Anti-rituximab antibodies demonstrate neutralizing capacity, associate with lower circulating drug levels and earlier relapse in lupus

Abstract

Objectives High rates of anti-drug antibodies (ADA) to rituximab have been demonstrated in patients undergoing treatment for systemic lupus erythematosus (SLE). However, little is known with regards to their long-term dynamics, impact on drug kinetics and subsequent implications for treatment response. In this study, we aimed to evaluate ADA persistence over time, impact on circulating drug levels, assess clinical outcomes and whether they are capable of neutralising rituximab. Methods Patients with SLE undergoing treatment with rituximab were recruited to this study (n = 35). Serum samples were collected across a follow-up period of 36 months following treatment (n = 114). Clinical and laboratory data were collected pre-treatment and throughout follow-up. ADA were detected via electrochemiluminescent immunoassays. A complement dependent cytotoxicity assay was used to determine neutralising capacity of ADA in a sub-cohort of positive samples (n = 38). Results ADA persisted over the 36-month study period in 64.3% of patients undergoing treatment and titres peaked earlier and remained higher in those who had previously been treated with rituximab when compared with than those who were previously treatment naïve. ADA positive samples had a significantly lower median drug level until six-months post rituximab infusion (p= 0.0018). Patients with persistent ADA positivity showed a significant early improvement in disease activity followed by increased rates of relapse. In vitro analysis confirmed neutralising capacity of ADA to rituximab. Conclusions ADA to rituximab were common and persisted over the 36-month period of this study. They associated with earlier drug elimination, an increased rate of relapse and demonstrated neutralising capacity in vitro.

Response to Biologic Drugs in Patients With Rheumatoid Arthritis and Antidrug Antibodies

“…In the present study, we found no association between the frequently observed anti-rituximab antidrug antibodies and response to treatment. However, anti-rituximab antidrug antibodies have been shown to be frequently present in other diseases, such as multiple sclerosis, and to be associated with relapse in lupus . The importance of transient antidrug antibodies remains unknown.…”

Anti-rituximab antibodies in patients with refractory autoimmune nodopathy with anti-neurofascin-155 antibody

“…For example, the number and frequency of rituximab injections are likely to affect the formation of ARAs in MS but not in lymphoma, leukemia, or Crohn’s disease ( 23 , 28 , 29 ). Moreover, ARAs development was associated with reduced B-cell depletion in rituximab-treated patients in MS, but this association is controversial in SLE ( 23 , 30 , 31 ). Therefore, the factors inducing ARAs formation in nodopathy should be deeply explored.…”

“…Therefore, we assumed that the poor outcome of anti-NF155-positive patients who did not respond well to rituximab might be attributed to the occurrence of ARAs. Besides, ARAs in patients with SLE can neutralize drug level and counteract the cytotoxicity of rituximab in vitro ( 31 ). In nodopathy, the functional assessment of ARAs and drug level are worthy of deep exploration and research.…”

“…Specifically, there was a significant association between ARAs’ presence and titers and incomplete B-cell depletion in MS, and the ARA-positive group had a faster B-cell reconstitution in SDNS and MN ( 14 , 22 ). The count of CD19 + B cells after rituximab infusion in the ARAs group in SLE varied as Chris Wincup showed that no difference was found in CD19 + lymphocyte counts at the early and six-month time points between ARAs persistently positive and negative patients and Francesca Faustini reported that a higher proportion of CD19 + lymphocytes was seen in ARA-positive patients compared to ARA-negative patients ( 31 , 36 ). Moreover, most patients with MOGAD had a B-cell counts <1% at the time of disease activity ( 37 ) and B-cell counts have been found to be unrelated to clinical relapse in NMOSD ( 38 ).…”

Towards Personalized Medicine in Rheumatoid Arthritis

“… 153 , 154 , 156 , 157 It has also been found for IL-6 receptor inhibitors: tocilizumab and sarilumab 158 , 159 and, most recently, rituximab. 160 …”