Clinical Rheumatology

, 30:1499

Estimation of BVAS in patients with microscopic polyangiitis in Japan

Authors

    • Department of Medicine, Kidney CenterTokyo Women’s Medical University
  • Takashi Takei
    • Department of Medicine, Kidney CenterTokyo Women’s Medical University
  • Taku Morito
    • Department of NephrologyTokyo Metropolitan Komagome General Hospital
  • Yasuko Yabuki
    • Department of NephrologyTokyo Metropolitan Komagome General Hospital
  • Hitoe Suzuki
    • Department of NephrologyTokyo Metropolitan Komagome General Hospital
  • Minoru Ando
    • Department of NephrologyTokyo Metropolitan Komagome General Hospital
  • Mayuko Akamatsu
    • Department of NephrologySaiseikai Kurihashi Hospital
  • Mayuko Yamazaki
    • Department of NephrologySaiseikai Kurihashi Hospital
  • Michihiro Mitobe
    • Department of NephrologySaiseikai Kurihashi Hospital
  • Yoshihiko Watanabe
    • Department of NephrologyKameda Medical Center
  • Takahiro Mochizuki
    • Department of NephrologyKameda Medical Center
  • Kosaku Nitta
    • Department of Medicine, Kidney CenterTokyo Women’s Medical University
Original Article

DOI: 10.1007/s10067-011-1838-7

Cite this article as:
Itabashi, M., Takei, T., Morito, T. et al. Clin Rheumatol (2011) 30: 1499. doi:10.1007/s10067-011-1838-7

Abstract

The validity of the Birmingham Vasculitis Activity Score (BVAS) as an index of disease activity and a predictor of the prognosis and outcome in patients with MPA has not yet been established in Japan. We conducted a retrospective study of the data of 73 patients with MPA who were followed up for at least 2 years. We divided the patients into two groups according to the BVAS, namely, the high-BVAS group (≥16) and the low-BVAS group (<16), and compared the clinical characteristics. In addition, the distribution of the BVAS items in the patients and the items contributing to the total score in MPA patients were analyzed. Remission was achieved in 85% of patients at 1 month. There were no significant differences in the serum CRP, creatinine (Cre), or MPO-ANCA between the high- and low-BVAS group; however, the survival time was significantly shorter (p = 0.048) and the mortality rate significantly higher in the high-BVAS group (p = 0.04). The items of the BVAS contributing to the total score were motor neuropathy, sensory neuropathy, pulmonary infiltrate, hematuria, proteinuria, Cre ≥5.6 mg/dL, hypertension, scleritis, rise in Cre by ≥30%, and myalgia. BVAS was found to be a useful tool for determining the disease activity and outcome in patients with MPA in Japan. The initial BVAS was also predictive of the mortality and survival time and can also be used as a prognostic tool; therefore, use of the tool may facilitate the selection of appropriate treatment.

Keywords

BVASDisease activityMPA

Introduction

Microscopic polyangiitis (MPA) is a systemic vasculitis characterized histologically by pauci-immune necrotizing small-vessel vasculitis, without granulomatous inflammation. The American College of Rheumatology published classification criteria for Wegener's granulomatosis (WG), Churg–Strauss syndrome (CSS), and polyarteritisnodosa (PAN), but not MPA, while the Chapel Hill Consensus Conference (CHCC) recommended definitions for WG, CSS, and MPA. The CHCC definitions were not intended for classification, but for providing a method for describing MPA [14]. Watts et al. recently reported an algorithm, derived by consensus, for systemic vasculitis, for reevaluating existing definitions and developing new criteria [5]. However, the classification of vasculitis including MPA has been controversial for many years.

The typical clinical manifestations of MPA are rapidly progressive glomerulonephritis and alveolar hemorrhage. The disease is characterized by complex multisystem processes that usually threaten vital organs and are associated with substantial morbidity and increased mortality. MPA also belongs to the group of ANCA-associated vasculitides, and 75–80% of patients have myeloperoxidase (MPO)-ANCA [6].

The clinico-epidemiological characteristics of MPA show geographic variations. According to a nationwide, hospital-based survey, the number of patients with MPA is higher than that with WG in Japan [7].Therefore, it is important to establish evidence for Japanese patients with MPA.

The current standard assessment tool for scoring disease activity in patients with systemic vasculitis is the Birmingham Vasculitis Activity Score (BVAS). The BVAS is a clinical index of disease activity that is based on symptoms and signs pertaining to nine separate organ systems. Disease features are only considered when they are attributable to active vasculitis [811]. We examined the association between the BVAS and the activity of MPA, which has not previously been analyzed in detail in Japan.

Patients and methods

Patients

Among the patients who were diagnosed as having MPA between 1995 and 2006 at the Department of Medicine of the Kidney Center at Tokyo Women's Medical University, Department of Nephrology at Kameda Medical Center, Department of Nephrology at Saiseikai Kurihashi Hospital, and Department of Nephrology at Tokyo Metropolitan Komagome General Hospital, the data of 73 patients were reviewed. The diagnosis of MPA was established by the presence of the characteristic clinical features and histological findings, and all the patients satisfied the criteria proposed by the CHCC for MPA. Inclusion criteria for MPA were the following signs and symptoms, in variable combinations: (1) presence of RPGN and/or alveolar hemorrhage, which could be associated with other systemic manifestations of vasculitis; (2) histologic demonstration of small-sized vessel vasculitis or segmental pauci-immune necrotizing glomerulonephritis (GN); or (3) symptoms suggesting small-vessel involvement, e.g., purpura, without GN and/or alveolar hemorrhage [6].

Only patients with MPA were included, and patients with other small-vessel vasculitides, such as renal-limited vasculitis (RLV), WG, and CSS, were excluded from this study. For each patient, the following data were recorded: gender, age, clinical features (including symptoms, signs and organ involvement at presentation, and duration of follow-up), laboratory data, treatment, outcome, and cause of death. Laboratory data included 24-h urinary protein excretion (in grams/day), urinary red blood cell counts (per HPF), serum creatinine (in milligrams per deciliter), serum albumin (in grams per deciliter), estimated glomerular filtration rate (in milliliters per minute/1.73 m2) [12], serum immunoglobulin G (in milligrams per deciliter), and serum C-reactive protein (CRP, in milligrams per deciliter). Serum titers of MPO-ANCA and PR3-ANCA were measured by enzyme-linked immunosorbent assay (SRL Inc., Tokyo, Japan). Patients were observed for a follow-up period of at least 2 years, and the laboratory data were measured at the time of diagnosis, at 3 months, 6 months, and 2 years after the diagnosis. Same researcher scored BVAS each time.

Evaluation criteria

We applied the BVAS to evaluate the disease activity. The BVAS form is divided into symptoms/signs pertaining to nine organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The clinician only scored features that were believed to be due to active vasculitis. Upon completion of the form, a numerical score was obtained. The BVAS form was first published in 1994. Over the past years, there have been a number of changes to further improve the assessment form. We used BVAS 2003 for this study [10], although subsequently a newer version has been developed called BVAS V3.0 [11].

Disease outcome was defined by BVAS. Remission was defined as the absence of new or worse signs of disease activity on the BVAS. We defined relapse as the recurrence or first appearance of at least one BVAS item indicating organ function attributable to active vasculitis.

Treatment

All patients received induction therapy with a corticosteroid at various doses. Thirty-one MPA patients with multiorgan involvement received intravenous pulse methylprednisolone (dose, 0.5–1.0 g) for 3 consecutive days. Twenty-seven patients who had rapidly progressive glomerulonephritis or were less than 60 years old received more than 0.8 mg/kg/day of prednisolone orally for 4 weeks or more as the subsequent maintenance therapy. Cyclophosphamide was administered to 17 patients. Among these 17 patients, 12 were given intravenous cyclophosphamide (250–500 mg/day × one to four courses) and the others, oral cyclophosphamide (0.5–1.5 mg/kg body weight). One patient received mizoribine for maintenance therapy. Four patients underwent plasma exchange. No strict protocol was followed in regard to prophylaxis against opportunistic infections.

Statistical analysis

Data are expressed as means±standard deviation (SD). The significance of differences between groups was examined using Student's t test for nonpaired samples, and by the χ2 test. The evolution of the clinical parameters was analyzed in both groups by repeated measures analysis of variance. When differences could be demonstrated, values were compared with the baseline using the paired-sample t test. A p value of less than 0.05 was considered to denote statistical significance. Stepwise multiple regression analysis was used to identify independent risk factors among the parameters selected by univariate analyses. The parameters with an F value of more than 4 were adopted. A p value less than 0.05 was considered to denote statistical significance. Survival was assessed by the Kaplan–Meier method. All statistical analyses were performed using the JUMP 7 software (SAS Institute, Cary, NC, USA).

Results

Clinical features and laboratory findings

Of the 73 patients, 23 were men and 50 were women, with a mean age at diagnosis of 71 ± 10 (range, 41–90) years. The laboratoty data (Table 1) and pattern of organ involvement during the 2-year follow-up are shown in Fig. 1. At the time of diagnosis, 71 patients (97%) had renal vasculitic involvement. At the first admission, dialysis therapy was initiated in 19 patients, of whom 2 recovered and did not require further dialysis. A total of 49patients (67%) had systemic manifestations of vasculitis, such as fever, weight loss, and myalgia; 32 patients (44%) had pulmonary involvement, manifesting as abnormal findings on chest X-rays or CT images. The pulmonary involvement was most frequently represented by interstitial pneumonia (32.9%), followed in frequency by pulmonary hemorrhage (8.2%). The diagnosis of interstitial pneumonia was based on chest CT. Eleven patients (15%) had neurological involvement; 7 patients (10%) had sensory peripheral neuropathy; 5 patients (7%) had mononeuritis multiplex; 9 patients (12%) had cutaneous involvement, mostly purpura; 6 patients (8%) had cardiovascular involvement, mainly pericarditis. Serum titer of MPO-ANCA was a mean titer of 338.4 ± 254.1 EU, and serum CRP was 7.9 ± 7.1 mg/dL. Serum PR3-ANCA was negative (1.0 ± 3.7 EU).
Table 1

Clinical features during 2-year follow-up period

 

At diagnosis, N = 73

1 month, N = 72

3 months, N = 63

6 months, N = 60

2 years, N = 54

Cre (mg/dL)

4.0 ± 2.6

3.0 ± 2.1

2.4 ± 1.6

2.1 ± 1.1

2.2 ± 1.8

eGFR (mL/min/1.73 m2)

16.9 ± 16.6

22.0 ± 17.3

22.5 ± 17.5

25.0 ± 16.9

25.0 ± 16.0

Albumin (g/dL)

2.9 ± 0.7

3.2 ± 0.5

3.4 ± 0.6

3.6 ± 0.6

3.9 ± 0.4

CRP (mg/dL)

7.9 ± 7.1

1.1 ± 2.6

0.8 ± 2.0

0.4 ± 1.0

0.6 ± 1.4

MPO-ANCA (EU)

338.4 ± 254.2

136.2 ± 176.4

35.7 ± 82.0

11.8 ± 22.7

5.3 ± 87.8

U-P (g/day)

1.3 ± 1.2

1.0 ± 1.1

0.8 ± 1.4

0.4 ± 0.7

0.1 ± 0.3

U-RBC (/HPF)

54 ± 37

32.9 ± 37.8

11 ± 15

6 ± 9

3 ± 6

BVAS (new/worse)

16.2 ± 5.5

1.4 ± 4.0

0.8 ± 2.7

0.3 ± 1.1

0.5 ± 2.1

BVAS (persistent)

1.8 ± 2.8

5.8 ± 2.3

4.8 ± 2.8

3.8 ± 2.8

3.2 ± 2.2

Values are expressed as mean±SD

Cre serum creatinine, eGFR estimated glomerular filtration rate, CRP C-reactive protein, U-P proteinuria, U-RBC urinary red blood cell, NS not significant

https://static-content.springer.com/image/art%3A10.1007%2Fs10067-011-1838-7/MediaObjects/10067_2011_1838_Fig1_HTML.gif
Fig. 1

Changes in the incidence of organ involvement in patients with MPA. a Change of the BVAS new/worse major items. b Change of the BVAS persistent major items. ENT ear, nose, and throat

Outcome

The patient life survival rate is shown in Fig. 2. The survival rate at 6 months after the diagnosis was 84.4% and that at 2 years after the diagnosis was 79.5%. Fifteen patients (20.5%) died during the 2-year follow-up. Infection during therapy of active vasculitis, such as interstitial pneumonia and pulmonary bleeding, was the cause of seven deaths; infection alone accounted for five deaths, active vasculitis alone for two deaths, and cardiac involvement or VT for one death. The complicating infections which caused death were Pneumocystis jiveroci pneumonia in four patients, Cytomegalovirus infection in three patients, and sepsis and bacterial pneumonia in three patients. The renal survival rate at 6 months after diagnosis was 60.2% and that at 2 years after diagnosis was 57.5%.
https://static-content.springer.com/image/art%3A10.1007%2Fs10067-011-1838-7/MediaObjects/10067_2011_1838_Fig2_HTML.gif
Fig. 2

Comparison of the survival rate between the high-BVAS group (≥16; n = 37) and low-BVAS group (<16; n = 36). X-axis indicates the follow-up period (in years) and the Y-axis the survival rate (in percent). p = 0.04 between the high-BVAS group and low-BVAS group by the logrank test

Change of the BVAS

We assessed the changes in the BVAS during the 2-year follow-up period. The mean BVAS, which was 16.2 ± 5.5 at the time of diagnosis (Table 1), decreased dramatically by 1 month after the diagnosis to 1.4 ± 4.0. The BVAS decreased to 0, suggestive of remission, in 62 patients (85%). The rate of complete remission at 2 years without deceased patients was 94.7%. After falling once to 0, the BVAS increased again in 11 patients (15%), suggestive of relapse. We found no correlation between the BVAS and the serum MPO-ANCA titer, serum CRP, or UP at the time of diagnosis to the levels at 1, 3, or 6 months.

The distribution of the items of BVAS

Figure 3 shows the BVAS items in descending order of the frequency. The BVAS items of renal involvement, especially hematuria and proteinuria, were found at a high frequency. Only 20 of the 62 items of BVAS were covered in the MPA patients, excluding system involvement occurring at a frequency of 3% or lower. Thus, clustering of the BVAS items was found in the MPA patients.
https://static-content.springer.com/image/art%3A10.1007%2Fs10067-011-1838-7/MediaObjects/10067_2011_1838_Fig3_HTML.gif
Fig. 3

BVAS items in descending order of frequency, except for items occurring at frequencies of 3% or less than

Evaluation of each of the BVAS items

We analyzed the items that contributed to the total BVAS score in the MPA patients. Multiple regression analysis (Table 2) identified 10 items, including motor neuropathy (p < 0.0001), sensory neuropathy (p = 0.0001), pulmonary infiltrate (p = 0.0004), hematuria (p = 0.001), proteinuria (p = 0.003), Cre ≥5.6 mg/dL (p = 0.01), hypertension (p = 0.01), scleritis (p = 0.02), rise in Cre by ≥30% (p = 0.02), and myalgia (p = 0.049). Next, we analyzed the items that influenced the survival times; multiple regression analysis identified seven items, including presence of respiratory failure (p = 0.006), congestive heart failure (p = 0.009), Cre ≥5.6 mg/dL (p = 0.03), organic confusion (p = 0.04), valvular heart disease (p = 0.04), alveolar hemorrhage (p = 0.04), and pleurisy (p = 0.04, Table 3).
Table 2

BVAS items which was contributed to BVAS total score (multivariate studies)

 

BVAS score

F value

P value

Motor neuropathy

9

18.9

4.73E−05

Sensory neuropathy

6

16.6

0.0001

Lungs infiltrate

4

13.7

0.0004

Hematuria ≧10 RBC/HPF

6

11.0

0.001

Proteinuria >1+

4

9.3

0.003

Creatinine ≧5.6 mg/dL

8

7.0

0.01

Hypertension

4

6.6

0.01

Scleritis

2

5.8

0.02

Rise in creatinine >30%

6

5.6

0.02

Myalgia

3

4.0

0.049

Table 3

BVAS items which was regulated to survival time (multivariate studies)

 

F value

P value

Respiratory failure

8.2

0.006

Congestive heart failure

7.2

0.009

Creatinine ≧5.6 mg/dL

4.9

0.03

Organic confusion

4.5

0.04

Valvular heart disease

4.5

0.04

Alveolar hemorrhage

4.3

0.04

Pleurisy

4.3

0.04

Comparison between the high-BVAS group and low-BVAS group

We divided the patients into two groups using the median score of BVAS at diagnosis, namely the high-BVAS group and the low-BVAS group, and examined the clinical data, therapy, and the prognosis and outcome of the two groups. The comparative clinical characteristics of the two groups are shown in Table 4. There were no significant differences in the serum CRP or MPO-ANCA titers between the two groups. A significantly higher frequency of proteinuria was observed in the low-BVAS group (p = 0.015). BVAS (persistent) score at diagnosis was higher in the low-BVAS group (p = 0.002). There was no significant difference in the induction therapy administered between the two groups. As to the prognosis, the survival time was significantly shorter (p = 0.048) and the mortality rate significantly higher in the high-BVAS group (p = 0.04, Fig. 2).
Table 4

Comparison of clinical data, therapy, and prognosis between high-BVAS group and low-BVAS group

 

Low-BVAS group (>16, n = 37)

High-BVAS group (≦16, n = 36)

P value

MPO-ANCA (EU)

321.5 ± 263.6

363.3 ± 245.2

NS

CRP (mg/dL)

6.9 ± 6.3

9.1 ± 7.9

NS

Alb (g/dL)

3.0 ± 0.6

2.8 ± 0.7

NS

Cre (mg/dL)

3.9 ± 2.3

4.2 ± 2.9

NS

U-protein (g/day)

1.6 ± 1.4

1.0 ± 0.7

0.015

U-RBC (/HPF)

61.8 ± 38.5

44.7 ± 34.3

NS

BVAS persistent

2.8 ± 3.4

0.8 ± 1.4

0.0018

Steroid pulse (n)

17

15

NS

PSL (mg)

35.1 ± 14.6

32.5 ± 19.7

NS

Cyclophosphamide (n)

7

11

NS

PE or DFPP (n)

1

3

NS

Survival time

638.9 ± 209.3

518.9 ± 291.8

0.048

Renal survival time

467.8 ± 334.4

409.1 ± 338.4

NS

Remission rate (%)

94.5

94.5

NS

Relapse rate (%)

11.1

22.2

NS

Mortality rate (%)

13.5

33.3

0.04

Survival time was significantly shorter and mortality was significantly higher in high-BVAS group than in low-BVAS group. Values are expressed as mean±SD

Cre serum creatinine, CRP C-reactive protein, U-RBC urinary red blood cell, PE plasma exchange, DFPP double filtration plasmapheresis, NS not significant

Discussion

MPA has been reported to show both epidemiological and serological differences between Japan and European countries. The incidence of WG, among the ANCA-associated small-vessel vasculitides, is higher than that of MPA and/or RLV in northern Europe [1315], whereas conversely, the incidence of MPA/RLV is markedly higher than that of WG in Japan [7]. Two nationwide Japanese surveys demonstrated that the number of patients with MPA and/or RLV is sixfold higher than that of patients with WG in Japan [7, 1315]. In addition, serologically, MPO-ANCA-positive patients occur at a higher frequency than PR3-ANCA-positive patients in Japan, whereas patients with PR3-ANCA are more common in Europe. The percentage of patients showing seropositivity for MPO-ANCA is 79–93% in Japan, whereas it is reported to be in the range of 44–69% in Europe [7, 14]. Patients with MPA in Japan are mostly older in age than those in Europe. The mortality has also been shown to be associated with older age. The main causes of death in patients with MPA in Japan were infection and progression of vasculitis. Prophylactic therapy with trimethoprim–sulfamethoxazole was associated with a reduction in the incidence of Pneumocystis spp. pneumonia, with a significant decrease of the Pneumocystis spp. pneumonia-related mortality [16]. Because intense immunosuppression increases the risk of infections, it is necessary to use prophylactic sulfamethoxazole–trimethoprim treatment during the induction therapy and to use the minimum needed doses of the steroids or immunosuppressant drugs. In the EULARguidline, cyclophosphamide and glucocorticoids are consistently recommended as the “standard of care,” but the risks of myelosuppression, infection, infertility, and malignancy with cyclophosphamide have influenced protocols aiming at minimizing cyclophosphamide exposure. MPA in Japan are mostly found in older age, especially patients 70 years old and over; dialysis-dependent people tend to avoid immunosuppressant agents. According to a nationwide survey of RPGN in Japan, immunosuppressive treatment as an initial treatment such as cyclophosphamide was administered only 21.5%. The survival rate was similar between our trial and a nationwide survey of RPGN in Japan [17].

Clinical assessment tools are important for accurate measurement of the disease activity. Serum CRP may be related to the disease activity; however, it is often difficult to distinguish between disease activity and infection based on the serum CRP. The BVAS is a validated tool for assessment of disease activity in systemic vasculitis [8]. The importance of BVAS is to ensure that an abnormality is recorded only when it is attributed to active vasculitis. The role of assessment of the disease activity in systemic vasculitis has been summarized as follows: (1) it assists in treatment decisions; (2) it can be used as a prognostic tool and thereby allow selection of appropriate treatment; and (3) it can be used as an outcome assessment measure (to predict morbidity and mortality). Mukhtyar et al. reported that the BVAS was correlated with the treatment decision in systemic vasculitis, but MPA patients were included in less than 10% [11]. In our study, there was no difference in the frequency of use of induction therapies, such as cyclophosphamide and steroid pulse therapy, between the high-BVAS group and low-BVAS group. One of the reasons could be that the physicians selected the therapies taking into consideration the patient's high age and the high frequency of renal dysfunction. The BVAS has also been shown to have prognostic value, at least in relation to the short- to medium-term mortality. The relationship between the initial disease activity and the risk of mortality is not clear in patients with MPA. In a large prospective cohort study of 278 patients with MPA, PAN, or CSS, Martine Gayraud showed that both FFS and BVAS at the diagnosis were predictors of a poor prognosis (p = 0.04 for FFS, p < 0.0002 for BVAS) [18]. We showed, by a retrospective analysis, that the initial BVAS was predictive of both the mortality and survival time in patients with MPA. FFS serves as a useful prognostic index, especially in cases of PAN and CSS. Patients with higher FFS (≥2) values at onset showed a survival advantage if they were treated with cyclophosphamide in combination with a steroid as compared with a steroid alone. In this study, some BVAS items such as congestive heart failure and Cre ≥5.6 mg/dL, which were related to the survival time overlapped with the FFS items.

Definition of the disease status is an important requirement to measure the effectiveness of treatment. The BVAS form is a useful checklist for patients with active vasculitis. The EUVAS group used definitions based on the BVAS in their trial, and BVAS 0 or 1 was defined as remission. Continued monitoring of the BVAS after remission is important. In this study, BVAS increased again after remission in 15.9% of the patients during the 2-year follow-up.

We evaluated the BVAS for the first time in patients with MPA in Japan. The majority of the BVAS items (67.7%) occurred at a frequency of less than 3% in the MPA patients. According to the French vasculitis study group, clinical manifestations observed in MPA mainly included renal manifestations (78.8%), weight loss (72.9%), skin involvement, such as purpura and livedo (62.4%), mononeuritis multiplex (57.6%), gastrointestinal tract involvement (30.6%), and lung involvement (24.7%) [18]. Lane et al. reported that ENT involvement occurred at a frequency of 29% and respiratory involvement, including interstitial pneumonia, also at a frequency of 29%, whereas renal involvement was found in 92% of the patients [9]. The clinical features of the patients in our study were generally similar to those reported by Savage et al., although a smaller proportion of our patients had renal involvement as compared with that in their report [19]. BVAS has been modified from the original BVAS to BVAS (ver.3). Some new items have been added, and some items of low specificity for vasculitis have been omitted. BVAS is not disease specific. For a comparatively rare disease, such as the vasculitis, it would be highly desirable to develop a single standard structured clinical disease activity measure, in order to allow comparisons among different studies. However, the distribution of the BVAS items in our MPA patients was biased. To evaluate the individual organ system manifestations occurring in MPA, it is possible that a BVAS form for MPA needs to be designed to measure the disease activity.

In conclusion, we conducted this study to determine the distribution of the items of the BVAS in patients with MPA and also the changes of the BVAS during a 24-month follow-up period in patients with MPA. BVAS, which is a complex scale, but also quite detailed with multiple items, allowed estimation of the patient prognosis and of the disease activity. The individual contributions of the BVAS items may also be applied in treatment decisions.

Acknowledgment

This study was supported by a grant from the Research Group on Progressive Glomerular Disease of the Ministry of Health, Labour, and Welfare of Japan. The authors thank Dr. Wako Yumura for advice of BVAS.

Disclosures

None.

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