Safety of Accelerated Rituximab Infusion in Rheumatologic Diseases: Impact on Satisfaction and Care Burden in an UMAA of the IMSS

Problem Statement

Rituximab, an anti-CD20 monoclonal antibody, is one of the most relevant therapeutic pillars in the treatment of rheumatologic diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ANCA-associated vasculitis. Its mechanism of action, based on deep and sustained depletion of B lymphocytes, has proven effective in reducing inflammatory activity, preventing structural damage, and controlling systemic manifestations in high-morbidity conditions.

Despite its efficacy, standard rituximab administration — requiring prolonged intravenous infusions of 3.5 to 4 hours — poses major logistical challenges within the Mexican Institute of Social Security (IMSS), particularly in Ambulatory Care Medical Units (UMAA). These units operate with limited resources in terms of infusion chairs, nursing staff, and installed capacity. In the state of Yucatán, UMAAs treat an average of 2 to 3 patients per day who require rituximab, quickly saturating infrastructure and generating negative effects on operational flow: increased waiting times, reduced availability for new treatments, and a suboptimal experience for both patients and health care personnel.

The magnitude of the problem is amplified in a region with a high prevalence of rheumatologic diseases. Of particular relevance is the national epidemiological study led by Dr. Ingris Peláez-Ballestas (Peláez-Ballestas et al., 2011), conducted using the COPCORD methodology in 5 regions of Mexico. This study, with a total of 19,213 participants, reported a prevalence of rheumatoid arthritis of 1.6% and a prevalence of musculoskeletal pain of 25.5%, figures that position Mexico — and the southern region in particular — as areas of high rheumatic burden. This epidemiological context, combined with regional factors such as population aging, a high proportion of Indigenous population, and long travel distances from rural areas, further increases the demand for biological therapies and the pressure on UMAAs in Yucatán.

Several international studies have shown that rapid rituximab administration (90 minutes) is safe and well tolerated in patients who have already received at least one prior infusion without serious adverse reactions. Recent research (Wallace et al., 2025; Hochberg et al., 2023) shows that reducing infusion time by 40–50% does not compromise safety or efficacy, since the risk of infusion-related reactions is significantly lower after the first dose, when the initial B-cell depletion has already been achieved.

Implementing a rapid infusion protocol in IMSS UMAAs in Yucatán represents a strategic opportunity with direct operational benefits: it optimizes the use of infusion chairs and rooms, reduces nursing staff person-hours, increases daily care capacity, decreases waiting times, and improves access to essential therapies. This is especially relevant in patients coming from rural areas who must travel long distances and whose adherence depends largely on the duration of infusions.

Despite favorable international evidence, there is a significant lack of local studies supporting the safety, efficiency, and applicability of rapid rituximab infusion in the Mexican population, whose demographic characteristics, comorbidities — particularly obesity and diabetes mellitus — and social determinants differ from the cohorts studied in other countries. Therefore, generating local evidence is essential to support potential institutional adoption of this model and to establish recommendations applicable within the IMSS.

In this context, evaluating the safety and operational feasibility of rapid rituximab infusion in rheumatology patients at IMSS Yucatán constitutes a high-impact intervention with the potential to improve service efficiency, optimize resources, and raise the quality of care in a region with high demand and structural limitations.

2. Justification

Adopting rapid rituximab infusion represents a highly strategic intervention for IMSS in Yucatán, where three key factors converge: high prevalence of rheumatologic diseases, operational saturation of UMAAs, and international clinical evidence supporting the safety of shorter infusion times in patients previously exposed to the drug.

In Mexico, the COPCORD epidemiological study led by Dr. Ingris Peláez-Ballestas demonstrated a high burden of musculoskeletal disease (25.5%) and an RA prevalence of 1.6%, one of the highest in Latin America. In Yucatán, local findings are even more striking: data from the regional study report an RA prevalence of up to 2.8% in the southern population, as well as an SLE prevalence of 0.07%, highlighting the concentration of demand in this region. Additionally, a recent study in three regions of the country showed that the discontinuation rate of biologics due to adverse events is 9.4% in the south, with no significant differences compared with other regions, and that patients from the south have higher seropositivity, which may be associated with greater disease severity and, therefore, a higher likelihood of requiring rituximab as control or rescue therapy.

In this high-demand epidemiological context, standard rituximab administration — requiring 3.5 to 4 hours per infusion — generates considerable pressure on Ambulatory Care Medical Units (UMAA). In Yucatán, where infusion chairs are a critical and limited resource, the prolonged infusion time contributes to structural saturation, long waiting lines, lower patient turnover, and reduced opportunities to initiate or maintain timely treatments. This directly affects disease progression, adherence, and quality of life.

By contrast, rapid infusion (approximately 90 minutes) has been shown to be safe and non-inferior to standard infusion in multiple clinical trials:

Tuttle et al., 2022 (n=150): No increase in adverse reactions (2.5% vs. 2.8%; p=0.89).
Davies et al., 2024 (n=200): 45% reduction in total time, with no increase in infusion-related adverse reactions.
Wallace et al., 2025 and Hochberg et al., 2023: Severe reactions occur almost exclusively during the first infusion, when B-cell burden is high; thereafter, risk drops significantly.
Pharmacokinetics (Cmax, AUC) remain unchanged with accelerated infusion schemes.

This clinical evidence, combined with data from IMSS Yucatán — where most patients have already received at least one prior infusion without severe reactions — provides a strong rationale for evaluating the transition to an accelerated protocol.

The operational impact is also noteworthy. When comparing standard infusion (4 h) with rapid infusion (1.5 h), there is an approximate savings of 5 hours per patient per cycle, which, extrapolated to the current volume at the UMAA of HGR1, represents an estimated saving of 1,562 hours per year, equivalent to 195 working days. This could increase operational capacity by 40–50%, enabling treatment of 3 to 4 additional patients per day, improving therapeutic adherence, reducing deferrals, and optimizing nursing staff utilization.

The benefit is even more significant in Yucatán, where a high percentage of patients come from rural and Maya Indigenous communities, with travel times of 2–4 hours, making infusion duration a critical determinant of access and treatment continuity. Reducing the total length of stay — including post-infusion observation — lowers geographic, economic, and mobility barriers.

Finally, generating local evidence is essential. Although the safety of rapid infusion is well established internationally, there are no published studies in the Mexican population, which presents relevant clinical particularities: higher prevalence of diabetes mellitus, obesity, cardiovascular comorbidities, and documented genetic differences in the Maya population. Therefore, validating safety and operational efficiency in a real IMSS setting will support future updates of institutional protocols and contribute to the standardization of best practices at the national level.

Taken together, rapid rituximab infusion is justified as a high-impact clinical, operational, and social intervention, essential to improve system efficiency, expand access to biological therapies, and enhance the quality of rheumatologic care at IMSS Yucatán.

3. Hypothesis

Null hypothesis (H0):
Rapid rituximab infusion is inferior to standard infusion in terms of safety, defined as an increase ≥ 8% in the proportion of infusion-related adverse events (p₂ – p₁ ≥ δ, where δ = 0.08).

Alternative hypothesis (H1):
Rapid rituximab infusion is not inferior to standard infusion in terms of safety, maintaining a difference < 8% in the frequency of adverse events (p₂ – p₁ < δ).

Definitions:

p₁: Proportion of adverse events in the standard infusion group.
p₂: Proportion of adverse events in the rapid infusion group.
δ = 0.08 (8%): Non-inferiority margin, selected based on international evidence and local prevalence of adverse events reported in the Mexican population.

The choice of a non-inferiority margin (δ) is a critical element in the methodological design of any non-inferiority trial. In this study, δ = 0.08 (8%) is proposed, based on epidemiological, clinical, and operational data relevant to the IMSS Yucatán context and the international evidence on rapid rituximab infusion.

Justification of the non-inferiority margin (δ = 0.08)

The margin selection was based on four methodological criteria:

Previous evidence on the frequency of infusion-related adverse reactions (IRR)
International clinical studies show very low rates of severe IRR (2–5%) after the first rituximab infusion:

Tuttle et al., 2022 (n=150): 2.5% vs. 2.8% between rapid and standard.
Davies et al., 2024 (n=200): no differences in Grade ≥3 reactions.
Wallace et al., 2025; Hochberg et al., 2023: most reactions occur only during the first infusion.

In the protocol file, this expected proportion is already recognized as p₁ ≈ 5%, which is consistent with Biobadamex and IMSS Yucatán.

Since the “natural” rate of reactions after the first infusion is ~5%, an additional maximum difference of 8 percentage points (δ = 0.08) implies that:

Rapid infusion could reach, at most, 13% total IRR,
without exceeding clinically accepted low-to-moderate risk thresholds,
and without compromising the overall safety of the procedure.

This margin keeps safety within the range accepted by multicenter studies and clinical practice guidelines.

In a non-inferiority design, the margin must be narrow enough to ensure that:

No more than a minimal fraction of the demonstrated benefit of the standard intervention is lost.
The historical safety profile is preserved.

Taking as reference:

Severe IRR with standard infusion: 2–5%.
Severe IRR with rapid infusion: 2–4% in comparative studies.
Acceptable range in non-inferiority protocols for IV biologic therapies: 6–10%.

A margin of 8%:

Preserves more than 50% of the clinical benefit regarding standard safety.
Is consistent with biologic drug trials where margins up to 10–12% in relative safety are accepted.
Fits the real clinical context at IMSS, where the population has a higher prevalence of diabetes and obesity, without a demonstrated increase in IRR in Mexican cohorts.

Objectives

General Objective
To determine, with methodological rigor and under a non-inferiority design, whether rapid rituximab infusion maintains a safety profile comparable to the standard scheme and, simultaneously, to quantify its impact on operational efficiency, resource utilization, and care experience in an UMAA of the IMSS in Yucatán.

Specific Objectives

To comparatively evaluate the clinical safety of both infusion schemes through standardized measurement of immediate and delayed adverse events, their severity, need for therapeutic interventions, and their temporal distribution during and after drug administration.
To accurately measure the effective occupation time of infusion chairs in both schemes, incorporating key operational components such as preparation time, IV setup, post-infusion observation, and patient turnover, in order to estimate the real performance of the service.
To quantify variations in the demand for human and material resources, including nursing person-hours, clinical monitoring, consumables, and overall operating costs, in order to determine the potential annual savings associated with the rapid infusion model.
To explore the perception and level of satisfaction of both patients and health care personnel regarding each infusion modality, integrating dimensions such as comfort, perception of safety, clarity of the process, workload, and service flow.
To analyze the feasibility of institutional implementation by identifying logistical barriers, training needs, infrastructure requirements, and elements that would allow projecting scalability of the protocol to other UMAAs in the region or the IMSS at the national level.

5. Theoretical Framework

5.1 History of Rituximab

The development of rituximab is one of the most influential advances in the modern history of immunotherapy. Its origins date back to the 1980s, when monoclonal antibodies were just beginning to emerge as potential therapeutic tools. In 1985, Tedder and colleagues identified the CD20 antigen as a highly attractive target due to its consistent expression on B lymphocytes and absence on hematopoietic stem cells, allowing a safe immunological target without compromising regeneration of the B-cell compartment. This discovery marked the conceptual beginning of what would later become rituximab.

Over the following years, multiple research groups focused on understanding CD20 biology, its role in cell activation, structural organization, and stability as an ideal marker for specific cytotoxic therapies. By the early 1990s, IDEC Pharmaceuticals had developed the first chimeric monoclonal antibody against CD20, known as IDEC-C2B8. In 1994, Reff and colleagues published preclinical studies demonstrating that this antibody was capable of efficiently depleting B lymphocytes in animal models without inducing significant toxicity, supporting its feasibility for clinical use.

The next major milestone occurred in 1997, when the FDA approved rituximab under the trade name Rituxan® for the treatment of low-grade B-cell non-Hodgkin lymphoma. This transformed the field of oncology, making it the first monoclonal antibody approved for a solid or hematologic malignancy. Pivotal trials demonstrated objective response rates close to 50%, unprecedented in such refractory lymphomas at that time.

After its initial approval, rituximab was rapidly incorporated into combined regimens in oncology, particularly with CHOP and CHOP-like protocols, increasing overall survival in multiple randomized studies in the late 1990s and early 2000s. In parallel, rheumatology researchers began exploring its use in B-cell-mediated autoimmune diseases. In 2001, Edwards and Cambridge published the first study in patients with severe, refractory rheumatoid arthritis, showing a significant reduction in inflammatory activity using a regimen combined with methotrexate. This study opened the door to subsequent multicenter trials that confirmed its efficacy in seropositive RA, especially in patients who had failed anti-TNF therapy.

From 2006 onward, rituximab received approval from multiple regulatory agencies for use in RA, ANCA vasculitis (GPA and MPA), multiple sclerosis, and other immune-mediated conditions. During this therapeutic expansion, its B-cell depletion mechanism was recognized as a strategy distinct from other cytokine-targeting biologics, as it acts more deeply on the architecture of the adaptive immune system.

In Mexico, IMSS incorporated rituximab into its institutional formulary in 2006 for RA and later for SLE and immunosuppression in specific cases. Over the past 15 years, its use in public institutions has steadily grown, driven by greater availability of biosimilars as well as robust clinical evidence supporting its safety and efficacy even in populations with comorbidities such as diabetes and obesity. Today, rituximab is considered an essential part of the therapeutic arsenal for highly complex autoimmune diseases and serves as a reference point for cost-effectiveness assessments within IMSS.

Moreover, the development of newer anti-CD20 antibodies (ofatumumab, ocrelizumab, obinutuzumab) has further highlighted rituximab’s historical relevance, as it remains the standard against which new agents are compared. Its clinical longevity — more than 25 years since initial approval — demonstrates its sustained efficacy and cross-disciplinary therapeutic value. In this sense, studying schemes that optimize its administration, such as rapid infusion, is a natural extension of the drug’s historical trajectory.

5.2 Molecular and Pharmacological Characteristics

Rituximab is a chimeric IgG1κ monoclonal antibody with a molecular weight of approximately 145 kDa. Its structure integrates murine variable regions (which determine specificity for CD20) with human constant regions (responsible for interaction with the effector machinery of the immune system). This chimeric configuration was initially designed to minimize immunogenicity while maintaining optimal affinity for its target.

The CD20 antigen is a transmembrane phosphoprotein with four domains, expressed exclusively on B lymphocytes from late pre-B stages to mature B cells, but absent on terminally differentiated plasma cells. This feature grants rituximab a unique therapeutic window: it allows elimination of B lymphocytes implicated in autoimmune pathophysiology without affecting baseline immunoglobulin production established by long-lived plasma cells.

Rituximab’s mechanism of action involves several effector pathways:

Antibody-dependent cellular cytotoxicity (ADCC):
Rituximab facilitates recognition of the B lymphocyte by NK cells and macrophages via its Fc fragment, inducing cell lysis mediated by FcγRIIIa receptors. The efficacy of this pathway may depend on genetic polymorphisms of the Fc receptor, which helps explain interindividual variability in therapeutic response.
Complement-dependent cytotoxicity (CDC):
Binding of rituximab to CD20 activates the complement cascade, leading to membrane attack complex formation and cell lysis. This pathway is particularly relevant in populations with adequate serum levels of C1q, C3, and C4.
Direct antibody-induced apoptosis:
Through signaling mediated by redistribution of CD20 into lipid rafts, rituximab can induce apoptotic signals independent of the previous pathways.
Prolonged immunologic depletion:
B-cell elimination occurs in peripheral blood, lymph nodes, spleen, and other secondary tissues. B-cell repopulation typically takes 6 to 12 months, which underlies the need for semiannual or annual cycles depending on the disease.

From a pharmacokinetic standpoint, rituximab follows a two-compartment model. Its volume of distribution (~4.6 L) reflects predominately intravascular confinement, with limited penetration into deep tissues. The prolonged half-life (22–32 days) is related to progressive saturation of the B-cell compartment, reducing clearance as CD20+ cell burden decreases. Effective minimum concentration and trough levels show little variability between cycles, provided adequate B-cell depletion is achieved.

Immunogenicity is an important aspect. Although rituximab can induce anti-drug antibodies (ADA), their incidence is relatively low compared with fully murine or earlier-generation humanized antibodies. Currently available biosimilars maintain high similarity in affinity, kinetics, and structure, which has facilitated expanded pharmacologic access in public health systems without compromising clinical efficacy.

Compared with other anti-CD20 antibodies, rituximab presents notable differences:

Ofatumumab recognizes a different epitope with greater CDC activity.
Ocrelizumab is a humanized IgG1 with lower immunogenicity and greater preference for ADCC.
Obinutuzumab, a glyco-engineered type II antibody, promotes more efficient apoptosis.

Nevertheless, rituximab continues to be the most extensively studied agent with the greatest volume of real-world data, positioning it as the reference drug in rheumatology and justifying its continued evaluation in optimization contexts such as infusion time reduction.

Finally, from an operational perspective, its pharmacologic characteristics — particularly limited extravascular distribution and absence of hepatic metabolism — support the feasibility of accelerated infusion schemes in patients who have previously tolerated the drug. Pharmacodynamic studies show that infusion rate does not clinically significantly alter Cmax or modify the rate of B-cell depletion, which supports the safety of rapid infusion and its integration into UMAAs with high patient volumes.

5.3 Mechanisms of Action

CD20 is a transmembrane phosphoprotein stably expressed on late pre-B and mature B lymphocytes, with no expression on hematopoietic stem cells or plasma cells, enabling deep but reversible depletion of the B-cell compartment without compromising the bone marrow’s regenerative capacity (Tedder et al., 1985; Polyak & Deans, 2002).

The main mechanisms of action include:

Complement-dependent cytotoxicity (CDC)
Binding of rituximab’s Fc fragment to C1q initiates the classical complement pathway, promoting sequential activation of C4, C2, and C3. Membrane attack complex (MAC, C5b-9) formation culminates in osmotic lysis of the B lymphocyte (Golay et al., 2000). Recent studies confirm that CDC efficacy depends on CD20 density, complement system integrity, and C1qA polymorphisms (Dall’Ozzo et al., 2021).
Antibody-dependent cellular cytotoxicity (ADCC)
The Fc portion of rituximab activates effector cells such as NK cells, monocytes, and macrophages through interaction with FcγRIIIa (CD16). These cells release perforin, granzymes, and reactive oxygen species, inducing apoptosis in tagged cells (Clynes et al., 2000). Allelic variants of FcγRIIIa (especially 158V/V) have been associated with greater clinical efficacy, a phenomenon well documented in RA and lymphoma (Koene et al., 1997; Ruiz-Larrañaga et al., 2024).
Direct apoptosis via intracellular signaling
Rituximab can trigger CD20 reorganization in lipid rafts, activating caspases 3, 8, and 9, DNA fragmentation, and mitochondrial collapse. This mechanism was first described in pioneering studies by Maloney et al. (1997) and has been confirmed by super-resolution microscopy (Sáez de Guinoa et al., 2021).
Profound immunomodulation of the inflammatory microenvironment
Beyond direct cytotoxicity, rituximab modifies key immunologic processes:
- Sustained reduction of IL-6, TNF-α, BAFF, and APRIL.
- Decrease in memory B cells and peripheral plasmablasts.
- Remodeling of ectopic germinal centers in inflamed tissues (Takemura et al., 2001).
- Reduced antigen presentation and chronic stimulation of autoreactive T cells.

These effects explain the prolonged clinical benefits even after partial recovery of the B-cell compartment.

5.3.1 Modulation of Signaling Pathways

B-cell depletion alters multiple intracellular signaling programs, impacting key pathways in immune cell survival, proliferation, and differentiation:

PI3K/AKT/mTOR
Rituximab decreases AKT phosphorylation, inhibiting mTORC1 and mTORC2 and thus suppressing proliferation and protein synthesis (Hennessy et al., 2005). This contributes to cell cycle arrest in autoreactive B lymphocytes.
NF-κB
B cells depend on NF-κB for expression of survival genes such as Bcl-2 and Bcl-xL. Rituximab disrupts this pathway through both direct mechanisms and reduction of signals from the BCR and BAFF (Karin & Lin, 2002).
MAPK (ERK1/2, p38, JNK)
Decreased ERK and p38 signaling has been observed, reducing proliferation, migration, and activation (Dong et al., 2002). JNK modulation promotes apoptosis.
BCR/BTK
Inhibition of the BCR-BTK-PLCγ2 axis reduces intracellular calcium influx, preventing full B-cell activation (Tedder & Engel, 1994). This mechanism is especially relevant in autoimmune diseases characterized by BCR hyperactivation.
JAK/STAT
Reduced STAT3/5 activity has been documented in rituximab-treated patients, with lowering of key regulatory cytokines for B-cell proliferation (Johnston et al., 2024).
Differentiation pathways (Wnt/β-catenin and Notch)
Elimination of immature and memory B cells disrupts signals responsible for establishing ectopic niches, modulating inflammatory tissue remodeling (Wang et al., 2023).

Taken together, these mechanisms explain why rituximab acts not only as a cytotoxic agent but also as a global modulator of adaptive immunity.

5.4 Clinical Applications and Experience of Cited Studies

Rituximab has robust evidence across multiple immune-mediated diseases. The breadth of its indications is explained by its ability to disrupt autoreactive circuits driven by B cells, antibodies, cytokines, and antigen-presenting cells.

Rheumatoid Arthritis (RA)
The pivotal DANCER and REFLEX trials (Cohen et al., 2006) included more than 1,000 patients with RA refractory to anti-TNF therapy. Rituximab achieved:
- ACR20 in 51% vs. 18% (placebo).
- Significant reductions in HAQ and DAS28.
- Decreased RF and anti-CCP titers.
Subsequent genetic studies (Ruiz-Larrañaga et al., 2024) identified that carriers of the FcγRIIIa-V/V allele show almost twice the response rate compared with other genotypes.
Longitudinal European data (Finckh et al., 2020) confirm:
- Sustained remission rates of 30% at 5 years.
- Discontinuation due to adverse events < 5%.
- Excellent safety profile in populations with diabetes and obesity.
Systemic Lupus Erythematosus (SLE)
Although the EXPLORER and LUNAR trials did not meet primary endpoints due to patient heterogeneity and strong placebo effects, multiple secondary analyses and observational studies have demonstrated efficacy in specific clinical subgroups:
- Proliferative lupus nephritis: RR 1.8 (CI 1.2–2.7).
- Refractory neuropsychiatric SLE: 65% response (Rodríguez-Álvarez, 2023).
- Reduction of severe flares by up to 40% in Mexican cohorts (Sanchez-Guerrero et al., 2023).
Rituximab is particularly useful in B-cell-dependent SLE phenotypes, characterized by high anti-DNA titers, low complement, and persistent plasmablastosis.
ANCA-associated Vasculitis (GPA/MPA)
The RAVE trial (Stone et al., 2010) demonstrated that rituximab is not only equivalent to cyclophosphamide for induction, but superior in:
- Relapse rates (HR 0.67).
- Control of refractory disease.
Recent maintenance trials (Specks et al., 2024) show:
- Sustained remission of 80% at 18 months.
- Significant reduction in cumulative glucocorticoid toxicity.
Other indications with growing evidence
- Catastrophic antiphospholipid syndrome: hemodynamic stabilization and reduced microangiopathy.
- Types II and III cryoglobulinemia: response rates > 65%.
- Inflammatory myopathies associated with anti-SRP or anti-HMGCR: significant improvement in muscle strength and CK.
- Relapsing-remitting multiple sclerosis: comparative studies with ocrelizumab show similar efficacy in reducing MRI lesions.

5.5 Clinical Pharmacology

Rituximab is a chimeric IgG1κ monoclonal antibody directed against CD20, with a wide spectrum of clinical applications in autoimmune and oncologic diseases. Its pharmacologic profile combines selective B-cell depletion, prolonged pharmacokinetics, and deep modulation of adaptive immunity. More than 25 years after its initial approval, it remains a reference drug, with multiple formal indications and a growing number of off-label uses supported by solid scientific evidence.

5.5.1 Dosing Regimens

Regimens vary according to disease, inflammatory burden, seropositivity, and international guideline recommendations (EULAR, ACR, KDIGO, BSR).

Rheumatoid Arthritis (RA)
- Approved regimen: 1,000 mg IV × 2 doses separated by 2 weeks, with retreatment every 6–12 months.
- Clinical considerations: greater efficacy in RF/anti-CCP–positive patients. EULAR recommends retreatment based on disease activity (treat-to-target).
Systemic Lupus Erythematosus (SLE)
- Regimens used:
  - Lymphoma regimen (375 mg/m² weekly × 4).
  - RA regimen (1,000 mg × 2), used in proliferative nephritis or severe SLE.
- Evidence: marked response in autoantibody-producing phenotypes. High utility in neuropsychiatric, hematologic, and refractory SLE.
ANCA-associated Vasculitis (GPA/MPA)
- Induction: 375 mg/m² weekly × 4, or 1,000 mg × 2 on days 1 and 15.
- Maintenance (MAINRITSAN): 500 mg at months 0, 6, 12, and 18.
Non-Hodgkin Lymphoma
- 375 mg/m² weekly × 4 or as part of R-CHOP.
Multiple Sclerosis (off-label in some countries)
- 1,000 mg × 2 every 6 months.
- Extensive evidence of relapse reduction (Hauser et al., 2017).

Relevant regulatory approvals

FDA/EMA:
- Non-Hodgkin lymphoma (1997).
- Chronic lymphocytic leukemia (2006).
- Rheumatoid arthritis (2006).
- Granulomatosis with polyangiitis and microscopic polyangiitis (2011).
Health Canada / EMA / United Kingdom:
- Severe cryoglobulinemia (formal use in several European countries).
Mexico (COFEPRIS):
- RA, refractory SLE, ANCA vasculitis, lymphomas, CLL.

Off-label uses with strong scientific support

Inflammatory myopathies (anti-SRP and anti-HMGCR): 60–80% response in strength and CK (Allenbach et al., 2020).
Catastrophic antiphospholipid syndrome: adjuvant therapy to control microangiopathy.
Neuromyelitis optica (anti-AQP4): efficacy comparable to eculizumab in preventing relapses (Pittock et al., 2019).
Dermatomyositis and IgG4-related disease: significant reduction of inflammatory activity and lesion regression.
Immune thrombocytopenic purpura (ITP): long-term remission in 45–60% (Ghanima et al., 2023).
Membranous glomerulonephritis and autoantibody-mediated nephropathies: KDIGO 2021 recognizes it as preferred therapy in high-risk disease.

5.5.2 Pharmacokinetics

Rituximab exhibits a two-compartment behavior with nonlinear elimination. Its pharmacokinetics are strongly influenced by available B-cell mass (target-mediated drug disposition).

Key parameters:

Volume of distribution: ~4.6 L (mainly intravascular).
Clearance:
- 0.23 L/day at the first infusion,
- 0.13 L/day at the fourth, due to lower CD20 availability.
Terminal half-life: 22–32 days, varying with antigen burden.
Tissue absorption: limited; does not significantly cross the blood-brain barrier, although it may exert peripheral effects in CNS diseases mediated by B cells.
B-cell depletion: occurs within 24–96 hours.
Reconstitution: between 6 and 18 months, depending on indication and baseline BAFF levels.

Factors influencing pharmacokinetics:

BAFF/APRIL levels (higher = faster repopulation).
Seropositivity (RF, CCP, ANCA): associated with greater initial clearance.
Obesity: alters Vd without clinically meaningful changes in efficacy.
Use of biosimilars: equivalent pharmacokinetics (EMA, 2023).

5.5.3 Rapid Infusion

Rapid infusion (90 minutes) has emerged as a safe and efficient strategy in patients previously tolerant to rituximab. Evidence shows that pharmacokinetic profile and adverse event rates do not change when increasing drip velocity.

Pathophysiologic rationale

Most adverse reactions occur only during the first infusion, when B-cell burden is high.
After the first dose, CD20 availability decreases drastically, reducing IL-6 and TNF-α release.
This explains why tolerant patients can safely receive accelerated schemes.

Relevant clinical evidence

Tuttle et al., 2022:
- 150 RA patients.
- Similar IRR rates between rapid and standard infusion: 2.5% vs. 2.8% (p=0.89).
Davies et al., 2024:
- 200 patients with IMIDs.
- Time reduced from 210 to 90 minutes.
- Satisfaction scores 4.3/5 vs. 3.7/5 (p=0.02).
Wallace et al., 2025:
- Grade 3–4 IRR: 2–5%, no differences between modalities.
Zhou et al., 2024:
- No significant changes in Cmax, AUC, or overall exposure.

Proven operational advantages

40–60% reduction in time per patient.
Greater turnover of infusion chairs.
Less saturation in high-demand UMAAs.
Reduced nursing person-hours and operational costs.

5.6 Adverse Effects

Rituximab has a well-characterized safety profile due to decades of use in millions of patients.

5.6.1 Immediate Reactions

Frequent (50–77% in the first infusion): fever, chills, urticaria, headache.
Mechanism: cytokine release syndrome due to B-cell lysis.
Prevention: methylprednisolone 100 mg IV, antihistamines, and acetaminophen.

5.6.2 Intermediate Reactions

Progressive hypogammaglobulinemia (10–20%).
Late-onset neutropenia (3–5%).
Hepatitis B reactivation: 5–10% risk in carriers.
PML (extremely rare): <0.01%.

5.6.3 Mandatory Pre-treatment Screening

Hepatitis B/C, HIV, TB.
Serum immunoglobulins.
Vaccination before treatment (influenza, pneumococcus).

5.7 Scientific Rationale for Rapid Infusion

Accumulated evidence shows that after a first infusion without severe adverse events, patients have:

lower B-cell burden,
reduced cytokine release,
reduced complement activation,
lower probability of severe IRR,

so that accelerated infusion does not compromise safety.

This has led centers in the United States, the United Kingdom, Canada, and Western Europe to adopt rapid infusion as the standard for re-administration even in complex autoimmune diseases.

5.8 Estimated Hours Saved

Considering typical UMAA volume (2–3 patients/day), implementing a rapid protocol can free approximately 195 working days per year, increasing capacity by 40–50% and reducing deferrals, saturation, and operating costs.

5.9 Institutional Context of IMSS and Use of Rituximab

The Mexican Institute of Social Security (IMSS), founded in 1943, is the largest health institution in Mexico, serving more than 69 million people (55% of the Mexican population) (IMSS, 2024). In Yucatán, IMSS operates 56 Family Medicine Units (UMF) and 4 secondary-level hospitals, including the Regional General Hospital No. 1 (HGR1) in Mérida, which has an UMAA for biological therapies. In 2023, IMSS Yucatán treated ~1,200 patients with rheumatologic diseases, of whom approximately 150–200 received rituximab for RA, SLE, or ANCA vasculitis, representing 12–15% of all rheumatology patients (IMSS Yucatán, 2023).

5.9.1 Use of Rituximab at IMSS

Rituximab was incorporated into IMSS’s basic formulary in 2006 for RA and SLE, and in 2010 for ANCA vasculitis after evidence from the RAVE and REFLEX trials (Stone et al., 2010; Cohen et al., 2006). Its use is regulated by IMSS Clinical Practice Guidelines (GPC) for RA (ICD-10 M05-M06) and SLE (ICD-10 M32), which indicate rituximab in patients with inadequate response to disease-modifying antirheumatic drugs (DMARDs) or TNF inhibitors (IMSS, 2023). At IMSS, rituximab is administered in UMAAs under strict protocols, with premedication (methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, acetaminophen 1 g PO) and continuous monitoring to prevent IRR.

The estimated cost per cycle (2 infusions of 1,000 mg) is approximately 10,000 MXN, representing a budgetary challenge for IMSS, particularly in high-demand regions such as Yucatán (IMSS, 2024).

IMSS participates in the Mexican Registry of Adverse Events of Biologic Therapies in Rheumatologic Diseases (Biobadamex), coordinated by the Mexican College of Rheumatology. This registry, active since 2016, collects safety and efficacy data for rituximab and other biologics at IMSS, reporting an incidence of serious adverse events of 4–6 per 100 patient-years, consistent with international literature (Ventura-Ríos et al., 2012). A retrospective IMSS study (2013–2018) at the Hospital de Especialidades Centro Médico Nacional La Raza reported a prevalence of persistent hypogammaglobulinemia of 3.1% in rituximab-treated patients, with no clear predictive factors, underscoring the need for long-term immunologic monitoring (Revista Alergia México, 2023).

5.9.2 Context in Yucatán

In Yucatán, RA prevalence is ~1.6% (approximately 35,000 cases among the insured population) and SLE prevalence is ~0.1% (2,200 cases), with a 10% annual increase in demand for biologic therapies due to population aging, improved diagnosis, and a high proportion of Maya Indigenous population (30% of the insured) with unique genetic and socioeconomic characteristics (IMSS Yucatán, 2023). HGR1 in Mérida, the main referral center, has 6 infusion chairs in its UMAA, treating 2–3 patients per day with rituximab, resulting in 85–90% occupancy (IMSS Yucatán, 2024). High demand, combined with prolonged infusion times (3.5–4 h), limits capacity, particularly for patients from rural areas (e.g., Tizimín, Valladolid), who face travel times of 2–4 hours.

A local HGR1 report (2022) indicated that 80% of RA patients treated with rituximab achieved partial remission (DAS28 < 3.2) at 6 months, but 15% had mild infections (respiratory, urinary) associated with therapy, highlighting the importance of pharmacovigilance (IMSS Yucatán, internal data). Additionally, the Maya population in Yucatán has a higher prevalence of comorbidities such as type 2 diabetes mellitus (20–25% in rheumatologic patients) and obesity, which may influence treatment response and adverse event risk (Sanchez-Guerrero et al., 2023).

5.9.3 Rituximab Biosimilars

In Mexico, rituximab biosimilars are available and approved by the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) for the same clinical indications as the original rituximab (Mabthera®), including RA, SLE, and ANCA vasculitis (Oncoespecializados, 2025). Biosimilars such as Rixathon® and Truxima® are up to 30% less expensive than the original rituximab, making them attractive to IMSS, which aims to optimize resources in a high-demand public health system.

Although there are no specific data on biosimilar use at IMSS Yucatán, IMSS nationally has begun incorporating biosimilars into its formulary since 2019, with preliminary reports indicating efficacy and safety comparable to original rituximab (Mexican College of Rheumatology, 2013). Adoption of biosimilars could reduce operating costs by approximately 3,000 MXN per cycle, increasing access in regions like Yucatán (IMSS, 2024).

5.9.4 Institutional Initiatives

IMSS has implemented programs to optimize the use of biologic therapies, such as the Biobadamex registry, which includes data from rituximab-treated patients at IMSS. Since 2018, HGR1 in Yucatán has participated in multicenter studies on rituximab, focusing on response biomarkers (e.g., FcγRIIIa polymorphisms) and dosing optimization strategies (IMSS, 2024). These initiatives aim to reduce operating costs and improve access in regions with high disease burden.

IMSS Yucatán collaborates with the Universidad Autónoma de Yucatán (UADY) and the Centro Universitario de Ciencias de la Salud (CUCS) to train personnel in biologic management and develop local guidelines adapted to the Maya population, which presents genetic variations (e.g., HLA-DRB1) associated with greater RA susceptibility (IMSS Yucatán, 2023).

IMSS has also strengthened digital services, such as the online appointment platform (IMSS Digital), to facilitate access to UMAA treatments, especially in rural areas of Yucatán (IMSS, 2022). Additionally, the “IMSS-Bienestar” program in Yucatán, which serves uninsured populations, has begun integrating biologic therapies in Indigenous communities, although access to rituximab remains limited by cost and logistics (IMSS, 2024).

5.10 Advances and Perspectives

Formulations: Subcutaneous rituximab with hyaluronidase (5–7 min) and humanized antibodies (ocrelizumab, ofatumumab) offer lower immunogenicity (Davies et al., 2024; Hauser et al., 2023).
CAR-T therapies: In development for refractory autoimmune diseases (Li et al., 2025).
Biomarkers: FcγRIIIa polymorphisms, BAFF/APRIL levels, and transcriptomic signatures predict therapeutic response (Ruiz-Larrañaga et al., 2024).
Dose optimization: Population pharmacokinetic models and adaptive dosing based on disease activity (Zhou et al., 2024).

5.11 Regulatory Implications

Implementing rapid infusion at IMSS requires:

Validation in the Mexican population, considering the high prevalence of comorbidities (diabetes, hypertension) in Yucatán.
Updating IMSS Clinical Practice Guidelines, aligned with NOM-024-SSA3-2010.
Staff training in IRR management and active pharmacovigilance.
Integration of data into the Biobadamex registry for continuous monitoring.

6. Methodology

6.1 Design

Prospective quasi-experimental clinical trial with pragmatic, week-based quasi-randomization, comparing standard infusion (3.5–4 h) vs. rapid infusion (90 min).

6.2 Population

Patients ≥18 years with confirmed diagnosis (ACR/EULAR) of RA, SLE, or ANCA vasculitis treated with rituximab at the UMAA of HGR1, IMSS Yucatán.

6.3 Inclusion Criteria

Age ≥18 years.
Confirmed diagnosis of RA, SLE, or ANCA vasculitis.
≥1 prior rituximab infusion without IRR (Grade ≥2).
Stable cardiopulmonary function.

6.4 Exclusion Criteria

Previous anaphylactic or allergic reactions to rituximab.
Unstable pulmonary/cardiac disease.
Active infections or severe immunosuppression.
Pregnancy or breastfeeding.

6.5 Intervention

Control group: Standard infusion (3.5–4 h) with progressive titration according to EULAR recommendations.
Intervention group: Rapid infusion (90 min) with the following rate scheme:
- 0–15 min: 50 mg/h
- 15–30 min: 100 mg/h
- 30–60 min: 200 mg/h
- 60–90 min: maximum rate allowed by device
Premedication: All patients will receive methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, and acetaminophen 1 g PO prior to infusion.
Conventional monitoring: Recording of vital signs every 15 minutes and documentation of any infusion-related adverse event (IRR), classified according to CTCAE v5.0.

To improve the precision of clinical recording, standardize data capture, and strengthen active pharmacovigilance, a real-time digital follow-up system will be implemented using iPads assigned to the nursing team and research staff.

Operational flow with iPads

Patient admission:
- At the start of the infusion session, staff open the corresponding module on the iPad (REDCap/Google Forms/IMSS internal app, depending on availability).
- A unique ID linked to the patient and type of infusion (standard or rapid) is generated.
Automated vital signs recording:
- Every 15 minutes, nursing staff enter blood pressure, heart rate, respiratory rate, oxygen saturation, and temperature.
- The system generates visual and audible alerts for critical values or abrupt changes.
Immediate adverse event capture:
- Preconfigured buttons with CTCAE v5.0.
- One-click recording of intensity, time of onset, intervention performed, and outcome.
- Ability to attach photos (rash, infiltration, local edema) if applicable.
Integrated timer:
- The module automatically records:
  - Exact start and end times of infusion.
  - Changes in infusion rate.
  - Total length of stay.
Surveys on iPad:
- At the end of infusion and the 1-hour observation period:
  - The patient completes a Likert-scale survey directly on the tablet.
  - Health care staff complete their own survey in a separate module.

This strategy reduces paper use, standardizes data, and prevents information loss.

Linkage to central database:

Information is automatically synchronized to the study database (REDCap/Drive), enabling:
- Centralized monitoring.
- Rapid audits.
- Immediate reports to pharmacovigilance.
- Clean data extraction for SPSS/R.

6.6 Follow-up

1 hour post-infusion.
Recording of adverse events (frequency, severity).
Satisfaction surveys (Likert scale 1–5) for patients and staff.

6.7 Sample Size

Sample size will be calculated for a non-inferiority design, assuming:

Expected proportion of adverse events (p₁, p₂) = 5%.
Non-inferiority margin (δ) = 8%.
Statistical power = 80%, α = 0.05.

Non-inferiority formula:
n = 2 × [(Z₁₋α/₂ + Z₁₋β)² × p(1–p)] / δ².

Estimated: ~100 patients per group (200 total), adjusted by 10% for potential loss to follow-up.

6.8 Data Collection Plan

Instruments:
- Clinical form for vital signs, adverse events (CTCAE v5.0), and infusion time.
- Satisfaction survey (Likert scale) validated for patients and staff.
- Record of operating costs (person-hours, chair use, supplies).
Procedure:
- Data collected by trained personnel during infusion and post-infusion follow-up.

7. Variables

			VariableTypeMeasurement ScaleNature
Infusion scheme	Independent	Categorical nominal	Categorical
Infusion time (min)	Dependent	Quantitative continuous	Continuous
Adverse events (yes/no)	Dependent	Dichotomous categorical	Categorical
Number of adverse events	Dependent	Quantitative discrete	Discrete
Event severity	Secondary dependent	Ordinal categorical (CTCAE)	Ordinal
Staff person-hours	Dependent	Quantitative continuous	Continuous
Operating costs	Secondary dependent	Quantitative continuous	Continuous
Patient age	Control / Independent	Quantitative continuous	Continuous
Diagnosis (RA, SLE, etc.)	Independent	Categorical nominal	Categorical
Comorbidities	Independent	Categorical nominal	Categorical
Satisfaction (patient/staff)	Secondary dependent	Ordinal categorical (Likert)	Ordinal

8. Statistical Analysis

Descriptive:
- Means with standard deviations for normally distributed variables.
- Medians with interquartile ranges for non-normally distributed variables.
- Proportions for categorical variables.
Comparative:
- Proportions: Chi-squared test or Fisher’s exact test.
- Means: Student’s t-test or ANOVA (normal distributions).
- Medians: Mann–Whitney test (non-normal distributions).
Non-inferiority:
- 95% confidence interval for p₂ – p₁, compared with δ = 0.08.
Cost analysis:
- Cost per patient/hour (staff, equipment, supplies).
Multivariable analysis:
- Logistic regression to evaluate factors associated with adverse events (age, diagnosis, comorbidities).
Significance: p < 0.05.
Software: R v4.3, SPSS v26.

9. Ethical Considerations

Approval by the Local Health Research and Ethics Committee of IMSS.
Written informed consent detailing objectives, procedures, risks, benefits, freedom to withdraw, and anonymity.
Compliance with the General Health Law (Title Five) and NOM-024-SSA3-2010.
Protection of personal data (Federal Law on Protection of Personal Data).
Reporting of serious adverse events to the IMSS Pharmacovigilance Committee and Biobadamex.

10. Timeline

						ActivityMonth 1Month 2Month 3Month 4Month 5Month 6
Protocol drafting	X
Ethics approval		X
Recruitment and implementation			X	X	X
Data analysis				X	X
Final report writing					X	X

11. Expected Academic Outputs

Scientific article in an indexed journal (e.g., Arthritis Research & Therapy, Reumatología Clínica).
Presentation at the National Rheumatology Congress (CMR) and/or EULAR.
Institutional guideline for rapid infusion at IMSS.
Anonymized database for future studies.
Proposal to integrate rapid infusion into IMSS Clinical Practice Guidelines.

12. References (APA 7th edition)

(References already appear in English; they are preserved as provided.)

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Funding

Funding

Safety of Accelerated Rituximab Infusion in Rheumatologic Diseases: Impact on Satisfaction and Care Burden in an UMAA of the IMSS

Funding Progress

Nonprofit Recipient

Topics

DOI

Funding Progress

Nonprofit Recipient

Topics

DOI

Safety of Accelerated Rituximab Infusion in Rheumatologic Diseases: Impact on Satisfaction and Care Burden in an UMAA of the IMSS

Funding Progress

Nonprofit Recipient

Topics

DOI