Clinical Characteristics Of Different Types Of Lupus Erythematosus In China Based On A Real-world Study

Background:Lupus erythematosus(LE)is a highly heterogeneous spectrum of diseases,ranging from systemic lupus erythematosus(SLE),which affects multiple organs,to cutaneous lupus erythematosus(CLE),which only involves LE-specific skin manifestations without visceral involvement.Current real-world studies(RWS)of LE have many limitations,including the lack of a comprehensive evaluation of LE-related skin manifestations,a limited number of studies focusing on CLE,and the absence of studies that simultaneously include patients with SLE and patients with CLE.A detailed and comparative analysis of the clinical characteristics of different types of LE in China can promote precision medicine and enable better hierarchical management of patients with LE.Objective:To compare the clinical characteristics of LE patients with different LE-specific skin manifestations,different genders and different age of onset,respectively,and to explore the occurrence pattern and clinical significance of autoantibodies in LE patients based on multicenter realworld data that simultaneously included patients with SLE and patients with CLE.Methods:This is a multicenter cross-sectional study based on the Lupus Erythematosus Multicenter Case-control Study in Chinese populations(LEMCSC)(registration number: Chi CTR2100048939).LEMCSC is the first RWS with a relatively large sample size to simultaneously include patients with SLE and CLE.From December 2013 to December 2015,the LEMCSC recruited patients with LE from 29hospitals(30 centers)in 15 provinces in China.The data analysis was performed using the R software(version 4.1.2),and the two-step cluster analysis was performed using SPSS(version 26.0).Results:1.Comparison of clinical characteristics of LE-specific skin manifestations among patients with different types of LE in China(1)A total of 2,097 patients with LE were enrolled in LEMCSC,with1,865 patients with SLE and 232 with CLE.Multivariate logistic regression was performed in 1648 patients with LE-specific skin manifestations to investigate the association between LE-specific skin manifestations and other clinical characteristics.The results of multivariate logistic regression showed that the clinical characteristics significantly associated with the occurrence of acute CLE(ACLE)lesions included female(OR=3.76,95%CI: 2.61-5.40),age of onset(OR=0.99,95%CI:0.98-1.00),arthritis(OR=1.68,95%CI: 1.25-2.24),renal involvement(OR=2.11,95%CI: 1.50-2.96),hematological abnormalities(OR=1.62,95%CI: 1.21-2.16),ANA(+)(OR=2.27,95%CI: 1.31-3.93),anti-ds DNA Abs(+)(OR=1.51,95%CI:1.07-2.12),anti-U1-n RNP Abs(+)(OR=1.49,95%CI: 1.05-2.12)and antihistone Abs(+)(OR=1.86,95%CI: 1.12-3.09).Female,renal involvement,hematological abnormalities,ANA(+),anti-ds DNA Abs(+),anti-U1-n RNP Abs(+)and anti-histone Abs(+)were significantly positively correlated with the occurrence of ACLE lesions,while the increase of onset age was significantly negatively correlated with the occurrence of ACLE lesions.All P values <0.05.(2)The results of multivariate logistic regression showed that the clinical characteristics significantly associated with the occurrence of subacute CLE(SCLE)lesions included female(OR=0.52,95%CI: 0.33-0.80),anti-ds DNA Abs(+)(OR=0.58,95%CI: 0.38-0.89),anti-U1-n RNP Abs(+)(OR=0.35,95%CI: 0.22-0.56)and anti-SSB Abs(+)(OR=2.09,95%CI: 1.39-3.15).Anti-SSB Abs(+)was significantly positively correlated with the occurrence of SCLE lesions,while female,anti-ds DNA Abs(+)and anti-anti-U1-n RNP Abs(+)were significantly negatively correlated with the occurrence of SCLE lesions.All P values <0.05.(3)The results of multivariate logistic regression showed that the clinical characteristics significantly associated with the occurrence of chronic CLE(CCLE)lesions included female(OR=0.49,95%CI: 0.36-0.67),renal involvement(OR=0.66,95%CI: 0.52-0.84),ANA(+)(OR=0.48,95%CI: 0.29-0.79),anti-ds DNA Abs(+)(OR=0.68,95%CI:0.53-0.88),anti-SSB Abs(+)(OR=2.09,95%CI: 1.39-3.15)and antinucleosome Abs(+)(OR=0.72,95%CI: 0.52-0.99).Female,renal involvement,ANA(+),anti-ds DNA Abs(+),anti-SSB Abs(+)and antinucleosome Abs(+)were significantly negatively correlated with the occurrence of SCLE lesions.All P values <0.05.(4)The median(Q1,Q3)SLE disease activity index(SLEDAI)scores for SLE patients with only ACLE lesions,SLE patients with only SCLE lesions,and SLE patients with only CCLE lesions were 8.0(4.0,14.0),6.0(4.0,12.0)and 5.0(3.0,10.5),respectively.The SLEDAI score for SLE patients with only ACLE lesions was significantly higher than that of SLE patients with only CCLE lesions(P<0.001).2.Comparison of gender-related clinical characteristics among patients with different types of LE in China(1)The clinical characteristics that showed significant frequency differences between female and male patients with SLE included arthritis(female vs male,same as the following,66.0% vs 57.1%),ACLE lesions(67.2% vs 56.6%),SCLE lesions(5.5% vs 11.4%),Discoid LE(DLE)lesions(10.2% vs 22.3%),non-cicatricial alopecia(51.8% vs 37.7%)and anti-U1-n RNP Abs(+)(40.5% vs 31.2%).In patients with SLE,females had a significantly higher proportion of arthritis,ACLE lesions,noncicatricial alopecia,and anti-U1-n RNP Abs(+),while a lower proportion of SCLE lesions and CCLE lesions than males.All P values <0.05.(2)The clinical characteristics that differed significantly between female and male patients with CLE included age of onset [median(Q1,Q3),28.0(21.0,37.8)vs 39.0(24.0,48.0)],ACLE lesions(55.1% vs 12.2%),DLE lesions(31.6% vs 64.9%),oral ulcers(22.2% vs 8.1%),noncicatricial alopecia(42.4% vs 25.7%),other autoimmune diseases(8.8%vs 0%),ANA(+)(82.8% vs 62.0%),anti-ds DNA Abs(+)(25.0% vs 2.9%),anti-Sm(+)(25.6% vs 11.4%),anti-SSA/Ro60(+)(65.4% vs 50.0%),antiU1-n RNP Abs(+)(25.0% vs 10.0%),anti-histone Abs(+)(10.3% vs 0%)anti-nucleosome Abs(+)(10.9% vs 0%)and anti-SSB Abs(+)(19.9% vs37.1%).In patients with CLE,females had an earlier age of onset,a significantly higher proportion of ACLE lesions,oral ulcers,noncicatricial alopecia,other autoimmune diseases,ANA(+),anti-ds DNA Abs(+),anti-Sm(+),anti-SSA/Ro60(+),anti-U1-n RNP Abs(+),anti-histone Abs(+)and anti-nucleosome Abs(+)than males;while males had a higher proportion of DLE lessions and anti-SSB Abs(+)than females.All P values <0.05.3.Comparison of clinical characteristics associated with age of onset among patients with different types of LE in China(1)The clinical characteristics that showed significant frequency differences between patients with childhood-onset SLE(c-SLE,<18 years of onset),adult-onset SLE(a-SLE,18-50 years of onset)and late-onset SLE(l-SLE,≥50 years of onset)included female(childhood-onset vs adult-onset vs late-onset,same as the following,88.1% vs 91.8% vs 82.0%),family history of LE(9.5% vs 4.5% vs 4.7%),renal involvement(58.1%vs 55.7% vs 40.6%),arthritis(58.5% vs 65.7% vs 71.9%),fever(52.2% vs38.2% vs 39.8%),mucocutaneous involvement(92.9% vs 91.3% vs78.9%),LE-specific skin manifestations(82.6% vs 76.2% vs 59.4%),ACLE lesions(75.5% vs 66.4% vs 45.3%),LE-nonspecific skin manifestations(81.0% vs 80.8% vs 69.5%),photosensitivity(51.8% vs43.4% vs 39.1%),anti-ds DNA Abs(+)(69.2% vs 58.7% vs 53.5%),antiSSA/Ro52 Abs(+)(25.2% vs 35.3% vs 42.1%),anti-Sm(+)(41.2% vs 42.3%vs 26.0%),anti-U1-n RNP Abs(+)(40.8% vs 40.8% vs 23.0%),antihistone Abs(+)(28.0% vs 25.1% vs 15.1%),hypertension(17.7% vs 20.3%vs 39.2%),type 2 or secondary diabetes(0.5% vs 3.4% vs 15.0%)and other autoimmune diseases(9.4% vs 15.3% vs 30.8%).Patients with c-SLE had a significantly higher proportion of family history of LE,ACLE lesions,anti-ds DNA Abs(+)than a-SLE and l-SLE patients,a significantly higher proportion of fever and photosensitivity than a-SLE patients,and a significantly lower proportion of anti-SSA/Ro52 Abs(+)than a-SLE and l-SLE patients.Patients with l-SLE had a significantly lower proportion of female than a-SLE patients,a significantly lower proportion of renal involvement,mucocutaneous involvement,LE-specific skin manifestations,ACLE lesions,LE-nonspecific skin manifestations,antiSm Abs(+),anti-U1-n RNP Abs(+)and anti-histone Abs(+)than c-SLE and a-SLE patients,but a significantly higher proportion of hypertension,type 2 or secondary diabetes and other autoimmune diseases than c-SLE and a-SLE patients,and a significantly higher proportion of arthritis than c-SLE patients.All P values <0.017(Bonferroni corrected,same as the following).(2)The clinical characteristics that showed significant frequency differences between patients with childhood-onset CLE(c-CLE,<18 years of onset),adult-onset CLE(a-CLE,18-50 years of onset)and late-onset CLE(l-CLE,≥50 years of onset)included female(84.8% vs 70.2% vs35.7%),localized ACLE lesions(36.4% vs 25.7% vs 7.1%),DLE lesions(27.3% vs 42.1% vs 64.3%),photosensitivity(42.4% vs 64.9% vs 89.3%)and hypertension(0% vs 5.8% vs 47.6%).Patients with l-CLE had a significantly lower proportion of female and a significantly higher proportion of photosensitivity and hypertension than c-CLE and a-CLE patients.And l-CLE patients had a significantly higher proportion of DLE lesions than c-CLE patients,but a lower proportion of localized ACLE lesions than c-CLE patients.All P values <0.017.4.Autoantibody profiles among patients with different types of LE in China(1)The results of multivariate logistic regression showed that autoantibodies were closely associated with clinical manifestations in patients with SLE.Anti-ds DNA Abs(+)was the independent risk factor for renal involvement(OR=3.44,95%CI: 2.77-4.27)and fever(OR=1.40,95%CI: 1.13-1.73);anti-SSA/Ro52 Abs(+)was the independent risk factor for arthritis(OR=1.42,95%CI: 1.12-1.80)and serositis(OR=1.72,95%CI: 1.25-2.35);anti-Sm Abs(+)(OR=1.27,95%CI: 1.02-1.57)and anti-SSB Abs(+)(OR=1.35,95%CI: 1.03-1.77)were independent risk factors for hematological abnormalities;anti-P Abs(+)(OR=1.52,95%CI:1.22-1.88)was the independent risk factor for non-cicatricial alopecia.All P values <0.05.(2)Taking nine autoantibodies with positivity rates higher than 5% as cluster variables for two-step cluster analysis in patients with SLE,three clusters were obtained.Cluster 1 was dominated by anti-SSA/Ro60 Abs;cluster 2 was dominated by anti-ds DNA Abs;and the positivity rates of anti-ds DNA,anti-nucleosome,anti-SSA/Ro60,anti-histone,anti-Sm,antiP and anti-U1-n RNP Abs in cluster 3 were all ≥50%.Among the three clusters,cluster 1 had the latest age of onset,the lowest frequency of renal involvement,and the highest frequency of LE-specific skin manifestations,SCLE lesions and chilblain LE(CHLE)lesions;while cluster 3 had the earliest age of onset,the highest frequency of fever,a higher frequency of arthritis and hematological abnormalities than cluster 2,and a higher frequency of serositis than cluster 1.The SLEDAI score of cluster 3 was significantly higher than that of cluster 1 and cluster 2.And the proportion of patients with Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index(SDI)≥1 in cluster 3 was significantly higher than that in cluster 1.All P values <0.017.(3)Taking nine autoantibodies with positivity rates higher than 5%as cluster variables for two-step cluster analysis in patients with CLE,three clusters were obtained.Cluster 1 showed the absence of positive autoantibodies,cluster 2 was dominated by anti-SSA/Ro60 and antiSSA/Ro52 Abs,and cluster 3 was dominated by anti-P and anti-SSA/Ro60 Abs.Among the three clusters,cluster 1 had the lowest frequency of female and the highest frequency of DLE lesions;while cluster 3 had the highest frequency of female,ACLE lesions and non-cicatricial alopecia.All P values <0.017.Conclusion:(1)The presence of ACLE lesions indicates a higher level of disease activity and a greater risk of systemic involvement compared to SCLE and CCLE lesions.The positive rate of anti-SSB Abs is characteristically higher in patients with SCLE lesions compared to patients with ACLE and CCLE lesions.(2)Male patients with CLE have a later onset age than females.Male patients with LE are more likely to develop SCLE and DLE lesions than females,while female patients with LE are more likely to develop ACLE lesions,non-cicatricial alopecia and anti-U1-n RNP Abs(+)than males.(3)Compared with a-SLE and l-SLE patients,c-SLE patients are more likely to have family history of LE,fever and anti-ds DNA Abs(+),but less likely to have anti-SSA/Ro52 Abs(+).Compared with c-SLE and a-SLE patients,l-SLE patients have lower frequency of female,renal involvement,LE-specific skin manifestations,LE-nonspecific skin manifestations,antiSm Abs(+),anti-U1-n RNP Abs(+)and anti-histone Abs(+),but a higher frequency of arthritis and comorbidities.The incidence of ACLE lesions decreases with the age of onset,and the incidence of DLE lesions increases in late-onset patients.The frequency of self-reported photosensitivity decreases with the age of onset in patients with SLE,but increases with the age of onset in patients with CLE.(4)Anti-ds DNA Abs(+)indicates a higher risk of renal involvement and fever,anti-SSA/Ro52 Abs(+)indicates a higher risk of arthritis and serositis,anti-Sm Abs(+)and anti-SSB Abs(+)indicate a higher risk of hematological abnormalities,anti-P Abs(+)indicates a higher risk of noncicatricial alopecia.Autoantibodies in patients with LE tend to coexist,forming different clusters in patients with SLE and patients with CLE and reflecting different clinical phenotypes.Patients exhibiting the phenotype characterized by anti-chromatin and multiple autoantibodies tend to have the most severe disease status.This thesis contains 60 graphs,11 tables and 150 references.