textbf{ANCA specificity} Anti-MPO, n (\%) Anti-PR3, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
23 (88.5) 3 (11.5)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
11 (84.6) 2 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
9 (42.9) 12 (57.1)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
24 (61.5) 15 (38.5)\strut
\end{minipage} & \begin{minipage}[t]{0.16\columnwidth}\raggedright\strut
0.004\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Clinical features} Constitutional symptoms, n (\%) Fever, n (\%)
Anemia, n (\%) Microhaematuria, n (\%) Renal failure, n (\%) Alveolar
haemorrhage, n (\%) Pulmonary infiltrates, n (\%) Pulmonary nodules, n
(\%) Mononeuritis multiplex, n (\%) CNS involvement, n (\%) ENT
involvement, n (\%) Purpura, n (\%) Arthritis, n (\%) Ocular
involvement, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
22 (84.6) 15 (57.7) 22 (84.6) 16 (61.5) 16 (61.5) 7 (26.9) 6 (23.1) 2
(7.7) 5 (19.2) 2 (7.7) 6 (23.1) 2 (7.7) 13 (50.0) 0\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9 (69.2) 5 (38.5) 12 (92.3) 11 (84.6) 9 (69.2) 2 (15.4) 0 3 (23.1) 1
(7.7) 0 2 (15.4) 3 (23.1) 3 (23.1) 1 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
17 (81.0) 11 (52.4) 21 (100) 16 (76.2) 14 (66.7) 6 (28.6) 5 (23.8) 5
(23.8) 4 (19.0) 1 (4.8) 10 (47.6) 5 (23.8) 14 (66.7) 3 (14.3)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
24 (61.5) 23 (59.0) 29 (74.4) 25 (64.1) 21 (53.8) 13 (33.3) 11 (28.2) 10
(25.6) 6 (15.4) 2 (5.1) 15 (38.5) 4 (10.3) 19 (48.7) 6 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NS NS 0.05 NS NS NS NS NS NS NS NS NS NS NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Treatment} Cyclophosphamide, n (\%) Azathioprine, n (\%)
Mycophenolic acid, n (\%) Methotrexate, n (\%) Plasmapheresis, n (\%)
Rituximab, n (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
18 (69.2) 10 (38.5) 3 (11.5) 0 10 (38.5) 10 (38.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
12 (92.3) 6 (46.2) 3 (23.1) 0 1 (7.7) 2 (15.4)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
19 (90.5) 9 (42.9) 7 (33.3) 2 (9.5) 3 (14.3) 6 (28.6)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
29 (74.4) 14 (35.9) 7 (17.9) 10 (25.6) 3 (7.7) 14 (35.9)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
NS NS NS 0.007 0.009 NS\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Outcome} Follow-up, yrs, median (IQR) Clinical
relapse\textsuperscript{a}, n (\%) Worsening renal function, n (\%)
End-stage renal disease, n (\%) -ESRD at baseline, n (\%) -ESRD during
follow-up, n (\%) Mortality, n (\%) Mortality related to vasculitis, n
(\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5.7 (3.3) 6 (23.1) 0 7 (26.9) 6 (23.1) 1 (3.8) 6 (23.1) 2 (7.7)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
7.1 (7.5) 4 (30.8) 0 1 (7.7) 0 1 (7.7) 4 (30.8) 3 (23.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
9.6 (7.5) 15 (71.4) 2 (9.5) 3 (14.3) 0 3 (14.3) 5 (23.8) 8 (38.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
8.6 (8.0) 34 (87.2) 3 (7.7) 8 (20.5) 2 (5.1) 6 (15.4) 14 (35.9) 13
(33.3)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.07 \textless{}0.001 0.06 NS 0.01 NS NS NS\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a} [?]1 clinical relapses during
follow-up.\textsuperscript{b}Chi square (categoric variables) or ANOVA
(continuous variables). NS: 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.

\textbf{Table 3. Variables associated with clinical relapses in GPA amd
MPA (n=91)}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\textbf{Univariate analysis} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Age} \textbf{Female sex}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.99 (0.97-1.01) 0.94 (0.56-1.56)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.19 0.82\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{Diagnosis} MPA GPA\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 1.90 (1.12-3.22)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.02\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{Antigenic specificity} Anti-MPO Anti-PR3\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 2.34 (1.38-3.97)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.002\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic Remitting Persistent Recurrent\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 0.91 (0.26-3.24) 3.36 (1.29-8.79) 4.31 (1.78-10.42)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.88 0.01 0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Clinical features} Constitutional symptoms Fever Anemia
Microhaematuria Renal failure Alveolar haemorrhage Pulmonary infiltrates
Pulmonary nodules Mononeuritis multiplex CNS involvement ENT involvement
Purpura Arthritis Ocular involvement\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.65 (0.36-1.16) 0.63 (0.37-1.09) 0.99 (0.40-2.50) 0.73 (0.42-1.29) 0.58
(0.34-0.98) 1.09 (0.62-1.91) 1.66 (0.90-3.06) 1.24 (0.67-2.27) 1.40
(0.68-2.87) 2.83 (0.86-9.29) 2.36 (1.38-4.03) 1.22 (0.57-2.58) 1.82
(1.07-3.12) 2.34 (1,10-4.99)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.15 0.10 0.99 0.28 0.04 0.78 0.10 0.49 0.36 0.09 0.002 0.61 0.03
0.03\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Treatment} Cyclophosphamide Azathioprine Methotrexate
Mycophenolic acid Plasmapheresis Rituximab\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.68 (0.32-1.42) 1.74 (1.02-2.98) 2.72 (1.38-5.36) 1.41 (0.77-2.60) 0.50
(0.20-1.27) 2.10 (1.20-3.68)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.30 0.04 0.004 0.27 0.15 0.009\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

MPA: microscopic polyangiitis GPA: granulomatosis with polyangiitis
Anti-MPO: anti-myeloperoxidase. Anti-PR3: anti-proteinase



\textbf{Table 4. Variables associated with clinical relapses in GPA and
MPA (n=91). Multivariate analysis}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Model 1*}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Cox regression} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Model 2*}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Cox regression} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic Remitting Persistent Recurrent
\textbf{Fever} \textbf{Arthritis} \textbf{Ocular involvement}
\textbf{Rituximab treatment}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.92 (0.25-3.42) 2.94 (1.08-7.99) 3.67 (1.48-9.06) 0.42 (0.23-0.78) 2.48
(1.36-4.52) 2.80 (1.22-6.44) 2.47 (1.39-4.39)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.90 0.03 0.005 0.006 0.003 0.015 0.002\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic/remitting Persistent/recurrent
\textbf{Fever} \textbf{Arthritis} \textbf{Ocular involvement}
\textbf{Rituximab treatment}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.55 (1.75-7.21) 0.42 (0.23-0.79) 2.40 (1.33-4.32) 2.80 (1.22-6.40) 2.54
(1.43-4.50)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textless{}0.001 0.006 0.004 0.015 0.001\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*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.



\textbf{Table 5. Variables associated with worsening renal failure in
anti-MPO vasculitis. Univariate analysis (n=52)\textsuperscript{a}.}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\textbf{Univariate analysis} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.32\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Age} \textbf{Female sex}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1.00 (0.97-1.04) 0.95 (0.40-2.27)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.88 0.92\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
\textbf{Diagnosis} GPA MPA\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 1.83 (0.42-7.96)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0.42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic Remitting Persistent Recurrent\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 1.93 (0.32-11.59) 3.45 (0.63-18.87) 4.26 (0.95-19.07)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.47 0.15 0.06\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Clinical features} Constitutional symptoms Fever Anemia
Microhaematuria Alveolar haemorrhage Pulmonary infiltrates Pulmonary
nodules Mononeuritis multiplex ENT involvement Purpura Arthritis Ocular
involvement\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.33 (0.14-0.78) 0.33 (0.13-0.86) 1.34 (0.18-10.05) 1.88 (0.44-8.07)
1.18 (0.48-2.94) 0.85 (0.20-3.72) 1.52 (0.20-11.51) 0.04 (0.00-8.13)
0.28 (0.04-2.12) 0.87 (0.11-6.67) 0.25 (0.08-0.76) 1.07
(0.25-4.62)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.01 0.02 0.78 0.40 0.71 0.83 0.69 0.23 0.22 0.89 0.01 0.93\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\textbf{Treatment} Cyclophosphamide Azathioprine Methotrexate
Mycophenolic acid Plasmapheresis Rituximab\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.38 (0.10-1.47) 0.54 (0.21-1.41) 0.04 (0.00-141.05) 0.83 (0.30-2.29)
1.76 (0.50-6.24) 2.18 (0.86-5.52)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0.16 0.21 0.45 0.71 0.38 0.10\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a}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.



\textbf{Table 6. Variables associated with worsening renal failure in
anti-MPO vasculitis (n=52)\textsuperscript{a}. Multivariate analysis}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Model 1*}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Cox regression} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Model 2*}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Cox regression} Hazard ratio (95\% CI)\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{p}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic Remitting Persistent Recurrent
\textbf{Arthritis}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1.92 (0.32-11.62) 3.39 (0.62-18.62) 5.68 (1.24-26.05) 0.19
(0.06-0.62)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.48 0.16 0.03 0.006\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{ANCA pattern} Monophasic/remitting Persistent/recurrent
\textbf{Constitutional symptoms} \textbf{Arthritis}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.10 (1.11-8.64) 0.40 (0.16-1.00) 0.24 (0.08-0.75)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.03 0.05 0.01\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*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.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure2/Figure2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

