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.

Abstract and Introduction

Abstract

Objective: To investigate the significance of RF positivity in ANCA-associated vasculitis (AAV) patients.

Methods: AAV patients were divided into groups as follows: RF (+)/ANCA (+) (n = 94), RF (−)/ANCA (+) (n = 80), RF (+)/ANCA (−) (n = 15) and RF (−)/ANCA (−) (n = 25). Their clinical data, organ involvement patterns, laboratory data, and patient outcomes were assessed. Kaplan–Meier analysis and propensity score matching (PSM) were performed to compare outcomes and analyse differences between the groups.

Results: Of the 214 patients, RF and ANCA positivity was found in 109 (50.9%) and 174 (81.3%) patients, respectively. RF (+)/ANCA (+) patients more frequently presented with general manifestations (58.5%) than the other groups. Additionally, compared with those of RF (−)/ANCA (+) group, RF (+)/ANCA (+) patients were older, had higher white blood cell, neutrophil, platelet counts and acute phase reactants; however, creatinine and albumin levels were lower. The end-stage kidney disease-free survival rate was significantly higher in the RF (+)/ANCA (+) group (P =0.013), while the proportion of renal involvement was comparable to the RF (−)/ANCA (+) group. PSM showed no difference in patient outcomes between the two groups after adjustment.

Conclusion: RF positivity was associated with a distinct phenotype in AAV patients. In particular, difference was observed in clinical features and outcomes between RF (+)/ANCA (+) and RF (−)/ANCA (+) groups, although the direct prognostic implication of RF was not evident.

Introduction

Primary systemic vasculitides (PSV) refer to a group of chronic autoimmune disorders affecting various-sized vessels.^[1,2] Among the primary systemic vasculitides, ANCA-associated vasculitis (AAV) is characterized by necrotizing inflammation of the small- and medium-sized vessels, which is typically associated with the production of ANCAs against MPO or proteinase 3 (PR3). A traditional approach of categorizing AAV is to classify it into three different subgroups clinically according to the patterns of affected organs and the types of ANCAs detected: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA).^[3] However, the features of AAV are largely variable and substantial genetic and geographic disparities exist; therefore, continuous efforts have been made to better define the subtypes of AAV patients.^[4] Recently, accumulating evidence has suggested that categorizing AAV patients based on ANCA specificity could aid in identifying patients with similar characteristics.^[5] This method of classification is significant because it could provide more information on treatment response, disease relapse and long-term outcomes that are relevant to patient prognosis.^[6,7] Nevertheless, owing to the diverse clinical spectrum of AAV in patients, a better understanding of this complex, heterogeneous disorder is necessary.

RF, a classic autoantibody that was initially identified in patients with RA, is widely tested in clinical practice for differentiating between the causes of joint pain.^[8] However, considering that RF is detected in cases of several rheumatic and non-rheumatic diseases as well as in healthy subjects, its accuracy in diagnosing RA is restricted when clinical features suggestive of inflammatory arthritis are absent.^[9] Further, there are reports suggesting that RF is also frequently found in the peripheral circulation of patients with systemic vasculitis.^[10] Similarly, we have previously found that RF was present in ~40% of patients with AAV, although the effect that RF had on the risk of relapse was unclear.^[11] We have also demonstrated that RF positivity was associated with cutaneous manifestation in EGPA patients at the time of diagnosis, suggesting that this antibody could have clinical relevance in AAV and should be further investigated. Therefore, in this study, we aimed to evaluate whether patients with AAV possessing RF had distinct clinical features and different outcomes.

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Table 1. Baseline clinical characteristics of patients tested for RF
	Total patients (n = 214)
Clinical data
Age (years)	60.5 (49.0–69.0)
Male sex, n (%)	75 (35.0)
BMI (kg/m²)	22.2 (3.0)
BVAS	12.0 (8.0–18.0)
FFS	1.0 (1.0–2.0)
Diagnosis, n (%)
MPA	118 (55.1)
GPA	52 (24.3)
EGPA	44 (20.6)
Organ involvement, n (%)
General	91 (42.5)
Cutaneous	43 (20.1)
Mucous membranes/eyes	9 (4.2)
Ear, nose and throat	97 (45.3)
Chest	132 (61.7)
Infiltrate	71 (33.2)
Nodule or cavity	48 (22.4)
Pleural effusion	20 (9.3)
Massive hemotypsis/alveolar haemorrhage	7 (3.3)
Wheeze	3 (1.4)
Endobronchial involvement	2 (0.9)
Cardiovascular	43 (20.1)
Congestive heart failure	31 (14.5)
Pericarditis	10 (4.7)
Cardiomyopathy	7 (3.3)
Abdominal	10 (4.7)
Peritonitis	6 (2.8)
Bloody diarrhea	4 (1.9)
Renal	127 (59.3)
Nervous system	69 (32.2)
Neuropathy	44 (20.6)
Mononeuritis multiplex	13 (6.1)
Headache	8 (3.7)
Stroke	4 (1.9)
Meningitis	1 (0.5)
Cranial nerve palsy	1 (0.5)
Laboratory data
RF positivity, n (%)	109 (50.9)
ANCA positivity, n (%)	174 (81.3)
White blood cell count (/mm³)	9210.0 (6450.0–13150.0)
Neutrophil count (/mm³)	6220.0 (4100.0–9740.0)
Platelet count (×1000/mm³)	301.5 (227.0–389.0)
Haemoglobin (g/dl)	11.1 (9.3–13.0)
ESR (mm/h)	62.0 (23.0–97.0)
CRP (mg/l)	14.9 (1.7–76.5)
Creatinine (mg/dl)	0.9 (0.7–1.9)
Albumin (mg/dl)	3.6 (3.0–4.1)
Aspartate aminotransferase (IU/l)	18.0 (15.0–24.0)
Alanine aminotransferase (IU/l)	15.0 (11.0–25.0)
Patient outcomes during follow-up, n (%)
All-cause mortality	23 (10.7)
ESKD	39 (18.2)
Relapse	70 (32.7)

Continuous data are presented as median [interquartile range (IQR)] or mean (S.D.) as appropriate, whereas categorical data are shown as numbers (percentage). BVAS: Birmingham vasculitis activity score; FFS: five factor score; MPA: microscopic polyangiitis; GPA: granulomatosis with polyangiitis; EGPA: eosinophilic granulomatosis with polyangiitis; ESKD: end-stage kidney disease.

Table 2. Patterns of organ involvement according to RF and ANCA status
Organ involvement, n (%)	RF (+)/ANCA (+) group (n = 94)	RF (−)/ANCA (+) group (n = 80)	RF (+)/ANCA (−) group (n = 15)	RF (−)/ANCA (−) group (n = 25)	P-value
General	55 (58.5)	27 (33.8)	4 (26.7)	5 (20.0)	<0.001
Cutaneous	12 (12.8)	10 (12.5)	9 (60.0)	12 (48.0)	<0.001
Mucous membranes/eyes	3 (3.2)	3 (3.8)	1 (6.7)	2 (8.0)	0.706
Ear, nose and throat	44 (46.8)	31 (38.8)	9 (60.0)	13 (52.0)	0.121
Chest	65 (69.1)	50 (62.5)	8 (53.3)	9 (36.0)	0.022
Cardiovascular	21 (22.3)	15 (18.8)	3 (20.0)	4 (16.0)	0.886
Abdominal	5 (5.3)	3 (3.8)	1 (6.7)	1 (4.0)	0.940
Renal	59 (62.8)	55 (68.8)	5 (33.3)	8 (32.0)	0.002
Nervous system	34 (36.2)	16 (20.0)	9 (60.0)	10 (40.0)	0.007

Data are shown as numbers (percentage).

Table 3. Comparison between RF (+)/ANCA (+) and RF (−)/ANCA (+) groups
	RF (+)/ANCA (+) group (n = 94)	RF (−)/ANCA (+) group (n = 80)	P-value
Clinical data
Age (years)	65.5 (54.0–71.0)	55.6 (14.7)	0.004
Male sex, n (%)	30 (31.9)	33 (41.3)	0.203
BMI (kg/m²)	21.9 (3.0)	22.3 (3.2)	0.400
BVAS	13.0 (9.0–19.0)	12.0 (7.5–18.0)	0.262
FFS	2.0 (1.0–2.0)	1.0 (1.0–2.0)	0.469
Diagnosis, n (%)			0.565
MPA	57 (60.6)	46 (57.5)
GPA	22 (23.4)	24 (30.0)
EGPA	15 (16.0)	10 (12.5)
Laboratory data
p-ANCA (or MPO-ANCA) positivity, n (%)	84 (89.4)	66 (82.5)	0.193
c-ANCA (or PR3-ANCA) po sitivity, n (%)	12 (12.8)	21 (26.3)	0.024
Double ANCA positivity, n (%)	2 (2.1)	7 (8.8)	0.082
White blood cell count (/mm³)	11833.2 (4690.7)	7510.0 (5950.0–10540.0)	<0.001
Neutrophil count (/mm³)	8798.3 (4195.6)	5325.0 (3850.0–8275.0)	<0.001
Platelet count (×1000/mm³)	356.5 (269.0–477.0)	268.5 (209.5–340.5)	<0.001
Haemoglobin (g/dl)	10.3 (9.2–12.4)	10.9 (2.5)	0.637
ESR (mm/h)	78.5 (49.0–119.0)	56.5 (36.7)	<0.001
CRP (mg/l)	44.5 (4.0–112.4)	7.7 (1.6–48.3)	<0.001
Creatinine (mg/dl)	0.9 (0.7–1.5)	1.3 (0.7–4.1)	0.003
Albumin (mg/dl)	3.3 (0.8)	3.7 (0.7)	<0.001
Aspartate aminotransferase (IU/l)	19.0 (15.0–24.0)	18.0 (15.0–22.5)	0.482
Alanine aminotransferase (IU/l)	15.0 (10.0–23.0)	15.5 (11.0–25.0)	0.330
Urinary findings, n (%)
Haematuria	41 (43.6)	48 (60.0)	0.032
Proteinuria	46 (48.9)	41 (51.3)	0.762
Renal histology, n (%)^a			0.066
Sclerotic	4 (4.3)	10 (12.5)
Focal	22 (23.4)	10 (12.5)
Cresenteric	7 (7.4)	8 (10.0)
Mixed	10 (10.6)	6 (7.5)

^aRenal biopsy was performed in 77 patients. Continuous data are presented as median [interquartile range (IQR)] or mean (S.D.) as appropriate, whereas categorical data are shown in number (percentage). BVAS: Birmingham vasculitis activity score; C: cytoplasmic; EGPA: eosinophilic granulomatosis with polyangiitis; FFS: five factor score; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; P: perinuclear; PR3: proteinase 3.

Table 4. Risk factors associated with end-stage kidney disease in patients with renal manifestation at baseline ( n = 127)
	Univariate analysis			Multivariate analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age	1.002	0.978, 1.027	0.865
Male sex	1.084	0.531, 2.214	0.825
BMI	0.919	0.819, 1.033	0.155
BVAS	1.033	0.972, 1.098	0.292
FFS	1.588	1.115, 2.263	0.010	1.272	0.850, 1.902	0.242
RF positivity	0.458	0.226, 0.927	0.030	0.784	0.368, 1.673	0.529
ANCA positivity	1.302	0.398, 4.259	0.663
White blood cell count	1.000	1.000, 1.000	0.900
Neutrophil count	1.000	1.000, 1.000	0.546
Platelet count	0.998	0.995, 1.000	0.087
Haemoglobin	0.783	0.649, 0.944	0.011	0.933	0.792, 1.099	0.404
ESR	1.000	0.992, 1.009	0.967
CRP	1.001	0.995, 1.007	0.737
Creatinine	1.793	1.560, 2.061	<0.001	1.762	1.519, 2.044	<0.001
Albumin	0.751	0.469, 1.203	0.234
Aspartate aminotransferase	0.948	0.895, 1.004	0.066
Alanine aminotransferase	0.958	0.917, 1.001	0.056
Haematuria	1.975	0.763, 5.112	0.161
Proteinuria	2.000	0.820, 4.878	0.128

BVAS: Birmingham vasculitis activity score; FFS: five factor score.

Table 5. RF (+)/ANCA (+) and RF (−)/ANCA (+) group characteristics after propensity score matching
	RF (+)/ANCA (+) group (n = 63)	RF (−)/ANCA (+) group (n = 63)	P-value
Clinical data
Age (years)	63.0 (48.3–71.8)	59.0 (50.0–67.0)	0.237
Male sex, n (%)	23 (36.5)	21 (33.3)
BMI (kg/m²)	21.9 (3.0)	22.3 (3.0)	0.399
BVAS	15.0 (10.0–18.8)	13.0 (7.2)	0.178
FFS	2.0 (1.0–2.0)	1.0 (1.0–2.0)	0.320
Diagnosis, n (%)			0.630
MPA	40 (63.5)	35 (55.6)
GPA	13 (20.6)	19 (30.2)
EGPA	10 (15.9)	9 (14.3)
Laboratory data
p-ANCA (or MPO-ANCA) positivity, n (%)	56 (88.9)	52 (82.5)	0.310
c-ANCA (or PR3-ANCA) positivity, n (%)	9 (14.3)	17 (27.0)	0.079
Double ANCA positivity, n (%)	2 (3.2)	6 (9.5)	0.273
White blood cell count (/mm³)	11883.0 (5125.4)	7340.0 (5920.0–10550.0)	<0.001
Neutrophil count (/mm³)	8667.4 (4380.9)	5040.0 (3827.5–8210.0)	<0.001
Platelet count (× 1000/mm³)	359.0 (288.3–480.0)	294.3 (115.4)	<0.001
Haemoglobin (g/dl)	11.0 (9.3–12.3)	11.1 (2.4)	0.434
ESR (mm/h)	92.0 (49.5–120.0)	44.0 (23.0–84.0)	<0.001
CRP (mg/l)	38.0 (3.1–114.1)	6.2 (1.4–27.8)	0.005
Creatinine (mg/dl)	0.8 (0.7–1.8)	1.0 (0.7–2.0)	0.349
Albumin (mg/dl)	3.4 (0.8)	3.7 (0.7)	0.020
Aspartate aminotransferase (IU/l)	18.0 (15.0–23.8)	18.0 (15.0–24.8)	0.674
Alanine aminotransferase (IU/l)	14.0 (9.3–22.5)	17.0 (11.0–25.8)	0.087
Urinary findings, n (%)
Haematuria	30 (47.6)	36 (57.1)	0.286
Proteinuria	33 (52.4)	29 (46.0)	0.478
Renal histology, n (%)^a			0.198
Sclerotic	3 (4.8)	8 (12.7)
Focal	12 (19.0)	10 (15.9)
Cresenteric	6 (9.5)	5 (7.9)
Mixed	8 (12.7)	3 (4.8)

^aRenal biopsy was performed in 55 patients. Continuous data are presented as median [interquartile range (IQR)] or mean (S.D.) as appropriate, whereas categorical data are shown in number (percentage). BVAS: Birmingham vasculitis activity score; C: cytoplasmic; EGPA: eosinophilic granulomatosis with polyangiitis; FFS: five factor score; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; P: perinuclear; PR3, proteinase 3.