Racial Disparities Result in Unprecedented Differences in Outcomes for SLE Patients

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The differences between Caucasian and minority patients with lupus are striking: In almost all aspects of the disease, black, Hispanic and many Asian lupus patients do poorly compared with their white counterparts. Although racial disparities in outcomes in the practice of medicine are widespread, the scope and degree of the differences in lupus is, with only a few exceptions, unprecedented. From disease risk and severity, to treatment response, to mortality, there are stark differences in how the disease affects patients of different racial backgrounds. Despite decades of research, improvements in outcomes for minority patients with lupus remain largely elusive.

Magnitude of the Problem

We have known for almost half a century that a dramatic difference exists in the prevalence and severity of lupus in black patients in particular, compared with white patients. Epidemiologic studies from the 1960s showed an almost threefold increase in the prevalence of lupus among black individuals, with an almost threefold difference specifically in women. Later studies showed similar findings among Hispanics and individuals from certain Asian backgrounds.^1,2 Moreover, as far back as the mid-1970s, significant mortality risks were apparent in black females, in whom the mortality rate was almost four times as high in white females.³

Subsequent research demonstrated that lupus tends to occur at a younger age and tends to be more severe in non-white patients. Black patients, for example, are more likely to have renal and neurologic involvement due to lupus, and black, Asian and Hispanic patients are up to twice as likely to develop lupus nephritis within 10 years of diagnosis. Worse still, the incidence of progression to end-stage renal disease from lupus nephritis is actually on the rise for black patients, according to U.S. Renal System data.⁴ Furthermore, black lupus patients are much more likely to have high-risk histological features on renal biopsy, such as crescents and high chronicity indexes, and are much more likely to have WHO class III nephritis, which has been associated with poor outcomes.⁵

Complicating matters are clear differences in response to treatment among non-white patients, especially with lupus nephritis—an all-too-common manifestation. Intravenous cyclophosphamide, the gold standard treatment for lupus since the early 1990s, has been shown to be markedly less effective in black patients. A landmark study by Dooley et al in 1996, for example, demonstrated a dramatic difference among black patients in the response to monthly pulse-dose IV cyclophosphamide, in which renal survival five years after a diagnosis of lupus nephritis was only 58% in black patients compared with 95% among white patients who had similar biopsy findings and treatment regimens.⁶ Until recently, little was known about the response of individuals of Asian and Hispanic backgrounds to IV Cytoxan, although recent evidence suggests that the response to cyclophosphamide among Hispanics, in particular, is poor.

Nature vs. Nurture

The inevitable question must be asked: What role do socioeconomic factors play in the observed racial and ethnic differences in pathogenesis of lupus? Can the relative differences in outcomes among white and minority patients be ascribed to such factors as barriers to obtaining care and economic factors, or are there genetic factors that predispose these individuals to more severe or treatment-resistant lupus?

These are not easy questions to answer for many reasons, including the lack of clear definitions and surrogate markers for low socioeconomic status, a lack of tools by which to measure such key factors as medication compliance, and the difficulties with performing long-term longitudinal studies in underserved populations. Early attempts to delineate the role of socioeconomic status argued against a significant role for race that was independent of socioeconomic factors, but were hampered by the inherent difficulties of undertaking these types of studies.

Perhaps the clearest picture of the respective roles of race and socioeconomic factors in lupus disease pathogenesis comes from the Lupus in Minorities Nature vs. Nurture (LUMINA) cohort studies. The LUMINA cohort consists of more than 600 patients from mixed ethnic and racial backgrounds who were recruited from sites in the southern United States, as well as Puerto Rico, beginning in the 1990s. These studies had several strengths: the use of robust assessment tools for measuring disease activity and damage accrual and the inclusion of multiple socioeconomic factors, such as income, education, home ownership and insurance status, as markers for poverty. Additionally, the cohort included a diverse patient population that included a sizable contingent of Hispanic patients—a group that was often underrepresented in previous lupus studies. Finally, patients were recruited relatively soon after diagnosis, allowing for a better assessment of the risk factors for worsening disease.

The LUMINA trials had several striking findings. At the time of diagnosis, race, ethnicity and genetic factors were strongly associated with organ involvement, but socioeconomic factors had less of an impact. Over time, however, these same markers for socioeconomic status gained increased significance with regard to disease progression over time, even when the initial disease severity was taken into account.^7,8 Together, these findings suggest that there is likely a strong genetic component to the risk of developing lupus, as well as the risk of more severe disease. However, the risk of progression of organ involvement—particularly kidney involvement—over time is complicated by social factors as well. Other studies support this notion as well. Recent genetic studies, for example, point to African, Asian and Hispanic genetic ancestry as independent risk factors for the development of lupus nephritis, and long-term cohort studies have emphasized the role of poverty in disease progression over time.^9,10

Reasons for Optimism

Although the gap between white lupus patients and black, Hispanic and Asian lupus patients remains significant, important strides have been made, particularly in treatment regimens for lupus nephritis. The introduction of mycophenolate mofetil (MMF) has proved a game-changer for black and Hispanic patients with severe renal involvement. In the Asperva Lupus Management Study (ALMS), which compared pulse dose cyclophosphamide to daily MMF, black and Hispanic patients had a significantly improved response to MMF compared with pulse dose cyclophosphamide.¹¹ The response rates at six months were similar for both groups, with 54% of black patients achieving remission with MMF compared with 40% with cyclophosphamide, and 61% of Hispanic patients achieving remission with MMF vs. 39% with cyclophosphamide.

Lupus tends to occur at a younger age & tends to be more severe in non-white patients.

Undoubtedly, the ALMS trial was a significant breakthrough for treating black and Hispanic patients—although our optimism must be tempered by the fact that white and Asian patients in this trial were still much more likely to achieve remission overall. Furthermore, the subjects in the ALMS trial had relatively well-preserved renal function, and there remain few options for the treatment of severe lupus nephritis beyond IV cyclophosphamide.

Although the advent of the MMF era has brought forth important gains for black patients in particular, many questions remain unanswered. Will advances in our understanding of genetics lead to the identification of new genetic contributors to severe lupus? Recent studies suggest that alleles of APOL1 that are commonly found in individuals of African heritage may be strong predictors of ESRD from lupus nephritis.¹² Similarly, early evidence suggests that there may be a genetic contribution to the rates of MMF metabolism that may predispose black patients to a lack of response to MMF therapy. Can we glean new knowledge about the role of socioeconomic and environmental factors that contribute to worsening lupus?

These differences may now be more apparent, given our greater understanding of the racial differences in response to therapy. The issues of access and adherence to therapy strategies remain poorly addressed topics. Can we improve access to, and delivery of, care by adapting strategies developed in the fight against HIV for lupus patients?

As we enter the era of personalized medicine, we will ultimately have to develop approaches that account for the various genetic, social and environmental factors and are tailored to the needs of the individual patient.

Eric L. Wise, MD, is a rheumatologist in Ann Arbor, Mich.

W. Joseph McCune, MD, is a rheumatologist at the University of Michigan, in Ann Arbor, Mich., and was recognized as a Master by the ACR in 2014.

References

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