Rituximab combined with intravenous immunoglobulin in autoimmune diseases: a systematic review

Abstract

Background

Although using Rituximab (RTX) and intravenous immunoglobulin (IVIg) alone or sequentially is a well-established treatment for several autoimmune diseases, the combination of these two forms of therapy is still rare, and its use is poorly studied.

Aim

To perform a systematic review on the use of RTX associated with IVIG in autoimmune conditions.

Methods

PubMed/MEDLINE, EMBASE, and Scielo databases were screened for articles on RTX plus IVIg in autoimmune diseases until May 2024.

Results

The review encompassed 21 studies evaluating RTX and IVIg for autoimmune diseases. Ten studies focused on pemphigus, involving 85 patients with diverse subtypes (47 pemphigus vulgaris, 27 pemphigoids, and 11 other variants). Most were case reports or series, with one retrospective study including controls. Positive outcomes were reported across all but one case of paraneoplastic pemphigus. Infections, such as P. jirovecii pneumonia, were noted in three studies, highlighting a potential risk. The other 11 studies involved 24 patients with conditions like polyneuropathies, lupus with CNS involvement, and neuromyelitis optica. While most reported favorable outcomes, one trial on IVIg-dependent polyneuropathies found RTX ineffective in reducing IVIg needs. Adverse events included pneumonia, venous thrombosis with pulmonary embolism, and infusion reactions, demonstrating the need for careful monitoring.

Conclusion

RTX plus IVIg seems to be an alternative option for the treatment of refractory autoimmune diseases. However, more studies with a larger number of participants and in different autoimmune diseases are desired.

Key summary

• Rituximab (RTX) and intravenous immunoglobulin (IVIg) alone or sequentially is a well-established treatment for autoimmune diseases.

• Herein, the authors reviewed the studies that used the combination of RTX plus IVIg in autoimmune conditions.

• Pemphigus, polyneuropathies, lupus, Susac’s syndrome, neuromyelitis optica and acquired factor 8 inhibitor were the studied diseases.

• The outcomes were good and the treatment was well tolerated.

Introduction

Rituximab (RTX) is a monoclonal antibody directed against B lymphocytes, primarily used to treat lymphoma and autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), scleroderma (SSc), and others. The Fab portion of this antibody identifies a sequence of four amino acids of the CD20, a transmembrane protein, leading to a significant depletion of peripheral B cells, which play a crucial role in immune responses and the production of antibodies [1, 2]. Rituximab has emerged as a promising therapeutic option for ameliorating several autoimmune diseases that are presumed to be B-cell driven [3].

Intravenous immunoglobulin (IVIg) is a pool of immunoglobulins from thousands of blood donors with immunomodulatory properties in autoantibody-mediated, T-cell-mediated autoimmune disorders and systemic inflammatory diseases [4]. It controls T and B lymphocytes’ activation and effector functions, interferes with antigen presentation, neutralizes pathogenic autoantibodies, and has an anti-inflammatory effect due to its interaction with cytokines, complement, and endothelial cells [5].

Both drugs are used separately or sequentially to treat diseases refractory to other treatments or where conventional therapies result in unacceptable side effects [6,7,8]. The combination of these two drugs (RTX plus IVIg) was first used in highly human leucocyte antigen (HLA)-sensitized patients to reduce anti-HLA antibody levels, allowing kidney transplantation [9], and its use has spread to other forms of refractory autoimmune diseases. Nevertheless, there are few reports on the safety and efficiency of using this combination in autoimmune diseases.

This article aims to perform a systematic review of the data on RTX plus IVIg in autoimmune diseases.

Methods

This systematic review was conducted in accordance with internationally recognized guidelines for systematic reviews, using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology [10]. The literature search was performed across three major databases: PubMed, Scielo, and Embase, until May 2024. No language restrictions were applied.

Search strategy

The following specific MeSH entry terms: “Intravenous immunoglobulin” AND “rituximab” AND “autoimmune” were used. These terms were selected to maximize sensitivity and specificity, ensuring the inclusion of relevant studies.

Inclusion criteria: Studies involving adult patients (age ≥ 18 years); and prospective studies investigating RTX associated with IVIg as treatment of autoimmune diseases.

Exclusion criteria: Narrative or systematic reviews, protocols, opinion papers, editorials; and preclinical studies, including in vivo and in vitro research.

Study selection and data extraction

Articles identified during the search were initially screened by title and abstract to determine eligibility. Full-text articles of potentially relevant studies were subsequently reviewed. Two reviewers (JFC and TLS) conducted the screening and data extraction to minimize bias. If there were any discordance, a third reviewer would be included.

Extracted data included

Sample size and demographic characteristics of participants; diagnosis of the autoimmune disease; dosage and duration of RTX and IVIg therapy; methods used to assess outcomes, such as disease activity indices, and clinical parameters; and reported adverse events.

Results

Figure 1 shows the flowchart of the included studies.

Fig. 1

Flowchart of the included studies

Twenty-one papers were selected for review [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31].

Table 1 describes the 10 articles on RTX and IVIg used for pemphigus treatment [11,12,13,14,15,16,17,18,19,20]. The countries that reported those articles were the United States (n = 5) [11, 12, 14, 17, 19], Germany (n = 1) [13], Japan (n = 1) [15], UK (n = 1) [18], India (n = 1) [20], Canada (n = 1) [31], and Saudi Arabia (n = 1) [16], encompassing 85 patients (47 on pemphigus vulgaris; 27 on pemphigoids and 11 with miscellaneous forms of pemphigus). These works were prospective (n = 1) [12], retrospective (n = 4) [11, 14, 16, 17], and reports of cases or series of cases (n = 5) [13, 15, 18,19,20].

Table 1 Studies on rituximab associated with intravenous Immunoglobulin in pemphigus

All studies had a small number of patients; the biggest had n = 23 [16]. Only one retrospective study had a comparison with controls [11]. Also, but one study found positive clinical results of this form of treatment with improvement in skin pemphigus lesions; the negative clinical response were from a case report on paraneoplastic pemphigus [15].

The combination was well tolerated, but infections were a problem in 3 studies, including one with pneumonia by P. jiroveci [14, 16, 19].

Table 2 summarizes the 11 studies in other autoimmune entities encompassing another 24 patients [21,22,23,24,25,26,27,28,29,30,31]. They were from the USA (n = 5) [21, 23, 24, 27, 28], Spain (n = 2) [22, 29], Australia (n = 1) [25], Turkey (n = 1) [26], Saudi Arabia (n = 1) [30], and Canada (n = 1) [31]. There was 1 small prospective open-label trial [23] with 6 individuals with IVIG dependent polyneuropathies; all others were case or series of case reports [21, 22, 24,25,26,27,28,29,30,31]. They studied polyneuropathies (n = 3) [23, 27, 28], Lupus with central nervous system manifestations (n = 2) [25, 30], Susac syndrome (n = 1) [24], neuromyelitis optica (n = 1) [22], acquired factor 8 inhibitor (n = 1) [21], thrombotic thrombocytopenic purpura (n = 1) [29], autoimmune hemolytic anemia (n = 1) [31], and bullous epidermolysis acquisita (n = 1) [26]. The results were clinically positive in all but one observation: the open trial with IVIG-dependent polyneuropathies in which the addition of rituximab did not reduce IVIg requirements in most patients [23]. Patients with hematological manifestations had clinical and blood cell count improvements. Most neurological studies showed a clinical improvement and a few article showed MRI improvement and autoantibodies decrease (e.g. anti-aquaporine).

Table 2 Studies of rituximab associated with intravenous Immunoglobulin in several autoimmune conditions

The treatment was well tolerated despite 2 cases of pneumonia [28, 31], one of venous thrombosis complicated with pulmonary embolism [28], and one with infusion reactions [26].

Discussion

The evidence about the efficiency of combining RTX with IVIg is low and supported mainly by case descriptions. However, the preliminary results suggest that this field deserves further investigation, especially because this combination is used in severely ill patients in whom other drugs have been ineffective.

Autoimmune diseases associated with autoantibodies are presumed to be B cell-determined. Rituximab is a B cell depletion therapy that targets the CD20 molecule expressed on the surface of B lymphocytes from the pre-B cell stage to memory B lymphocytes, sparing stem cells and plasma cells. By depleting autoreactive B cells, it reduces the production of pathogenic autoantibodies [32].

Intravenous immunoglobulin (IVIg) exerts several anti-inflammatory and immunomodulatory effects, but not all mechanisms have been fully elucidated. It interacts with complement fragments C3b and C4b in the complement cascade, preventing the formation of the membrane attack complex and avoiding complement-mediated cell death and tissue damage [33,34,35]. It also counteracts C3a and C5a anaphylatoxins via an F(ab′)2-mediated mechanism. Furthermore, IVIg inhibits autoantibodies through idiotype networks [36]. Additionally, IVIg can bind to the neonatal Fc receptor (FcRn), blocking this protective receptor, which normally prevents the catabolism of IgG, thereby inducing the clearance of antibodies, including pathogenic ones [37, 38]. It also upregulates the inhibitory receptor FcγRIIB, which increases the threshold for immune-complex-mediated activation of innate immune cells [39].

Moreover, IVIg exerts inhibitory actions on monocytes and macrophages, inducing the release of anti-inflammatory cytokines such as IL-1 receptor antagonist (IL-1RA), TGF-β, and IL-10 [40, 41]. It also impedes the proliferation and antigen-presenting activities of B cells, as well as their activation through IL-4, CD40, TLR, and BCR signaling [42, 43]. However, while these immunomodulatory actions are well-documented, the complete range of IVIg’s mechanisms of action, particularly in autoimmune contexts, remains an area of ongoing research.

Rituximab treatment brings an essential risk for infection. Studies done on RA patients described that 10% of patients using RTX have hypogammaglobulinemia after the first course and 30% after the fourth course [44]. IVIg therapy prevents and fights severe infections [45, 46]. So, this combination is not only synergistic in treating autoimmune diseases, but IVIG helps prevent the collateral effects of RTX, becoming an ideal partner in this context.

The cases described are mainly on the several forms of pemphigus, which are severe diseases with a high risk of infection due to mucosal and skin blistering. In the 85 patients with pemphigus, few infections were seen with the use of this combination: 2 cases of pneumonia [18, 19], 1 ocular infection [18], 1 molluscum contagiosum [16], and 2 skin infection [16]. Also, several bacterial and fungal infections were seen in one patient with paraneoplastic pemphigus, who also received chemotherapy for lymphoma [15]. Two deaths were observed in this group, but both were unrelated to the treatment [15, 16]. In the group of other autoimmune diseases, two cases of pneumonia were seen among the 24 studied patients, and both were resolved with antibiotic treatment [28, 31].

The small study by Foster et al. [11] was particularly striking because it showed that this combination of drugs can prevent scarring blindness secondary to pemphigus mucosal involvement, while conventional immunosuppression cannot.

Some protocols for RTX and IVIg combination have been proposed [46, 47], and they may uniformize the doses and timing used, allowing better analysis of results in the future.

A limitation of this analysis is that most included studies are case reports, case series, or retrospective analyses, generating a limited number of patients. This type of evidence is, therefore, generally lower in quality, and the present findings should be interpreted with caution.

In conclusion, this review of RTX/IVIg shows that this therapy seems to effectively treat refractory autoimmune disorders with mild/moderate adverse effects. Future studies using RTX/IVIg using a significant number of autoimmune conditions in large cohorts of patients with autoimmune diseases are desired.