Elsevier

Autoimmunity Reviews

Volume 8, Issue 4, February 2009, Pages 343-348
Autoimmunity Reviews

Use of rituximab in patients with systemic lupus erythematosus: An update

https://doi.org/10.1016/j.autrev.2008.11.006Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a chronic, occasionally life threatening, multisystem disorder. Patients suffer from a wide group of symptoms and have a variable prognosis that depends of the severity and type of organ involvement. The clinical manifestations include fever, skin lesions, arthritis, neurologic, renal, cardiac, and pulmonary disease. The pathogenesis of this serious multisystem autoimmune disease is based on polyclonal B cell immunity, which involves connective tissue and blood vessels. The novel biologic therapies have raised hope for more effective and safer treatment for SLE. Although definitive studies are still under development, the impressive preliminary results of therapies specifically targeting B cells and the signaling pathways involved in B-T-cell interactions suggest that the depletion of memory cells accounts, at least in part, for the clinical efficacy of rituximab therapy in patients whose disease is resistant to other immunosuppressive therapies. However these findings, although provocative, require further investigation in larger cohorts.

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoreactive T cells and polyclonally activated B cells that produce autoantibodies directed against self-antigens, immune complex formation, and immune dysregulation. The clinical course of SLE is variable and may be characterized by periods of remissions and chronic or acute relapses. The most common pattern is a mixture of constitutional complaints with skin, musculoskeletal, hematologic, renal, or central nervous system manifestations. Women, especially in their 20 s and 30 s, are affected more frequently than men [1].

Treatment of SLE is based on preventive measures, reversal of inflammation, prevention of organ impairment, and alleviation of symptoms based on immunosuppression, cytotoxic treatment, plasma exchange and immunoglobulin therapy. Because management of patients refractory to standard treatment approaches is difficult, currently biologic therapies have raised hope for more effective and safer treatment for those patients. Some studies have showed good results of therapies specifically targeting B cells and the signaling pathways involved in B-cell–T-cell interactions which suggest that these approaches may represent an outstanding therapy [2].

T cells have been considered the cornerstone of autoimmunity; however, B cells have an important role in the pathogenesis of SLE because, in addition to the production of autoantibodies, B cells participate in the activation of the immune system through the production of various cytokines and serving as potent antigen-presenting cells that are hyperactive following the engagement of the B-cell receptor which may be driven not only by extrinsic factors but also by intrinsic defects resulting in an excessive response to immunologic stimulation. For this reason, B-cell–directed therapies will become an important tool in the treatment of autoimmune disorders [3].

Rituximab (RTX) has been widely investigated in SLE because of the potentially serious toxicities of immunosuppressive agents, such as glucocorticoids in moderate or high doses, azathioprine, mycophenolate mofetil, and cyclophosphamide, that are currently in use for the treatment of this disease. It is a chimeric monoclonal IgG1 antibody which selectively binds with high affinity to the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and on more than 90% of B cell non-Hodgkin’s lymphomas [4]. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region and human constant region sequences. The Fab domain (murine) of RTX binds to the CD20 antigen in B cells, and the Fc domain (human) recruits immune effector functions to mediate B cell lysis. The antigen CD20 regulates the early step in the activation process for cell cycle initiation and differentiation. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation; thus, a drug that reacts with CD20, such as an antibody, would not be neutralized before binding to its target cell. RTX is thought to deplete CD20-positive cells via antibody-dependent cell-cytotoxicity and complement-mediated cell lysis [5].

After a single course of RTX, peripheral blood routinely remains depleted of B cells for 6–12 months. It is important to note that although treatment with RTX depletes mature B cells from blood and tissue, it does not eliminate long-lived plasma cells, the major source of protective antibodies. According to the results obtained by Sutter et al. [6] in 12 patients with active SLE, the number and phenotype of peripheral blood B lymphocytes, T lymphocytes and natural killer cells were correlated with the extent and longevity of B lymphocyte depletion. This analysis generated three candidate biomarkers for lymphocyte monitoring in patients with autoimmune disease who are treated with RTX: circulating transitional B cells, the kappa:lambda ratio and natural killer cells. RTX has a half-life of 21 days, to eliminate 99% of circulating specific antibody would require at least 4 months, and this only if antibody production completely and immediately ceased with RTX. Since antibodies are made primarily by plasma cells that have minimal expression of CD20 and, therefore, are not eliminated by RTX, such a mechanism is further questioned. A debate in the literature exists as to whether plasma cells are long or shortlived [7].

In autoimmune disorders, RTX treatment has produced a range of clinical and serologic effects depending on the disease. Several studies have reported successful treatment of resistant SLE manifestations, including central nervous system, renal, vasculitic, and hematologic features using RTX [4], [8], [9].

Additionally, based on the results obtained by Galarza et al. [10] RTX might be used as the first-choice treatment for patients with severe autoimmune rheumatic diseases. They showed a significant decrease in activity with a reduction higher than 50% in SLEDAI score (p < 0.001), and a significant steroid-sparing effect (p < 0.001) in half of their SLE treated patients.

Section snippets

Rituximab in pediatric lupus

SLE is often more severe in children than in adults, with proliferative nephritis as predominant feature and, therefore, usually requires more aggressive treatment. Childhood-onset SLE is a multisystemic autoimmune disease associated with significant morbidity and mortality with lupus nephritis being a major prognostic factor [1].

Recent studies show that there are risks from both under-treatment, with resultant severe flares of disease activity, and over-treatment, with additional drug adverse

Rituximab in lupus nephritis

Lupus nephritis (LN) remains as a major cause of morbidity and mortality in around 30–40% of patients with SLE. Although the combinations of corticosteroids and immunosuppressive agents such as azathioprine or cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have considerable side effects.

New immunosuppressive drugs, such as mycophenolate mofetil and more targeted therapies as anti-CD20 have improved outcomes, but a significant proportion of

Rituximab in lupus vasculitis

Vasculitis is histologically defined as inflammatory cell infiltration and destruction of blood vessels. It is a frequent and often significant component of many systemic autoimmune syndromes such as SLE and others diseases. In most instances, cutaneous vasculitis represents a self-limited, single-episode phenomenon but in severe cutaneous and systemic disease requires a potent immunosuppression. Plasma exchange and intravenous immunoglobulins are often used in refractory cases. The new

Rituximab in central nervous system involvement

The involvement of the central nervous system (CNS) is one of the most important causes of morbidity and mortality in SLE patients. Since a standard treatment for these patients is not available due to the lack of controlled randomized trials, current therapeutic approach is still empirical and based on clinical experience. The therapeutic choice depends on accurate diagnosis, identification of underlying pathogenic mechanism, severity of the presenting neuropsychiatric symptoms, and on prompt

Rituximab in patients with autoimmune thrombocytopenic purpura associated to systemic lupus erythematosus

Current treatment regimens for hematological autoimmune diseases are relatively non-selective and are often associated with considerable toxicity. In recent years, great advances have been made in elucidating the pathogenesis of thrombocytopenia and the mechanisms of thrombopoiesis.

Although uncommon, autoimmune thrombocytopenic purpura (ATP) is one of the most serious complications in patients with SLE [1]. When this occurs, it has a high mortality rate and is refractory to conventional

Precautions for the use of rituximab and side effects of rituximab

Precautions for the use of RTX in SLE are summarized in Table 1. Side effects correlated with the number of circulating CD20 cells and consisted of fevers, chills, rigor, orthostatic hypotension and bronchospasm (Table 2) Fever is the most common side effect (48%). Other adverse events, including chills, headache, nausea, vomiting, rhinitis and mild hypotension, occurred primarily during RTX infusions and typically responded to an interruption of the infusion and resumption at a slower rate [36]

Take-home messages

  • The pathogenesis of systemic lupus erythematosus (SLE) is based on polyclonal B cell immunity, which involves connective tissue and blood vessels.

  • The impressive preliminary results of therapies specifically targeting B cells and the signaling pathways involved in B-T-cell interactions suggest that the depletion of memory cells accounts, at least in part, for the clinical efficacy of rituximab therapy in patients whose disease is resistant to other immunosuppressive therapies.

  • Additionally,

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