Abstract
Background Identification of prognostic and predictive biomarkers in lupus nephritis (LN) is an area of intense study and interest. Non-invasive laboratory markers that associate with the likelihood of responding to therapy and/or assess clinical response in patients with active LN remains an unmet need. The Lupus Risk Index is a score that associates with the risk of developing SLE.1 It is lowest in Caucasian females and increases in populations with increased risk of developing SLE (African American, Sister's of patients with SLE), and is highest in SLE. Its components (IgM and IgG anti-DNA antibodies and C1q) are each associated with renal disease (or protection from renal disease).
LRI
Objective To assess the LRI as a LN biomarker that predicts a clinical response to induction therapy, or whose early changes may precede a clinical response, or that associates with a clinical therapeutic response.
Methods The LRI was determined on retrospective specimens collected from two LN clinical trials sponsored by the Immune Tolerance Network (ITN): CALIBRATE (n=43) and ACCESS (n=134) as well as healthy controls (n=70). Both trials enrolled subjects with active proliferative LN (Class III, IV, ± Class V). All subjects participating in CALIBRATE received rituximab (coupled with cyclophosphamide) and half received open-label belimumab through week 48 of the study. In ACCESS, all participants received the Euro-lupus cyclophosphamide protocol and subjects were randomized to receive either placebo or abatacept infusions. Sera obtained at weeks 0, 12, 24, and 48/52 (CALIBRATE/ACCESS) were studied. Levels of IgG αDNA, IgM αDNA and C1q were determined by ELISA. Response at 24 weeks was defined using the ITN’s definitions of renal response. This is a categorical assessment; a Complete Response (CR) requires a Urine protein:creatinine ratio (UPCR) ≤0.5 and creatinine normal or no greater than 125% of baseline, and a prednisone (or equivalent) dose ≤10 mg/d. 2), Partial Response (PR): UPCR ≥50% reduction from baseline plus identical creatinine and steroid criteria as CR, or 3) Non-response (NR) all others.
Results Baseline LRI determined from ACCESS and CALIBRATE samples were both significantly higher than normal controls. Baseline LRI from CALIBRATE which recruited non-naïve disease LN patients, i.e., patients who were resistant to current therapy, or had a repeat LN episodes was significantly greater than those from ACCESS which allowed subjects with new onset lupus nephritis (Figure 1A). Neither the LRI at baseline nor the change of the LRI from baseline to week 12 predicted a subsequent renal response at 24 weeks (figure 2A and 2B).
Moreover, the LRI at week 24 did not associate with a renal response at that timepoint (figure 2C). These results were confirmed when samples from ACCESS and CALIBRATE were assessed separately, or if only subjects receiving the active comparator (abatacept in ACCESS or belimumab in CALIBRATE) were examined.
Conclusions The LRI, a measure associating with the risk of developing SLE, is not a predictive or prognostic biomarker in patients with active LN.
LRI at baseline in participants enrolled in ACCESS, CALIBRATE and healthy controls
A. LRI at baseline and response status at week 24; B. Change of LRI from baseline to Week 12 and response status at Week 24, C. Week 24 LRI and response status at Week 24
Reference
Bhattacharya J, Pappas K, Toz B, Aranow C, Mackay M, Gregersen PK, Doumbo O, Traore AK, Lesser ML, McMahon M, Utset T, Silverman E, Levy D, McCune WJ, Jolly M, Wallace D, Weisman M, Romero-Diaz J, Diamond B. Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus. Mol Med 2018 Jun 1;24(1):24. doi: 10.1186/s10020-018-0019-4. PMID: 30134810; PMCID: PMC6016868.
Acknowledgements Immune Tolerance Network; Autoimmunity Centers of Excellence--NIAID, NIH
