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Abstract

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an uncommon condition with heterogeneous multisystem organ involvement and significant morbidity and mortality. This study aimed to characterize the clinical features and laboratory characteristics, including B cell depletion, the ability to reduce corticosteroid dosage, and outcomes, of patients with AAV following rituximab treatment.

Methods: Retrospective clinical and laboratory data were collected from patients with AAV who visited our lupus unit, including 50 treated with rituximab. Numeric response variables (median and range) were collected, including age, follow-up duration, disease duration, and Birmingham Vasculitis Activity Score (version 3). Statistical analyses were conducted using the SPSS 25.0 software. Statistical significance was considered a p-value <.05.

Results: Of the 50 patients, 40 (80%) had granulomatosis with polyangiitis, 30 (75%) achieved remission, and 10 (25%) had active disease. Fifteen patients (30%) had positive ANCA levels at their last ANCA level assessment follow-up. Thirty-seven patients (74%) had B cell depletion, and 30 (81.1%) were in remission. Their median immunoglobulin levels were 7.6 (2.7–21.2) g/L for IgG, 0.5 (0.07–1.71) g/L for IgM, and 1.83 (0.14–4.87) g/L for IgA. Forty-two patients (84%) were able to lower their steroid dose to <7.5 mg, with 36 (85.7%) in remission and six (14.3%) having active disease (p = .003).

Conclusion: Our data suggests that most patients experience clinical remission after rituximab maintenance treatment. Half the patients were in remission, with normal creatinine levels and inflammatory markers. In addition, our patients could reduce steroid use.

Keywords

antineutrophil cytoplasmic antibody rituximab vasculitis treatment B- cell depletion steroid reduction

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare autoimmune disease that predominantly affects small vessels, leading to endothelial injury and tissue damage.¹ The three primary clinicopathological types of AAV—granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA)—share several clinical traits, pathophysiological origins, and treatment approaches.² AAV affects an average of 0.4–24 individuals per million annually.³ GPA’s incidence and prevalence rates are 9.7 and 62.9 per million individuals in the United Kingdom, respectively, compared to 13 and 218 per million individuals in the United States of America.^4,5 It has been estimated that there are 9–94 MPA cases per million individuals worldwide. MPA is more common in Southern Europe and Asia, while GPA is more common in Northern Europe. Their incidence increases with age, reaching a high level in the 60–70-year-old age group.^6,7

Immunosuppressive drugs are used to induce remission and for long-term maintenance therapy. Cyclophosphamide or rituximab with glucocorticoids is recommended as induction therapy for severe life-threatening AAV. Plasmapheresis may be added for severe diffuse pulmonary hemorrhage or rapidly progressing renal failure.⁵ Recommendations for maintenance therapy include tapering glucocorticoids, rituximab, azathioprine, or methotrexate.⁸ Rituximab is a chimeric monoclonal anti-membrane spanning 4-domains A1 (MS4A1/CD20) immunoglobulin G subclass 1 (IgG1) antibody that binds to the transmembrane protein CD20 with high specificity.⁹ Most patients involved in landmark randomized clinical trials that assessed rituximab as a remission induction and maintenance medication were Caucasian; only small percentages of the included patients were of Hispanic or African ancestry.¹ In addition, several non-randomized observational studies have provided further details regarding the effectiveness and safety of rituximab.¹⁰ The use of rituximab depends on its availability and cost.¹¹ In this study, we evaluated the results of patients with AAV treated with rituximab at a single tertiary center.

Materials and methods

Clinical and laboratory data were retrospectively collected from patients with AAV who visited the Louise Coote Lupus unit. We describe the clinical features and laboratory results of patients with AAV following rituximab treatment, including their ability to reduce corticosteroid dosage to <7.5 mg daily, B cell depletion, and outcomes. The inclusion criteria were adult patients with AAV who were treated with rituximab and received either 1 g every 6 months for the following 2 years or at least two standard doses, one standard course with a total of three doses, or one standard course of three doses with another dose repeated in 6 months. The exclusion criteria were patients with AAV who did not receive rituximab. This study adhered to the Declaration of Helsinki and was approved by the Research and Development Office of Guy and St. Thomas’ Hospital (approval number: No-13492). Written consent was not required since this was a retrospective study using anonymized data.

Statistical analysis

The statistical analysis was performed using the IBM SPSS software (version 25.0). Numeric response variables were collected and described as median and range, including disease duration, age, follow-up duration, and Birmingham Vasculitis Activity Score BVAS version 3.¹² Categorical variables are presented as frequencies and percentages, including sex, ethnicity, clinical manifestation, type of ANCA autoantibodies, laboratory features, B cell depletion, ability to reduce corticosteroid dosage, immunosuppression therapy used, and patient outcomes (remission vs active disease) following rituximab use. The chi-square test was used to compare categorical variables between patient outcomes. The level of statistical significance was defined as a p < .05.

Results

Among the 50 patients with AAV administered rituximab, 39 (78%) achieved remission, and 11 (22%) had active disease. There were 25 (50%) male patients with a median follow-up duration of 6 (1–14) years. The median age was 55.5 (24–83) years, and the median disease duration was 8 (1–36) years (Table 1). Of the 50 patients, 30 (75%) had GPA that had achieved remission, seven (14%) had EGPA that achieved remission, and two (66.7%) had MPA that had achieved remission. There was no association between the ANCA type and disease outcomes. Of the 50 patients, 26 (74.3%) with positive anti-proteinase 3 (PRTN3/PR3) ANCAs achieved remission compared to nine with active disease (25.7%). In addition, we identified that 39 patients (78%) had negative anti-MPO antibody results, while 11 patients (22%) had anti-MPO antibodies. Only 2 of the 11 patients (18.2%) had an active disease outcome, whereas 9 patients (81.8%) had remission, but the correlation between anti-MPO positive and disease outcome was not statistically significant (p = .729) (Table 1). Thirty-two of the 50 patients (64.0%) tested positive for cytoplasmic ANCA, while 15 of the 50 patients (30.0%) tested positive for perinuclear ANCA. At the last ANCA level assessment follow-up, 15 patients (30%) had positive ANCA levels, of which 12 (80%) were in remission and three (20%) had active disease, while 35 patients (70%) had negative ANCA levels, of which 27 (77.1%) were in remission and eight (22.9%) had active disease (p = .823). Forty-four patients (88%) had upper respiratory tract involvement, 36 (72%) had lower respiratory tract involvement, 25 (50%) had musculoskeletal involvement, 23 (46%) had ear-nose-and-throat involvement, 11 (22%) had ANCA-related glomerulonephritis, 20 (40%) had eye involvement, and eight (16%) had cutaneous, neurologic, and subglottic stenosis (Table 2). Forty-four patients (88%) received the standard two 1 g doses and multiple courses of rituximab, of which 22 received 1 g every 6 months for the following 2 years and 22 received at least two standard doses. In addition, five patients received one standard course with three doses. Moreover, one patient received one standard course of three rituximab doses, with another given after 6 months. The median baseline BVAS was 9 (4–26) before rituximab treatment and 0 (0–15) following rituximab, with most outcomes being remission (p = .000).

Table 1.

Patients’ characteristics and AAV outcome.

Variable	Patients in remissionN = 39 (78%)	Active patientsN = 11 (22%)
Median age, years	56	54
Median disease duration, years	8	4
Ethnicity n (%)
Caucasian	26 (78.8%)	7 (21.2%)
African	-	1 (100%)
Asian	3 (100%)	-
Mixed	1 (100%)	-
NA	9 (75%)	3 (25%)
GPA n (%)	30 (75%)	10 (25%)
EGPA n (%)	7 (100%)	-
MPA n (%)	2 (66.7%)	1 (33.3%)
PR3(+) n (%)	26 (74.3%)	9 (25.7%)
MPO (+) n (%)	9 (81.8%)	2 (18.2%)
B-cell <100 cls/mL) n (%)	30 (81.1%)	7 (18.9%)
Abnormal creatinine n (%)	17 (70.8%)	7 (29.2%)
Significant UPCR n (%)	9 (69.2%)	4 (30.8%)
Normal ESR n (%)	24 (85.7%)	4 (14.3%)
Normal CRP n (%)	23 (85.2%)	4 (14.8%)
Median BVAS pre rituximab	8	11
Median BVAS post rituximab	0	5

AAV: antineutrophil cytoplasmic antibody-associated vasculitis; GPA: granulomatosis with polyangiitis; EGPA: eosinophilic granulomatosis with polyangiitis; MPA: microscopic polyangiitis; PR3: anti-proteinase-3; MPO: (please define this); UPCR: urine protein-creatinine ratio; ESR: erythrocyte sedimentation rate; CRP: C Reactive protein; BVAS: Birmingham Vasculitis Activity Score.

Table 2.

Association between study variables and disease outcome.

	Disease outcome		Total	p Value
	Remission	Active
	N (%)
Gender				0.733
Male	20 (80.0)	5 (20.0)	25 (100.0)
Female	19 (76.0)	6 (24.0)	25 (100.0)
Disease duration				0.084
1–5 years	14 (70.0)	6 (30.0)	20 (100.0)
6–10 years	13 (100.0)	0 (0.0)	13 (100.0)
>10 years	12 (70.6)	5 (29.4)	17 (100.0)
Type of ANCA vasculitis				0.300
GPA	30 (75.0)	10 (25.0)	40 (100.0)
EGPA	7 (100.0)	0 (0.0)	7 (100.0)
MPA	2 (66.7)	1 (33.3)	3 (100.0)
Glomerulonephritis				0.193
Yes	7 (63.6)	4 (36.4)	11 (100.0)
No	32 (82.1)	7 (17.9)	39 (100.0)
Upper respiratory tract				0.737
Yes	34 (77.3)	10 (22.7)	44 (100.0)
No	5 (83.3)	1 (16.7)	6 (100.0)
Lower respiratory tract				0.951
Yes	28 (77.8)	8 (22.2)	36 (100.0)
No	11 (78.6)	3 (21.4)	14 (100.0)
Presence of subglottic stenosis				0.248
Yes	5 (62.5)	3 (37.5)	8 (100.0)
No	34 (81.0)	8 (19.0)	42 (100.0)
Presence of cardiac manifestation				0.909
Yes	4 (80.0)	1 (20.0)	5 (100.0)
No	35 (77.8)	10 (22.2)	45 (100.0)
Presence of eye involvement				0.094
Yes	18 (90.0)	2 (10.0)	20 (100.0)
No	21 (70.0)	9 (30.0)	30 (100.0)
Presence of ENT involvement				0.468
Yes	19 (82.6)	4 (17.4)	23 (100.0)
No	20 (74.1)	7 (25.9)	27 (100.0)
Presence of cutaneous manifestation				0.823
Yes	6 (75.0)	2 (25.0)	8 (100.0)
No	33 (78.6)	9 (21.4)	42 (100.0)
Presence of musculoskeletal manifestation				0.119
Yes	21 (87.5)	3 (12.5)	24 (100.0)
No	18 (69.2)	8 (30.8)	26 (100.0)
Presence of neurological involvement				0.651
Yes	5 (71.4)	2 (28.6)	7 (100.0)
No	34 (79.1)	9 (20.9)	43 (100.0)
Biopsy confirmed AAV				0.033*
Yes	6 (15.4)	5 (45.5)	11 (22.0)
No	33 (84.6)	6 (54.5)	39 (78.0)
Ability to reduce steroid				0.003**
Yes	36 (92.3)	6 (54.5)	42 (84.0)
No	3 (7.7)	5 (45.5)	8 (16.0)

**p<.01, *p<.05. ANCA: antineutrophil cytoplasmic antibody; AAV: antineutrophil cytoplasmic antibody-associated vasculitis; GPA: granulomatosis with polyangiitis; EGPA: eosinophilic granulomatosis with polyangiitis; MPA: microscopic polyangiitis; ENT: ear, nose, and throat.

Thirty-seven patients (74%) had B cell depletion (<100 cells/mL), and 30 (81.1%) were in remission. The median Ig levels after treatment were 7.6 (2.7–21.2) g/L for IgG, 0.5 (0.07–1.71) g/L for IgM, and 1.83 (0.14–4.87) g/L for IgA. Twelve (70.6%) of the 17 patients (34%) with a high erythrocyte sedimentation rate (ESR) were in remission, and 14 (66.7%) of the 21 patients (42%) with a high C-reactive protein (CRP) level were in remission. Twenty-four patients (48.0%) had an abnormal creatinine level. The median creatinine level was 80 (53–441) µmol/L across all patients, 79 (53–441) µmol/L in remission patients, and 91 (59–172) µmol/L in active patients. However, 44 patients (88.0%) had normal albumin levels, and 13 (26%) had a normal urine protein-to-creatinine ratio (PCR). Regarding adverse effects, five patients (10.0%) administered rituximab developed infections with no other adverse effects such as malignancy or severe reaction. Forty-two patients (84%) were able to lower their steroid dose to <7.5 mg, of which 36 patients (85.7%) were in remission and six (14.3%) had active disease (p = .003). Fifteen patients were immunosuppressed with cyclophosphamide and azathioprine (30.0%) (Table 3).

Table 3.

Type of immunosuppression in induction and maintenance.

Immunosuppression	N (%)
Cyclophosphamide	3 (6.0)
Cyclophosphamide +MMF+AZA	3 (6.0)
Cyclophosphamide + AZA+MTX	4 (8.0)
Cyclophosphamide +MMF+AZA+MTX	3 (6.0)
MMF+AZA+MTX	2 (4.0)
AZA+MTX	2 (4.0)
MMF+AZA	1 (2.0)
Cyclophosphamide +MTX	4 (8.0)
MTX+HCQ	1 (2.0)
Cyclophosphamide +MMF+AZA+Tacroliums	1 (2.0)
MMF	2 (4.0)
AZA	3 (6.0)
MTX	4 (8.0)
Cyclophosphamide +AZA	15 (30.0)

MMF: mycophenolatemofetil; AZA: azathioprine; MTX: methotrexate; HCQ: hydroxychloroquine.

Discussion

This study evaluated the outcomes of 50 patients with AAV treated with rituximab as a remission induction or maintenance therapy based on real-world experience. Our findings showed that most patients experienced clinical remission after rituximab maintenance treatment. Despite being of various ethnicities, most of our patients were Caucasian (78.8%). Only one patient was of African ancestry, limiting the generalizability of these data.

The disease duration in our study group ranged from one to 10 years, and there were equal numbers of male and female patients.¹³ Unlike the male predominance in Western cohorts, our data are consistent with other studies.^14,15 Clinical signs and symptoms of AAV typically impact several body areas.¹⁶ Depending on their disease severity and prognostic factors, patients with AAV frequently have poor prognoses.¹⁷ This prognosis is attributable to the high rate of the disease’s relapse and its associated complications, either due to the disease or its complications or the adverse side effects of treatment. The long-term exposure to glucocorticoids caused by AAV’s relapsing/remitting nature is frequently associated with serious adverse effects and considerable morbidity.¹⁸ Similar to other autoimmune disorders, attempts are being made to create alternative therapies that require lower levels of glucocorticoid use.¹⁹ Most previous clinical trials and retrospective studies have examined the relationship between high dosages of glucocorticoids and rituximab as remission induction therapy for AAV.^20–23 In our study, we used two standard rituximab doses of 1 g, followed by multiple doses (median = 2 [1–9]), along with different combinations of immunosuppressants, achieving remission in 39 patients. Low-dose rituximab has shown similar results as conventional doses in other autoimmune diseases.²⁴ Takakuwa et al.²⁵ reported similar cumulative complete remission in patients treated with low-dose and high-dose rituximab.^26–28

The most diagnosed type of AAV was GPA, with 30 patients (75%) in remission and 10 (25%) with active disease. In our study, GPA was relatively more common than EGPA or MPA (Table 1). The most frequently reported involvement in this study was pulmonary, particularly lower respiratory involvement. Other studies have reported similar results.^29,30

Pulmonary manifestations were common in our cohort of patients with GPA and MPA, similar to previous studies.^29,30 Due to the high percentage of patients with lower lung involvement (77.8%), various complications were identified, with infection (10%) being the most common. While pulmonary manifestations were slightly more common in our patients with GPA, more serious respiratory conditions were present in our patients with MPA. A recent review of patients with AAV living in Chicago also concluded that Hispanic patients with AAV present more severe disease activity. However, GPA is the predominant subtype of this disease.³¹

Unlike in Holle et al.,²³ the presence of granulomatous lesions was not associated with poor response to rituximab treatment in our study. This finding can likely be attributed to the high frequency of pulmonary masses in our patients since such patients generally respond better to treatment than those with other granulomatous manifestations.²³ However, low response rates have been associated with subglottic stenosis.^23,32,33 In our cohort, the median BVAS was 9 (4–26) at baseline and 0 (0–15) at the latest follow-up. Relapse rates were higher in patients whose pre-to post-rituximab BVAS scores decreased from 9 to 0, consistent with Yoo et al.,³¹ who reported that patients with high and low BVAS ratings experienced higher relapse rates. Nevertheless, the limitations of this study included its retrospective design and small sample size due to the disease’s rarity, which impacted the statistical significance of some correlations. In addition, several data were missing or incomplete in the patient records due to its retrospective collection.

Conclusions

Our data show that most patients experienced clinical remission following rituximab maintenance treatment. Half the patients were in remission, with normal creatinine levels and inflammatory markers. In addition, our patients were able to reduce steroid use. This single-center real-world data corroborates the extensive clinical trial data regarding AAV outcomes after rituximab therapy.

Study limitations

This retrospective study had a limited sample size due to the rarity of the disease and the possibility of missing or incomplete patient records.

Footnotes

Author contributions

Conceptualization: FA, SS, and DDC; data curation: FA, SS, and DDC; formal analysis and methodology: FA; supervision: SS and DDC; writing—original draft: FA; writing—review and editing: SS and DDC. All authors have read and approved the published version of the manuscript.

Declaration of conflicting interests

The authors declare no conflicts of interest regarding the research authorship and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors extend their appreciation to to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia, for funding this research (project number: RI-44-0018).

ORCID iDs

Fahidah Alenzi

Shirish R Sangle

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Anti-neutrophil cytoplasmic antibody associated vasculitis following rituximab: Outcomes of 50 patients in a tertiary single centre

Abstract

Keywords

Introduction

Materials and methods

Statistical analysis

Results

Discussion

Conclusions

Study limitations

Footnotes

Author contributions

Declaration of conflicting interests

Funding

ORCID iDs

References