Difference and connection of clinical features and antinuclear antibody patterns in new-onset Systemic Lupus Erythematosus cross age groups

doi:10.21203/rs.3.rs-4903780/v1

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Difference and connection of clinical features and antinuclear antibody patterns in new-onset Systemic Lupus Erythematosus cross age groups

https://doi.org/10.21203/rs.3.rs-4903780/v1

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To investigate the differences in clinical features, and the relationship between antinuclear antibody (ANA) patterns, autoantibodies, and symptoms among different age groups in new-onset Systemic Lupus Erythematosus (SLE), we conducted a retrospective cohort study involving 556 patients diagnosed with SLE. These patients were classified into three groups: Group 1: juvenile-onset SLE (< 18 years); Group 2: early-onset adult SLE (18-50 years); and Group 3: late-onset SLE (≥ 50 years). We utilized a clustering heatmap to identify variations and associations of autoantibodies among the groups. The Kruskal-Wallis test was performed to compare clinical feature across the groups. The correlation heatmap were used to analyze the relationship of ANA patterns with symptoms. We found late-onset SLE patients exhibited more severe kidney damage and a higher likelihood of infection. ;Late-onset patients with a speckled ANA pattern were more prone to developing Raynaud's phenomenon. It is important for early-onset adult SLE patients with a homogeneous ANA pattern to be vigilant about the possibility of renal disorders and skin involvement. It is the first Chinese JSLE, early-onset ASLE and late-onset SLE study for ANA patterns, which enrolled a large number of newly diagnosed patients. These novel findings contribute to the diagnosis and prevention of SLE.

Health sciences/Diseases/Rheumatic diseases/Systemic lupus erythematosus

Biological sciences/Immunology

New-onset SLE

Juvenile-onset SLE

Late-onset SLE

ANA patterns

1. Patients with late-onset SLE were related to ILD, more severe kidney damage and infection.

2. Early-onset adult patients with homogeneous pattern need to be aware of renal disorder.

3. Late-onset patients with speckled pattern are more likely to develop Reynold's phenomenon.

4. Homogeneous pattern linked to anti-dsDNA antibody in late-onset SLE can assist in diagnosis.

Systemic lupus erythematosus (SLE) is an autoimmune disease, the infectious, drug, and other factors can stimulate the production of multiple autoantibodies that can cause inflammation and other damages in multiple organs^1,2. However, the mechanism of SLE is undefined.

Juvenile-onset SLE (JSLE) is a rare disease, which accounts for 10%- 20% of all SLE cases^3,4. Some studies reported that patients with JSLE had more severe condition compared to that with adult-onset SLE (ASLE)^5,6. Late-onset SLE which less clinical manifestations occurred accounts for 2–20% of all SLE cases⁷. It often have delayed diagnosis because of its concealment⁸. Previous studies showed that the mortality may be higher in patients with JSLE and late-onset SLE^4,7,9,10. Therefore, comparing autoantibodies, clinical and serological features among newly diagnosed patients of different age groups can provide insights into the correlation between age of onset and organ involvement, this information can guide drug therapy, prevent complications, and delay the progression of SLE at an early stage.

Testing autoantibody by the indirect immunofluorescence assay (IIFA) on HEp-2 cells is the common diagnostic method of SLE¹¹. Some antinuclear antibody (ANA) staining patterns are associated with specific autoantibodies. For instance, the homogenous staining pattern may be linked with anti-histone antibody¹². Using ANA patterns and autoantibody can aid diagnosis of suspected SLE¹², and detecting the correlation between ANA patterns and symptoms in initial patients can predict severe complications for timely intervention in early phase of the disease. However, there are less studies on the correlation of ANA patterns with symptoms in different age groups.

This study aims to compare autoantibodies, disease progression, laboratory data, and clinical features among various age groups, including JSLE, early-onset ASLE and late-onset SLE. Additionally, it explored the relationship of ANA patterns with autoantibodies and symptoms through a retrospective cohort study.

Comparison of autoantibodies in three groups

The distribution of autoantibodies in three groups is shown in Fig. 1. The positive frequency of anti-chromatin antibody was highest in three groups. The presence of anti-dsDNA (56.0% vs 70.5%, P = 0.016) and anti-Sm (46.8% vs 60.6%, P = 0.036) antibodies in Group 3 were significantly lower than that in Group 2. The positive rate of anti-R52 antibody in Group 1 was 25.7% compared to 54.6% in Group 2 (P = 0.004), according to the heatmap and statistical analysis (Supplemental Table S1). As shown in Fig. 1, the autoantibodies were divided into 4 clusters: cluster 1 consisted of anti-Sm and anti-SmRNP antibodies; cluster 2 was composed of anti-dsDNA and anti-chromatin antibodies; cluster 3 was formed by anti-R60, anti-R52 and anti-SSB antibodies; anti-P antibody was a separate cluster.

The difference on initial clinical features and course of disease between three groups

The comparison of initial symptoms among three groups are summarized in Table 1. Arthritis was common first sign of all patients with SLE in this study. Patients in Group 1 (54.3% vs 17.4%, P<0.001) and Group 2 (36.5% vs 17.4%, P = 0.001) were more likely to present with malar rash as first symptom than that in Group 3. The proportion of patients with initial symptoms of alopecia (18.4% vs 4.6%, P = 0.001) in Group 2 were more than that in Group 1. Interstitial lung disease (ILD) was more frequent at the time of diagnosis in Group 3 than that in Group 2 (16.5% vs 4.8%, P<0.001). The patients in Group 3 had longer course of the disease than that in Group 1 (16.70 ± 35.67 vs 4.22 ± 10.32, P = 0.031) and 2 (16.70 ± 35.67 vs 10.44 ± 31.05, P = 0.012).

Comparison of disease activity and laboratory data among three groups

Figure 2 showed the difference on disease activity and serological results between three groups. The levels of serum creatinine (SCr) and blood urea nitrogen (BUN) in Group 3 were significantly higher compared to Group 1 (P<0.001; P = 0.002, respectively) and Group 2 (P = 0.006; P = 0.039, respectively), while Group 2 had higher SCr levels than that in Group 1 (P = 0.018). The albumin (Alb) concentrations of Group 2 (P = 0.001) and 3 (P<0.001) were lower than Group 1, and Group 1 had a lower levels of globulin (Glb) compared to Group 2 (P = 0.030) and 3 (P = 0.014). The SLEDAI score of Group 2 was significantly higher than Group 3 (P = 0.004). Group 1 had a lower level of C-reactive protein (CRP) than that in Group 2 (P = 0.007) and 3 (P = 0.002). Higher levels of Immunoglobulin A (IgA) and lower levels of Immunoglobulin M (IgM) were observed in Group 3 than that in Group 1 (P<0.001; P = 0.014, respectively) and Group 2 (P<0.001; P = 0.019, respectively), while the levels of IgA of Group 2 was higher than Group 1 (P<0.001).

The relationship between ANA patterns and autoantibodies

Table 2 shows the correlation between ANA patterns and autoantibodies in different groups. The patients with anti-Sm antibody were more likely to have speckled staining pattern in Group 1 (70.6% vs 26.7%, P = 0.032) and Group 2 (53.3% vs 40.8%, P = 0.020), but had fewer homogeneous pattern in Group 1(23.5% vs 66.7%, P = 0.031). The percentage of homogeneous pattern in patients with anti-SmRNP antibody was lower than that without it in Group 1 (25.0% vs 75.0%, P = 0.010) and Group 2 (34.2% vs 44.8%, P = 0.043), while the proportion of speckled pattern in patients with anti-SmRNP antibody was higher in Group 2 (55.3% vs 36.3%, P<0.001). The patients with anti-dsDNA in Group 2 (48.5% vs 12.8%, P<0.001) and Group 3 (57.1% vs 4.8%, P<0.001) were more likely to have homogeneous pattern, but had fewer speckled pattern (39.7% vs 69.7%, P<0.001; 28.6% vs 66.7%, P<0.001, respectively). The prevalence of homogeneous pattern in patients with anti-P (42.6% vs 31.6%, P = 0.032), anti-SSB (46.2% vs 34.3%, P = 0.028) and anti-chromatin antibodies (44.9% vs 20.2%, P<0.001) was higher in Group 2. Speckled pattern was less frequent in Group 2 of patients with anti-R60 (44.8% vs 56.3%, P = 0.039) and anti-chromatin (45.3% vs 56.7%, P = 0.048) antibodies. The proportion of speckled pattern in Group 3 of patients with anti-R52 antibody was 56.8% compared to 36.2% in patients without it (P = 0.048).

Table 2

The relationship between autoantibodies and ANA pattern among three groups.
Group	Autoantibody	ANA pattern	Patients with the autoantibody (%)	Patients without the autoantibody (%)	P
< 18 years	Sm	Speckled	12/17 (70.6%)	4/15 (26.7%)	0.032
		Homogeneous	4/17 (23.5%)	4/15 (66.7%)	0.031
	SmRNP	Homogeneous	5/20 (25.0%)	9/12 (75.0%)	0.010
18–50 years	dsDNA	Speckled	104/262 (39.7%)	76/109 (69.7%)	<0.001
		Homogeneous	127/262 (48.5%)	14/109 (12.8%)	<0.001
	Sm	Speckled	122/229 (53.3%)	58/142 (40.8%)	0.020
	P	Homogeneous	92/216 (42.6%)	49/155 (31.6%)	0.032
	R60	Speckled	113/252 (44.8%)	67/119 (56.3%)	0.039
	SSB	Homogeneous	54/117 (46.2%)	87/254 (34.3%)	0.028
	chromatin	Speckled	121/267 (45.3%)	59/104 (56.7%)	0.048
		Homogeneous	120/267 (44.9%)	21/104 (20.2%)	<0.001
	SmRNP	Speckled	131/237 (55.3%)	49/134 (36.3%)	<0.001
		Homogeneous	81/237 (34.2%)	60/134 (44.8%)	0.043
≥ 50 years	dsDNA	Speckled	14/49 (28.6%)	28/42 (66.7%)	<0.001
		Homogeneous	28/49 (57.1%)	2/42 (4.8%)	<0.001
	R52	Speckled	25/44 (56.8%)	17/47 (36.2%)	0.048
P: anti-ribosomal P protein.

The correlation of ANA patterns with initial clinical features between three groups

As shown in Fig. 3, there was no correlation between ANA pattern and initial symptoms in Group 1. The speckled pattern was negatively correlated with malar rash and renal disorders, while malar rash and renal disorders were associated with the presence of a homogeneous pattern in Group 2. There was a positive correlation between the speckled pattern and Raynaud's phenomenon in Group 3.

An overall understanding on the significance of ANA patterns can assist in diagnosis and predict organs involvement. There are less studies on association of ANA patterns with autoantibodies and symptoms among patients of different age groups, especially in the newly diagnosed patients, which can hardly influenced by treatment, and the results can better reflect the difference and association. In addition, the relationship between age of onset and symptoms is controversial. In this study, we detect the relationship of age of onset and ANA patterns with autoantibodies and clinical features in initial patients to do early diagnosis and targeted treatment timely to postpone the development of SLE and avoid the organ injury as soon as possible.

Anti-dsDNA and anti-Sm antibodies are included in ACR criteria for SLE because of their high specificity. In this study, we found lower presence of them in patients with late-onset SLE compared to those with early-onset ASLE, which conformed to previous studies by Riveros Frutos A et al⁷ and Boddaert J et al¹³. It may explain delayed diagnosis of late-onset patients. But the results of some early researches were inconsistent or contradictory to our findings ^{14, 9}. Meanwhile, anti-R52 antibody was more prevalent in patients with early-onset ASLE than those with JSLE, which was also observed in other study⁴. The relationship of autoantibodies with age is controversial, which could be explained by different grouping methods, course of disease and ethnicity. The correlation among autoantibodies was detected by cluster analysis, and the autoantibodies were classified into 4 clusters, which were essentially comparable with earlier findings¹⁵.

Incidence of malar rash in patients with early-onset SLE compared to late-onset SLE, consistent with previous studies^7,9,10. Malar rash, as an initial presentation, was rarer with increasing age according to our results, and it was regarded as an important reason for missed-diagnosis of late-onset SLE¹⁰. Patients with early-onset ASLE were more likely to present alopecia than patients with late-onset SLE, as earlier researches reported^8,14. It may be attribute to the rarity of skin rash in patients with late-onset SLE¹⁶. In addition, patients with late-onset SLE were more likely to develop ILD. It was consistent with previous studies that have reported more pulmonary manifestation in patients with late-onset SLE⁸. ILD was usually seen in patients with a long history of SLE¹⁷. Late-onset SLE is often delayed diagnosis⁸, which was also found in this study. Therefore, it may be the possible explanation of higher incidence of ILD in patients with late-onset SLE.

In our study, we found that patients with early-onset ASLE had inferior renal function, and patients with late-onset SLE had the worst renal function at the time of initial diagnosis, which may be attributed to the effects of SLE or degenerative changes. It could explain the higher levels of Alb observed in patients with JSLE in our study. However, a study by Abdel-Nabi HH et al. did not show significant differences in SCr and BUN levels between patients with JSLE and ASLE¹⁸. This discrepancy could be due to variations in ethnicity and study design. Although reports suggest a lower incidence of severe symptoms in patients with late-onset SLE⁸, it's important to remain cautious about the potential for more serious kidney damage. Our findings also revealed that disease activity was lower in patients with late-onset SLE compared to those with early-onset ASLE, which is consistent with previous research⁷. According to our results, C-Reactive Protein (CRP) levels were lower in patients with JSLE than in other age groups. Previous study showed that the level of CRP did not remarkably increased related to SLE². Therefore, it need to consider the possibility of infection. Further follow-up is needed to explore the relationship between late-onset SLE and infection which is the principal reason of hospitalization and death¹⁹. Regarding antibodies, patients with JSLE exhibited increased levels of IgM, while patients with late-onset SLE showed an increase in IgA. We did not observe any differences in blood cell counts, Erythrocyte Sedimentation Rate (ESR), complement levels, and liver enzymes among the three age groups.

ANA staining patterns are correlated to the nuclear antigens targeted. Previous study reported that homogeneous pattern was associated with anti-dsDNA antibody, and speckled pattern was related to anti-Sm/RNP antibody^12,20, which were conformed in patients with ASLE and early-onset SLE respectively according to our results. Anti-R52 antibody was associated to higher prevalence of speckled pattern, which was consistent with early studies^12,20, but the result of anti-R60 antibody in patients with early-onset ASLE was opposite. In an investigation from Sweden, anti-SSA antibody was related to homogeneous/speckled pattern (a mixed type) in patients with SLE²¹. It may explained the difference. Homogeneous pattern was associated to anti-P, anti-chromatin and anti- SSB antibody in patients with early-onset ASLE in this study, which were essentially comparable with previous investigation^{21, 22,23}. Moreover, we had some noteworthy findings: the prevalence of homogeneous pattern was positive correlated with malar rash and renal involvement in patients with early-onset ASLE (speckled pattern was opposite). Anti-dsDNA antibody which was common among early-onset ASLE in this study was associated to homogeneous pattern and less often associated to speckled pattern. Kidney and skin involvement were intimately linked to anti-dsDNA antibody²⁴. These may be the possible explanation. Speckled pattern was positive correlated with Raynaud's phenomenon in patients with late-onset SLE, which may be explained by the relationship between anti-Sm/RNP antibody and Raynaud's phenomenon^25,26. These new findings need more confirmation by others, and we will collect more data and follow up.

It is the first Chinese JSLE, early-onset ASLE and late-onset SLE retrospective cohort study for ANA patterns, which enrolled a large number of newly diagnosed patients without treatment. All the data we collected were at early stage of the disease, so our research can assist in diagnosis and predict organ involvement in patients of different ages by detecting the relationship of ANA patterns with autoantibodies, initial symptoms and complications which had less studies on, to control disease progression at very early stages. Nevertheless, sample with JSLE were few, so we did not find the association of ANA patterns with symptoms. In addition, we only detect homogeneous and speckled patterns in this study because of less presence of other staining patterns in patients. We will collect more cases to perfect our research in the future.

In conclusion, we suggested that patients with late-onset SLE need to consider serious renal damage, ILD and infection. The physicians need to pay attention to ANA pattern for the correlation of homogeneous pattern with anti-dsDNA antibody in elderly patients, because of delayed diagnosis of them. Late-onset patients with speckled pattern are more likely to develop Raynaud's phenomenon, if patients have chest distress and oppressed, pulmonary arterial hypertension (PAH) should be noted²⁷. Patients with early-onset ASLE are likely to have high disease activity, and they with homogeneous pattern need to be aware of renal disorder.

Subjects

The essential information, the course of disease and the clinical data were collected from 556 hospitalized patients with new-onset SLE between 2012 and 2022 at the First Affiliated Hospital of Bengbu Medical College after giving informed consent, 90.3% was female. All cases met the updated 1997 American College of Rheumatology (ACR) classification criteria for SLE²⁸, which are used to diagnose symptoms and complications. Disease activity was assessed using the SLE Disease Activity Index 2000 (SLEDAI-2000) criteria. There were 34 patients (6.1%) developed JSLE with age of diagnosis < 18 years (Group 1: < 18 years)⁴, 108 patients (19.4%) had late-onset SLE with age of diagnosis ≥ 50 years (Group 3: ≥ 50 years)⁷, and the other 414 patients (74.5%) were assigned to the early-onset adult group (Group 2: 18-50 years).

Ethical approvals and informed consent were obtained and provided from all participants. The study had received ethical approval by the Ethics Committee of the First Affiliated Hospital of Bengbu Medical College [No.2022 (149)]. All experiments were performed in accordance with relevant guidelines and regulations.

Laboratory tests

The autoantibodies were tested by using line immunoassay. ANA titers were detected by immunofluorescence assay. ANA-staining patterns were visualized under fluorescence microscopy.

Statistical analysis

Cluster analysis with Ward’s method was used to detect the relationship between autoantibodies, and plotting the clustering heatmap by Origin 2021 software. Using SPSS 27.0 software to perform statistical analysis. The Kruskal-Wallis test was used to compare the autoantibodies, clinical manifestations, laboratory measurements, disease activity and course of disease among three groups. The correlation between ANA pattern and autoantibodies among three groups was determined by the Chi-square test. Spearman correlation analysis of ANA pattern and clinical features were performed by using Correlation Heatmap tool in Hiplot Pro (https://hiplot.com.cn/), a comprehensive web service for biomedical data analysis and visualization. A value of P < 0.05 was considered significant for the above-mentioned tests.

Competing interests:

The authors declare that they have no competing interests.

Ethic statement

Funding:

This study was supported by the Natural Science Foundation of Anhui Provincial (2108085MH258)

Author Contribution

CX, MG designed the work. ZL, TW, CX, XW, MY, CS performed patient clinical assessment. DH, NL, MG collected the data of patients. MG analyzed the data. CX, MG wrote the manuscript. CX reviewed the manuscript. All authors read and approved the final version of the manuscript.

Acknowledgement

We thank Xiaoyue Xu for her excellent statistical advice.

Data Availability

The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

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Difference and connection of clinical features and antinuclear antibody patterns in new-onset Systemic Lupus Erythematosus cross age groups

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Version 1

Abstract

Figures

Highlights

Introduction

Results

Comparison of autoantibodies in three groups

The difference on initial clinical features and course of disease between three groups

Comparison of disease activity and laboratory data among three groups

The relationship between ANA patterns and autoantibodies

The correlation of ANA patterns with initial clinical features between three groups

Discussion

Methods

Declarations

Competing interests:

Ethic statement

Funding:

Author Contribution

Acknowledgement

Data Availability

References

Table

Additional Declarations

Supplementary Files

Status:

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