This retrospective comparative study adds to our existing knowledge of the induction treatment and outcome of lupus nephritis in Australia. It is, to our knowledge, the first study examining and comparing the differences in outcome between Indigenous Australian and non-Indigenous Australian lupus nephritis patients of Northern Territory.
MMF was the most frequently prescribed initial induction immunosuppressive agents in 20 of the 23 patients. The routine use of mycophenolate as first-line agent for induction therapy is in keeping with recommendations from society guidelines. The American College of Rheumatology, European League Against Rheumatism and Kidney Disease: Improve Global Outcome guidelines recommended the use of MMF/MPA or low dose cyclophosphamide as reasonable first line therapy for induction,4–7 with a recommended target dose of 2-3g daily (336-504g cumulative over 24 weeks. Preferential use of MMF/MPA over low-dose cyclophosphamide in our unit was an established practice based on anecdotal evidence suggesting of higher risk of neutropenia and infectious complications associated with cyclophosphamide.
When compared to non-Indigenous Australians, Indigenous Australians were less likely to be in CR at 12 months and had a higher incidence of composite adverse renal outcomes over the follow-up period. The poor rate of CR observed in Indigenous Australians were consistent with those reported in the literature.19,20 The reason for the observed poor rate of CR and higher incidence of composite adverse renal outcomes were likely multifactorial. In addition to receiving a lower cumulative dose of MMF over induction period, lower socio-economic status, higher prevalence of co-morbid conditions such as diabetes and geographical barrier to healthcare were likely to have all contributed to the observed worse outcome. When compared to non-Indigenous Australians, Indigenous Australians of the Northern Territory were more likely to be residing in remote communities, occupy the lowest quintile of equivalised weekly household income and were less likely to have access to health provider when necessary.21 These factors may have also contributed to late presentation of disease, leading to delay in diagnosis and commencement of treatment.
A higher incidence of hospitalisation secondary to infections was observed in Indigenous Australian patients in our study. This is in spite of the routine use of trimethoprim-sulfamethoxazole antimicrobial prophylaxis for melioidosis and Pneumocystis pneumonia in our centre24 The higher incidence of infection in immunosuppressed Indigenous Australians was consistent with observations from other comparative studies in Indigenous LN patients and in renal transplant recipients.20,22 As an example, Ghazanfari et al. reported infections as the leading cause of mortality in their cohort of Indigenous Australian LN patients, occurring in 38% of death.23 The higher incidence of infection observed in our study may have led to the lower cumulative dose of mycophenolate prescribed to Indigenous Australian patients, whether deliberate or reactionary. Elevated existing background risk of infection including pneumococcal disease,25 group A Streptococcus infection,26 strongyloidiasis,27 and tuberculosis 28 in Indigenous Australians are known and documented in literature,29 and are likely exacerbated by social inequities such as inadequate housing, overcrowding and poverty.30–33.
In addition to optimising the cumulative dosage of induction therapy in line with guideline recommendation, strategies aimed at improving LN outcome in Indigenous Australians of Northern Territory may necessitate a system-wide approach aimed at improving disparities in social inequities and barrier to accessing healthcare in order to reduce exposure to background infection risks and diagnostic latency.
Targeted immunosuppressive therapy aimed at suppressing specific pathogenic humoral immunity pathways could an alternative approach to optimize LN outcome. The sparing of the innate immune system and cell-mediated adaptive immunity may potentially limit the risk of infection. The efficacy and safety of intravenous anti-CD20 + B cell depleting antibody rituximab for the induction treatment was previously examined in the LUNAR trial. Despite some promising biochemical results with statistically significant reduction in anti-dsDNA and improvement in complement C3 and C4 levels, the trial failed to achieve the primary end point.34 Rituximab, since then, had largely been reserved for patients with refractory or relapsed disease.1,4−6 The safety and efficacy of rituximab in the Top End of Northern Territory was examined in a retrospective descriptive study examining the off-label use of rituximab in patients with autoimmune diseases.35 The authors of the study reported 18 episodes of infection in 66 patients, of whom, 41(62.1%) self-identified as Indigenous Australians.35 A ‘clinically significant response’ was seen in 3 of the 4 patients treated for Lupus Nephritis. Accepting the limitations of retrospective study and the inconsistent documentation of objective disease activity, the authors concluded that off-label use of rituximab for treatment of autoimmune diseases is common and safe in majority of cases. Further studies of rituximab for management of LN in the Top End are warranted to support its use as upfront therapy in Indigenous Australians.
The major strength of our study is the unique population examined. To our knowledge, this is the first study examining the treatment and outcome of LN in an Indigenous Australian predominant patient cohort. Despite having a known higher incidence and prevalence of SLE and LN, Indigenous Australians are underrepresented in the existing medical literature. Our study was limited by its retrospective uncontrolled nature of the study design. As data collection was highly reliant on hospital medical records, the lack of information, particularly pertaining to vaccination records makes the adjustment of potential confounders challenging. The relatively small sample size of 23 patients also underpowered our study. A prospective study involving multiple geographical centres with a high Indigenous Australian patient population should be therefore be considered in order to better understand the differences in treatment response between Indigenous Australian and non-Indigenous Australian LN patients.