Background
Anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis (AAV) is a group of small vessel vasculitis including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis. It can cause severe damage to organs, especially kidneys. Early diagnosis of AAV is essential for the preservation of organ function [
1]. It has been reported that AAV may coexist with rheumatoid arthritis (RA) [
2]. ANCA-associated glomerulonephritis patients with RA appear to have smoldering clinical features and may result in late referral from rheumatologists to nephrologists and therefore have a poor prognosis [
3]. However, research on patients with the coexistence of AAV and RA is limited, and most studies are case reports. It is unclear whether there are any differences between AAV with and without coexisting RA. We therefore reviewed cases with these coexisting diseases in our hospital and in the literature, and summarized the clinical manifestations in these patients. We also attempted to identify the clinicopathological characteristics of AAV patients superimposed on RA by comparing them to those with AAV without RA. In consideration of the poor prognosis of AAV-associated glomerulonephritis, we analyzed the risk factors for AAV renal involvement in RA patients by renal biopsy in our center to timely identify these patients.
Methods
Study subjects
Patients with both AAV and RA in the Peking Union Medical College Hospital from January 2000 to December 2018 were included in this study. AAV was diagnosed based on the criteria proposed by the Chapel Hill Conference [
4]. The diagnosis of RA complied with the 2010 ACR/EULAR RA classification criteria [
5]. Cases before 2010 were reassessed and re-diagnosed. We also searched for cases of both AAV and RA published in English or Chinese between January 2000 and December 2018 in MEDLINE, EMBASE, and Chinese databases including China National Knowledge Infrastructure, Wanfang Database, and VIP Database. The keyword for RA was “rheumatoid arthritis”. The keywords for AAV were “anti-neutrophil cytoplasmic antibody associated vasculitis”, “anti-neutrophil cytoplasmic antibody associated nephritis”, “anti-neutrophil cytoplasmic antibody”, “small vessel vasculitis”, “rapidly progressive glomerulonephritis”, “microscopic polyangiitis”, “granulomatosis with polyangiitis”, “Wegener’s granulomatosis”, “Churg-Strauss syndrome”, “eosinophilic granulomatosis with polyangiitis” and “allergic granulomatous angiitis” (Supplementary Fig.
1). We excluded patients exposed to potential AAV-inducing drugs such as tumor necrosis factor-α inhibitors, penicillamine, and propylthiouracil [
6].
Study design
We pooled all the patients from our center and the literature to demonstrate the clinical manifestations of AAV coexisting with RA. In order to assess clinical features and renal pathology of AAV coexisting with RA, we 1:4 matched patients with both AAV and RA in our center with those having isolated AAV by sex, age, AAV subtypes, and presence of renal involvement and renal pathology. We then evaluated the association between RA and ANCA-associated glomerulonephritis in renal-biopsied patients in our hospital. In order to identify potential predictors for ANCA-associated glomerulonephritis in RA patients, we compared the clinical features between renal-biopsied RA patients with ANCA-associated glomerulonephritis and primary glomerulonephritis.
Data on sex, age, serology, clinical manifestation, interval between diagnosis of RA and AAV, renal pathology, and therapeutic regimens, if applicable, were collected retrospectively from medical records or the literature. Tubulointerstitial chronic index, assessed by the percentage of tubular atrophy and interstitial fibrosis in the total area of the cortical tubulointerstitium was classified into four grades:1: ≤25%, 2: 26–50%, 3: 51–75%, and 4: >75%. Histopathology of ANCA associated glomerulonephritis was re-classified according to the criteria proposed in 2010 [
7].
Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (interquartile range) and compared using the Student t-test or Mann-Whitney U test as appropriate. Categorical variables are presented as n (%) and compared using the chi-square test or Fisher’s exact test. Logistic regression was employed to assess the association between RA and ANCA associated glomerulonephritis in renal-biopsied patients by adjusting for sex and age. All statistical tests were 2-sided, with significance defined as p < 0.05. All statistical analyses were performed using the SPSS 23.0 (IBM).
Discussion
RA is largely an inflammatory disease limited to joints, whereas AAV is a systemic autoimmune disease usually with multi-organ destructive processes and devastating outcomes. It has been reported that AAV can coexist with RA [
3,
8‐
24]. This coexistence may not be entirely coincidental, as evidenced by facts such as ANCA positivity in 20% of RA patients [
25], a positive association between ANCA titer and rapid joint destruction in early RA [
26], the presence of myeloperoxidase-ANCA in synovial fluid of RA patients [
27], and AAV sharing susceptibility loci with RA [
28,
29]. Our finding, that renal-biopsied patients with RA were more likely to have AAV than those without RA, adds new evidence to the inherent association between RA and AAV.
In our center, as well as in the literature, AAV usually occurred after RA in patients with both RA and AAV [
10‐
24]. This may partially be ascribed to the successful inhibition of RA occurrence by intense immunosuppression in the treatment of AAV. Alternatively, disease modifying antirheumatic drugs used for RA may also change the typical manifestations of AAV to a less extra-renal and extra-articular presentation, with a lower frequency of rapidly progressive glomerulonephritis, and more chronicity in renal pathology, as demonstrated in our and Kurita’s study [
3]. This deviation may hamper or delay our recognition of AAV in RA patients and finally result in a poor outcome.
Renal involvement is a major feature of AAV and is not rare in RA patients. In RA patients with biopsy-proved primary glomerulonephritis, membranous nephropathy and IgA nephropathy were the top two histopathological patterns as revealed by our and previous studies [
30]. RA patients with ANCA-associated glomerulonephritis were more likely to have renal dysfunction than those with primary glomerulonephritis. Therefore, ANCA should be assessed in RA patients with renal dysfunction.
Our study revealed an overwhelming predominance of MPA in AAV patients when AAV coexists with RA. This is consistent with findings in the literature. However, the underlying mechanism of this phenomenon is unclear.
There are some limitations in this study. First, because this was a retrospective study and the patients enrolled were highly selected, there was inevitable bias, which may have undermined the robustness of the study findings. Second, most of the patients from our center underwent renal biopsy. As such, the findings of the present study may be biased by the variable indications of renal biopsy for different underlying renal disease. Third, given the small sample in the study, care should be taken regarding generalization of the results of the study.
In conclusion, AAV may not be as rare as we thought in patients with RA. In patients with both AAV and RA, AAV usually developed after RA, was more likely to be asymptomatic, and manifested as MPA with renal involvement. We recommend routine assessment to determine the presence of AAV in RA patients with renal involvement, especially in those with renal dysfunction.
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