PRESENTED BY
VLADIMIR TESAR

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Vladimir Tesar

Thanks to the modern immunopathologic investigation techniques the understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably in recent years, opening doors for potential new treatment strategies. The fundamental discovery that in the background of each of these disorders is the development of antigen-specific immune response, followed by the effector stage of inflammation, led to the option of blocking this immune response with antigen-specific therapy. In order to reduce glomerular inflammation, several effector systems have been targeted by new therapeutic agents, such as C5 in the complement system.

ANCA-associated vasculitis – rituximab and avacopan
Before the 1970s severe cases of ANCA-associated vasculitis (AAV) were considered invariably fatal. The introduction of corticosteroids and cyclophosphamide in the 1980s contributed to significant improvement in patients outcomes, transforming AAV into a chronic illness. These therapeutics considerably altered the main causes of death, shifting them from the primary disease to infection within the first year from diagnosis, and cardiovascular disease and malignancies thereafter (1). The latter, however, is associated with high cumulative doses of cyclophosphamide, thus calling for similarly effective but less toxic treatment options. In early 2000s, rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, was first introduced as vasculitis therapy for patients whose condition was refractory to or intolerant of standard agents and had persisting ANCA positivity (2). The initial promising results were confirmed in a subsequent retrospective analysis of 65 consecutive patients with refractory AAV of whom 75% achieved complete, and 23% achieved partial remission. Relapses occurred, but re-treatment was effective and safe (3).

The RAVE study was the most important randomized controlled clinical trial which confirmed the efficacy of rituximab in patients with AAV. It corroborated that rituximab therapy was not inferior to cyclophosphamide treatment for inducing remission in severe AAV and may even be superior in relapsing disease, with comparable safety (4). The efficacy of rituximab was also assessed in comparison to azathioprine in a study that included 115 AAV patients in remission and substantiated that rituximab was more effective than azathioprine in preventing major relapses (5). Furthermore, the patients on rituximab also had better overall and relapse-free survival (6). The safety of rituximab therapy was also addressed in a recent large single-center study, concluding that the risk of malignancy was lower with rituximab than with cyclophosphamide and comparable with the risk in the general population (7). Based on all this evidence, rituximab has found its place in the 2014 British Society of Rheumatology guidelines for the management of adults with AAV and also in new KDIGO guidelines 2021 (not yet published) (Figure 1).

Figure 1. Algorithm of the treatment guideline for AAV (8, 9)

The complement 5a receptor (C5aR) is another attractive therapeutic target for AAV since it plays a central role in the pathogenesis of AAV. However, the development of a selective and potent C5aR antagonist has been challenging. CCX168, avacopan, is an orally administered, recently introduced agent that blocks C5a binding and C5a-mediated migration in freshly isolated human neutrophils, as well as C5a-mediated neutrophil vascular endothelial margination (10). The Phase 1 clinical trial on 48 healthy volunteers demonstrated that CCX168 was well tolerated and blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% (10). In experimental model of AAV CCX168 prevented the development of glomerular crescents (11). Another randomized, placebo-controlled trial randomized 67 adults with newly diagnosed or relapsing vasculitis to receive either placebo plus prednisone starting at 60 mg daily (control group); avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily); or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. Clinical response after 12 weeks, as well as sustained remission at week 52, was achieved in significantly more patients receiving avacopan than in the control group, with a comparable incidence of adverse events and added benefits of a significant reduction in glucocorticoid-related toxicity, improvement of kidney function and health-related quality of life (12). These data were recently confirmed in not yet published phase 3 trial (ADVOCATE), C5a receptor inhibition with avacopan is a promising new strategy for was effective replacing of high-dose glucocorticoids in treating vasculitis (12).

Membranous nephropathy – rituximab
Idiopathic membranous nephropathy (IMN) is an antibody-mediated autoimmune glomerular disease. A majority of patients have antibodies against a conformation-dependent epitope in PLA(2)R, indicating that PLA(2)R is a major antigen in this disease (13). The first trials with rituximab in the treatment of IMN originated even before the identification of PLA(2)R reporting a favorable short-term risk-benefit profile (14). Rituximab effectively reduced proteinuria and achieved B-cell, CD20 and CD19 depletion in IMN patients (15, 16). However, later studies suggested that some patients might need prolonged treatment with rituximab to achieve sustained remission (17). The introduction of anti-PLA(2)R immunoassays in routine practice showed that immunologic remission with rituximab precedes proteinuric response by several months, suggesting that proteinuria should be assessed after at least 12 months (18).

GEMRITUX was the first multicenter, controlled trial which randomized 75 patients with IMN and nephrotic syndrome to receive nonimmunosuppressive antiproteinuric treatment alone or combined with rituximab for six months. The positive effect of rituximab on proteinuria remission occurred even after 6 months, and the remission rate nearly doubled at 17 months with no safety issues (20). Another recently published study, the MENTOR trial, randomly assigned 130 patients with membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml/min to receive intravenous rituximab or oral cyclosporine. Patients were followed for 24 months. Complete or partial remission was achieved in 60% subjects on rituximab and 52% on cyclosporine after 12 months, and persisted in 60% individuals on rituximab and 20% on cyclosporine after 24 months. Serious adverse effects were significantly rarer in the rituximab group (20).

Lupus nephritis – rituximab, belimumab, obinutuzumab, and beyond
Treatment of systemic lupus erythematosus (SLE) represents a challenge due to variable disease manifestations, clinical course, and outcome. The introduction of corticosteroids and cyclophosphamide remarkably improved the outcome of patients with either SLE and/or lupus nephritis (21). Nowadays, patients seldom die from the primary disease. Instead, the leading causes of death are cardiovascular disease, infection, and malignancy (22). An abundance of drugs with different structures and mechanisms of action have been tested for LN treatment in the last years (23). Despite expectations, most of them did not reach expected outcomes, and only belimumab has been licensed (24). The most important pitfalls in investigations with these agents were inclusion criteria, sample size and power, outcome measures, and study length, and these should be considered with caution when designing future clinical trials (25). The last years’ EULAR recommendations for the management of SLE advise optimization of clinical trial design and study endpoints, the inclusion of organ-specific endpoints, and better handling of background medication to avoid polypharmacy and underestimation of positive effects of drugs under study (26).

Belimumab, a human monoclonal antibody that inhibits B-lymphocyte stimulator, provided a new option for the management of SLE (27). It was tested in two large randomized placebo-controlled studies which included nearly 1,700 patients with SLE to explore whether it offered additional renal benefit to patients receiving mycophenolate mofetil at baseline. Patients with severe active lupus nephritis were excluded from the trials. Over 52 weeks, rates of renal flare, renal remission, renal organ disease improvement, proteinuria reduction, grade 3/4 proteinuria, and serologic activity favored belimumab, albeit not significantly (28, 29). The yet unpublished results of the BLISS-LN study confirm belimumab superiority over the current treatments (mycophenolate-mofetil or cyclophosphamide) in achieving complete renal response after two years, primary efficacy renal response after one year and time to death and renal event in active LN.

Rituximab has also been evaluated as a potential therapeutic agent for LN in a randomized, double‐blind, placebo‐controlled phase III trial. Patients with class III or IV LN were randomized to receive rituximab or placebo on days 1, 15, 168, and 182, and although rituximab therapy led to more responders and greater reductions in anti‐dsDNA and C3/C4 levels, it did not improve remission rate and renal response rate after 52 weeks of treatment (30). However, it is possible that the follow-up time in this study was too short to observe the full effect of rituximab therapy. Furthermore, the recent secondary analysis of the LUNAR trial showed that achievement of complete peripheral B cell depletion, as well as the rapidity and duration of complete peripheral depletion, are associated with complete response achieved with rituximab (31). Thus, future trials should be carefully designed to reliably reflect the full potential of this therapeutic.

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