Sage Journals: Discover world-class research

Abstract

Background

Lupus enteritis (LE) is prone to incorrect and missed diagnoses. LE primarily occurs during the active stage of systemic lupus erythematosus (SLE), which often manifests with alterations in peripheral blood cell that may serve as indicators of disease activity and organ damage. This study aims to investigate the alterations and predictive value of routine blood parameters for LE diagnosis.

Methods

This exploratory study retrospectively analyzed the medical records of 36 patients with SLE who were admitted to Suining Central Hospital between January 2006 and April 2023. Additionally, a control group consisting of 72 SLE patients without LE, matched for sex and age, was enrolled. A comparison was made between the two groups regarding clinical characteristics and changes in routine blood parameters. Binary logistic regression and receiver operating characteristic (ROC) curve analyses were conducted to identify independent risk factors and evaluate their diagnostic performance for LE.

Results

The LE group exhibited significantly higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), along with a lower lymphocyte count (LYM), compared to the control group (p < .05). Binary logistic regression analysis revealed that NLR independently predicted the onset of LE, with an odds ratio of 1.347 and a 95% confidence interval of 1.070–1.696 (p < .01). ROC curve analysis demonstrated that NLR had an area under the curve of 0.68 for diagnosing LE (p < .05). When the cutoff value was set at 2.44, the Youden Index was only 0.31.

Conclusion

Significant differences were observed in several routine parameters between patients with LE and the control group, which can be attributed to the occurrence of LE during the active stage of SLE. However, only the NLR emerged as an independent risk factor for LE,and its predicting vulue for was insufficient; no blood routine parameter has been identified as an reliable predictor for LE.

Keywords

systemic lupus erythematosus lupus enteritis neutrophil/lymphocyte ratio platelet/lymphocyte ratio

Introduction

Lupus enteritis (LE) refers to vasculitis or inflammation of the intestines associated with systemic lupus erythematosus (SLE), supported by imaging and/or biopsy evidence.¹ LE predominantly occurs during the active stage of SLE, and patients often present with typical SLE symptoms such as rash, fever, and joint pain. However, some patients with LE may exhibit solely non-specific gastrointestinal symptoms without other manifestations of SLE, posing challenges in distinguishing it from other acute abdominal conditions. Consequently, This can lead to incorrect or missed diagnoses. Although commonly used clinical tests such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can partially aid in detecting the activity of SLE, they lack diagnostic value for LE. Active SLE often presents with alterations in morphology, size, and count of peripheral blood cells, which may indicate disease activity and organ damage. Lee et al.² reported a significant decrease in white blood cell (WBC) count among patients with LE, which exhibited a strong correlation with the presence of the disease. In contrast, Wang et al.³ observed no significant difference in WBC count between the LE and non-LE groups; however, they did report a notable reduction in lymphocyte count among patients with LE, indicating its potential diagnostic value. The red cell distribution width (RDW), Which is an indicator of chronic inflammation, has been demonstrated as a valuable marker for determining the activity of SLE.⁴ furthermore, composite inflammatory indicators derived from routine blood parameters, such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have shown superior predictive value compared to single indicators. Previous studies have not only established the utility of these two parameters as indicators for the active stage of immune rheumatic diseases,^5,6 but they have also highlighted the association between NLR and renal involvement in SLE.⁵ Howerever, there have been limited studies conducted on the alterations in routine blood parameters among patients with LE; nevertheless, their findings have exhibited inconsistency. Furthermore, there is a lack of reports regarding the predictive efficacy of blood routine parameters in LE. Therefore, this study aims to analyze the alterations in blood routine parameters among individuals with LE to identify potential indicators for early diagnosis.

Materials and methods

General information

A total of 36 inpatients or outpatients with LE, who were admitted to Suining Central Hospital between January 2006 and April 2023 and had complete data, were included in the study. The patients were matched for age and sex at a ratio of 1:2 with 72 SLE patients without LE serving as the control group. The inclusion criteria were as follows: each Patient with SLE met the 1997 classification criteria for SLE established by the American College of Rheumatology (ACR),and patients with LE were required to meet the following three conditions⁷: (i) presence of abdominal symptoms along with at least one of the following: nausea, abdominal pain, vomiting,diarrhea, or bloating; (ii) presence of at least one of these three imaging manifestations: mesenteric vasodilation, bowel wall thickening, or increased attenuation of mesenteric fat¹; (iii) lack of relief from digestive symptoms following use of mucosal protective agents, acid inhibitors, antibiotics, or gastrointestinal motility drugs, but successful alleviation after use of an increased dosage of glucocorticoids.

The following exclusion criteria were applied: (1) Patients with primary gastrointestinal lesions、adverse drug reactions, and other acute abdominal conditions; (2) Patients with co-morbid circulatory system diseases such as rheumatic valve disease or heart failure); (3) Patients who had received blood transfusions, steroid hormones, immunosuppressants or drugs affecting WBC count in the past 3 months; (4) Patients with missing key clinical data. The initial test data performed at admission were extracted for all enrolled patients. Patients in the LE group consisted of 33 females and three males, aged between 20 and 66 years, with a mean age of (39.22 ± 11.48) years. The disease durations ranged from 0.2 to 18.0 years, with a mean duration of (7.28 ± 4.65) years. The control group comprised 67 females and five males, aged between 21 and 73 years, with a mean age of (39.47 ± 12.19) years. The disease durations ranged from 0.9 to 19.0 years, with a mean duration of (7.85 ± 4.80) years. No statistically significant differences were observed between the two groups regarding age, sex or disease duration (p > .05). This study was conducted in accordance with the Declaration of Helsinki on human research and received approval from the hospital ethics committee (approval date: March23,2023;approval number: KYLLKS20230048). Written consents were obtained from patients or their legally authorized representatives.

Study measures

General information, clinical symptoms, physical signs, laboratory test findings, imaging findings, SLE Disease Activity Index (SLEDAI) score, various routine blood parameters, NLR, and PLR were assessed in both groups.

Statistical methods

Statistical analyses were conducted using SPSS 15.0 and GraphPad Prism 5.0 software packages. Normally distributed measurement data were presented as $(\bar{X} \pm s)$ , and an independent samples T-test was employed for between-group comparisons. Measurement data with skewed distribution were expressed as [M(P25, P75)], and a non-parametric rank sum test was used for between-group comparisons. Count data were reported as frequencies and percentages, with the chi-squared test utilized for between-group comparison. Receiver operating characteristic (ROC) curves were analyzed and plotted using GraphPad Prism and SPSS software packages. A significance level of p < .05 denoted statistical significance.

Results

Comparison of general information

Compared to the non-LE group, the LE group exhibited a higher proportion of patients presenting with clinical manifestations and systemic damage, including fever, abdominal pain, intestinal obstruction, nerve system damage, blood system damage, urinary system damage, etc. Furthermore, they demonstrated elevated SLEDAI and SDI scores along with decreased levels of complement C3. These differences between the two groups were statistically significant (Table 1).

Table 1.

Comparison of general information between two groups.

Items	Research group (n = 36)	Control group (n = 72)	X ² /t	P
Family history [n (%)]	0 (0)	2 (2.78)	X² = 1.01	0.55
Fever [n (%)]	13 (36.11)	4 (5.56)	X² = 16.89	<0.01
Rash [n (%)]	9 (25.00)	31 (43.60)	X² = 3.85	0.05
Arthralgia [n (%)]	16 (44.44)	20 (27.78)	X² = 3.00	0.08
Mouth ulcers [n (%)]	5 (13.89)	4 (5.56)	X² = 2.18	0.14
Abdominal pains [n (%)]	34 (94.44)	0 (0)	X² = 99.24	<0.01
Intestinal obstruction [n (%)]	26 (72.22)	0 (0)	X² = 68.48	<0.01
Lupus headache [n (%)]	3 (8.33)	2 (2.78)	X² = 1.68	0.19
Visual disturbance [n (%)]	2 (5.56)	1 (0.09)	X² = 1.53	0.21
Crinial nerve disorder [n (%)]	0 (0.00)	1 (0.09)	X² = 0.50	0.47
Hematuria or proteinuria [n (%)]	18 (50.00)	10 (13.89)	X² = 16.29	<0.01
Thrombocytopenia or leukopenia [n (%)]	17 (47.22)	15 (20.83)	X² = 8.01	<0.01
Pleurisy [n (%)]	12 (33.33)	2 (2.78)	X² = 9.86	<0.01
Lesions of ureter and bladder related to SLE [n (%)]	4 (11.11)	1 (1.38)	X² = 9.86	0.02
Complement C3 (g/L)	0.46 ± 0.18	0.64 ± 0.20	t = −4.59	<0.01
Complement C4 (g/L)	0.63 ± 0.17	0.11 ± 0.16	Z = −1.06	<0.01
SLEDAI score	12.83 ± 4.79	5.69 ± 3.10	Z = −6.88	<0.01
SDI score	3.50 (3.00, 4.00)	6.00 (4.00, 8.00)	Z = −7.06	<0.01

Comparison of hematological parameters

The LE group exhibited significantly elevated NLR and PLR, as well as a significant reduction in LYM, compared to the control group; these differences were found to be statistically significant (p < .05). No significant differences were observed in the remaining parameters when compared to the control group (p < .05) (Table 2).

Table 2.

Comparison of hematological parameters between two groups.

Items	Research group	Control group	Z	P
Neutrophils (10⁹/L)	3.89 (1.73, 6.82)	3.05 (2.11, 4.02)	Z = −1.36	0.17
Lymphocytes (10⁹/L)	1.04 (0.45, 1.37)	1.17 (0.89, 1.57)	Z = −2.31	0.02
WBC (10⁹/L)	5.45 (3.40, 9.22)	4.75 (3.50, 5.98)	Z = −1.11	0.26
RBC (10¹²/L)	3.95 (3.22, 4.74)	3.40 (3.72, 4.41)	Z = −0.21	0.83
RDW-SD (f l)	46.40 (43.30, 50.00)	45.80 (42.50, 47.90)	Z = −1.17	0.23
RDW-CV (%)	14.70 (13.80, 17.10)	14.00 (13.1, 14.90)	Z = −2.40	0.16
PLT (10⁹/L)	169.00 (84.25, 219.00)	143.50 (107.50, 194.75)	Z = −0.29	0.76
NLR	3.75 (2.60, 7.35)	2.43 (1.69, 3.63)	Z = −3.14	0.00
PLR	195.07 (86.63, 294.44)	107.79 (79.78, 169.30)	Z = −2.20	0.02

Note: RDW is the red cell distribution width, MPV is the mean platelet volume, PLR is the platelet-to-lymphocyte ratio, and NLR is the neutrophil-to-lymphocyte ratio.

Analysis of LE risk factors

In the binary logistic regression analysis, examination of the full model revealed non-significant between-group differences for certain parameters. Consequently, a stepwise regression was conducted to screen independent variables, which demonstrated that only NLR emerged as an independent risk factor for LE (odds ratio = 1.347, 95% confidence interval: 1.070–1.696, p < .01) (Table 3).

Table 3.

Logistic regression analysis of LE risk factors.

Items	Regression weights	Standard Error	Wald	Degree of freedom	P	OR	95%CL
N	−0.83	0.082	4.950	1	0.026	0.833	0.709∽0.978
NLR	0.298	0.118	6.430	1	0.011	1.347	1.070∽1.696
Routine	−1.144	0.305	14.143	1	0.000	0.318

Diagnostic performance of NLR for LE

The analysis of the receiver operating characteristic (ROC) curves revealed that the area under the curve for diagnosing LE using NLR was 0.68 (p < .05). Employing a cutoff value of 2.44, the sensitivity and specificity for LE diagnosis were determined to be 51.39% and 80.56%, respectively, with a lower Youden Index of 0.31. The statistical results are depicted in Figure 1.

Figure 1.

ROC curve of NLR for diagnose LE.

Discussion

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by significant variations in clinical manifestations due to the involvement of different organs. Studies have demonstrated that approximately 40%–50% of SLE patients present with symptoms related to the digestive system,⁸ most commonly associated with other gastrointestinal disorders (such as small intestinal malabsorption, autoimmune liver disease, and inflammatory bowel disease), drug side effects or infection; However, it should be noted that some of these symptoms may also arise directly from SLE itself. The underlying pathophysiology of LE involves vasculitis, leading to local ischemia of the gastrointestinal tract and subsequent manifestation of symptoms such as nausea, vomiting, diarrhea, and abdominal pain.^9,10 However, some patients with LE only exhibit intestinal involvement during new-onset^11–13 or recurrent LE.¹⁴ In highly rare cases, patients with LE may present with intestinal emphysema¹⁵ or acute gastric dilatation.¹⁶ Renal involvement can also coexist with Some cases of LE.^17,18 These non-specific symptoms cannot be used to differentiate between LE and other gastrointestinal diseases easily, which can easily lead to incorrect and missed diagnosis. Patients with LE who do not receive prompt diagnosis and treatment are at risk of developing severe complications, including intestinal bleeding, disseminated intravascular coagulation, intestinal perforation, and intestinal infarction,⁷ which can endanger the lives of the patients. Therefore, when managing SLE patients presenting with digestive system symptoms, particularly in cases where initial symptoms involve gastrointestinal lesions, it is imperative to consider not only the potential for acute abdomen and infectious diseases (such as acute cholecystitis, acute appendicitis, acute pancreatitis, perforated peptic ulcer, and intestinal infection) but also the possibility of LE. Additionally, careful evaluation should be conducted to exclude abdominal pain caused by gastrointestinal ischemia associated with conditions like antiphospholipid syndrome (APS) and thromboembolism.

Due to the non-specific nature of its symptoms, LE is susceptible to incorrect and missed diagnoses which necessitates an urgent need for identifying effective markers or diagnostic models for it. Currently, numerous studies have been published on the risk factors associated with this condition. Aso et al.¹⁹ discovered that antibodies against the α3 subunit of anti-ganglionic nicotinic acetylcholine receptors could potentially serve as biomarkers for LE. Yoshida et al.²⁰ reported that a lower CH50 level may indicate intractable or recurrent cases of lupus erythematosus (LE). Liu et al.²¹ developed a highly accurate nomogram for predicting this condition accurately. Furthermore, APS, elevated peripheral blood CD19 cell count, urinary system involvement, and elevated d-dimer levels have also been identified as risk factors for LE. These prediction methods are either overly complexor costly, limiting their accessibility to all healthcare facilities.

Studies have shown that LE mainly occurs during active SLE22–24. Although LE cases have also been reported in patients with SLEDAI <4, these occurrences are relatively infrequent.^2,25 Our study demonstrated that all 35 patients with lupus erythematosus (LE), except for one who had a SLEDAI score <5, exhibited SLEDAI scores >5. Additionally, the LE group showed significantly higher SLEDAI scores compared to the non-LE group, which supports the idea that LE mainly presents during the active stage of systemic lupus erythematosus (SLE). Simultaneously, alongside general symptoms and digestive tract symptoms, we observed a higher prevalence of systemic damage in the blood system, urinary system, nervous system, and other systems among patients in the LE group compared to those in the non-LE group. Additionally, the SDI score was significantly elevated in the LE group compared to the non-LE group. This observation can be attributed to the predominant occurrence of LE during SLE's active stage and its relatively severe manifestation.

Routine hematological parameters may exhibit alterations during the onset or active phase of the disease, and certain variations among these parameters could potentially serve as indicators for predicting the likelihood of LE onset. For instance, leukopenia² or lymphocytopenia³ may suggest a higher probability of LE occurrence. NLR and PLR are indicators derived from routine blood parameters that offer greater utility in comprehending a patient's systemic inflammatory state due to their ability to integrate two distinct immune pathways. NLR and PLR can serve as indicators for determining the active stage of rheumatoid arthritis and spondyloarthropathy, while NLR has also been associated with renal involvement and pathological types in SLE. These studies suggest that routine blood parameters in patients with LE may undergo changes, some of which might be linked to organ damage and have predictive value for organ dysfunction. In this study, a combination of binary logistic regression analysis and ROC curve analysis was employed to identify risk factors for LE from routine blood parameters and determine their predictive value. Our findings suggest that NLR may serve as an independent risk factor for LE, while the other parameters did not demonstrate any association with LE. However, the ROC curve analysis further demonstrated that the practical utility of NLR in predicting LE is limited, as evidenced by its modest area under the curve and low Youden index.

In this study, we observed significant differences in the three parameters of NLR, PLR, and LYM between the LE group and non-LE group. Specifically, NLR and PLR were significantly increased while LYM was significantly decreased in the LE group, which is consistent with the active phase of SLE. Regression analysis revealed that only NLR was an independent risk factor for LE; however, its predictive value for LE was limited to promoting disease activity rather than predicting occurrence. Since no effective blood routine parameter has been found to predict LE, a comprehensive approach encompassing immunological, imaging, and pathological tests should be adopted in clinical practice to ensure a thorough evaluation of LE and mitigate the risks associated with misdiagnosis and inappropriate treatment.

Conclusion

Based on the available data, significant differences were observed in several parameters between patients with lymphedema (LE) and the control group, which can be attributed to the occurrence of LE during the active stage of SLE. Although we identified NLR as an independent risk factor for LE, its predictive value for LE was limited to promoting disease activity rather than predicting occurrence. Since no effective blood routine parameter has been found to predict LE, a comprehensive approach encompassing immunological, imaging, and pathological tests should be adopted in clinical practice to ensure a thorough evaluation of LE and mitigate the risks associated with misdiagnosis and inappropriate treatment.

Footnotes

Acknowledgements

The authors would like to thank the reviewers and authors of all the references, We also thank all the editors of the European Journal of inflammation.

Author contributions

Wen–Xin Zhang was the main contributor to this manuscript, and she wrote the initial version. Jin–He Xiong (corresponding author) finalized the manuscript. Wen–Xin Zhang downloaded the references and collected data, while Jin–He Xiong evaluated the data critically. All authors have read and approved the final manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iDs

Wen-Xin Zhang

Jin-He Xiong

References

Isenberg

Rahman

Allen

, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus. Rheumatology 2005; 44(7): 902–906.

Lee

Ahn

Lee

, et al. Acute abdominal pain in systemic lupus erythematosus: focus on lupus enteritis (gastrointestinal vasculitis). Ann Rheum Dis 2002; 61(6): 547–550.

Wang

Song

, et al. Clinical features and risk factors of lupus mesenteric vasculitis. HENAN Med Res 2021; 30(11): 1943–1947.

Zheng

Qin

, et al. Evaluation of disease activity of systemic lupus erythematosus by D-dimer combined with red blood cell distribution width. Clin Lab 2021; 67(9): 2086–2092.

Zinellu

Mangoni

. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio and disease activity in rheumatoid arthritis: a systematic review and meta-analysis. Eur J Clin Invest 2023; 53(2): e13877.

Sen

Kim

Napier

, et al. Neutrophil-to-Lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers in axial spondyloarthritis: observational studies from the program to understand the longterm outcomes in spondyloarthritis registry. Arthritis Rheumatol 2023; 75(2): 232–241.

Chen

Luo

, et al. Clinical features of lupus enteritis: a single-center retrospective study. Orphanet J Rare Dis 2021; 16(1): 396.

Brewer

Kamen

. Gastrointestinal and hepatic disease in systemic lupus erythematosus. Rheum Dis Clin N Am, 2018; 44(1): 165–175.

Janssens

Arnaud

Galicier

, et al. Lupus enteritis: from clinical findings to therapeutic management. Orphanet J Rare Dis 2013; 8: 67.

10.

Gupta

Garg

. Lupus cheilitis: an uncommon manifestation of systemic lupus erythematous. Lupus 2021; 30(12): 2022–2023.

11.

Potera

Palomera Tejeda

Arora

, et al. Lupus enteritis: an uncommon presentation of lupus flare. Cureus 2021; 13(9): e18030.

12.

Quintero

Pelayo

Salacup

, et al. Lupus enteritis as a lone manifestation of SLE: rare but possible. BMJ Case Rep 2021; 14(8): e239072.

13.

Pavli

Gioti

Spyridopoulos

, et al. Acute abdominal situations as presenting or flaring manifestations of systemic lupus erythematosus: a case series. Mediterr J Rheumatol 2022; 33(3): 339–345.

14.

Tsuda

Nagata

Yamaguchi

, et al. A case of lupus enteritis in which multiple colorectal ulcers were the only signs of relapse. Tokai J Exp Clin Med 2022; 47(4): 194–198.

15.

Chandwar

Sahoo

Wakhlu

, et al. Pneumatosis intestinalis: a rare manifestation of lupus enteritis. BMJ Case Rep 2022; 15(1): e247779.

16.

Ezhilnilavan

Priyamvada

Haridasan

, et al. Acute gastric dilatation in a patient with lupus nephritis: an uncommon presentation of lupus mesenteric vasculitis. Saudi J Kidney Dis Transpl 2018; 29(2): 429–434.

17.

Wang

Zhuo

Tian

, et al. Two complications in patients with systemic lupus erythematosus: lupus cystitis and lupus enteritis. Arch Med Sci 2022; 18(3): 822–824.

18.

Shimizu

Shimbo

Yamazaki

, et al. Concurrent lupus enteritis and cystitis. Pediatr Int 2021; 63(9): 1142–1143.

19.

Aso

Kono

Abe

, et al. Anti-ganglionic nicotinic acetylcholine receptor alpha3 subunit antibody as a potential biomarker associated with lupus enteritis. Mod Rheumatol 2023; 33(1): 154–159.

20.

Yoshida

Omoto

Kohno

, et al. Lower CH50 as a predictor for intractable or recurrent lupus enteritis: a retrospective observational study. Mod Rheumatol 2021; 31(3): 643–648.

21.

Liu

Guo

Cai

, et al. A nomogram to predict the risk of lupus enteritis in systemic lupus erythematosus patients with gastroinctestinal involvement. EClinicalMedicine 2021; 36: 100900.

22.

Albuquerque-Netto

Cavalcante

Sallum

, et al. Mesenteric vasculitis in a juvenile systemic lupus erythematosus patient. Rev Bras Reumatol 2013; 53(2): 219–222.

23.

Medina

Ayala

Jara

, et al. Acute abdomen in systemic lupus erythematosus: the importance of early laparotomy. Am J Med 1997; 103(2): 100–105.

24.

Kwok

Seo

, et al. Lupus enteritis: clinical characteristics, risk factor for relapse and association with anti-endothelial cell antibody. Lupus 2007; 16(10): 803–809.

25.

Yuan

Lian

Chen

, et al. Clinical features and associated factors of abdominal pain in systemic lupus erythematosus. J Rheumatol 2013; 40(12): 2015–2022.

Alterations and predictive value of blood routine parameters in patients with lupus enteritis: A retrospective study

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Materials and methods

General information

Study measures

Statistical methods

Results

Comparison of general information

Comparison of hematological parameters

Analysis of LE risk factors

Diagnostic performance of NLR for LE

Discussion

Conclusion

Footnotes

Acknowledgements

Author contributions

Declaration of conflicting interests

Funding

Ethical statement

ORCID iDs

References