Rheumatoid Factor Positivity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

A Distinct Clinical Entity or Innocent Bystander?

Sung Soo Ahn; Jang Woo Ha; Yong-Beom Park; Sang-Won Lee


Rheumatology. 2022;61(4):1366-1375. 

In This Article

Materials and Methods

Patient Selection

We conducted a retrospective electronic medical record analysis to identify AAV patients in the Division of Rheumatology, Severance Hospital, between October 2005 and October 2020. To identify eligible patients, we extracted the data of 320 patients diagnosed with MPA, GPA or EGPA from the hospital's database. Subsequently, 106 patients were excluded according to the following criteria: (i) infectious diseases (including hepatitis B and hepatitis C, Epstein–Barr virus and cytomegalovirus infection, and infective endocarditis), concomitant malignancies and other connective tissue diseases including RA (using the 2010 ACR/European League Against Rheumatism criteria for RA[12,13]); (ii) incompatibility with the diagnosis of MPA, GPA or EGPA based on the 1990 ACR criteria, the 2007 European Medicines Agency algorithm and the definitions from the 2012 Chapel Hill Consensus Conference;[1,14–16] (iii) insufficient medical records to assess clinical manifestations and calculate the Birmingham vasculitis activity score (BVAS) version 3 and five factor score (FFS) (2009);[17,18] (iv) follow-up of <3 months; and (v) no RF testing or routine laboratory tests performed at the time of initial diagnosis (Supplementary Figure S1, available at Rheumatology online). Finally, 214 patients were selected and their data were analysed. The Severance Hospital's Institutional Review Board approved this study and all study procedures were performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards (IRB approval number 4–2020-1071). Owing to the retrospective study design, the requirement for informed consent was waived.

Assessment of Baseline Data, Patient Outcomes and Treatment

All baseline patient data collected on the date of AAV diagnosis were assessed. Clinical data including age, sex, BMI, BVAS version 3 and FFS (2009) were obtained, and the organ involvement pattern was investigated as defined through the assessment categories of BVAS version 3. Laboratory test results of RF positivity, ANCA positivity, white blood cell (WBC), neutrophil, and platelet counts, and ESR, along with levels of haemoglobin, CRP, creatinine, albumin, aspartate aminotransferase and alanine aminotransferase were included. RF levels were measured using the latex agglutination test (Denka Seiken Co., Ltd, Tokyo, Japan), and RF positivity was defined as a titre above 15 IU/ml, according to the institutional reference range. Patients were considered as p (perinuclear)-ANCA- or MPO-ANCA-positive, c (cytoplasmic)-ANCA- or PR3-ANCA-positive, and ANCA-negative according to the results of the indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for MPO-ANCA and PR3-ANCA.[19] Urinary findings of haematuria and proteinuria were investigated as per the definitions of BVAS version 3, and the results of renal histology were categorized in accordance with the previous literature.[17,20]

Regarding patient outcomes, the events of all-cause mortality, end-stage kidney disease (ESKD) and relapse were searched. The initiation of renal replacement therapy was considered as the date of ESKD and relapse was defined as recurrence or new onset of disease attributable to active vasculitis, in accordance with the European League Against Rheumatism recommendations.[21] In patients who experienced outcomes of interest, the follow-up duration was estimated as the time interval between the date of diagnosis and the first occurrence of the corresponding event, whereas cases with no outcomes of interest were evaluated up to the last follow-up date. The data of patients who were lost to follow-up were censored, and the last follow-up date of the patients was designated as January 2021. Treatment protocols consisted of glucocorticoids and immunosuppressive medications administered during the follow-up duration.

Statistical Analysis

All statistical analyses were performed using IBM SPSS Statistics for Windows, version 25 (IBM Corp., Armonk, NY, USA). Normally and non-normally distributed continuous variables were presented as mean (S.D.) and median (interquartile range) as appropriate, and normality testing was conducted using the Kolmogorov–Smirnov test. Categorical variables are shown as numbers (percentage). Differences between two continuous variables were compared using the student's t test or the Mann–Whitney U test, while the analysis of variance or the Kruskal–Wallis test was conducted for the comparison of three continuous variables. The χ 2 test or the Fisher's exact test was used to analyse the differences between categorical variables. The cumulative all-cause mortality-, ESKD- and relapse-free survival rates of the patients were evaluated and compared using the Kaplan–Meier analysis. Factors associated with the development of ESKD during the follow-up period were identified by the Cox proportional hazard analysis. In addition, we conducted a propensity score matching (PSM) analysis to reduce the difference in baseline characteristics between the RF (+)/ANCA (+) and RF (−)/ANCA (+) groups, and 1:1 matching was performed according to age, sex, renal involvement and creatinine levels. A P-value <0.05 was considered statistically significant in all analyses.