Observations suggest that the mechanisms of LN may differ among racial and ethnic subsets; hence, the effectiveness of therapeutic interventions may also vary. For instance, Black and Hispanic patients have an increased risk of aggressive disease [12
], and a greater prevalence of renal failure has also been reported among Black patients [25
], with genetic rather than socio-economic factors believed to be a more likely cause.
Previous trials have found MMF to be at least as effective as IVC as induction treatment for LN; but analyses were limited to patients in single countries and the trial sizes did not allow for comparisons between racial groups [26–30
]. ALMS, however, provides the most extensive dataset to date that allows variations in response to the two most commonly used treatments for LN to be addressed directly.
The results from this global study suggest that race and geographical region do influence response to therapy. Possible reasons that may have contributed to this observation include differences between subgroups with respect to disease characteristics at baseline, differences in how subgroups metabolize the respective drugs, variations in treatment tolerability and regional differences in patient management/socio-economic factors. The greater number of responders with MMF than IVC in the Black and Latin American groups suggests a difference in efficacy between the two drugs in these populations. This difference in efficacy observed in Black and Latin American groups is supported by the reduction in mean IVC dose among patients in the Black group compared with other racial groups.
Further, more patients in the Black group receiving IVC were likely to withdraw prematurely from the study due to AEs than other racial groups, resulting in differences in exposure across racial groups. Variation in exposure to either of the treatments was also seen across regional groups; exposure to IVC was lower in the USA and Canada than other regions because of differences in the proportions of patients completing the full 24 weeks of treatment (withdrawal rates were higher in USA/Canada). Lower exposure was driven by fewer infusions due to premature withdrawal rather than patients requiring a reduced dose due to renal failure. Conversely, patients in the Asian group demonstrated a reduced tolerability to MMF, exhibiting a higher withdrawal rate due to AEs, compared with other racial groups.
However, it is difficult to draw firm conclusions from drug exposure according to patient weight, because dosing of both drugs was frequently reduced due to AEs, which confounds the apparent outcome in patients taking lower doses. Despite differences in withdrawal due to AEs in patients from Asia, there was no effect on overall efficacy MMF and IVC compared with other regions. Indeed, the overall efficacies of MMF and IVC were comparable, but for certain racial and ethnic groups, MMF may offer better efficacy and tolerability as induction treatment. ALMS provides the most compelling data currently available that certain patient populations are less likely to respond to IVC, supporting the anecdotal evidence from clinical practice that the efficacy of IVC varies between racial and ethnic groups.
Baseline disease characteristics did not appear to have any noticeable predictive value for response to therapy. There were differences in baseline factors observed between racial/regional groups and within some racial groups. More patients in the Black group and from USA/Canada had Class V LN, and these patients were also more likely to be hypertensive and taking immunosuppressive co-medications. However, there is no indication that these parameters had an impact on treatment response. Overall, patients from Asia reported the fewest infections, but those infections were more likely to be severe, resulting in hospitalization or death. Notably, these events were largely localized to one region within Asia. Analysis of the potential impact of possible predictor variables on adverse outcomes did not explain the numerical differences between treatment groups in the numbers of deaths, SAEs and infections.
Firm conclusions cannot be drawn from this study as a number of the assessments described here were exploratory analyses performed on a post hoc basis subsequent to the initial, prospectively planned, primary efficacy analysis, and thus must be interpreted as such. Furthermore, the trial was not designed to be powered to detect an effect of a specific region, race or ethnicity; the small numbers of patients in each subgroup do not allow these findings to be generalized to the larger population of patients with LN.
Also, due to the complex nature of the relationship between race, ethnicity and geographical region, we cannot distinguish between these factors in terms of importance. Designations of race and ethnicity are often arbitrary (and in this study, self-reported) and heterogeneous [31
], and there can be notable differences in clinical, prognostic and socio-economic features, education and access to medical care within a geographical region [32
]. Further, these categories are not discrete, and the overlap of races and ethnicities may have masked differences in response among these groups. In spite of the attempt to standardize the management of LN across regions by strict trial monitoring, differences in treatment response were observed in Latin America compared with the other regions. Although the role of some socio-economic factors can be reduced in a clinical study, they cannot be removed entirely, and their differentiation from genetic factors remains a challenge.
Other factors that were uncontrolled in this study may have been a source of bias, such as regional differences in prior immunosuppressive drug use. For example, patients who had received previous IVC therapy might have been less likely to respond to IVC in ALMS. As details on prior therapy were not collected, it is not clear whether this potential source of bias contributed, for example, to the difference in IVC response seen across regions.
Another limitation may have been the 24-week induction period, which may have been too short to differentiate between the treatments. The duration of this induction phase was comparable with that of previous studies, however [15
], and further data will be collected during the ongoing maintenance phase.
In conclusion, exploratory findings from this large, international study indicate that although MMF and IVC are of similar efficacy, race, ethnicity and geographical region may be important factors in response to treatment among patients with LN. More patients from the Black and Hispanic groups appeared to respond to MMF than IVC, and more patients from the Asian group withdrew from MMF than IVC treatment. However, due to the complex nature of the relationship between race, ethnicity and geographical region, we cannot distinguish between these factors in terms of importance. Nonetheless, the ALMS data provide some valuable insights regarding the interaction of these factors.