**5.2 Future novel therapeutic options**

Developing more effective treatment strategies in LN remains a priority among clinicians and researchers across the globe; however, major challenges exist in its advancement due to the complex pathophysiology and heterogeneity, which directly impact on clinical trial design and overall outcome. Moreover, most trials are conducted with background therapy, which is difficult to control during the study and its subsequent analysis, as there is no clear definition in the SOC [76]. Notwithstanding this, extensive therapeutic strategies have emerged with wide array of novel treatments to improve patient outcomes. Major trend in current treatment landscape for LN focuses on reduction of steroid use.

There is gathering evidence, especially in more recent times, documenting the successful safe use of Belimumab, a monoclonal antibody (mAb) directed against BlyS as an add-on therapy in LN, especially in patients with low complement levels and high anti-DNA antibodies [75, 77]. It is the first targeted therapy and currently the only biological agent approved specifically for LN. There is also increasing interest in the sequential use of two B-cell targeting agents, RTX and Belimumab in active LN [78, 79] with a phase III trial already underway [80]. The rationale for this approach is due to the hypothesis that their co-administration may enhance depletion of circulating and tissue-resident autoreactive B cells.

Another potent BAFF-inhibitor, Blisibimod, was associated with reduction in steroid use, decreased proteinuria and biomarker responses in a multinational phase III trial [81]. Tabalumab, a selective mAb that neutralises both membrane and soluble BAFF, despite having the same therapeutic class, on the contrary did not yield the expected positive statistical significance results in two phase III studies involving SLE patients; however, only approximately 10% of patients in these studies had renal involvement [82, 83].

Voclosporin, a novel next generation CNIs (an analogue of cyclosporin) with enhanced calcineurin inhibition, better safety profile and consistent predictable dose response, despite initial safety concerns in the prior phase II study [84], has recently been demonstrated in a phase III trial to be highly effective for treatment of LN when combined with MMF, with acceptable safety profile, at least for the short term (52 weeks) [85]. More importantly, it has just received the approval by the United States' Food and Drug Administration (FDA) on the 22nd of January 2021, making it the only second targeted therapy approved specifically for LN [86].

There is emerging theoretical evidence for targeting autoantibody-secreting long-lived plasma cells (PCs) that recide in dedicated survival niches in the bone marrow or inflammed tissues of LN patients. Bortezomib, a proteasome inhibitor has been shown to be effective in both animal models and real-world setting but is limited by treatment related toxicity [87–89]. Recently, Ostendorf and colleagues have demosntrated succesful use of Daratumumab, a mAb that targets CD38 and depletes PCs with acceptable safety profile in a patient with refractory LN [90]. The experience of its use however is still limited and more data will be required.

Obinutuzumab, a novel anti-CD20 mAb demonstrated encouraging sustained 18-months B-cell depletion and renal response in a phase II trial with further evaluation in phase III trial underway (can be accessed at ClinicalTrials.gov with identification number: NCT04221477) [91]. BI 655064 (anti CD40 mAb; NCT02770170) has recently completed a phase II trial as add-on therapy to SOC treatment in active LN and awaiting evaluation. Other biological agents currently undergoing clinical trials in the treatment of LN include Anifrolumab (Type I IFN receptor mAb; NCT02547922) in phase II, while Dapirolizumab (pegylated anti CD40 ligand; NCT04294667) and Secukinumab (anti-IL-17 mAb; NCT04181762) are both in phase III trials [92].

A pipeline of novel agents in LN are being developed or asssesed in clinical trials including Ravulizumab (novel anti complement C5 antibody; NCT04564339), Guselkumab (IL-23 inhibitor; NCT04376827), Itolizumab, (anti CD6 antibody; NCT04128579), KZR-616 (proteasome inhibitor; NCT03393013), Iguratimod (novel small molecule; NCT02936375), and BMS-986165 (novel tyrosine kinase 2 (TYK2) inhibitor; NCT03943147) among many others [92].

Targeting the JAK/STAT signalling pathway with Tofacitinib, or CP-690, 550 have been shown to be effective in murine LN model and may potentially serve as therapeutic target in LN [93, 94]. Successful Bruton's Tyrosine Kinase (BTK) inhibition in several studies involving mice LN models supports *Kong et al.* finding of significantly upregulated BTK expression in glomerulus of LN patients and may potentially be a therapeutic target in LN [95–97].

Despite looking promising in SLE, a placebo-controlled phase II/III study to evaluate Atacicept (recombinant fusion protein that inhibits BAFF/BLyS or APRIL) in combination with MMF and corticosteroids in active LN patients was prematurely terminated due to unexpected substantial decline in serum IgG and serious pneumonia infections in Atacicept-treated patients [98, 99]. Abatacept, a recombinant fusion protein co-stimulation modulator, trialled as add on to SOC in LN failed the primary end point of a phase III trial despite demonstarating more rapid reduction of proteinuria and earlier sustained remission [100].

**45**

*Lupus Nephritis: Current Updates*

*DOI: http://dx.doi.org/10.5772/intechopen.96891*

as a novel therapy target in LN [107].

**6.1 Pregnancy and lupus nephritis**

**6. Special considerations**

pregnancy should be planned.

exclude them from its' benefits.

comes (**Table 5**) [109, 114–118].

*6.1.2 During pregnancy*

failure and increases miscarriage rate [110].

*6.1.1 Pre-pregnancy*

Newer treatment paradigms showing promising results include succesful use of autologous haematopoietic and allogeneic mesenchymal stem cell transplantations for LN in animal studies and among Asian patients [101–106] while *Yu et al.* demonstrated in vitro the protective role by vitamin D in podocyte injury induced by autoantibodies from patients with LN and suggested possible role of vitamin D

Women of childbearing age with LN should understand and be counselled about the potential risks of pregnancy, even if she is in complete remission. Age, previous pregnancy complication, duration from last LN relapse, medication exposure, treatment adherence, blood pressure (BP) control and current disease status are among the important factors that may determine the outcome of future pregnancy. Baseline complement levels, antibody status for dsDNA, SS-A and SS-B, presence of antiphospholipid antibodies (aPL; notably lupus anticoagulant antibody) and

Possible maternal complications include flare of nephritis, uncontrolled hypertension, pre-eclampsia, risk of Caesarean section, worsening renal function and thrombosis. Foetal risks include prematurity, growth retardation, congenital heart block and intrauterine death [108]. Patients with active disease at conception, uncontrolled hypertension, proteinuria of >1 g/day and abnormal renal function have the highest risk for complications; therefore, good control of disease prior to pregnancy is critically important to optimise pregnancy outcome and ideally the

Patients on MMF should be transitioned to pregnancy-safe immunosuppressive drugs such as AZA or TAC, while HCQ should be continued throughout pregnancy. MMF exposure especially after the first trimester increases the risk of miscarriage and congenital malformation [109], and practically should be stopped at least 3–6 months prior to conception to ensure disease control is maintained with the new agent(s) [47]. CYC is also teratogenic, associated with premature ovarian

RAAS blockers should ideally be stopped before conception due to possible teratogenicity risk [111]; however, later publications seemed to suggest that they may be safe to be used until pregnancy is confirmed [112]. This is important especially for those who have residual proteinuria as attempt to conceive may take months or even years of effort. Stopping RAAS blockers early on in these patients would essentially

Multidisciplinary team approach is important during pregnancy and should ideally involve the obstetrician, neonatologist, nephrologist and rheumatologist. Majority of patients (80%) with quiescent LN would have successful pregnancies [113]; however, about a third may relapse during pregnancy [108]. Identification of patients who are at higher risk is important when pregnancy begins, as these patients will require closer observation to ensure good maternal and foetal out-

urinalysis for proteinuria should be obtained prior to pregnancy.

#### *Lupus Nephritis: Current Updates DOI: http://dx.doi.org/10.5772/intechopen.96891*

Newer treatment paradigms showing promising results include succesful use of autologous haematopoietic and allogeneic mesenchymal stem cell transplantations for LN in animal studies and among Asian patients [101–106] while *Yu et al.* demonstrated in vitro the protective role by vitamin D in podocyte injury induced by autoantibodies from patients with LN and suggested possible role of vitamin D as a novel therapy target in LN [107].
