Written by Jasna Trbojevic-Stankovic
Reviewed by Gabriella Moroni
Owing to the improvement in the standard of care therapy for the most severe forms of lupus nephritis (LN), long-time renal survival has continuously improved, and the clinical presentation of LN has become less severe . Despite these facts, renal damage is still the most important predictor of mortality within the damage index .
There exist still several unmet needs in LN such as: low and incomplete response to therapy, frequent relapses, high treatment-related toxicity as well as high number of non-responders. Biological drugs can be of help in meeting these needs by acting at different levels of pathophysiological cascade of LN . Unfortunately, several completed clinical trials with biological drugs in LN failed to meet the primary endpoint (Slide 7 ).
One possibility is to intervene on T-B cell interactions that are driven by several co-stimulatory molecules.The first study on anti-CD40 ligand antibodies was terminated early because of thromboembolic events . Subsequent study was carried with abatacept, but primary endpoint was not met as there was no difference between the abatacept treatment in two different doses and a placebo, on top of mycophenolate mofetil (MMF) and corticosteroids (CS) . Additionally, ACESS trial failed to meet its primary endpoint, although there was no significant difference in adverse events between the groups that received abatacept in comparison to placebo .
B cells are attractive therapeutic targets because they have a central role in LN pathogenesis. The most popular is rituximab (RTX), chimeric humanised mouse monoclonal antibody, directed against the surface CD20 molecule on B cells. It is very effective in depleting CD20 B cells in peripheral blood. Unfortunately, the potential efficacy of RTX was not confirmed by LUNAR study since the overall renal response was not different between the RTX and placebo groups [9, 10]. In order to reduce the immunogenicity of RTX, ocrelizumab was developed and evaluated in a trial that was terminated early due to serious infections in ocrelizumab-treated patients.
The failures of these studies were attributed to their poor designs and the definition of the primary outcome. Therefore, using alternative definition of complete response criteria, it was reported to better determine whether LN trial was a success or a failure .
Other uses of rituximab in LN
Despite bad results, RTX continues to be employed successfully in the number of studies involving refractory LN patients. A revision of published studies that included around 300 patients with refractory LN with a mean follow-up 60 weeks reported a complete plus partial response in 74% of patients .Another proposed use is RTX monotherapy, which is at least as effective as MMF and cyclophosphamide pulses for induction therapy of frequent relapses LN, with a rate of reduction in proteinuria and of complete remission comparable to that of MMF and of cyclophosphamide pulses, and with reduced doses of CS . The effects of RTX as steroids-sparing agent were demonstrated in the study where the complete and partial response was very good as compared to methylprednisolone and MMF groups, without maintenance oral CS, despite that one quarter of patients experienced renal and extra-renal flares during follow up and required courses of CS . The following trial, which could have validated these results, was terminated prematurely due to the low number of randomized patients and similarly, another study evaluating the efficacy of RTX in maintenance therapy in patients with suboptimal response to induction therapy never recruited patients. It was also recently reported that the systemic lupus erythematosus (SLE) relapse risk after 2-year follow-up was higher in RTX maintenance therapy, as compared to the one after single RTX course .However, patients with LN who received RTX maintenance therapy had significantly longer time to RTX failure as compared to the patients treated with a single RTX infusion .
Overall, regarding controlled and non-controlled studies, complete B cell depletion after one month after taking RTX is associated with renal response. Additionally, the development of antibodies after taking RTX is associated with reduced efficacy, around 13 to 20% of patients developed infusion reaction, from 10 to 25% severe infections, and renal flares occurred in 15 to 40% of patients 3 to 6 months after RTX, but the majority of them responded to re-treatment (slide 31 ).
Targeting B cell survival
This biological treatment consists of neutralizing membrane and soluble B cell activating factors. Two drugs, atacicept and tabalumab, have been evaluated but their trials stopped due to adverse events and non-efficacy in LN treatment, respectively. The only biological drug that achieved the complete response in a large study in SLE patients was belimumab, which is now registered for treatment of SLE non responsive to standard of care therapy, although severe forms of LN were excluded from the trial. The drug has advantages on musculoskeletal and mucocutaneous manifestations, on immunological activity, with reduced dosage of CS [19, 20]. A post hoc analysis of patients included in registration studies with mild and moderate forms of LN demonstrated that those receiving belimumab had more frequent renal response particularly when belimumab was associated with MMF, with lower number of flares during follow-up, reduced proteinuria and CS dosage . The efficacy of belimumab in LN was confirmed in other observational studies [22, 23]. Waiting for the results of BLISS LN in which belimumab is used in induction and in maintenance therapy of LN (slide 36 ), the potential indication for belimumab today, lies in case of persistence of extra-renal activity after the induction therapy. It is efficient when it is needed to reduce or stop the CS therapy or halt the chronic damage, as well as in patients with incomplete remission of proteinuria.
All in all, none of the biological agents evaluated so far is a valid option for the first-line LN management. According to EULAR recommendations, belimumab should be considered as treatment in both LN and SLE patients with inadequate response to standard-of-care, defined as residual disease activity, where there is a need to reduce or stop CS as well as in patients with frequent relapses. RTX can be considered in organ-threatening disease refractory or intolerant/contraindicated to standard immunosuppressive agents .