Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature

Figures & data

Figure 1. Flow chart of patients, the treatment they received and their subsequent treatment response. AIP = autoimmune pancreatitis, ICDC = International Consensus Diagnosis Criteria, GC = glucocorticoid.

Figure 2. Flow chart on the study selection process.

Table 1. Studies on rituximab in AIP type 1.

Author Year Country	Patients (cohort and N)	Results
#1 Hart et al. [10] 2013, USA	AIP n = 116	Of the 12 patients treated with RTX that had previously relapsed on both GC and IM, 10 achieved complete remission. Three patients (25%) had RTX-related side effects (infusion-related, late-onset neutropenia and bronchiolitis obliterans organizing pneumonia).
#2 Carruthers et al. [23] 2015, USA	IgG4 RD n = 30 AIP type 1 n = 18 (60%)	At month 3, one patient had an acute disease flare on RTX. At 6 months, one patient had a persistent disease activity with failure to achieve complete remission on RTX. Six patients were hospitalized, two (11%) due to infection and four to other causes unrelated to RTX therapy.
#3 Ebbo et al. [20] 2017, France	IgG4 RD n = 33 AIP n = 15 (45.5%)	Of the patients with AIP treated with RTX, 4/15 (26.7%) relapsed. The hazard ratio for AIP relapse after RTX treatment was estimated to 1.08 using Cox regression analysis. Side effects included severe infections in four (12.1%) patients, mild in 7 (21.2%) and (6%) infusion-related side effects in two.
#4 Majumder et al. [24] 2018, USA	Pancreaticobiliary IgG4 RD n = 43 AIP n = 29 (67.4%)	In patients with pancreaticobiliary disease RTX therapy successfully induced remission in 37 (86%) at 6 months. Maintenance therapy of RTX had a lower relapse rate and a prolonged relapse-free period than patients who only received induction treatment. Side effects included infusion reaction episodes of infection requiring antibiotic therapy (eight patients, 18%) or hospitalization (six patients, 14%).
#5 Soliman et al. [3] 2019, France	AIP n = 163	Some 17 patients were treated with RTX. The efficacy of RTX in preventing relapse of AIP was 94%, significantly better than immunomodulator drugs (p = 0.03), even in cases of previous resistance /intolerance to standard therapy.
#6 Campochiaro et al. [21] 2020, Italy	IgG4 RD n = 14 AIP n = 4 (28 %)	Of the four patients with AIP, three relapsed after treatment (range 7–12 months). However, they achieved successful remission with re-treatment. The patient without relapse was in the regular maintenance treatment group. Side effects of the cohort were infusion reactions (14%) and infections (43%).
#7 Barresi et al. [22] 2020, Italy	AIP n = 106	Rituximab was used in 2/37 (5.4%) patients after the first relapse and 1/10 (10%) after the second relapse.
#8 Backhus et al. [19] 2021, Germany	AIP type 1 n = 46	Eight of the 13 patients (61%) treated with RTX relapsed within a median of 16 months from the first dose. Adverse effects included a varicella-zoster infection (n = 1), atypical pneumonia (n = 1) and a postoperative pulmonary embolism
Present study 2021 Sweden	AIP type 1 n = 103	Of 12 patients treated with RTX, 8 achieved complete remission and 4 partial remission during a median follow-up of 17 months. 2 /12 patients had infections (tuberculosis reactivation and Borrelia infection)

N: number of patients included in the study; AIP: autoimmune pancreatitis; IgG4-RD: IgG4 related disease; RTX: rituximab.

Table 2. Characteristics of patients with rituximab.

Parameters	Patients treated with rituximab N = 12
Male	8 (66.7%)
Female	4 (33.3%)
Median age at diagnosis	57.7 years
Median follow-up since AIP diagnosis	72 months
Median follow-up since RTX treatment	17 months
Symptoms at diagnosis
Asymptomatic	0 (0.0%)
New-onset diabetes	2 (16.7%)
Acute pancreatitis	3 (25.0%)
Obstructive jaundice	8 (66.7%)
Weight loss	5 (41.7%)
Abdominal pain	10 (83.3%)
Elevated IgG4	8 (66.7%)
OOI	11 (91.7%)
RTX 1^st line treatment	0 (0.0%)
RTX last line of treatment	9 (75.0%)
Lines of treatment
2nd	3 (25.0%)
3rd	5 (41.7%)
4th	1 (8.3%)
5th	2 (16.7%)
6th	1 (8.3%)
Long-term consequences
PEI	11 (91.7%)
DM	7 (58.3%)
Bone mineral density
osteoporosis	2 (16.7%)
osteopenia	1 (8.3%)
Number of relapses before RTX
0	2 (16.7%)
1	3 (25.0%)
2	3 (25.0%)
3	2 (16.7%)
4	1 (8.3%)
5	1 (8.3%)
Clinical remission after RTX
complete	10 (83.3%)
partial	2 (16.7%)
Radiological remission after RTX
complete	8 (66.7%)
partial	4 (33.3%)

N: number of patients treated with rituximab; AIP: autoimmune pancreatitis; RTX: rituximab; OOI: other organ involvement; PEI: pancreatic endocrine insufficiency; DM: diabetes mellitus; DXA: dual-energy X-ray absorptiometry.

Hart PA, Topazian MD, Witzig TE, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo clinic experience. Gut. 2013;62(11):1607–1615.

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Carruthers MN, Topazian MD, Khosroshahi A, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74(6):1171–1177.

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Ebbo M, Grados A, Samson M, et al. Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a french nationwide study of thirty-three patients. PLoS One. 2017;12(9):e0183844.

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Majumder S, Mohapatra S, Lennon RJ, et al. Rituximab maintenance therapy reduces rate of relapse of pancreaticobiliary immunoglobulin G4-related disease. Clin Gastroenterol Hepatol. 2018;16(12):1947–1953.

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Soliman H, Vullierme MP, Marie F, et al. Risk factors and treatment of relapses in autoimmune pancreatitis: Rituximab is safe and effective. United European Gastroenterol J. 2019;7(8):1073–1083.

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Campochiaro C, Della-Torre E, Lanzillotta M, et al. Long-term efficacy of maintenance therapy with rituximab for IgG4-related disease. Eur J Intern Med. 2020;74:92–98.

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Barresi L, Tacelli M, Crino SF, Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO), Italian Association for the Study of the Pancreas (AISP), et al. Multicentric italian survey on daily practice for autoimmune pancreatitis: Clinical data, diagnosis, treatment, and evolution toward pancreatic insufficiency. United European Gastroenterol J. 2020;8(6):705–715.

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Backhus J, Neumann C, Perkhofer L, et al. A Follow-Up study of a european IgG4-Related disease cohort treated with rituximab. J Clin Med. 2021;10(6):1329.

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