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2022ACR ends today Lupus nephritis has attracted much attention, and various research results have exploded, and this article will take you to unlock the most informative content!

 Last Update: 2023-01-06
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The ACR Annual Meeting was directly on the spot, comprehensively explaining the heavy data and new explorations
in the field of lupus nephritis.

As an authoritative academic conference in the field of rheumatology, the annual American College of Rheumatology (ACR) annual meeting is in full swing, and a large number of important advances in the latest and most cutting-edge fields are constantly emerging, and one of the most serious complications of systemic lupus erythematosus (SLE) - lupus nephritis (LN) related research and clinical diagnosis and treatment progress is one of the important highlights of this ACR annual meeting.
This article will select a number of important LN-related studies during the annual meeting for the majority of clinicians to learn and communicate
.

Biologics are among the best, and belimumab significantly improves renal outcomes in patients with lupus kidney involvement

LN is a common complication of SLE, progressing to end-stage renal disease (ESRD) within 10 years in approximately 20 percent of patients with LN ^[1].
Belimumab is the world's first and only targeted biologic approved
for LN indications in China.
A large global multicenter randomized controlled BLLSS-LN study published in the New England Journal of Medicine showed that patients treated with berylimumab had a complete renal response rate of up to 47% at 1 year compared with patients receiving usual therapy alone, a 55% reduction in the risk of renal recurrence at 24 years, a reduction of 49% of renal endpoint events and outcomes, and adverse effects comparable to those in the placebo group ^[2].
。

▌A sample size of 3000+ cases once again confirmed that belimumab significantly reduced the risk of kidney recurrence in patients with lupus kidney involvement; Renal outcomes are improved with or without renal impairment at baseline

The efficacy and safety of belimumab in the treatment of LN have been fully demonstrated in the BLISS-LN study, so how effective is belimumab in improving kidney involvement in patients with lupus?

At ACR 2022, a large post-hoc analysis pooled data from 3086 patients with SLE in five clinical trials (BLISS-76, BLISS-52, BLISS-NEA, BLISS-SC, and EMBRACE) to evaluate the effectiveness of belimumab in the treatment of SLE and LN ^[3].
The results showed that in the general population, the 1-year renal recurrence rate was significantly reduced by 42% in the belimumab group compared with usual care (p=0.
0005).
In people with baseline proteinuria > 0.
5 g/24 hours, the 1-year renal recurrence rate was significantly reduced by 47% (p=0.
0011).

There was no significant difference in the median time to recurrence between the belimumab group and the usual care group in the general population and the baseline proteinuria >0.
5 g/24 hours and one renal recurrence
.
This result suggests that belimumab significantly reduces the risk of renal recurrence and improves renal outcomes in patients with LN compared with placebo, regardless of baseline combined with renal impairment.

Figure 1.
Renal improvement in patients with documented renal organ system involvement at baseline* (A: SELENA-SLEDAI, C: BILAG) and renal deterioration in patients without clear BL renal organ system involvement at baseline‡ (B: SELENA-SLEDAI, D: BILAG)

Table 1 Time to first recurrence in different treatment groups in the general population and the population with baseline proteinuria > 0.
5 g/24 h

▌Toronto Lupus Cohort Data Again: Realizing mPERR can help improve the long-term renal survival rate of LN patients, and mPERR can be used in clinical research and practice to predict long-term renal prognosis in LN patients

Achieving renal remission through treatment is also one of the important goals in the clinical practice of LN patients, but the definition of renal remission in previous clinical studies is still inconsistent, and the relationship with the long-term renal prognosis of patients is not clear enough, so Canadian scholars based on the data of the Toronto Lupus Cohort Study retrospectively analyzed the renal remission status of LN patients 2 years after biopsy diagnosis, and the correlation between long-term kidney survival ^[4].
。

A total of 179 patients were included in the analysis using a modified primary efficacy renal response (mPERR), which is based on the PERR criteria used in the belimumab BLISS-LN study, defined as a 24-hour urine protein ≤ of 0.
7 g and an estimated glomerular filtration rate (eGFR) decrease of ≤20%, or ≥60, compared with pre-biopsy ml/min/1.
73㎡； Long-term renal survival is defined as the absence of end-stage renal disease (ESKD) or death
during the follow-up period.

The results showed that a total of 128 patients (71.
5%) achieved mERR 2 years after biopsy diagnosis, and compared with patients who did not achieve mPERR, achieving mPERR was significantly associated with an increased likelihood of achieving long-term renal survival (see Figure 2, P=0.
013).
In 154 patients who had not yet achieved moderate to severe CKD 2 years after the diagnosis of biopsy, this conclusion still held (P<0.
0001), so this analysis suggests that mPERR can be used in clinical research and practice to predict long-term renal prognosis
in patients with LN.

Figure 2.
Achieving mPERR is associated with a higher likelihood of long-term renal survival

How to accurately and effectively predict the efficacy and prognosis of LN?

Focus on these novel biomarkers

Accurate evaluation of treatment effects and patient prognosis through clinical characteristics and various biomarkers is a major trend in the entire medical field, and LN diagnosis and treatment is no exception
.

▌Autoantibody levels against dsDNA, C1q, chromatin and ribosomal P can be used as non-invasive biomarkers for proliferating LN in the field of autoantibodies, a study published at ACR2022 innovatively explored the specificity of autoantibodies in different LN subtypes and the impact of
autoantibodies on longitudinal changes in LN.
The results showed that autoantibody levels against dsDNA, C1q, chromatin, and ribosomal P could be used as non-invasive biomarkers for proliferative LN (Figure 3A) and correlated
with treatment response.
These autoantibody titers were also significantly higher in patients with simple proliferative (class III or IV) and mixed (class III + V or class IV + V) LN than in patients with mesangial (class I or II), membranous class II, and advanced sclerosis (class VI) LN (Figure 3B-D) ^[5].

Figure 3.
Autoantibody distribution in patients with LN

▌Neutrophil extracellular traps (NETs) effectively predicted renal prognosis in LN patients, and Elastase-DNA and HMGB1-DNA levels were linearly correlated with decreased renal function

In addition, a study from Canadian scholars proposed that neutrophil extracellular traps (NETs) involved in the LN progression process can be used as biomarkers for predicting patient prognosis ^[6], and the study indirectly measures the presence of
NETs by elastase DNA and high mobility group protein B1 (HMGB1) DNA levels associated with NETs production.

In the exploration cohort, patients with active LN (n=49) were compared with inactive patients (n=23) and healthy controls (n=20), and it was found that Elastase-DNA and HMGB1-DNA levels were significantly higher in patients with active LN, and patients with active LN had relatively higher levels of both DNA, and the levels of both DNA in patients with proliferative LN were significantly higher than those in non-proliferative patients
.

In the validation cohort of 109 patients with active LN, the levels of Elastase-DNA and HMGB1-DNA in patients with proliferative LN were also significantly higher than those in non-proliferative patients (P < 0.
05).
In terms of clinical outcomes, higher baseline levels of both DNA were associated with greater difficulty in achieving complete renal remission (defined as a 24-hour urine protein quantification < 0.
5 g, serum creatinine ≤15% change from baseline) in LN patients, and more likely to have severe renal impairment (eGFR<30 ml/min) after renal recurrence, and better predictive efficacy than traditional markers (see Table 2).
Both DNA levels were also linearly correlated with the decline in kidney function at 24 months, suggesting that Elastase-DNA and HMGB1-DNA could be used to predict renal prognosis
in patients with LN.

Table 2.
NET correlation with patient clinical outcomes and predictive efficacy compared to conventional biomarkers

▌Serum soluble mediator levels correlated with treatment response, more pronounced in patients with proliferative LN, another study focused on the value of serum soluble mediator as a biomarker of LN, including 268 biopsy-confirmed patients who met ACR or SLICI criteria and urine protein/ In patients with a creatinine ratio (UPCR) of ≥0.
5, serum levels of various chemokines, cytokines, and tumor necrosis factor receptor (TNFR) superfamily members at 3, 6, and 12 months after biopsy were analyzed, and the correlation of the above serum soluble mediators with LN type and clinical outcomes was evaluated by comparing them with healthy normal people ^[7].

The analysis showed that there was obvious heterogeneity in the serum soluble mediator level of LN patients, but most of them increased compared with healthy normal people, among which the proliferative type, especially the pure proliferative LN (type III or IV LN), had higher levels of immune mediators such as IFN-β and IL-1β in serum.
The levels of inflammatory mediators such as CD138 and TNF-RII correlated with renal disease activity or chronic index in LN patients (see Figure 4 for details), while the levels of these two inflammatory mediators decreased in patients who achieved complete remission/partial remission, suggesting that they may be involved in the development of LN and can be used
as biomarkers.

Figure 4.
Correlation of serum soluble mediators with disease activity, degree of chronicness, and response to treatment

▌Urine markers are an important direction for exploration, urine complement C9/CD59 ratio is closely related to tubulointerstitial fibrosis in LN patients, urine ALCAM can assess the severity of active LN to find biomarkers from urine is also an exploration direction, from a study by American scholars ^[8]. That is, the relationship between urinary complement C9/CD59 ratio and LN tubulointerstitial fibrosis was evaluated, in which urinary complement C9 levels suggested the participation of the complement pathway in tubulointerstitial fibrosis, while CD59 could inhibit the addition of complement C9 to the membrane attack complex (MAC), so the imbalance between the levels between the two or disease progression could be used
as a noninvasive biomarker.
A total of 46 patients with LN were included in the analysis, of which 10 had moderate/severe tubulointerstitial fibrosis and tubular atrophy (IFTA), and proteomic analysis showed that the C9/CD59 ratio in these patients was significantly higher than that in patients without IFTA/mild IFTA (mean 0.
95 vs.
0.
83, P=0.
003), and the C9/CD59 ratio was not significantly correlated with proteinuria, so the increase in urinary complement levels was not caused by renal barrier damage, and the analysis conclusions further suggested the role of
complement pathway in LN.
In addition, previous animal studies have hinted that CD6 expression on T cells and ALCAM expression on antigen-presenting cells/tubular cells (i.
e.
, CD6-ALCAM pathway) play an important role
in LN development.
In order to verify the authenticity of this conclusion in patients with LN, the researchers analyzed real patient serum and urine samples ^[11].
The results showed that urinary ALCAM assessment was a biomarker of the severity of active LN, and a decrease in urinary ALCAM levels during treatment could predict a patient's response to treatment, while CD6 did not show predictive potential
for the time being.
In the future, the investigators will further evaluate the possibility of ALCAM in combination with other disease severity assessment criteria and explore the predictive potential
of ALCAM for long-term disease outcomes.

▌The decrease of IL-6, CD163, and macrophage mannose receptors predicted the efficacy of LN patients for 1 year of treatment, and the accuracy was high

A decrease in the urine protein-to-creatinine ratio (UPCR) to <0.
5 is significantly associated with long-term renal function preservation, so UPCR<0.
5 is used as a criterion<b10> for a complete response at 1 or 2 years.
However, early in the onset of LN, there are no biomarkers that can accurately assess efficacy
.
At the ACR2022 conference, a clinical study including 127 patients with LN showed that the decrease in urine biomarkers (IL-6, CD163, macrophage mannose receptor) at three months was more predictive of the efficacy of LN at one year compared with UPCR ^[9].

Figure 5.
Urine biomarkers for predicting early efficacy

▌ LN is a pan-renal disease, and "panstromal inflammation" predicts the progression of LN patients to CKD

On the basis of ITFA and other indicators, this ACR annual meeting also proposed to use "total interstitial inflammation", that is, interstitial inflammation that includes both fibrotic/nonfibrotic areas, to predict the progression of LN patients to CKD earlier, so as to carry out necessary interventions ^[12]. , a retrospective analysis of 125 patients diagnosed with III/IV/V or mixed (III/IV, IV/V) between 2005 and 2018, biopsy samples were evaluated to grade panstromal inflammation (grade 0-3, corresponding to <10%, 10-25%, 26-50%, > 50% inflammatory infiltrates in the interstitium), and analyzed the correlation
with clinical outcomes.

The results of the analysis showed that patients with moderate to severe panstromal inflammation had a significantly increased risk of CKD progression compared with no-mild panstromal inflammation (adjusted HR=2.
76), while the NIH interstitial inflammation score was not significantly correlated with CKD progression, suggesting the predictive value
of panstromal inflammation.

Drug side effects should not be ignored,

There is still a huge unmet need in patients with LN

▌Hormone shock therapy is closely related to glucocorticoid-induced diabetes, and timely assessment and management are particularly important

Although LN diagnosis and treatment has made great progress in recent years, adverse reactions or complications related to hormones and other treatments are still a problem that clinicians often encounter and are difficult to fully control, and there are some related research reports during this ACR annual meeting, such as a nested case-control study from Mexico ^[13].
The occurrence of glucocorticoid-induced diabetes mellitus (SID) and risk factors
associated with the onset of LN were assessed.

The study included a total of 358 patients with LN with no prior history of diabetes diagnosed in a single center in Mexico City between 2012 and 2017, of whom 35 developed SID, and a control
was set up in a 1:2 ratio 。 The analysis showed that LN patients with SID had more metabolic risk factors (see Table 3), lower lymphocyte count, higher neutrophil/lymphocyte ratio (P < 0.
01), and higher SLEDAI score and SLIC damage index (P < 0.
01).
In terms of hormonal use, patients with SID were more likely to use hormonal shock therapy (P=0.
001), and the proportion of antimalarial drugs used was lower (P=0.
02).

In conclusion, from the perspective of this study, LN patients with SID have both metabolic risk factors and SLE-specific risk factors, and clinicians need to be aware of the existence of SID and evaluate and manage
it in time.

Table 3.
Comparison of characteristics of patients with SID with healthy controls

▌ GTI can be used as a valid indicator of hormone-related toxicity in patients with LN in long-term treatment

Glucocorticoid-related toxicity, especially in high doses, is also of great concern
.
The glucocorticoid toxicity index (GTI) has been quantitatively evaluated in other rheumatic diseases, but no previous studies have evaluated the use of GTI in LN, but a study from the United States that retrospectively evaluated 49 patients with LN exposed to high doses of glucocorticoids ^[14].

Patients used a mean monthly dose of glucocorticoids of 699 mg of prednisone equivalent in the first year after diagnosis, with a mean GTI of 23.
7, with the most common toxicity being neuropsychiatric toxicity and increased body mass index (BMI), 303 mg of prednisone equivalent at year 5, and a mean GTI of 60.
3, with the most common toxicity being severe infection, neuropsychiatric toxicity, and increased BMI except in the first year after diagnosis The higher the cumulative dose of glucocorticoids, the higher the GTI, which suggests that GTI can be used as a valid indicator
of hormone-related toxicity in patients with LN in long-term treatment.

Figure 7.
GTI level of patients at year 1/5 after diagnosis

▌Patients with LN face insufficient diagnosis and treatment, low proteinuria levels may still have renal histological changes, LN is a common cause of death in SLE patients, and existing clinical guidelines recommend renal biopsy at UPCR ≥ 0.
5 to confirm the diagnosis of
LN.
However, cross-sectional studies have shown that renal histologic changes may also occur in SLE patients who do not meet this criterion, which may delay treatment if UPCR≥0.
5 is adhered to
.
At the ACR 2022 Annual Academic Conference, Shudan Wang and others published an analysis report
on patients with low-grade proteinuria (0.
2≤UPCR<0.
5) SLE.
</b14>

In addition to inadequate diagnosis and treatment, patients with LN face generally poor quality of life
.
A quality of life survey study incorporating 4126 clinical records was presented at the ACR 2022 Annual Meeting ^[16].
The study showed that active LN led to negative impacts on all areas covered in the Patient's Self-reported Health Level Questionnaire (SF-36), indicating that the quality of life of patients with active LN deteriorated across the board, with fertility, physical strength, limited physical functioning, and increased negative emotions being the main affected areas
.
In addition, the study noted that LN was perceived most strongly by patients compared to other complications of SLE, and that LN patients had a lower
quality of life than other non-LN SLE patients.
This also suggests that active treatment of LN is significant
for improving patients' quality of life.

The annual ACR conference has been successfully concluded, and we look forward to the blockbuster research progress we have collated, which will bring new inspiration
to experts and scholars in the field of rheumatology and nephrology.

References:

[1] Liu Y, et al.
focal segmental glomerulosclerosis lagged behind the onset of rheumatoid arthritis by 7 years a case report and literature review[J].
2017，96(1):e5789.

[2] Furie R, et al.
N Engl J Med.
2020,383 (12):1117-1128.

[3] ACR2022.
ABSTRACT NUMBER: 0352

[4] Urowitz M, et al.
ACR 2022, Abstract 1636.

[5] ACR2022.
ABSTRACT NUMBER: 0333

[6] Whittall-Garcia L P, et al.
.
ACR 2022, Abstract 0537.

[7] Fava A, et al.
ACR 2022, Abstract 0636.

[8] Wang S, et al.
.
ACR 2022, Abstract 0650.

[9] ACR2022.
ABSTRACT NUMBER:0536

[10] ACR2022.
ABSTRACT NUMBER:1135

[11] ACR2022.
ABSTRACT NUMBER:1478

[12] Wang S, et al.
ACR 2022, Abstract 0634.

[13] Barrera-Vargas A, et al.
ACR 2022, Abstract 0353.

[14] Usiskin I, et al.
ACR 2022, Abstract 2072.

[15] ACR2022.
ABSTRACT NUMBER: 1463

[16] ACR2022.
ABSTRACT NUMBER: 1347

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