**5. Management**

#### **5.1 Current management strategies**

Early treatment in LN has been shown to improve outcome; however, effective management remains a challenge. It requires a multidisciplinary team approach (MDT), ideally by rheumatologists, nephrologists and nephropathologists. The cornerstone of treatment entails corticosteroids, antimalarial, and steroid-sparing agents (conventional immunomodulators and/or biological therapies) tailored to individual patients based upon histological class and severity to achieve rapid resolution of inflammation, proteinuria <0.5–0.7 g/day by 12 months (or up to 24 months in baseline nephrotic range proteinuria) [47] and prevention of relapsing episodes.

#### *5.1.1 Induction phase*

While there is little agreement for class II LN, in active proliferative class III, IV and pure membranous class V (with nephrotic range proteinuria or proteinuria >1 g/ day despite optimal use of renin-angiotensin-aldosterone system (RAAS) blockers), the current recommendation for initial induction treatment options include either low-dose intravenous cyclophosphamide (CYCi; 500 mg fortnightly infusions for 3 months) or mycophenolate mofetil (MMF; 2-3 g/day or mycophenolic acid (MPA) at equivalent dose) [47, 65–68]. This is combined with high-dose pulsed intravenous methylprednisolone followed by oral corticosteroid taper. High-dose CYCi is reserved for patients with severe LN due to its' various unfavourable side effects (mainly severe cytopenias and infection, cystitis, ovarian failure, cervical dysplasia and malignancy).

The use of calcineurin inhibitors (CNIs) namely tacrolimus (TAC) and cyclosporin (Cys) either as monotherapy or as part of a multitarget regimen therapy (with MMF/MPA and glucocorticoid) may have a favourable efficacy to induce remission. Meta-analysis in 2017 which included 45 induction trials of diverse participant background confirmed superior efficacy in induction by multitarget

**43**

*Lupus Nephritis: Current Updates*

*5.1.2 Maintenance phase*

ophthalmological screening.

*5.1.3 Refractory lupus nephritis*

response or recurrent LN flares [47, 65].

**5.2 Future novel therapeutic options**

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

therapy compared to CYCi [69]; however, safety concern with its long term use mainly of chronic progressive irreversible nephrotoxicity remains an issue [70].

In the maintenance phase of treatment where less intensive therapy is required, MMF (1-2 g/day or MPA at equivalent dose) or azathioprine (AZA) are the drugs of choice [47, 71, 72] (with or without low dose <7.5 mg/day corticosteroid), depending on the induction regimen and plan for pregnancy. Hydroxychloroquine (HCQ ) is recommended for all LN patients in the absence of contraindications [47]. Due to possible ocular toxicity, the dose should not exceed 5 mg/kg body weight and should be adjusted in patients with renal and liver disease, with regular

Rituximab (RTX), although off-label, is not only indicated in patients refractory to conventional therapy or after great cumulative dose of CYCi, but also in patients of child bearing age [47, 73, 74]. Another B-cell targeting therapy which inhibits BlyS, Belimumab has recently been proven to be beneficial as add-on to the standard of care (SOC) therapy (mainly in the MMF subgroup) with primary efficacy

It is recommended not to discontinue immunosuppression too early as most renal flares occurs during this period. Treatment withrawal can be considered in patients with sustained complete remission for 3–5 years, with treatment deescalation prior to complete withrawal of therapy [47]. Close monitoring of patients and management of co-morbidities including blood pressure (BP) control, treatment of hyperlipidaemia with statins and proteinuria with RAAS blockers are important, while vaccination against influenza and *Streptococcus pneumoniae* are strongly recommended. Repeat renal biopsy may be considered to guide the duration of maintenance immunotherapy and may be required in patients with incomplete

Developing more effective treatment strategies in LN remains a priority among

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 deple-

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.

tion of circulating and tissue-resident autoreactive B cells.

renal response seen by week 24 and sustained through week 104 [75].

therapy compared to CYCi [69]; however, safety concern with its long term use mainly of chronic progressive irreversible nephrotoxicity remains an issue [70].
