B-cell depletion therapy with rituximab has been increasingly utilized in the management of various immune-mediated glomerular diseases, both newly diagnosed and relapsing diseases. This agent is a chimeric mouse-human monoclonal antibody (mAb) made up of a murine variable region directed against the CD20 antigen on B lymphocytes. It induces B-cell depletion through various mechanisms, including Fc receptor 𝛾-mediated antibody-dependent cytotoxicity (ADCC), complement-mediated cell lysis, B-cell growth arrest and B-cell apoptosis.
Resistance to rituximab is a clinically pertinent adverse sequela, which is defined as a lack of response to rituximab-containing regimens, in particular, disease progression within 6 months of therapy. The true incidence remains unknown. Clinical suspicion of rituximab resistance is important in individuals with relapsing disease, suboptimal treatment response and rapid B-cell reconstitution. It is more commonly observed in autoimmune diseases, such as systemic lupus erythematosus (SLE), membranous nephropathy and rheumatoid arthritis. The mechanism remains uncertain, and numerous hypotheses have been proposed.
Primary rituximab resistance has been observed in treatment-naïve individuals. The cause is poorly understood; however, B-cell sequestration and disruption of B-cell development and tolerance pathways may be contributory. The balance of protective and pathogenic B-cell subsets established following B-cell repopulation are also significant. In addition, the underlying disease pathophysiology is relevant to primary resistance, particularly when antigen-presenting cells do not play a critical role in pathogenesis. Furthermore, rapid urinary loss of rituximab in heavy proteinuric states is likely to yield a suboptimal treatment response. This has been illustrated in the LUNAR trial, where the addition of rituximab to lupus nephritis induction therapy did not influence remission rates. Secondary analysis of the LUNAR trial displayed that heavier proteinuria at the time of rituximab treatment was associated with lower peak rituximab levels, incomplete peripheral B-cell depletion and lower odds of clinical response to rituximab.
Secondary rituximab resistance occurs with repeated drug exposure. Here, the major effector pathways of rituximab’s mechanism of action are involved. Such pathways include the downregulation of CD20, complement depletion, resistance to ADCC and resistance to apoptosis. Additionally, anti-drug antibodies (ADAs) may form, which not only target the mAb binding domain but can also alter drug pharmacokinetics via the formation of immune complexes and increased mAb metabolism. The emergence of human anti-chimeric antibodies (HACA) to the mouse-derived variable region of rituximab is a recognized consequence of rituximab therapy. These ADAs may contribute to increased infusion reactions, poor B-cell depletion and reduced therapeutic efficacy of rituximab by enhanced drug clearance. Enzyme-linked immunoassays (ELISA) can be used for the quantitative assessment of serum rituximab and anti-rituximab antibodies. Serial testing may be performed to monitor serum levels.