Lupus nephritis: Challenges and gaps in the treatment landscape of Asia

29 Jun 2019

Dr. Mok, Chi-Chiu

Chief of the Division of Rheumatology,
Department of Medicine,
Tuen Mun Hospital

Lupus nephritis (LN) is a manifestation of the systemic lupus erythematosus (SLE). Among SLE patients, around 60% will develop LN, which is a major contributor to morbidity and mortality.1 Compared to Caucasians, Asians have a higher tendency to develop LN.2 In Asia, the severity of LN is higher and is one of the main causes for chronic renal failure.1 When optimizing the management for LN, these racial predilections should be considered in the choice of treatment regimens in order to alleviate the healthcare burden. In an interview conducted with Dr. Chi-Chiu Mok, he shared the insights on the current treatment landscape of LN and challenges pertaining to treatment.

Management of LN in Asia

In Hong Kong, SLE is common among females at childbearing age. The prevalence of SLE is 0.1% and annual incidence rate is 6.7 per 100,000 population.3 It is a polygenic disease, where genetic component contributes to 30-40% of SLE susceptibility. Environmental factors such as ultraviolet light, hormonal changes, viral infections and vitamin D deficiencies are responsible for triggering the onset of the disease. Clinically relevant LN is developed in 60% of SLE patients.1 There is a strong racial and ethnic predilection on the incidence, prevalence, severity and prognosis of LN.4 In view of the racial differences in disease manifestations, response to therapy and the significant disease burden in Asia, the Asian Lupus Nephritis Network (ALNN) has published treatment recommendations for LN (Figure 1).5

New avenues in the management of LN

The goals of LN treatment are to induce remission, reduce flares, preserve kidney function and minimize vascular- or treatment-related conditions.6 The management of LN consists of an initial induction therapy followed by maintenance. The induction of immunosuppression aims to suppress the inflammation in kidneys to minimize the damage to nephrons. Non-biologic induction therapy of LN includes a combination of glucocorticoids with cyclophosphamide, mycophenolate mofetil or the calcineurin inhibitors.7 The conventional induction therapy for severe LN is a combination of glucocorticoids with cyclophosphamides. This regimen has preserved the renal function better than glucocorticoids alone, which was the practice in the past few decades.8 However, long-term cyclophosphamide treatment is associated with ovarian toxicity and increased risk of infections. With the availability of alternative agents, cyclophosphamide is currently less commonly used as first-line treatment and often reserved for salvage therapy in high-risk patients or those with refractory LN.9

Mycophenolate mofetil, an immunosuppressive agent with lesser ovarian toxicity is the preferred first-line treatment for LN.7 It is not superior to cyclophosphamide, and lacks long-term efficacy data. According to Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA- EDTA) guideline, mycophenolate mofetil, in combination with glucocorticoids, is one of the recommended first-line induction treatment regimens for LN.10 In patients with more serious LN such as those who present with rapidly deteriorating renal function, higher doses of cyclophosphamide remain the treatment of choice. For patients with mild disease, azathioprine is an alternative. For patients who fail to respond to multiple immunosuppressive regimens, rituximab may be considered a salvage therapy, as around 50% of clinical response has been reported in registry studies.11 Although rituximab combined with mycophenolate mofetil in the absence of high-dose glucocorticoid has been successful in LN, this regimen has not been compared with conventional regimens in randomized controlled trials.12

The calcineurin inhibitors, cyclosporin A and tacrolimus, have been used in the management of SLE.13 In LN, tacrolimus has shown similar short term efficacy with cyclophosphamide or mycophenolate mofetil during induction therapy.14,15 Low-dose combinations of mycophenolate mofetil and tacrolimus with glucocorticoid have been shown to be superior to conventional intravenous pulse cyclophosphamide therapy in Chinese patients with LN.16 Tacrolimus can be considered for induction therapy for LN in patients with contraindications or lack of response to cyclophosphamide or mycophenolate mofetil. However, the clinical evidence for its efficacy as induction is limited to 18 months and long-term efficacy and safety data are necessary.

Maintenance therapy is beneficial in suppressing residual disease activity and avoiding reactivation. The EULAR/ERA-EDTA guideline recommends that mycophenolate mofetil should be selected as maintenance therapy for patients who respond to mycophenolate mofetil as the induction therapy.10 Although the optimal duration of therapy is still controversial, the maintenance of immunosuppression should be continued for at least 3 years in patients who respond to the induction therapy.10 In patients who are at an increased risk of deterioration of the renal function, the duration of treatment should be prolonged.

Recently, interest has been drawn towards new drugs for the management of LN. Voclosporin, an analogue of cyclosporin, has been shown to be more effective than placebo when added to the standard of care in the treatment of LN.17 Anifrolumab, a type 1 interferon receptor blocker, is an another biologic being developed in the treatment of LN. It was shown in a phase II study to reduce disease activity in moderate-to-severe SLE.18 Additionally, immune target agents, such as rapamycin are also newer agents that are under investigation.19,20 Janus-Kinase (JAK) inhibition in LN is also an attractive therapeutic option. Additional clinical data are necessary to incorporate JAK inhibitors in the practice.21

Strategies to overcome the treatment challenges for LN

Progression to renal failure despite different treatment modalities is the challenge being faced in LN. Newer drugs with higher efficacy, but lower side effects are needed to prevent the progression of LN to renal failure. Alternatively, maximizing the efficacy of existing drugs with tailored dosage based on the response of each individual patient so as to reduce adverse effects could be a sustainable option. Serum mycophenolic acid (MPA) level monitoring can be used to titrate the dosages of mycophenolate mofetil to optimize the efficacy of the drug and reduce toxicities.

A combination strategy of several immunosuppressive drugs at lower dosages is a viable option in the treatment of LN to enhance the treatment efficacy as well as to reduce adverse effects. A multi-target approach with lower doses of glucocorticoids, mycophenolate mofetil and tacrolimus has been already tested in Chinese patients as fore-mentioned.16 Alternatively, newer and less-toxic immunosuppressive agents, such as voclosporin are being developed for the treatment of LN. Limiting the dosages and duration of high-dose glucocorticoid treatment is another important strategy to reduce treatment-related adverse events. Most rheumatologists in Hong Kong are using a combination of mycophenolate mofetil and glucocorticoids for the induction treatment of LN to limit the period of high-dose glucocorticoid treatment to less than 8 weeks. Moreover, given the complex nature of the LN, the treatment should be individualized according to the histological characteristics of renal biopsy, severity of LN, renal function, previous treatment, age, sex, ethnicity, tolerability, compliance, patient’s concern over fertility, and the anticipated risk of toxicities.

LN screening and the need for biomarkers

Current laboratory biomarkers that are routinely used in LN include urinary protein to creatinine ratio, anti-dsDNA (double stranded DNA) antibody titers and complement levels.7 These parameters lack the sensitivity and the specificity for differentiating the ongoing disease activity and kidney damage in LN. On the contrary, severe histological activity may occur in patients with apparently low levels of proteinuria or persistent proteinuria may be observed in patients who develop chronic kidney disease without histological activity of LN. Therefore, renal biopsy, albeit invasive and sometimes contraindicated or unacceptable in some patients, remains the gold standard for determining the disease activity of SLE in kidneys and differentiating it from chronic kidney damage. However, frequent renal biopsies to determine disease activity is impractical and this is the reason for developing novel LN biomarkers to improve the monitoring of LN and help deciding the best treatment for individual patients. Several serum and urine biomarkers have been studied in the past decade, but further validation studies are necessary before they can be used routinely in clinical practice.

Enhancing the quality of life in patients with LN

Non-immunosuppressive therapies are equally important in the management of LN. These include minimizing the risk of cardiovascular complications, controlling blood glucose and lipid levels, preventing osteoporosis, and managing psychological issues. General measures such as reduction of salt intake, regular exercises and weight control are recommended. Osteoporosis is another common complication of glucocorticoid treatment, which requires vitamin D, calcium supplementation, and anti-osteoporotic treatment in patients at risk of major fragility fractures. Moreover, vaccination for common infections such as influenza, pneumococcus, and human papillomavirus should also be advised.

Psychological aspect is also an important area that needs management attention. Many LN patients would suffer from depressive symptoms and some might even have suicidal ideation, therefore, identifying patients’ psychological needs, having regular assessment of depressive/anxiety symptoms by questionnaires and referring them to clinical psychologists/psychiatrists are required.

Since the majority of LN patients are women in their childbearing age, pregnancy counselling and assisted reproduction are other aspects that need to be addressed. With risk stratification, pre-conception counselling and close multi-disciplinary surveillance put in place, the outcomes of pregnancies could be improved in these patients.

Future perspectives: Addressing key barriers in the treatment of LN

The clinical outcomes in terms of remission, reactivation, renal function, and safety profile of treatment should be further enhanced in patients with LN, and this must be achieved through multicenter collaboration with international networks. While identifying potential serum and urine biomarkers are essential to fill the treatment gaps, being able to assess different drug levels and synergize novel drug combinations are of utmost importance for treatment optimization and its efficacy monitoring. Undoubtedly, there is a need for adopting the constantly developing new drug therapies as well as monitoring methods in order to achieve a more effective management of LN.

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