Children systemic lupus erythematosus-associated pancreatitis

Objective To early recognise and improve the prognosis of children systemic lupus erythematosus (cSLE)-associated pancreatitis by summarising and analysing clinical features and prognosis data from 12 cases. Methods Retrospective analysis of clinical data from 12 cases of cSLE-associated pancreatitis diagnosed and treated from January 2016 to December 2021 at hospitals such as Children’s Hospital of Capital Institute of Paediatrics. Results The median SLEDAI-2K score for disease activity was 18.00 (range 12.25–21.00) in the case group and 10.00 (range 7.00–18.00) in the control group, with a statistically significant difference (P < 0.05) between the two groups. The case group had a higher proportion of abdominal pain, vomiting, abdominal distension, pleural effusion, Raynaud’s phenomenon (RP), splenic infarction, and concurrent macrophage activation syndrome (MAS) than the control group, with a statistically significant difference (P < 0.05). Serum ferritin (SF), alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), amylase, and increased 24-h urine protein levels were statistically different between the two groups (P < 0.05); platelet counts (PLT) reduction was also statistically different (P < 0.05). The case group had a higher proportion of methylprednisolone pulse therapy, cyclophosphamide pulse therapy during remission induction, and therapeutic plasma exchange than the control group, with a statistically significant difference (P < 0.05) between the two. Conclusion CSLE-associated pancreatitis has a high fatality rate. The presence of RP, splenic infarction, pleural effusion, and MAS warrants attention from clinicians regarding the possibility of pancreatitis. Once pancreatitis is detected, the primary disease needs active treatment for better prognosis.


Introduction
Children systemic lupus erythematosus (cSLE) refers to SLE that occurs in childhood.It is an autoimmune disease of unknown aetiology that can involve multisystem organs.Gastrointestinal tract involvement is common in cSLE, with an incidence of 19% [1][2][3][4].But lupus-associated pancreatitis is rare, with an incidence of only 0.7-4% [5] and can be life-threatening in severe cases.There is no large-sample clinical study on cSLEassociated pancreatitis.This study analysed the clinical characteristics and prognosis data of 12 cases of cSLEassociated pancreatitis, compares them with cSLE without pancreatitis, and explores the aetiology and risk factors of cSLE-associated pancreatitis for early identification and better prognosis.

Study design
In a retrospective case-control study, 12 children with cSLE and pancreatitis were selected as the case group.They were diagnosed and treated at the Department of Rheumatology and Immunology, Children's Hospital of Capital Institute of Paediatrics (CIP), the Department of Paediatrics, The Second Hospital of Hebei Medical University, the Department of Paediatric Nephrology and Rheumatology, Shengjing Hospital of China Medical University, the Department of Rheumatology and Immunology, etc., from January 2016 to December 2022.A control group was randomly selected from children with cSLE but without pancreatitis who were diagnosed and treated during the same period at the Department of Rheumatology and Immunology, Children's Hospital of Capital Institute of Paediatrics.Cases in the control group were matched with the age and gender of the case group in a 1:4 sample-size ratio of case group to control group.Exclusion criteria included the following diseases: (1) tumours; (2) inherited metabolic disorders; (3) pre-existing pancreatic and gallbladder diseases; and (4) other pre-existing chronic diseases, such as hypertension, diabetes mellitus.CSLE diagnosis had to comply with the 1997 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE diagnostic criteria [6].This study was approved by the CIP Ethics Committee, which waived informed consent.

Relevant diagnostic criteria and disease activity index
Diagnostic criteria for pancreatitis are as follows: (1) persistent upper abdominal pain; (2) serum amylase and/ or lipase three times the upper limit of normal range; (3) abdominal imaging examination shows changes consistent with the imaging of acute pancreatitis.Diagnosis can be made if two out of the three criteria are met.Macrophage activation syndrome (MAS) conforms to the 2009 preliminary diagnostic guidelines for SLE-MAS in children [7].The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) was used to assess cSLE disease activity: a score under four indicates inactive disease, while a score above five suggests disease activity, with higher scores indicating higher disease activity [8].

Statistical analysis
Data processing was performed using IBM SPSS Statistics 26.0.A P-value of < 0.05 (two-tailed) was considered statistically significant.We first analysed measurement data by Kolmogorov-Smirnov test to see whether the data follows a normal distribution.Normally distributed continuous variables are expressed as mean ± standard deviation (mean ± SD), using the t-test for two-group comparison.Non-normally distributed continuous variables are expressed as the median (M) [interquartile range (IQR) p25-p75], using the rank-sum test for twogroup comparison.Categorical data were expressed as frequency (n) and percentage (%), using the chi-squared (χ 2 ) test for two-group comparison.

General information
The case group comprised 12 female children aged 9-17, with the median age of onset at 13.00 (range 11.25-14.00).The median duration of cSLE-associated pancreatitis at diagnosis was 0.83 (range 0.37-10.00)months.The control group included 48 children aged 9-17, among whom were eight males and 40 females with a ratio of 1:5.The median age of onset was 13.00 (range 11.25-14.00).The median duration of cSLE at diagnosis was 1.00 (0.50-3.00) month.There were no statistically significant differences in gender and age of onset between the two groups.The median SLEDAI-2K score for disease activity was 18.00 (range 12.25-21.00)in the case group and 10.00 (range 7.00-18.00) in the control group, with a statistically significant difference (P < 0.05) between the two groups.

Clinical manifestations
Clinical manifestations between the two groups are shown in Table 1.Three cases in the case group were diagnosed as MAS due to persistent fever, hepatosplenomegaly, thrombocytopenia, elevated SF, and ALT/AST.The case group had a higher proportion of abdominal pain, vomiting, abdominal distension, pleural effusion, RP, splenic infarction, and concurrent MAS than the control group, with a statistically significant difference (P < 0.05) between the two groups.

Laboratory tests
Laboratory results between the two groups are shown in Table 2. SF, ALT, AST, LDH, amylase, and increased 24-h urine protein levels were statistically different between the two groups (P < 0.05); platelet count (PLT) reduction was statistically different between the two groups (P < 0.05).

General treatment
All 12 children in the case group who developed pancreatitis were given symptomatic treatment with water fasting, intravenous fluid replacement, and inhibition of gastric acid and pancreatic enzyme secretion.

Surgical treatment
Among the 12 children in the case group with pancreatitis, two underwent exploratory laparotomy (16.7%).During surgery, we incised the pancreatic capsule and performed abdominal lavage.Drainage tubes were placed postoperatively.
Medication for the two groups is shown in Table 3. Methylprednisolone pulse therapy, cyclophosphamide pulse therapy during remission induction, and therapeutic plasma exchange were statistically different between the two groups (P < 0.05).

Prognosis and outcome
Prognosis and outcome between the two groups are shown in Table 4. Twelve children in the case group were followed up for 1-7 years.Within 1 week to 2 months of disease duration, eight of them recovered completely from pancreatitis, with amylase levels returning to normal and remission in SLE.Among them, case 3 had high disease activity and developed secondary MAS.The case transiently improved after aggressive treatment, experienced severe infections during the treatment of primary disease, and saw her MAS worsened.The family gave up treatment.Case 8 had high disease activity, refused surgery after developing pancreatitis complicated by peritonitis, and eventually died.Cases 9 and 12 had high disease activity with presence of multi-organ failure and MAS.They both died.

Discussion
This is a multicentre clinical study of cSLE-associated pancreatitis in China.Given the disease's low incidence in children [5] and previous domestic reports of it were all on isolated cases, this study represents the largest number of cases included in the case group of its kind in China.First, the study results reveal that the SLE-DAI-2K score at the onset of disease in the case group was 18, higher than that of the control group, indicating that cSLE-associated pancreatitis is a critical complication of cSLE.The fatality rate in the case group was as high as 33.3%, similar to the reported rate of 37.04% in the literature [6].Secondly, this study found that cSLEassociated pancreatitis is more likely to present with RP, splenic infarction, pleural effusion, and concurrent Fourthly, this study also found higher levels of 24-h urine protein, SF, ALT, AST, LDH, and amylase in the case group.Therefore, clinicians should closely monitor abdominal symptoms in cSLE cases.When lupus pancreatitis is suspected, renal function, SF, liver enzymes, and amylase should be assessed more attentively to monitor the disease progression.Lastly, during induction, the case group received methylprednisolone pulse therapy, cyclophosphamide pulse therapy, and therapeutic plasma exchange more frequently than the control group.This suggests that for early detection of pancreatitis, high-intensity treatment regimen should be chosen as mentioned above.In the presence of surgical indications, active surgical intervention should be administered to gain more time for remission of the primary disease of SLE.The pathogenesis of SLE-associated pancreatitis remains unclear, but vascular trauma is one of the main causes [6,[9][10][11][12][13][14].Vascular trauma includes necrotising vasculitis, arterial thromboembolism caused by severe hypertension and antiphospholipid syndrome, vascular endothelial injury, immune complex deposition, and complement activation in pancreatic arterial walls, among others.The mechanism by which RP occurs with SLE is not entirely clear, but endothelial dysfunction might underlie its pathophysiology.It is currently believed to be caused by increased endothelin, decreased calcitonin gene-related peptide, the presence of antifibrin-binding tissue-type plasminogen activator (t-PA) in circulating blood, decreased fibrinolytic activity in the organism, and coagulation in small blood vessels.In addition, increased protein tyrosine kinase (PTK) activity in vascular endothelial cells might be associated with RP development [6], suggesting that vascular endothelial injury could be a mechanism leading to RP in SLEassociated pancreatitis.Literature reports suggest that splenic infarction in SLE is associated with the deposition of circulating immune complexes on vascular walls and the activation of the complement pathway by the circulating immune complexes; both the deposition and the activation stimulate vascular endothelial injury [14][15][16], potentially explaining the higher proportion of splenic infarction cases in the study's case group compared to the control group.Lupus anticoagulant and antiphospholipid antibodies are risk factors for arteriovenous thrombosis or embolism in SLE, and these mechanisms are also considered to be the pathogenesis of SLE-associated pancreatitis [17].
Risk factors for cSLE-associated pancreatitis remain unclear.In this study, one child in the case group exhibited fever, neurological damage, intravascular haemolytic anaemia, thrombocytopenia, and renal failure, combined with pancreatitis and heart failure.The patient tested positive for ADAMTS-13 antibodies and was diagnosed with thrombotic thrombocytopenic purpura (TTP).Thus, TTP may be a high-risk factor for cSLE-associated pancreatitis.Among the four deceased cases in the case group, three (25%) had MAS, a severe, acute and lethal syndrome.In 2009, Parod et al. proposed preliminary diagnostic guidelines for childhood SLE-MAS through statistical analysis of laboratory indicators of SLE-MAS [18].In this study, the proportion of MAS cases in the case group was higher than in the control group (P < 0.05).Therefore, in cSLE cases presenting clinical features that are difficult to be explained by the primary disease activity, such as fever, bleeding, hepatosplenomegaly, lymphadenectasis, neurological dysfunction, and heart and renal failure, the diagnosis of SLE-associated MAS is considered, particularly when SF, AST, and LDH are consistently elevated, and dynamic erythrocyte sedimentation rate decreases.Further attention should be given to the occurrence of pancreatitis.
Literature search did not reveal any correlation between pleural effusion and the occurrence of pancreatitis in SLE  patients.In this study, 24-h urine protein levels were significantly higher in the case group than in the control group.Thus, whether the occurrence of pleural effusion is caused by renal protein loss requires further research.Currently, there is limited research on cSLE-associated pancreatitis at home and abroad, and there is a lack of large-sample data.Although this study is the multicentre study with the biggest number of cases in China at present, limitations still exist due to the small sample size.

Conclusion
In conclusion, cSLE-associated pancreatitis has a high fatality rate.The presence of RP, splenic infarction, pleural effusion, and MAS warrants attention from clinicians regarding the possibility of pancreatitis.During remission induction, methylprednisolone pulse therapy, cyclophosphamide pulse therapy, and therapeutic plasma exchange are effective.In addition, TTP and MAS could be risk factors for cSLE-associated pancreatitis.Based on the conclusions of this study, we hope that clinicians can recognise cSLE-associated pancreatitis early for better prognosis and lower fatality rate.

What does this mean for patients?
CSLE is an autoimmune disease of unknown aetiology that can involve multisystem organs.It can lead to gastrointestinal damage, with lupus-associated pancreatitis being a highly fatal complication.Therefore, early detection of the disease and active treatment are essential for improving the prognosis of patients with cSLE-associated pancreatitis.
In our study, we conducted a retrospective analysis of clinical data on 12 paediatric patients with cSLE-associated pancreatitis from several children's hospitals in China over a 6-year period.We compared these cases with 48 cSLE patients without pancreatitis who were treated at the Rheumatology Department, Children's Hospital of Capital Institute of Paediatrics, during the same period.Results reveal that abdominal pain, vomiting, abdominal distension, pleural effusion, RP, and splenic infarction were the primary clinical symptoms of cSLE-associated pancreatitis.Once this condition is suspected clinically, it is necessary to closely monitor SF, ALT, AST, LDH, amylase, and 24-h urine protein.
And aggressive treatments such as glucocorticoid pulse therapy and cyclophosphamide pulse therapy are recommended for better prognosis.

Table 1
Univariate analysis of clinical manifestations in control and case groups N Number of patients in the group, n Number of cases, SLE Systemic lupus erythematosus, IQR Interquartile range, SLEDA-2K Systemic Lupus Erythematosus Disease Activity Index-2000, RP Raynaud's phenomenon, MAS Macrophage activation syndrome

Table 2
Univariate analysis of laboratory tests in control and case groups N Number of patients in the group, n Number of cases, SLE Systemic lupus erythematosus, ESR Erythrocyte sedimentation rate, IQR Interquartile range, CRP C-reactive protein, SF Serum ferritin, WBC White blood count, NEU Neutrophil, LYM Lymphocyte, PLT Platelet counts, HGB Haemoglobin, ALT Alanine transaminase, AST Aspartate transaminase, HBDH Hydroxybutyrate dehydrogenase, LDH Lactate dehydrogenase, ALB Albumin, BUN Blood urea nitrogen, SCr Serum creatinine, C3 Complement component 3, C4 Complement component 4, IgG ACA Anti-cardiolipin antibody IgG, IgM ACA Anti-cardiolipin antibody IgM

Table 3
Univariate analysis of treatment in case and control groups N Number of patients in the group, n Number of cases, SLE Systemic lupus erythematosus

Table 4
Prognosis and outcome in case groups