Safety of Accelerated Rituximab Infusion in Rheumatic Diseases: A Systematic Review

Abstract

Objective

To systematically evaluate the safety and feasibility of rapid rituximab (RTX) infusion protocols in patients with autoimmune rheumatic diseases.

Methods

A comprehensive literature review was conducted using PubMed, LILACS, and Scielo databases from 1965 to May 2024 without language restrictions. Studies reporting infusion reactions associated with accelerated RTX protocols (infusion over 90 to 120 min) in rheumatologic conditions were included. Infusion-related adverse events were assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (Grades 1–5). Key variables extracted included patient demographics, underlying diseases, RTX dosage, use of premedication, number of infusions, and frequency and severity of infusion reactions.

Results

Seven studies encompassing 538 patients aged 14–78 years were included. The patient cohort covered a spectrum of autoimmune rheumatic conditions, including systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, Sjögren’s syndrome, systemic sclerosis, IgG4-related disease, and anti-synthetase syndrome. All studies implemented rapid RTX infusion protocols exclusively for the second and subsequent doses. Premedication with acetaminophen, diphenhydramine, and corticosteroids was routine in most studies. RTX dosage varied between 375 mg/m² and 1000 mg, administered in two infusions spaced two weeks apart. The incidence of infusion reactions ranged from 3 to 15%, predominantly of mild severity (Grades 1 and 2), with only six cases classified as Grade 3. No Grade 4 or 5 reactions were reported. Rapid infusion protocols consistently reduced the total time patients spent in infusion clinics.

Conclusion

Rapid infusion of RTX in patients with autoimmune rheumatic diseases appears to be a safe and efficient alternative to standard infusion protocols. The frequency and severity of infusion reactions were comparable to traditional infusion rates, with the added benefit of reduced clinic time. These findings support the broader implementation of rapid infusion protocols in rheumatology. However, larger prospective studies with standardized reporting of adverse events are necessary to validate these results and explore the feasibility of even shorter infusion durations, as seen in oncology.

Key Summary Points

Rituximab (RTX) is increasingly used to treat autoimmune rheumatic diseases, prompting interest in faster infusion protocols to improve clinic efficiency.

This review included seven studies with 538 patients receiving rapid RTX infusions from the second dose onward, all with premedication.

Infusion reactions occurred in 3–15% of cases, mostly mild (Grade 1–2), with only six Grade 3 events and no life-threatening reactions.

Rapid RTX infusion appears safe and time-saving, supporting broader use in rheumatology; further standardized, prospective studies are needed.

Introduction

Biological therapy has been widely used to treat rheumatic autoimmune diseases [1]. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody with a boxed warning indicating that fatal infusion reactions may occur within 24 h of infusion. Specifically, 80% of fatal infusion reactions occur with the first infusion.

Therefore, infusions following the Federal Drug and Administration should be done as If, 1st infusion: initiate at a rate of 50 mg/h. In the absence of infusion toxicity, increase the infusion rate by 50 mg/h. increments every 30 min to a maximum of 400 mg/h. The infusion was administered at 100 mg/h. in the subsequent infusions. In the absence of infusion toxicity, increase the rate by 100 mg/h. increments at 30-min intervals to a maximum of 400 mg/h. [2]. With the significant increase in RTX prescriptions for different rheumatic autoimmune diseases, the number of patients receiving this drug has significantly increased, associated with a wide range of registered and off-label indications, leading to scheduling difficulties in several infusion clinics [2]. Faster RTX infusion would reduce overall costs and patients' time spent in the infusion clinic [3]. In oncology, the safety of an accelerated infusion of RTX has been demonstrated in several trials [4]. Rapid or accelerated infusion comprises infusing RTX over 90–120 min (20% over the first 30 min and the remaining 80% over 60 min, with gradual increasing: 0–30 min, 100 mg; 30–60 min, 200 mg; 60–90 min, 300 mg; and 90–120 min, 400 mg for a total of 120 min, and 100 ml/hour for 30 min and then titrated to a rate of 200 ml/hour for 60 min for a total of 90 min) [4].

The objective of this study was to review the literature on accelerated RTX infusion in autoimmune rheumatic diseases.

Methods

Considering the above data, we reviewed the literature on accelerated RTX infusion in autoimmune rheumatic diseases. We searched Pubmed, LILACS, and Scielo without any language restriction from 1965 to May 2024. Infusion reactions reported in the studies were evaluated through review of nursing assessment progress notes and were graded (grades 1–5) using the National Cancer Institute Common Terminology Criteria for Adverse Events: Grade 1 reactions: least severe and do not require intervention; Grade 2: require medication intervention or temporary cessation of RTX infusion; Grade 3: Infusions that could not be completed due to adverse drug reactions or that required prolonged medical treatment; Grade 3: life-threatening infusion reactions and Grade 5: reactions resulting in death [5].

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Table 1 displays the identified 7 studies [3, 6–11], including a total of 538 individuals. The patient’s ages ranged from 14 to 78 years old, and the prevalence of female sex varied from 23 to 90%. Patients with a variety of rheumatic autoimmune diseases were included in the studies, such as systemic lupus erythematosus, mixed connective tissue diseases, rheumatoid arthritis, systemic vasculitis, Sjogren's syndrome, systemic sclerosis, IgG4-related disease, and anti-synthetase syndrome. Disease duration varied from 2.75 ± 2.87 to 17.5 ± 0.7 years. None of the studies included gave rapid rituximab as an initial infusion. They all used rapid infusion protocols for second and subsequent infusions. RTX dosage ranged from 375mg/m² or 1,000mg, with two infusions, two weeks apart.

Table 1.

Summary of main findings of the included studies in this systematic review

Author, year, reference	N	Study design	Disease	Age, gender	Disease duration	RTX dosage	Number of rapid RTX infusions	Infusion regime and time
Bernhardt et al. (2017) [6]	10	Open prospective,	Pediatric SLE (9) and mixed connective tissue disease (1)	16.7 (14–19) yo 90% Women	ND	500mg/m2 750mg/m2 or 1g	10	120 min
Can et al. (2013) [7]	68	Open prospective	RA (60), SLE (4), lymphoma plus SLE (1) and vasculitis (3)	52.4 ± 10.6 yo 87% women	12.7 ± 6.4 years for RA	1g twice 2 weeks apart	71	120 min
Larsen et al. (2013) [8]	54	Open prospective	GPA (16), RA (16), Sjögren’s syndrome (11), SLE (6) and other (5)	46.4 yo 80% women	10.3 y	1g twice 2 weeks apart	54	!st infusion (195 min) Subsequent infusions (90 min)
Swan et al. (2014) [3]	1 out of 64	Open prospective	Sjögren’s syndrome	66 (52–77) yo (all patients) 48% women	ND	375mg/m2	195 (all patients)	90 min
Pritchard et al. (2014) [9]	337	Open prospective multicenter	RA	55.6 ± 11.4 yo 79.5% women	12.4 ± 9.6 years	1g twice 2 weeks apart, repeated after 24 weeks	337	(120 min
Hartinger et al. (2019) [10]	35 out of 53 patients	Opena prospective	SLE (9) and ANCA-associaed vasculitis (26)	47.0 (35.0–60.5) yo (for rheumatic diseases)	6.0 (4.0–12.5) years	1g twice 2 weeks apart	Maximum 3 infusions	120 min
Nahra et al. (2024) [11]	33	Retrospective chart review study	RA (20), SS (2), ANCA vasculitis (4), SLE (2), SSc (2), anti-synthetase syndrome (1), IgG4-related disease (2)	48–78 yo, 23% women	2.75 ± 2.87–17.5 ± 0.7 years	375mg/m2 or 1g twice 2 weeks apart	74	90 min

ANCA antineutrophil cell antibodies, N number, ND not described, yo years old, RA rheumatoid arthritis, RT rituximab, SS Sjögren’s syndrome, SLE systemic lupus erythematosus, GPA granulomatosis with polyangiitis, SSc systemic sclerosis

Table 2 shows adverse reactions in the included studies. The number of RTX infusions per article varied from 10 to 337. Interestingly, infusion reactions were observed in 3% to 15% of the patients, and most were mild [grades 1 and 2], and six patients had grade 3. All studies performed premedication as routine with acetaminophen and diphenhydramine, and 6 out of 7 used glucocorticoids [5–7]. In the Bernhardt article, 2/10 patients received corticoids as premedication [5]. The studies observed reduced time spent by patients in the clinic [3, 6–8].

Table 2.

Summary of adverse effects of the included studies

Author, year, reference	N	Adverse effects	Graduation of adverse effects
Bernhardt et al. (2017) [6]	10	3/20 (15%)-not clear if in rheumatic conditions	Grade 1: 2 Grade 2: 1
Can et al. (2013) [7]	68	3 (4.4%)	Grade 1: 6 Grade 2: 3
Larsen et al. (2013) [8]	54	5 (9.2%);	Grade 1: 7 grade 2: 1 Grade 3: 2
Swan et al. 92014) [3]	1 out of 64	3% (all patients)	Grade 2: 1
Pritchard et al. (2014) [9]	337	22 (6.5%) after the 2nd infusion, 5.9% after the 3rd, and 0.7% after the 4th	Grade 1: ND Grade 2: ND Grade 3: 2
Hartinger et al. (2019) [10]	35 out of 53 patients	2/35 (5.7%)	Grade 1: 1 Grade 3: 1
Nahra et al. (2024) [11]	33	2/31 (6.4%)	Grade 1: 1 Grade 3: 1

Adverse effects according to using the National Cancer Institute Common Terminology Criteria for Adverse Events

Discussion

This review highlights that the rapid infusion of RTX appears to be a safe and cost-effective option, enabling infusion centers to accommodate a larger number of patients. This is an important point taking into account the growing indication for this medication mainly in rheumatology. The observed adverse reactions were generally mild, with only six cases classified as grade 3. Additionally, the underlying indication for RTX treatment did not influence the occurrence of infusion reactions. However, some considerations must be noted: none of the studies administered a rapid infusion at the initial dose, and all cases involved premedication.

This study has the following strengths: 1. All kinds of studies on infusion reactions in rheumatic conditions were included; 2. All but one [11] studies included were prospective studies; 4. Standardized evaluation of infusion reaction. 5. Exclusion of studies from grey literature.

In oncology and hematology, some studies used 60-min RTX infusion [12] and, more impressively, 30-min RTX infusion in the treatment of oncological patients with safety [13]. This interesting topic needs to be investigated in the rheumatology field.

Conclusion

In conclusion, this systematic review found seven articles with a total of 536 patients on rapid infusion of RTX in rheumatic autoimmune diseases. The frequency of infusion reactions was similar to the ones observed during non-rapid injection, and the time patients spent in the clinic was reduced [3, 8]. Therefore, rapid RTX infusion is safe and feasible for infusion centers. Prospective studies with standardized infusion reaction reports are warranted to confirm these findings further.

Author Contributions

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and approve for this version to be published. Jozélio Freire de Carvalho: design, data collection, data analysis, manuscript review, submission. Samuel de Oliveira Andrade: data analysis, drafting, revision. Ana Teresa Amoedo Martinez: analysis, drafting, revision. Thelma Skare: data analysis, drafting, revision. Simone Appenzeller: data analysis, writing, revision.

Funding

Simone Appenzeller received funds from CAPES 001; CNPq 305981/2023–4 for this review. No funding or sponsorship was received for the publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Jozelio Freire de Carvalho is an Editorial Board member of Rheumatology Therapy, he was not involved in selecting peer reviewers for the manuscript or any subsequent editorial decisions. Samuel de Oliveira Andrade has nothing to disclosure. Ana Teresa Amoedo Martinez has nothing to disclosure. Thelma Skare has nothing to disclosure. Simone Appenzeller has nothing to disclosure.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.