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Focus on the cutting-edge progress in the field of lupus, ACR2022 first day conference wonderful research report!

 Last Update: 2023-01-06
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The latest data on biologics, CAR-T therapy, molecular profiling.
.
.

The annual American College of Rheumatology (ACR) Annual Meeting is a widely acclaimed and internationally recognized authoritative academic conference
in the field of rheumatology.
Today, the 2022 ACR Annual Meeting is hotly opened, and wonderful academic reports are emerging one after another
.
Focusing on the field of lupus, we will bring you a full of dry goods information reports, don't miss it!

Biologics play a role, and disease control + organ protection go hand in hand

With the continuous improvement of clinical diagnosis and treatment, systemic lupus erythematosus (SLE) has changed from an acute, highly fatal disease to a chronic and controllable disease
.
Nevertheless, the limitations of traditional therapeutic agents (such as glucocorticoids and traditional immunosuppressants) often lead to poor disease control, recurrent and even progression, and there is still a huge unmet need
in the clinic.
Therefore, the prevention, control and treatment of SLE has always been an important research topic
for experts and scholars in the field of rheumatism.

Among the various schedules and research topics announced at this ACR Annual Meeting, there are many explorations and studies on the treatment of SLE
.
As the world's first and currently the only biologic approved for SLE and lupus nephritis (LN) in China, belimumab has attracted countless experts and scholars to devote themselves to related research, creating surprises
for us.

In a retrospective study of 442 patients [1], belilumab combination therapy for 12 months significantly reduced SLEDAS disease activity scores in SLE patients compared with usual care (SoC) (Figure 1), and more patients achieved treatment goals of low disease activity (LDA) or remission (Figure 2), suggesting that belimumab helps patients with SLE achieve LDA (HR).
6.
893, 95% CI 2.
351-26.
35, P<0.
001) or mitigation (HR 8.
195, 95% CI 2.
276-52.
34, P=0.
001).
<b21>
Figure 1: Change in SLEDAS scores in the SoC and SoC+BEL groups (BEL: belimumab) Figure
2: Proportion of patients in the SoC and SoC+BEL groups achieving LDA and remission (based on SLEDAS scores).

The SLEDAS score used in the study is a new measure of disease activity in SLE, which is more sensitive and specific than previous assessments, incorporating and weighting multiple factors (including assessment parameters such as joint pain count, proteinuria, and leukocyte and platelet levels).
It can reflect the activity status of the disease more scientifically and comprehensively ^[²^]
。

In addition, belimumab can help patients with SLE to further reduce hormone use in addition to low hormone doses while controlling disease activity
.
The daily dose of prednisolone at baseline in the SoC + belimumab group was 7.
0 mg/day, and after 12 months of treatment, the hormonal dose was reduced to 5.
0 mg/day (P<</b21>0.
001) ^[1].

Achieving LDA or remission in SLE patients is associated with
lower rates of organ damage.
The effect of belimumab treatment on kidney protection and delay renal function damage in LN patients has been confirmed in large clinical studies BLISS-LN [3], so what about its effect on other organ damage? Results from a systematic review and meta-analysis showed that in patients with cutaneous lupus erythematosus (CLE) with or without SLE, clinical response rates were significantly improved by 44% with 52 weeks of treatment with belimumab compared with no user (odds ratio OR 1.
44, 95% CI 1.
20-1.
74, P<</b22>0.
001, ^I20%, Figure 3).

。 A significant clinical response* in patients with CLE was observed for the first time approximately 20 weeks after initiation of belimumab, which lasted until a peak 1 year later (Figure 4).

In addition, the risk of severe relapse was significantly reduced by 49% in patients treated with belimumab compared with those who did not receive belilumab (OR 0.
51, 95% CI 0.
31-0.
84, P< 0.
001,</b11> This study supports the efficacy of belimumab in the treatment of skin lesions in patients with CLE, and further demonstrates its protective effect on damage to organs other than kidneys.
Figure 3: Clinical response of CLE patients in clinical response to CD27B cells), immunoglobulin (IgM), and autoantibodies (e.
g.
, anti-ds-DNA antibodies, anti-Sm antibodies, anti-RNP antibodies) decreased more significantly (P<0.
0001), while complement levels increased significantly <b126>(Table 1) – noteworthy The improvement of belimumab on these biomarkers was seen at week 8 and continued up to 52 weeks, demonstrating rapid onset of action and long-lasting efficacy.

CAR-T cell therapy "crossover" lupus has begun to appear

In the field of tumor treatment, chimeric antigen receptor T cell immunotherapy (CAR-T) can be described as famous and popular
.
CAR-T therapy is one of the most promising cellular immunotherapies in recent years, and has achieved breakthrough results
in the treatment of refractory B-cell and plasma cell malignancies.
So, for autoimmune diseases that are also associated with B cell abnormalities, can CAR-T therapy also relieve the difficulties of patients with refractory SLE?
At this annual meeting, researchers reported the results of the use of CAR-T to treat refractory SLE [6].

A total of 5 patients with severe SLE who failed conventional treatment and were active (all with active renal disease, histologically confirmed glomerulonephritis, and proteinuria >1 g/24 hours)
were included.
Follow-up observations showed that B cells were completely cleared from the peripheral blood from day 2 after administration of CD19-targeting CAR-T cells, and all patients achieved sustained drug-free remission, meeting SLE criteria for low disease activity (LLDAS) and DOMIS remission
.

Seroconversion of anti-ds-DNA antibodies occurred, and two patients with prolonged follow-up turned negative for antinuclear antibodies (ANA
).
All patients were discontinued with immunosuppressive drugs
, including glucocorticoids.
After 126±48 (mean ± standard deviation) days, B cells recovered without autoantibody recurrence or signs of
disease recurrence.
Preliminary analysis of the B-cell receptor repertoire at baseline and follow-up of the patient suggests a restart of the B-cell system
.
This study shows that CAR-T therapy is well tolerated during SLE treatment and helps patients with severely refractory SLE achieve long-term remission
.

Sequencing technology and molecular portrait lead SLE treatment to a new era of individualization

With the development of modern molecular genetic technology, bioinformation technology, chip technology and other high-tech, the clinical treatment of complex diseases has gradually moved from the original conventional treatment to individualized treatment
.
SLE is a highly heterogeneous disease and clinical care should be individualized
.
At this conference, many researchers discussed this topic, discussed SLE disease classification from genetic, molecular, cellular and other levels, and explored potential therapeutic targets, in order to promote more accurate drug guidance and drug development
.

The use of next-generation sequencing (NGS) technology to identify the molecular characteristics of patient disease subpopulations is a promising research direction
in the field of SLE.
At the meeting, researchers reported that gene set variation analysis (GSVA) using informative gene modules combined with machine learning technology to identify the intramolecular type of SLE patients based on specific biological pathway dysregulation was discussed, and its application effect in clinical practice was discussed [7].

The results showed that the gene expression profiles of SLE patients in the constituent year could be divided into 6 different endotyping through 32 molecular markers related to immune cells and inflammatory processes, and the relevant patient metadata characteristics showed significant differences between internal typing of different disease activities - the subsets with the least abnormal gene expression profiles generally showed lower SLEDAI scores, ANA titer, Higher serum complement levels and lower incidence of lymphopenia; Subpopulations with more abnormal transcription profiles clearly exhibited more abnormal clinical features
.

In addition, patients with different endotyping also had significant differences in the use and response to glucocorticoids and immunosuppressants, and the frequency of disease recurrence was significantly reduced
in patients with fewer endotyping with fewer abnormal transcription profiles.
This study fully demonstrates the importance and necessity of SLE individualized diagnosis and treatment in clinical practice, and shows the great application potential
of disease molecular typing.

Figure 5: Differences
in clinical features of different SLE classifications are unique, and another study also reported
on the exploration of SLE molecular typing.
The researchers introduced MyPROSLE(https://myprosle.
genyo.
es/), a workflow based on omics analysis, to measure and generate molecular portraits of individual patients [8].

The MyPROSLE aggregated 206 gene modules of SLE patients and clustered them into 9 major SLE features, the combination of which revealed the pathological mechanism
of highly differentiated SLE.
Studies have shown that dysregulation of some of these gene modules is strongly associated with specific clinical manifestations, disease recurrence, drug response, and the likelihood of long-term remission
.
As a result, MyPROSLE can be used to accurately predict clinical outcomes and support clinicians in making more accurate treatment decisions
by extracting critical molecular information.

Figure 6: Example of MyPROSLE on the web, in addition, scholars have used immunochip technology to explore single nucleotide polymorphisms (SNPs) associated with SLE
in different ethnic populations.

A study comparing differences in pathogenesis in patients with SLE of East Asian and European ancestry [9] found that biological pathway abnormalities significantly associated with SLE in East Asian patients included elevated levels of oxidative stress, metabolic alterations, and mitochondrial dysfunction, while in European patients, the main biological pathway abnormalities were enhanced
interferon signaling (type I and II) associated with cytoplasmic nucleic acid sensing.

At the same time, the gene expression data of East Asian patients and the molecular pathways and dominant cell types predicted by SNP association also corroborated
each other.
These findings suggest that the pathogenesis in East Asian patients and SLE patients in Europe is similar, but also fundamentally different—pathogenic pathways that play a key role may differ in different patient populations (Figure 7).

Predicting key pathogenic molecular pathways from risk analysis may help us clarify disease differences between ethnic populations and guide future targeted therapies
.

Figure 7: Summarizing the different key molecular pathways, dominant cell types, and potential treatment
options in East Asian and European SLE patient populations, these findings confirm the molecular heterogeneity of SLE and highlight the great application prospects
of personalized medicine.
The exploration and application of new tools and methods will provide a convenient, fast and effective way
to realize the individualized treatment of SLE.

Real-time hot spots: Under the epidemic, don't ignore SLE

The patient's risk of infection with medication

Autoimmune disorders + use of immunosuppressants may result in an increased risk of COVID-19 infection in people with SLE, resulting in serious outcomes
.

Adults with SLE treated with belimumab or four other immunosuppressants (azathioprine, methotrexate, mycophenolic acid, rituximab) compared the risk of COVID-19 in adults treated with belimumab or four other immunosuppressants (azathioprine, methotrexate, mycophenolic acid, rituximab) by analyzing information from the U.
S.
Multicenter Electronic Health Record Database (TriNetX) [10].

Compared with the other four immunosuppressants, the risk of COVID-19 infection was lower with 1 year of treatment with belimumab, with a combined risk ratio (95% CI: 0.
42 to 0.
98) of 0.
64 (95% CI: 0.
42 to 0.
98) and 2 years of treatment, with a combined risk ratio of 0.
83 (95% CI: 0.
59 to 1.
16).

The investigators believe that the results of this study show that the risk of COVID-19 in SLE patients treated with belimumab is similar or lower than that of other immunosuppressants, further demonstrating the good safety profile
of belimumab.
This study provides important reference information
for the choice of treatment for SLE patients in the current epidemic.

Figure 8: Risk ratio of COVID-19 associated with 1 year of treatment with belimumab with other immunosuppressants in patients with SLE

Conclusion

Did today's ACR Conference Express make you feel overwhelmed? In the coming days, we will continue to follow up on this conference to provide you with more and more cutting-edge academic knowledge
.
We'll see you tomorrow!

References:

[1] Yasuhiro Hasegawa,et al.
ACR Convergence 2022.
Abstract Number:0351.

[2] Jesus D, et al.
Ann Rheum Dis.
2021, 80:1568-1574.

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

[4] Rachel Kneeland,et al.
ACR Convergence 2022.
Abstract Number:0348.

[5] Jason S Knight,et al.
ACR Convergence 2022.
Abstract Number:0977.

[6] Georg Schett,et al.
ACR Convergence 2022.
Abstract Number:1651.

[7] Erika Hubbard,et al.
ACR Convergence 2022.
Abstract Number:0633.

[8] Daniel Toro-Domínguez,et al.
ACR Convergence 2022.
Abstract Number:0329.

[9] Katherine Owen,et al.
ACR Convergence 2022.
Abstract Number:1139.

[10] April Jorge,et al.
ACR Convergence 2022.
Abstract Number:0367.

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