Treatment of lupus nephritis: A glance into the future

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ACHAIKI IATRIKI | 2024; 43(3): 140–148

Review

Konstantina A. Bounia

“Agios Andreas” Patras General Hospital, Patras, Greece

Received: 15 Jan 2024; Accepted: 14 May 2024

Corresponding author: Konstantina Bounia, Rheumatology Consultant, Patras General Hospital “Agios Andreas”, 26332 Patras, Greece, Tel: +30 6942984648 e-mail: kbounia@gmail.com

Key words: Systemic lupus erythematosus, lupus nephritis, induction and maintenance remission therapy, molecules targeted

 

Abstract

Lupus nephritis is a severe manifestation of systemic lupus erythematosus that may be fatal. International guidelines have suggested immunosuppressive treatments with satisfactory results on kidney function of patients with lupus nephritis. Yet, it remains a difficult to treat manifestation as it may be unresponsive to existing therapies. Moreover, patients may show intolerance to drugs, or a flare may always come up despite the initial response. Cyclophosphamide or mycophenolate mofetil in combination with high doses of steroids are acceptable treatments to induce remission of the most severe histopathologic types of nephritis. Calcineurin inhibitors such as Tacrolimus may be an alternative, safe and effective treatment option. Maintenance of remission is achieved by mycophenolate mofetil or azathioprine or tacrolimus. Newer medications show promising results; Obinutuzumab an anti-CD-20 monoclonal antibody, voclosporin a new calcineurin inhibitor and Belimumab an anti-BAFF monoclonal antibody have displayed great effects on preserving Glomerular Filtration Rate and reducing proteinuria in patients with lupus nephritis. Anifrolumab, an anti – interferon receptor antibody also is one of the agents that target molecules implicated in pathogenesis of lupus nephritis. There are numerous studies that have highlighted several treatments as efficacious in lupus nephritis and others still ongoing whose results are expected with great interest.

INTRODUCTION

Systemic lupus erythematosus (SLE) is a worldwide known multiorgan systemic disease. It has a preference for young women and several races. Among the organs that may be severely affected in patients with SLE, the kidneys are to be referred on top. Lupus nephritis (LN) may present early, up to the first 5 years after lupus diagnosis at nearly 2/3 of newly diagnosed patients [1]. LN is more common in African Americans, African- Caribbean, Hispanics and Asians. LN that may progress to end stage renal failure (ESRD) is observed mostly in African Americans and non-white populations. LN is associated with more cardiovascular events observed and increased morbidity and mortality as well.

Treatment of SLE is defined by targeting cells of innate and adaptive immunity that may be implicated in pathogenesis of the disease, like B lymphocytes, T lymphocytes, plasmacytoid dendritic cells (pDCs) or long-lived plasma cells (PCs) through surface molecules or innate pathways [2,3]. Antimalarials, glucocorticoids (GCs) and cytostatic agents that inhibit cell division are used to treat lupus manifestations.

The treatment of LN needs to be initiated at once in order to preserve renal function and save the kidney of a patient with LN before it is too late [1-3]. The approved medications that rheumatologists have been using aggressively so far are in accordance with international guidelines -either a kidney biopsy has been performed or not- in order to achieve remission of LN. Usually high doses of GCs are administered in combination with immunosuppressive cytostatic agents such as cyclophosphamide (CYC) [4, 5, 7-10] and mycophenolate mofetil (MMF) [6,7-10]. In addition, calcineurin inhibitors (CNIs) are an alternative therapy like tacrolimus (TAC), cyclosporine A (CsA) and the newer voclosporin (VOC) [1,2]. The CNIs inhibit calcineurin, which is responsible for activating the transcription of IL-2 in lymphocytes, thus suppressing T lymphocytes. In addition, CNIs restore the actin cytoskeleton and ameliorate podocyte injury in this way, having an antiproteinuric effect as a consequence. Table 1 shows the main immunosuppressants used for LN, their targets and their effects on proteinuria and glomerular filtration rate (GFR).

After remission has been achieved, MMF may be given to preserve remission of LN. Alternatively, Azathioprine (AZA), a purine analogue that interferes with DNA replication and purine synthesis in T and B lymphocytes may be used for maintenance therapy or small dosages of CNIs like TAC or CsA may be used as well [7-10].

There are also non immunosuppressive interventions to treat LN such as Angiotensin-converting enzyme inhibitors (ACEs), Angiotensin receptor blockers (ARBs) and sodium-glucose transport protein 2 inhibitors (SGLT2i).

The aim of treatment selected depends on outweighing the effectiveness vs. toxicity of the medications. The patients should achieve complete or partial response through certain parameters chosen such as GFR and levels of proteinuria. In case there is no response or there is intolerance of the medications, the treatment should be altered. The recurrence of nephritis should be acknowledged rapidly in order to treat aggressively and save as many nephrons as possible. For all these reasons, quite a few agents are being investigated. This review refers to old and new treatments of LN with more emphasis on newer treatments and their result on LN.

Induction and maintenance therapy for LN approved so far

LN is subdivided in 6 subtypes in accordance with the histopathologic findings of the kidney biopsy in patients with lupus [11, 12]. The biopsy classification of lupus nephritis according to the International Society of Nephrology/Renal Pathology Society criteria (ISN/ RPS 2003) [11] is depicted in Table 2. Classes I and II of glomerulonephritis (GN) are non-proliferative types with a relatively better prognosis, while classes III and IV are proliferative types and more severe that need to be aggressively treated. Class V is a membranous type that can be diagnosed as pure membranous type in biopsy or in coexistence with classes III or IV, therefore in the second case the treatment should target the active or chronic proliferative lesions. Class VI is a sclerosing type involving >90% of glomeruli which are globally sclerosed with residual activity, so no immunosuppressive treatment could be efficacious. The guidelines that European Alliance of Associations for Rheumatology- European Renal Association-European Dialysis and Transplant Association (EULAR- ERA- EDTA) [7], American college of Rheumatologists (ACR) [8], Kidney Disease: Improving Global Outcomes (KDIGO) [9] and, Asia Pacific League of Associations for Rheumatology (APLAR) [10] follow to achieve and sustain remission according to the type of nephritis are included in Table 3.

All patients with a diagnosis of SLE have already been taking hydroxychloroquine (HCQ). In case of presentation of kidney involvement, CYC [4, 5] or MMF [6] in combination with high dosage of corticosteroids is considered to be the first line medication option for induction therapy in severe LN. CYC is administered intravenously (IV) at 500-1000mg/m2 every month for six monthly cycles or at 500mg every two weeks for six cycles, the three-month EUROLUPUS scheme called [13]. MMF is preferred to CYC in women in reproductive age at a dosage of 3g/d. It is important to point out that MMF at a smaller dosage of 2 g/d is more commonly used in Asiatic patients with LN because of the smaller weight of this population and of lesser risk for infections.

CNIs, like TAC are more effective in type V membranous LN. ΤΑC is also considered as a rescue therapy in Asian patients with refractory LN. TAC combined with a small dose of MMF for 12 months has been proven a good alternative treatment for non-responding patients with LN to standard treatments [14]. Another randomized controlled study (RCT) proved non inferiority of TAC vs. IV CYC, with a complete or partial response rate of 83.0% (117 of 141 patients) in the TAC group and 75.0% (93 of 124 patients) in the IV CYC group at 24 weeks after treatment [15]. In addition, kidney function and immunological parameters of patients in both groups were similar and serious adverse events were observed in 18.5% of patients in the TAC group and in 24.6% in the CYC group.

GCs are used combined with immunosuppressive therapy in a large dosage of three consecutive pulses of 1 gr methylprednisolone / d IV at the initiation of treatment. Then, prednisone is given orally at 0.3–0.5 mg/kg/day for one month and tapered to ≤7.5 mg/day at an interval of three to six months (EULAR–ERA–EDTA) [7]. All guidelines tend to agree and have similarities in reducing the dosage of IV pulses of methylprednisolone and in tapering as soon as possible the oral dosage of prednisone to the smallest dosage ≤7.5 mg/d at least in 3 months after the induction therapy [7-10]. This seems highly important if we take into account the serious adverse effects that the long use and high dose of GCs might provoke.

Since remission of LN has been achieved, induction therapy is continued for three to five years aiming mainly to reduce the number of flares and the extent of kidney damage. MMF is used at a dosage of 2 g or 1 g/d. AZA in a dosage of 2g /kg or Leflunomide (LEF) or low dose of CNIs like TAC or CsA are alternative agents [7, 9,10]. A recent trial compares administration of LEF vs. AZA [16] for maintaining remission in LN. Kidney flares were similar between the two groups compared: 15.7% in the LEF group vs.17.8% in the AZA group. The non-inferiority of LEF vs. AZA taking into account the safety of the drug makes LEF a good alternative for remission maintenance therapy.

WIN-LUPUS is a multicentre RCT [17] in which patients with LN that had achieved remission were randomized in two groups: 1) one group that continued immunosuppressive therapy with AZA or MMF plus HCQ (n=48) and 2) the other group that did not continue immunosuppressive therapy (n=48). The discontinuation of immunosuppressive therapy was non inferior for renal relapse rate for two or three years compared to the continuation of immunosuppressive therapy. Only severe renal or extra renal SLE flares were less frequent in patients who continued to take immunosuppressive therapy vs. patients that did not continue immunosuppressants (5/40 vs. 14/44 patients, p=0.035).

Newer medications for therapy of LN

Biologic agents other than the immunosuppressants described above have been used in cases of LN. Rituximab (RTX), one of these agents is a monoclonic antibody (mAb) against CD-20 of B lymphocytes thus inducing B cell depletion. RTX has been an excellent rescue therapy in refractory cases of LN. RTX administered in combination with GCs and immunosuppressive agents as CYC and MMF in patients with LN had as a result a significant improvement in 24-h proteinuria at 12 months (4.41 g. baseline vs. 1.31 g. post-therapy, p=0.006[18]. RTX has given equally great results in LN when co administered with MMF even in the absence of oral GCs [19].

BEL is a mAb against B-cell activating factor (BAFF), therefore it is another molecule targeting B cells. Although at first approved for active non renal lupus, the past few years has presented satisfactory results to control LN as an add-on agent to standard-of-care (SOC) therapy for LN. BEL in the BLISS-LN study showed that BEL when added to SOC either MMF and GCs or EUROLUPUS CYC followed by AZA in a period of 108 weeks was superior to placebo added in SOC in the control group [20]. More specifically, the BEL group had a primary efficacy renal response 43% vs. placebo 32%, p=0.03 and a complete renal response 30% vs. placebo 20%, p= 0.02. These were reflected by non worsening of GFR and reduction of renal flares or renal damage in the reported time interval. The adverse events between the two groups taking and not taking BEL were similar implying a good safety profile for BEL.

Obinutuzumab (OBI) is a newer and more drastic B-cell depleting agent that targets CD20 in a more efficacious manner. The phase II RCT (NOBILITY) displayed that OBI when added to MMF and GCs was superior to placebo for the achievement of complete and overall renal responses at week 52 [21]. Complete renal response was succeeded with OBI at week 52 (35%) vs. (23%) with placebo, p=0.115) and at week 104 (41%) vs. (23%), p=0.026. OBI was associated with improvements in GFR and lowering of proteinuria and was safe enough according to the observed serious adverse effects, infections or deaths. Phase III RCT (REGENCY NCT04221477) is expected upon completion to evaluate the addition of OBI vs. placebo in patients with class III or IV lupus nephritis (LN) already on SOC with MMF plus CS [22].

A newer CNI called Voclosporin (VOC) has been recently approved for the treatment of LN. Its pharmacokinetic and pharmacodynamic profile makes therapeutic drug monitoring unnecessary. VOC is not able to act when GFR is ≤45 ml/min/1.73 m2.

In the AURORA 1 study, a multicenter double-blind phase III study, patients with LN class III, IV, or V or combination of these classes already on therapy with MMF 1 g twice daily, were randomly assigned (1:1) to receive oral VOC (23·7 mg twice daily) vs. placebo for 52 weeks; meanwhile oral steroids were attempted to be rapidly tapered to low dose [23]. Complete renal response at week 52 was achieved in more patients in the VOC group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients, p=<0·0001. Adverse events, even serious ones, were presented at a similar rate between the two groups.

The AURORA 2 phase III study displayed equally satisfactory results at three years of treatment with VOC vs. placebo as well [24]. Complete renal response was achieved in 59% of the VOC group vs. 39% of the placebo group. Proteinuria was more rapidly and persistently reduced in the VOC group while kidney function was almost preserved in a good level in both groups.

Anifrolumab (ANF), a mAb to type I interferon receptor subunit 1 was approved after TULIP2 phase III RCT study for the treatment of medium / severe SLE [25]. TULIP-LN study evaluates the addition of ANF in patients with active Class III/IV LN already on MMF and GCs [26]. One hundred forty-seven patients were assigned to receive ANF 1:1:1 basic scheme monthly ANF IV 300 mg, or an intensified scheme ANF 900 mg ×3 at first for 4 weeks and 300 mg thereafter, or placebo. The primary endpoint of this study which was the relative difference in the mean change of 24-hour urine protein-creatinine ratio (UPCR) from baseline to week 52 was not met. The percentage of patients who had a complete renal remission (which required inactive urinary sediment) at week 52 was greater in the intensified ANF group than the placebo group 40.9% vs. 13.3%, and lower in the basic scheme ANF group than in the placebo group 7.0% vs. 13.3%. Response rates were higher with ANF IR vs. placebo as early as week 12 and remained higher over time. The patients who had a sustained oral glucocorticoid dosage tapering ≤7.5 mg/day were more in the ANF intensified group compared to the placebo group (55.6% vs. 33.3%) as well. Herpes zoster infections had higher incidence in the ANF groups, but a larger study is warranted to make more safe conclusions for the drug.

Regulatory T cells (Tregs) have been found lessened and less functional in SLE. IL-2 is a cytokine that promotes expansion of Tregs, so administration of low dose IL-2 seems promising for treatment of SLE and LN. A double-blind placebo-controlled trial of He et al. compared 60 patients with active SLE, 30/60 received low dose IL-2 and the rest 30/60 received placebo on top of SOC treatment for 12 weeks and were observed for a total interval of 24 weeks [27]. At week 12 and at week 24 the Systemic Lupus Erythematosus Responder Index (SRI-4) response rates were higher for IL-2 vs. placebo, p= 0.052(week 12) and p=0,027 (week 24), respectively. Seven out of 13 patients with LN achieved complete remission by taking low dose IL-2 compared with 2 out of 12 patients with LN in the placebo group, p=0.036.

Studies of combining medications for LN

An interesting study was conducted to evaluate the effect of OBI with MMF and no oral steroids co administration vs. MMF plus oral steroids co administration (NCT04702256) [28].

In the CALIBRATE study, the authors tried to assess the efficacy of BEL added after the administration of RTX and CYC in patients with refractory lupus nephritis vs. placebo added after this combination of RTX and CYC [29]. The clinical outcomes between the two groups were not outstanding. The number of total B cells and autoreactive B cells compared to baseline was unsurprisingly reduced in the BEL group.

The BEAT-LUPUS study in a similar way compared RTX as induction therapy followed by BEL four to eight weeks after the first RTX infusion in patients with refractory SLE (only 38 % of patients had LN) vs. RTX, followed by placebo for 52 weeks [30]. The BEL group had a bigger reduction of B cells, of anti -ds-DNA Abs titles and of severe disease flares.

Refractory LN

A kidney response -as it is defined according to worldwide criteria- may not be achieved despite all immunosuppressive drugs approved so far have been administered. Therefore, LN is considered resistant after we have excluded the patient’s tolerance and good adherence [31]. Rescue therapies include LEF, intravenous immunoglobulin/plasma exchange (especially for patients at high risk for infection or recurrent infections), anti plasma cell therapies like Bortezomib, a proteasome inhibitor and anti-CD38 a mAb followed by RTX or BEL, autologous stem cell transplant, chimeric antigen receptor (CAR)-T therapy or anti-complement therapy.

There are a couple of studies published for cases of patients with refractory lupus. Two patients only, one with LN and the other with hemolytic anemia with unsuccessful treatments in the past, were treated with daratumumab, a mAb that targets CD38 of long-lived PCs [32]. The results were remarkable, as disease activity scores were reduced in both patients; proteinuria was diminished in the first patient and preservation of kidney function was achieved too. In the second one hemoglobin and platelet levels were restored. The addition of BEL in these 2 patients helped to sustain the satisfactory effect and outcome of daratumumab depleting PCs, which in cases of multiple myeloma is rather transient.

Another therapy that has been tested for lupus refractory cases is CAR T cells. Despite their use in cancer and other hematologic diseases, the use of CAR T cells that target CD19, a specific marker of B lymphocytes, has shown promising results in mouse models of lupus and patients with SLE. T cells from patients with SLE are transduced with a lentiviral anti-CD19 CAR vector, are then expanded and reinfused after immunodepletion. Five patients with refractory lupus to previous immunosuppressive therapy were enrolled to this CAR-T cell treatment. A significant depletion of B cells was observed as well as an improvement of clinical symptoms, of laboratory and immunological tests [33]. All patients had severe proteinuria that was astonishingly decreased to normal levels. Disease remission was maintained for almost 8 to 12 months after CAR T cell administration with a great tolerance.

No RCTs of rescue therapies for LN have been performed. Mostly observational uncontrolled studies for refractory disease have been published. The groups of patients selected lack homogeneity in clinical picture, in disease activity and in previous treatment administered.

Non immunosuppressive treatments in LN

We should not disregard the avoidance of smoking, exercise, the control of high blood pressure, the treatment of diabetes mellitus, hyperlipidemia and metabolic derangements. Renin–angiotensin–aldosterone system inhibitors may offer renoprotection and amelioration of proteinuria in patients with LN [34, 35].

SGLT2i has been highly expressed in kidney podocytes. SGLT2i might reverse the damage of podocytes through inhibition of NLRP3 inflammasome-mediated inflammation and through inhibition of mammalian target of rapamycin complex 1 (mTORC1) signaling as histopathologic findings suggest [36, 37]. Their use has been displaying promising results in LN in animal models and patients with LN. For instance, empagliflozin reduced the titre of anti-ds-DNA Abs in mrl/lrp mice and improved proteinuria kidney function and abnormal histologic findings in mices’ glomeruli [38]. A retrospective study showed that administration of SGLT2i in 9 patients with LN for more than 2 months had a significant decrease of their proteinuria and improvement of their kidney function [38].

DISCUSSION

LN is a severe manifestation, and the initiation of therapy is considered emergent to prevent a fatal outcome. Lots of therapies have been proved to be lifesaving for the kidneys of patients with LN. Except the cytostatic agents [3-10], B-cell targeted therapies with mAbs show hopeful results in treating LN such as BEL, RTX and OBI [18-22,28-30]. VOC the newest CNI is also a promising factor [23,24].

It should be emphasized that there are a lot of agents under experimental use that target one or more molecules involved in the pathogenesis of LN [1-3]; these agents are depicted in figure 1. The results of a few ongoing clinical trials of these agents are expected in the near future. Surface antigens and growth factors of B cells as CD19, CD22, B cell receptor (BCR), Fc Receptor (FcR), a proliferation-inducing ligand (APRIL) and Bruton’s tyrosine kinase (BTK) are therapeutic targets as well. Co-stimulatory molecules may be targeted also like anti- inducible T cell co-stimulator ligand (ICOS)/ICOS ligand (L) or anti-CD40/CD40L. Double-action mAbs should not be missed like anti BAFF/ anti- APRIL (atacicept, telitacicept), peptide conjugate anti – BAFF and anti- ICOSL and finally mAb against BAFF -R and FcR (lanalumab).

Figure 1. medications and drug combinations with few trials or uncompleted trials in LN. Targets of surface molecules or inner molecules of B, T cells, pDCs and PCs in patients with LN that have been approved or are under investigation are depicted in the above scheme.
Abbreviations: (pDCs): plasmacytoid dendritic cells, (PCs): plasma cells LN: lupus nephritis, TAC: Tacrolimus, BEL: Belimumab, RTX: Rituximab, OBI: Obinutuzumab. VOC: Voclosporin , ANF: Anifrolumab, Tc R:Tcell receptor, BcR: B cell receptor, FcR: Fc Receptor BAFF: B cell activating factor, APRIL: A proliferation-inducing ligand, MHC II: major histocompatibility complex II, (CAR)-T: chimeric antigen receptor, BDCA: Blood Dendritic Cell Antigen, JAK: Janus kinase, TYK 2: tyrosine kinase-2, ILT7: immunoglobulin-like transcript 7, BTK: bruton tyrosine kinase, ICOS: Inducible T cell co-stimulator, ICOS-L: Inducible T cell co-stimulator-Ligand, mTOR: mammalian or mechanistic target of Rapamycin

Other treatments approved or under investigation are IFN-I signaling inhibition as ANF does [25,26], complement system inhibition like eculizumab, ravulizumab and other drugs targeting many of the molecules – key points in the pathogenesis of SLE. Targeting intracellular proteins of T cells like mTOR inhibitors e.g. sirolimus may be effective, too. pDCs may be targeted with mAbs against surface molecules like blood dendritic cell antigen 2 (BDCA2)/ daxcilimab, immunoglobulin-like transcript 7 (ILT7)/ litifilimab or MHCII / rigerimod are a few of them. Moreover, long lived PCs are targeted with proteasome inhibitors or mAbs against their surface molecules [32]. There are also mAbs against cytokines and their receptors like IL-2, IL-12, IL-23 (secukinumab and ustekinumab) that have been tested in lupus [1-3]. In the end, the results of interventions in intracellular downstream signaling pathways, like JAK and TYK2 pathways are expected with great interest.

The basic research and understanding of pathogenesis of SLE has been dramatically improved and aided the treatment of the severe manifestations of the disease, such as LN. The biopsy findings and further classification of GN types with additive findings of activity or chronicity of lesions of kidneys as well as molecular profiling of patients with LN may be a further stepping stone for choosing the proper therapy for each patient. The biopsy still remains a prerequisite to settle the diagnosis of LN and thus to select the appropriate treatment even though biomarkers of serum and urine have been tried to replace it.

CONCLUSION

There are numerous treatments to induce and preserve LN remission. The old medications used so far are quite effective, but the unresponsiveness and the recurrence of LN forces the rheumatologists to shift towards more precise therapies. Research focuses on targeting more specific molecules of immune cells involved in the pathogenesis of LN. The first results are quite encouraging so far, but bigger and better designed studies are required to make more safe conclusions for treating LN.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare.

Author Contributions

Konstantina A. Bounia was solely responsible for the conceptualization, design, data collection, analysis, and interpretation of the study. She also drafted and revised the manuscript and approved the final version for publication.

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