Intravenous Immunoglobulin Plus Rituximab Effective Alternative Option for Refractory Autoimmune Disease Treatment

Combination therapy with a regimen of rituximab (Rituxan; Genentech) and intravenous immunoglobulin (IVIG) can effectively treat refractory autoimmune disorders, including several forms of pemphigus, though further studies of the regimen with a varied number of featured diseases and a large patient cohort should be undergone, according to a systematic review conducted by investigators and published in Advances in Rheumatology.¹

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Rituximab, a monoclonal antibody directed against B lymphocytes, is used when treating patients with lymphoma and autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. IVIG—which is pooled immunoglobulins from blood donors—has positive impacts on pathogenic autoantibodies, producing an anti-inflammatory effect in patients.¹

In combination, the treatments have shown effectiveness in numerous fashions. Its first reported use in combination was in a liver transplant setting, in which Vo et al found that the combination could be effective as a desensitization regimen for patients awaiting a liver transplant. Since then, the combination has been investigated in other forms of refractory autoimmune diseases. These include pemphigoid-associated conjunctivitis, in which high-dose IVIG and rituximab were effective at managing the condition, especially in patients with severe recalcitrant disease. Most patients in that trial—approximately 93.5% of the cohort—had a positive response to treatment, though there was a risk of severe adverse events (AEs).^2,3

Despite the pearls of positive data, to date, there have been low levels of reports on the safety and efficiency of rituximab and IVIG in autoimmune diseases. The present investigators conducted a systematic review to elucidate these important factors and gain more knowledge on the potential use of this combination. To be included in the review, studies must have involved adult patients, have been prospective, and investigated rituximab associated with IVIG as a treatment for an autoimmune condition. In total, 21 papers were selected for review.¹

The reviewers split up the studies into 10 concerning rituximab and IVIG specifically for the treatment of pemphigus, which is a severe disease that carries a high risk of infection due to skin blistering, and 11 others that encompassed other autoimmune entities. A trend observed across the review of pemphigus trials—constituting a major limitation of the investigation—was that the included trials all had a small cohort. The largest trial only included 23 patients, and only 1 retrospective trial had a comparison with controls. Positively, all but 1 study found positive clinical results of this treatment, with improvements observed in skin pemphigus lesions. Furthermore, the combination was well-tolerated, though infections appeared in 3 of the included trials, according to the investigators.¹

Moving to the section of studies comprising other autoimmune conditions, the included trials were all case studies or series of case reports, aside from 1 small prospective, open-label trial with 6 individuals. Conditions included were polyneuropathies (n = 3), lupus with a central nervous system manifestation (n = 2), Susac’s syndrome (n = 1), and autoimmune hemolytic anemia (n = 1). In all but 1 study, the efficacy and safety results were clinically positive; the investigators report that most patients with hematological manifestations demonstrated clinical and blood cell count improvements, while neurological studies also indicated clinical improvement, the investigators wrote.¹

The combination works well together because IVIG combats rituximab’s essential risk for infection, according to the investigators. Because IVIG is designed to prevent and fight severe infections, “this combination is not only synergistic in treating autoimmune diseases, but IVIG helps prevent the collateral effects of rituximab, becoming an ideal partner in this context,” the authors wrote in their discussion.¹

REFERENCES

1. de Carvalho JF, Skare TL. Rituximab combined with intravenous immunoglobulin in autoimmune diseases: A systematic review. Adv Rheumatol. 2025;65(19). doi:10.1186/s42358-025-00450-x

2. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359:242-251. doi:10.1056/NEJMoa0707894

3. Halpern L. High-dose IVIG, rituximab effective in patients with pemphigoid-associated conjunctivitis. Pharmacy Times. Published December 3, 2024. Accessed April 1, 2025. https://www.pharmacytimes.com/view/high-dose-ivig-rituximab-effective-in-patients-with-pemphigoid-associated-conjunctivitis