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


Despite substantial recent progress in the diagnosis and management of AAV, a growing body of research clearly indicates its higher mortality, with the overall 5-year survival rate reportedly reaching 70–80%. Furthermore, studies showed that those with renal involvement experience renal relapse more frequently and have an estimated 5-year ESKD-free survival rate of ~75% even in the recent decade.[22–24] Given the unfavourable clinical outcomes and considerable disease heterogeneity of AAV, continuous attempts are being made to better classify patients with this condition. In this study, we investigated the detection rate of RF in patients with AAV and categorized them according to the presence of RF and ANCA, and observed several findings regarding clinical characteristics and outcomes. First, RF was detected in nearly half the study subjects, suggesting that RF positivity is relatively common in AAV patients. Second, patients in the RF (+)/ANCA (+) group more frequently presented with general manifestations compared with the other groups, and the RF (+)/ANCA (+) and RF (−)/ANCA (−) groups exhibited differences in baseline clinical and laboratory data. Third, ESKD-free survival rates of the RF (−)/ANCA (+) group were significantly lower than those of the other groups. In the meantime, although the RF (+)/ANCA (+) group had a similar proportion of subjects with renal involvement compared with those in the RF (−)/ANCA (+) group, a worse prognosis concerning the occurrence of ESKD was confirmed in the RF (−)/ANCA (+) patients. Fourth, the Cox proportional hazard and PSM analyses demonstrated that the effect of RF on patient prognosis may not be directly relevant; however, there was a difference in the clinical presentation between patients in the RF (−)/ANCA (+) and RF (+)/ANCA (+) groups.

RF is defined as an antibody directed against the Fc region of immunoglobulin G and is generally detected in nearly three-quarters of patients with RA.[25] However, in the present study, the detection rate of RF was ~50%, which was slightly higher than that reported in our previous publication, and similar to the rate reported in a study from Japan.[26] These findings indicate that the presence of RF should not be overlooked in patients with AAV, and RF positivity could be higher than the estimated values reported in the existing literature. In contrast to the results obtained by Watanabe et al., we did not find a definite association between RF titres and BVAS. Taking into consideration the large genetic and geographic differences among AAV patients in Asia and Europe,[27] future research should be focused on verifying whether the detection rates of RF are influenced by ethnicity and severity of the disease.

Our results illustrated that AAV patients with double positivity for RF and ANCA had significantly higher rates (58.5%) of presenting with general manifestations compared with the other groups. Further, direct comparison of features between the RF (+)/ANCA (+) and RF (−)/ANCA (+) groups revealed distinct clinical characteristics. In particular, the RF (+)/ANCA (+) patients were older and had increased markers of inflammation such as WBC and neutrophil counts besides acute phase reactants of ESR and CRP levels; this may be partly explained by the fact that RF is usually tested to evaluate fever of unknown origin or when accompanied by constitutional/joint symptoms as included in the BVAS version 3.[17] Additionally, because RF titre is detected more commonly in the elderly in general, adjustment through a PSM was done to analyse this finding in detail. Of interest, as this laboratory finding was replicated even after PSM, it is possible that the co-existence of RF and ANCA positivity in AAV patients may be associated with a distinct phenotype indicating a higher degree of systemic inflammation.[9]

Notably, on comparing the outcomes of patients after dividing into four groups based on RF and ANCA status, a significant difference was identified in the ESKD- and relapse-free survival rates; the ESKD-free survival rate, particularly, was lower in the RF (−)/ANCA (+) group compared with that of the other groups. Although the rates of renal involvement were comparable between the RF (+)/ANCA (+) and RF (−)/ANCA (+) groups, the baseline creatinine levels were significantly lower in the RF (+)/ANCA (+) group, while the ESKD-free survival rate was significantly lower in the RF (−)/ANCA (+) group. These results indicate that patients in the RF (+)/ANCA (+) group seemed to possess different clinical characteristics and prognosis compared with those in the RF (−)/ANCA (+) group. Meanwhile, patients with ANCA positivity at baseline were more likely to experience disease relapse than those without; this is similar to the result of a previous study that showed ANCA is associated with relapse in a subgroup of patients with AAV.[28] It is unclear why patients with RF and ANCA positivity had better renal prognosis compared with those in the RF (−)/ANCA (+) group; nonetheless, there are two plausible explanations for this observation. First, there are experimental evidences suggesting that RF may have protective effects in autoimmune diseases by inhibiting the function of the complement system.[29,30] Moreover, studies by Skare et al. and Fedrigo et al. described that RF positivity in patients with SLE is associated with decreased risk of lupus nephritis.[31,32] Even though the immune complex is not observed in kidney tissues of AAV patients, systemic activation of the complement pathway is known to play a crucial role in the pathogenesis of AAV and is implicated in the development of glomerulonephritis.[33,34] Therefore, complement inhibition is now suggested as a potential therapeutic target for the treatment of AAV.[35,36] In this context, RF positivity in AAV patients may protect against the occurrence of ESKD. Further, RF positivity was associated with decreased odds of developing ESKD in the univariate Cox proportional analysis, although it was not significant after adjustment. Second, given that the proportion of those with general manifestations was higher in the RF (+)/ANCA (+) group, AAV might have been diagnosed in these patients before acute deterioration of renal function because they had complaints related to systemic features more often. Supported by this assumption, it was revealed that baseline creatinine was significantly lower in the RF (+)/ANCA (+) group than in the RF (−)/ANCA (+) group. Nonetheless, the PSM analysis conducted to investigate whether RF had a direct renoprotective role in AAV patients showed that the ESKD-free survival rate was comparable between the RF (+)/ANCA (+) and RF (−)/ANCA (+) groups after matching was performed. Therefore, despite differences in clinical features and prognosis between the patients in the two groups, we could not conclude that RF had a mitigating effect on kidney inflammation in AAV patients.

One of the important results of this study is that the patients in the RF (+)/ANCA (+) group with AAV presented with different clinical features compared with patients in other groups. In particular, a higher rate of general involvement in those with double positivity for RF and ANCA implies that the possibility of AAV should also be considered in those presenting with constitutional symptoms, given that different therapeutic approaches are required for patients with AAV.[22] In addition, another key finding was that the patients in the RF (+)/ANCA (+) group were less likely to progress to ESKD compared with patients in the RF (−)/ANCA (+) group. Of note, as presented in Supplementary Table S3 (available at Rheumatology online), there were no significant differences in the medications that were used in the RF (+)/ANCA (+) and RF (−)/ANCA (+) groups. Therefore, compared with the patients in the RF (−)/ANCA (+) group, the implementation of optimal treatment may be especially beneficial for those in the RF (+)/ANCA (+) group to prevent the development of ESKD.

This study has several limitations. First, this was a retrospectively designed, single-centre study, and the influence of treatment on the prognosis of patients could not be analysed precisely. Second, a relatively small number of patients was included; therefore, we were unable to perform a subgroup analysis to evaluate the differential effect of RF in AAV patients according to ANCA specificity. Third, putative mechanisms leading to the decreased incidence of ESKD in the RF (+)/ANCA (+) group compared with that in the RF (−)/ANCA (+) group could not be elucidated in this study. Fourth, RF testing in AAV patients was done on the discretion of the attending physician; this might have resulted in a selection bias and influenced the rates of RF detection in our study population. Analysis from well-designed prospective studies and a larger number of AAV patients is necessary in the future to validate our results and provide answers to unresolved issues.

In conclusion, we found that RF was detected in approximately half the AAV patients who underwent RF testing. Double positivity for RF and ANCA was associated with a distinct clinical phenotype indicating a higher proportion of those presenting with general manifestations. In addition, compared with the RF (−)/ANCA (+) patients, those in the RF (+)/ANCA (+) group demonstrated higher systemic inflammation, but had a favourable renal prognosis. Additional investigations are required to provide a better understanding of the clinical significance of RF in patients with AAV.