
==== Front
Clin Exp Med
Clin Exp Med
Clinical and Experimental Medicine
1591-8890
1591-9528
Springer International Publishing Cham

39249581
1461
10.1007/s10238-024-01461-6
Review
The efficacy of rituximab in the treatment of IgA vasculitis nephritis
Xiong Yi 1
Cuevas Santiago 2
Xu Gaosi gaosixu@163.com

1
Zou Honghong honghzou195@163.com

1
1 https://ror.org/042v6xz23 grid.260463.5 0000 0001 2182 8825 The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006 Jiangxi People’s Republic of China
2 grid.411372.2 0000 0001 0534 3000 Molecular Inflammation Group, Biomedical Research Institute of Murcia, University Clinical Hospital Virgen de Arrixaca, Murcia, Spain
9 9 2024
9 9 2024
2024
24 1 21321 3 2024
31 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
The utility of Rituximab (RTX) for IgA vasculitis nephritis (IgAVN) is not well established. Up to now, we analysed the largest samples of IgAVN patients treated by RTX with a total of 41 retrieved subjects up to December 29, 2023 in the present systematic review. We assessed the clinical profiles, efficacy, and safety of RTX treatments. The present review showed that the renal function tended to be stabilized (P = 1.000) and urinalysis tended to normalize after RTX treatment with no serious adverse events reported. Moreover, 40% (16/40) of patients was freed use of glucocorticoid after RTX administration (P < 0.001). The remission rate was 92.7% (38/41) and complete remission rate was 46.3% (19/41) in IgAVN patients. Interestingly, 76.9% (10/13) of IgAVN child patients achieved complete remission when compared with 32.1% (9/28) of adult patients (P = 0.017). In summary, our results support the benefit of RTX therapy in IgAVN patients, especially children subjects.

Keywords

IgA vasculitis nephritis
Rituximab
Efficacy
"Thousand Talents Plan" project of Jiangxi ProvinceJXSQ2023201030 Xu Gaosi Kidney Disease Engineering Technology Research Centre Foundation of Jiangxi ProvinceNo. 20164BCD40095 Xu Gaosi http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China No. 82260143 Zou Honghong the Science and Technology Plan of Health Commission of Jiangxi ProvinceSJKP220210087 Zou Honghong issue-copyright-statement© Springer Nature Switzerland AG 2024
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pmcIntroduction

IgA vasculitis (IgAV), also known as Henoch-Schönlein purpura (HSP), is a systemic vasculitis characterized by IgA immune complex deposition within the blood vessels of the affected tissue [1]. IgA vasculitis nephritis (IgAVN) is a systematic vessel inflammation with renal involvement which is histologically indistinguishable from IgA nephropathy (IgAN), present with microscopic (and/or macroscopic) haematuria with or without proteinuria, nephritic and/or nephrotic syndrome [2–4]. Studies have found that abnormal Gd-IgA and elevated levels of IgA-IgG immunes complexes deposits in renal contribute to IgAN and IgAVN, suggesting they share the same pathomechanism, where the “Multiple Hits” theory was widely accepted [5, 6]. Given the current hypothesis about IgAN and IgAVN, many traditional immunosuppressive agents have been tried. However, the role of glucocorticoids (GSs) remains was an area of unknown. In addition, there is a lack of convincing evidence to support the efficacy of mycophenolate mofetil, cyclophosphamide, and azathioprine in patients [7].

Rituximab (RTX), first approved for clinical use in the late 1990s, is a chimeric monoclonal IgG1 antibody that exerts its B-cell depleting effect by binding to CD20, was initially used in the treatment of B cell lymphoma [8, 9]. RCT studies suggested that the efficacy of RTX in treating IgAN is not as satisfactory as desired [10]. Interestingly, although IgAN and IgAVN are similar in histopathology, literature data revealed the potential therapeutic effectiveness of RTX in IgAVN [11, 12]. As RTX depletes antibody-producing B cells, it may deplete the antibodies that drive IgAN and IgAVN.

Evidence and indications for the use of RTX continue to evolve and rapidly changed, however, its role in IgAVN has not been demonstrated. In the present literature review, we focus on the available cases published in the literature with biopsy proven IgAVN that received RTX, to assess the efficacy and safety of RTX in the treatment of IgAVN.

Method

Information sources and search strategy

All included studies were derived from PubMed, EMBASE, Scopus, Cochrane, and Web of Science as of December 29, 2023. The following keywords were used: (“Anaphylactoid purpura” OR “Henoch-Schönlein purpura” OR “Immunoglobulin A vasculitis” OR “Allergic purpura” OR “IgA vasculitis” OR “IgA vasculitis nephritis”) AND Rituximab. References from relevant articles retrieved in the initial search were manually identified, reviewed and data extracted, without language limitation.

Selection criteria

We included in our review all cases with biopsy proven IgAVN treated with rituximab. IgAV cases without renal function involvement and short of a set of available individual data including demographic, clinical, treatment and outcomes were excluded. IgAVN was classified following the 1990 ACR or 2010 EULAR/PRINTO/PRES IgAV criteria and renal involvement [13, 14]. Nephritis defined as present with microscopic (and/or macroscopic) haematuria with or without proteinuria, nephritic and/or nephrotic syndrome. All biopsy proven IgAVN adults and children who present as active nephritis and treat with RTX were included. IgAV cases without renal function involvement were excluded from the analysis. Children were defined as patients < 18 years at the time of diagnosis. Refractory diseases were defined as an inadequate response to treatment with glucocorticoids and or other immunosuppressants.

Disease outcome was classified as “remission” or “not response” based on any improvement/recovery or persistence/worsening of clinical manifestations. Complete response (CR) defined as proteinuria with a urinary albumin-creatinine ratio < 30 mmol/mg, 24-h urine protein < 0. 15 g/d, stable renal function with a decrease in the estimated glomerular filtration rate (eGFR) of < 5 ml/min/1.73 m2 from the baseline eGFR at the end of the follow-up, disappearance of haematuria (< 5 red blood cells/high power field), and additional extrarenal manifestation vanished in IgAVN patients. Relapse was defined as glucocorticoids dependence following RTX or recurrence of clinical symptoms. The eGFR was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula developed by Levey et al. [15].

Data extract and assessment

Structured table was used to abstract and collect data from articles in the present review (Table 1). Categorical variables were used to report the number and percentage of patients, analysed using the Pearson chi-square test. The Fisher Exact Test was used when the theoretical frequency T value < 5. Continuous variables were presented as a median, range, interquartile range (IQR), and qualitative values. McNemar’s test was used to compare differences of paired nominal data between the groups. Continuity correction was applied as some data for categorical variables had theoretical frequency T values less than five. All statistical analyses were performed using SPSS 27.0 software, and P < 0.05 indicated statistically significant differences.Table 1 Summary of 41 IgAVN patients included in the study

Case	Reference	Ethnicity/nationality	Age/Sex	Biopsy	Other disease	Reasons for RTX use	Organ involvement before RTX	Time elapsed between diagnosis and RTX (M)	Baseline	
Renal function before RTX	Urinalysis before RTX	Treatment before RTX	
1	Chung et al. [43]	NA	23/F	IgAVN (Skin biopsy)	–	Refractory disease	K, S	NA	Scr: 1.4 mg/dl	Haematuria	GS, AZA, CYC	
2	Bollee et al. [42]	NA	28/M	cIgAVN (Renal biopsy)	c-ANCA	NA	K, S	5	Scr: 1.6 mg/dl eGFR 55 ml/min/1.73 2	Haematuria and (UP: 11 g/d)	GS	
3	Donnithorne et al. [41]	Caucasian	17/M	IgAVN (M1E0S0T0C0)a	–	Refractory disease	A, J, K, N, S	NA	Scr: 0.7 mg/dl	Haematuria and proteinuria	GS, CTX	
4	Donnithorne et al. [41]	Caucasian	14/M	IgAVN (Skin biopsy)	–	Refractory disease	A, J, K, N, S	18	Scr: 1.0 mg/dl	Haematuria	GS	
5	Havill et al. [39]	Caucasian	38/F	cIgAVN	p-ANCA	Refractory disease	J, K, L, S	120	Abnormal	Haematuria and proteinuria	CTX, GS, AZA	
6	Pillebout et al. [38]	NA	22/M	cIgAVN (M0E0S0T0C1)a	–	First-line therapy	K, S	Immediately	Scr: 1.07 mg/dl	Haematuria and (UP: 1.1 g/d)	None	
7	El-Husseini et al. [37]	Caucasian	27/M	cIgAVN	–	Refractory disease	A, J, K, S	NA	Scr: 2.0 mg/dl	Haematuria and (UP: 8.0 g/d)	GS, CTX, PE	
8	Ishiguro et al. [36]	Japanese	68/F	cIgAVN (M1E1S1T0C1)a	–	Refractory disease	K	NA	Scr: 0.58 mg/dl	Haematuria and (UP:6.6 g/d)	GS, CTX	
9	Kostik et al. [35]	NA	7/F	cIgAVN (M1E1S1T0C2)a	–	Refractory disease	K	2	Scr: Normal	Haematuria and (UP:15–16 g/d)	GS, CTX, MMF, PE	
10	Pindi Sala et al. [34]	Mediterranean	49/F	IgAVN (Skin biopsy)	KT	Refractory disease	K, N, S	16	Scr: 1.21 mg/dl	Proteinuria (UP:0.26 g/d)	GS, TAC, AZA	
11	Abdo et al. [44]	NA	60/M	IgAVN	–	Refractory disease	P, K, S, C	Immediately	NA	NA	GS	
12	Hamilton et al. [33]	NA	27/M	cIgAVN (M1E1S0T0C1)a	–	Refractory disease	K, S	NA	Scr: 6.69 mg/dl	Proteinuria (UPCR: 2.40 g/g)	GS, CTX, HD, PE	
13	Bellan et al. [32]	NA	37/F	IgAVN (Renal biopsy)	–	Refractory disease	K, S	240	NA	Proteinuria	GS, CTX	
14	Perre et al. [30]	Caucasian	49/F	IgAVN (Renal biopsy)	–	Refractory disease	J, K, S	24	Scr: 1.47 mg/dl	NA	GS, LEF, PE	
15	Fenoglio et al. [45]	Caucasian	70/F	cIgAVN (M1E1S1T1C1)a	–	Refractory disease	J, K, S	NA	NA	Haematuria and proteinuria (UP: 2 g/d)	GS, MMF, IVIG	
16	Fenoglio et al. [45]	Caucasian	21/M	IgAVN (M1E1S1T1C0)a	–	Refractory disease	A, K, S	NA	NA	Haematuria and sub-nephrotic proteinuria	GS, CTX, CYC, AZA, IVIG, MMF	
17	Fenoglio et al. [45]	Chinese	43/M	IgAVN (M1E1S0T0C0)a	–	Contraindication to GS	A, J, K, S	NA	Scr: 5.6 mg/dl	Haematuria and proteinuria	GS	
18	Fenoglio et al. [45]	Caucasian	26/F	cIgAVN (M1E0S1T0C1)a	Rokitansky’s syndrome	Refractory disease	J, K, S	NA	Scr: Normal	Haematuria and proteinuria (UP: 1 g/day)	GS	
19	Fenoglio et al. [45]	Caucasian	55/M	IgAVN (M1E0S1T0C0)a	–	Contraindication to GS	A, J, K, S	NA	NA	Haematuria and proteinuria (UP: 1.5 g/d)	GS	
20	Lundberg et al. [29]	NA	19/F	IgAVN (M1E1S0T0C0)a	–	Refractory disease	K, S	D9	Scr: 1.09 mg/dl eGFR 74 ml/min/1.73 2	Haematuria and proteinuria (UACR: 1589 mg/mmol)	GS	
21	Lundberg et al. [29]	NA	49/F	IgAVN (M0E1S0T0C0)a	–	Refractory disease	A, K, S	Immediately	Scr: 1.14 mg/dl eGFR 56 ml/min/1.73 2	Haematuria and proteinuria (UACR: 653 mg/mmol)	GS, MMF	
22	Yeh et al. [28]	NA	7/M	cIgAVN	–	Refractory disease	A, K	NA	NA	Proteinuria	GS, AZA	
23	Crayne et al. [27]	Caucasian	2mo/M	IgAVN (Skin biopsy)	–	Refractory disease	K, S	26	NA	Haematuria and/or proteinuria	MTX, MMF, GS	
24	Crayne et al. [27]	Caucasian	16/M	IgAVN	–	Refractory disease	A, K, S	1.5	NA	Haematuria and/or proteinuria	MTX, GS	
25	Crayne et al. [27]	Caucasian	8/M	IgAVN	–	Refractory disease	A, J, K, S	27	NA	Haematuria and/or proteinuria	AZA	
26	Crayne et al. [27]	Caucasian	5/F	IgAVN	–	Refractory disease	A, K, S	3	NA	Haematuria and/or proteinuria	CTX, GS	
27	Crayne et al. [27]	Caucasian	14/M	IgAVN	–	Refractory disease	A, K, S	7	NA	Haematuria and/or proteinuria	HD, GS	
28	Crayne et al. [27]	Caucasian	8/M	IgAVN	–	Refractory disease	A, K, S	25	NA	Haematuria and/or proteinuria	MTX, MMF, GS	
29	Crayne et al. [27]	Hispanic	5/F	IgAVN	–	Refractory disease	A, K, S	3	NA	Haematuria and/or proteinuria	MTX, GS	
30	Crayne et al. [27]	Caucasian	13/F	IgAVN (Skin biopsy)	–	Refractory disease	A, J, K, S	96	NA	Haematuria and/or proteinuria	MTX, GS	
31	Torosoff et al. [26]	NA	61/M	IgAVN	–	Contraindication to CTX	A, C, K, S	Immediately	Renal insufficiency	Haematuria and proteinuria (UP: 2.0 g/d)	GS	
32	El-Reshaid et al. [25]	Arabian	30/F	IgAVN	–	Refractory disease	K	NA	Scr: Normal	Proteinuria (UP: 3 g/d)	GS	
33	Al Harash et al. [24]	Caucasian	45/F	IgAVN	–	Refractory Disease	K, S, L	Immediately	Scr: 2.3 mg/dl	Haematuria and proteinuria (UPCR: 6 g/d)	GS, PE, MMF	
34	Mamlouk et al. [23]	Caucasian	50/F	cIgAVN	CPI toxicity	Refractory disease	K	Immediately	Scr: 5.07 mg/dl	Haematuria and proteinuria (UP: 13.74 g/d)	GS, PE, RRT	
35	Suso et al. [22]	Hispanic	78/M	cIgAVN (M1E1S1T0C2)a	COVID-19 pneumonia	Refractory disease	K, S	Immediately	Scr: 1.96 mg/dl	Haematuria and proteinuria (UP: 10.7 g/d)	GS	
36	Uppal et al. [21]	Asia	46/M	cIgAVN	COVID-19 c-ANCA ( +)	First-line therapy	K, S	Immediately	Scr: 4.0 mg/dl	Haematuria and proteinuria	GS	
37	Amarapur et al. [20]	Indian	49/F	IgAVN (Skin biopsy)	–	Refractory disease	A, K	Immediately	Scr: 0.8 mg/dl	Haematuria and Proteinuria (UP: 1.2 g/d)	MMF, GS	
38	Hernanz et al. [19]	Hispanic	45/M	IgAVN (Skin biopsy)	–	Refractory disease	K, O	Immediately	eGFR > 60 ml/min/1.73m2	Haematuria and proteinuria	AZA, GS, dapsone	
39	Riley et al. [18]	NA	67/F	IgAVN (Skin biopsy)	–	Refractory disease	J, N, K, S	Immediately	Scr: 1.0 mg/dl eGFR 55 ml/min/1.73m2	Proteinuria (UP: 2.43 g/d)	GS	
40	Patel et al. [46]	NA	8/M	cIgAVN	–	Contraindication to GS	J, K, S	NA	Scr: Normal	Haematuria and proteinuria (UP: 0.33 g/d)	GS	
41	Valero et al. [16]	Hispanic	62/F	cIgAVN	p-ANCA COVID-19 ( +)	First-line therapy	K, S, O, J	NA	NA	Haematuria and proteinuria (UP: 1.4 g/d)	GS	
Case	Reference	RTX Protocol	Last follow-up	
Treatment after RTX	Urinalysis after RTX	Renal function after RTX	Follow-up (M)	Organ involvement after RTX	B cell depletion	Outcomes	AE	
1	Chung et al. [43]	(1 g/biw) RTX*2	GS (tapered), AZA, CYC	Normal	Scr: 1.1 mg/dl (M5)	5	None	achieved B cell depletion (M4)	CR. Symptom free and GS taper to 7.5 mg/d without recurrence. (M5)	NA	
2	Bollee et al. [42]	(375 mg/1.73 m2/week) RTX*4	None	Proteinuria (UP: 6 g/d)	Scr: 1.36 mg/dl eGFR 66 ml/min/1.73m2	5	K	achieved B cell depletion (M5)	R. Proteinuria decreased and Scr was improved. (M5)	NA	
3	Donnithorne et al. [41]	(1 g/biw) RTX*2	MMF (Finally stopped)	Proteinuria improved	Scr: 1.1 mg/dl	5	J, K	NA	R. The purpura, fevers, and hematochezia completely resolved; proteinuria improved. (M1)	NA	
4	Donnithorne et al. [41]	(375 mg/1.73 m2/week) RTX*4	GS (Finally stopped)	Normal	Scr: 0.8 mg/dl	33	None	NA	CR. Symptom free without recurrence. (M4.5)	NA	
5	Havill et al. [39]	NA	CTX, GS	NA	Scr: 1.1 mg/dl	120	None	NA	R. Scr is now stable at 1.1 mg/dl	NA	
6	Pillebout et al. [38]	(1 g/biw) RTX*2	None	Normal	Scr: 0.85 mg/dl	22	None	achieved B cell depletion (M1)	CR. Symptom free, Scr was 0.85 mg/ml, no proteinuria and Haematuria without recurrence	NA	
7	El-Husseini et al. [37]	(1 g/biw) RTX*3	GS (tapered)	Proteinuria (UP: 1.2 g/d)	Scr: 1.6 mg/dl	3	K	NA	R. Renal and extra-renal signs improved, Scr 1.6 mg/dl and proteinuria 1.2 g/ day with oral GS 20 mg/day. (M1.5)	NA	
8	Ishiguro et al. [36]	(375 mg/1.73 m2/week) RTX*4	GS (tapered)	Proteinuria (UP: normal)	Normal	12	None	achieved B cell depletion (M12)	CR. UP and Scr was normal with GS taper to 7.5 mg/d. (M12)	NA	
9	Kostik et al. [35]	(375 mg/1.73 m2/week) RTX*4	CTX, AZA, Tonnes, RTX, HD	Proteinuria (UP:0.3–1.0 g/d)	Normal	42	K	NA	R. UP was improved, renal sign relapse, additional RTX ineffective with finally ESRD need HD	NA	
10	Pindi Sala et al. [34]	(1 g/biw) RTX*2	GS, TAC	NA	NA	30	K	achieved B cell depletion (M1)	R. Extrarenal sign improved	Infection (M3)	
11	Abdo et al. [44]	(325 mg/1.73 m2/week) RTX*4	GS	NA	NA	2.5	None	NA	R. Free of symptoms	NA	
12	Hamilton et al. [33]	1 g, 0.7 g/week*3, 0.7 g, 1 g	RTX, PE, IVIG, HD, KT	Proteinuria (UPCR: 0.88 g/g)	Scr: 2.04 mg/dl	49	K	NA	R. Extrarenal sign improved, but renal sign relapse, additional RTX ineffective with finally ESRD need KT	NA	
13	Bellan et al. [32]	(375 mg/1.73 m2/week) RTX*4	(375 mg/1.73m2/week) RTX*4	Normal	NA	96	None	NA	CR. Normal urinalysis and free of symptoms with additional RTX. (M36)	NA	
14	Perre et al. [30]	(1 g/biw) RTX*2	RTX, GS (tapered), BTZ, IFX, MMF, TAC, CTX, IVIG, MTX, Tonnes, PE	NA	Scr: 1.13 mg/dl	69	J, K, S	NA	R. Clinical improvement and GS tapered	NA	
15	Fenoglio et al. [45]	(375 mg/1.73 m2/week) RTX*4	None	Normal	NA	96	None	NA	CR. One transient cutaneous relapse, UP remained undetectable (M1)	NA	
16	Fenoglio et al. [45]	(1 g/biw) RTX*2	MMF + GS (finally stopped), (1 g/biw) RTX*2	Normal	NA	33	None	NA	CR. Urinalysis normalization and symptom free with additional and maintained RTX. (M33)	NA	
17	Fenoglio et al. [45]	1 g RTX	None	Normal	Scr: 1.1 mg/dl	18	None	NA	CR. Free of symptoms, Scr was 1.1 mg/dl, urinary protein excretion is undetectable. (M18)	NA	
18	Fenoglio et al. [45]	(375 mg/1.73 m2/week) RTX*4	None	Normal	Scr: Normal	7	None	NA	CR. Scr normal and proteinuria is undetectable. (M7)	NA	
19	Fenoglio et al. [45]	(375 mg/1.73 m2/week) RTX*4	None	Proteinuria (UP: 0.5 g/d)	Scr: 1.0 mg/dl	3	K	NA	R. Symptom free and the Scr is 1.0 mg/dl and urinary protein excretion is 0.5 g/day	NA	
20	Lundberg et al. [29]	0.28 g RTX	OFAB 300 mg first dose, then (500 mg/week)*3	Haematuria and proteinuria (UACR: 9 mg/mmol)	Scr: 0.66 mg/dl eGFR 117 ml/min/1.73 2	22	K	achieved B cell depletion (M0.5)	R Albuminuria was below < 0.2 g/d, Scr was normal, but along with haematuria. (M12)	Allergic reaction	
21	Lundberg et al. [29]	(0.6 g/1.73 m2/biw) RTX*4	MMF + AZA + GS (finally stopped), RTX	Haematuria and proteinuria (UACR 23 mg/mmol)	Scr: 0.98 mg/dl eGFR 67 ml/min/1.73m2	22	K	achieved B cell depletion (M0.5)	R Abdomen relapse, finally creatinine was improved and UACR was < 250 mg/mmol and have haematuria with additional RTX. (M22)	Recurrent bronchospasm	
22	Yeh et al. [28]	Two doses of RTX	None	No proteinuria	NA	36	None	NA	CR. No abdominal symptom and proteinuria and without recurrence	NA	
23	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	GS (finally stopped), RTX	Normal	NA	96	None	achieved B cell depletion	CR. No active rash, nephritis (haematuria or proteinuria) with additional RTX	NA	
24	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	GS (finally stopped), RTX	Normal	NA	NA	None	achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria) with additional RTX	NA	
25	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	None	Normal	NA	NA	None	achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria), or gastrointestinal distress	NA	
26	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	GS (finally stopped)	Normal	NA	63	None	achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria)	NA	
27	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	GS (finally stopped)	Normal	NA	73	None	achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria)	NA	
28	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	GS (finally stopped)	Normal	NA	116	None	achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria)	NA	
29	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	RTX, MMF, IVIG, GS (finally stopped)	Normal	NA	NA	None	Not achieved B cell depletion	CR. No active rash, arthritis, nephritis (haematuria or proteinuria) with additional RTX	NA	
30	Crayne et al. [27]	(0.75 g/1.73 m2/biw) RTX*2	RTX, MMF, MTX	Normal	NA	96	A	Not achieved B cell depletion	R. No active rash, arthritis, nephritis (haematuria or proteinuria) with additional RTX, ongoing abdominal complaints, successfully weaned off GS	NA	
31	Torosoff et al. [26]	(375 mg/1.73 m2/week) RTX*4	HD	NA	Uremia	NA	K	NA	R. Cutaneous and cardiac manifestations completely resolved but ESRD need HD	NA	
32	El-Reshaid et al. [25]	(1 g/biw) RTX*2	GS (stopped)	Proteinuria (UP: 0.8 g/d)	Scr: 1.87 mg/dl	24	K	NA	NR. Because of the recurrence of AKI, re-kidney biopsy showed crescent formation, and RTX was discontinued and changed to high-dose GS therapy	NA	
33	Al Harash et al. [24]	(1 g/biw) RTX*2	HD	NA	Real function deteriorates	1	K, S, L	NA	NR. Infection, death. (M1)	NA	
34	Mamlouk et al. [23]	(1 g/biw) RTX*2	RRT (finally stopped)	Normal	Scr: 2.68 mg/dl	4	K	NA	CR. Renal function improved and urinalysis normalized	NA	
35	Suso et al. [22]	NA	GS	Haematuria and proteinuria (UP:6.0 g/d)	Scr: 1.4 mg/dl	NA	K	NA	R. Although proteinuria 6 g/d and haematuria, cutaneous purpura and Scr had improved	NA	
36	Uppal et al. [21]	(375 mg/1.73 m2/week) RTX*4	GS	Haematuria	Scr: 1.27 mg/dl	4	K	NA	R. Renal function improved, mild haematuria and PR3 titer decreased	NA	
37	Amarapur et al. [20]	(0.6 g/week) RTX*4	None	Normal	Normal	NA	None	NA	CR. Urinalysis normalization, and symptom free, without recurrence	NA	
38	Hernanz et al. [19]	(1 g/biw) RTX*2	AZA, GS, dapsone	NA	NA	NA	K	NA	R. Ocular condition free without recurrence	NA	
39	Riley et al. [18]	(375 mg/1.73 m2/week) RTX*4	GS	Proteinuria (UP: 0.8 g/d)	Scr: 0.88 mg/dl eGFR > 60 ml/min/1.73m2	2	K, N	NA	R. Symptom, renal function, and urinalysis improved, but neuropathy persisted	NA	
40	Patel et al. [46]	(375 mg/1.73 m2/biw) RTX*2	GS (finally stopped)	Normal	Scr: Normal	12	None	NA	CR. Symptom free, urinalysis normalization without recurrence	NA	
41	Valero et al. [16]	(375 mg/1.73 m2/week) RTX*4	GS	NA	NA	K	None	NA	R. renal function was recovered, proteinuria and ANCA levels were notably reduced, and cutaneous lesions were improved	NA	
A abdomen, AE adverse event, ASS antisynthetase syndrome, AZA azathioprine, Biw twice weekly, BSA body surface area, BTZ bortezomib, c crescent, C cardiac, CR complete remission, CTX cyclophosphamide, Cyc cyclosporine, eGFR evaluated glomerular filtration rate, Eve everolimus, F female, GSs glucocorticoids, HD haemodialysis, IgAN IgA nephropathy, IgAVN IgA vascular nephritis, IFX infliximab, IVIG intravenous immune globulin, J joint, K kidney, KT kidney transplant, LEF leflunomide, L lung, M male, MMF mycophenolate mofetil, MTX methotrexate, N neuropathy, NA not available, NR no response, O ocular, OFAB ofatumumab, PE plasmapheresis, R remission, RRT renal replacement therapy, RTX rituximab, SARS-CoV-2 severe acute respiratory syndrome coronavirus-2, SCr serum creatinine, TAC tacrolimus, Tons tonsillectomy, UACR urinary albumin-creatinine ratio, UP 24-h urine protein, UPCR urine protein-to-creatinine ratio, 2mo, two months

a(MESTC) means Oxford classification, including mesangial cell proliferation was seen in 50% of glomeruli (M1), capillary hyperplasia (E1), and segmental glomerulosclerosis/adhesions (S1), otherwise, it will be M0, E0, and S0. Tubular atrophy/interstitial fibrosis(T): ≤ 25% (T0); 26% ~ 50% (T1); > 50% (T2). Crescents construction: without crescent (C0); 1% ≤ crescentic proportion ≤ 25% (C1); crescentic proportion ≥ 25% (C2)

Results

Clinical characteristics of patients

As shown in Fig. 1, there were 28 studies included and 41 biopsy proven IgAVN patients with available individual data were finally involved,. [16–46]﻿. 48.8% (20/41) of the included IgAVN patients were female. The median age of the included patients at diagnosis was 28 years with a range from 14 to 49 years. All patients were renal involvement, including 16 with a creatinine value higher to 1.2 mg/dl and 39 with microscopic (and/or macroscopic) haematuria with or without proteinuria. 19.5% (8/41) of cases was performed cutaneous biopsy. Kidney biopsy was performed in 80.5% (33/41) of cases, and glomerular crescents were found in 36.6%(15/41). Oxford classification was recorded in 12 patients, 83.3% (10/12) of patients with mesangial cell proliferation (M1), 58.3% (7/12) of patients with capillary hyperplasia (E1), 50.0% (6/12) with segmental glomerulosclerosis/adhesions (S1), and 16.7% (2/12) occurred 26%-50% of tubular atrophy/interstitial fibrosis(T1). 9.8% (4/41) of IgAVN patients suffered from anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Interestingly, two cases were diagnosed IgAVN and ANCA simultaneously, one case was diagnosed after ANCA turned negative, and one case was diagnosed with previous IgAVN and new ANCA.Fig. 1 The flow diagram for the included studies

Previous to RTX administration, 97.5% (39/41) of patients had received GSs. Additional immunosuppressants (cyclophosphamide, azathioprine and mycophenolate) had been given to 60.0% (24/41) of patients. Other treatments (plasma exchange, renal replacement and kidney transplant) were used in 17.5% (7/41) of patients. The reason of RTX use was the existence of a recurrent or refractory disease despite the use of the previous treatments in 80.5% (33/41) patients. RTX was given because of contraindication to GSs or cytotoxic agents in 9.8% (4/41) patients, and 7.5% (3/41) of cases RTX was used as first line therapy. Among of them, 37 patients received RTX as add-on therapy and 3 patients as monotherapy.

RTX remission induction regimen was reported in 64.1% (25/41) of cases, consisted in four weekly doses of 375 mg/m2 in 30.8% (12/41) of patients, and in two biweekly doses of 1000 mg in 33.3% (13/41) of individuals. In 35.9% (16/41) of cases, no RTX dose and modality was described. These B cell values were recorded in 31.7% (13/41) of patients after 1 to 12 months of RTX infusion, and all of them were CD19 + cell depleted. Time from disease diagnosis until RTX administration was reported in 27 patients. In 66.7% (18/41) of patients, RTX was given in less than one year, in 29.7% (8/41) patients, from one to ten years, and in 4.2% (1/41) of patients, RTX was used after ten years of disease diagnosis. During the average follow-up of 36 months, patient’s urinalysis was prone to be normalized and renal function tended to stable after treatment with RTX in most patients. No serious adverse events were reported in these studies. The main clinical and laboratory features at disease onset, diagnostic procedures, treatment received prior to RTX infusion and response to RTX during the follow-up are shownd in Table 1.

Efficacy of RTX in IgAVN patients

After RTX treatment, the remission rate was 92.7% (38/41) and complete remission rate was 46.3% (19/41) in IgAVN patients. Among the relapsing patients, 22.0% (9/41) of individuals received RTX retreatment and 4.9% (2/41) of patients treated predetermined fixed doses RTX for remission maintenance, with good response in all of them. Interestingly, 76.9% (10/13) of child patients achieved complete remission when compared with 32.1% (9/28) of adult patients (P = 0.017, Table 2). 4.9% (2/41) of patient showed not responds to RTX and 2.4% (1/41) of patients death finally, all were adult.Table 2 Clinical characteristics of the 41 IgAVN patients

Characteristics	Children, n = 13(%)	Adult, n = 28(%)	Total, N = 41(%)	P value	
Sex (female)	4 (30.8)	16 (57.1)	20 (46.3)	0.196	
Age at diagnosis, median (IQR) years	–	–	28 (14–49)	–	
Clinical manifestations before RTX	
 Skin	11 (84.6)	22 (78.6)	33 (80.5)	1.000	
 Abdomen	10 (76.9)	6 (21.4)	16 (39.0)	0.001	
 Joint	5 (38.5)	9 (32.1)	14 (34.1)	0.734	
 Kidney					
 Renal function (abnormal)a	0 (0.00)	16 (72.7)	16 (61.5)	–	
 Urinalysis (abnormal)b	13 (100.0)	26 (100.0)	39 (100.0)	–	
Diagnostic tests				0.692	
 Cutaneous biopsy	3 (23.1)	5 (17.9)	8 (19.5)	–	
 Renal biopsy	10 (76.9)	23 (82.1)	33 (80.5)	–	
 Crescents	3 (23.1)	12 (42.9)	15 (36.6)	0.305	
Treatment before RTX	
 Glucocorticoids (any)	12 (92.3)	27 (100)	39 (97.5)	0.325	
 Additional immunosuppressants	10 (76.9)	14 (51.9)	24 (60.0)	–	
 Cyclophosphamide	2 (15.4)	6 (22.2)	8 (20.0)	1.000	
 Azathioprine	2 (15.4)	6 (22.2)	8 (20.0)	1.000	
 Mycophenolate mofetil	3 (23.1)	5 (18.5)	8 (20.0)	1.000	
 Other drugs	0 (0.0)	4 (14.8)	4 (10.0)	0.284	
Other treatments	
 Plasma exchange	1 (7.7)	5 (18.5)	6 (15.0)	0.643	
 Renal replacement treatment	0 (0.0)	1 (3.7)	1 (2.5)	1.000	
 Kidney transplant	0 (0.0)	0 (0.0)	0 (0.0)	–	
Reasons for RTX use					
 Refractory/Relapse disease	12 (92.3)	21 (63.6)	33 (80.5)	0.398	
 Contraindication to traditional therapy	1 (7.7)	3 (10.7)	4 (9.8)	1.000	
 First line therapy	0 (0.0)	3 (11.1)	3 (7.5)	0.538	
RTX Protocols	
 (375 mg/1.73 m2/week) RTX*4	3 (23.1)	9 (34.6)	12 (30.8)	0.714	
 (1 g/biw) RTX*2	1 (7.7)	12 (46.2)	13 (33.3)	0.029	
Response after RTX	
 Remission (any)	12 (92.3)	26 (92.9)	38 (92.7)	1.000	
 Complete remission	10 (76.9)	9 (32.1)	19 (46.3)	0.017	
 RTX retreatment	5 (38.5)	4 (14.3)	9 (22.0)	0.113	
 RTX maintenance	0 (0.0)	2 (7.1)	2 (4.9)	1.000	
 RTX adverse events	0 (0.0)	0 (0.0)	0 (0.0)	–	
 Not response	0 (0.0)	2 (7.1)	2 (4.9)	1.000	
 Death	0 (0.0)	1 (3.6)	1 (2.4)	1.000	
IQR interquartile range, biw every two weeks, RTX rituximab

aRenal function (abnormal) including a creatinine value higher to 1.2 mg/dl

bUrinalysis (abnormal) defined as present with microscopic (and/or macroscopic) haematuria with or without proteinuria

Among all renal function results, eGFR were obtained in 26 patients, 42.3% (11/26) of patients with eGFR < 60 ml/min/1.73 m2 pre-RTX, but the rate was dropped to 30.7% (8/26) at last follow-up (P = 0.425, Table 3). Moreover, the results showed that 84.8% (28/33) of patients had haematuria at the beginning of treatment, while only 12.1% (4/33) of patients had haematuria at the last follow-up (P < 0.001). Proteinuria had also been collected in above 33 patients, the number of patients with proteinuria increased from 11 to 26 (P = 0.003). Notably, the rate of glucocorticoids use was statistically reduced following RTX administration (P < 0.001, Table 3).Table 3 The response rates before and after rituximab in IgAVN patients

Characteristics	Before RTX (Baseline)	After RTX (Last follow-up)	P value	
Clinical manifestations	
 Skin	33 (80.5)	2 (4.9)	 < 0.001	
 Abdomen	16 (39.0)	1 (2.4)	 < 0.001	
 Joint	14 (34.1)	2 (4.9)	 < 0.001	
 Kidney	
Urinalysis (abnormal)a	33 (100.0)	13 (39.4)	–	
Haematuria (any)	28 (84.8)	4 (12.1)	 < 0.001	
Proteinuria (any)	26 (78.8)	11 (33.3)	0.003	
Renal function (abnormal)b	13 (61.5)	12 (52.2)	1.000	
Creatinine (> 1.2 mg/dl)	10 (45.5)	8 (36.4)	0.625	
eGFR (< 60 ml/min/1.73 m2)	11 (42.3)	8 (30.7)	0.425	
Renal Replacement	0 (0.0)	1 (2.5)	–	
Use of medication	
 Glucocorticoids	39 (97.5)	23 (57.5)	 < 0.001	
 Other Immunosuppressants	24 (60.0)	26 (60.5)	0.774	
eGFR evaluated glomerulus filtration rate

aUrinalysis (abnormal) defined as present with microscopic (and/or macroscopic) haematuria with or without proteinuria

bRenal function (abnormal) including a creatinine value higher to 1.2 mg/dl and/or eGFR < 60 ml/min/1.73 m2

In 41 IgAVN patients with RTX treatment, 80.5% (33/41) of patients presented with cutaneous manifestations, 39.0% (16/41) with abdominal involvement, 34.1% (14/41) with joint involvement. At last follow-up, only 4.9% (2/41) of patients presented with skin involvement (P < 0.001), 2.4% (1/41) with abdominal involvement (P < 0.001), and 4.9% (2/41) with joint involvement (P < 0.001). All above mentioned clinical symptoms showed statistically significant recovery after RTX treatment (Table 3).

Discussion

At present, the needs of treatment efficacy in IgAVN patients, especially adult patients, have not been met [1]. The use of RTX seems to have good therapeutic effects and may become a potential drug for these unmet patients. It was reported that RTX achieve remission and showed preferable efficacy in patients with IgAV, results of our review were consistent with those reported case series [12, 47, 48]. The research of Maritati et al. included 22 adult IgAV patients, 90.9% (20/22) of the patients had renal involvement, 72.7% (16/22) of the patients received RTX as add-on therapy and 27.3% (6/22) of the patients as monotherapy, with 90.9% of patients (20/24) achieved remission, and 35% of (7/20) patients (35%) had subsequent relapse of disease at last follow-up. Another research reported 12 adult-onset patients with severe IgAVN. All of them received RTX as add-on therapy, with 91.7%(11/12) of patients achieved a clinical response at last follow-up and 8.3% (1/12) of patients unresponsive to RTX and was switched to MMF [48]. Besides, Hernandez-Rodriguez et al. reported that IgAV patients in adults and children (88.6% of patients with renal involvement) with RTX treatment showed good clinical response by marked reduce glucocorticoid doses and additional immunosuppressive drugs [12]. However, our review differs from the above review. This present review updated the current literature on the treatment of RTX in adults and children with IgAVN and is the review with a largest sample size at present. A total of 41 IgAVN patients from 28 articles were included in the present review, of which 27 patients from 16 articles were the same as in the review reported by Hernandez-Rodriguez et al. and 14 patients were newly added. Besides, the remission rates were consistent with Maritati et al. and Fenoglio et al., with the remission rate was 92.7% (38/41) and complete remission rate was 46.3% (19/41) at last follow-up, although with 4.9% (2/41) of patient showed not responds to RTX and 2.4% (1/41) of patient death finally.

Nevertheless, Lafayette et al. revealed that the IgAN patients treated with RTX showed no significant improvement in renal function or reduction in proteinuria [10]. The negative results might suggest previously not appreciated differences between IgAN and IgAV. The exact reason for the discrepancy still unknown, interaction between genetic and environmental components was thought to contribute to it [49]. Although increasing researchers support that IgAN and IgAVN shared the same pathogenesis, the “Multiple Hits” theory, it hard to explain why IgAN patients scarcely present extrarenal manifestations, while IgAV patients may not appear renal involvement [3, 50–54]. Above all, we believed that our results, while validating the conclusions from previous studies, somewhat further supported the potential role of RTX, which requires prospective and controlled studies.

In a considerable portion of the studies that included in the present review, IgAVN patients also suffered from ANCA [16, 21, 39, 42]. It should be noted that although patients had positive ANCA, their renal-biopsy showed IgA (+), glomerulonephritis with dominant IgA immune deposits, and purpura appearance, which indicated rule out the AAV were present. Besides, in the final case, the absence of ANCA in the patient´s previous history, along with C3 consumption in a well-documented IgAV prompted us to consider a newly induced ANCA-associated vasculitis, however, recurrent low C3 levels pointed to a relapse of a hypocomplementemic IgAVN, likely in the context of an overlapping vasculitis [16]. Patients with overlapping vasculitis tended to choose RTX as the preferred treatment and often achieve better results [16, 21, 39, 42]. As stated in the KDIGO guidelines, when patients may have overlapping syndromes, RTX as the preferred treatment would be a better choice [55].

The present review has its limitations. The sample size was very small, and the baseline data was highly diverse in the present review. As the relevant pieces of literature were case reports, itis difficult to get the data of different time point to compare the renal function, which is a limitation of the present review. In addition, given that we are conducting a statistical analysis of a small sample size of case reports, it is hard to generalize the results to the entire population. Besides, the source of our data was from published case reports and series, which inevitably suffer from publication bias and may overestimate the efficacy of rituximab, and there is a possibility of the author’s subjectivity, while understanding the article.

Conclusions

RTX therapy significantly reduced the use of glucocorticoids and increased the complete remission rates in IgAVN patients, especially in the child subjects.

Author contributions

Yi Xiong performed the data collection, reviewed articles, and wrote the manuscript. Santiago Cuevas completed the data analysis, Gaosi Xu designed the study and revised the manuscript, Honghong Zou provided the second views during the manuscript preparation and revised the manuscript, and all the authors read and approved the final version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82260143), the “Thousand Talents Plan” project of Jiangxi Province (JXSQ2023201030), the Kidney Disease Engineering Technology Research Centre Foundation of Jiangxi Province (No. 20164BCD40095), the Science and Technology Plan of Health Commission of Jiangxi Province (SJKP220210087).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Yaseen K Herlitz LC Villa-Forte A IgA vasculitis in adults: a rare yet challenging disease Curr Rheumatol Rep 2021 23 7 50 10.1007/s11926-021-01013-x 34196893
Yaseen K, Herlitz LC, Villa-Forte A. IgA vasculitis in adults: a rare yet challenging disease. Curr Rheumatol Rep. 2021;23(7):50.34196893 10.1007/s11926-021-01013-x
2. Pillebout E IgA vasculitis and IgA nephropathy: same disease? J Clin Med 2021 10 11 2310 10.3390/jcm10112310 34070665
Pillebout E. IgA vasculitis and IgA nephropathy: same disease? J Clin Med. 2021;10(11):2310.34070665 10.3390/jcm10112310
3. Davin JC Ten Berge IJ Weening JJ What is the difference between IgA nephropathy and Henoch-Schonlein purpura nephritis? Kidney Int 2001 59 3 823 834 10.1046/j.1523-1755.2001.059003823.x 11231337
Davin JC, Ten Berge IJ, Weening JJ. What is the difference between IgA nephropathy and Henoch-Schonlein purpura nephritis? Kidney Int. 2001;59(3):823–34.11231337 10.1046/j.1523-1755.2001.059003823.x
4. Nakamoto Y Asano Y Dohi K Primary IgA glomerulonephritis and Schonlein-Henoch purpura nephritis: Clinicopathological and immunohistological characteristics Q J Med 1978 47 188 495 516 375278
Nakamoto Y, Asano Y, Dohi K, et al. Primary IgA glomerulonephritis and Schonlein-Henoch purpura nephritis: Clinicopathological and immunohistological characteristics. Q J Med. 1978;47(188):495–516.375278
5. Berthelot L Jamin A Viglietti D Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort Nephrol Dial Transplant 2018 33 9 1579 1590 29126311
Berthelot L, Jamin A, Viglietti D, et al. Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort. Nephrol Dial Transplant. 2018;33(9):1579–90.29126311
6. Pillebout E Jamin A Ayari H Biomarkers of IgA vasculitis nephritis in children PLoS ONE 2017 12 11 e0188718 10.1371/journal.pone.0188718 29190714
Pillebout E, Jamin A, Ayari H, et al. Biomarkers of IgA vasculitis nephritis in children. PLoS ONE. 2017;12(11):e0188718.29190714 10.1371/journal.pone.0188718
7. Hahn D Hodson EM Craig JC Interventions for preventing and treating kidney disease in IgA vasculitis Cochrane Database Syst Rev 2023 2 2 005128
Hahn D, Hodson EM, Craig JC. Interventions for preventing and treating kidney disease in IgA vasculitis. Cochrane Database Syst Rev. 2023;2(2):005128.
8. Salles G Barrett M Foa R Rituximab in B-cell Hematologic Malignancies: a review of 20 years of clinical experience Adv Ther 2017 34 10 2232 2273 10.1007/s12325-017-0612-x 28983798
Salles G, Barrett M, Foa R, et al. Rituximab in B-cell Hematologic Malignancies: a review of 20 years of clinical experience. Adv Ther. 2017;34(10):2232–73.28983798 10.1007/s12325-017-0612-x
9. Kattah AG Fervenza FC Roccatello D Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases Autoimmun Rev 2013 12 8 854 859 10.1016/j.autrev.2012.09.002 23000633
Kattah AG, Fervenza FC, Roccatello D. Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Autoimmun Rev. 2013;12(8):854–9.23000633 10.1016/j.autrev.2012.09.002
10. Lafayette RA Canetta PA Rovin BH A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction J Am Soc Nephrol 2017 28 4 1306 1313 10.1681/ASN.2016060640 27821627
Lafayette RA, Canetta PA, Rovin BH, et al. A randomized, controlled trial of rituximab in IgA nephropathy with proteinuria and renal dysfunction. J Am Soc Nephrol. 2017;28(4):1306–13.27821627 10.1681/ASN.2016060640
11. Cancarevic I, Malik BH. Use of rituximab in management of rapidly progressive glomerulonephritis. Cureus 2020.
12. Hernandez-Rodriguez J Carbonell C Miron-Canelo JA Rituximab treatment for IgA vasculitis: a systematic review Autoimmun Rev 2020 19 4 102490 10.1016/j.autrev.2020.102490 32062030
Hernandez-Rodriguez J, Carbonell C, Miron-Canelo JA, et al. Rituximab treatment for IgA vasculitis: a systematic review. Autoimmun Rev. 2020;19(4): 102490.32062030 10.1016/j.autrev.2020.102490
13. Ozen S Pistorio A Iusan SM EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008 Part II: final classification criteria Ann Rheum Dis 2010 69 5 798 806 10.1136/ard.2009.116657 20413568
Ozen S, Pistorio A, Iusan SM, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008 Part II: final classification criteria. Ann Rheum Dis. 2010;69(5):798–806.20413568 10.1136/ard.2009.116657
14. Mills JA Michel BA Bloch DA The American college of rheumatology 1990 criteria for the classification of Henoch-Schonlein purpura Arthritis Rheum 1990 33 8 1114 1121 10.1002/art.1780330809 2202310
Mills JA, Michel BA, Bloch DA, et al. The American college of rheumatology 1990 criteria for the classification of Henoch-Schonlein purpura. Arthritis Rheum. 1990;33(8):1114–21.2202310 10.1002/art.1780330809
15. Levey AS Becker C Inker LA Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review JAMA 2015 313 8 837 846 10.1001/jama.2015.0602 25710660
Levey AS, Becker C, Inker LA. Glomerular filtration rate and albuminuria for detection and staging of acute and chronic kidney disease in adults: a systematic review. JAMA. 2015;313(8):837–46.25710660 10.1001/jama.2015.0602
16. Valero C Baldivieso-Achá JP Uriarte M Vasculitis flare after COVID-19: report of two cases in patients with preexistent controlled IgA vasculitis and review of the literature Rheumatol Int 2022 42 9 1643 1652 10.1007/s00296-022-05153-w 35691980
Valero C, Baldivieso-Achá JP, Uriarte M, et al. Vasculitis flare after COVID-19: report of two cases in patients with preexistent controlled IgA vasculitis and review of the literature. Rheumatol Int. 2022;42(9):1643–52.35691980 10.1007/s00296-022-05153-w
17. Patel K, Kariya P, Makwana P. Henoch-Schoenle in purpura with IgA nephropathy treated with rituximab: a case report. 2022.
18. Riley ML Maheshwari A Peredo-Wende R Late-onset hemorrhagic cutaneous immunoglobulin a vasculitis J Rheumatol 2021 48 3 463 464 10.3899/jrheum.200358 34237003
Riley ML, Maheshwari A, Peredo-Wende R. Late-onset hemorrhagic cutaneous immunoglobulin a vasculitis. J Rheumatol. 2021;48(3):463–4.34237003 10.3899/jrheum.200358
19. Hernanz I Larque AB Quintana LF Scleritis and sclerokeratitis associated with IgA vasculitis: a case series Am J Ophthalmol Case Rep 2021 22 101100 10.1016/j.ajoc.2021.101100 33997470
Hernanz I, Larque AB, Quintana LF, et al. Scleritis and sclerokeratitis associated with IgA vasculitis: a case series. Am J Ophthalmol Case Rep. 2021;22:101100.33997470 10.1016/j.ajoc.2021.101100
20. Amarapur M Biradar S Adult-onset immunoglobulin A vasculitis APIK J Intern Med 2021 9 2 120 122 10.4103/AJIM.AJIM_6_20
Amarapur M, Biradar S. Adult-onset immunoglobulin A vasculitis. APIK J Intern Med. 2021;9(2):120–2.10.4103/AJIM.AJIM_6_20
21. Uppal NN Kello N Shah HH De Novo ANCA-associated vasculitis with glomerulonephritis in COVID-19 Kidney Int Rep 2020 5 11 2079 2083 10.1016/j.ekir.2020.08.012 32839744
Uppal NN, Kello N, Shah HH, et al. De Novo ANCA-associated vasculitis with glomerulonephritis in COVID-19. Kidney Int Rep. 2020;5(11):2079–83.32839744 10.1016/j.ekir.2020.08.012
22. Suso AS Mon C Oñate Alonso I IgA vasculitis with nephritis (Henoch-Schönlein Purpura) in a COVID-19 patient Kidney Intern Rep 2020 5 11 2074 2078 10.1016/j.ekir.2020.08.016
Suso AS, Mon C, Oñate Alonso I, et al. IgA vasculitis with nephritis (Henoch-Schönlein Purpura) in a COVID-19 patient. Kidney Intern Rep. 2020;5(11):2074–8.10.1016/j.ekir.2020.08.016
23. Mamlouk O, Lin JS, Abdelrahim M, et al. Checkpoint inhibitor-related renal vasculitis and use of rituximab. Journal for Immunotherapy of Cancer 2020; 8 (2).
24. Al Harash A Saeli S Lucke M IgA vasculitis nephritis: a case series and comparison of treatment guidelines Case Rep Rheumatol 2020 2020 8863858 33343961
Al Harash A, Saeli S, Lucke M, et al. IgA vasculitis nephritis: a case series and comparison of treatment guidelines. Case Rep Rheumatol. 2020;2020:8863858.33343961
25. El-Reshaid K Al-Bader S The limited role and risky profile of Rituximab in nephritis associated with Henoch-Schönlein purpura J Drug Deliv Ther 2019 9 6 12 15 10.22270/jddt.v9i6-s.3744
El-Reshaid K, Al-Bader S. The limited role and risky profile of Rituximab in nephritis associated with Henoch-Schönlein purpura. J Drug Deliv Ther. 2019;9(6):12–5.10.22270/jddt.v9i6-s.3744
26. Torosoff M Breen T Balulad S Resolution of sinus bradycardia, high-grade heart block, and left ventricular systolic dysfunction with rituximab therapy in Henoch-Schonlein purpura Intern Med J 2018 48 7 868 871 10.1111/imj.13948 29984516
Torosoff M, Breen T, Balulad S, et al. Resolution of sinus bradycardia, high-grade heart block, and left ventricular systolic dysfunction with rituximab therapy in Henoch-Schonlein purpura. Intern Med J. 2018;48(7):868–71.29984516 10.1111/imj.13948
27. Crayne CB Eloseily E Mannion ML Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature Pediatr Rheumatol 2018 16 1 6 10.1186/s12969-018-0285-2
Crayne CB, Eloseily E, Mannion ML, et al. Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature. Pediatr Rheumatol. 2018;16:1–6.10.1186/s12969-018-0285-2
28. Yeh C-Y Davis CM Long-lasting remission of severe refractory Henoch-Schonlein purpura nephritis with rituximab J Allergy Clin Immunol 2017 139 2 213 213 10.1016/j.jaci.2016.12.691
Yeh C-Y, Davis CM. Long-lasting remission of severe refractory Henoch-Schonlein purpura nephritis with rituximab. J Allergy Clin Immunol. 2017;139(2):213–213.10.1016/j.jaci.2016.12.691
29. Lundberg S Westergren E Smolander J B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis Clin Kidney J 2017 10 1 20 26 28638602
Lundberg S, Westergren E, Smolander J, et al. B cell-depleting therapy with rituximab or ofatumumab in immunoglobulin A nephropathy or vasculitis with nephritis. Clin Kidney J. 2017;10(1):20–6.28638602
30. Van de Perre E Smith RM Bardsley V Successful outcome using bortezomib in adult refractory IgA vasculitis: a case report Rheumatology 2016 55 11 2089 2091 10.1093/rheumatology/kew286 27453187
Van de Perre E, Smith RM, Bardsley V, et al. Successful outcome using bortezomib in adult refractory IgA vasculitis: a case report. Rheumatology. 2016;55(11):2089–91.27453187 10.1093/rheumatology/kew286
31. Fenoglio R Roccatello D Successfull rituximab treatment for adult patients with severe IgA Vasculitis-Henoch-Schoenlein purpura nephritis (HSPN) J Am Soc Nephrol 2016 27 503A
Fenoglio R, Roccatello D. Successfull rituximab treatment for adult patients with severe IgA Vasculitis-Henoch-Schoenlein purpura nephritis (HSPN). J Am Soc Nephrol. 2016;27:503A.
32. Bellan M Pirisi M Sainaghi PP Long-term remission of corticosteroid- and cyclophosphamide-resistant Henoch-Scholein purpura with rituximab Scand J Rheumatol 2016 45 1 83 84 10.3109/03009742.2015.1058417 26312648
Bellan M, Pirisi M, Sainaghi PP. Long-term remission of corticosteroid- and cyclophosphamide-resistant Henoch-Scholein purpura with rituximab. Scand J Rheumatol. 2016;45(1):83–4.26312648 10.3109/03009742.2015.1058417
33. Hamilton P Ogundare O Raza A Long-term therapeutic plasma exchange to prevent end-stage kidney disease in adult severe resistant Henoch-Schonlein purpura nephritis Case Rep Nephrol 2015 2015 269895 269895 26613053
Hamilton P, Ogundare O, Raza A, et al. Long-term therapeutic plasma exchange to prevent end-stage kidney disease in adult severe resistant Henoch-Schonlein purpura nephritis. Case Rep Nephrol. 2015;2015:269895–269895.26613053
34. Pindi Sala T Michot JM Snanoudj R Successful outcome of a corticodependent Henoch-Schönlein purpura adult with rituximab Case Rep Med 2014 2014 619218 10.1155/2014/619218 24799911
Pindi Sala T, Michot JM, Snanoudj R, et al. Successful outcome of a corticodependent Henoch-Schönlein purpura adult with rituximab. Case Rep Med. 2014;2014:619218.24799911 10.1155/2014/619218
35. Kostik M Chikova I Solovyev A The initial effectiveness of rituximab for nephrotic syndrome in severe pediatric Henoch-Schonlein glomerulonephritis Ann Paediatr Rheumatol 2013 2 124 10.5455/apr.082920130003
Kostik M, Chikova I, Solovyev A, et al. The initial effectiveness of rituximab for nephrotic syndrome in severe pediatric Henoch-Schonlein glomerulonephritis. Ann Paediatr Rheumatol. 2013;2:124.10.5455/apr.082920130003
36. Ishiguro H Hashimoto T Akata M Rituximab treatment for adult purpura nephritis with nephrotic syndrome Intern Med 2013 52 10 1079 1083 10.2169/internalmedicine.52.9325 23676594
Ishiguro H, Hashimoto T, Akata M, et al. Rituximab treatment for adult purpura nephritis with nephrotic syndrome. Intern Med. 2013;52(10):1079–83.23676594 10.2169/internalmedicine.52.9325
37. El-Husseini A Ahmed A Sabucedo A Refractory Henoch-Schonlein purpura: atypical aetiology and management J Ren Care 2013 39 2 77 81 10.1111/j.1755-6686.2013.12007.x 23551765
El-Husseini A, Ahmed A, Sabucedo A, et al. Refractory Henoch-Schonlein purpura: atypical aetiology and management. J Ren Care. 2013;39(2):77–81.23551765 10.1111/j.1755-6686.2013.12007.x
38. Pillebout E Rocha F Fardet L Successful outcome using rituximab as the only immunomodulation in Henoch-Schonlein purpura: case report Nephrol Dial Transplant 2011 26 6 2044 2046 10.1093/ndt/gfr137 21436378
Pillebout E, Rocha F, Fardet L, et al. Successful outcome using rituximab as the only immunomodulation in Henoch-Schonlein purpura: case report. Nephrol Dial Transplant. 2011;26(6):2044–6.21436378 10.1093/ndt/gfr137
39. Havill JP Levine SM Kuperman M Falling through the cracks of vasculitis classification—a report of three patients NDT Plus 2011 4 5 327 330 25984180
Havill JP, Levine SM, Kuperman M, et al. Falling through the cracks of vasculitis classification—a report of three patients. NDT Plus. 2011;4(5):327–30.25984180
40. Hauck F Lee-Kirsch MA Aust D Complement C2 deficiency disarranging innate and adaptive humoral immune responses in a pediatric patient: treatment with rituximab Arthritis Care Res 2011 63 3 454 459 10.1002/acr.20361
Hauck F, Lee-Kirsch MA, Aust D, et al. Complement C2 deficiency disarranging innate and adaptive humoral immune responses in a pediatric patient: treatment with rituximab. Arthritis Care Res. 2011;63(3):454–9.10.1002/acr.20361
41. Donnithorne KJ Atkinson TP Hinze CH Rituximab therapy for severe refractory chronic Henoch-Schonlein purpura J Pediatr 2009 155 1 136 139 10.1016/j.jpeds.2008.12.049 19559299
Donnithorne KJ, Atkinson TP, Hinze CH, et al. Rituximab therapy for severe refractory chronic Henoch-Schonlein purpura. J Pediatr. 2009;155(1):136–9.19559299 10.1016/j.jpeds.2008.12.049
42. Bollee G Noel L-H Suarez F Pauci-immune crescentic glomerulonephritis associated with ANCA of IgA class Am J Kidney Dis 2009 53 6 1063 1067 10.1053/j.ajkd.2008.10.039 19084310
Bollee G, Noel L-H, Suarez F, et al. Pauci-immune crescentic glomerulonephritis associated with ANCA of IgA class. Am J Kidney Dis. 2009;53(6):1063–7.19084310 10.1053/j.ajkd.2008.10.039
43. Chung L Funke AA Chakravarty EF Successful use of rituximab for cutaneous vasculitis Arch Dermatol 2006 142 11 1407 1410 10.1001/archderm.142.11.1407 17116830
Chung L, Funke AA, Chakravarty EF, et al. Successful use of rituximab for cutaneous vasculitis. Arch Dermatol. 2006;142(11):1407–10.17116830 10.1001/archderm.142.11.1407
44. Abdo T, Jabari A, Meharg J. Diffuse alveolar hemorrhage: a rare complication of henoch-schönlein purpura successfully treated with rituximab. Chest 2014;146(4).
45. Fenoglio R, Naretto C, Basolo B et al. Rituximab therapy for IgA-vasculitis with nephritis: a case series and review of the literature. Immunol Res. 2017;65(1):186–192.
46. Patel K, Kariya P, Makwana P. Henoch-Schoenle in Purpura with IgA nephropathy treated with rituximab: a case report. 2021.
47. Maritati, F; Fenoglio, R; Pillebout, E , et al., Brief Report: Rituximab for the Treatment of Adult‐Onset IgA Vasculitis (Henoch‐Schönlein). Arthritis & Rheumatology 2018;70(1):109–114.
48. Fenoglio R Sciascia S Naretto C Rituximab in severe immunoglobulin-A vasculitis (Henoch-Schonlein) with aggressive nephritis Clin Exp Rheumatol 2020 124 2 195 200
Fenoglio R, Sciascia S, Naretto C, et al. Rituximab in severe immunoglobulin-A vasculitis (Henoch-Schonlein) with aggressive nephritis. Clin Exp Rheumatol. 2020;124(2):195–200.
49. Meadow SR Scott DG Berger disease: Henoch-Schönlein syndrome without the rash J Pediatr 1985 106 1 27 32 10.1016/S0022-3476(85)80459-5 2981307
Meadow SR, Scott DG. Berger disease: Henoch-Schönlein syndrome without the rash. J Pediatr. 1985;106(1):27–32.2981307 10.1016/S0022-3476(85)80459-5
50. Song Y Huang X Yu G Pathogenesis of IgA vasculitis: an Up-To-Date review Front Immunol 2021 12 771619 10.3389/fimmu.2021.771619 34858429
Song Y, Huang X, Yu G, et al. Pathogenesis of IgA vasculitis: an Up-To-Date review. Front Immunol. 2021;12: 771619.34858429 10.3389/fimmu.2021.771619
51. Jelusic M Sestan M Cimaz R Different histological classifications for Henoch-Schönlein purpura nephritis: which one should be used? Pediatr Rheumatol 2019 17 1 7 10.1186/s12969-019-0311-z
Jelusic M, Sestan M, Cimaz R, et al. Different histological classifications for Henoch-Schönlein purpura nephritis: which one should be used? Pediatr Rheumatol. 2019;17:1–7.10.1186/s12969-019-0311-z
52. Novak J Rizk D Takahashi K New Insights into the pathogenesis of IgA nephropathy Kidney Dis 2015 1 1 8 18 10.1159/000382134
Novak J, Rizk D, Takahashi K, et al. New Insights into the pathogenesis of IgA nephropathy. Kidney Dis. 2015;1(1):8–18.10.1159/000382134
53. Sanders JT Wyatt RJ IgA nephropathy and Henoch-Schonlein purpura nephritis Curr Opin Pediatr 2008 20 2 163 170 10.1097/MOP.0b013e3282f4308b 18332712
Sanders JT, Wyatt RJ. IgA nephropathy and Henoch-Schonlein purpura nephritis. Curr Opin Pediatr. 2008;20(2):163–70.18332712 10.1097/MOP.0b013e3282f4308b
54. Waldo FB Is Henoch-Schönlein purpura the systemic form of IgA nephropathy? Am J Kidney Dis 1988 12 5 373 377 10.1016/S0272-6386(88)80028-3 3055961
Waldo FB. Is Henoch-Schönlein purpura the systemic form of IgA nephropathy? Am J Kidney Dis. 1988;12(5):373–7.3055961 10.1016/S0272-6386(88)80028-3
55. Disease K Improving global outcomes glomerular diseases work, G, KDIGO 2021 clinical practice guideline for the management of glomerular diseases Kidney Int 2021 100 4S S1 S276 34556256
Disease K. Improving global outcomes glomerular diseases work, G, KDIGO 2021 clinical practice guideline for the management of glomerular diseases. Kidney Int. 2021;100(4S):S1–276.34556256
