The study population
Fifty-seven patients (47.4% male) with the age of 72.4 ± 5.6 years at diagnosis were included. The majority of the cohort tested positive for MPO-ANCA (n = 49, 85.9%), and four patients (7.0%) tested positive for PR3-ANCA. Two patients had nonspecific ANCA on immunofluorescence assay. Sixteen patients underwent renal biopsy and the results all supported the diagnosis of pauci-immune glomerulonephritis. The mean baseline BVAS score was 17.04 ± 4.40. The mean baseline eGFR was 18.64 ml/min × 1.73 m2 (7.63, 33.79). Ten patients needed dialysis at the time of diagnosis. The baseline demographics and clinical data were summarized in Table 1.
Table 1
Baseline Clinical characteristics of AVV patients.
| Total n = 57 | Patient with infection (n = 29) | Patient without infection (n = 28) | P value |
Demographics and muscle parameters |
Age, years | 72.38 ± 5.55 | 73.91 ± 6.21 | 70.90 ± 4.44 | 0.037* |
Male, n (%) | 27 (47.3%) | 13 (44.8%) | 14 (50%) | 0.700 |
BMI, kg/m2 | 23.30 ± 3.86 | 23.84 ± 4.70 | 22.76 ± 2.77 | 0.298 |
Muscle area, cm2 | 102.68 ± 24.41 | 94.55 ± 22.80 | 111.09 ± 23.49 | 0.009** |
Comorbidities, n(%) | | | | |
Diabetes | 14 (24.6%) | 6 (20.7%) | 8 (28.6%) | 0.490 |
Pulmonary diseases# | 17 (29.8%) | 8 (27.6%) | 9 (32.1%) | 0.707 |
Hypertension | 33 (57.9%) | 9 (75.0%) | 24 (53.3%) | 0.177 |
Vasculitis Disease Activity |
BVAS | 17 ± 4 | 17 ± 4 | 17 ± 5 | 0.440 |
Pulmonary vasculitis | 35 (61.4%) | 18 (62.1%) | 17 (60.7%) | 0.916 |
Baseline Lab results | | | |
Lymphocyte,×109/L | 1.14 ± 0.48 | 1.07 ± 0.45 | 1.20 ± 0.51 | 0.357 |
Hemoglobulin, g/L | 95.4 ± 16.30 | 95.6 ± 16.1 | 95.3 ± 16.8 | 0.945 |
Scr, µmol/L | 261.0 (149.5, 520.5) | 310.0 (160.0, 526.5) | 237.5 (134.3, 490.8) | 0.793 |
eGFR, ml/min × 1.73 m2 | 18.64 (8.31, 3.59) | 12.49 (7.35, 31.82) | 19.30 (7.87, 44.01) | 0.221 |
Albumin, g/L | 33.1 ± 4.7 | 32.0 ± 4.9 | 34.7 ± 4.3 | 0.05* |
Ig G, g/L | 13.26 (10.74, 18.31) | 13.26 (10.73, 15.50) | 14.07 (10.75, 19.02) | 0.269 |
hsCRP, mg/L | 23.22 (2.11, 99.39) | 46.55 (12.70, 134.40) | 5.61 (1.57, 68.49) | 0.018* |
ANCA titer±, RU/mL | 159.0 (87.0, 200.0) | 159.0 (89.0, 200.0) | 159.0 (86.0, 200.0) | 0.822 |
Treatment | | | | |
Pulse GC, n (%) | 21 (36.8%) | 10 (34.5%) | 11 (39.3%) | 0.707 |
PE, n (%) | 15 (26.3%) | 9 (31.0%) | 6 (21.4%) | 0.410 |
Abbreviation: # COPD, chronic obstructive pulmonary disease and other pulmonary disease; BVAS, Birmingham Vasculitis Activity Score (version 3); BMI, Body Mass Index; Scr, Serum Creatinine; eGFR: Estimated Glomerular Filtration Rate; IgG, Immunoglobulin G; hsCRP, high-sensitivity C-reactive protein; MPO ANCA, Myeloperoxidase-antineutrophil Cytoplasmic Antibodies; GC, glucocorticoid; PE, Plasmapheresis. |
±: All ANCA titers were measured by antigen-specific immunoassay, 200 RU/mL is the upper limit of ANCA titer. |
* P value < 0.05 |
** P value < 0.01 |
Muscle Area
The muscle area at the third lumbar vertebrae level was 102.68 ± 24.41 cm2. Muscle area correlated with age (r= -0.40, P = 0.002) and BMI (r = 0.39, P = 0.003), while age and BMI were also correlated (r= -0.34, P = 0.01). The difference in muscle areas between males and females was significant with a mean muscle area of 114.16 ± 23.63 cm2 for males and 92.34 ± 20.40 cm2 for females (P < 0.0001). There was no significant correlation between muscle area and other baseline characteristics, including whether having diabetes or pulmonary comorbidities, baseline serum albumin, creatinine, hemoglobulin, and lymphocyte level. There was also no correlation between muscle area and dialysis status, whether receiving plasma apheresis or glucocorticoid pulse therapy (Supplementary table).
Treatments
All patients received glucocorticoid therapy. The regimen usually consists of 40 to 80mg·d − 1 intravenous methylprednisolone for a week and subsequent oral methylprednisolone or prednisone at an initial dosage of 0.80 mg·kg − 1·d − 1 with tapering. Most patient received cyclophosphamide (CYC) for induction therapy (n = 52, 91.1%). CYC was administered either by intravenous infusion of 0.4 to 0.6 g every week or an oral dose of 0.05 g to 0.1g·d − 1. Two patients were treated with Rituximab given as 500 mg and 1000 mg once.
Twenty-one patients (36.8%) with rapidly progressive renal failure and/or severe vasculitis involving other systems received three intravenous pulses of methylprednisolone (0.25–1 g/day) before the induction therapy.
Fifteen patients (26.3%) with severe disease underwent plasma exchanges. Maintenance therapy was with oral cyclophosphamide in most patients (96.6%) during follow-up.
Risk Factors For Infection And Death
After a median follow-up of 555.0 (125.5, 970.5) days, twenty-nine patients experienced thirty-six episodes of serious infections, and ten infections resulted in ICU admission. The median time to the first infection was 26.5 (IQR: 10.5, 60.0) days from induction therapy. Pneumonia (n = 29) and CMV viremia (n = 7) were most common infections.
We split the cohort into patients with and without severe infections and compared the demographic characteristics, muscle areas, comorbidities, disease severity, and baseline laboratory results between groups (Results shown in Table 1). Patients with infections were older with a mean age of 73.9 years compared to a mean of 70.9 years in those without infections (P < 0.05) and have a lower muscle area (94.55 ± 22.80 cm2 verse 111.09 ± 23.49 cm2, P < 0.05). However, the BMIs between these two groups were not significantly different. Other parameters compared shown that patients with severe infections had higher hsCRP (P < 0.05) level at baseline and a trend toward lower albumin levels (P = 0.05).
In univariable logistic regression analysis, only increased age (OR = 1.11, CI 1.00 to 1.23, P = 0.04) decreased skeletal muscle area (OR = 0.98, CI 0.94 to 0.99, P = 0.008) and increased baseline hsCRP level (OR = 1.01, CI 1.00 to 1.02, P = 0.017) predicted serious infections during one year follow up. The other non-significant variables were BMI, BVAS score, eGFR at the onset of disease, diabetes, pulmonary comorbidities, vasculitis affecting the respiratory system, glucocorticoid pulse therapy, and baseline nutritional markers. Multiple logistic regression models didn’t find a significant relationship between muscle area, BVAS, baseline hsCRP, nor eGFR with severe infection (see Table 2).
Table 2
Univariate and multiple Logistic regression analysis of risk factors for serious infections
Variable | Unadjusted OR [95%CI] | P value | Adjusted§ OR [95% CI] | P value |
Age | 1.11 [1.00 to 1.23] | 0.044* | | |
Male | 0.70 [0.25 to 1.99] | 0.503 | | |
Muscle area | 0.97 [0.94 to 0.99] | 0.008** | 0.98 [0.97 to 1.01] | 0.169 |
BMI | 1.05 [0.91 to 1.21] | 0.480 | | |
Diabetes | 0.72 [0.21 to 2.42] | 0.590 | | |
Pulmonary comorbidities | 0.63 [0.20 to 1.99] | 0.633 | | |
BVAS | 1.05 [0.93 to 1.19] | 0.397 | 1.04 [0.95 to 1.14] | 0.439 |
Pulmonary Vasculitis | 0.94 [0.32 to 2.74] | 0.916 | | |
Dialysis at baseline | 0.64 [0.16 to 2.56] | 0.527 | | |
ANCA titer | 1.00 [0.99 to 1.01] | 0.954 | | |
eGFR | 0.98 [0.96 to 1.02] | 0.306 | 0.98 [0.96 to 1.00] | 0.089 |
Lymphocyte | 0.71 [0.23 to 2.19] | 0.555 | | |
Immunoglobulin G level | 0.96 [0.86 to 1.08] | 0.511 | | |
Albumin | 0.89 [0.79 to 1.01] | 0.899 | | |
Hemoglobin | 1.01 [0.97 to 1.04] | 0.722 | | |
hsCRP | 1.01 [1.00 to 1.02] | 0.017* | 1.01 [0.99 to 1.01] | 0.099 |
Plasmapheresis | 1.82 [0.55 to 6.01] | 0.329 | | |
Methylprednisolone Pulse | 0.91 [0.31 to 2.67] | 0.862 | | |
Abbreviations: BMI body mass index, BVAS Birmingham Vasculitis Activity Score (version 3), ANCA Antineutrophil Cytoplasmic Antibodies, eGFR estimated glomerular filtration rate, hsCRP high sensitivity C-Reactive Protein |
§ Variables included in multiple Logistic regression model: muscle area, BVAS, eGFR and hsCRP level |
* P value < 0.05 |
A total of twelve death occurred in our cohort, with a mortality rate of 21.1% for the first year. Ten patients died of infection, one died of gastrointestinal bleeding and one died of a ruptured aortic aneurysm. The median time to death was 59 (IQR 26.3, 75.0) days from diagnosis. The Kaplan-Meier survival plot was shown in Fig. 3. Except for the muscle area (P = 0.008), there are no significant differences in the clinical markers between the dead and survived patients. Patients who died within the first year had a trend toward older age (P = 0.051) and higher baseline hsCRP (P = 0.075).
In univariable Cox regression, age (HR = 1.14, CI 1.03 to 1.26, P = 0.014), skeletal muscle area (HR = 0.96, CI 0.94 to 0.99, P = 0.016), and undergoing plasmapheresis (HR = 3.43, CI 1.10 to 10.65, P = 0.03) significantly predicted 1-year mortality. In multiple Cox regression model because that muscle area correlates with age (see supplementary table) and our end events are limited we constructed the model with muscle area, BVAS and the status of plasmapheresis. Multiple Cox regression models indicated that muscle area (HR = 0.96, CI 0.94 to 0.98, P = 0.02) was an independent predictor of death, when adjusted by BVAS, and whether undergoing plasmapheresis (See Table 3).
Table 3
Predictors of 1 year mortality in univariable and multiple Cox regression analysis
Variable | Unadjusted HR [95%CI] | P value | Adjusted§ HR [95% CI] | P value |
Age | 1.14 [1.03 to 1.26] | 0.014* | | |
Male | 0.71 [0.23 to 2.23] | 0.556 | | |
Muscle area | 0.96 [0.94 to 0.99] | 0.016* | 0.96 [0.94 to 0.98] | 0.02* |
BMI | 0.97 [0.83 to 1.15] | 0.751 | | |
Diabetes | 1.49 [0.45 to 4.95] | 0.515 | | |
Pulmonary comorbidities | 0.21 [0.03 to 1.59] | 0.130 | | |
BVAS | 1.07 [0.94 to 1.23] | 0.309 | 1.12 [0.97 to 1.29] | 0.11 |
Pulmonary Vasculitis | 1.00 [0.32 to 3.17] | 0.990 | | |
Dialysis at baseline | 0.42 [0.06 to 3.27] | 0.410 | | |
ANCA titer | 1.00 [0.99 to 1.01] | 0.590 | | |
eGFR | 0.99 [0056 to 1.03] | 0.639 | | |
Lymphocyte | 0.71 [0.19 to 2.76] | 0.628 | | |
IgG level | 0.99 [0.87 to 1.13] | 0.931 | | |
Albumin | 0.98 [0.89 to 1.11] | 0.833 | | |
Hemoglobin | 0.99 [0.95 to 1.02] | 0.444 | | |
hsCRP | 1.06 [0.99 to 1.01] | 0.140 | | |
Plasmapheresis | 3.43 [1.10 to 10.65] | 0.03* | 2.87 [0.89 to 9.23] | 0.077 |
Methylprednisolone Pulse | 0.83 [0.25 to 2.75] | 0.758 | | |
Abbreviations: BMI body mass index, BVAS Birmingham Vasculitis Activity Score (version 3), ANCA Antineutrophil Cytoplasmic Antibodies, eGFR estimated glomerular filtration rate, hsCRP high sensitivity C-Reactive Protein |
§ Variables included in multiple Cox regression model: muscle area, BVAS score and whether receiving plasmapheresis treatment |
* P value < 0.05 |
** P value < 0.01 |