New research findings in lupus from ACR 2022 | Latest news for Doctors, Nurses and Pharmacists

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At the American College of Rheumatology (ACR) Convergence 2022 featuring recent updates in lupus research, various speakers covered topics including the potential role of autoantibodies as biomarkers of lupus nephritis (LN) subtypes and treatment response, factors that influence decline in estimated glomerular filtration rate (eGFR) in LN, comparative risk of infection with belimumab vs other immunosuppressants, and the effect of belimumab on renal outcomes in patients with systemic lupus erythematosus (SLE).

Autoantibody trajectories associated with LN classi
fication and treatment response

LN is characterized by the presence of a broad and heterogeneous group of autoantibodies. [Autoimmune Dis 2014;2014:321359] However, the association of autoantibodies with LN subtypes and the implications of their longitudinal changes in LN are not well understood. [Arthritis Rheumatol 2022;74(Suppl 9):abstract 0333]

To identify novel serum biomarkers of LN classes and treatment response, a study was conducted to quantify circulating autoantibodies in the Accelerating Medicines Partnership (AMP) LN longitudinal cohort. Serum samples were collected from 268 participants with urine protein/creatinine ratio (UPCR) >0.5 at the time of diagnostic kidney biopsy and 3, 6 and 12 months after biopsy.

Most LN patients exhibited autoantibodies against chromatin (78 percent), double-stranded DNA (dsDNA, 70 percent), Smith/RNP (SmRNP, 63 percent), C1q (56 percent), RNP (54 percent), and Smith (Sm, 52 percent) at the time of kidney biopsy.

Several autoantibodies, including dsDNA, chromatin, and C1q antibodies, were more frequent in proliferative (class III, IV, III+V, or IV+V) than membranous (class V) LN subtype. Higher titres of antibodies against dsDNA, C1q, chromatin, and ribosomal P corresponded to higher odds of having proliferative LN and lower odds of having nonproliferative LN.

“Proliferative LN patients with a complete renal response experienced a significant decline in several autoantibodies, including those against dsDNA, C1q, chromatin, Sm, and ribosomal P,” highlighted lead author, Dr Andrea Fava of the Johns Hopkins University, Maryland, US. “Autoantibody levels remained relatively stable in partial responders and nonresponders with proliferative LN, as well as in patients with membranous LN.” (Figure 1)

The authors concluded that levels of autoantibodies against dsDNA, C1q, chromatin, and ribosomal P may serve as noninvasive biomarkers of proliferative LN. In patients with proliferative LN who are responding to treatment, there were declines in titres of several autoantibodies, including some that are not routinely measured over time, such as anti-Sm, suggesting a possible role in LN pathogenesis. These antibodies may also serve as early biomarkers of treatment response.

Impact of time to remission, flares and time on immunosuppressives on eGFR in LN

Time to remission, subsequent flares and duration of immunosuppressive therapy after complete remission (CR) are major determinants of progression to advanced chronic kidney disease (CKD) in LN. [Arthritis Rheum 2004;50:3934-3940;
Clin J Am Soc Nephrol 2014;9:279-284]

To determine the impact of these factors on eGFR in LN, 418 LN patients from the Toronto Lupus Clinic long-term longitudinal database were followed for ≥5 years. The primary outcome was any annual change in eGFR. [Arthritis Rheumatol 2022;74(Suppl 9):abstract 1450]

The eGFR trajectory over 20 years showed that patients in CR after 3 years or no remission was associated with a significant reduction in eGFR (-12.31 mL/min/1.73 m2; p<0.0001), while patients in CR at 1–3 years after LN diagnosis did not have significantly decreased renal function (-1.60 mL/min/1.73 m2; p=0.581) vs those who achieved CR <1 year after LN diagnosis. Patients who experienced ≥2 flares also had a significant decline in eGFR (-14.79 mL/min/1.73 m2; p<0.0001), whereas patients who experienced one or no flares did not (-3.48 mL/min/1.73m2; p=0.358) vs those who did not experience any flare. Longer time on immunosuppressants after CR was protective against eGFR decline. (Table)

“Our findings emphasize the importance of rapid remission and flare prevention by prolonged maintenance treatment with immunosuppressives to optimize renal outcomes,” concluded Dr Konstantinos Tselios of McMaster University, Ontario, Canada.

Comparative risks of infection with belimumab vs oral immunosuppressants in nonrenal SLE

Infection is a leading cause of morbidity and mortality in patients with SLE. Up to 45 percent of SLE patients may develop severe infections requiring hospitalization. [Rheumatology 2021;60:5300-5309]

Belimumab was US FDA–approved as add-on therapy for SLE in 2011 and for LN in 2020. Initial phase III placebo-controlled trials reported no increased risk of infection in patients who initiated belimumab in addition to standard therapy. [Arthritis
Rheum 2011;63:3918-3930; Lancet 2011;377:721-731] However, the comparative risk of infection associated with initiating belimumab vs oral immunosuppressants is not known. Therefore, a cohort study was conducted to assess this risk by analyzing observational data from the TriNetX electronic health record database. [Arthritis Rheumatol 2022;74(Suppl 9):abstract 0349]

Adult patients with nonrenal SLE who initiated immunosuppressive therapy between 2011 and 2021 were identified, and the cumulative incidence and hazard ratios (HRs) of severe infection (primary outcome) and of hospitalization for severe infection (secondary outcome) were estimated for initiation of belimumab (n=2,841) vs azathioprine (n=6,343), belimumab (n=2,642) vs methotrexate (n=8,242), and belimumab (n=2,813) vs mycophenolate (n=8,407).

Belimumab was associated with a lower incidence of severe infection (HR, 0.78; 95 percent confidence interval [CI], 0.71–0.87) and hospitalization for severe infection (HR, 0.73; 95 percent CI, 0.59–0.91) than oral immunosuppressants through 5 years of use. (Figure 2) “Our findings should inform future decisions around initiating belimumab vs oral immunosuppressant therapy for patients with SLE,” noted the study’s lead author, Dr Emma Materne of the Massachusetts General Hospital, Boston, US.

Belimumab’s effect on kidney outcomes in SLE

About 50 percent of patients with SLE have kidney involvement. [Clin J Am Soc Nephrol 2017;12:825-835] In
phase III studies, belimumab improved kidney outcomes in patients with SLE.
[Lupus 2013;22:63-72; Ann Rheum Dis 2012;71:1833-1838]

A post hoc analysis of pooled data from five clinical trials was performed to
evaluate the effect of belimumab on kidney outcomes in SLE patients without severe
active LN. Participants received standard therapy plus belimumab (n=1,869) or
placebo (n=1,217), and endpoints were analyzed every 4 weeks over 52 weeks.  [Arthritis Rheumatol
2022;74(Suppl 9):abstract 0352]

A lower proportion of belimumab-treated patients had ≥1 kidney flares vs placebo recipients. Belimumab was also associated with a shorter median time to first flare in the overall population (HR, 0.58; 95 percent CI, 0.42–0.78; p=0.0005), and among patients with baseline proteinuria of >0.5 g/24 hours (HR, 0.53; 95 percent CI, 0.37–0.78; p=0.0011). (Figure 3)

Patients receiving belimumab plus standard therapy experienced significantly greater kidney improvement (p=0.0033 for patients with baseline kidney involvement), less kidney worsening (p<0.0001 for patients without baseline kidney involvement), and were less likely to experience a ≥30 percent decline in eGFR (p=0.0463 for overall population) vs patients receiving placebo. Additionally, more belimumab- vs placebo-treated patients shifted from baseline proteinuria of >0.5 g/24 hours to ≤0.5 g/24 hours (45 percent vs 33.7 percent).

“This robust analysis demonstrated favourable kidney outcomes in patients treated with belimumab vs placebo in both the overall population and among those with proteinuria >0.5 g/24 hours,” concluded study author Dr Maria Dall’Era of the University of California, San Francisco, US.

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