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ACR Congress Day2, large sample size and high-quality cohort studies continue to be released!
From November 10 to 14, Eastern Time, the annual 2022 American College of Rheumatology Annual Meeting (ACR 2022) was grandly held
.
As the world's largest and most prestigious rheumatology conference, ACR Annual Meeting has not only been committed to improving the care of rheumatology patients and promoting the development of rheumatology specialties, but also providing an important platform
for medical professionals to obtain cutting-edge rheumatology research and clinical application information.
As a representative of common chronic systemic rheumatic immune diseases, systemic lupus erythematosus (SLE) is a high-prevalent, chronic, systemic autoimmune disease in young women, with variable clinical manifestations, easy to cause multiple system and important organ damage, and seriously threaten the health of China[1].
At this ACR Annual Meeting, disease management, biomarkers, conventional therapy and innovative drug treatment of SLE have been the focus
of participating experts.
I believe that you before the article, you must be eager to know these wonderful contents
.
Don't worry, set off with us to this academic feast
.
Strong attack: biological agents effectively improve multi-system symptoms in SLE patients, and the recurrence rate of long-term use is significantly reduced
SLE often involves the skin, kidneys, blood system and other organ systems, of which the skin and mucous membranes are affected in SLE up to 80% [2,3], facial butterfly erythema is a unique skin symptom of SLE and easy to identify, but due to the complex clinical manifestations of SLE, various atypical skin lesions are more likely to be overlooked
.
However, damage to the skin and mucous membranes often leads to a serious decline
in the quality of life of patients.
Therefore, how to correctly understand and improve the symptoms of skin lesions is the key
to early diagnosis and treatment of SLE patients.
At this ACR Annual Meeting, a large post-hoc analysis was presented to further analyze the efficacy of belimumab (BEL) in improving mucosal organ systems in SLE patients based on large comprehensive data [4].
This post-hoc pooled analysis included data
from five phase III, randomized, placebo-controlled BEL trials (BLISS-76, BLISS-52, BLISS-NEA, BLISS-SC, and EMBRACE) in adults with SLE.
In addition to usual care, patients are randomized to receive either BEL (intravenous 10 mg/kg per month or subcutaneous 200 mg per week) or PBO
.
The study included more than 3000 patients, most of whom had mucocutaneous manifestations [SELENA-SLEDAI, 85.
0%; BILAG (category A or B, moderate or heavy activity): 59.
6%].
The results of the study showed that at week 52, patients treated with BEL had significant improvements
in SELENA-SLEDAI* and BILAG** scores for mucocutaneous membranes and vasculitis compared with usual care 。 For the SELENA-SLEDAI score, the response rate of vasculitis in the BEL group was as high as 66.
7%, which was significantly higher than that of 25.
4% in the PBO group (P<0.
0001), while for the BILAG score, the response rate in the BEL group in terms of cutaneous vasculitis was as high as 75.
4%, which was significantly higher than that of 34.
1% (P=0.
0039) in the PBO group (Figure 1).
<b21>
This large pooled analysis strongly confirms the significant effect
of belimumab in combination with usual care in patients with SLE in terms of mucocutaneous system and vasculitis.
Fig.
1 Proportion of patients with SLE at week 52 with improved outcomes of SELENA-SLEDAI, BILAG and vasculitis*SELENA-SLEDAI* (vasculitis, rash, alopecia and mucosal ulcers)**BILAG** (mild maculopapular rash, locally active discoid lesions, mild alopecia, small mucosal ulcers, zygomatical erythema, Subcutaneous nodules, swelling of the fingers, severe cutaneous vasculitis, and mild cutaneous vasculitis)
In addition, a high recurrence rate is one of the most important features of SLE, which can further lead to increased organ damage and poor
prognosis.
The 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus [5] pointed out that SLE treatment should control disease activity, prevent and reduce disease recurrence, and maximize disease prognosis
.
At this ACR Annual Meeting, a cohort study from the United States demonstrated that patients treated with BEL had a significantly lower risk of disease recurrence (P=0.
004), with a 28% reduction in severe relapse compared with usual care over a follow-up period of up to 24 months (P=0.
036) [6] (Figure 2).
Fig.
2 Recurrence rate of SLE within 24 months
Down to earth: Facing the unmet clinical needs of SLE patients
Of course, in addition to discussing the innovative drugs of SLE, the participating experts also turned their attention to the unmet needs of SLE patients in conventional treatment and comorbidity management, in order to bring us the latest diagnosis and treatment directions and research frontiers
of SLE in a more comprehensive way.
From the perspective of meeting the "unmet needs" of SLE patients, this ACR conference mentioned that a retrospective observational study based on data from a large SLE cohort study in Canada showed that for the 1255 patients with SLE, the current treatment of traditional treatment options, including glucocorticoids, is still limited and has clear long-term side effects
.
The incidence of organ damage (SDI >0) is higher in patients with higher
mean dose and longer glucocorticoid dose and longer duration.
In multiple organ systems, as the average daily dose of glucocorticoids increases, so does the proportion of patients who experience impairment
.
In particular, patients with moderate to severe SLE are prone to irreversible organ damage such as musculoskeletal system, nervous system, and cardiovascular system after receiving high-dose glucocorticoid therapy (Figure 3).
Currently, in Canada, the use of these biologics is low
due to the lack of effective access to belimumab in patients.
These findings underscore that the current need for clinical treatment of SLE is far from being met, and that access to alternative treatment regimens such as glucocortical shock is critical for SLE patients [7]
.
Fig.
3 Organ damage rate during follow-up of patients with moderate to severe SLE In the conventional treatment of SLE, hydroxychloroquine (HCQ) is a commonly used drug in rheumatology and immunology and occupies an important position in the treatment of
SLE.
However, it should not be ignored that HCQ is also cardiotoxic, and long-term use may lead to cardiomyopathy
associated with arrhythmias and heart failure.
A study published in this edition of ACR evaluated the drug's effects
on cardiac conduction in people with SLE.
Results suggest significant changes in cardiac conduction in SLE patients treated with HCQ, but the link between the two requires extensive longitudinal studies [8] (Figure 4).
Fig.
4 Cardiac conduction changes develop with the increase of the cumulative dose
of hydroxychloroquine, and "comorbid management" has also been a hot topic
in the clinical treatment of SLE in recent years.
It has been found that patients with SLE often have multiple chronic diseases, which affect the quality of life and prognosis [9].
Studies have shown that patients with SLE in the UK have a greater burden of comorbidities than the general population [10], for example, SLE combined with cardiovascular disease mortality is about 50% [11].
At this ACR conference, experts also discussed
the comorbid burden of SLE 。 A related study showed that from January 2006 to September 2015, patients with SLE were found to have a fourfold higher risk of comorbidities than the general population by using SLE cohort analysis in the OptumLabs database (OLDW), and disease progression analysis also showed that many comorbidities may have existed before SLE and progressed more rapidly than SLE itself [12].
Standardized treatment: The 1600+ Hopkins lupus cohort once again confirmed the importance of "long and short standards"
In recent years, the concept of "long and short standards" has also been mentioned many times in the diagnosis and treatment of SLE, which refers to the short-term realization of disease activity control at low hormone doses (≤7.
5mg/d), long-term realization of the treatment goal of delaying the progression of organ damage and reducing mortality [5].
The benefits of achieving complete disease as early as possible on long-term organ protection and prognosis in SLE patients are undoubted, but in practice, the proportion of patients who can achieve complete remission under current conventional care is still low
.
At the ACR conference, a study from the Hopkins SLE cohort explored the relationship
between low lupus disease activity status (LLDAS) and duration of disease control and long-term organ damage (OD).
Studies included patients
enrolled in the Hopkins Lupus cohort for ≥ one year and were ≥ 18 years of age at enrollment.
At each monthly follow-up, patients were classified as LLDAS or disease control
based on systemic lupus erythematosus disease activity [measured using SLEDAI or physician global assessment (PGA)] and medication use.
LLDAS is defined as SLEDAI≤4, PGA≤1, prednisone equivalent dose ≤7.
5 mg/day, without major organ involvement or increased activity score; The use of immunosuppressants and biologics
is permitted.
Disease control is defined as SLEDAI≤2, prednisone equivalent dose ≤ 5 mg / day, biologic agents are allowed but not immunosuppressants
.
OD is defined using the SLICC/ACR Impairment Index (SDI).
The comprehensive logistic model was used to estimate the duration of disease control or LLDAS (0%; >0%-<25%； 25％- 49%； 50％-74%； Adjusted rates and 95% confidence intervals between ≥75%) and OD rates during follow-up
.
5 years, 91.
9% female) experienced 1246 OD events
at 9841.
1 person-years of follow-up.
Overall, 1079 (66.
1%) patients achieved disease control at 42.
4% of follow-up (49,948 months) and 1348 (82.
6%) patients achieved LLDAS
during 55.
0% of follow-up time (64,866 months).
The longer the follow-up period in disease control or LLDAS status, the lower the rate of new OD [13] (Figure 5).
Fig.
5 Incidence and adjustment rate ratio of new organ injury in patients who achieved SLE disease control (A) and low lupus disease activity (B).
New biomarkers: New biomarkers are expected to be used in the accurate diagnosis and prognosis of NPSLE
Neuropsychiatric lupus (NPSLE) is a group of serious complications of neurological and/or psychiatric symptoms resulting from SLE lesions involving the nervous system, and cognitive impairment (CL) is one of its common clinical manifestations and can have a significant negative impact
on daily functioning and quality of life.
Therefore, early identification of high risk of developing CI is essential
to prevent injury and disability in patients.
However, because its pathogenesis is largely unknown, biomarkers to identify CI risk are currently lacking
clinically.
At this ACR conference, a study was announced that 291 people aged 18~65 who met the 2019 EULAR/ACR SLE classification criteria were included and were cognitively assessed by psychoassessors; Serum levels of nine cytokines (IL-10, IL-6, IFN-g, TNF-ɑ, TWEAK, MMP-9, S100 A8/A9, NGAL, and S100B) were determined using the ELISA kit (R&D Systems); The Mann-Whitney U test was used to compare the difference
in serum cytokine profiles between CI patients and non-CI patients.
(defined as a z-score of ≤-1.
5 for two or more domains in ACR-NB); Spearman rank correlation coefficient and logistic regression were used to analyze the correlation
between different cytokine levels and CI test scores.
The findings suggest that CI is present in 40% of patients
.
Although no differences in demographic characteristics and disease activity were observed between CI and non-CI patients, serum S100A8/A9 levels and MMP-9 levels were significantly higher in CI patients than in the control group (Figure 6).
When the regions of ACR-NB were examined separately, patients with impaired simple attention and processing ability also had significantly higher levels of S100A8/A9 in visuospatial construction, learning and memory, or executive function than those without impairment (Figure 7).
S100A8/A9 and MMP-9 were moderately correlated with each other (Rho=0.
52, P<0.
0001) and both were associated with NGAL (Rho=0.
64, p<0.
0001; Rho=0.
56, P<0.
0001).
This experiment showed us that of the multiple cytokines detected, only heterodimer and MMP-9 of calcium-binding proteins S100A8 and S100A9 were elevated in SLE and CI patients, and the lack of correlation with other pro-inflammatory marker levels and differential association with different cognitive regions may indicate that S100A8/A9 mediates a regional neuroinflammatory response rather than a systemic pro-inflammatory response
in the setting of CI 。 These results open up new avenues for studying the role of S100A8/A9 and MMP-9 in CI in adult SLE patients [14].
Figure 6 Serum S100A8/A9 levels and MMP-9 levels are significantly elevated in patients with CI
Fig.
7 Serum S100A8/A9 levels based on the cognitive region of ACR-NB
References:
[1] Ocampo-PiraquiveV, Nieto Aristizábal I, et al.
Mortality in systemic lupus erythematosus：causes, predictors and interventions
[J].
Expert review of clinical immunology, 2018, 14 (12)：1043-1053.
[2] Uva L, Miguel D, Pinheiro C, et al.
Cutaneous manifestations of systemic lupus erythematosus[J].
Autoimmune diseases, 2012, 2012.
[3] Diplomatico M, Marzuillo P, La Manna A, et al.
From skin to kidneys: cutaneous clues of renal disease in children[J].
Dermatology Practical & Conceptual, 2020, 10(4).
[4] Belimumab Effects on Skin in Patients with Systemic Lupus Erythematosus: A Pooled Post Hoc Analysis of Five Phase 3, Randomized, Placebo-Controlled Clinical Trials
2020 Chinese guidelines for the diagnosis and treatment of systemic lupus erythematosus[J].
Chinese Journal of Internal Medicine,2020(03):172-173-174-175-176-177-178-179-180-181-182-183-184-185 [6]RealWorld Effectiveness of Belimumab in Patients with SLE in the United States
[7] Unfavorable Outcomes Associated with Current Standard of Care in the Management of Patients with Systemic Lupus Erythematosus
[8] Association Between Cumulated Hydroxychloroquine in Systemic Lupus Erythematosus and Development of Cardiac Conduction Alterations: A Multiple Logistic Regression Analysis
[9] World Health Organization.
The World Health Report2008.
Primary Health Cared Now more than ever[M].
New York:The World Health Report, 2008:148
[10] REES F, DOHERTY M, GRAINGE M.
Burden ofComorbidity in Systemic Lupus Erythematosusin the UK, 1999-2012 [J].
Arthritis care research (Hoboken) , 2016, 68 (6) : 819-827
[11] THOMAS G,MANCINI J,JOURDE CHICHEN, et al.
Mortality associated with systemic lupuserythematosus in France assessed by multiple-causeof death analysis [J].
Arthritis rheumatology, 2014, 66 (9) : 2503-2514.
[12] Association Between Cumulated Hydroxychloroquine in Systemic Lupus Erythematosus and Development of Cardiac Conduction Alterations: A Multiple Logistic Regression Analysis
[13] Achieving Systemic Lupus Erythematosus Disease Control or Low Lupus Disease Activity State Is Associated with Lower Rates of Organ Damage: Results from the Hopkins Lupus Cohort
[14] SMART-SLE: Serology Monitoring and Repeat Testing in Systemic Lupus Erythematosus
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